Methods and compositions comprising hyperimmune colostrum

Abstract

The present invention relates to methods of preventing, treating, or reducing frequency or clinical severity of one or more symptoms of, a gastrointestinal condition or disorder caused by a gastrointestinal infection in a subject, decreasing gut inflammation in a subject and improving at least one biomarker of gut health of a subject. In particular, the methods relate to administering a composition comprising hyperimmune colostrum or a fraction thereof comprising hyperimmune antibodies, wherein the hyperimmune colostrum or fraction thereof is administered as a single dosage per day of at least about 200 mg per dose.

Description

[0001] METHODS AND COMPOSITIONS I FIELD The present invention relates to methods of preventing, treating, or reducing 5 frequency or clinical severity of one or more symptoms of, a gastrointestinal condition or disorder caused by a gastrointestinal infection in a subject, decreasing gut inflammation in a subject and improving at least one biomarker of gut health of a subject. In particular, the methods relate to administering a composition comprising hyperimmune colostrum or a fraction thereof comprising hyperimmune antibodies, 10 wherein the hyperimmune colostrum or fraction thereof is administered as a single dosage per day of at least about 200 mg per dose. BACKGROUND Gastrointestinal infections cause significant morbidity in the form of acute 15 diarrheal illness in the United States (Scallan et al., 2011) and among travelers to low- and middle-income countries (Olson et al., 2019). Among infants, young children, and vulnerable populations such as travelers or the military in resource-limited countries, the acute morbidity and mortality stemming from infectious diarrhea are particularly meaningful (GBD 2016 Diarrhoeal Disease Collaborators, 2018). Nearly 500,000 deaths 20 occurred among children aged ≤5 years in 2016 alone (GBD 2016 Diarrhoeal Disease Collaborators, 2018). Although the number of pediatric deaths due to diarrhea has decreased over the last several decades, morbidity remains unchanged. In addition to the acute illness, diarrhea can lead to the development of wasting and stunting in the most vulnerable children, causing long-term chronic disease and cognitive limitation 25 (GBD 2016 Diarrhoeal Disease Collaborators, 2018). Diarrhea continues to be the most frequent health problem among travelers with destinations in lower- and middle-income regions (Steffen, 2017). Deployed US military personnel, essentially representing a long-term traveler population, are particularly affected given their population dynamics and the context in which they seek care and 30 treatment (Connor et al., 2012). Diarrhea is the leading infectious disease threat to the overall health and preparedness of deployed US armed forces, with diarrheagenic E. coli, Campylobacter spp., and Shigella spp. among the most commonly reported etiologies (Olson et al., 2019; Riddle et al., 2006). Diarrheal illness threatens operational capability through lost duty days and mission degradation and has had historically devastating effects on military units in almost all identifiable military campaigns (Connor et al., 1999 and 2012). Enterotoxigenic E. coli (ETEC), one of several pathotypes of diarrheagenic E. coli, causes a secretory diarrhea that can range in presentation from mild discomfort to 5 cholera-like purging. It is among the most prevalent bacterial causes of childhood diarrhea in developing countries; the estimated number of ETEC episodes and deaths in 2016 was 75 million and 19,000 (respectively) among children aged ≤5 years (GBD 2016 Diarrhoeal Disease Collaborators, 2018). Among all age groups, these estimated episodes and deaths were 223 million and 51,000 (respectively) (GBD 2016 Diarrhoeal 10 Disease Collaborators, 2018). Repeated episodes of ETEC illness in pediatric populations have also been associated with growth faltering and declines in cognitive development, which are then considered to have attendant macroeconomic consequences in countries and regions most heavily afflicted (GBD 2016 Diarrhoeal Disease Collaborators, 2018; Bartsch and Lee, 2014; Bloom et al., 2000). ETEC 15 remains the most common cause of TD, implicated in 44% or more of cases (Olson et al., 2019); however, this may be markedly underestimated due to the insensitivity of testing methods. One modality that has shown considerable promise in, for example, diarrhea prevention is passive, oral administration of hyperimmune colostrum, particularly 20 hyperimmune bovine colostrum. Briefly, cows immunized with antigens derived from viral, bacterial, or parasitic enteropathogens, produce high levels of antigen-specific IgG in their colostrum. Manufacturing processes to make concentrates of these products that are highly enriched for IgG are well-developed, reliable, and effective (Otto et al., 2011; Gore et al., 2023). 25 Travelan®, which comprises hyperimmune bovine colostrum derived antibodies and is produced by Immuron Ltd in Melbourne, Australia, underwent independent double-blinded placebo-controlled ETEC challenge trials in Europe and the USA. The trials showed protection of up to 90% against infection and the development of diarrhea in healthy volunteer challenge studies with ETEC Participants who took dose regimens 30 of 1 caplet (200 mg) and 2 caplets (400 mg) of Travelan® three times a day (TID) for 2 days prior to challenge and continued dosing for a total of 7 days, had significantly less discomfort and diarrhea compared to those who did not receive Travelan® (Otto et al., 2011). Travelan has been administered in larger doses for longer periods of time in clinical studies for other indications. The safety of Travelan® is also supported by a phase 2 randomized double-blind placebo controlled clinical study in 133 patients with non-alcoholic steatohepatitis. Doses of up to 1,200mg of Travelan TID (3600 mg / day) 5 for 24 weeks were administered safely with no severe adverse events SAEs (Clinicaltrials.gov Identifier NCT02316717). However, this TID dosing regimen can be cumbersome and impractical for some individuals and travellers. It is against this background that the present inventors have developed new methods of preventing, treating, or reducing frequency or clinical severity of one or more 10 symptoms of, a gastrointestinal condition or disorder caused by a gastrointestinal infection in a subject, decreasing gut inflammation in a subject and improving at least one biomarker of gut health of a subject. SUMMARY 15 In an aspect, the present invention provides a method of preventing a gastrointestinal condition or disorder caused by a gastrointestinal infection in a subject, comprising administering a composition comprising hyperimmune colostrum or a fraction thereof comprising hyperimmune antibodies, wherein the hyperimmune colostrum or fraction thereof is administered as a single dosage per day, or two doses 20 per day, of at least about 200 mg per dose. In an aspect, the present invention provides a method of treating a gastrointestinal condition or disorder caused by a gastrointestinal infection in a subject, comprising administering a composition comprising hyperimmune colostrum or a fraction thereof comprising hyperimmune antibodies, wherein the hyperimmune 25 colostrum or fraction thereof is administered as a single dosage per day, or two doses per day, of at least about 200 mg per dose. In an aspect, the present invention provides a method of reducing frequency and / or clinical severity of one or more symptoms of a gastrointestinal condition or disorder caused by a gastrointestinal infection in a subject, comprising administering a 30 composition comprising hyperimmune colostrum or a fraction thereof comprising hyperimmune antibodies, wherein the hyperimmune colostrum or fraction thereof is administered as a single dosage per day, or two doses per day, of at least about 200 mg per dose. In an aspect, the present invention provides a method of decreasing gut inflammation in a subject, comprising administering a composition comprising hyperimmune colostrum or a fraction thereof comprising hyperimmune antibodies, wherein the hyperimmune colostrum or fraction thereof is administered as a single 5 dosage per day, or two doses per day, of at least about 200 mg per dose. In an aspect, the present invention provides a method of improving at least one biomarker of gut health of a subject, comprising administering a composition comprising hyperimmune colostrum or a fraction thereof comprising hyperimmune antibodies, wherein the hyperimmune colostrum or fraction thereof is administered as a single 10 dosage per day, or two doses per day, of at least about 200 mg per dose. In an aspect, the present invention provides the use of hyperimmune colostrum or a fraction thereof comprising hyperimmune antibodies in the manufacture of a medicament for preventing a gastrointestinal condition or disorder caused by a gastrointestinal infection in a subject, wherein the medicament will be administered at 15 single dosage per day, or two doses per day, of at least about 200 mg per dose. In an aspect, the present invention provides the use of hyperimmune colostrum or a fraction thereof comprising hyperimmune antibodies in the manufacture of a medicament for treating a gastrointestinal condition or disorder caused by a gastrointestinal infection in a subject, wherein the medicament will be administered at 20 single dosage per day, or two doses per day, of at least about 200 mg per dose. In an aspect, the present invention provides the use of hyperimmune colostrum or a fraction thereof comprising hyperimmune antibodies in the manufacture of a medicament for reducing frequency and / or clinical severity of one or more symptoms of, a gastrointestinal condition or disorder caused by a gastrointestinal infection in a subject, 25 wherein the medicament will be administered at single dosage per day, or two doses per day, of at least about 200 mg per dose. In an aspect, the present invention provides the use of hyperimmune colostrum or a fraction thereof comprising hyperimmune antibodies in the manufacture of a medicament for decreasing gut inflammation in a subject, wherein the medicament will 30 be administered at single dosage per day, or two doses per day, of at least about 200 mg per dose. In an aspect, the present invention provides the use of hyperimmune colostrum or a fraction thereof comprising hyperimmune antibodies in the manufacture of a medicament for improving at least one biomarker of gut health of a subject, wherein the medicament will be administered at single dosage per day, or two doses per day, of at least about 200 mg per dose. In an aspect, the present invention provides a composition comprising a hyperimmune colostrum or a fraction thereof comprising hyperimmune antibodies for 5 preventing a gastrointestinal condition or disorder caused by a gastrointestinal infection in a subject by administration of the hyperimmune colostrum or fraction thereof at single dosage per day, or two doses per day, of at least about 200 mg per dose. In an aspect, the present invention provides a composition comprising a hyperimmune colostrum or a fraction thereof comprising hyperimmune antibodies for 10 treating a gastrointestinal condition or disorder caused by a gastrointestinal infection in a subject by administration of the hyperimmune colostrum or fraction thereof at single dosage per day, or two doses per day, of at least about 200 mg per dose. In an aspect, the present invention provides a composition comprising a hyperimmune colostrum or a fraction thereof comprising hyperimmune antibodies for 15 reducing frequency and / or clinical severity of one or more symptoms of a gastrointestinal condition or disorder caused by a gastrointestinal infection in a subject by administration of the hyperimmune colostrum or fraction thereof at single dosage per day, or two doses per day, of at least about 200 mg per dose. In an aspect, the present invention provides a composition comprising a 20 hyperimmune colostrum or a fraction thereof comprising hyperimmune antibodies for decreasing gut inflammation in a subject by administration of the hyperimmune colostrum or fraction thereof at single dosage per day, or two doses per day, of at least about 200 mg per dose. In an aspect, the present invention provides a composition comprising a 25 hyperimmune colostrum or a fraction thereof comprising hyperimmune antibodies for improving at least one biomarker of gut health in a subject by administration of the hyperimmune colostrum or fraction thereof at single dosage per day, or two doses per day, of at least about 200 mg per dose. 30 BRIEF DESCRIPTION OF THE FIGURES Preferred embodiments of the present disclosure will be further described and illustrated, by way of example only, with reference to the accompanying drawings: Figure 1: Bovine colostrum antibodies according to the present invention (henceforth referred to as Travelan®) is reactive with a wide range of ETEC strains. Whole cell lysates prepared from a variety of ETEC strains representative of the major antigens CS1, CS2, CS3, CS4, CS5, CS6, CS7, CS14, CS17, CS19, CS21, PCFO71, CFA / I, and CF -negative isolates were analyzed by SDS-PAGE and western blotting followed by immunodetection with Travelan® or ProMilk 85. Arrows show prominent 5 protein bands. Figure 2: Immunoblot analysis of Travelan® cross-react with all 4 shigella species and major shigella antigens. (A) Immunoblotting of whole cell lysates of shigella strains (1-8) representative of Shigella spp., S. flexneri (2a, 3a, 4 and 6), S. sonnei Moseley, S. dysenteriae and S. boydii and recombinant shigella antigens IpaB, IpaC 10 and IpaD (9-11) probed with Travelan®. Ipa recombinant protein predicted major subunit (s) molecular weight (kDa) are listed. (B) Immunoblot with the same samples as in (A) probed with ProMilk 85. (C) Immunoreactivity of Travelan® with recombinant LPS and Ipa antigens compared to Promilk analysed by ELISA. Figure 3: Analysis of clinical symptoms, survival and S. flexneri 2a shedding. 15 (A) Average clinical score for each animal in the Travelan® and Promilk 85 groups over the course of post-infection monitoring. Daily scores were averaged for each animal until euthanasia / death and represented as individual values. Mean values are represented as a horizontal line and SEM displayed as error bars, significance between groups was analysed by Mann Whitney U statistics. (B) Number of animals in the Travelan® or 20 placebo groups with dysentery / shigellosis following S. flexneri 2a challenge analysed by Chi squared statistics. (C) Average fecal consistency (diarrhea) score in placebo and Travelan® groups. Daily stool scores were averaged for each animal until euthanasia / death and represented as individual values. Mean of the group is shown by a horizontal line and SEM shown by error bars and significance between groups 25 analysed by Mann Whitney U statistics. (D) Survival of NJRMs in the Travelan® and the promilk 85 placebo group, measured daily as a percentage. Statistics between groups was measured by Chi squared analysis. (E) Shedding of S. flexneri 2a challenge strain as percent of survived monkeys in the Promilk 85 and Travelan® groups analysed by Mann Whitney U statistical analysis. 30 Figure 4: Analysis of inflammatory cytokines and biomarkers in fecal samples. NJRM were grouped into a ‘not protected’ group including the animals who suffered from dysentery symptoms i.e., all 4 animals in the Promilk placebo group (red dots) plus two of the Travelan® group were not protected (blue dots). The second group denoted ‘protected’ group included the 6 animals not suffering from symptoms all in the Travelan® group (blue squares). The dot / square points represent the peak cytokine levels per animal, the mean level is shown by a horizontal line and SEM as the error bars. Statistical analysis (Mann Whitney U) levels of significance are shown. Figure 5: Histological evaluation of NJRM after challenge. Representative H&E 5 staining images of colon sections from shigella- infected NJRM animals (A) NJRM from the Promilk 85 placebo group with highest colon and rectum severity score of 3-4, displaying all histological changes a-e (refer to list below). (B) NJRM #M11 from the Travelan® group who displayed dysentery symptoms. Histologically had a moderate severity score in the colon and rectum of 2. Displaying histological changes: a, d and e. 10 (C) NJRM from the Travelan® group who did not display dysentery symptoms. Histologically tissue was shown to be healthy with a minor change (e). Histological changes observed: a) villi blunting, fusion and loss; b) crypt hyperplasia with degenerative neutrophils; c) fibrin, hemorrhage and edema; d) crypt abscess with necrotic debris and degenerative neutrophils; e) infiltration of neutrophils. Examples are 15 shown by arrows. Figure 6: Histological rectal severity score of NJRM post Shigella challenge. Histological samples for all NJRMs were analysed and scored (severity score levels 0- 4). The values are plotted per animal and the mean values are shown as a horizontal line and SEM as error bars. Mann Whitney U statistical analysis was performed. 20 Figure 7: Shigella-specific IgG, IgA and IgM antibody responses following challenge. Serum IgA, IgG and IgM antibody titers against S. flexneri 2a 2457T strain LPS and Invaplex (which contains IpaB, IpaC and IpaD proteins and LPS) antigens in all NJRM infected with S. flexneri 2a 2457T strain. Dots (Promilk 85 group) and squares (Travelan® group) represent individual animal peak antibody titer as fold increase over 25 baseline values. Mean values are shown by a horizontal line and error bars represent SEM. Statistical analysis was performed using Mann Whitney U analysis where values *p <0.05 were significant. Figure 8: Manufacturing flow diagram for IMM-124E drug substance. Figure 9: Systemic and mucosal antibody responses against O78 LPS 30 expressed as Geometric mean (GMN) for the Travelan group and the Placebo group for the study period and follow up to 29 days post challenge with ETEC strain H10407. (A) Serum IgA, (B) Serum IgG and (C) Fecal IgA titers per ng of total IgA. Figure 10: Serum IgA antibody endpoint titers to O78 LPS, measured by ELISA, for subjects who received Travelan or placebo. Data is grouped into disease (diarrhea) severity, where ND= no disease, MD=mild disease and MSD=moderate to severe disease. Timepoints include baseline study day -3 and 2, 4, 8, 15 and 29 days post ETEC H10407 challenge. Figure 11: Serum IgG antibody endpoint titers to O78 LPS, measured by ELISA, 5 for subjects who received Travelan or placebo. Data is grouped into disease (diarrhea) severity, where ND= no disease, MD=mild disease and MSD=moderate to severe disease. Timepoints include baseline study day -3 and 2, 4, 8, 15 and 29 days post ETEC H10407 challenge. Figure 12: Fecal IgA antibody endpoint titers to O78 LPS, measured by ELISA, 10 for subjects who received Travelan or placebo. Data is grouped into disease (diarrhea) severity, where ND= no disease, MD=mild disease and MSD=moderate to severe disease. Timepoints include baseline study day -2 and, 4, 8, 15 and 29 days post ETEC H10407 challenge. Due to the high level of scattering it was not possible to fit a full ANOVA model for data analysis for the fecal IgA levels. 15 Figure 13: Alpha Diversity measurement of the richness and evenness of the microbial composition of the Travelan group compared with the Placebo group A. Richness test. B. Shannon diversity (Richness and Evenness test) C. Pielou’s Evenness test. Box plots represent median and whiskers represent 1.5x interquartile range (Tukey method). Kruskal Wallis statistics was performed on the whole data set and boxes show 20 the differences between the diarrhea severity (none, mild, moderate or severe). Figure 14: Alpha Diversity measurement of the richness and evenness of the microbial composition of the Travelan group compared with the Placebo group for each day of the challenge study and follow up time points day 15 and day 29. (A) Richness test. (B) Shannon diversity (Richness and Evenness test) (C) Pielou’s Evenness test. 25 Box plots represent median and whiskers represent 1.5x interquartile range (Tukey method). Kruskal Wallis statistics was performed on the whole data set. Figure 15: Beta Diversity analysis of the Travelan and the Placebo groups grouped into diarrhea severity. (A) Weighted UniFrac,is a measurement of the abundance of specific bacterial species (B) Unweighted UniFrac measures the 30 presence or absence of bacterial species. Figure 16: Beta Diversity analysis of the Travelan and the Placebo groups per study day, where day -3 is baseline, day -2 and day -1 is study drug or placebo alone, day 1 is challenge day accompanied by dosing with study drug or placebo for a 5 day period. Antibiotics are administered after completion of Travelan or placebo for a 3 day period from day 6 to day 8 and follow up was measured at day 15 and day 29. (A) Weighted UniFrac,is a measurement of the abundance of specific bacterial species (B) Unweighted UniFrac measures the presence or absence of bacterial species. Figure 17: Analysis of the phylum of the bacterial species present in the Travelan 5 and the Placebo groups, according to the severity of diarrhea, None (no diarrhea), mild moderate or severe diarrhea. The arrow highlights the large increase in Verrucomicrobiota phylum, clearly visible in the Travelan group with severe diarrheal symptoms. Figure 18: Genera of the bacterial species present in the Travelan and the 10 Placebo groups, according to the severity of diarrhea, None (no diarrhea), mild moderate or severe diarrhea. The arrow highlights the large increase in Faecalibacterium, in the Travelan group with moderate diarrheal symptoms and in the Travelan group with severe diarrhea have a greater abundance of Akkermansia. Figure 19: Analysis of the phylum of the bacterial species present in the Travelan 15 and the Placebo groups, according to the over the study period where day -3 is baseline, day -2 and day -1 is study drug or placebo alone, day 1 is challenge day accompanied by dosing with study drug or placebo for a 5 day period. Antibiotics were administered after completion of Travelan or placebo for a 3 day period from day 6 to day 8 and follow up was measured at day 15 and day 29. The data indicates fluctuating levels of the most 20 abundant bacterial species Bacillota and Bacterioidota over the whole study period, a reduction in the level of Pseudomonadota (black arrows) in the Travelan group post challenge on days 3-5 and an increase in Verrucomicrobiota (light grey arrows) at later time points day 8, 9 and 15. Figure 20: Genera of the bacterial species present in the Travelan and the 25 Placebo groups, over the study period where day -3 is baseline, day -2 and day -1 is study drug or placebo alone, day 1 is challenge day accompanied by dosing with study drug or placebo for a 5 day period. Antibiotics were administered after completion of Travelan or placebo for a 3 day period from day 6 to day 8 and follow up was measured at day 15 and day 29. The light grey arrows highlight the large increase in Akkermansia, 30 in the Travelan group on study day 9 and 15. There are notable differences in the level of Escherichia-Shigella genus on days 3-5, indicated by the dark grey double arrows. Notably, levels of Pseudobutyrivibrio were also increased in the Travelan group (Day 15), as well as Faecalibacterium (Day 15, Day 29). DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION Preferred embodiments of the present invention are described below by way of example only. 5 Definitions Unless specifically defined otherwise, all technical and scientific terms used herein shall be taken to have the same meaning as commonly understood by one of ordinary skill in the art (e.g., cell culture and serum). The term “and / or”, e.g., “X and / or Y” shall be understood to mean either “X and 10 Y” or “X or Y” and shall be taken to provide explicit support for both meanings or for either meaning. Throughout this specification the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion 15 of any other element, integer or step, or group of elements, integers or steps. Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present disclosure as it existed before the priority 20 date of each of the appended claims. As used herein, the term “about”, unless stated to the contrary, refers to + / - 10%, more preferably + / - 5%, even more preferably + / - 1%, of the designated value. All publications discussed and / or referenced herein are incorporated herein in their entirety. 25 As used herein, the phrase “at least one of”, when used with a list of items, means different combinations of one or more of the listed items may be used and only one of the items in the list may be needed. The item may be a particular object, thing, or category. In other words, “at least one of” means any combination of items or number of items may be used from the list, but not all of the items in the list may be required. 30 For example, “at least one of item A, item B, and item C” may mean item A; item A and item B; item B; item A, item B, and item C; or item B and item C. In some cases, “at least one of item A, item B, and item C” may mean, for example and without limitation, two of item A, one of item B, and ten of item C; four of item B and seven of item C; or some other suitable combination. As used herein, terms such as “increased”, “higher”, “decreased”, “reduced”, and similar, are made in reference to a baseline level. For example, the baseline level is calculated based on a control population. Examples of a suitable control population include a normal or a healthy population, or an untreated population. For example, 5 wherein the improvement relates to an increase in a particular biomarker of gut health, it should be understood that the increase in that biomarker is relative to a baseline level, for example, based on the levels of that biomarker in an untreated population, such as a population of subjects that has a gastrointestinal condition or disorder and has not received the compositions defined herein. 10 It is to be appreciated that certain features that are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any sub-combination. Throughout the present specification, various aspects and components of the 15 invention can be presented in a range format. The range format is included for convenience and should not be interpreted as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible sub-ranges as well as individual numerical values within that range, unless specifically indicated. For example, description of a range such 20 as from 1 to 5 should be considered to have specifically disclosed sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 5, from 3 to 5 etc., as well as individual and partial numbers within the recited range, for example, 1, 2, 3, 4, 5, 5.5 and 6, unless where integers are required or implicit from context. This applies regardless of the breadth of the disclosed range. Where specific values are required, 25 these will be indicated in the specification. Colostrum As used herein, “colostrum” refers to the first milk produced by mammals after birth and is rich in antibodies / immunoglobulins (Ig). As used herein, “hyperimmune 30 colostrum” refers to colostrum that has been collected from a mammal that has been immunized with particular vaccine(s) such as those comprising an antigen(s) of a bacterial species. Repeated immunization of pregnant mammals, such as dairy cows, can stimulate production of high levels of immunogen-specific Ig in colostrum. When harvested, this hyperimmune colostrum, such as hyperimmune bovine colostrum (HBC), is enriched predominantly with immunogen-specific IgG’s. Colostrum also contains lower levels of IgA and IgM, cytokines, growth factors, and antimicrobial peptides are also present. In cows Ig’s are not transferred to the unborn calf during gestation, transmission only occurs post-partum via mammary secretions (Hurley et al., 2011). The 5 content of bovine colostrum is enriched in immunoglobulin with levels of >50mg / ml, with IgG1 accounting for 85-95% of the total Ig concentration (Hurley et al., 2011; Warny et al., 1999). Colostrum Ig’s are known to reside longer in the GI tract due to the presence of casein proteins and unlike antibiotics, do not adversely disrupt the resident microbiota (Warny et al., 1999). 10 As used herein, “comprising hyperimmune antibodies” are antibodies (immunoglobulins) of the colostrum that bind an antigen of the vaccine(s). In an embodiment, the hyperimmune colostrum is bovine hyperimmune colostrum. In an embodiment, the hyperimmune colostrum is ungulate hyperimmune colostrum. In an embodiment, the hyperimmune colostrum is ovine hyperimmune 15 colostrum. In an embodiment, the hyperimmune colostrum is caprine hyperimmune colostrum. The colostrum may be subjected to one or more processing steps after collection. Such processing steps would be suitably ascertained by a person skilled in the art depending on the specific components of the colostrum desired. For example, 20 the colostrum may be processed to remove solids, cellular debris, precipitates, fat, carbohydrates such as milk oligosaccharides, proteins such as lactose, noncasein and casein proteins. Thus, the invention also encompasses fractions of the colostrum comprising hyperimmune antibodies. Put differently, the invention also encompasses purified colostrum, being colostrum that has had particular non-desirable components 25 removed. Examples of suitable processing steps include ultrafiltration, diafiltration, chromatography, centrifugation, electrophoresis, ultracentrifugation, precipitation or acidification. For example, colostrum may be processed by methods such as high and low speed centrifugation, optionally with the use of gradients formed using sucrose, percoll, cesium and the like. Chromatographic methods such as size exclusion 30 chromatography, affinity chromatography, high performance liquid chromatography, reverse phase chromatography, and the like are also useful. Electrophoretic methods (such as capillary electrophoresis), filtration methods (such as tangential flow ultrafiltration), partitioning methods (such as protein precipitation) are further examples of useful methods. In the following detailed description of the invention reference is made predominantly to the production and use of hyperimmune colostrum and hyperimmune colostrums extract that is obtained from suitably immunized bovines. The term “antibody” as used herein includes both intact molecules as well as 5 fragments thereof, such as, for example, Fab and F(ab′)2, which are capable of binding antigen. Fab and F(ab′)2 fragments lack the Fc fragment of intact antibody, clear more rapidly from the circulation, and may have less non-specific tissue binding than an intact antibody. It will be appreciated that Fab and F(ab′)2 and other fragments of the antibodies useful in the present invention may be used, according to the methods 10 disclosed herein for intact antibody molecules. Such fragments are typically produced by proteolytic cleavage, using enzymes such as papain (to produce Fab fragments) or pepsin (to produce F(ab′)2 fragments). The term “antigen” as used herein refers to a molecule or structure containing one or more epitopes that induce, elicit, augment or boost a cellular and / or humoral 15 immune response. Antigens can include, for example, proteins and peptides from a pathogen such as a virus or bacteria. The term “recombinant” shall be understood to mean the product of artificial genetic recombination. In some embodiments, the hyperimmune colostrum or fraction thereof comprises 20 monomeric, dimeric or multimeric immunoglobulin selected from the group consisting of IgG, IgA and IgM and any fragments thereof. In ruminants, the principal compositional difference between colostrum and mature milk is the very high content of colostral immunoglobulin, of which IgG class makes up 80-90%. In one embodiment, the hyperimmune colostrum or fraction thereof comprises 25 IgG1 and IgG2. In some embodiments, the hyperimmune colostrum or fraction thereof comprises a secretory antibody, specifically, sIgA. Dimeric and multimeric IgA and IgM are secreted by a number of exocrine tissues. IgA is the predominant secretory immunoglobulin present in colostrum, saliva, 30 tears, bronchial secretions, nasal mucosa, prostatic fluid, vaginal secretions, and mucous secretions from the small intestine. IgA output exceeds that of all other immunoglobulins, making it the major antibody produced by the body daily and is the major immunoglobulin found in human milk, whey and colostrum. IgM secretion is less abundant but can increase to compensate for deficiencies in IgA secretion. J chain containing IgA is produced and secreted by plasma B immunocytes located in the lamina propria just beneath the basement membrane of exocrine cells. IgA has a typical immunoglobulin four-chain structure (Mr 160,000) made up of two heavy chains (Mr 55,000) and two light chains (Mr 23,000). In humans, there are two subclasses of IgA. 5 These are IgA1 and IgA2 that have one and two heavy chains, respectively. IgA can occur as monomers, dimers, trimers or multimers. In plasma, 10% of the total IgA is polymeric while the remaining 90% is monomeric. The secreted IgA binds to a Mr 100,000 poly-Ig receptor positioned in the basolateral surface of most mucosal cells. The receptor-IgA complex is next translocated to the apical surface where IgA is 10 secreted. The binding of dimeric IgA to the poly-Ig receptor is completely dependent upon the presence of a J chain. Monomeric IgA will not bind to the receptor. The difference in function of IgG and IgA, follows the position where the molecules operate. IgA is found mainly on mucosal surfaces where there is little in the way of tissue fluid to carry immune cells and chemicals. Therefore, IgA (often as a dimer) 15 would be preferably used for physical neutralisation of pathogens, and may be too effective at other immune functions. IgGs are present in the tissue fluid and blood where there is the full collection of leukocytes, complement system, macrophages etc. may physically neutralize a pathogen effectively and are also more effective in a communication / presentation role than IgA, i.e., they tend to induce better opsonisation 20 by phagocytes (e.g., Killer T cells and macrophages) and switch on the complement system better. In some embodiments, the hyperimmune colostrum is obtained from any one of colostrum, colostrum serum, hyperimmunised milk or colostrum, colostrum whey (either cheese or casein), cheese or casein whey, directly from skim milk, whole milk, or a 25 reconstituted form of such streams. In some embodiments, the hyperimmune colostrum is obtained from colostrum. In some embodiments, the hyperimmune colostrum is obtained from colostrum serum. In some embodiments, the hyperimmune colostrum is obtained from hyperimmunised milk or colostrum. In some embodiments, the hyperimmune colostrum is obtained from colostrum whey cheese or casein. In some 30 embodiments, the hyperimmune colostrum is obtained from cheese or casein whey. In some embodiments, the hyperimmune colostrum is obtained directly from skim milk, whole milk, or a reconstituted form of such streams. In some embodiments, the hyperimmune colostrum within the composition useful for the invention is a fraction of colostrum. Thus, the term colostrum as used herein includes colostral milk, processed colostral-milk such as colostral milk processed to partly or completely removes one or more of solids, cellular debris, precipitates, fat, carbohydrates such as milk oligosaccharides, proteins such as lactose, noncasein and casein proteins. 5 In some embodiments, the fraction of colostrum is colostrum processed to partly or completely remove one or more of: solids, cellular debris, precipitates, fat, carbohydrates such as milk oligosaccharides, proteins such as lactose, noncasein and casein proteins. In some embodiments, the fraction of colostrum is colostrum processed to partly or completely remove solids. In some embodiments, the fraction of colostrum 10 is colostrum processed to partly or completely remove cellular debris. In some embodiments, the fraction of colostrum is colostrum processed to partly or completely remove precipitates. In some embodiments, the fraction of colostrum is colostrum processed to partly or completely remove fat. In some embodiments, the fraction of colostrum is colostrum processed to partly or completely remove carbohydrates. In 15 some embodiments, the carbohydrates are milk oligosaccharides. In some embodiments, the fraction of colostrum is colostrum processed to partly or completely remove proteins. In some embodiments, the proteins are one or more of: lactose, noncasein and casein proteins. In some embodiments, the fraction of colostrum is colostrum processed to partly or completely remove types of antibodies. In some 20 embodiments, the antibodies are one or more of: IgG, IgM or IgA antibodies. In an embodiment, the hyperimmune colostrum or fraction thereof comprises 60% to 95% proteins, or about 80% proteins, out of which approximately 35% to 40% are immunoglobulins. In an embodiment, at least 10% of the fraction are antibodies. In an embodiment, at least 20% of the fraction is antibodies. In an embodiment, at least 25 30% of the fraction is antibodies. In an embodiment, at least 40% of the fraction is antibodies. In an embodiment, at least 50% of the fraction is antibodies. In an embodiment, at least 60% of the fraction is antibodies. In an embodiment, at least 70% of the fraction is antibodies. Methods for the (partial) purification of antibodies from colostrum or milk are 30 known in the art. In some embodiments, the fraction of colostrum is produced by one or more of: ultrafiltration, diafiltration, chromatography, electrophoresis, centrifugation, ultracentrifugation, precipitation or acidification. In some embodiments, the fraction of colostrum is produced by ultrafiltration. In some embodiments, the fraction of colostrum is produced by tangential flow ultrafiltration. In some embodiments, the fraction of colostrum is produced by diafiltration. In some embodiments, the fraction of colostrum is produced by chromatography. In some embodiments, the fraction of colostrum is produced by size exclusion chromatography. In some embodiments, the fraction of colostrum is produced by affinity chromatography. In some embodiments, the fraction 5 of colostrum is produced by high performance liquid chromatography. In some embodiments, the fraction of colostrum is produced by reverse phase chromatography. In some embodiments, the fraction of colostrum is produced by electrophoresis. In some embodiments, the fraction of colostrum is produced by capillary electrophoresis. In some embodiments, the fraction of colostrum is produced by centrifugation. In some 10 embodiments, the fraction of colostrum is produced by high speed centrifugation. In some embodiments, the fraction of colostrum is produced by low speed centrifugation. In some embodiments, the fraction of colostrum is produced by gradient centrifugation. In some embodiments, the fraction of colostrum is produced by ultracentrifugation. In some embodiments, the fraction of colostrum is produced by precipitation. In some 15 embodiments, the fraction of colostrum is produced by protein precipitation. In some embodiments, the fraction of colostrum is produced by acidification. An example of the production of a composition useful for the invention is summarized in Figure 8. In some embodiments, the composition further comprises an adjuvant. 20 Appropriate adjuvants therefore may be any antigen, antibody, glycosphingolipids, proteins, cytokines, adhesion molecules, and components that can activate or alter the function of antigen presenting cell or of any other cell related to the immune system in a direct and indirect manner. In some embodiments, the adjuvant is one or more of: an antigen, an antibody, glycosphingolipids, proteins, cytokines, adhesion molecules.25 In some embodiments, the composition further comprises a pro-biotic or pre- biotic. In some embodiments, the hyperimmune preparation comprises affinity purified antibody or any fragment thereof. In some embodiments, the composition comprises colostrum component / s such 30 as for example, alarmins, defensins, colostrinin, and any other colostrum or milk derived carbohydrates, glycolipids or any other molecules or components that may further enhance or inhibit modulation of an immune response, or any preparations, mixtures or combinations thereof. In some embodiments, the hyperimmune colostrum or fraction thereof of the present disclosure are processed so as to largely remove all isotypes except IgG. In some embodiments, the immunoglobulins are derived from numerous donors. Any number of donors may be used. In some embodiments, the antibodies are derived from 5 one donor. In some embodiments, the antibodies are derived from about 1 to about 10 donors. In some embodiments, the antibodies are derived from about 10 to about 100 donors. In some embodiments, the antibodies are derived from about 100 to about 1000 donors. In some embodiments, the antibodies are derived from over 1000 donors. In some embodiments, the hyperimmune colostrum or a fraction thereof 10 comprises antibodies which bind to one or more genus of Gram negative bacteria selected from the group consisting of: Enterobacteriaceae, Enterobacter, Escherichia, Klebsiella, Bacteroid, Salmonella, Campylobacter, Helicobacter, Vibrio, Shigella, Yersinia, Rumminococcus and Aeromonas. In one embodiment, the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to Enterobacteriaceae. 15 In one embodiment, the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to Enterobacter. In one embodiment, the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to Escherichia. In one embodiment, the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to Klebsiella. In one embodiment, the hyperimmune colostrum or a fraction 20 thereof comprises antibodies which bind to Bacteroid. In one embodiment, the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to Salmonella. In one embodiment, the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to Campylobacter. In one embodiment, the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to 25 Helicobacter. In one embodiment, the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to Vibrio. In one embodiment, the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to Shigella. In one embodiment, the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to Yersinia. In one embodiment, the hyperimmune colostrum or a fraction 30 thereof comprises antibodies which bind to Rumminococcus. In one embodiment, the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to Aeromonas. In one embodiment, the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to Enterobacteriaceae and Klebsiella. In one embodiment, the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to Enterobacter and Klebsiella. In one embodiment, the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to Escherichia and Klebsiella. In one embodiment, the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to Enterobacteriaceae and Bacteroid. In one 5 embodiment, the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to Enterobacter and Bacteroid. In one embodiment, the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to Escherichia and Bacteroid. In one embodiment, the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to Enterobacteriaceae and Salmonella. In one 10 embodiment, the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to Enterobacter and Salmonella. In one embodiment, the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to Escherichia and Salmonella. In one embodiment, the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to Enterobacteriaceae, and Campylobacter. In one 15 embodiment, the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to Enterobacter and Campylobacter. In one embodiment, the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to Escherichia and Campylobacter. In one embodiment, the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to Enterobacteriaceae and Helicobacter. In one 20 embodiment, the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to Enterobacter and Helicobacter. In one embodiment, the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to Escherichia and Helicobacter. In one embodiment, the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to Enterobacteriaceae and Vibrio. In one embodiment, 25 the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to Enterobacter and Vibrio. In one embodiment, the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to Escherichia and Vibrio. In one embodiment, the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to Enterobacteriaceae and Shigella. In one embodiment, the hyperimmune colostrum or a 30 fraction thereof comprises antibodies which bind to Enterobacter and Shigella. In one embodiment, the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to Escherichia and Shigella. In one embodiment, the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to Enterobacteriaceae and Yersinia. In one embodiment, the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to Enterobacter and Yersinia. In one embodiment, the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to Escherichia and Yersinia. In one embodiment, the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to Enterobacteriaceae and Rumminococcus. 5 In one embodiment, the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to Enterobacter and Rumminococcus. In one embodiment, the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to Escherichia and Rumminococcus. In one embodiment, the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to Enterobacteriaceae and 10 Aeromonas. In one embodiment, the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to Enterobacter and Aeromonas. In one embodiment, the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to Escherichia and Aeromonas. In one embodiment, the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to Enterobacteriaceae, Shigella, and 15 Salmonella. In one embodiment, the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to Enterobacter, Shigella, and Salmonella. In one embodiment, the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to Escherichia, Shigella, and Salmonella. In one embodiment, the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to 20 Enterobacteriaceae, Shigella, and Klebsiella. In one embodiment, the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to Enterobacter, Shigella, and Klebsiella. In one embodiment, the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to Escherichia, Shigella, and Klebsiella. In one embodiment, the hyperimmune colostrum or a fraction thereof comprises antibodies 25 which bind to Enterobacteriaceae, Shigella, and Bacteroid. In one embodiment, the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to Enterobacter, Shigella, and Bacteroid. In one embodiment, the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to Escherichia, Shigella, and Bacteroid. In one embodiment, the hyperimmune colostrum or a fraction thereof 30 comprises antibodies which bind to Enterobacteriaceae, Shigella, and Campylobacter. In one embodiment, the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to Enterobacter, Shigella, and Campylobacter. In one embodiment, the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to Escherichia, Shigella, and Campylobacter. In one embodiment, the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to Enterobacteriaceae, Shigella, and Helicobacter. In one embodiment, the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to Enterobacter, Shigella, and Helicobacter. In one embodiment, the hyperimmune colostrum or a 5 fraction thereof comprises antibodies which bind to Escherichia, Shigella, and Helicobacter. In one embodiment, the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to Enterobacteriaceae, Shigella, and Vibrio. In one embodiment, the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to Enterobacter, Shigella, and Vibrio. In one embodiment, the hyperimmune 10 colostrum or a fraction thereof comprises antibodies which bind to Escherichia, Shigella, and Vibrio. In one embodiment, the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to Enterobacteriaceae, Shigella, and Aeromonas. In one embodiment, the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to Enterobacter, Shigella, and Aeromonas. In one embodiment, the 15 hyperimmune colostrum or a fraction thereof comprises antibodies which bind to Escherichia, Shigella, and Aeromonas. In one embodiment, the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to Enterobacteriaceae, Shigella, and Vibrio. In one embodiment, the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to Enterobacter, Shigella, and Vibrio. In one 20 embodiment, the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to Escherichia, Shigella and Vibrio. In one embodiment, the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to Enterobacteriaceae, Shigella and Yersinia. In one embodiment, the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to Enterobacter, Shigella and Yersinia. In one 25 embodiment, the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to Escherichia, Shigella and Yersinia. In one embodiment, the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to Enterobacteriaceae, Shigella, Vibrio and Campylobacter. In one embodiment, the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to Enterobacter, Shigella, Vibrio and 30 Campylobacter. In one embodiment, the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to Escherichia, Shigella, Vibrio and Campylobacter. In some embodiments, the antibodies bind to an antigen of two, three, or four species of Gram negative bacteria. In one embodiment, the antibodies bind to an antigen of two species of Gram negative bacteria. In one embodiment, the antibodies bind to an antigen of three species of Gram negative bacteria. In one embodiment, the antibodies bind to an antigen of four species of Gram negative bacteria. In some embodiments, the composition comprises antibodies that bind to an antigen of a Gram negative bacteria selected from the group consisting of: E. coli., E. 5 albertii, E. fergusonii, E. hermannii, E. ruysiae, E. marmotae, C. jejuni, C. coli, C. lari, C. upsaliensis, Salmonella enterica, Salmonella bongori, Vibrio cholerae, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, and Shigella boydii. In one embodiment, the antibodies bind to an antigen of E. coli. In one embodiment, the antibodies bind to an antigen of E. albertii. In one embodiment, the antibodies bind to an antigen of E. 10 fergusonii. In one embodiment, the antibodies bind to an antigen of E. hermannii. In one embodiment, the antibodies bind to an antigen of E. ruysiae. In one embodiment, the antibodies bind to an antigen of E. marmotae. In one embodiment, the antibodies bind to an antigen of C. jejuni. In one embodiment, the antibodies bind to an antigen of C. coli. In one embodiment, the antibodies bind to an antigen of C. lari. In one embodiment, 15 the antibodies bind to an antigen of C. upsaliensis. In one embodiment, the antibodies bind to an antigen of Salmonella enterica. In one embodiment, the antibodies bind to an antigen of Salmonella bongori. In one embodiment, the antibodies bind to an antigen of Salmonella enterica. In one embodiment, the antibodies bind to an antigen of Vibrio cholerae. In one embodiment, the antibodies bind to an antigen of Shigella dysenteriae. 20 In one embodiment, the antibodies bind to an antigen of Shigella flexneri. In one embodiment, the antibodies bind to an antigen of Shigella sonnei. In one embodiment, the antibodies bind to an antigen of Shigella boydii. In one embodiment, the antibodies bind to an antigen of E. coli. and C. jejuni. In one embodiment, the antibodies bind to an antigen of E. coli. and Salmonella enterica. In one embodiment, the antibodies bind to 25 an antigen of E. coli and Shigella dysenteriae. In one embodiment, the antibodies bind to an antigen of E. coli. and Shigella flexneri. In one embodiment, the antibodies bind to an antigen of E. coli., C. jejuni, and Salmonella enterica. In one embodiment, the antibodies bind to an antigen of E. coli., C. jejuni and Shigella dysenteriae. In one embodiment, the antibodies bind to an antigen of E. coli., C. jejuni, and Shigella flexneri. 30 In one embodiment, the antibodies bind to an antigen of E. coli., C. jejuni and Shigella sonnei. In one embodiment, the antibodies bind to an antigen of E. coli, C. jejuni and Shigella boydii. In one embodiment, the antibodies bind to an antigen of Salmonella enterica. In one embodiment, the antibodies bind to an antigen of E. coli and Vibrio cholerae. In one embodiment, the antibodies bind to an antigen of E. coli., Vibrio cholerae, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, and Shigella boydii. In one embodiment, the antibodies bind to an antigen of Shigella dysenteriae, Shigella flexneri, Shigella sonnei, and Shigella boydii. In one embodiment, the antibodies bind to an antigen of Vibrio cholerae, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, 5 and Shigella boydii. In some embodiments, the E. coli comprises one or more or all of Enterotoxigenic E. coli (ETEC), Enterohemorrhagic E. coli (EHEC) and Enteropathogenic E. coli (EPEC). In one embodiment, the E. coli comprises Enterotoxigenic E. coli (ETEC), Enterohemorrhagic E. coli (EHEC) and Enteropathogenic E. coli (EPEC). In one 10 embodiment, the E. coli comprises Enterohemorrhagic E. coli (EHEC). In one embodiment, the E. coli comprises Enteropathogenic E. coli (EPEC). In one embodiment, the E. coli comprises Enterotoxigenic E. coli (ETEC) and Enterohemorrhagic E. coli (EHEC). In one embodiment, the E. coli comprises Enterotoxigenic E. coli (ETEC) and Enteropathogenic E. coli (EPEC). In one 15 embodiment, the E. coli comprises Enterotoxigenic E. coli (ETEC), Enterohemorrhagic E. coli (EHEC) and Enteropathogenic E. coli (EPEC). In some embodiments, the hyperimmune colostrum or fraction thereof comprises antibodies which bind to one or more antigens selected from the group consisting of: E. coli O group serotype, Shigella spp. LPS, Shigella spp. toxins and invasion plasmid 20 antigen (Ipa) proteins. In one embodiment, the hyperimmune colostrum or fraction thereof comprises antibodies which bind to E. coli O group serotype. In one embodiment, the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to Shigella spp. LPS. In one embodiment, the hyperimmune colostrum or fraction thereof comprises antibodies which bind to Shigella spp. toxins. In one 25 embodiment, the hyperimmune colostrum or fraction thereof comprises antibodies which bind to invasion plasmid antigen (Ipa) proteins. In one embodiment, the hyperimmune colostrum or fraction thereof comprises antibodies which bind to E. coli O group serotype and Shigella spp. LPS. In one embodiment, the hyperimmune colostrum or fraction thereof comprises antibodies which bind to E. coli O group serotype and Shigella spp. 30 toxins. In one embodiment, the hyperimmune colostrum or fraction thereof comprises antibodies which bind to E. coli O group serotype and invasion plasmid antigen (Ipa) proteins. In one embodiment, the hyperimmune colostrum or fraction thereof comprises antibodies which bind to Shigella spp. LPS and Shigella spp. toxins. In one embodiment, the hyperimmune colostrum or fraction thereof comprises antibodies which bind to Shigella spp. LPS and invasion plasmid antigen (Ipa) proteins. In one embodiment, the hyperimmune colostrum or fraction thereof comprises antibodies which bind to Shigella spp. toxins and invasion plasmid antigen (Ipa) proteins. In one embodiment, the hyperimmune colostrum or fraction thereof comprises antibodies which bind to E. coli O 5 group serotype, Shigella spp. LPS and Shigella spp. toxins. In one embodiment, the hyperimmune colostrum or fraction thereof comprises antibodies which bind to E. coli O group serotype, Shigella spp. LPS, and invasion plasmid antigen (Ipa) proteins. In one embodiment, the hyperimmune colostrum or fraction thereof comprises antibodies which bind to E. coli O group serotype, Shigella spp. toxins and invasion plasmid antigen (Ipa) 10 proteins. In one embodiment, the hyperimmune colostrum or fraction thereof comprises antibodies which bind to Shigella spp. LPS, Shigella spp. toxins and invasion plasmid antigen (Ipa) proteins. In one embodiment, the hyperimmune colostrum or fraction thereof comprises antibodies which bind to E. coli O group serotype, Shigella spp. LPS, Shigella spp. toxins and invasion plasmid antigen (Ipa) proteins. 15 In some embodiments, the hyperimmune colostrum or fraction thereof comprises antibodies which bind to one or more antigens selected from the group consisting of: E. coli O group serotype, Shigella spp. LPS, Shigella spp. toxins and invasion plasmid antigen (Ipa) proteins. In one embodiment, the hyperimmune colostrum or fraction thereof comprises antibodies which bind to E. coli O group serotype. In one 20 embodiment, the hyperimmune colostrum or fraction thereof comprises antibodies which bind to Shigella spp. LPS. In one embodiment, the hyperimmune colostrum or fraction thereof comprises antibodies which bind to Shigella spp. toxins. In one embodiment, the hyperimmune colostrum or fraction thereof comprises antibodies which bind to invasion plasmid antigen (Ipa) proteins. In one embodiment, the hyperimmune colostrum or 25 fraction thereof comprises antibodies which bind to E. coli O group serotype and Shigella spp. LPS. In one embodiment, the hyperimmune colostrum or fraction thereof comprises antibodies which bind to E. coli O group serotype and Shigella spp. toxins. In one embodiment, the hyperimmune colostrum or fraction thereof comprises antibodies which bind to E. coli O group serotype and invasion plasmid antigen (Ipa) proteins. In one 30 embodiment, the hyperimmune colostrum or fraction thereof comprises antibodies which bind to Shigella spp. LPS and Shigella spp. toxins. In one embodiment, the hyperimmune colostrum or fraction thereof comprises antibodies which bind to Shigella spp. LPS and invasion plasmid antigen (Ipa) proteins. In one embodiment, the hyperimmune colostrum or fraction thereof comprises antibodies which bind to Shigella spp. toxins and invasion plasmid antigen (Ipa) proteins. In one embodiment, the hyperimmune colostrum or fraction thereof comprises antibodies which bind to E. coli O group serotype, Shigella spp. LPS and Shigella spp. toxins. In one embodiment, the hyperimmune colostrum or fraction thereof comprises antibodies which bind to E. coli O 5 group serotype, Shigella spp. LPS, and invasion plasmid antigen (Ipa) proteins. In one embodiment, the hyperimmune colostrum or fraction thereof comprises antibodies which bind to E. coli O group serotype, Shigella spp. toxins and invasion plasmid antigen (Ipa) proteins. In one embodiment, the hyperimmune colostrum or fraction thereof comprises antibodies which bind to Shigella spp. LPS, Shigella spp. toxins and invasion plasmid 10 antigen (Ipa) proteins. In one embodiment, the hyperimmune colostrum or fraction thereof comprises antibodies which bind to E. coli O group serotype, Shigella spp. LPS, Shigella spp. toxins and invasion plasmid antigen (Ipa) proteins. In some embodiments, the hyperimmune colostrum or fraction thereof comprises antibodies which bind to one or more E. coli O group serotype antigens selected from 15 the group consisting of: O6, O8, O15, O25, O27, O63, O78, O114, O115, O128, O148, O153, and O159. In one embodiment, the hyperimmune colostrum or fraction thereof comprises antibodies which bind to E. coli O group serotype antigens comprising O6, O8, O15, O25, O27, O63, O78, O114, O115 and O128. In one embodiment, the hyperimmune colostrum or fraction thereof comprises antibodies which bind to E. coli O 20 group serotype antigens comprising O6, O8, O15, O25, O27, O63, O78, O114, O115 and O148. In one embodiment, the hyperimmune colostrum or fraction thereof comprises antibodies which bind to E. coli O group serotype antigens comprising O6, O8, O15, O25, O27, O63, O78, O114, O115 and O153. In one embodiment, the hyperimmune colostrum or fraction thereof comprises antibodies which bind to E. coli O 25 group serotype antigens comprising O6, O8, O15, O25, O27, O63, O78, O114, O115 and O159. In one embodiment, the hyperimmune colostrum or fraction thereof comprises antibodies which bind to E. coli O group serotype antigens comprising O6, O8, O15, O25, O27, O63, O78, O114, O115, O128 and O148. In one embodiment, the hyperimmune colostrum or fraction thereof comprises antibodies which bind to E. coli O 30 group serotype antigens comprising O6, O8, O15, O25, O27, O63, O78, O114, O115, O128 and O153. In one embodiment, the hyperimmune colostrum or fraction thereof comprises antibodies which bind to E. coli O group serotype antigens comprising O6, O8, O15, O25, O27, O63, O78, O114, O115, O128 and O159. In one embodiment, the hyperimmune colostrum or fraction thereof comprises antibodies which bind to E. coli O group serotype antigens comprising O6, O8, O15, O25, O27, O63, O78, O114, O115, O128, O148 and O153. In one embodiment, the hyperimmune colostrum or fraction thereof comprises antibodies which bind to E. coli O group serotype antigens comprising O6, O8, O15, O25, O27, O63, O78, O114, O115, O128, O148 and O159. In one 5 embodiment, the hyperimmune colostrum or fraction thereof comprises antibodies which bind to E. coli O group serotype antigens comprising O6, O8, O15, O25, O27, O63, O78, O114, O115, O128, O148, O153, and O159. In some embodiments, the hyperimmune colostrum or fraction thereof comprises antibodies which bind to one or more E. coli O group serotype antigens selected from 10 the group consisting of: O6, O8, O15, O25, O27, O63, O78, O114, O115, O128, O148, O153, and O159. In one embodiment, the hyperimmune colostrum or fraction thereof comprises antibodies which bind to E. coli O group serotype antigens comprising O6, O8, O15, O25, O27, O63, O78, O114, O115 and O128. In one embodiment, the hyperimmune colostrum or fraction thereof comprises antibodies which bind to E. coli O 15 group serotype antigens comprising O6, O8, O15, O25, O27, O63, O78, O114, O115 and O148. In one embodiment, the hyperimmune colostrum or fraction thereof comprises antibodies which bind to E. coli O group serotype antigens comprising O6, O8, O15, O25, O27, O63, O78, O114, O115 and O153. In one embodiment, the hyperimmune colostrum or fraction thereof comprises antibodies which bind to E. coli O 20 group serotype antigens comprising O6, O8, O15, O25, O27, O63, O78, O114, O115 and O159. In one embodiment, the hyperimmune colostrum or fraction thereof comprises antibodies which bind to E. coli O group serotype antigens comprising O6, O8, O15, O25, O27, O63, O78, O114, O115, O128 and O148. In one embodiment, the hyperimmune colostrum or fraction thereof comprises antibodies which bind to E. coli O 25 group serotype antigens comprising O6, O8, O15, O25, O27, O63, O78, O114, O115, O128 and O153. In one embodiment, the hyperimmune colostrum or fraction thereof comprises antibodies which bind to E. coli O group serotype antigens comprising O6, O8, O15, O25, O27, O63, O78, O114, O115, O128 and O159. In one embodiment, the hyperimmune colostrum or fraction thereof comprises antibodies which bind to E. coli O 30 group serotype antigens comprising O6, O8, O15, O25, O27, O63, O78, O114, O115, O128, O148 and O153. In one embodiment, the hyperimmune colostrum or fraction thereof comprises antibodies which bind to E. coli O group serotype antigens comprising O6, O8, O15, O25, O27, O63, O78, O114, O115, O128, O148 and O159. In one embodiment, the hyperimmune colostrum or fraction thereof comprises antibodies which bind to E. coli O group serotype antigens comprising O6, O8, O15, O25, O27, O63, O78, O114, O115, O128, O148, O153, and O159. In some embodiments, the Shigella spp. LPS are from one or more of: S. flexneri 2a, S. flexneri 3a, S. flexneri 6 and S. sonnei. In one embodiment, the Shigella spp. LPS 5 are from S. flexneri 2a, S. flexneri 3a, S. flexneri 6 and S. sonnei. In one embodiment, the Shigella spp. LPS are from S. flexneri 2a and S. flexneri 3a. In one embodiment, the Shigella spp. LPS are from S. flexneri 2a and S. flexneri 6. In one embodiment, the Shigella spp. LPS are from S. flexneri 2a and S. sonnei. In one embodiment, the Shigella spp. LPS are from S. flexneri 2a, S. flexneri 3a, and S. flexneri 6. In one embodiment, 10 the Shigella spp. LPS are from S. flexneri 2a, S. flexneri 3a, and S. sonnei. In one embodiment, the Shigella spp. LPS are from S. flexneri 2a, S. flexneri 3a, S. flexneri 6 and S. sonnei. In some embodiments, the hyperimmune colostrum or fraction thereof comprises antibodies which bind to one or more Shigella spp. toxins selected from the group 15 consisting of: Shigella enterotoxin 1 (ShET-1), Shigella enterotoxin 2 (ShET-2) and Shiga toxin (Stx). In one embodiment, the hyperimmune colostrum or fraction thereof comprises antibodies which bind to Shigella enterotoxin 1 (ShET-1). In one embodiment, the hyperimmune colostrum or fraction thereof comprises antibodies which bind to Shigella enterotoxin 2 (ShET-2). In one embodiment, the hyperimmune colostrum or 20 fraction thereof comprises antibodies which bind to Shiga toxin (Stx). In one embodiment, the hyperimmune colostrum or fraction thereof comprises antibodies which bind to one or more Shigella spp. toxins comprising Shigella enterotoxin 1 (ShET-1) and Shigella enterotoxin 2 (ShET-2). In one embodiment, the hyperimmune colostrum or fraction thereof comprises antibodies which bind to one or more Shigella spp. toxins 25 comprising Shigella enterotoxin 1 (ShET-1), and Shiga toxin (Stx). In one embodiment, the hyperimmune colostrum or fraction thereof comprises antibodies which bind to one or more Shigella spp. toxins comprising Shigella enterotoxin 1 (ShET-1), Shigella enterotoxin 2 (ShET-2) and Shiga toxin (Stx). In some embodiments, the invasion plasmid antigen (Ipa) proteins comprise one 30 or more of IpaB, IpaC and IpaD. In one embodiment, the invasion plasmid antigen (Ipa) proteins comprise IpaB. In one embodiment, the invasion plasmid antigen (Ipa) proteins comprise IpaB and IpaC. In one embodiment, the invasion plasmid antigen (Ipa) proteins comprise IpaB and IpaD. In one embodiment, the invasion plasmid antigen (Ipa) proteins comprise IpaC and IpaD. In one embodiment, the invasion plasmid antigen (Ipa) proteins comprise IpaB, IpaC and IpaD. In some embodiments, the composition further comprise a therapeutic agent, carrier or adjuvant and / or non-hyperimmune colostrum. 5 Methods of preparing colostrum and hyperimmune preparations In some embodiments, the preparation of hyperimmune colostrum comprises immunising a host mammal, typically an ungulate animal, with a vaccine comprising at least one antigen. In an embodiment, the vaccine comprises bacterial components, 10 such as the cell wall antigens of O group serotype at least some of which are separated from intact cell walls. The vaccine is used to induce production in the host animal of immunoglobulins which are recovered in the milk of the host. In some embodiments, the ungulate animal is a bovine (cow), ovine (sheep) or caprine (goat). In one embodiment, the ungulate animal is a bovine. In one embodiment, 15 the ungulate animal is an ovine. In one embodiment, the ungulate animal is a caprine. In one embodiment, the bovine is a dairy cow. Examples of dairy cows include, but are not limited to, Friesian, Brown Swiss, Guernsey, Ayrshire, Jersey, and Milking Shorthorn. According to one embodiment, lipopolysaccharides (LPS) or any antigen used 20 for immunizing a female mammal, preferably a female bovine, may be provided as any one of an isolated and purified peptide, a purified recombinant protein, a fusion protein, cell lysate, membranal preparation, nuclear preparation, or cytosolic preparation of any one of tissue culture cells, primary cells or tissue samples. In some embodiments, the hyperimmune colostrum from the host animal 25 immunized with the cell wall antigens vaccine is administered directly in the form of milk. In some embodiments, the hyperimmune colostrum is treated to enrich or isolate the immunoglobulins. In some embodiments, the hyperimmune colostrum is in the form of a food product. In some embodiments, the food product is whole milk, skim milk or whey protein. In one embodiment, the food product is whole milk. In one embodiment, the 30 food product is skim milk. In one embodiment, the food product is whey protein. The O antigens can be separated from the bacterial cell walls by application of an effective amount of shear, homogenisation or heat or by effective combinations thereof. Preferred conditions are such as those described in U.S. Pat 9,402,902. In some embodiments, the hyperimmune preparation was prepared by immunizing the host animal with a vaccine composition comprising one or more antigens selected from the group consisting of: E. coli O group serotype, Shigella spp. LPS, Shigella spp. toxins and invasion plasmid antigen (Ipa) proteins. In one embodiment, 5 the hyperimmune preparation was prepared by immunizing a host animal with a vaccine composition comprising E. coli O group serotype. In one embodiment, the hyperimmune preparation was prepared by immunizing a host animal with a vaccine composition comprising Shigella spp. LPS. In one embodiment, the hyperimmune preparation was prepared by immunizing a host animal with a vaccine composition comprising Shigella 10 spp. toxins. In one embodiment, the hyperimmune preparation was prepared by immunizing a host animal with a vaccine composition comprising invasion plasmid antigen (Ipa) proteins. In one embodiment, the hyperimmune preparation was prepared by immunizing a host animal with a vaccine composition comprising E. coli O group serotype and Shigella spp. LPS. In one embodiment, the hyperimmune preparation was 15 prepared by immunizing a host animal with a vaccine composition comprising E. coli O group serotype and Shigella spp. toxins. In one embodiment, the hyperimmune preparation was prepared by immunizing a host animal with a vaccine composition comprising E. coli O group serotype and invasion plasmid antigen (Ipa) proteins. In one embodiment, the hyperimmune preparation was prepared by immunizing a host animal 20 with a vaccine composition comprising Shigella spp. LPS and Shigella spp. toxins. In one embodiment, the hyperimmune preparation was prepared by immunizing a host animal with a vaccine composition comprising Shigella spp. LPS and invasion plasmid antigen (Ipa) proteins. In one embodiment, the hyperimmune preparation was prepared by immunizing a host animal with a vaccine composition comprising Shigella spp. toxins 25 and invasion plasmid antigen (Ipa) proteins. In one embodiment, the hyperimmune preparation was prepared by immunizing a host animal with a vaccine composition comprising E. coli O group serotype, Shigella spp. LPS and Shigella spp. toxins. In one embodiment, the hyperimmune preparation was prepared by immunizing a host animal with a vaccine composition comprising E. coli O group serotype, Shigella spp. LPS, and 30 invasion plasmid antigen (Ipa) proteins. In one embodiment, the hyperimmune preparation was prepared by immunizing a host animal with a vaccine composition comprising E. coli O group serotype, Shigella spp. toxins and invasion plasmid antigen (Ipa) proteins. In one embodiment, the hyperimmune preparation was prepared by immunizing a host animal with a vaccine composition comprising Shigella spp. LPS, Shigella spp. toxins and invasion plasmid antigen (Ipa) proteins. In one embodiment, the hyperimmune preparation was prepared by immunizing a host animal with a vaccine composition comprising E. coli O group serotype, Shigella spp. LPS, Shigella spp. toxins and invasion plasmid antigen (Ipa) proteins. 5 In some embodiments, the hyperimmune colostrum was prepared by immunizing a host animal with a vaccine composition comprising one or more antigens selected from the group consisting of: E. coli O group serotype, Shigella spp. LPS, Shigella spp. toxins and invasion plasmid antigen (Ipa) proteins. In one embodiment, the hyperimmune colostrum was prepared by immunizing a host animal with a vaccine 10 composition comprising E. coli O group serotype. In one embodiment, the hyperimmune colostrum was prepared by immunizing a host animal with a vaccine composition comprising Shigella spp. LPS. In one embodiment, the hyperimmune colostrum was prepared by immunizing a host animal with a vaccine composition comprising Shigella spp. toxins. In one embodiment, the hyperimmune colostrum was prepared by 15 immunizing a host animal with a vaccine composition comprising invasion plasmid antigen (Ipa) proteins. In one embodiment, the hyperimmune colostrum was prepared by immunizing a host animal with a vaccine composition comprising E. coli O group serotype and Shigella spp. LPS. In one embodiment, the hyperimmune colostrum was prepared by immunizing a host animal with a vaccine composition comprising E. coli O 20 group serotype and Shigella spp. toxins. In one embodiment, the hyperimmune colostrum was prepared by immunizing a host animal with a vaccine composition comprising E. coli O group serotype and invasion plasmid antigen (Ipa) proteins. In one embodiment, the hyperimmune colostrum was prepared by immunizing a host animal with a vaccine composition comprising Shigella spp. LPS and Shigella spp. toxins. In 25 one embodiment, the hyperimmune colostrum was prepared by immunizing a host animal with a vaccine composition comprising Shigella spp. LPS and invasion plasmid antigen (Ipa) proteins. In one embodiment, the hyperimmune colostrum was prepared by immunizing a host animal with a vaccine composition comprising Shigella spp. toxins and invasion plasmid antigen (Ipa) proteins. In one embodiment, the hyperimmune 30 colostrum was prepared by immunizing a host animal with a vaccine composition comprising E. coli O group serotype, Shigella spp. LPS and Shigella spp. toxins. In one embodiment, the hyperimmune colostrum was prepared by immunizing a host animal with a vaccine composition comprising E. coli O group serotype, Shigella spp. LPS, and invasion plasmid antigen (Ipa) proteins. In one embodiment, the hyperimmune colostrum was prepared by immunizing a host animal with a vaccine composition comprising E. coli O group serotype, Shigella spp. toxins and invasion plasmid antigen (Ipa) proteins. In one embodiment, the hyperimmune colostrum was prepared by immunizing a host animal with a vaccine composition comprising Shigella spp. LPS, 5 Shigella spp. toxins and invasion plasmid antigen (Ipa) proteins. In one embodiment, the hyperimmune colostrum was prepared by immunizing a host animal with a vaccine composition comprising E. coli O group serotype, Shigella spp. LPS, Shigella spp. toxins and invasion plasmid antigen (Ipa) proteins. In some embodiments, the hyperimmune colostrum was prepared by immunizing 10 a host animal with a vaccine composition comprising E. coli O group serotype antigens selected from the group consisting of: O6, O8, O15, O25, O27, O63, O78, O114, O115, O128, O148, O153, and O159. In one embodiment, the hyperimmune colostrum was prepared by immunizing a host animal with a vaccine composition comprising E. coli O group serotype antigens comprising O6, O8, O15, O25, O27, O63, O78, O114, O115 15 and O128. In one embodiment, the hyperimmune colostrum was prepared by immunizing a host animal with a vaccine composition comprising E. coli O group serotype antigens comprising O6, O8, O15, O25, O27, O63, O78, O114, O115 and O148. In one embodiment, the hyperimmune colostrum was prepared by immunizing a host animal with a vaccine composition comprising E. coli O group serotype antigens 20 comprising O6, O8, O15, O25, O27, O63, O78, O114, O115 and O153. In one embodiment, the hyperimmune colostrum was prepared by immunizing a host animal with a vaccine composition comprising E. coli O group serotype antigens comprising O6, O8, O15, O25, O27, O63, O78, O114, O115 and O159. In one embodiment, the hyperimmune colostrum was prepared by immunizing a host animal with a vaccine 25 composition comprising E. coli O group serotype antigens comprising O6, O8, O15, O25, O27, O63, O78, O114, O115, O128 and O148. In one embodiment, the hyperimmune colostrum was prepared by immunizing a host animal with a vaccine composition comprising E. coli O group serotype antigens comprising O6, O8, O15, O25, O27, O63, O78, O114, O115, O128 and O153. In one embodiment, the 30 hyperimmune colostrum was prepared by immunizing a host animal with a vaccine composition comprising E. coli O group serotype antigens comprising O6, O8, O15, O25, O27, O63, O78, O114, O115, O128 and O159. In one embodiment, the hyperimmune colostrum was prepared by immunizing a host animal with a vaccine composition comprising E. coli O group serotype antigens comprising O6, O8, O15, O25, O27, O63, O78, O114, O115, O128, O148 and O153. In one embodiment, the hyperimmune colostrum was prepared by immunizing a host animal with a vaccine composition comprising E. coli O group serotype antigens comprising O6, O8, O15, O25, O27, O63, O78, O114, O115, O128, O148 and O159. In one embodiment, the 5 hyperimmune colostrum was prepared by immunizing a host animal with a vaccine composition comprising E. coli O group serotype antigens comprising O6, O8, O15, O25, O27, O63, O78, O114, O115, O128, O148, O153, and O159. In some embodiments, the hyperimmune preparation was prepared by immunizing a host animal with a vaccine composition comprising E. coli O group 10 serotype antigens selected from the group consisting of: O6, O8, O15, O25, O27, O63, O78, O114, O115, O128, O148, O153, and O159. In one embodiment, the hyperimmune preparation was prepared by immunizing a host animal with a vaccine composition comprising E. coli O group serotype antigens comprising O6, O8, O15, O25, O27, O63, O78, O114, O115 and O128. In one embodiment, the hyperimmune 15 preparation was prepared by immunizing a host animal with a vaccine composition comprising E. coli O group serotype antigens comprising O6, O8, O15, O25, O27, O63, O78, O114, O115 and O148. In one embodiment, the hyperimmune preparation was prepared by immunizing a host animal with a vaccine composition comprising E. coli O group serotype antigens comprising O6, O8, O15, O25, O27, O63, O78, O114, O115 20 and O153. In one embodiment, the hyperimmune preparation was prepared by immunizing a host animal with a vaccine composition comprising E. coli O group serotype antigens comprising O6, O8, O15, O25, O27, O63, O78, O114, O115 and O159. In one embodiment, the hyperimmune preparation was prepared by immunizing a host animal with a vaccine composition comprising E. coli O group serotype antigens 25 comprising O6, O8, O15, O25, O27, O63, O78, O114, O115, O128 and O148. In one embodiment, the hyperimmune preparation was prepared by immunizing a host animal with a vaccine composition comprising E. coli O group serotype antigens comprising O6, O8, O15, O25, O27, O63, O78, O114, O115, O128 and O153. In one embodiment, the hyperimmune preparation was prepared by immunizing a host animal with a vaccine 30 composition comprising E. coli O group serotype antigens comprising O6, O8, O15, O25, O27, O63, O78, O114, O115, O128 and O159. In one embodiment, the hyperimmune preparation was prepared by immunizing a host animal with a vaccine composition comprising E. coli O group serotype antigens comprising O6, O8, O15, O25, O27, O63, O78, O114, O115, O128, O148 and O153. In one embodiment, the hyperimmune preparation was prepared by immunizing a host animal with a vaccine composition comprising E. coli O group serotype antigens comprising O6, O8, O15, O25, O27, O63, O78, O114, O115, O128, O148 and O159. In one embodiment, the hyperimmune preparation was prepared by immunizing a host animal with a vaccine 5 composition comprising E. coli O group serotype antigens comprising O6, O8, O15, O25, O27, O63, O78, O114, O115, O128, O148, O153, and O159. In an alternate embodiment, hyperimmune antibody preparations are prepared using avian eggs such as described in WO 2014 / 169344. 10 Methods of treatment and formulations As used herein, the terms “treating”, “treat” or “treatment” include administering a composition described herein to thereby reduce or eliminate at least one symptom of a specified disease or condition. As used herein, the term “preventing”, “prevent” or “prevention” includes 15 providing prophylaxis with respect to occurrence or recurrence of a specified disease or condition in an individual. An individual may be predisposed to or at risk of developing the disease but has not yet been diagnosed with the disease. As used herein, the term “subject” shall be taken to mean any animal including humans, for example a mammal. Exemplary subjects include but are not limited to 20 humans and non-human primates. In some embodiments, the subject is a human. As used herein, the term “dosage” or “dose” shall be taken to mean the total dose to be delivered at one single time point. This can be as a single administration (such as a single tablet) or multiple administrations (such as two or more tablets taken simultaneously or sequentially). As a non-limiting example, a dosage of 1,200 mg can 25 mean the delivery of a single 1,200 mg tablet, three 400 mg tablets, four 300 mg tablets, six 200 mg tablets, and so on. In one embodiment, the dosage is six 200 mg tablets once a day. In one embodiment, the dosage is three 200 mg tablets twice a day for two doses a day. In one embodiment, the dosage is two 600 mg tablets once a day. In one embodiment, the dosage is one 600 mg tablet twice a day for two doses a day. However, 30 it will be appreciated that the dose can also be delivered in any appropriate form such as a powder contained in a sachet. In one embodiment, the hyperimmune colostrum or fraction thereof is administered as a single dosage / dose per day. In an embodiment, the single dose is taken before the subjects first meal of the day. In an embodiment, the single dose is taken before the subject consumes any liquid for the day. In an embodiment, the single dose is taken before the subjects first meal of the day and before the subject consumes any liquid for the day. In an embodiment, the liquid is water. In another embodiment, the hyperimmune colostrum or fraction thereof is 5 administered as two doses per day. In an embodiment, the two doses are administered about 12 hours apart. In an embodiment, at most one dose is administered no more than 18 hours from the other dose. In an embodiment, at most one dose is administered no more than 17 hours from the other dose. In an embodiment, at most one dose is administered no more than 16 hours from the other dose. In an embodiment, at most 10 one dose is administered no more than 14 hours from the other dose. In an embodiment, at most one dose is administered no more than 13 hours from the other dose. In an embodiment, the subject has one dose before breakfast and another dose before dinner (evening meal). In an embodiment, the subject has one dose before lunch (meal about midday) and another dose before dinner (evening meal). 15 The use of a single dose a day, or possibly to a lesser extent two doses a day, provides a number of benefits, most notably patient compliance (or adherence) and ease of prescription. The term “patient compliance” as used herein refers to the extent to which a patient’s behaviour matches the prescriber’s advice, usually that of a medical practitioner or the manufacturer of the pharmaceutical compound. Patient adherence to20 the prescribed therapy is a key determinant in treatment success. Patient non- compliance or non-adherence typically involves either non-persistence or non- conforming behaviour. These include unintentional lapses or miscommunication about therapeutic plans. Specific examples include patients skipping doses, unintentionally taking incorrect doses of medication, improper timing of drug administration, or 25 miscommunication regarding the correct dose. In some embodiments, a method of the invention prevents or treats a gastrointestinal condition or disorder caused by a gastrointestinal infection in a subject. In an embodiment, the infection is a Gram negative bacteria infection. In some embodiments, the gastrointestinal condition or disorder is a gut-immune 30 related disorder. In some embodiments, the gastrointestinal condition or disorder is selected from the group consisting of: inflammatory bowel disease, irritable bowel syndrome (IBS), gastroenteritis, dysentery, food poisoning and traveller’s diarrhea. In one embodiment, the gastrointestinal condition or disorder is inflammatory bowel disease. In one embodiment, the gastrointestinal condition or disorder is irritable bowel syndrome (IBS). In one embodiment, the gastrointestinal condition or disorder is gastroenteritis. In one embodiment, the gastrointestinal condition or disorder is dysentery. In one embodiment, the dysentery is bacillary dysentery (clinical shigellosis). In one embodiment, the 5 gastrointestinal condition or disorder is food poisoning. In one embodiment, the gastrointestinal condition or disorder is traveller’s diarrhea. In some embodiments, the inflammatory bowel disease is ulcerative colitis or Crohn’s disease. In one embodiment, the inflammatory bowel disease is ulcerative colitis. In one embodiment, the inflammatory bowel disease is Crohn’s disease. 10 In some embodiments, the method reduces frequency and / or clinical severity of one or more symptoms of the gastrointestinal condition or disorder. In some embodiments, the one or more symptoms of the gastrointestinal condition or disorder comprise vomiting, diarrhea, dysentery, reduced activity level, dehydration, abdominal cramps, fatigue, gas, bloating, bloody stools, loss of appetite, 15 and / or weight loss. In some embodiments, the one or more symptoms of the gastrointestinal condition or disorder comprise vomiting, diarrhea, dysentery, reduced activity level and / or dehydration. In one embodiment, the symptom of the gastrointestinal condition or disorder is vomiting. In one embodiment, the symptom of the gastrointestinal condition or disorder is diarrhea. In one embodiment, the symptom 20 of the gastrointestinal condition or disorder is dysentery. In one embodiment, the dysentery is bacillary dysentery (clinical shigellosis). In one embodiment, the symptom of the gastrointestinal condition or disorder is reduced activity level. In one embodiment, the symptom of the gastrointestinal condition or disorder is dehydration. In one embodiment, the symptom of the gastrointestinal condition or disorder is abdominal 25 cramps. In one embodiment, the symptom of the gastrointestinal condition or disorder is fatigue. In one embodiment, the symptom of the gastrointestinal condition or disorder is gas. In one embodiment, the symptom of the gastrointestinal condition or disorder is bloating. In one embodiment, the symptom of the gastrointestinal condition or disorder is bloody stools. In one embodiment, the symptom of the gastrointestinal condition or 30 disorder is loss of appetite. In one embodiment, the symptom of the gastrointestinal condition or disorder is weight loss. In an embodiment, a method of the invention provides a protective efficacy of at least 20%. In an embodiment, a method of the invention provides a protective efficacy of at least 30%. In an embodiment, a method of the invention provides a protective efficacy of at least 35%. In an embodiment, a method of the invention provides a protective efficacy of about 36%. As used herein, protective efficacy (PE) is determined as ETEC-induced moderate-severe diarrhea defined as > 4 Grade 3-5 stools in any 24 hour period post 5 challenge days or >401grams of grade 3-5 stools in any 24 hour period occurring during the post-challenge period. PE determination is represented below: PE (%) = incidence1 (placebo) – incidence1 (Travelan®) X 100% incidence1 (placebo) 10 In an embodiment, a method of the invention reduces the chance a subject will require antibiotics following exposure to a gastrointestinal infection such as by a Gram negative bacteria. In an embodiment, a method of the invention reduces the chance a subject will 15 require fluids intravenously following exposure to a gastrointestinal infection such as by a Gram negative bacteria. In an embodiment, a method of the invention reduces the chance a subject will have diarrhea following exposure to a gastrointestinal infection such as by a Gram negative bacteria. 20 In an embodiment, a method of the invention reduces the chance a subject will have a fever following exposure to a gastrointestinal infection such as by a Gram negative bacteria. In an embodiment, a method of the invention reduces the chance a subject will be nauseous following exposure to a gastrointestinal infection such as by a Gram 25 negative bacteria. In an embodiment, a method of the invention reduces the chance a subject will vomit following exposure to a gastrointestinal infection such as by a Gram negative bacteria. In some embodiments, the reduction in clinical severity of the one or more 30 symptoms is represented by a reduction in a clinical score of diarrhea or one or more biomarkers of gut inflammation. In some embodiments, the reduction in clinical severity of the one or more symptoms is represented by a reduction in a clinical score of diarrhea. In an embodiment, the method reduces frequency or clinical severity of one or more symptoms of the gastrointestinal condition or disorder within 72 hours, 48 hours, 36 hours or 24 hours of administration of the composition. In an embodiment, the method reduces frequency or clinical severity of one or more symptoms of the 5 gastrointestinal condition or disorder within 72 hours of administration of the composition. In an embodiment, the method reduces frequency or clinical severity of one or more symptoms of the gastrointestinal condition or disorder within 48 hours of administration of the composition. In an embodiment, the method reduces frequency or clinical severity of one or more symptoms of the gastrointestinal condition or disorder 10 within 36 hours of administration of the composition. In an embodiment, the method reduces frequency or clinical severity of one or more symptoms of the gastrointestinal condition or disorder within 24 hours of administration of the composition. In some embodiments, the reduction in a clinical score of diarrhea is relative to a baseline level. In one embodiment, the baseline level is calculated based on a control 15 population. In one embodiment, the control population is a normal or healthy population. In some embodiments, the clinical score of diarrhea is calculated by allocating weighted scores to one or more variables, and calculating the sum of the weighted scores to obtain the clinical score of diarrhea. In some embodiments, the one or more variables comprises: activity level, 20 appetite level, fecal consistency, fecal mucus and / or blood, skin turgor, duration of diarrhea in days, frequency of defecation per day, body temperature, heart rate, blood pressure, red blood cell count, white blood cell count, blood haemoglobin level, total protein level, serum albumin level, creatinine level and / or C-reactive protein level. In some embodiments, the one or more variables comprises: activity level, appetite level, 25 fecal consistency, fecal mucus and / or blood and / or skin turgor. In some embodiments, the one or more variables comprises: duration of diarrhea in days, frequency of defecation per day, body temperature, heart rate, blood pressure, red blood cell count, white blood cell count, blood haemoglobin level, total protein level, serum albumin level, creatinine level and / or C-reactive protein level. In some embodiments, the one or more 30 variables comprises activity level and appetite level. In some embodiments, the one or more variables comprises: activity level, appetite level, fecal consistency, and fecal mucus and / or blood. In some embodiments, the one or more variables comprises: duration of diarrhea in days and frequency of defecation per day. In some embodiments, the methods of the invention decrease gut inflammation in the subject. In some embodiments, the methods of the invention improve at least one biomarker of gut health of a subject. 5 In some embodiments, at least one biomarker of gut health and / or gut inflammation comprises: C-reactive protein (CRP), erythrocyte sedimentation rate, microbiome diversity, beneficial bacterial species, butyrate synthesis pathway, antineutrophil cytoplasmic antibodies, anti-E. coli antibodies, anti-S. flexnerii antibodies, anti-Saccharomyces cerevisiae antibodies, anti-Vibrio cholerae antibodies, leucine-rich10 α2 glycoprotein, fecal calprotectin (FCP), a fecal immunochemical test, prostaglandin E- major urinary metabolite and anti-αvβ6 antibody. In one embodiment, the biomarker is C-reactive protein (CRP). In one embodiment, the biomarker is erythrocyte sedimentation rate. In one embodiment, the biomarker is microbiome diversity. In one embodiment, the biomarker is beneficial bacterial species. In one embodiment, the 15 biomarker is antineutrophil cytoplasmic antibodies. In one embodiment, the biomarker is anti-Saccharomyces cerevisiae antibodies. In one embodiment, the biomarker is anti- E. coli antibodies. In one embodiment, the biomarker is anti-S. Flexnerii antibodies. In one embodiment, the biomarker is anti-Vibrio cholerae antibodies. In one embodiment, the biomarker is leucine-rich α2 glycoprotein. In one embodiment, the biomarker is fecal 20 calprotectin (FCP). In one embodiment, the biomarker is a fecal immunochemical test. In one embodiment, the biomarker is prostaglandin E-major urinary metabolite. In one embodiment, the biomarker is anti-αvβ6 antibody. The person skilled in the art will appreciate that in certain circumstances, the measuring of a single biomarker would be sufficient to make a clinical diagnosis or 25 determination of gut health in a subject. However, in other circumstances the measurement of multiple biomarkers is needed to confirm such a diagnosis or make a determination on the gut health of a subject. CRP and FCP have been reported as disease activity biomarkers in disease or conditions involving gut inflammation, such as inflammatory bowel disease. Other tests 30 such as the fecal immunochemical test, leucine-rich α2 glycoprotein (also known as serum leucine-rich glycoprotein) and prostaglandin E-major urinary metabolite (PGE- MUM) have been more widely used in recent years. Different biomarkers such as erythrocyte sedimentation rate and fibrinogen are used as their rates of change during gut inflammation can be distinguished from other more established biomarkers. In some embodiments, the improvement comprises decreasing the levels of CRP. In some embodiments, the improvement comprises decreasing the levels of FCP. The fecal immunochemical test (FIT) is a screening test typically used for colon cancer. However, the FIT tests for hidden blood in the stool, and is also accepted as a 5 biomarker of gut inflammation. The test comprises the use of a take-home kit that comprises a brush in the kit to brush the surface of stool, then touching the brush onto the test card provided in the kit. The test sample is then sent to a pathology laboratory for further testing. In some embodiments, the improvement comprises a decreased amount of blood detected in the FIT. 10 The term "microbiota" or "microbiome" designates the population of microorganisms living in an environment, such as in the gut or intestine of a subject. Increased gut microbiome diversity is typically accepted as an indication of a healthier microbial community. On the other hand, loss of gut microbiome diversity is associated with chronic health conditions and poor gut health. In some embodiments, 15 the improvement comprises increasing the microbiome diversity. The term "alpha diversity" is a measure of intra-sample diversity and can be described as a measurement of the richness (how many different species) and evenness (abundance or number of different species) of the microbiome. The term "beta diversity" is a measure of inter-sample diversity, and involves the 20 comparison of samples to each which provides a measure of the distance or dissimilarity between each sample pair. In some embodiments, the increase in microbiome diversity comprises increased alpha-diversity of the gut microbiome. In some embodiments, the increase in microbiome diversity comprises increased 25 beta-diversity of the gut microbiome. Beneficial bacterial species exist which are associated with reduced inflammation and reparation of damaged and / or inflamed intestinal lining. Typically, levels of beneficial bacterial species are reduced in subjects with poor gut health. Here, the present inventors have shown that the present methods and compositions are able to 30 increase the levels of beneficial bacterial species, improving gut health and addressing gut conditions and disorders. Beneficial bacterial species include butyrate-producing bacteria. Butyrate is a short-chain fatty acid (SCFA) important for maintaining gut health. Example butyrate-producing bacteria include those from the genus Agathobaculum, Pseudobutyrivibrio, Eubacterium and Faecalibacterium. In some embodiments, the improvement comprises an increased colonization of beneficial bacterial species. In some embodiments, the method increases colonization of one or more genus of beneficial bacterial species selected from the group consisting of: Eubacterium, 5 Slackia, Agathobaculum, Pseudobutyrivibrio, Faecalibacterium and / or Akkermansia. In some embodiments, the method increases colonization of beneficial bacterial species comprising bacteria from the genus Agathobaculum. In some embodiments, the method increases colonization of beneficial bacterial species comprising bacteria from the genus Pseudobutyrivibrio. In some embodiments, the method increases colonization of 10 beneficial bacterial species comprising bacteria from the genus Faecalibacterium. In some embodiments, the method increases colonization of beneficial bacterial species comprising bacteria from the genus Akkermansia. In some embodiments, the bacteria from the genus Eubacterium comprise one or more species selected from Eubacterium eligens and / or Eubacterium siraeum. In 15 some embodiments, the bacteria from the genus Eubacterium comprise Eubacterium eligens. In some embodiments, the bacteria from the genus Eubacterium comprise Eubacterium siraeum. In some embodiments, the bacteria from the genus Eubacterium comprise Eubacterium eligens and Eubacterium siraeum. In some embodiments, the method increases colonization of beneficial bacterial 20 species comprising Eubacterium and Slackia. In some embodiments, the method increases colonization of beneficial bacterial species comprising Eubacterium and Agathobaculum. In some embodiments, the method increases colonization of beneficial bacterial species comprising Eubacterium and Pseudobutyrivibrio. In some embodiments, the method increases colonization of beneficial bacterial species 25 comprising Eubacterium and Faecalibacterium. In some embodiments, the method increases colonization of beneficial bacterial species comprising Eubacterium and Akkermansia. In some embodiments, the method increases colonization of beneficial bacterial species comprising Slackia and Agathobaculum. In some embodiments, the method increases colonization of beneficial bacterial species comprising Slackia and 30 Pseudobutyrivibrio. In some embodiments, the method increases colonization of beneficial bacterial species comprising Slackia and Faecalibacterium. In some embodiments, the method increases colonization of beneficial bacterial species comprising Slackia and Akkermansia. In some embodiments, the method increases colonization of beneficial bacterial species comprising Agathobaculum and Pseudobutyrivibrio. In some embodiments, the method increases colonization of beneficial bacterial species comprising Agathobaculum and Faecalibacterium. In some embodiments, the method increases colonization of beneficial bacterial species comprising Agathobaculum and Akkermansia. In some embodiments, the method 5 increases colonization of beneficial bacterial species comprising Pseudobutyrivibrio and Faecalibacterium. In some embodiments, the method increases colonization of beneficial bacterial species comprising Pseudobutyrivibrio and Akkermansia. In some embodiments, the method increases colonization of beneficial bacterial species comprising Faecalibacterium and Akkermansia. In some embodiments, the method 10 increases colonization of beneficial bacterial species comprising Eubacterium, Slackia, and Agathobaculum. In some embodiments, the method increases colonization of beneficial bacterial species comprising Eubacterium, Slackia, and Pseudobutyrivibrio. In some embodiments, the method increases colonization of beneficial bacterial species comprising Eubacterium, Slackia, and Faecalibacterium. In some embodiments, the 15 method increases colonization of beneficial bacterial species comprising Eubacterium, Slackia, and Akkermansia. In some embodiments, the method increases colonization of beneficial bacterial species comprising Eubacterium, Agathobaculum, and Pseudobutyrivibrio. In some embodiments, the method increases colonization of beneficial bacterial species comprising Eubacterium, Agathobaculum, and 20 Faecalibacterium. In some embodiments, the method increases colonization of beneficial bacterial species comprising Eubacterium, Agathobaculum, and Akkermansia. In some embodiments, the method increases colonization of beneficial bacterial species comprising Eubacterium, Pseudobutyrivibrio, and Faecalibacterium. In some embodiments, the method increases colonization of beneficial bacterial species 25 comprising Eubacterium, Pseudobutyrivibrio, and Akkermansia. In some embodiments, the method increases colonization of beneficial bacterial species comprising Eubacterium, Faecalibacterium, and Akkermansia. In some embodiments, the method increases colonization of beneficial bacterial species comprising Slackia, Agathobaculum, and Pseudobutyrivibrio. In some embodiments, the method increases 30 colonization of beneficial bacterial species comprising Slackia, Agathobaculum, and Faecalibacterium. In some embodiments, the method increases colonization of beneficial bacterial species comprising Slackia, Agathobaculum, and Akkermansia. In some embodiments, the method increases colonization of beneficial bacterial species comprising Slackia, Pseudobutyrivibrio, and Faecalibacterium. In some embodiments, the method increases colonization of beneficial bacterial species comprising Slackia, Pseudobutyrivibrio, and Akkermansia. In some embodiments, the method increases colonization of beneficial bacterial species comprising Slackia, Faecalibacterium, and Akkermansia. In some embodiments, the method increases colonization of beneficial 5 bacterial species comprising Agathobaculum, Pseudobutyrivibrio, and Faecalibacterium. In some embodiments, the method increases colonization of beneficial bacterial species comprising Agathobaculum, Pseudobutyrivibrio, and Akkermansia. In some embodiments, the method increases colonization of beneficial bacterial species comprising Agathobaculum, Faecalibacterium, and Akkermansia. In 10 some embodiments, the method increases colonization of beneficial bacterial species comprising Pseudobutyrivibrio, Faecalibacterium, and Akkermansia. In some embodiments, the method increases colonization of beneficial bacterial species comprising Eubacterium, Slackia, Agathobaculum, and Pseudobutyrivibrio. In some embodiments, the method increases colonization of beneficial bacterial species 15 comprising Eubacterium, Slackia, Agathobaculum, and Faecalibacterium. In some embodiments, the method increases colonization of beneficial bacterial species comprising Eubacterium, Slackia, Agathobaculum, and Akkermansia. In some embodiments, the method increases colonization of beneficial bacterial species comprising Eubacterium, Slackia, Pseudobutyrivibrio, and Faecalibacterium. In some 20 embodiments, the method increases colonization of beneficial bacterial species comprising Eubacterium, Slackia, Pseudobutyrivibrio, and Akkermansia. In some embodiments, the method increases colonization of beneficial bacterial species comprising Eubacterium, Slackia, Faecalibacterium, and Akkermansia. In some embodiments, the method increases colonization of beneficial bacterial species 25 comprising Eubacterium, Agathobaculum, Pseudobutyrivibrio, and Faecalibacterium. In some embodiments, the method increases colonization of beneficial bacterial species comprising Eubacterium, Agathobaculum, Pseudobutyrivibrio, and Akkermansia. In some embodiments, the method increases colonization of beneficial bacterial species comprising Eubacterium, Agathobaculum, Faecalibacterium, and Akkermansia. In some 30 embodiments, the method increases colonization of beneficial bacterial species comprising Eubacterium, Slackia, Agathobaculum, Pseudobutyrivibrio, Faecalibacterium, and Akkermansia. In some embodiments, the improvement comprises increased butyrate synthesis pathway activity. In some embodiments, the improvement comprises reduced colonization of one or more genus of Gram negative bacteria. In some embodiments, the method reduces colonization of one or more genus of Gram negative bacteria selected from the group consisting of: Enterobacteriaceae, 5 Enterobacter, Escherichia, Klebsiella, Bacteroid, Shigella, Salmonella, Campylobacter, Helicobacter, Vibrio, Yersinia, Rumminococcus and Aeromonas. In one embodiment, the method reduces colonization of Enterobacteriaceae. In one embodiment, the method reduces colonization of Enterobacter. In one embodiment, the method reduces colonization of Escherichia. In one embodiment, the method reduces colonization of 10 Klebsiella. In one embodiment, the method reduces colonization of Bacteroid. In one embodiment, the method reduces colonization of Shigella. In one embodiment, the method reduces colonization of Salmonella. In one embodiment, the method reduces colonization of Campylobacter. In one embodiment, the method reduces colonization of Helicobacter. In one embodiment, the method reduces colonization of Vibrio. In one 15 embodiment, the method reduces colonization of Yersinia. In one embodiment, the method reduces colonization of Ruminococcus. In one embodiment, the method reduces colonization of Aeromonas. In one embodiment, the method reduces colonization of Enterobacteriaceae and Shigella. In one embodiment, the method reduces colonization of Enterobacter and Shigella. In one embodiment, the method 20 reduces colonization of Escherichia and Shigella. In one embodiment, the method reduces colonization of Enterobacter and Klebsiella. In one embodiment, the method reduces colonization of Escherichia and Klebsiella. In one embodiment, the method reduces colonization of Enterobacter and Bacteroid. In one embodiment, the method reduces colonization of Escherichia and Bacteroid. In one embodiment, the method 25 reduces colonization of Enterobacteriaceae and Salmonella. In one embodiment, the method reduces colonization of Enterobacter and Salmonella. In one embodiment, the method reduces colonization of Escherichia and Salmonella. In one embodiment, the method reduces colonization of Enterobacteriaceae and Campylobacter. In one embodiment, the method reduces colonization of Enterobacter and Campylobacter. In 30 one embodiment, the method reduces colonization of Escherichia and Campylobacter. In one embodiment, the method reduces colonization of Enterobacteriaceae and Helicobacter. In one embodiment, the method reduces colonization of Enterobacter and Helicobacter. In one embodiment, the method reduces colonization of Escherichia and Helicobacter. In one embodiment, the method reduces colonization of Enterobacteriaceae and Vibrio. In one embodiment, the method reduces colonization of Enterobacter and Vibrio. In one embodiment, the method reduces colonization of Escherichia and Vibrio. In one embodiment, the method reduces colonization of Enterobacteriaceae and Yersinia. In one embodiment, the method reduces colonization 5 of Enterobacter and Yersinia. In one embodiment, the method reduces colonization of Escherichia and Yersinia. In one embodiment, the method reduces colonization of Enterobacteriaceae, and Aeromonas. In one embodiment, the method reduces colonization of Enterobacter and Aeromonas. In one embodiment, the method reduces colonization of Escherichia and Aeromonas. In one embodiment, the method reduces 10 colonization of Enterobacteriaceae, Shigella and Salmonella. In one embodiment, the method reduces colonization of Enterobacter, Shigella, and Salmonella. In one embodiment, the method reduces colonization of Escherichia, Shigella, and Salmonella. In one embodiment, the method reduces colonization of Enterobacteriaceae, Shigella and Klebsiella. In one embodiment, the method reduces colonization of Enterobacter, 15 Shigella, and Klebsiella. In one embodiment, the method reduces colonization of Escherichia, Shigella, and Klebsiella. In one embodiment, the method reduces colonization of Enterobacteriaceae, Shigella and Bacteroid. In one embodiment, the method reduces colonization of Enterobacter, Shigella, and Bacteroid. In one embodiment, the method reduces colonization of Escherichia, Shigella, and Bacteroid. 20 In one embodiment, the method reduces colonization of Enterobacteriaceae, Shigella, and Campylobacter. In one embodiment, the method reduces colonization of Enterobacter, Shigella, and Campylobacter. In one embodiment, the method reduces colonization of Escherichia, Shigella, and Campylobacter. In one embodiment, the method reduces colonization of Enterobacteriaceae, Shigella, and Helicobacter. In one 25 embodiment, the method reduces colonization of Enterobacter, Shigella, and Helicobacter. In one embodiment, the method reduces colonization of Escherichia, Shigella, and Helicobacter. In one embodiment, the method reduces colonization of Enterobacteriaceae, Shigella, and Vibrio. In one embodiment, the method reduces colonization of Enterobacter, Shigella, and Vibrio. In one embodiment, the method 30 reduces colonization of Escherichia, Shigella, and Vibrio. In one embodiment, the method reduces colonization of Enterobacteriaceae, Shigella and Yersinia. In one embodiment, the method reduces colonization of Enterobacter, Shigella and Yersinia. In one embodiment, the method reduces colonization of Escherichia, Shigella and Yersinia. In one embodiment, the method reduces colonization of Enterobacteriaceae, Shigella and Rumminococcus. In one embodiment, the method reduces colonization of Enterobacter, Shigella and Rumminococcus. In one embodiment, the method reduces colonization of Escherichia, Shigella and Rumminococcus. In one embodiment, the method reduces colonization of Enterobacteriaceae, Shigella and Aeromonas. In one 5 embodiment, the method reduces colonization of Enterobacter, Shigella, and Aeromonas. In one embodiment, the method reduces colonization of Escherichia, Shigella, and Aeromonas. In some embodiments, the method reduces colonization of one or more species of Gram negative bacteria selected from the group consisting of: E. coli., E. albertii, E. 10 fergusonii, E. hermannii, E. ruysiae, E. marmotae, C. jejuni, C. coli, C. lari, C. upsaliensis, Salmonella enterica, Salmonella bongori, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, and Shigella boydii. In one embodiment, the method reduces colonization of E. coli. In one embodiment, the method reduces colonization of E. albertii. In one embodiment, the 15 method reduces colonization of E. fergusonii. In one embodiment, the method reduces colonization of E. hermannii. In one embodiment, the method reduces colonization of E. ruysiae. In one embodiment, the method reduces colonization of E. marmotae. In one embodiment, the method reduces colonization of C. jejuni. In one embodiment, the method reduces colonization of C. coli. In one embodiment, the method reduces 20 colonization of C. lari. In one embodiment, the method reduces colonization of C. upsaliensis. In one embodiment, the method reduces colonization of Salmonella enterica. In one embodiment, the method reduces colonization of Salmonella bongori. In one embodiment, the method reduces colonization of Salmonella enterica. In one embodiment, the method reduces colonization of Vibrio cholerae. In one embodiment, 25 the method reduces colonization of Shigella dysenteriae. In one embodiment, the method reduces colonization of Shigella flexneri. In one embodiment, the method reduces colonization of Shigella sonnei. In one embodiment, the method reduces colonization of Shigella boydii. In one embodiment, the method reduces colonization of E. coli. and C. jejuni. In one embodiment, the method reduces colonization of E. coli. 30 and Salmonella enterica. In one embodiment, the method reduces colonization of E. coli and Shigella dysenteriae. In one embodiment, the method reduces colonization of E. coli. and Shigella flexneri. In one embodiment, the method reduces colonization of E. coli., C. jejuni, and Salmonella enterica. In one embodiment, the method reduces colonization of E. coli., C. jejuni and Shigella dysenteriae. In one embodiment, the method reduces colonization of E. coli., C. jejuni, and Shigella flexneri. In one embodiment, the method reduces colonization of E. coli., C. jejuni and Shigella sonnei. In one embodiment, the method reduces colonization of E. coli, C. jejuni and Shigella boydii. In one embodiment, the method reduces colonization of Salmonella enterica. In 5 one embodiment, the method reduces colonization of E. coli and Vibrio cholerae. In one embodiment, the method reduces colonization of E. coli., Vibrio cholerae, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, and Shigella boydii. In one embodiment, the method reduces colonization of Shigella dysenteriae, Shigella flexneri, Shigella sonnei, and Shigella boydii. In one embodiment, the method reduces colonization of 10 Vibrio cholerae, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, and Shigella boydii. In some embodiments, the E. coli comprises one or more or all of Enterotoxigenic E. coli (ETEC), Enterohemorrhagic E. coli (EHEC) and Enteropathogenic E. coli (EPEC). In one embodiment, the E. coli comprises Enterotoxigenic E. coli (ETEC). In one 15 embodiment, the E. coli comprises Enterohemorrhagic E. coli (EHEC). In one embodiment, the E. coli comprises Enteropathogenic E. coli (EPEC). In one embodiment, the E. coli comprises Enterotoxigenic E. coli (ETEC) and Enterohemorrhagic E. coli (EHEC). In one embodiment, the E. coli comprises Enterotoxigenic E. coli (ETEC) and Enteropathogenic E. coli (EPEC). In one 20 embodiment, the E. coli comprises Enterohemorrhagic E. coli (EHEC) and Enteropathogenic E. coli (EPEC). In one embodiment, the E. coli comprises Enterotoxigenic E. coli (ETEC), Enterohemorrhagic E. coli (EHEC) and Enteropathogenic E. coli (EPEC). In some embodiments, the improvement comprises an increase in antibodies to 25 one or more Gram negative bacteria. In some embodiments, the method increases the levels of one or more of: anti- E. coli antibodies, anti-S. flexnerii antibodies and anti-Saccharomyces cerevisiae antibodies, anti-Vibrio cholerae antibodies. In some embodiments, the improvement comprises a decrease in erythrocyte 30 sedimentation rate. In some embodiments, the improvement comprises a decrease in antineutrophil cytoplasmic antibodies. In some embodiments, the improvement comprises a decrease in leucine-rich α2 glycoprotein. In some embodiments, the improvement comprises a decrease in prostaglandin E-major urinary metabolite. In some embodiments, the improvement comprises a decrease in anti-αvβ6 antibody. 5 In some embodiments, the method reduces the levels of one or more cytokines or chemokines in the subject selected from the group consisting of: IL-1β, IL-6, IL-8, calprotectin and Myeloperoxidase (MPO). In one embodiment, the method reduces the levels of IL-1β. In one embodiment, the method reduces the levels of IL-6. In one embodiment, the method reduces the levels of IL-8. In one embodiment, the method 10 reduces the levels of calprotectin. In one embodiment, the method reduces the levels of Myeloperoxidase (MPO). In one embodiment, the method reduces the levels of IL-1β and IL-6. In one embodiment, the method reduces the levels of IL-1β and IL-8. In one embodiment, the method reduces the levels of IL-1β and calprotectin. In one embodiment, the method reduces the levels of IL-1β and Myeloperoxidase (MPO). In 15 one embodiment, the method reduces the levels of IL-6 and IL-8. In one embodiment, the method reduces the levels of IL-6 and calprotectin. In one embodiment, the method reduces the levels of IL-6 and Myeloperoxidase (MPO). In one embodiment, the method reduces the levels of IL-8 and calprotectin. In one embodiment, the method reduces the levels of IL-8 and Myeloperoxidase (MPO). In one embodiment, the method reduces the 20 levels of calprotectin and Myeloperoxidase (MPO). In one embodiment, the method reduces the levels of IL-1β, IL-6 and IL-8. In one embodiment, the method reduces the levels of IL-1β, IL-6 and calprotectin. In one embodiment, the method reduces the levels of IL-1β, IL-6 and Myeloperoxidase (MPO). In one embodiment, the method reduces the levels of IL-6, IL-8 and calprotectin. In one embodiment, the method reduces the levels 25 of IL-6, IL-8 and Myeloperoxidase (MPO). In one embodiment, the method reduces the levels of IL-8, calprotectin and Myeloperoxidase (MPO). In one embodiment, the method reduces the levels of IL-1β, IL-6, IL-8 and calprotectin. In one embodiment, the method reduces the levels of IL-1β, IL-6, IL-8 and Myeloperoxidase (MPO). In one embodiment, the method reduces the levels of IL-1β, IL-6, IL-8, calprotectin and Myeloperoxidase 30 (MPO). In some embodiments, the dose of the hyperimmune colostrum or a fraction thereof comprising hyperimmune antibodies is about 200 mg, about 400 mg, about 600 mg, about 800 mg, about 1,000 mg, about 1,200 mg, about 1,400 mg, about 1,600 mg, about 1,800 mg, about 2,000 mg, about 3,000 mg, about 4,000 mg, about 5,000 mg, about 6,000 mg, about 7,000 mg, about 8,000 mg, about 9,000 mg, or about 10,000 mg a day. In one embodiment, the dose of the hyperimmune colostrum or a fraction thereof comprising hyperimmune antibodies is about 200 mg a day. In one embodiment, the dose of the hyperimmune colostrum or a fraction thereof comprising hyperimmune 5 antibodies is about 400 mg a day. In one embodiment, the dose of the hyperimmune colostrum or a fraction thereof comprising hyperimmune antibodies is about 600 mg a day. In one embodiment, the dose of the hyperimmune colostrum or a fraction thereof comprising hyperimmune antibodies is about 800 mg a day. In one embodiment, the dose of the hyperimmune colostrum or a fraction thereof comprising hyperimmune 10 antibodies is about 1,000 mg a day. In one embodiment, the dose of the hyperimmune colostrum or a fraction thereof comprising hyperimmune antibodies is about 1,200 mg a day. In one embodiment, the dose of the hyperimmune colostrum or a fraction thereof comprising hyperimmune antibodies is about 1,400 mg a day. In one embodiment, the dose of the hyperimmune colostrum or a fraction thereof comprising hyperimmune 15 antibodies is about 1,600 mg a day. In one embodiment, the dose of the hyperimmune colostrum or a fraction thereof comprising hyperimmune antibodies is about 1,800 mg a day. In one embodiment, the dose of the hyperimmune colostrum or a fraction thereof comprising hyperimmune antibodies is about 2,000 mg a day. In one embodiment, the dose of the hyperimmune colostrum or a fraction thereof comprising hyperimmune 20 antibodies is about 3,000 mg a day. In one embodiment, the dose of the hyperimmune colostrum or a fraction thereof comprising hyperimmune antibodies is about 4,000 mg a day. In one embodiment, the dose of the hyperimmune colostrum or a fraction thereof comprising hyperimmune antibodies is about 5,000 mg a day. In one embodiment, the dose of the hyperimmune colostrum or a fraction thereof comprising hyperimmune 25 antibodies is about 6,000 mg a day. In one embodiment, the dose of the hyperimmune colostrum or a fraction thereof comprising hyperimmune antibodies is about 7,000 mg a day. In one embodiment, the dose of the hyperimmune colostrum or a fraction thereof comprising hyperimmune antibodies is about 8,000 mg a day. In one embodiment, the dose of the hyperimmune colostrum or a fraction thereof comprising hyperimmune 30 antibodies is about 9,000 mg a day. In one embodiment, the dose of the hyperimmune colostrum or a fraction thereof comprising hyperimmune antibodies is about 10,000 mg a day. In some embodiments, the dose of the hyperimmune colostrum or a fraction thereof comprising hyperimmune antibodies is about 200 mg to about 10,000 mg, about 200 mg to about 5,000 mg, about 200 mg to about 2,000 mg, about 200 mg to about 1,000 mg, about 600 mg to about 1,500 mg, about 800 mg to about 1,200 mg or about 200 mg to about 800 mg a day. In one embodiment, the dose of the hyperimmune colostrum or a fraction thereof comprising hyperimmune antibodies is about 200 mg to 5 about 10,000 mg a day. In one embodiment, the dose of the hyperimmune colostrum or a fraction thereof comprising hyperimmune antibodies is about 200 mg to about 5,000 mg a day. In one embodiment, the dose of the hyperimmune colostrum or a fraction thereof comprising hyperimmune antibodies is about 200 mg to about 2,000 mg a day. In one embodiment, the dose of the hyperimmune colostrum or a fraction thereof 10 comprising hyperimmune antibodies is about 200 mg to about 1,000 mg a day. In one embodiment, the dose of the hyperimmune colostrum or a fraction thereof comprising hyperimmune antibodies is about 200 mg to about 800 mg a day. In one embodiment, the dose of the hyperimmune colostrum or a fraction thereof comprising hyperimmune antibodies is about 2,000 mg to about 4,000 mg a day. In one embodiment, the dose of 15 the hyperimmune colostrum or a fraction thereof comprising hyperimmune antibodies is about 600 mg to about 1,500 mg a day. In one embodiment, the dose of the hyperimmune colostrum or a fraction thereof comprising hyperimmune antibodies is about 800 mg to about 1,200 mg a day. In one embodiment, the dose of the hyperimmune colostrum is about 2,000 mg to about 6,000 mg a day. 20 In some embodiments, the composition is administered at least two times a week. In some embodiments, the composition is administered two, three, four, five, six, or seven times a week. In one embodiment, the composition is administered two times a week. In one embodiment, the composition is administered three times a week. In one embodiment, the composition is administered four times a week. In one embodiment, 25 the composition is administered five times a week. In one embodiment, the composition is administered six times a week. In one embodiment, the composition is administered seven times a week. In an embodiment, the subject is administered with one dose of the hyperimmune colostrum or a fraction thereof comprising hyperimmune antibodies a day. 30 In another embodiment, the subject is administered with two doses of the hyperimmune colostrum or a fraction thereof comprising hyperimmune antibodies a day. In some embodiments, the composition is administered for at least one week. In some embodiments, the composition is administered for one week, two weeks, three weeks, four weeks, five weeks, six weeks, one month, two months, three months, four months, five months or six months. In one embodiment, the composition is administered for one week. In one embodiment, the composition is administered for two weeks. In one embodiment, the composition is administered for three weeks. In one embodiment, the composition is administered for four weeks. In one embodiment, the 5 composition is administered for five weeks. In one embodiment, the composition is administered for six weeks. In one embodiment, the composition is administered for one month. In one embodiment, the composition is administered for two months. In one embodiment, the composition is administered for three months. In one embodiment, the composition is administered for four months. In one embodiment, the composition is 10 administered for five months. In one embodiment, the composition is administered for six months. In some embodiments, the composition is administered by oral administration, by inhalation as an aerosol, or by parenteral, intravaginal, intranasal, mucosal, sublingual, topical, or rectal administration, or any combination thereof. In one 15 embodiment, the composition is administered by oral administration. In some embodiments, a composition useful for the invention is sold under the tradename Travelan®. In an embodiment Travelan®comprises colostrum powder obtained from a process generally as described in Figure 8, one or more binders such as microcrystalline cellulose and dextrose anhydrous, one or more disintegrants such 20 as microcrystalline cellulose and croscarmellose sodium, one or more flow agents such as colloidal silicon dioxide and one or more lubricants such as Magnesium Stearate. An example of a formulation comprising a 200mg fraction of hyperimmune bovine colostrum comprising hyperimmune antibodies (colostrum powder) is provided in Table 1. 25 Table 1: 200 mg Formulation / w 7 9 / w 0% NF = National Formulary; USP = United States Pharmacopeia; w / w = weight / weight In some embodiments, the hyperimmune colostrum or fraction thereof comprise immunoglobulins that recognize and bind LPS. 5 In some embodiments, the composition comprising the hyperimmune colostrum or fraction thereof are in the form of food additives, aqueous solutions, oily preparations, emulsions or gels. In some embodiments, the composition is administered orally, topically, rectally, nasally, bucally, or vaginally. In some embodiments, the composition is administered in dosage formulations containing conventional non-toxic acceptable 10 carriers. In some embodiments, the composition further comprises one or more acceptable additives, including acceptable salts, polymers, solvents, buffers, excipients, bulking agents, diluents, excipients, suspending agents, lubricating agents, adjuvants, vehicles, delivery systems, emulsifiers, disintegrants, absorbents, preservatives, surfactants, colorants, flavorants or sweeteners. In some embodiments, the composition 15 in the form of a powder for incorporation into beverages, pills, syrup, capsules, tablets, sachets, granules, beads, chewable lozenges or food additives, using techniques known in the art. In some embodiments, the composition is administered in a form selected from the group consisting of orally-active powders, pills, capsules, teas, extracts, dried extracts, subliguals, sprays, dispersions, solutions, suspensions, emulsions, foams, 20 syrups, lotions, ointments, gels, pastes, dermal patches, injectables, vaginal creams and suppositories. In the case where the composition is administered as a tablet, the tablet may be made by compressing or moulding the active ingredient, with one or more accessory ingredients optionally included. Compressed tablets may be prepared by compressing, 25 in a suitable machine, the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active, or dispersing agent. Moulded tablets may be made in a suitable machine, by moulding together a mixture of the powdered active ingredient and a suitable carrier, moistened with an inert liquid diluent. In the case where the composition is administered as a powder, the composition may be incorporated into a suitable form for administration, such as into pills or sachets. 5 Therapeutic formulations may be administered in any conventional dosage formulation. Formulations typically comprise at least one active ingredient, as defined above, together with one or more acceptable carriers thereof. Each carrier should be both pharmaceutically and physiologically acceptable in the sense of being compatible with the other ingredients and not injurious to the patient. 10 Suitably, the pharmaceutically acceptable carrier, diluent and / or excipient may be or include one or more of diluents, solvents, pH buffers, binders, carriers, additives, adjuvants, microemulsions, coarse emulsions, liquid crystals, fillers, emulsifiers, disintegrants, polymers, lubricants, oils, fats, waxes, coatings, viscosity-modifying agents, glidants / flow agents and the like. 15 Diluents may include one or more of microcrystalline cellulose, lactose, mannitol, calcium phosphate, calcium sulfate, kaolin, dry starch, powdered sugar, and the like. Binders may include one or more of povidone, dextrose anhydrous, starch, stearic acid, gums, hydroxypropyl methyl cellulose, cellulose, pre-gelatinized starch and the like. 20 Disintegrants may include one or more of starch, sodium starch glycolate, croscarmellose sodium, microcrystalline cellulose, crospovidone, povidone, sodium starch glycolate and the like. Solvents may include one or more of ethanol, methanol, isopropanol, chloroform, acetone, methylethyl ketone, methylene chloride, water and the like. 25 Lubricants may include one or more of magnesium stearate, zinc stearate, calcium stearate, stearic acid, sodium stearyl fumarate, hydrogenated vegetable oil, glyceryl behenate and the like. Glidants / flow agents may be one or more of colloidal silicon dioxide, magnesium stearate, talc or cornstarch and the like. 30 Buffers may include phosphate buffers, borate buffers and carbonate buffers, although without limitation thereto. Fillers may include one or more gels inclusive of gelatin, starch and synthetic polymer gels, although without limitation thereto. Coatings may comprise one or more of film formers, solvents, plasticizers and the like. Suitable film formers may be one or more of hydroxypropyl methyl cellulose, methyl hydroxyethyl cellulose, ethyl cellulose, hydroxypropyl cellulose, povidone, 5 sodium carboxymethyl cellulose, polyethylene glycol, acrylates and the like. Suitable solvents may be one or more of water, ethanol, methanol, isopropanol, Plasticizers may be one or more of propylene glycol, castor oil, glycerin, polyethylene glycol, polysorbates, and the like. Formulations include those suitable for oral, rectal, nasal, or parenteral (including 10 subcutaneous, intramuscular, intravenous and intradermal or by inhalation) administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The nature, availability and sources, and the administration of all such compounds including the effective amounts necessary to produce desirable effects in a subject are well known in 15 the art and need not be further described herein. The preparation of pharmaceutical compositions is well known in the art and has been described in many articles and textbooks, see e.g., Remington's Pharmaceutical Sciences, Gennaro A. R. ed., Mack Publishing Co., Easton, Pa., 1990, and especially pp.1521-1712 therein. 20 The composition typically comprises one or more acceptable carriers. Each carrier should be both pharmaceutically and physiologically acceptable in the sense of being compatible with the other ingredients and not injurious to the patient. Formulations include those suitable for oral, nasal, or parenteral (including subcutaneous (s.c.), intramuscular (i.m.), intraperitoneal (i.p.), intravenous (i.v.) and 25 intradermal or by inhalation to the lung mucosa) administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The pharmaceutical compositions useful for the invention generally comprise a buffering agent, an agent that adjusts the osmolarity thereof, and optionally, one or more 30 pharmaceutically acceptable carriers, excipients and / or additives as known in the art. Supplementary active ingredients can also be incorporated into the compositions. The carrier can be solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. As used herein “pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents and the like. 5 The use of such media and agents for pharmaceutical active substances is well known in the art. Except as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic composition is contemplated. In instances in which oral administration is in the form of a tablet or capsule, the active can be combined with a non-toxic pharmaceutically acceptable inert carrier such 10 as lactose, starch, sucrose, glucose, modified sugars, modified starches, methylcellulose and its derivatives, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, and other reducing and non-reducing sugars, magnesium stearate, stearic acid, sodium stearyl fumarate, glyceryl behenate, calcium stearate and the like. For oral administration in liquid form, the active drug components can be combined with non- 15 toxic pharmaceutically acceptable inert carriers such as ethanol, glycerol, water and the like. When desired or required, suitable binders, lubricants, disintegrating agents and coloring and flavoring agents can also be incorporated into the mixture. Stabilizing agents such as antioxidants, propyl gallate, sodium ascorbate, citric acid, calcium metabisulphite, hydroquinone, and 7-hydroxycoumarin can also be added to stabilize 20 the dosage forms. Other suitable compounds can include gelatin, sweeteners, natural and synthetic gums such as acacia, tragacanth, or alginates, carboxymethylcellulose, polyethylene, glycol, waxes and the like. EXAMPLES 25 The present invention is further described below by reference to the following non-limiting Examples. Example 1: Materials and Methods Bacterial isolates 30 ETEC and Shigella spp. field sample isolate strains were used to evaluate the in vitro immune-reactivity of Travelan®(Lot 1510002493) compared with Promilk 85, a protein rich milk powder 85% pure milk protein (Tatura Milk Industries Ltd., Australia). Bacterial isolates (72 ETEC and 65 Shigella isolates) were collected from Africa, Argentina, Bangladesh, Bhutan, Brazil, Cambodia, Egypt, France, Nepal, Thailand and Turkey. Analysis was also performed using well-characterized, historical isolates: ETEC H10407 (LT / ST / CFA / I), S. flexneri 2a 2457T, S. flexneri 3a J17B, S. flexneri 6CCH60 5 and S. sonnei Moseley. ETEC strains were grown on colonization factor antigen (CFA) agar plates with or without bile salts (as appropriate) (Evans et al., 1977). Immunoblots were performed on all isolates and representative blots for ETEC strains expressing LT and ST toxins, CS1, CS2, CS3, CS4, CS5, CS6, CS7, CS14, CS17, CS19, CS21, PCFO71, CFA / I, and CF -negative isolates are shown. 10 Shigella strains included Shigella spp. (S. flexneri 2a 2457T, S. flexneri 3a J17B, S. flexneri 6CCH60, S. sonnei Moseley, S. dysenteriae, S. boydii). These strains were grown in media specific for each type of strain to prepare whole cell lysates. Shigella strains were initially grown on tryptic soy agar (TSA) plates and isolated colonies grown in Luria Bertani (LB) broth. In addition to Shigella strains, purified Shigella antigens were 15 also used to evaluate the in vitro immune-reactivity of Travelan® and Promilk 85. Recombinant antigens and Invaplex The shigella antigen proteins IpaB, IpaC, IpaD, and LPS from Shigella flexneri 2a, S. flexneri 3a, S. flexneri 6, and S. sonnei Moseley were produced in house. Briefly 20 recombinant clones harboring the Ipa proteins of interest were cloned in the pET15b system and expressed in BL21 E. coli as reported previously (Turbyfill et al., 2018; Venkatesan et al., 1988). The IpaB and IpaC proteins were purified via a histidine tagged IpgC chaperone protein. The chaperone protein was subsequently purified from the IpaB / IpaC. IpaD was purified as a GST tagged protein from recombinant E. Coli and the 25 GST tag was subsequently removed. Invaplex is a large, macromolecular complex consisting of the major shigella antigens: Lipopolysaccharide (LPS) and the invasion plasmid antigen (Ipa) proteins B, C and D derived from Shigella flexneri (Coster et al., 1999; Islam et al., 2014; Turbyfill et al., 2000). Travelan® immunoblot analysis of shigella isolates 30 Sodium dodecyl-sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and immunoblotting was performed with whole cell lysates of Shigella spp. isolates and shigella antigens. The freshly harvested bacterial cell pellet in non-reducing sample buffer was heated and centrifuged at high speed to remove cell debris, supernatants were loaded onto 4-15% Mini-PROTEAN® TGX™ Precast Protein Gels. Bio-Rad Precision Plus Protein™ Dual Color Standards were used as molecular weight markers. Immunoblots were incubated with Travelan® or Promilk 85, and after a series of washing steps probed with Alkaline phosphatase conjugated goat anti-bovine antibodies (SeraCare life sciences, Massachusetts, USA). Blots were developed according to the 5 manufacturer’s instructions with SIGMA FASTTMFast Red TR / Naphthol AS-MX Alkaline Phosphatase Substrate (Sigma-Aldrich, Missouri, USA). Travelan® binding by ELISA to Shigella spp. Cross reactivity of Travelan®to Shigella spp. isolates was also measured by10ELISA. Travelan®and Promilk 85 were rehydrated in PBS-0.05% Tween 20 at 16 mg / mL total product weight as previously described (37). Four shigella LPS antigens (S. flexneri 2a, S. flexneri 3a, S. flexneri 6 and S. sonnei) and three Ipa proteins (IpaB, IpaC and IpaD) antigens were coated at 1 µg / mL onto Immulon 1B 96-well plates (Thermo Fisher Scientific) for ELISA (63). Promilk 85 was used as the negative control. Coated plates 15 were blocked with 1% Blocker Casein buffer (Thermo Fisher Scientific). Travelan®, Promilk 85 and positive controls were analysed in duplicates and diluted in 0.5% casein- PBS buffer. Travelan® antibodies binding to Shigella spp. antigens were detected using HRP conjugated anti-bovine, -mouse, or -rabbit IgG, followed by 3,3’, 5,5’- Tetramethylbenzidine (TMB) microwell peroxidase substrate. Absorbance values at 450 20 nm were measured on a microplate spectrophotometer (Thermo Fisher Multiskan FC) and analysed by 4PL regression (GraphPad Prism). Endpoint titers were calculated as the inverse of the sample dilutions that produced an absorbance value at 450 nm of 3 standard deviations above the mean of the blank. 25 Efficacy assessment of Travelan®for prevention of shigellosis in the naïve juvenile rhesus macaque (NJRM) model Ethical approval to conduct the study was provided by the USAMD-AFRIMS Institutional Animal Care and Use Committee. The study was conducted by the Department of Veterinary Medicine (DVM), accredited by the Association for the 30 Assessment and Accreditation of Laboratory Animal Care, International (AAALAC), in accordance with the “Guide for the Care and Use of Laboratory Animals” published by the National Research council, 2011, 8th Edition. Naïve juvenile rhesus macaque (Macaca mulatta) selected for the study were negative for tuberculosis (TB), simian immunodeficiency virus (SIV), simian T-cell lymphotropic virus type 1 (STLV-I), and type-D retrovirus (SRV-D). All animals selected for the study were in good health, as shown by physical examination (PE), complete blood counts (CBC), and blood chemistry profiles. Animal activity, feed consumption, and other clinical observations were recorded twice daily during the study. 5 NJRMs are born and raised in pairs then group housed within the facility which has insect screens enabling exposure to the environmental conditions in Thailand. An enrichment program is focused on providing a stimulating environment using the latest industry accepted practices. Veterinary staff are available at all times on site 24 hours per day 7 days per week, and all animals are observed at least twice per day. Animals 10 are fed a commercial primate feed that is supplemented with locally procured produce and commercially available vitamins as directed by veterinary staff. During the study, animals are confined in single or double cages in a separate wing of the facility that receives HVAC control for temperature, ventilation and humidity that is continuously monitored by an automated system. 15 Twelve NJRMs were screened for inclusion in this study using the following criteria: age within 3 – 5 years old, weight ≥ 3.2 kg; serum anti-S. flexneri 2a LPS specific IgA antibody titers ≤ 200; IgG and IgM antibody titers ≤ 400; no diarrheal symptoms for 14 days prior to study initiation; good health; CBC and blood chemistry values within veterinary assigned normal limits. After selection, NJRM were treated with enrofloxacin 20 antibiotic for 5 consecutive days as a prophylactic measure to minimize any pre-existing diarrheal diseases. Prophylaxis Study Two weeks after antibiotic treatment, 12 NJRMs were randomly assigned into 25 two groups, 8 received Travelan®(Lot # 1510002493) treatment and 4 received the Promilk 85 as placebo control. NJRMs were fasted overnight and anesthetized with ketamine hydrochloride before nasogastric placement. Travelan®or placebo was delivered intragastrically twice daily, 12 hrs apart, for a total of 12 doses over 6 days (study days 0 to 5). On study day (SD) 3, all NJRM received the challenge dose (2.76 30 x 109CFU) of S. flexneri 2a 2457 T strain (Islam et al., 2014). Travelan®and Promilk 85 solution was prepared daily as a 500 mg / dose diluting in water for injection (WFI). Each inoculation was administered after a CeraVacx oral vaccine buffer (Cera Products Inc., South Carolina, USA) administration (Harro et al., 2011; Sack et al., 1997). S. flexneri 2a, 2457T was grown in Luria-Bertani broth (BD DifcoTM) and the bacterial suspension diluted in PBS (Diamedix, OH, USA) and adjusted to the appropriate OD600 corresponding to 2-5 x108CFU / ml. Approximately 10 ml of the challenge inoculum was administered on SD3 to all NJRM. 5 Disease assessment NJRM were monitored during the study for any symptoms that suggested an adverse reaction, including diarrhea, fever, vomiting, reduced activity and recumbency, allergic reactions (e.g., swelling, itchiness, and rash), or anaphylactic reactions (e.g., 10 collapse, anemia, hypotension, tachypnea, dyspnea, hypothermia, tremors, seizure, and urinary incontinence). Animals were observed frequently and offered medical intervention when indicated by their clinical condition. All interventions requiring animal handling were performed under anesthesia. All NJRM were closely observed and scored at least twice daily according to the 15 previously defined criteria (Islam et al., 2014; Morton et al., 1985). The observed clinical parameters were: (i) activity level (active / reduced / recumbent / non- responsive / inactive); (ii) appetite level: (≥90% / ≥70% / ≥50% / ≤50%); (iii) fecal consistency: (normal: score 1 / soft: score 2 / loose: score 3 / watery: score 4); (iv) fecal mucus and / or blood: (absent / only mucus / only blood / both mucus and blood); (v) skin 20 turgor: (normal / return 2-4 sec / return 5-9 sec / >10 sec return). If the total clinical score was ≤ 4 = NJRM was in normal health; 5-9 = NJRM was closely monitored and electrolytes may be provided in the drinking water; 10-14 = electrolytes provided in the drinking water or sub-cutaneous normal saline / intra-venous infusion of acetated Ringer’s with or without 5% dextrose solution and analgesics considered 25 (Metoclopramide [N-diethylamino ethyl)-2-methoxy-4-amino-5-chlorobenzamide] to relieve the symptoms of vomiting and Brupenex to treat pain); and ≥ 15 = NJRM euthanized. Under some circumstances, based upon attending veterinary guidance, NJRM with lower clinical scores were euthanized. Dysentery was defined as at least one watery or loose stool containing blood 30 and mucus. All NJRM were humanely euthanized by intravenous pentobarbital injection at the end of all experimental procedures on day 13 / 14 or earlier if they met humane endpoint criteria. Shedding of Shigella challenge strain Shedding of the challenge strain was evaluated by standard bacterial culture methods. After euthanasia, fecal materials were collected from different portions of the GI tract corresponding to the stomach, duodenum, cecum, jejunum, ileum, colon 5 (ascending, transverse and descending), rectum and evaluated by qualitative culture methods. Assessment of inflammatory response: cytokine and biomarker levels and histological examination 10 The inflammatory response induced by S. flexneri 2a 2457T challenge strain in NJRM was assessed. Pro-inflammatory cytokines (IL-1β, IL-6, and IL-8) and fecal biomarkers (calprotectin and myleoperoxidase) were measured in fecal extract samples using MilliplexⓇMap Non-Human Primate Cytokine Magnetic Bead Panel Kits (EMD Millipore Corporation, MA, USA) and analysed by a MAGPIX Multiplex Reader or by 15 using a commercial ELISA kit (Epitope Diagnostics Inc., California, USA). Tissue samples from different portions of the GI tract including jejunum, ileum, cecum, colon (ascending, transverse and descending) and rectum were collected from euthanized / deceased animals in 10% neutral buffered formalin, processed routinely, and stained with standard hematoxylin and eosin stain (H&E) for a descriptive20 morphologic diagnosis. All slides were coded, interpreted and scored blindly by a board- certified veterinary pathologist, as previously reported (Islam et al., 2014 and 2016). The severity of inflammation in the tissue sections was scored on a scale of 0 – 4, where 0 (none); 1 (minimal); 2 (mild); 3 (moderate); 4 (severe). Severity scoring was a subjective assessment combining the extent of the necrotic lesion (how much of the tissue was 25 affected) with how much damage, inflammation, or tissue change occurred. Immune responses Promilk 85 treated NJRM serum samples were collected on SD 3, 6, and 8 and analysed for antibody titers. Travelan®treated serum samples were collected on SD 6 30 and 8 (from early euthanized NJRMs), day 10 for IgA and IgM analysis and day 14 for IgG antibody titer measurements. Serum IgA, IgG and IgM antibody titers against S. flexneri 2a 2457T strain LPS and S. flexneri Invaplex were evaluated by ELISA as previously described (Islam et al., 2016). Invaplex contains a mix of Shigella spp. antigens LPS and IpaB, IpaC and IpaD proteins (Coster et al., 1999; Islam et al., 2014; Turbyfill et al., 2018). Values were presented as the fold increase of peak antibody titers over the baseline level, and seroconversion was defined as a ≥ 4-fold increase over baseline titers measured on day 0 the starting day of Travelan® / Promilk 85 treatment. 5 Data analysis Data analyses was performed using IBM SPSS Statistics, version 26 and Graph Pad Prism software. The cytokine concentrations of the samples were calculated using ELISA Plus software, version 3.01 (MedData Inc., New York, USA). Data was 10 statistically analysed using where appropriate either nonparametric Chi-squared or Mann Whitney U analysis. Data showing statistical significance was noted in the text and Figures where statistical significance is defined as * p < 0.05. Example 2: In vitro reactivity of Travelan® with ETEC strains, Shigella spp. cell 15 lysates and Shigella virulence factor antigens Figure 1 shows representative blots with strains expressing the major antigens LT and ST toxins, CS1, CS2, CS3, CS4, CS5, CS6, CS7, CS14, CS17, CS19, CS21, PCFO71, CFA / I, that included some of the strains / serotypes used for immunization. The SDS-PAGE patterns of all ETEC strains were similar. Western blot analysis of the whole 20 cell ETEC lysates with Travelan® showed that antibodies in Travelan® reacted with many proteins consistent with the use of whole ETEC cells as the vaccine antigen, as well as E. coli DH5α strain, which do not express CF antigens. ETEC strains expressing high levels of CFA / l (lane 1), CS2 (lane 3) and CS3 (lane 4) when probed with Travelan® (Fig.1) showed prominent bands with approximate size range 13–17 kDa. Background 25 binding was observed with the Promilk 85 blot, weakly detected only a few higher molecular weight proteins indicating insignificant or background binding. Whole cell lysates of multiple Shigella spp. were analysed by immunobloting with Travelan® and Promilk 85. Antibodies in Travelan® reacted with many proteins bands in the whole cell lysate preparations and among these there were several prominent 30 bands of apparent molecular weight ~65kDa, ~45kDa and ~40 kDa (Fig.2A). Similarly, Travelan® antibodies also showed reactivity to recombinant Ipa proteins IpaB, IpaC and IpaD, with the highest binding to IpaC. There was no immunoreactivity to shigella lysates or antigens with Promilk 85 (Fig.2B). To further characterize the binding specificity of Travelan® antibodies the antibody titers to shigella LPS preparations from (S. flexneri 2a, S. flexneri 3a, S. flexneri 6 and S. sonnei Moseley) and Ipa proteins (IpaB, IpaC and IpaD) were measured. The endpoint IgG titers of Travelan®and Promilk 85 are shown in Fig. 2C. Travelan® 5 antibodies reacted strongly with all four species of LPS recombinant proteins and titers were slightly lower to Ipa proteins IpaB and IpaC and approximately 4-fold lower reactivity was observed for Travelan® antibody binding to IpaD. No shigella-specific IgG reactivity was detected in Promilk 85 by ELISA. These results clearly indicate that antibodies present in Travelan® are cross-reactive against Shigella spp. and major 10 virulent shigella antigens. Example 3: Travelan® protects NJRMs against shigellosis following oral challenge with S. flexneri 2a 2457T Prior to administration of the challenge strain clinical monitoring revealed no 15 immediate adverse reactions including diarrhea, loose, or watery stool, vomiting, inactivity or posturing associated with pain or illness was observed in any of the NJRM during SD 0 to 2. This indicates Travelan® or Promilk 85 treatment was safe and well tolerated in NJRMs. Each NJRM received clinical scores daily (based on presence of clinical 20 symptoms) summarized in Table 2. Occurrence of clinical symptoms, such as vomiting, diarrhea, dysentery, activity level, medication and dehydration treatment was noted between the two groups on each study day. On SD3, all NJRM were challenged with S. flexneri 2a, 2457T, there were no clinical symptoms on SD3. 25 On SD4 (day 1 post-infection), all 4 / 4 NJRM (M1-4) in the Promilk 85 placebo group had watery stools with mucus, and 2 / 4 vomited. In the Travelan®treated group 3 / 8 animals vomited (M10, M11 and M12). All animals affected with vomiting received electrolytes in water bottles, SC or IV and medications as detailed in Table 2. Diarrhea on SD4 was significantly higher in the Promilk 85 group compared to Travelan®group 30 (*p=0.01, Chi-squared test).yadydSC1<1<1<1<1<1<tu 41 hycay uredEu utfya E EdD6atuydDS s e eey y y y,CrSut moE,D,AD,Rht octolhtlhtlhtylhtylhtCRS,A) StpmsyDR,ssN,aeaeaeaeae lae,sy R,sM,Bla21ySyDsyD H H H H H HDyDicM n-1liMSC 60151die21 5 2 3 3 3 5 8 8c(D dM n,aRJ5s,C,CVI,CsN Sy y y ymlloaDSmoS,eR,,e,Dhtlht y ylhtlhtlhthtB, CStrtpDm,yVD,Vsy,s,M,yDB, V,aseHaeHaeHae lHae lHaeVI H,D,syDpofSDRm NyD y)esgln 8 6 7 8 6al ieclSC 5 3 3 3 6 6 6nahli c 4smM,,V ICS, y y y yMctDS ot,p CSC,S ,Ae M E,htlhtlhtlhtlM,E,M,Mso,pmV,DR,D,DVDa,eHaeHaeHaeHE,VD, EV,VRJy yS D DNa:d21(#lpe4)MRu o o o o ®nanananananananaJorbebebebelev lev lev lele0le1le2lebaD G1caTS(N MlP2McalP3McalP4McalP5MarT6MarT 7MarT 8vMarT 9vMarT 1vMarT 1vMarT1vMarT Symptom abbreviations for Table 2: D = Diarrhea, V = Vomiting, Dys = Dysentery, De = Dehydration. Activity level : RA = Reduced activity, RC = Recumbent, RC = Non-responsive and inactive. Medication: M = Metoclopramide treatment for nausea, B = Buprenex to treat pain. Dehydration treatment: E = electrolytes added to 5 water bottle, SC= subcutaneous saline solution, IV = intravenous infusion of acetated Ringer’s with or without 5% dextrose solution. Clinical score : <4 = Normal health, 5-9 = monitored carefully electrolytes added to water, 10-14 = SC or IV and / or analgesics and euthanasia considered, >15 = NJRM evaluated for euthanasia. On SD5, vomiting and dysentery were significantly higher (*p=0.03, Chi-square 10 test, for both symptoms) in the Promilk 85 group.3 / 4 NJRMs in the placebo group had dysentery. Two of the NJRM with dysentery and the one with diarrhea vomited. One of this group M3 died whilst being assessed for euthanasia on SD5 with severe symptoms, low body temperature, abdominal cramping and no movement with a clinical score of 15. In contrast only 1 / 8 NJRM in the Travelan®group had diarrhea (M11) and one had 15 dysentery (M12). The two NJRMs treated with Travelan® who suffered from diarrhea on SD4 (M5) and vomiting (M10) by SD5 had recovered, following electrolyte and nausea treatment where appropriate. Both M5 and M10 on SD5 had clinical scores of 5 and but appeared healthy with regards to symptoms. On SD 6 (3 days after challenge), two NJRMs in the Promilk 85 group (clinical 20 scores of 12 & 15) and one NJRM in the Travelan®group (clinical score 14) were euthanized by the attending veterinarian. One NJRM in the Travelan®group had dysentery and reduced activity the remaining 6 / 8 NJRMs in the Travelan® group remained healthy (clinical scores 1-3). On SD 7 the remaining animal in the Promilk 85 group and one of the 25 symptomatic animals in the Travelan®group were severely dehydrated and suffering from dysentery and on SD 8 these two animals were euthanized. The remaining 6 / 8 animals in the Travelan®group remained healthy throughout the remainder of the study to SD13-14. To compare the clinical score post-infection for each group, the daily clinical 30 score per animal over the post infection period until euthanized was averaged. The average clinical score was significantly higher (*p =0.02) in the Promilk 85 placebo group compared to Travelan®group (Fig. 3A). The Travelan® group had fewer clinical symptoms which indicates Travelan® offered protection against the onset of diarrheal symptoms post-challenge. Over the course of the post-infection monitoring period, all four of NJRM in the Promilk 85 group developed dysentery (M1-4), whereas only 2 of 8 animals in the Travelan®group (M11-M12) developed dysentery with 6 of 8 being protected from dysentery (M5-10), as shown in Fig.3B. 5 The average fecal consistency score was significantly higher in the Promilk 85 group compared to the Travelan®group, further demonstrating that Travelan®protected animals from developing Shigella-mediated diarrhea (Fig.3C). Travelan®treatment prolonged the survival of NJRMs compared to those receiving the placebo Promilk 85 treatment (Fig.3D). NJRMs (6 / 8) receiving Travelan® 10 were protected from dysentery symptoms and remained healthy resulting in 75% protective efficacy and this was statistically significant (*p=0.014, Chi squared Test). This study indicates that the active antibody components of Travelan®are functionally cross-reactive against S. flexneri 2a and afford protection against shigellosis in the NJRM model. 15 Example 4: Travelan® prophylaxis treatment reduces Shigella colonization To assess the clearance of the challenge strain the levels of S. flexneri 2a shedding were measured in stool cultures after challenge. All NJRM in the Promilk 85 control group were Shigella-positive until they were euthanized or died. Levels of 20 shigella were significantly lower in the Travelan®treated group compared to levels in the Promilk 85 treated group. In Fig.3E shedding levels were measured as the number of animals who shed challenge strain (as percent of total animals) on each study day. To further assess effects of treatment on colonization, stool samples present in different sections of the large and small intestine were collected and cultured during 25 dissections following early or planned termination in severely symptomatic or healthy animals, respectively. For all four Promilk 85 treated animals and the two symptomatic Travelan® treated animals, fecal materials from different parts of GI tract were shown by culture to all be positive for S. flexneri 2a on termination. Conversely, the six non- symptomatic Travelan®treated animals all had negative GI tract S. flexneri cultures at 30 termination indicating the positive effects of Travelan® prophylaxis in assisting with clearance of the challenge strain. Example 5: Travelan® protects against Shigella-induced gut inflammation The inflammatory changes induced by challenge with S. flexneri 2a, 2457T in all NJRM was assessed by measuring levels of inflammatory cytokines IL-1β, IL-6, IL-8, calprotectin (a fecal protein marker for inflammation) and Myeloperoxidase (MPO; an 5 enzyme associated with inflammation) in fecal stool samples collected on SD 0, 1, 3, 5, 7, 9, 11 and 13. The peak fecal cytokine levels in animals treated with Promilk 85 versus Travelan® was compared, however due to the 2 / 6 animals suffering from diarrheal symptoms in the Travelan® treated group, the groups were modified into the following 10 two groups: (i) ‘Protected’ all animals who did not encounter severe symptoms, and (ii) ‘Not-protected’ animals suffering from adverse symptoms, i.e., those in the placebo group plus two of the Travelan® group (M11 and M12) who displayed dysentery symptoms. Cytokine and inflammatory markers levels for the not-protected and protected 15 groups is shown in Fig. 4. Pro-inflammatory cytokine levels were significantly higher (*p<0.05) in the ‘Not protected’ group for IL-1b, IL-6 and IL-8 compared to the ‘Protected’ animals. However there was no significant difference (p>0.05) in the levels of fecal MPO and calprotectin biomarker expression in the ‘Protected’ group who received Travelan® 20 compared with the ‘non protected’ group. Example 6: Intestinal damage is reduced in Travelan® treated NJRM To further examine the effects of Shigella infection on the GI tract and to investigate if Travelan® provided any beneficial protective effects, histological samples 25 were collected from euthanized animals and analysed. Gut tissue sections, jejunum, ileum, cecum, colon (ascending, transverse and descending) and rectal tissues were analysed for hemorrhage, necrosis, edema, ulceration or erosion of the epithelium, or lymphoid necrosis of the gut-associated lymphoid tissue. Inflammation following challenge was categorized by the presence of neutrophils, lymphocytes, plasma cells, 30 lymphoplasmacytic, and macrophages. Proliferation was noted as either being present or absent, and included epithelial hyperplasia and regeneration. The microscopic findings in the NJRMs displaying dysentery symptoms included tissue damage in the rectum characterized by proctitis, necrotizing, diffuse (epithelial and submucosal), acute, marked with fibrin, hemorrhage, and edema. Histological change also occurred in the colon characterized as colitis, necrotizing, proliferative and lymphoplasmacytic diffuse (epithelial and submucosal), acute, marked with fibrin, hemorrhage, and edema, multifocal epithelial necrosis, erosions, villas blunting, fusion, and loss; hemorrhage, and suppurative lymphoid necrosis. 5 In the NJRMs treated with Promilk 85 who died within 72 hrs of challenge, pathology findings were more severe. In particular, the rectum of these animals had proctitis, necrotizing, multifocal, acute, moderate with mixed inflammation; colon (ascending, transverse, and descending): colitis, proliferative and lymphoplasmacytic, diffuse, subacute, mild to moderate, with multifocal epithelial necrosis, erosions, villar 10 blunting, fusion, and loss. The ascending colon and rectum were the most affected area in this group where one animal had the highest observed histology severity score 4 both in the ascending colon and the rectum (Fig.5A). There was no evidence of inflammation in the colon in any of the Travelan® group who did not develop dysentery, and only one animal displayed minor infiltration15of neutrophils in the ileum (Fig.5C). Two of eight Travelan®treated animals became symptomatic, their histological analysis revealed less severe damage compared to all of the Promilk 85 group. An example is shown in Fig.5B, the NJRM receiving Travelan® with dysentery symptoms (M11) had a histological severity score of 2, this image indicates much lower tissue inflammation than in the Promilk 85 treated animal (Fig.5A) 20 displaying severe histological changes. The severity score between the Travelan® and the Promilk 85 groups for rectal histology was measured and found to be significantly higher for the placebo group (Fig. 6. (*p=0.01, Mann-Whitney U analysis). These results indicate Travelan® inhibits shigella colonization in the gut, thereby 25 reducing inflammation, measured by the reduction in inflammatory cytokines in Fig.4 and the reduction in histological colon and rectal severity score in Fig’s 5 and 6. Example 7: Shigella immunity is not hindered by Travelan® prophylaxis To assess the effects of Travelan® on adaptive pathogen-specific immune 30 response the IgM, IgA and IgG levels of antibodies in the serum of all NJRMs was measured by ELISA. The last serum sample collected from animals in the Promilk 85 group was 3-5 days after challenge, within this time frame animals could not mount peak antibody response against Shigella antigens (Fig.7). Only the 6 healthy Travelan® treated animals that survived the entire study had a >4 fold rise in IgA, IgG and IgM antibody titers against both S. flexneri 2a LPS and Invaplex antigens compared to pre-challenge sera. This suggests that prophylactic treatment with Travelan®prevents shigellosis and allows the development of immunity 5 against this pathogen. The elicited antibody responses between Travelan®and Promilk 85 treated animals were compared. Whilst the trend was higher immune responses for the Travelan® group, only the IgA (*p=0.03) and IgM (*p=0.02) antibody titers against S. flexneri 2a LPS and IgG (*p=0.04) antibody titers against Invaplex were significantly10higher in the Travelan®group (Fig.7). Example 8: Discussion of outcomes in NJRM studies In the absence of widely available and licensed vaccines for Shigella, ETEC or Campylobacter, alternative non-antibiotic immunoprophylactic treatments, such as 15 Travelan® hold tremendous value. Western blot analysis confirmed that antibodies in Travelan® reacted to proteins in whole cell lysates from ETEC as well as whole cell lysates from Shigella and purified Shigella antigens. In the current study, Travelan® prophylaxis prevented clinical shigellosis (bacillary dysentery) in 75% of Travelan® treated NJRM compared to a Promilk 85 20 placebo control treatment. These results clearly demonstrated that Travelan® protected animals from shigellosis. This apparent neutralization of Shigella may have occurred by blocking bacterial attachment to the intestinal wall and preventing invasion, facilitating bactericidal activity, or other immune mechanisms. There was a significant increase of Shigella-specific antibody titers in the Travelan®-treated NJRM after oral infection with 25 S. flexneri 2a, 2457T, even in the absence of severe disease. HBC treatment may protect from severe disease while facilitating antigen uptake and presentation to the immune system, allowing for generation of pathogen-specific immune responses, though further investigation is necessary to confirm. Activation of the adaptive immune system and generation of immune effectors such as antibodies and the induction of 30 memory B cells in the absence of disease may play a substantial role in protection when HBC is no longer present in the gut. If such mechanisms are intact, HBC could provide protection from infection, still allowing the generation of “natural immunity” against enteric pathogens. Understanding the molecular basis of the interaction between effectors of Shigella and host immune systems has advanced greatly during the past decade, which revealed the importance of manipulation of the host immune system during bacterial infection. Shigella delivers a subset of virulence proteins via the type III secretion system 5 (T3SS) that enable bacterial evasion from host immune systems, allowing for efficient colonization of the intestinal epithelium. The T3SS harbored by Shigella is pivotal to infection, approximately 50 T3SS effectors of Shigella are currently recognized, and only one third of these have been elucidated at the molecular level (Ashida et al., 2015). Shigella secretes virulence factors that induce severe inflammation and mediate 10 enterotoxic effects on the colon, producing the classic watery diarrhea seen early in infection. Once ingested, S. flexneri delivers shigella enterotoxin 1 (ShET1) in the jejunum to elicit fluid secretion (Fasano et al., 1997). Shigella also induces focally distributed ulceration in the intestine (Katakura et al., 1990). In the current study, NJRM treated with Travelan® prophylaxis and challenged 15 with a virulent form of Shigella were largely protected from disease. While a subset (2 / 8) of Travelan®-treated NJRM did exhibit diarrhea symptoms, the disease was less severe compared to placebo Promilk 85 treated NJRM. Despite the extensive research, pathophysiology of shigellosis remains incompletely understood and correlates of protection against shigellosis have not been defined. The largest immune network in the 20 body resides in the gut. Cytokines play a crucial role in driving, perpetuating, resolving, and wound healing of intestinal inflammation and inflammation is largely the body’s defense. The pro-inflammatory cytokine IL-6, and to a lesser degree IL-8, are involved in acute invasive gastroenteritis, such as shigellosis (Vaisman et al., 2003). NJRM which succumbed to disease had a very high levels of IL-6 in fecal extract samples, indicating 25 the IL-6 levels correlated with disease severity. Moreover, the inventors have shown that inflammation in gut tissues is co-related to excreted inflammatory cytokines as well as Shigella colonization. A more complete understanding of interactions between the host microbiome and enteric pathogens and mechanisms by which HBC can reduce inflammation in the intestinal environment may supply important information to design a 30 more effective prophylactic HBC product. Collectively, the results of this study confirmed cross-reactivity of Travelan® against Shigella, and showed 75% protection against shigellosis in NJRM model, This HBC product could prevent increasing antimicrobial resistance and could revolutionize current management of diarrhea caused by bacterial pathogens such as Shigella, Campylobacter and Vibrio cholera spp., yielding improved outcomes for patients and bolstering public health. Primary objective is to assess the protective efficacy of a single daily dose (1,200 mg) of Travelan against moderate-to-severe diarrhea following challenge with enterotoxigenic Escherichia coli (ETEC) strain H10407. The ETEC H10407 strain is an O78:H11 serotype, that expresses CFA / I, and produces both the LT and ST 10 enterotoxins. Secondary objectives are to assess the safety and tolerability of once-daily dosing with Travelan (1,200 mg). To assess a variety of clinical endpoints to further evaluate the efficacy of Travelan to further qualify the degree to which a participant experiences diarrhea. 15 A randomized, double-blind, placebo-controlled study was conducted to investigate whether once-daily dosing with Travelan® (1,200 mg) protects healthy adult volunteers from moderate-to-severe diarrhea upon challenge with Enterotoxigenic 20 Escherichia coli (ETEC) strain H10407. 60 subjects were randomized and received either the Travelan® product or a placebo once daily, followed by challenge with approximately 1x108colony-forming units (CFUs) of ETEC strain H10407. Randomization was stratified according to blood group based on the correlation between ABO typing and susceptibility to moderate-to-severe diarrhea. Subject demographics 25 are summarised in Table 3.

[0002] 69 Table 3: Subject demographics 5 N = Number of subjects in respective treatment arm in Safety Set, n = Number of subjects within each treatment, SD = Standard Deviation, BMI = Body Mass Index. Percentages are based on the number of subjects in Safety Set. Subjects received Travelan® or placebo caplets once daily in the morning (6 10 caplets per dose), beginning 2 days prior to experimental challenge with ETEC strain H10407. Travelan® / placebo was administered for a total of 7 days, or until antibiotic treatment was initiated. Antibiotic was initiated after early antibiotic treatment criteria are met or 5 days after challenge. Early antibiotic treatment commenced when any of the following criteria are met and a physician determined it to be warranted: ^ Severe diarrhea based on volume (800 g in 24 hours) ^ Diarrhea of any severity AND 2 or more of the following symptoms: severe 5 abdominal pain, severe abdominal cramps, severe nausea, severe headache, severe myalgias, severe arthralgia), any fever (≥ 38.0°C), or any vomiting ^ Any fever ≥ 39.0°C ^ Subjects who experienced unexpectedly severe events such as symptomatic hypotension (disproportionate to volume loss), renal dysfunction, or altered 10 mental state (e.g. somnolence) at the discretion of the investigators ^ A study physician determined that early treatment is warranted for other reasons. The placebo was a commercially-sourced high-protein milk product repackaged and masked to mirror the Travelan® product. Upon admission to the inpatient unit, clinical monitoring consisted of daily 15 medical assessments with adverse event (AE) determination, vital signs at least three times daily, examination and weighing of all stools, stool culture work-up for the challenge strain up to three times daily, and safety laboratory tests. Any subject passing a grade 3-5 stool was encouraged to start drinking oral fluids at a rate equal to 1.5 times their stool output (or at the same rate as their emesis output as applicable). Intravenous 20 (IV) rehydration was provided if pre-specified criteria were met. All subjects were treated with ciprofloxacin (500 mg by mouth twice daily for three days) starting five days after ingesting the H10407 challenge inoculum unless early treatment criteria were met. Subjects were discharged from the inpatient facility when clinical symptoms were resolved or resolving and two consecutive stool cultures (taken 25 at least 12 hours apart) were negative for the ETEC challenge strain. Subjects were discharged earlier than Day 8 if they meet criteria. The primary efficacy endpoint of this study was prevention and / or reduction of30 moderate-severe diarrhea, defined as ≥4 Grade 3-5 stools in any 24-hour period post- challenge or ≥401 grams of Grade 3-5 stools in any 24-hour period post-challenge. Secondary endpoints were chosen to assess the safety and tolerability of the Travelan® product, and support the primary endpoint in determining the protective efficacy of the Travelan® product by further quantifying and qualifying the degree to which a participant experiences diarrhea. Additional comparisons between the placebo and test article groups are outlined below: ^ Presence of Travelan®-associated AEs during the study period ^ Maximum 24-hour loose stool (Grades 3-5) output 5 ^ Total loose stool (Grades 3-5) output ^ Percent of subjects with severe diarrhea ^ Percent of subjects with diarrhea of any severity ^ Percent of subjects with fever, nausea, vomiting, anorexia, or abdominal pain / cramps rated as moderate-to-severe 10 ^ Percent of subjects who indicate they would have reduced their daily activity if they had been vacationing or traveling for business because of their ETEC illness ^ Time to diarrhea onset and diarrhea resolution ^ Number of CFUs of the challenge strain per gram of stool at 48 hours post- 15 challenge ^ Percent of subjects requiring early antibiotic treatment ^ Percent of subjects requiring IV fluids ^ ETEC disease severity score to grade the severity of all adverse events. 20 Protective efficacy (PE) was determined as ETEC-induced moderate-severe diarrhea defined as > 4 Grade 3-5 stools in any 24 hour period post challenge days or >401grams of grade 3-5 stools in any 24 hour period occurring during the post-challenge period. PE determination is represented below: 25 PE (%) = incidence1 (placebo) – incidence1 (Travelan®) X 100% incidence1 (placebo) Study Duration Volunteers completed 1-3 screening visits that occurred up to 60 days prior to 30 enrolment according to protocol. Consenting and eligible volunteers spent approximately 12 days on the inpatient isolation unit. They were asked to return for 2 outpatient follow-up visits at 15 and 29 days post-challenge, and complete a telephone assessment 6 months post-challenge. The total participation for an individual volunteer was up to 9 months. Inclusion Criteria 5 1. Male or female between 18 and 50 years of age, inclusive at time of screening visit. 2. General good health, without significant medical illness, abnormal vital signs or physical examination findings, or clinical laboratory abnormalities, as determined by the principal investigator (PI) in consultation with the Medical Monitor and Sponsor. 3. Demonstrated comprehension of the protocol procedures, requirements, and the 10 controlled human infection model (CHIM) evaluated by completing a multiple choice comprehension assessment (passing grade > 70%) during screening and in the consenting process. 4. Willing to participate, as evidenced by signing the informed consent document. 5. Available for all planned follow-up visits. 15 6. Negative serum pregnancy test at screening and negative serum and / or urine pregnancy test on the day of admittance to the inpatient unit for all female participants. All females agreed to use an efficacious hormonal or barrier method of birth control during the study. Efficacious methods of birth control include hormonal birth control methods (oral contraceptive pills, patches, vaginal rings, long-acting reversible 20 contraception, surgical sterilization, condoms with spermicide, or abstinence from intercourse with a male partner. Female participants unable to bear children must have this documented (e.g., tubal ligation or hysterectomy). 7. A negative Covid-19 PCR test was required on the day of admission to the unit to comply with Pharmaron’s Covid-19 policy (subjects reporting to admission for Cohort 1 25 who test positive for COVID-19 may rescreen for Cohort 2) 8. Acceptable hematology and blood chemistry levels as assessed by the PI. i.e., Serum creatinine <1.3 mg / dL. AST, GGT, amylase, lipase, alkaline phosphatase not to exceed 1.5x upper limit of normal (ULN) 9. Vital signs were assessed in the supine position and were within the following ranges: 30 ^ Oral body temperature between 35-37°C inclusive ^ Systolic blood pressure between 90-140 mmHg inclusive ^ Diastolic blood pressure between 55-90 mmHg inclusive ^ Pulse rate between 45-90 bpm inclusive Exclusion Criteria General health issues 1. Presence of a significant medical condition (e.g., psychiatric conditions such as significant anxiety, depression, or somatization disorder; gastrointestinal disease, such 5 as peptic ulcer, symptoms or evidence of active gastritis / dyspepsia, gastroesophageal reflux disease, inflammatory bowel disease, or irritable bowel syndrome (as suggested by medical history or medical diagnosis); history of major gastrointestinal surgery; or laboratory abnormalities that in the opinion of the investigator preclude participation in the study. Significant medical conditions include HIV, active Hepatitis B or C infection, 10 ongoing immunosuppression for any reason, autoimmune disease, any underlying cardiac, pulmonary, endocrine, or renal conditions, any gastrointestinal illness (chronic reflux, inflammatory bowel disease, ulcer), any diabetes mellitus, and other such illnesses that can put a volunteer at increased risk. Exclusionary laboratory abnormalities include any abnormality that is grade 2 or above, or any two grade 1 15 laboratory abnormalities. 2. Immunosuppressive illness or evidence of IgA deficiency (serum IgA levels outside the normal range). This includes any disease that requires immunosuppressive medication such corticosteroids, monoclonal antibodies that target key aspects of the immune system (e.g. rituximab or TNF-blockers, or any autoimmune disease). 20 3. Positive serology results for HIV, HBsAg, or HCV antibodies, and confirmatory tests if appropriate. 4. Positive urine drug screen (positive for the presence of amphetamines, barbiturates, opiates, phencyclidine, cocaine, benzodiazepines, methadone, and propoxyphene at screening and at the discretion of the study physician, with the exception of stable 25 persons with a diagnosis of ADHD that is well-controlled with a prescribed amphetamine. 5. History of alcohol abuse in the past 3 months or drug abuse in the past year 6. Significant abnormalities in screening laboratory hematology, serum chemistry or electrocardiogram, as determined by the PI or PI in consultation with the Medical Monitor 30 and Sponsor. Significant ECG abnormalities include the following: a. PR > 220 msec b. QRS complex > 120 msec c. QTcF > 450 msec (male) or >460 msec (female) 7. Serum bilirubin exceeded upper limit of normal 8. Use of any medication known to affect immune function (e.g., corticosteroids and others) within 30 days preceding receipt of the investigational products or planned to be used during the active study period. Any regular systemic corticosteroid will be exclusionary, while topical, intranasal, and inhaled steroids will be permitted. 5 9. Nursing or lactating on the day of admittance to the inpatient unit. 10. Inability to tolerate 150 ml of sodium bicarbonate buffer. 11. Recent vaccination (including licensed vaccines) or receipt of an investigational product (within 30 days before challenge through 30 days following the challenge dose). 12. History of diarrhea (> 3 unformed or liquid stools over a 24-hour period) in the 2 10 weeks prior to the planned inpatient phase. 13. Fewer than 3 stools per week or more than 3 stools per day as the usual frequency, or loose or liquid stools other than on an occasional basis. 14. Regular use of laxatives or any agent that increases gastric pH (regular defined as at least weekly). 15 15. Use of proton pump inhibitors, H2 blockers, or antacids within 48 hours of dosing. 16. A fever (≥38.0°C) in the 2 weeks prior to time of challenge. 17. Use of antibiotics during the 30 days before bacterial dosing or receipt of more than 3 courses of antibiotics over the two months prior to dosing. 18. Blood or plasma donation of one pint or more within 30 days preceding the receipt 20 of the investigational products. 19. Lactose intolerance or allergy to milk or milk products. 20. Employment as a health care worker, food handler, childcare worker, or caregivers for elderly or immunocompromised individuals. or 21. Allergy to fluoroquinolones, trimethoprim-sulfamethoxazole, doxycycline, or ampicillin / penicillin (excluded if allergic to two of four). 22. History of microbiologically confirmed ETEC infection in the last 3 years. 23. Occupation involving handling of ETEC currently, or in the past 3 years. 30 24. Symptoms consistent with travellers’ diarrhea defined as >3 unformed or liquid stools over a 24 hour period concurrent with travel to countries where ETEC infection is endemic (most of the developing world) within 3 years prior to dosing, OR planned travel to endemic countries during the length of the study. ETEC endemic countries include all countries in Asia (except for Japan and South Korea) the Middle East, Africa, Mexico, Central and South America. 25. Vaccination for or ingestion of ETEC, cholera, Shigella, or E. coli heat-labile toxin within 5 years prior to dosing. 5 26. Any prior experimental infection with ETEC strain H10407, or prior experimental infection with other ETEC strains or other bacterial enteric pathogens (Salmonella, Shigella, and Campylobacter) within the past 5 years. Results 10 There were no reported serious adverse events (SAEs) during the inpatient phase of the study or at the 2-week and 1-month follow-up visits. No new or previously identified clinically significant toxicities were reported. One subject who received one dose of Travelan suffered from some minor side effects Abdominal Cramping, (Grade 2) fever (Grade 2) and headache, (Grade 1), these side effects w e re not confirmed t o 15 be due to the Travelan study drug but the subject did not continue w ith the challenge . Follo wi ng chall enge the number of subjects who reported an adverse event was lower in the Tra v elan group than for the placebo group, as listed in T able 4. In addition the number of subjects with challenge related solicited AEs, (fev er, nausea, anorexia or abdominal pain / c ramps rate d as modera te to severe (CTCAE v5.0 Criteria) was also 20 lower for t h e T ra v elan group compared to the placebo (Table 5). Table 4: Summary of Drug Associated Adverse Events during study period relative to challenge-Intent To Treat Analysis Set. [ P- l ba o 2 e h [2] Ba on q re 30 Table 5: Summary of AEs - subjects with fever, nausea, vomiting, anorexia or abdominal pain / cramps rated as moderate to severe post challenge [1] P- ba o 2 h te [2] Ba on qare Pimary Efficacy Variable The number of Subjects ET in moderate- re diarrhea was l in Travelan® - t reated Subjects (n=7, 23.3%) than those treated with placebo ( 36.7%), resulting in a protective efficacy of 36.4% (-79.8%, 79 .1%), p=0.399 in the ITT Analysis Set. The incidenc e o f E TEC - indu ced moderate-severe diarrhea summarized by treatment group as well as derived protective efficacy for the ITT Analysis Set and full Safety An aly si s Set are described in Table 6 and Table Table 6: Summary of Protective Efficacy-Intent To Treat Analysis [ ed > = 3-5 sto in ay hor period post- challe days or >= 401 g of Grad stools in any 24 h ou pe o d o c c in u r i n t h p o s t - c h a ll e n g e p e r i o d . [2] Based o F e t test for difference in proportions [3] Protective Efficacy defined in the Statistical Analysis Plan, section 4.2.1 [4] Based on binomial distribution; Note: Intent-to-treat analysis set defined as randomized subjects who r ived study medication and were challenged.

[0003] 77 Table 7: Summary of Protective Efficacy-Safety Analysis Set [1] Defined as > =4 Grade 3-5 stools in any 24 hour period post-challenge days or > =401 g of Grade3-5 stools in a ny 24 hour per iod occurring during the post-challenge period. [2] Based on Fisher’s exact test for difference in proportions [3] Protective Efficacy defined in the Statistical Analysis Plan, section 4.2.1 [4] Based on binomial distribution; Note: Safety analysis set defined as randomized subjects who received either Travelan or placebo, irrespective of the number of doses of Travelan or receipt of the challenge. A further analysis was performed to account for Subjects who met the primary endpoint only after completion of Study Drug or placebo on day 5. After completion of Study Drug on Day 5 antibiotics were administered on Day 6. Analysis derived from these data resulted in a Protective Efficacy for Travelan® of 40.0% (-74.1%, 79.7%), p=0.274 in the Safety Analysis Set. These analyses are presented in Table 8. Table 8: Summary of Protective Efficacy for a 5 Day Period Post Challenge - Intent- to-treat Analysis Set Analysis period for 5 days post challenge inclusive of subjects who met early antibiotic criteria. [1] Defined as >= 4 Grade 3-5 stools in any 24 hour period post-challenge days or >= 401 g of Grade 3-5 stools in any 24 hour period occurring during the post-challenge period. [2] Based on Fisher’s exact test for difference in proportions [3] Protective Efficacy defined in the Statistical Analysis Plan, section 4.2.1 [4] Based on binomial distribution. Safety Evaluation Overview and analysis of Adverse Events Twenty-four Subjects (75.0%) receiving Travelan® and 28 Subjects (90.3%) receiving placebo therapy, respectively, enrolled in the study experienced AEs of any grade defined by the CTCAE scale v5.0. Two Subjects in each group (6.3% receiving Travelan® and 6.5% receiving placebo) experienced AEs that were classified as Grade ≥ 3 in severity. Overall, there were less Subjects with solicited AEs in the Travelan® group (n=13, 40.6%) than in the placebo-treated Subjects (n=17, 54.8%). Similarly, there were less Subjects with unsolicited AEs in the Travelan® group (n=20, 62.5%) than in the placebo-treated Subjects (n=26, 83.9%). There were no serious AEs or deaths in the study. One Subject who received Travelan® discontinued Study Drug as a result of a pre-challenge Treatment Emergent Adverse Event (TEAE). An overview of AEs is summarized in Table 9. Table 9: Overview of Adverse Events – Safety Analysis Set [1] Number of subjects with >=3 severity of AE. [2] For a list of Solicited AEs, refer to the Statistical Analysis Plan, Section 4.3.2 N = Number of subjects in Safety Analysis Set, n = Number of subjects with event. AE = Adverse event. Note: Percentages are based on the number of subjects in Safety Analysis Set. The most common, overall AE was Diarrhea in both the Travelan® (n=18 Subjects, 56.3%) and placebo (n=20 Subjects, 64.5%) groups. The most common solicited AE was abdominal pain in both the Travelan® (n=11 Subjects, 34.4%) and placebo (n=13, 41.9%) groups. The most common unsolicited AE was Diarrhea in both the Travelan® (n=18, 56.3%) and placebo (n=20, 64.5%) groups. An overview of the most common AEs (SOC occurring in more than 1 Subject) is summarized in Table 12- 3. Overall, the number of adverse events in all organ classes for the Travelan group was lower (n=58) than for the placebo group (n=109). The investigator classified this 5 difference as clinically significant. Results of selected Secondary Efficacy Variables (i) Treatment-Associated Adverse Events During the Study Period The number of Subjects with Treatment-associated TEAEs during the post- 10 challenge period was less in Travelan®-treated Subjects (n=6, 18.8%) than those treated with placebo (n=9, 29.0%) in the ITT Analysis Set. The most common Study Drug-treatment -associated SOC in both treatment groups was Gastrointestinal disorders. Overall, Gastrointestinal disorders were the most commonly reported AEs, reported in 52 (82.5%) of Subjects. The total number of AE 15 events encountered in the Travelan group (m=58) was lower than for the number of events reported in the placebo group (m=109). The Investigator classified this difference as clinically important. A summary of Gastrointestinal AEs is presented in Table 10-1. A number of Treatment-associated AEs were likely more attributable to the challenge agent than Study Drug.

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On day 6 antibiotics were administered to all Subjects for a 3 day period. A further analysis was performed limiting the reporting 5 period to the time after completion of Study Drug exposure (5 day period post challenge). In this analysis, it was noted that the number of Subjects who experienced diarrhea of any severity was decreased in the Travelan group by 43.8%, p = 0.0668. This difference was considered by the Investigator to be clinically significant. Details of this analysis are described in Table 10-2. 10 Table 10-2: Summary of Subjects with Diarrhea (Grade 3 - 5) of Any Severity Post Challenge for a 5 Day Period Post Challenge - Intent-to-treat Analysis Set Analysis period for 5 days post challenge inclusive of subjects who met early antibiotic criteria.15[1] P-value based on 2 sample Chi-square test [2] Based on Chi-square test (iii) Percent of Subjects with Fever, Nausea, Vomiting, Anorexia, or Abdominal Pain / Cramps Rated as Moderate-to-Severe 20 The number of Subjects that experienced fever, nausea, vomiting, anorexia or abdominal pain / cramps rated as moderate-to-severe post challenge during the study period was 57.1% lower in Travelan®-treated Subjects (n=3, 10%) than those treated with placebo (n=7, 23.3%). (-5.2, 31.9), p = 0.1659 in the ITT Analysis Set. This difference was considered by the Investigator to be clinically significant. 25 The number of Subjects that experienced fever, nausea, vomiting, anorexia, or abdominal pain / cramps rated as moderate-to-severe post challenge during the study period summarized by treatment group for the ITT Analysis Set are described in Table 10-3. Table 10-3: Summary of Subjects with Fever, Nausea, Vomiting, Anorexia, or Abdominal Pain / Cramps Rated as Moderate-to-Severe - Intent-to-treat Analysis Set 5 [1] P-value based on 2 sample Chi-square test [2] Based on Chi-square test (iv) Number of CFUs of the Challenge Strain per Gram of Stool at 48 Hours Post- Challenge 10 The number of Subjects with colony forming units (CFU) post challenge during the study period was less in Travelan®-treated Subjects (n=27, 90%) than those treated with placebo (n=29, 96.7%). The mean (SEM) number of CFUs of the challenge strain per gram of stool at 48 hours post-challenge during the study period was significantly greater in Travelan®-treated Subjects (2.13 x108, SEM= 1.77x108) than those treated 15 with placebo (1.53x108, SEM=4.47x107), (-1.10x108, 1.72x104), p = 0.0121 in the ITT Analysis Set. The higher CFUs in the stools of the Travelan group indicates faster clearance of H10407 at 48 hours post challenge than for the placebo group, likely due to Travelan antibodies binding to ETEC, assisting with removal from the GI tract. The number of CFUs of the challenge strain per gram of stool at 48 hours post- 20 challenge during the study period summarized by treatment group for the ITT Analysis Set are described in Table 10-4.

[0005] Table 10-4: Summary of CFUs of the Challenge Strain per Gram of Stool, Post- Challenge - Intent to Treat Analysis Set [1] P-value based on 2 sample T-test or Wilcoxon Rank Sum test (if normal assumption is violated) [2] Based on non-parametric Wilcoxon Rank Sum test (or 2 sample t-test) CFUs are measured by quantitative bacterial stool culture 48 hours post challenge per gram of stool (1g = 1ml) (v) Percent of Subjects requiring early antibiotic treatment The number of Subjects requiring early antibiotic treatment post-challenge during the study period was 71.4% lower in the Travelan®-treated Subjects (n=2, 6.7%) than those treated with placebo (n=7, 23.3%), (-0.9, 34.2%), p = 0.076 in the ITT Analysis Set. Although the sample size is small, the difference observed between Travelan®- and placebo-treated Subjects is clinically significant. The number of Subjects requiring early antibiotic treatment post-challenge during the study period summarized by treatment group for the ITT Analysis Set are described in Table 10-5. Table 10-5: Summary of Subjects Requiring Early Antibiotic Treatment Post Challenge-Intent To Treat Analysis Set [1] P-value based on 2 sample Chi-square test [2] Based on Chi-square test (vi) Percent of Subjects Requiring IV Fluids The number o f Subjects requiring IV fluids post-challenge during the stud y per io d was less in Travelan®-treated Subjects (n=0) than thos e t reated with placebo (n=3, 5 10%), (-0.7, 20. 7), p = 0.0756 in the ITT Analysis Set. The nu mber of Subjects requiring IV fluids post-challenge during the study period summariz ed by tre atment group for the ITT Analysis Set are described in Table 10-6. Table 10-6: Summary of Subjects Requiring IV Fluids Post Challenge-Intent To 10 Treat Analysis Set [1 P- a e b o 2 s le Chi-square test [ ] B d o - q t 15 Discussion and Conclusions The clinical study was completed, as planned, whi the study b . Regarding the Primary Objective, assessing the protective efficacy of a single daily dose (1,200 mg) of Travelan® against moderate-to-severe diarrhea following 20 challenge with ETEC strain H10407, the protective efficacy of Travelan® in the population was 36.4%, p=0.399. After completion of Study Drug on day 5, antibiotics were administered on day 6. Analysis derived from these later data resulted in a Protective Efficacy for Travelan® of 40.0%, a clinically significant difference, as established by the Investigator. In addition to the Primary Objective, the study included 25 a number of Secondary Objectives composed of clinical endpoints to further evaluate the efficacy of Travelan®. Importantly, in addition to a significant increase in the number of CFUs of the challenge strain per gram of stool at 48 hours post-challenge during the study period in Travelan®- versus placebo-treated. The higher CFUs in the stools of the Travelan® group indicates faster clearance of H10407 at 48 hours post challenge than 30 for the placebo group, likely due to Travelan antibodies binding to ETEC assisting with removal from the GI tract. Clinically important decreases were observed in the number of Travelan®-treated Subjects requiring early antibiotic treatment and post-challenge IV treatment post-challenge. For some secondary endpoints, Travelan®-treated Subjects experienced clinically important differences in response compared to placebo treated Subjects, while in other secondary endpoints, better, but not statistically significant outcomes in Travelan®-treated versus placebo- treated Subjects were recorded. There were no serious AEs or deaths in the study. One Subject who received 5 Travelan® discontinued Study Drug as a result of a TEAE. Most Subjects enrolled in the study experienced AEs, with diarrhea the most commonly reported AE in both Travelan® and placebo-treated Subjects. This finding is not unexpected given the study design. Most AEs were mild to moderate in intensity. Grade 3 Gastrointestinal disorders were recorded in both the Travelan® (n= 2 Subjects, 6.3%) and placebo (n=1 Subject, 10 3.2%) groups. It should be noted that TEAEs related to Travelan® administration were limited to 6 Subjects (18.8%) while 9 (29.0%) Subjects that received placebo experienced Study Drug-related TEAEs. Of note, Certain treatment-related AEs were likely a result of the challenge agent as demonstrated by more frequent clinically significant occurrences recorded after challenge compared to before. Further to that, no 15 Subjects experienced diarrhea related to Travelan®-administration, while diarrhea was attributed to the administration of placebo in 4 (12.9%) Subjects. These observations suggest that the majority of AEs resulted from the ETEC challenge. The single dose study described above in Example 9 also comprised exploratory objectives, and the analysis and results of these exploratory objectives are discussed 20 below in Example 10 and Example 11. The exploratory objectives of the single dose study are to measure the mucosal and systemic immune responses to the challenge organism and to obtain and archive samples for future immunologic, proteomic and microbiome analysis. 25 Example 10: Investigation of the Immune response in a controlled human infection model for ETEC to assess the efficacy of once daily dosing of Travelan® Materials and Methods Clinical samples were shipped from the clinical site (Pharmaron Clinical Pharmacology Center, Baltimore, MD) to the Operationally Relevant Infections 30 Department (ORI), Deployment Associated Infections Division (DAID) at the Naval Medical Research Command (NMRC). Blood, serum and Stool (fecal) samples were collected from all subjects and blinded with a code for analysis. These biological samples were handled, processed analyzed and archived according to appropriate procedures. Samples collected under this protocol were used to conduct protocol-related immunological evaluations. Blood samples collected in Cell Preparation tubes (CPT) and Serum Separating tubes (SST) were transferred from Pharmaron to the NMRC ORI laboratory and processed into peripheral blood mononuclear cells (PBMC) or serum, 5 respectively. PBMC and serum aliquots were cryopreserved and stored until immunologic assays were performed. Stools were collected, aliquoted and cryopreserved at Pharmaron prior to transfer to the NMRC ORI laboratory for extractions. Serum samples were assayed for IgG and IgA antibody titers against the H10407 lipopolysaccharide (LPS) using methods previously described (Ahren et al., 10 1998, Svennerholm et al., 1983). Stool sample extracts were prepared and used to determine total IgA content and LPS-specific fecal IgA responses. IgA and IgG in serum samples The systemic antibody response to oral challenge with ETEC strain H10407 in 15 subjects orally treated with Travelan and placebo was monitored by Enzyme linked Immunosorbent assay (ELISA). Pre- and post-challenge serum and stool samples from the same individual were tested side by side in duplicate on the same plate. All analysis was performed initially in a blinded manner to avoid bias. 20 The endpoint titer was interpolated using a four parameter logistic ( 4PL) Nonlinear regression (curve fit), in GraphPad Prism. Responder / seroconversion was defined as ≥ 4-fold rise in antibody titers between peak of response and baseline reciprocal endpoint titer. The results were analyzed as endpoint titers on days -3, 2, 4, 8, 15 and 29. Fold 25 increase of antibody titers to baseline (day -3). Two-way ANOVA analysis was performed and considered significantly different when P<0.05. Significance among groups are shown with asterisks in Figure 9 below. IgA in fecal samples 30 The mucosal antibody response measured in fecal pellet extract (FPE) samples to oral challenge with ETEC strain H10407 in subjects treated with Travelan and placebo was monitored by ELISA assay. FPE samples were analyzed for total IgA levels and LPS O78 specific IgA antibody levels. Total IgA antibody content was used to normalize antigen specific IgA antibodies in fecal extract samples. For measurement of total IgA concentration, the duplicate wells of the IgA standards were used to calculate a standard curve in Prism using a sigmoidal 4PL 5 regression model. By using the “Analyze” function in Prism the Nonlinear regression (curve fit) was performed and “Sigmoidal, 4PL, X is log (concentration)” values for samples were obtained and interpolated from the standard curve. Three or more dilutions were used to calculate the average ng / mL of IgA in the FPE samples and results were expressed as total FPE IgA mg / mL. To ensure high enough sensitivity to 10 detect antibodies, and consistency between the amount of sample collected and processed, samples were excluded from analysis if there was less than 10 µg / mL total IgA or if total IgA varied more that 10-fold among study days for each subject. For measurement of LPS specific IgA, FPE samples were analyzed in duplicate on the same plate. the endpoint titer was interpolated using a 4PL Nonlinear regression 15 (curve fit), in GraphPad Prism. The amount of total FPE samples IgA was used to normalize anti-LPS fecal IgA ELISA levels, in order to minimize fluctuations in IgA secretion throughout the study days. LPS specific IgA was expressed as FPE LPS IgA titers per FPE total IgA (mg / mL). 20 Results Comparison of the immunological response to ETEC infection in Travelan and Placebo groups A summary of the systemic and mucosal antibody responses against O78 LPS in Travelan and Placebo groups for the 29 day period post ETEC challenge is shown 25 graphically in Figure 9. For all subjects given Travelan or placebo, challenge with H10407 led to an immune response measured by serum IgA (Figure 9A) and IgG (Figure 9B) specific for O78 LPS, from 8 days post challenge. Peak endpoint titers were observed, 15 days post challenge for both IgA and IgG levels, at 29 days post challenge the antibody titers begin 30 to decline. The endpoint titers were generally lower for the Travelan group compared with the Placebo group, with significantly lower endpoint titers for IgA 8 days post challenge (P=0.0169) and 15 days (P=0.0011) and 29 days (P=0.0002) post challenge for IgG levels. Fecal IgA levels followed the same trend (Figure 9C) where the highest detected levels of mucosal IgA was observed for both the placebo and Travelan groups 15 days post challenge with a slight decline at day 29. Fecal IgA levels were generally lower in the Travelan group compared to the placebo group with significantly lower levels at day 5 15 (P=0.0116). Relationship of the immunological response to ETEC infection with the severity of disease To further investigate the immune response in the human ETEC challenge study 10 to observe any trends in the severity of diarrhea and the serum IgA, IgG and mucosal IgA levels, the data was grouped into subjects who had no disease or diarrhea (ND), mild disease or diarrhea (MD) or moderate to severe disease or diarrhea (MSD). Serum IgA antibody endpoint-titers against ETEC LPS O78 in different disease groups (ND, MD and MSD) are shown in Figure 10. The IgA titers measured in subjects 15 who received the placebo were generally higher than IgA titers in the Travelan group for all levels of disease. On study days 15 and 29. For Placebo subjects with moderate to severe diarrhea the IgA titer was significantly higher than for the subjects with moderate to severe diarrhea in the Travelan group (p=0.0044). Significant differences were observed on day 15, showing a correlation between 20 more severe disease with higher IgA responses. Subjects who received Travelan but had mild disease showed significantly higher IgA responses than subjects in the Travelan group with no disease, (p<0.0001). Travelan subjects with moderate to severe diarrhea had IgA levels that were significantly higher than the Travelan subjects with mild disease (p<0.0001). The same trend was observed for the subjects who received 25 placebo with IgA levels for subjects with mild disease significantly higher than for the placebo group with no diarrhea (p=0.0195). A similar trend was observed between serum LPS-specific IgG levels and severity of disease shown in Figure 11. IgG levels in the placebo group were generally higher than the Travelan group, especially in subjects with more severe disease. On 30 study day 29, IgG responses in placebo subjects with moderate to severe diarrhea were significantly higher than the IgG levels in subjects with moderate to severe diarrhea in the Travelan group (p=0.001). Similarly, IgG titers were higher for the majority of subjects with severe disease. On study day 15, IgG titers in the Travelan group were significantly higher in subjects who had both mild diarrhea (p=0.017) and moderate to severe diarrhea (p=0.015) compared to the subjects who had no diarrhea. The same trend was observed in the Placebo group where IgG levels in the moderate to severity diarrhea group were significantly higher compared to IgG in both the placebo-mild diarrhea (p=0.0011) and 5 placebo no diarrhea groups (p<0.0001). On day 29, IgG in the moderate to severe diarrhea placebo group were also significantly higher than IgG levels in the placebo-non diarrhea group (p<0.0001). Fecal IgA levels specific for ETEC O78 LPS were also analyzed by dividing subjects into disease outcomes (Figure 12). There was a similar trend in mucosal levels 10 of IgA which peaked at day 15. However the data did not fit the ANOVA model to compare the variance between groups as there were no significant differences or trends between the Travelan and the placebo antibody titers relating to the severity of disease. In Table 11 seroconversion for IgA and IgG is shown for subjects who received Travelan or placebo (total group) and grouped into severity of disease. Seroconversion 15 levels of IgA correlated with severity of disease where seroconversion was higher for subjects with moderate to severe disease in the Travelan and placebo groups. By Day 8 for the placebo group there was 100% IgA seroconversion in all subjects with mild to severe diarrhea, and 100% seroconversion in all subjects who received Travelan in the moderate to severe diarrhea category. Seroconversion of IgG followed a similar pattern 20 with higher seroconversion levels for more severe diarrhea in the Travelan group, but higher levels of seroconversion for subjects who received placebo in the mild diarrhea group.

[0006] fon ,e esswoahaeercsisisliedonato0) ) )3 ) )=4%0 8 %35 %31 %077%0 5 %3li,iIIE Tnin .eM n11( 11( 11( 76(019(019(E ehnTa.de)3pusaesi)%)%)%) ) )g- or d 50 0 0%0%0%nityar ag, ertD9ep D M=5 01( 5 01( 5 01( 5 01( 5 0( 50101(s(nl 2edveu n vn s orome lea to gde 5 eob41 ) ) ) ) ) )s in 1,8ta= rtclesy eecn %jdlaD1e saaoP N1 9%7(11 5%8( 9 51%7(19( 1%7 15( 1%8 159(bbdemusoft g=D)o de nlelSyD nraiaophMd(c dnutya 85192 85192trmts aS D D D D D D Dopoc oor rp esP etsyaeA G:isIg-Ig-1ityaddygyg1dylleod di looloobbaiuttsm r =DrerSeS Tna foM 5 Challenge with ETEC H10407 induced serum IgA and IgG antibody titers in subjects who received Travelan or placebo. There was a general trend towards higher titers in the placebo group with statistically significant increases on day 8 for serum IgA 5 and day 15 and 29 for serum IgG. A similar trend was observed for mucosal IgA with peak levels 15 days post challenge and a significant higher titer for the subjects who received placebo. The magnitude of the immune responses against O78 LPS significantly correlated with the severity level of disease. This led to significantly higher serum IgA 10 and IgG responses in subjects who had moderate to severe diarrhea compared to those who had mild or no diarrhea. This could be directly related to exposure of the ETEC pathogen, where greater or longer exposure to ETEC antigen, causing severe diarrheal symptoms elicits a higher immune response and higher level of IgA and IgG antibodies. Statistically significant lower levels of IgA and IgG were observed for the subjects 15 who received Travelan compared to those who received the placebo, which may also reflect levels of exposure to ETEC antigens. These immunologic data support the hypothesis that Travelan antibodies target and bind to ETEC in the gastrointestinal tract, likely blocking LPS epitopes and reducing colonization and, therefore, reducing antigenic exposure resulting in lower overall IgA and IgG antibody titers. 20 Clinical data also demonstrated there was a statistically significant reduction in the number of colony forming units (CFUs) in the stools of subjects who received Travelan (p =0.0121), measured 48hrs post challenge, indicating faster clearance of the challenge strain from the GI tract. analysis: Microbiota Fecal samples from the CHIM study of Example 9 were analyzed to assess how the human gut microbiome responds to ETEC infection and if a protective microbiota exists in the study participants who were given Travelan compared to placebo. 30 Methods Human fecal samples from 26 subjects in Cohort 1, were collected at baseline (Day -3), Day -2 and -1 (pre-challenge), Day 1-9 (post challenge) and follow up time points (Day 15 and 29). The fecal samples were processed to extract the DNA using high-throughput techniques. All analysis was performed initially in a blinded manner to avoid bias Sequencing [16S rRNA] of the V3-V4 region was completed on the 307 human fecal DNA samples provided, the data from the samples was analysed using QIIME2 5 and R Studio using the following packages: vegan, qiime2R, tidyverse, phyloseq, remotes, microbiome, magrittr, RColorBrewer, dplyr, pairwiseadonis, ape, FSA, ggplot2, ANCOMBC2, DESeq2, Masslin2, and ggpubr. Unblinding of the samples was performed post-analysis and is presented in this report. Data analysis was performed as a whole data set for Travelan or Placebo and 10 grouped into, no diarrhea, mild diarrhea, moderate diarrhea and severe diarrhea. Definitions of microbial analysis Alpha Diversity Alpha diversity describes the observed species diversity within a defined plot. 15 Alpha diversity does not compare one sample with another. Alpha Diversity includes “richness”, how many different species are within the plot, and “evenness” the abundance of these different species within the plot. Three alpha diversity tests were utilized to determine if microbial diversity within a specific group is driven by (i) richness, (ii) evenness (Pielou), or (iii) a combination of the two (Shannon diversity). 20 Beta Diversity Beta diversity uses a distance matrix to measure the distance between regional and local species diversity between samples. This test evaluates how many species are in a sample and the abundance of each species. The data can then be grouped into 25 samples that have similar communities. The distance matrix used for Beta diversity analysis is unifrac which has two variations. Weighted unifrac which takes into account the presence or absence of specific bacteria and the abundance (or amount ) of this bacteria. Unweighted unifrac takes into account only the presence or absence of bacterial species. 30 This analysis provides an indication of if the abundance of the bacterial community or the presence of a specific bacterial species is driving microbiota fluctuations. Results Alpha Diversity To investigate the effect of ETEC challenge between the Travelan group and the 5 placebo group, firstly the inventors measured alpha diversity of the microbial composition of the fecal samples. The analysis is shown in Figure 13 and Figure 14. Figure 13 shows the total analysis for all subjects in each group for the 3 alpha diversity tests according to diarrhoea severity and Figure 14 displays the alpha diversity comparison for each group for diarrhoea severity for each study day. 10 Statistically significant differences were observed between the Travelan and Placebo groups in the Richness and Shannon diversity tests but not in the Pielou evenness test (Figure 13). This finding indicates this difference in microbial composition is likely to be due to the presence or absence of specific bacterial species rather than the amount or abundance of the bacterial species in the microbial community. 15 Alpha diversity was also grouped into the severity of diarrhea encountered post challenge and the data in Figure 13 illustrates that when diarrhea is present the fluctuation in microbial diversity in the Travelan group is not as pronounced compared with the fluctuations in the Placebo group. This could indicate a more stable microbial community. When diarrhoea is not present the microbial community of the Travelan 20 group was more diverse which could also indicate a healthier microbial community. It is important to investigate the Alpha diversity results of the Travelan and Placebo group samples over time to identify how the microbial communities are changing within the test groups when exposed to the study drug (days -2 and -1), challenge (day 1-5), antibiotic (day 6-8) and follow up (day 15 and day 29) variables. 25 This analysis facilitates an understanding of how stable the microbial community is in the Travelan and Placebo groups after ETEC challenge and how well the bacterial community recovers. The Alpha diversity results for the Travelan and Placebo groups over the study time period revealed statistically significant results for all 3 alpha diversity analyses 30 (Figure 14). This indicates that diversity is driven by the presence of specific bacterial species and the changes in the abundance of bacterial species over time. At Baseline (day -3) there is some fluctuation between the Travelan and Placebo groups, this is common as there are multiple participants in each group and variation is expected between participants, however the difference was not statistically significant. During the challenge phase day 1 to day 5, the Travelan group had greater richness and Shannon results that were very similar to the Baseline and Study Drug timepoints, revealing stability in these microbial communities. The Travelan group also had a more stable community in richness, Shannon diversity, and evenness results during the 5 Antibiotics administration (day 6-8) when study drug administration was complete compared with the Placebo group. The Travelan group had an improved richness result during the Recovery period (Day 15 and Day 29) when compared with the Placebo group but the Shannon diversity and evenness results for this timepoint were comparable with the Placebo group. 10 Beta Diversity To investigate the similarity or dissimilarity between the Travelan and the Placebo groups Beta diversity analysis was performed. The data in Figures 15 and 16 shows that there are no strong groupings between the samples from the Travelan group 15 and Placebo group for both weighted and unweighted analyses. Due to the large number of samples it is difficult to visualize if there are sub-groupings based on the presence of diarrhea or timepoints. The UniFrac measurements although not visible on the plots showed strong differences between the Travelan and Placebo groups as well as strong differences in the diarrhea symptoms in both the weighted and unweighted UniFrac. 20 Figure 15 analysis showed grouping for the Travelan group for weighted and unweighted analyses for no diarrhea or mild diarrhea symptoms, indicating similarities for these samples. In Figure 16 weighted UniFrac results revealed no strong grouping for the Travelan and Placebo groups but a difference between the Travelan and Placebo groups for each timepoint. Unweighted UniFrac confirms there are differences between 25 the Travelan and Placebo groups with only grouping occurring during the Antibiotics timepoint for both the Travelan group indicating some similarities for these samples To determine if there is a statistically significant difference between the Travelan and Placebo groups and how the presence of diarrhea or the timepoints influence the Travelan and Placebo groups, PERMANOVA tests were conducted to compare the 30 variation between the groups. Table 12 PERMANOVA results show a statistically significant difference between the microbial communities in the Travelan group vs the Placebo group as a whole in both the presence and absence of bacterial species (unweighted UniFrac) and when abundance is taken into account (weighted UniFrac). This data indicates that Travelan treatment significantly impacted the structure of the microbial community. There is a statistically significant difference when comparing the Travelan and Placebo 5 groups over the whole study time period (Table 13). This indicates that there is a strong change in the microbial community over time for the Travelan and Placebo groups when abundance is considered. When the severity of diarrhea (None, Mild, Moderate, and Severe) per treatment group was considered (Table 14) there was a statistically significant difference between 10 the Travelan and Placebo groups measured by the PERMANOVA association test. These results indicate that there is a strong change in the microbial community in relation to the diarrhea symptom in the Placebo group. There is a statistically significant result for the Travelan between None and Mild groups but there are no further statistically significant changes. This could indicate a more stable microbial community 15 in the Travelan group even when diarrhea symptoms are present. There is also a statistically significant difference between the No diarrhea Placebo and the No diarrhea Travelan groups, confirming that there is a difference between the Travelan group and the Placebo groups, also shown in Table 12. 20 Table 12: PERMANOVA UniFrac results comparing the variance between the Travelan and Placebo groups lue4 * 4 * 2 * Statistically significant ** Strongly statistically significant 25 Table 13: PERMANOVA Unifrac results comparing the variance between the Travelan and Placebo groups over time e ** e** ** Statistically significant ** Strongly statistically significant Table 14: PERMANOVA Unifrac results for comparing the variance between the 5 Travelan and Placebo groups for diarrhea symptoms (no diarrhea, mild, moderate and severe diarrhea) lue1 ** 1 ** 1 ** Statistically significant ** Strongly statistically significant 10 To further understand these results and to visually examine the fluctuations in the microbial communities, Relative Abundance and Differential Abundance tests were conducted. Relative Abundance 15 The relative abundance is an indication of whether the community has more beneficial bacteria. It is important to assess if there is any microbial community change between the Travelan group and Placebo group as well as to observe if there is any specific change in relation to the onset of diarrhea. As diarrhea is a common symptom associated with inflammation, how this affects the microbial community could influence 20 how the microbial community responds to outside interventions. The relative abundance of the Phylum in Figure 17 demonstrates fluctuation in the microbiota depending on the presence of diarrhea. It should be noted that the Travelan group shows a strong increase in the Verrucomicrobiota phylum, specifically when severe diarrhea is present. This phylum contains the genera Akkermansia which 25 is a beneficial bacteria associated with repairing the intestinal mucosal lining. The genera data in Figure 18 confirms the fluctuations observed in the phyla results. Participants in the Travelan group do not have a strong presence of Escherichia- shigella genus compared with the Placebo group. This indicates that Travelan clears the ETEC challenge strain more rapidly than for the placebo group allowing for greater genus diversity. The Travelan group with moderate diarrhea has a greater abundance of Faecalibacterium and participants in the Travelan group with severe diarrhea have a greater abundance of Akkermansia. Both of these genera are associated with repairing the intestinal lining and promoting gut health. The inventors also compared the relative abundance of the phylum and genera for each study day to look for changes in the Travelan and Placebo groups. The phyla data in Figure 19 shows a reduction in the level of Pseudomonadota in the Travelan group on day 7, 8, 9 and 15 and an increase in Verrucomicrobiota on day 8, 9 and 15. The genus data in Figure 8 also highlights the large increase in Akkermansia, in the Travelan group on study day 9 and 15. There are also notable differences in the level of Escherichia-Shigella genus on days 3-5, indicated by the purple double arrows supporting the evidence of faster clearance of the ETEC challenge strain. Differential Abundance Four separate analyses were performed ANCOMBC2, DESeq2 Masslin2 and Wilcox to measure and compare the bacterial genus relative abundance between the samples in the Travelan group compared to the Placebo group. A summary of the abundance data is shown in Table 15. Table 15: Differential Abundance (Statistically significant) Results for the Travelan cohort compared to the Placebo group sted 37 03 69 03 03 29 sted 29 -06 12 -05 -27 -07 -78 86 70 12 17 17 05 52 72 72 76 08 06 25 43 88 73 The differential abundance results were able to confirm (in 3 or more statistical analyses) increases in Agathobaculum, Slackia, Eubacterium eligens and Eubacterium siraeum groups; and decreases in Rumminococcus and Bacteroides. Discussion and Summary Participants in the Travelan group have a more stable gastrointestinal microbiota over the treatment time period when compared with the Placebo group. Alpha diversity, a measurement of the richness (how many different species) and evenness (abundance or number of different species) revealed that the Travelan group had improved richness and Shannon diversity results compared to the Placebo group. The data indicated a difference in the richness in the diversity of certain species rather than just the abundance or number of bacterial species between the two groups. Statistically significant differences were identified between the two treatment groups in the Beta diversity tests (number of species and abundance). The Travelan 5 group was found to have statistically significant changes for the unweighted UniFrac. This indicates that Travelan had a significant effect when it was first introduced during the Study and had an effect on the microbial community. It also confirms that the presence or absence of bacterial species is the main driver of the fluctuation in the microbial community of the Travelan group, which was observed in the Alpha diversity 10 results. Unweighted UniFrac results examining the Travelan and Placebo groups in relation to diarrhea symptoms found there was a statistically significant result for the Travelan between None and Mild but there are no further statistically significant changes. This could indicate a more stable microbial community even when diarrhea symptoms are present. 15 To investigate the statistically significant differences in the microbial communities between the Travelan and Placebo groups identified in the Beta diversity testing, relative abundance graphs were generated. The relative abundance results revealed that the Travelan group had increased levels of beneficial bacteria such as Akkermansia, Pseudobutyrivibrio and Faecalibacterium which are associated with repairing the 20 intestinal lining and producing short chain fatty acids. The relative abundance over time also revealed that the Travelan group’s microbiota had an improved microbial community recovery post Challenge and Antibiotic timepoints compared to the Placebo group. This fluctuation in the gastrointestinal microbiota in the Travelan group towards an increase in beneficial bacteria post the Challenge and Antibiotic days is a promising 25 result. The differential abundance results confirmed increases in Agathobaculum, Slackia, the Eubacterium eligens group, and the Eubacterium siraeum group; and decreases in Rumminococcus and Bacteroides. The abundance data indicates a possible link between the species of bacteria associated with reduced inflammation. 30 Rumminococcus is a common genus in the gastrointestinal microbiota and is associated with increased inflammation in the gut as it aids in the modulation of pro-inflammatory cytokines. Beneficial species Agathobaculum and Pseudobutyrivibrio play a crucial role in maintaining balanced gut microbiota and enhancing intestinal mucosal barrier function. Slackia, and Eubacterium siraeum groups are beneficial gastrointestinal genera associated with a decreased risk for obesity and an increase in short chain fatty acid production. Eubacterium eligens group is also a beneficial bacteria that is a key member of healthy human colonic microbiota associated with decreasing inflammation in the intestines. Increase in genera such as Akkermansia could aid in repairing the 5 intestinal lining. This study data implies that Travelan appears to aid in the reduction and clearance over time of pathological ETEC bacteria, by shortening the recovery period after ETEC challenge. The mechanism indicates there is an increase in the propagation of bacteria associated with decreases in inflammation and repairing the intestinal lining. 10 Example 12: Two dose study Study Design A randomized, double-blind, placebo-controlled study is proposed to be conducted to investigate whether twice-daily dosing with Travelan® (1,200 mg) 15 maintains normal gut function during travel to high-risk areas in healthy adult volunteers. Enrolment of 868 deployed military personnel or travellers will occur at sites within the Uniformed Services University of the Health Sciences (USU) Infectious Disease Clinical Research Program (IDCRP) network and the UK military. Subjects will be randomized to receive a masked regimen of Travelan® or placebo taken as 1 sachet twice daily with 20 meals. Triple masking will be applied (participant, care provider, investigator). Chemoprophylaxis will be started 2 days prior to arrival and maintained for a maximum duration of 20 days (minimum of 10 days) during travel or deployment. Stool smears collected during travel will be used for evaluating the microbiome and for gut pathogen identification. Paired (pre and post-supplement administration) sera and stool samples 25 (pre- and post-supplement administration) will be collected for testing of exploratory objectives. ce f o Primary Endpoint (Efficacy) The primary efficacy endpoint is the combined endpoint of: ^ incidence of GH disruption (defined as 3 or more unformed stools in a 24-hour 5 period) OR ^ 2 or more unformed stools and one or more associated symptoms (nausea, vomiting, abdominal pain or cramps, fever, bloody stool) in a 24-hour period OR ^ antibiotic treatment for diarrhea per subject report, during the period of prophylaxis. 10 Primary endpoint data will be obtained from review of the Travel Diary. Secondary Objectives Secondary endpoints will include an evaluation of compliance with each dietary supplement and tolerability (e.g. taste, bloating, flatulence, etc.); these will be assessed 15 using the Travel Diary. Differences in GH associated enteropathogen distribution among the 2 treatment groups will be determined by testing stool smears collected by subjects during a GH deficit using a polymerase chain reaction (PCR) assay. Exploratory objectives related to changes in the gut microbiome with dietary supplement use and proteomic signatures of the host-pathogen interaction will be addressed contingent on 20 the availability of additional funding. Outcome Measures Outcome Measure Measure Description Time Frame Combined endpoint of incidence of GH deficiencies (defined as 3 or more unformed stools in a 24-hour period) OR 2 or more unformed stools and one or more associated symptoms (nausea, vomiting, abdominal pain, fever, bloody stool) in a 24-hour period OR antibiotic Incidence of gut treatment for diarrhea per subject report, up to 20 health deficiencies during the period of prophylaxis. days Inclusion Criteria 1. 18-70 years old, able to read and speak English fluently and provide informed 5 consent. 2. Travel or deployment with minimum of 10 consecutive days at intermediate to high risk for GH disruption destination (not counting quarantine period). 3. Ability to complete a follow-up visit following return from travel. 4. Ability to provide a stool sample prior to start of prophylaxis. 10 5. Willingness to comply with study procedures. Exclusion Criteria 1. Subject-reported history of any known functional bowel disorder (including Irritable Bowel Syndrome) or chronic gastrointestinal disease (e.g. Inflammatory Bowel Disease) which in the opinion of the investigator would preclude 15 assessment of study outcomes. 2. Antibiotic use within 7 days prior to start of prophylaxis (except for malaria prophylaxis including doxycycline, chloroquine, atovaquone / proguanil, mefloquine, primaquine, and tafenoquine). 3. Experiencing diarrheal illness (defined as 3 or more loose / liquid stools in a 24 20 hour period) within 3 days prior to start of prophylaxis. 4. Planned use of any investigational or non-registered drug, antibiotic or other probiotics or prebiotics (outside of the study product) during the study period. This does not include consumption of yogurt products. 5. Intended use of a GH disruption prophylactic (e.g. Pepto-Bismol, rifaximin) 25 during the study period. 6. Any planned medication usage during the study period that is deemed by the PI to interfere with GI function including but not limited to anti-diarrheals and prokinetics. 7. Any confirmed or suspected cancer, or use of immunosuppressant medication 5 (topical steroids are permitted) in the last 6 months which in the opinion of the investigator would impair interpretation of the study data.

[0007] REFERENCES Ahren et al. (1998) Infect Immun, 3311-6. Ashida et al. (2015) Front Immunol, 6:219. Bartsch and Lee (2014) Hum Vaccin Immunother, 10:1568-81. 5 Bloom and Canning (2000) Science, 287:1207-1209. Connor and Farthing (1999) J R Army Med Corps, 145:95-101. Connor and Riddle (2013) J Travel Med, 20:303-12. Connor et al. (2012) Curr Opin Infect Dis, 25:546-54. Coster et al. (1999) Infect Immun, 67:3437-43. 10 Curry et al. (2010) BMC Infect Dis, 10:266. Evans et al. (1977) Infect Immun, 330-7. Fasano et al. (1997) Gut, 40(4):505-11. GBD 2016 Diarrhoeal Disease Collaborators (2018) Lancet Infect Dis, 18:1211-1228. Gore et al. (2023) Infect. Immun, 91: e00097-23. 15 Harro et al. (2011) Clin Vaccine Immunol, 18:1719-27. Hurley et al. (2011) Nutrients, 3(4):442-74. Islam et al. (2014) APMIS, 122:463-75. Islam et al. (2016) Immunology, 147:178-89. Katakura et al. (1990) APMIS, 98(4):313-9. 20 Morton et al. (1985) Vet Rec.116:431-6. Olson et al. (2019) Trop Dis Travel Med Vaccines, 5:1. Otto et al. (2011) Scandinavian Journal of Gastroenterology, 46:862–868. Porter et al. (2017) Mil Med, 182:4-10. Riddle et al. (2006) Am J Trop Med Hyg, 74: 891-900. 25 Sack et al. (1997) Infect Immun, 65:2107-11. Scallan et al. (2011) Emerg Infect Dis, 17:7-15. Steffen (2017) J Travel Med, 24:S2-S5. Svennerholm et al (1983) J Infect Dis; 514-22.21 Turbyfill et al. (2000) Infect Immun.68:6624-32. 30 Turbyfill et al. (2018) mSphere, 3: e00583-17. Vaisman et al. (2003) Cytokine, 22(6):194-7. Venkatesan et al. (1988) Proc Natl Acad Sci U S A, 85:9317-21. Warny et al. (1999) Gut, 44(2):212-7 35

Claims

CLAIMS 1. A method of preventing, treating, or reducing frequency or clinical severity of one or more symptoms of, a gastrointestinal condition or disorder caused by a 5 gastrointestinal infection in a subject, comprising administering a composition comprising hyperimmune colostrum or a fraction thereof comprising hyperimmune antibodies, wherein the hyperimmune colostrum or fraction thereof is administered as a single dosage per day of at least about 200 mg per dose. 10 2. The method of claim 1, wherein the gastrointestinal condition or disorder caused by a Gram negative bacterial infection in the subject.

3. The method of claim 1 or claim 2, wherein the method reduces frequency or clinical severity of one or more symptoms of the gastrointestinal condition or 15 disorder within 72 hours, 48 hours, 36 hours or 24 hours of administration of the composition.

4. The method of any one of claims 1 to 3, wherein the reduction in clinical severity of the one or more symptoms is represented by a reduction in a clinical score of 20 diarrhea or one or more biomarkers of gut inflammation.

5. The method of any one of claims 1 to 4, wherein the gastrointestinal condition or disorder is selected from the group consisting of: inflammatory bowel disease, irritable bowel syndrome (IBS), gastroenteritis, dysentery, food poisoning and 25 traveller’s diarrhea.

6. The method of claim 5, wherein the inflammatory bowel disease is ulcerative colitis or Crohn’s disease. 30 7. A method of decreasing gut inflammation in a subject, comprising administering a composition comprising hyperimmune colostrum or a fraction thereof comprising hyperimmune antibodies, wherein the hyperimmune colostrum or fraction thereof is administered as a single dosage per day of at least about 200 mg per dose.

8. A method of improving at least one biomarker of gut health of a subject, comprising administering a composition comprising hyperimmune colostrum or a fraction thereof comprising hyperimmune antibodies, wherein the hyperimmune colostrum or fraction thereof is administered as a single dosage per day of at least about 200 5 mg per dose.

9. The method of any one of claims 1 to 8, wherein the method reduces colonization of one or more genus of Gram negative bacteria selected from the group consisting of: Enterobacteriaceae, Enterobacter, Escherichia, Klebsiella, Bacteroid, 10 Shigella, Salmonella, Campylobacter, Helicobacter, Vibrio, Yersinia, Rumminococcus and Aeromonas.

10. The method of any one of claims 1 to 9, wherein the method reduces colonization of one or more species of Gram negative bacteria selected from the group 15 consisting of: E. coli., E. albertii, E. fergusonii, E. hermannii, E. ruysiae, E. marmotae, C. jejuni, C. coli, C. lari, C. upsaliensis, Salmonella enterica, Salmonella bongori, Vibrio cholerae, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, and Shigella boydii. 20 11. The method of any one of claims 1 to 10, wherein the method reduces the levels of one or more cytokines or chemokines in the subject selected from the group consisting of: IL-1β, IL-6, IL-8, calprotectin and Myeloperoxidase (MPO).

12. The method of any one of claims 1 to 11, wherein the hyperimmune colostrum or a 25 fraction thereof comprises antibodies which bind to one or more genus of Gram negative bacteria selected from the group consisting of: Enterobacteriaceae, Enterobacter, Escherichia, Klebsiella, Bacteroid, Salmonella, Campylobacter, Helicobacter, Vibrio, Shigella, Yersinia, Rumminococcus and Aeromonas. 30 13. The method of any one of claims 1 to 12, wherein the antibodies bind to two, three, or four species of Gram negative bacteria.

14. The method of any one of claims 1 to 13, wherein the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to one or more species of Gramnegative bacteria selected from the group consisting of: E. coli., E. albertii, E. fergusonii, E. hermannii, E. ruysiae, E. marmotae, C. jejuni, C. coli, C. lari, C. upsaliensis, Salmonella enterica, Salmonella bongori, Vibrio cholerae, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, and Shigella boydii. 5 15. The method of claim 14, wherein the Gram negative bacteria is E. coli.

16. The method of claim 15, wherein the E. coli comprises one or more or all of Enterotoxigenic E. coli (ETEC), Enterohemorrhagic E. coli (EHEC) and 10 Enteropathogenic E. coli (EPEC).

17. The method of any one of claims 1 to 16, wherein the hyperimmune colostrum was prepared by immunizing a host animal with a vaccine composition comprising one or more antigens selected from the group consisting of: E. coli O group serotype, 15 Shigella spp. LPS, Shigella spp. toxins and invasion plasmid antigen (Ipa) proteins.

18. The method of claim 17, wherein the hyperimmune colostrum was prepared by immunizing a host animal with a vaccine composition comprising one or more E. coli O group serotype antigens selected from the group consisting of: O6, O8, O15, 20 O25, O27, O63, O78, O114, O115, O128, O148, O153, and O159.

19. The method of any one of claims 1 to 18, wherein the hyperimmune colostrum or a fraction thereof comprises colostrum antibodies which bind to one or more antigens selected from the group consisting of: E. coli O group serotype, Shigella 25 spp. LPS, Shigella spp. toxins and invasion plasmid antigen (Ipa) proteins.

20. The method of claim 19, wherein the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to one or more E. coli O group serotype antigens selected from the group consisting of: O6, O8, O15, O25, O27, O63, O78, O114, 30 O115, O128, O148, O153, and O159.

21. The method of any one of claims 1 to 20, wherein the hyperimmune colostrum or a fraction thereof comprises antibodies which bind to one or more Shigella spp.serotype antigens selected from the group consisting of: S. dysenteriae 1, S. flexneri 2a, S. flexneri 3a, S. flexneri 6 and S. sonnei.

22. The method of any one of claims 1 to 21, wherein the hyperimmune colostrum or a 5 fraction thereof comprises antibodies which bind to one or more Shigella spp. toxins selected from the group consisting of: Shigella enterotoxin 1 (ShET-1), Shigella enterotoxin 2 (ShET-2) and Shiga toxin (Stx).

23. The method of any one of claims 1 to 22, wherein the hyperimmune colostrum or a 10 fraction thereof comprises antibodies which bind to one or more Ipa protein antigens selected from the group consisting of: IpaA, IpaB, IpaC and IpaD.

24. The method of any one of claims 1 to 23, wherein the subject is a human. 15 25. The method of any one of claims 1 to 24, wherein the composition is administered by oral administration.

26. The method of any one of claims 1 to 25, wherein the composition is in the form of a tablet, capsule, powder, syrup, lozenge or food additive. 20 27. The method of any one of claims 1 to 26, wherein the dose of the hyperimmune colostrum or fraction thereof is about 200 mg, about 400 mg, about 600 mg, about 800 mg, about 1,000 mg, about 1,200 mg, about 1,400 mg, about 1,600 mg, about 1,800 mg, about 2,000 mg, about 3,000 mg, about 4,000 mg, about 5,000 mg, 25 about 6,000 mg, about 7,000 mg, about 8,000 mg, about 9,000 mg, about 10,000 mg, about 200 mg to about 10,000 mg, about 200 mg to about 5,000 mg, about 200 mg to about 2,000 mg, about 200 mg to about 1,000 mg, about 600 mg to about 1,500 mg, about 800 mg to about 1,200 mg or about 200 mg to about 800 mg. 30 28. The method of any one of claims 1 to 27, wherein the dose of the hyperimmune colostrum or fraction thereof is about 1,200 mg.

29. The method of any one of claims 1 to 28, wherein the composition is administered for one week, two weeks, three weeks, four weeks, five weeks, six weeks, one month, two months, three months, four months, five months or six months. 5 30. The method of any one of claims 1 to 29, wherein the hyperimmune colostrum is bovine hyperimmune colostrum.

31. Use of hyperimmune colostrum or a fraction thereof comprising hyperimmune antibodies in the manufacture of a medicament for preventing, treating, or reducing 10 frequency or clinical severity of one or more symptoms of, a gastrointestinal condition or disorder caused by a gastrointestinal infection in a subject, wherein the medicament will be administered at a single dosage per day of at least about 200 mg per dose. 15 32. Use of hyperimmune colostrum or a fraction thereof comprising hyperimmune antibodies in the manufacture of a medicament for decreasing gut inflammation in a subject, wherein the medicament will be administered at a single dosage per day of at least about 200 mg per dose. 20 33. Use of hyperimmune colostrum or a fraction thereof comprising hyperimmune antibodies in the manufacture of a medicament for improving at least one biomarker of gut health of a subject, wherein the medicament will be administered at a single dosage per day of at least about 200 mg per dose. 25 34. The use of any one of claims 31 to 33, wherein the medicament comprises about 600 mg or about 1,200 mg per dose.

35. A composition comprising a hyperimmune colostrum or a fraction thereof comprising hyperimmune antibodies for preventing, treating, or reducing frequency 30 or clinical severity of one or more symptoms of, a gastrointestinal condition or disorder caused by a gastrointestinal infection in a subject by administration of the hyperimmune colostrum or fraction thereof at a single dosage per day of at least about 200 mg per dose.

36. A composition comprising a hyperimmune colostrum or a fraction thereof comprising hyperimmune antibodies for decreasing gut inflammation in a subject by administration of the hyperimmune colostrum or fraction thereof at a single dosage per day of at least about 200 mg per dose. 5 37. A composition comprising a hyperimmune colostrum or a fraction thereof comprising hyperimmune antibodies for improving at least one biomarker of gut health in a subject by administration of the hyperimmune colostrum or fraction thereof at a single dosage per day of at least about 200 mg per dose. 10 38. The composition of any one of claims 35 to 37, comprising about 600 mg or about 1,200 mg per dose.

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