Use of live attenuated Salmonella Typhimurium bacteria for the manufacture of a vaccine composition

Abstract

The present invention relates to the use of live attenuated Salmonella Typhimurium bacteria for the manufacture of a vaccine composition intended to reduce the severity of symptoms associated with Salmonella Choleraesuis infection and / or to prevent Salmonella Choleraesuis infection in a pig, wherein the live attenuated Salmonella Typhimurium bacterium is the sole active ingredient of the vaccine composition.

Description

Title of the invention: Use of live attenuated Salmonella Typhimurium bacteria for the manufacture of a vaccine composition Scope of the invention

[0001] The present invention relates to the field of vaccination and concerns the use of a vaccine composition comprising live attenuated Salmonella Typhimurium bacteria for cross-protection against another serotype of Salmonella, in particular against Salmonella Choleraesuis. Context of the invention

[0002] Porcine salmonellosis is one of the most economically important enteric and septicemic diseases affecting young pigs. Of the 2,400 Salmonella serotypes, two host-adapted serotypes infect pigs: Salmonella choleraesuis and Typhisuis, while the non-host-adapted serotypes Typhimurium and Salmonella derby play a major role in infections in pigs. Salmonellosis is clinically characterized by one or more of the following three main symptoms: septicemia, acute enteritis, and chronic enteritis. The prevalence of infection varies among species and countries and is much higher than the incidence of clinical disease, which is generally precipitated by stressful situations such as sudden feed deprivation, transport, drought, overcrowding, farrowing, and the administration of certain medications.

[0003] Septicemic salmonellosis is often associated with Salmonella choleraesuis. Salmonella choleraesuis is a Gram-negative bacterium that generally affects growing pigs less than 5 months old by colonizing the intestinal tract, particularly the colon. The main route of transmission is fecal-oral, as the bacteria are rapidly excreted during infection and for up to 5 months post-infection. Generally, Salmonella choleraesuis causes septicemia in weaned pigs less than 5 months old. Occasionally, pigs of other ages may be affected. The duration of the disease is highly variable. The first symptom observed in infected pigs is fever, accompanied by lethargy and anorexia. The morbidity rate is approximately 10%, but cases tend to be fatal. Sudden death is therefore quite common, with pigs showing signs of cyanosis in their extremities: blue ears are often observed.In the days following infection, yellow diarrhea and a cough may be observed.

[0004] The clinical signs, severity, and duration of Salmonella choleraesuis infection can be reduced by aggressive antimicrobial therapy from the onset of the disease. Medications such as apramycin, ceftiofur, trimethoprim-sulfamethoxazole, or gentamicin can be used. However, it is important to monitor for antimicrobial resistance, which is common in all strains of Salmonella.

[0005] Therefore, robust and effective vaccination strategies are needed to prevent or reduce the resurgence of Salmonella choleraesuis in herds. Summary of the invention

[0006] In working on the development of a vaccination strategy to protect pigs against salmonellosis, the inventors have shown that a live avirulent vaccine containing the bacterium Salmonella Typhimurium can be used effectively to protect pigs, and in particular piglets, against infection by Salmonella Choleraesuis. More surprisingly, the inventors have shown that vaccination with a live avirulent vaccine containing the bacterium Salmonella Typhimurium reduces the mortality rate and / or improves the average daily weight gain (ADWG) of piglets in a herd experiencing a Salmonella Choleraesuis outbreak.

[0007] The present invention also provides for the use of live attenuated Salmonella Typhimurium bacteria for the manufacture of a vaccine composition intended to reduce the severity of symptoms associated with Salmonella Choleraesuis infection and / or to prevent Salmonella Choleraesuis infection in a pig.

[0008] Advantageously, the use consists solely of the administration of said vaccine composition.

[0009] In one particular embodiment, the use consists of a single administration of the vaccine composition comprising a live attenuated Salmonella Typhimurium bacterium. In another particular embodiment, the use consists of repeated administrations, i.e., two or more times, of the vaccine composition comprising a live attenuated Salmonella Typhimurium bacterium.

[0010] Preferably, live attenuated Salmonella Typhimurium is the sole active ingredient in the vaccine composition. Preferably, live attenuated Salmonella Typhimurium is the sole active ingredient, or antigen, in the vaccine composition.

[0011] In particular, the symptoms associated with Salmonella Choleraesuis infection are chosen from among the increased mortality rate and the negative impact on average daily weight gain (ADWG).

[0012] The purpose of this description is therefore to propose a vaccine composition comprising live attenuated Salmonella Typhimurium bacteria for use in a method aimed at reducing the severity of symptoms associated with infection by Salmonella Choleraesuis and / or to prevent Salmonella Choleraesuis infection in a pig.

[0013] In particular, the present description is intended to provide a vaccine composition comprising a live attenuated Salmonella Typhimurium bacterium for use in a method for reducing the severity of symptoms associated with Salmonella Choleraesuis infection and / or preventing Salmonella Choleraesuis infection in a pig, wherein the live attenuated Salmonella Typhimurium bacterium is the sole active ingredient of the vaccine composition, and wherein the method for reducing the severity of symptoms associated with Salmonella Choleraesuis infection and / or preventing Salmonella Choleraesuis infection in a pig consists of administering said vaccine composition.

[0014] In a particular embodiment, the method for reducing the severity of symptoms associated with Salmonella Choleraesuis infection and / or preventing Salmonella Choleraesuis infection in a pig consists of a single administration of the vaccine composition comprising a live attenuated Salmonella Typhimurium bacterium.

[0015] In another particular embodiment, the method for reducing the severity of symptoms associated with Salmonella Choleraesuis infection and / or preventing Salmonella Choleraesuis infection in a pig consists of repeated administrations, i.e. two or more times, of the vaccine composition comprising a live attenuated Salmonella Typhimurium bacterium.

[0016] Another object of the present description is to provide a method for reducing the severity of symptoms associated with Salmonella Choleraesuis infection and / or for preventing Salmonella Choleraesuis infection in a pig, wherein a vaccine composition comprising live attenuated Salmonella Typhimurium bacteria is administered to that pig.

[0017] Advantageously, the method for reducing the severity of symptoms associated with Salmonella Choleraesuis infection and / or preventing Salmonella Choleraesuis infection in a pig consists of administering said vaccine composition.

[0018] In one particular case, the method consists of a single administration of the vaccine composition comprising a live attenuated Salmonella Typhimurium bacterium. In another particular embodiment, the method consists of repeated administrations, that is, two or more times, of the vaccine composition comprising a live attenuated Salmonella Typhimurium bacterium.

[0019] In a particular embodiment, the vaccine composition is administered to piglets aged up to 6 weeks. Preferably, the vaccine composition is administered to piglets at 3 days of age or later, for example between 3 days and 6 weeks. In particular, the vaccine composition may be administered twice to a piglet between the age of 3 days, + / - 1 day, and the age of 4 weeks, + / - 7 days. The latency period between the two administrations is, for example, 3 weeks, + / - 3 days.

[0020] The vaccine composition can be administered orally or parenterally. Preferably, the vaccine composition is administered orally, for example via drinking water.

[0021] The present invention is particularly suited to pigs, especially piglets, from a herd affected by an outbreak of Salmonella choleraesuis. For example, the present invention can be implemented with pigs seropositive for Salmonella, such as pigs seropositive for Salmonella choleraesuis, and in particular piglets seropositive for Salmonella choleraesuis. In a particular embodiment, the present invention can be implemented with piglets having maternally derived anti-Salmonella antibodies.

[0022] Advantageously, vaccinated piglets exhibit an increase in average daily gain (ADG) during the fattening period compared to unvaccinated pigs from a herd affected by an outbreak of Salmonella choleraesuis. Alternatively, or in addition, vaccinated piglets may exhibit a decrease in mortality during the rearing and / or fattening period.

[0023] According to the invention, the vaccine composition is also effective for the treatment and / or prophylaxis of Salmonella Typhimurium infection.

[0024] In one case, the vaccine composition comprises between 5.108 and 5.109 CFU of bacteria per dose.

[0025] In one embodiment, the live attenuated bacterium Salmonella Typhimurium includes a histidine-adenine auxotrophy.

[0026] In one case, the Salmonella Typhimurium bacterium is Salmonella Typhimurium of strain 421 / 125.

[0027] In a particular case, the live attenuated bacterium Salmonella Typhimurium is a non-recombinant bacterium. Brief description of the figures

[0028] [Fig.1] [Fig.1]: Average mortality rate during nursery (i.e. from birth to about 80 days) and fattening (i.e. from about 80 days to slaughter) of unvaccinated and vaccinated piglets from a herd affected by an outbreak of SalmonellaCholeraesuis.

[0029] [Fig.2] [Fig.2]: Average GPMD during nursery (i.e. from birth to about 80 days) and fattening (i.e. from about 80 days to slaughter) of unvaccinated and vaccinated piglets from a herd affected by an outbreak of SalmonellaCholeraesuis, in g / day. Detailed description of the invention

[0030] The present invention is based on the discovery that a vaccine composition comprising exclusively live attenuated Salmonella Typhimurium as the active ingredient can be used effectively to protect pigs against infection by another Salmonella serotype, in particular against Salmonella choleraesuis infection. More specifically, the inventors have shown that vaccinating piglets with a vaccine composition based on live attenuated Salmonella Typhimurium reduces the mortality rate and / or increases the average daily weight gain of vaccinated piglets compared to unvaccinated piglets. Vaccination can be carried out on infected or uninfected piglets. Advantageously, vaccination is implemented in a herd experiencing a Salmonella choleraesuis outbreak.In other words, animals, particularly pigs and piglets, may be infected, for example, clinically or subclinically infected, or uninfected at the time of vaccination. Vaccination protects vaccinated animals against Salmonella choleraesuis, that is, it prevents infection and / or reduces the severity of symptoms associated with Salmonella choleraesuis infection. Advantageously, the vaccination regimen of the present invention consists exclusively of administering the vaccine composition described above.In other words, protection or prevention against Salmonella choleraesuis infection and / or a reduction in the severity of symptoms associated with Salmonella choleraesuis infection is achieved without the administration of a vaccine composition comprising the Salmonella choleraesuis antigen, either whole-cell Salmonella choleraesuis bacteria (attenuated or inactivated), or recombinant and / or isolated Salmonella choleraesuis antigen. According to the present invention, pigs do not receive any Salmonella choleraesuis antigens at all.

[0031] Definitions

[0032] In this document, the term "Salmonella Choleraesuis" refers to Salmonella enterica serotype Choleraesuis. The term "Salmonella Typhimurium" refers to Salmonella enterica serotype Typhimurium.

[0033] In this document, the terms "treatment," "treat," or "manage" refer to any action intended to improve the health status of subjects, particularly pigs, including piglets, such as therapy, prevention, prophylaxis, and delay of disease, especially bacterial infection. In some cases, these terms refer to the improvement or eradication of the disease or its associated symptoms. In other cases, the term refers to minimizing the spread or worsening of the disease resulting from the administration of one or more therapeutic agents to an subject suffering from such a disease.

[0034] In this document, the term "therapeutic effect" means an effect induced by a vaccine composition according to the invention, capable of preventing or delaying the onset of a disease, or of curing or alleviating the effects of a disease.

[0035] The terms "quantity", "amount" and "dose" are used interchangeably in this document and may refer to an absolute quantification of a molecule or a bacterium.

[0036] The term "attenuated bacterium" or "avirulent bacterium" used herein refers to a modified bacterial cell whose virulence has been reduced or weakened but which remains capable of eliciting an immune response, for example, a humoral or cellular response, in an animal subject administered a composition comprising the attenuated bacterial cell. The attenuated bacterial cells according to the invention are live bacteria.

[0037] The terms "vaccine" or "vaccine composition" used herein refer to a composition that can be used to provoke, stimulate or amplify an immune response in an organism, administered for the prevention, improvement or treatment of infectious diseases.

[0038] An "immune response" refers to the development in a host of a cellular and / or antibody-mediated immune response. Typically, an "immune response" includes the production of antibodies, B cells, helper T cells, and / or cytotoxic T cells, specifically directed against one or more antigens of interest. Preferably, the immune response is protective, such that resistance to reinfection is enhanced and / or the clinical severity of the disease is reduced. For the vaccine according to the invention, the immune response induced in the vaccinated target animal, for example, has the effect of reducing Salmonella choleraesuis infection. This involves a reduction in the level or extent of the infection, for example, by reducing the bacterial load or shortening the duration of bacterial replication in the host animal.This effect is achieved, for example, by preventing or reducing the establishment or proliferation of a productive Salmonella choleraesuis infection in its target organs. This results in a reduction, in the target animal, of the number, intensity, or severity of lesions and clinical signs that could be caused by the bacterial infection. A person skilled in the art can determine the efficacy of a vaccine according to the invention in reducing Salmonella choleraesuis infection. For example, this determination can be made by monitoring the immunological response after vaccination or after a challenge infection, for example, by monitoring the target animals' signs of disease, clinical scores, serological parameters, or by re-isolating the pathogen, and by comparing these results to a vaccination-defense response observed in sham vaccinated animals.

[0039] In the context of the invention, the expression "between x and y" means that the values ​​x and y are included.

[0040] In the context of the invention, the term "approximately" means the given value plus or minus 10%.

[0041] Vaccine composition

[0042] The present invention aims to provide a vaccine composition, comprising a live attenuated bacterium Salmonella Typhimurium as the sole active ingredient or antigen of said vaccine composition, for use in protecting pigs against Salmonella Choleraesuis. Indeed, the inventors have discovered that the live attenuated bacterium Salmonella Typhimurium can be effective against Salmonella Choleraesuis infection.

[0043] Any attenuated Salmonella Typhimurium bacterium can be used as an active ingredient in the vaccine composition. Advantageously, the Salmonella Typhimurium bacterium is not a recombinant bacterium, that is, it does not contain foreign nucleic acids encoding a foreign polypeptide or antigen. Thus, the Salmonella Typhimurium bacterium is preferably a non-recombinant Salmonella Typhimurium bacterium. In a particular case, the live attenuated Salmonella Typhimurium bacterium is doubly attenuated. Preferably, the live attenuated Salmonella Typhimurium bacterium is auxotrophic to histidine-adenine.

[0044] Examples of Salmonella Typhimurium bacteria that can be used for the composition of the vaccine are described in US document 3,856,935.

[0045] In one particular case, the vaccine composition comprises an attenuated isolate of Salmonella Typhimurium registered as 421 / 125 by Impfstoffwerk Dessau-Tomau (IDT), Germany, and derived from the wild-type isolate Salmonella Typhimurium 415 of the Metschnikov Institute, Moscow. The Salmonella Typhimurium 421 / 125 isolate is produced by conventional attenuation chemical mutagenesis (using methylnitroguanidine) and is a modification of isolate 415 with a deletion in the epimerase gene. In a further particular case, the vaccine composition is SALMOPORC®. The production of the Salmonella Typhimurium 421 / 125 isolate is described in the specification of patent DE2843295 C2.

[0046] In one particular case, live attenuated Salmonella Typhimurium bacteria are the only active ingredients in the vaccine composition. In other words, the vaccine composition is free of Salmonella of a serotype other than Salmonella Typhimurium. In a more particular embodiment, the vaccine composition comprises only live attenuated Salmonella Typhimurium bacteria as an active ingredient; that is, Salmonella Typhimurium bacteria are the only ingredients against which an immune response is generated.

[0047] In a particular case, the vaccine composition comprises live attenuated Salmonella Typhimurium bacteria and does not contain Salmonella Choleraesuis antigen.

[0048] In a particular case, the vaccine composition consists of live attenuated Salmonella Typhimurium bacteria and, optionally, a suitable carrier and / or adjuvant.

[0049] According to the present invention, the vaccine composition comprises an effective amount of live attenuated Salmonella Typhimurium bacteria. As used herein, the term "effective amount" refers to the quantity of an active ingredient or vaccine composition that prevents, suppresses, or reduces the deleterious effects of the disease. It is evident that the amount to be administered can be adjusted by a person skilled in the art according to the individual being treated, the nature of the disease, etc. In particular, the doses and administration schedule can be determined by the nature, stage, and severity of the disease being treated, as well as the weight, age, and overall health of the individual being treated, and the veterinarian's judgment.

[0050] In a particular embodiment, the vaccine composition comprises between 5x0A5 and 5x0A10 CFU (colony-forming units) of bacteria per dose, for example between 5x0A6 and 5x0A10 CFU, between 5x0OA7 and 5x0OA9 CFU, between 5x0A6 and 5x0A8 CFU. Preferably, the vaccine composition comprises between 5x0A8 and 5x0OA9 CFU of bacteria per dose.

[0051] The vaccine composition may also include an adjuvant. An "adjuvant" is a compound or combination of compounds that enhances, activates, potentiates, or modulates the quality and / or quantity of the immune response to an antigen. The choice and quantity of adjuvant(s) can be readily determined by those skilled in the art.

[0052] The vaccine may also include other components, such as preservatives and / or stabilizers.

[0053] The vaccine composition of the invention may include an excipient, an adjuvant, or a combination of excipients acceptable from a veterinary perspective. Those competent in the field will recognize that the choice of excipient, adjuvant, or combination will be determined by the route of administration, personal preferences, and the animal species, among other factors.

[0054] Administration of the vaccine composition

[0055] According to the present invention, the vaccine composition can be administered to all pigs, including sows and piglets. In a preferred embodiment, the vaccine composition is administered to piglets.

[0056] Advantageously, the pigs or piglets receive only the vaccine composition of the present invention. This means that the pigs or piglets do not have not been previously vaccinated with another Salmonella vaccine composition, in particular a Salmonella vaccine composition comprising Salmonella Choleraesuis antigens, for example an attenuated or inactivated Salmonella Choleraesuis, and that the pigs or piglets will also not be subsequently vaccinated with another Salmonella vaccine composition.

[0057] In a particular embodiment, the method for reducing the severity of symptoms associated with Salmonella Choleraesuis infection and / or preventing Salmonella Choleraesuis infection in a pig consists of a single administration of the vaccine composition comprising a live attenuated Salmonella Typhimurium bacterium.

[0058] In another embodiment, the method for reducing the severity of symptoms associated with Salmonella choleraesuis infection and / or preventing Salmonella choleraesuis infection in a pig consists of repeated administrations, i.e., two or more times, of the vaccine composition comprising a live attenuated Salmonella Typhimurium bacterium. In a preferred embodiment, the vaccine composition is administered to pigs from a herd with an outbreak of Salmonella choleraesuis. By definition, this herd includes infected animals, for example, clinically or subclinically infected animals, or uninfected animals. In other words, the animals, particularly pigs and piglets, may be infected at the time of vaccination. The vaccine composition may be administered indiscriminately to infected and uninfected pigs.These pigs, particularly piglets, may be seronegative or seropositive for Salmonella. According to the present invention, vaccination protects vaccinated animals against Salmonella choleraesuis, that is, it prevents infection and / or reduces the severity of symptoms associated with Salmonella choleraesuis infection. Vaccination can also treat Salmonella choleraesuis infection in pigs already infected, at least by reducing the severity of symptoms associated with Salmonella choleraesuis infection.

[0059] The vaccine composition can also be administered to pigs from herds free from Salmonella infection. These pigs, particularly piglets, may be seronegative or seropositive for Salmonella.

[0060] In a particular embodiment, the vaccine composition is administered to pigs seropositive for Salmonella, i.e., those with anti-Salmonella antibodies, in particular to piglets seropositive for Salmonella. Pigs seropositive for Salmonella include pigs already infected with Salmonella and / or pigs already vaccinated against Salmonella. In a particular embodiment, the vaccine composition is administered to pigs seropositive for Salmonella Choleraesuis and / or to pigs seropositive for Salmonella Typhimurium, in particularly to piglets seropositive for Salmonella Choleraesuis and / or to piglets seropositive for Salmonella Typhimurium.

[0061] In one embodiment, the vaccine composition is administered to piglets with maternally derived anti-Salmonella antibodies. In particular, the vaccine composition is administered to piglets with maternally derived anti-Salmonella choleraesuis antibodies and / or maternally derived anti-Salmonella Typhimurium antibodies.

[0062] Preferably, the vaccine composition is administered to piglets from a herd affected by a Salmonella choleraesuis outbreak. Vaccination can be carried out on infected or uninfected piglets. Both seronegative and seropositive piglets can be vaccinated.

[0063] Preferably, the vaccine composition is administered to piglets no more than 6 weeks old. In the context of the present invention, a week corresponds to approximately 7 consecutive days. For example, the vaccine composition is administered to piglets 3 days old or older. When several piglets in a herd are vaccinated, the age at vaccination can correspond to the average age of the piglet population.

[0064] Depending on the desired duration and effectiveness of the treatment, the vaccine composition can be administered once or several times, also intermittently, for example on a daily basis for several days, weeks or months, and at different dosages.

[0065] In a particular embodiment, the vaccine composition is administered twice to piglets between the ages of 3 days, + / - 1 day, and 4 weeks, + / - 7 days. For example, the first administration is given at 2, 3, or 4 days of age. The second administration is given at approximately 3, 4, or 5 weeks of age. In a preferred embodiment, the interval between the two administrations is 3 weeks, + / - 3 days. Preferably, the piglets receive one dose of the vaccine composition per administration.

[0066] Preferably, the vaccinated pigs or piglets were not vaccinated against Salmonella Choleraesuis before vaccination with the vaccine composition of the present invention. In particular, the pigs or piglets did not receive a vaccine composition comprising the Salmonella Choleraesuis antigen.

[0067] Preferably, vaccinated pigs or piglets will not receive any vaccine composition comprising the Salmonella Choleraesuis antigen, at least for one month, two months or more, after vaccination with the vaccine composition of the present invention.

[0068] The vaccine composition is administered orally or parenterally. Oral administration includes direct oral administration or oral gavage, and via drinking water, preferably using an automatic dosing device for the entire barn. In a preferred embodiment, administration is by mouth via drinking water.

[0069] In a particular embodiment, the vaccine composition is administered twice via drinking water to piglets from a herd affected by a Salmonella Choleraesuis outbreak. The first administration takes place at 3 days, + / - 1 day of age, and the second at 3 weeks, + / - 3 days of age.

[0070] Therapeutic effects

[0071] According to the present invention, the vaccine composition comprising live attenuated Salmonella Typhimurium is administered to pigs, in particular piglets, in order to prevent infection by Salmonella Choleraesuis or at least to reduce the severity of symptoms associated with infection by Salmonella Choleraesuis.

[0072] In this document, "prevention" or "reduction of the incidence and / or severity of clinical signs" or "reduction of clinical symptoms" means, among other things, reducing the number of infected animals in a group, reducing or eliminating the number of animals showing clinical signs of infection, or reducing the severity of one or more clinical signs present in one or more animals, compared to a wild-type infection. For example, this includes any reduction in pathogen load, pathogen shedding, pathogen transmission, or any symptomatic clinical sign of Salmonella choleraesuis infection. Preferably, these clinical signs are reduced in one or more animals receiving the vaccine composition of the present invention by at least 10% compared to infected animals that do not receive the vaccine composition.More preferably, clinical signs are reduced in animals receiving a composition of the present invention by at least 20%, preferably by at least 30%, more preferably by at least 40%, and even more preferably by at least 50%.

[0073] The term "increased protection" means, but is not limited to, a statistically significant reduction in one or more clinical symptoms associated with Salmonella choleraesuis infection in a group of vaccinated subjects compared to a group of unvaccinated control subjects. The term "statistically significant reduction in clinical symptoms" means, but is not limited to, that the frequency of the incidence of at least one clinical symptom in the group of vaccinated subjects is at least 10%, preferably 20%, preferably 30%, preferably 50%, and preferably 70% lower than that of the unvaccinated control group after Salmonella choleraesuis infection.

[0074] In a preferred embodiment, administration of the vaccine composition described above results in a reduction in the mortality rate and / or a reduction in weight loss associated with Salmonella Choleraesuis infection.

[0075] The vaccination according to the present invention is particularly suitable for preventing infection and / or reducing the severity of symptoms associated with Salmonella choleraesuis infection in piglets. In particular, the vaccination of the present invention makes it possible to significantly reduce the mortality rate and / or the negative impact on ADWG in vaccinated piglets exposed to Salmonella choleraesuis compared to unvaccinated piglets exposed to Salmonella choleraesuis.

[0076] The vaccine composition can also be used to treat Salmonella choleraesuis infection in infected pigs, reducing the severity of symptoms associated with Salmonella choleraesuis infection. In one embodiment, said treatment attenuates, reduces, and / or cures Salmonella choleraesuis infection in pigs, particularly piglets, that receive said vaccine composition. The treatment is selected from the group consisting of reducing signs of diarrhea (excretion), reducing the severity or incidence of clinical signs of Salmonella choleraesuis infection, reducing pig mortality due to Salmonella choleraesuis infection, reducing weight loss associated with Salmonella choleraesuis infection, and combinations thereof. Preferably, the treatment reduces the mortality rate and / or weight loss related to Salmonella choleraesuis infection.

[0077] Advantageously, this treatment can also attenuate, reduce, prevent and / or cure Salmonella Typhimurium infection.

[0078] In one embodiment, the vaccine composition is administered to piglets to reduce the mortality rate associated with Salmonella choleraesuis infection. In particular, administering the vaccine composition to piglets less than 6 weeks old from a herd with an outbreak of Salmonella choleraesuis significantly reduces the mortality rate compared to the mortality rate of unvaccinated piglets from a herd with an outbreak of Salmonella choleraesuis. Advantageously, the mortality rate of vaccinated piglets from a herd affected by an outbreak of Salmonella choleraesuis is similar to the mortality rate of piglets from a herd free of salmonella infection.

[0079] In one embodiment, the mortality rate of vaccinated piglets during the rearing period is reduced compared to the mortality rate of unvaccinated piglets from a herd affected by a Salmonella Choleraesuis outbreak. For example, the mortality rate is reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, or 99% compared to piglets that have not received vaccination. The vaccine composition of the present invention. Alternatively, or in addition, the mortality rate of vaccinated piglets during the fattening period can also be reduced compared to the mortality rate of unvaccinated piglets from a herd experiencing a Salmonella Choleraesuis outbreak. For example, the mortality rate is reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, or 99% compared to piglets that have not received the vaccine composition of the present invention. Preferably, the piglets are vaccinated twice, for example, at 3 days, + / - 1 day of age and at 3 weeks, + / - 3 days of age.

[0080] Alternatively or in addition, the vaccine composition is administered to piglets to reduce the negative impact associated with Salmonella choleraesuis infection on average daily weight gain (ADWG). In particular, administering the vaccine composition to piglets less than 6 weeks old from a herd affected by a Salmonella choleraesuis outbreak significantly increases their ADG compared to the ADG of unvaccinated piglets from a herd affected by a Salmonella choleraesuis outbreak. Advantageously, the ADG of vaccinated piglets from a herd affected by a Salmonella choleraesuis outbreak is similar to the ADG of piglets from a herd free of salmonella infection. Preferably, the piglets are vaccinated twice, for example, at 3 days, + / - 1 day of age and at 3 weeks, + / - 3 days of age. Examples

[0081] Experiments were conducted in a closed herd in Poland which experienced an outbreak of Salmonella Choleraesuis with a considerable impact on the health of pigs and production parameters.

[0082] Example 1: vaccination strategy

[0083] Materials and methods

[0084] A herd of 1060 sows in Poland experienced an outbreak of Salmonella choleraesuis. Clinical signs first appeared at the end of the rearing period and continued into the early finishing period. The animals exhibited severe diarrhea, blue ears, ear necrosis, and increased mortality. Necropsy determined whether Salmonella choleraesuis was the cause of the disease (see Example 2 below).

[0085] Four groups of approximately 500 suckling piglets per group from sow herds that had experienced a Salmonella Choleraesuis outbreak were vaccinated (vaccinated groups - VACC). The suckling piglets were vaccinated twice orally with a live vaccine against Salmonella Typhimurium (Salmoporc®, Ceva Animal Health) on days 3 and 21, at a dose of 1 ml of Salmoporc® per dip.

[0086] Four groups of approximately 500 suckled piglets per group from herds of sows affected by the Salmonella Choleraesuis outbreak were not vaccinated (negative groups - NEG).

[0087] Results

[0088] The effectiveness of the vaccination was assessed by evaluating body weight gain and mortality. More specifically, GPA and mortality rate were monitored from birth to the end of the fattening period, corresponding to slaughter age.

[0089] The results are summarized in tables and figures 1 and 2 below.

[0090] [Tables 1] Groups Average birth weight (kg) Average weaning weight (kg) Average weight at end of fattening (kg) Average age at slaughter (days) Average daily gain during nursery (g) Average daily gain during fattening (g) FCR VACC-1 1.4 5.90 117.9 173 465 1039 2.49 VACC-2 1.43 6.10 116.2 179 438 1040 2.61 VACC-3 1.39 6.30 117.3 179 424 1053 2.51 VACC-4 1.42 6.52 118.2 181 484 973 2.46 NEG-1 1.30 6.15 114.8 208 438 745 2.73 NEG-2 1.41 5.95 113.9 209 394 784 2.98 NEG-3 1.36 6.3 115.1 210 405 775 2.82 NEG-4 1.38 6.28 113.2 213 363 799 2.85

[0091] Production parameters from birth to slaughter (end of the fattening period)

[0092] The fattening period ends when the animals reach a certain weight (approximately 117 kg, + / - 5 kg). In this trial, the age of the piglets at the end of the fattening period ("average age at slaughter") was considerably reduced, from approximately 210 days for the unvaccinated groups to approximately 178 days for the vaccinated groups. Consequently, the vaccination of the present invention further improves production parameters, resulting in a shorter time between birth and slaughter.

[0093] It is interesting to note that the feed conversion ratio (FCR), which represents the ratio between the weight of feed given and the weight gain of piglets from birth to slaughter (i.e., feed given / animal weight gain), has also decreased significantly, from 2.845 for the infected-unvaccinated group (NEG) to 2.5175 for the infected-vaccinated group (VACC).

[0094] [Tables2] Groups % Mortality in Nursery % Mortality at Fattening VACC-1 2.26 3.29 VACC-2 1.86 3.62 VACC-3 2.27 3.10 VACC-4 2.79 3.32 NEG-1 5.66 6.60 NEG-2 5.28 7.57 NEG-3 5.49 8.71 NEG-4 6.98 7.80

[0095] Mortality rate

[0096] Another way to create a bulleted list is to start a new paragraph, remove the numbering (None), before creating a new one. During the epidemic, average farm losses were 5.9% in nurseries and 7.8% in fattening herds. After the implementation of vaccination, losses decreased significantly (p<0.001) to 2.3% in nurseries and 3.3% in fattening herds.

[0097] Example 2: Confirmation of a Salmonella Choleraesuis outbreak

[0098] To confirm the presence of Salmonella choleraesuis in the herds, unvaccinated piglets that died during the rearing and fattening period underwent necropsy. Specifically, the organs (liver, kidney, lung, small intestine, and large intestine) of three severely ill animals were examined for the presence of Salmonella. The results are summarized in the table below.

[0099] [Tables3] Choleraesuis Serovar Typhimurium 1st animal / liver POS NEG 1st animal / lung POS NEG 1st animal / small intestine POS NEG 2scd animal / lung POS NEG 2scd animal / small intestine NEG NEG 3rd animal / lung POS NEG 3rd animal / small intestine POS NEG

[0100] Detection of Salmonella, including differentiation of S. Typhimurium and S. Choleraesuis serovars by PCR after culture enrichment.

[0101] In all samples, Salmonella Choleraesuis was detected (serotyping: type C, validation of Salmonella Choleraesuis by PCR).

[0102] In addition, the environment of piglets from different groups during weaning (at 6 and 9 weeks) and the finishing period (at 12, 16, and 20 weeks) was routinely tested for the presence of Salmonella Typhimurium and other Salmonella species that survive in the environment. In infected herds, this method is more useful than individual fecal swabs because animals excrete intermittently, and the prevalence must be very high to detect Salmonella using individual fecal samples. Environmental sampling and assessment of Salmonella status were carried out according to the method described in K. Lillie-Jaschniski et al. 2023 (Animais 2023, 13, 1031 "Sock and Environmental Swabs as an Efficient, Non-Invasive Tool to Assess the Salmonella Status of Sow Farms"). No presence of Salmonella Typhimurium bacteria was reported during these tests.

Claims

Demands

1. Use of live attenuated Salmonella Typhimurium bacteria for the manufacture of a vaccine composition intended to reduce the severity of symptoms associated with Salmonella Choleraesuis infection and / or to prevent Salmonella Choleraesuis infection in a pig.

2. Use according to claim 1, wherein the live attenuated bacterium Salmonella Typhimurium is the sole active ingredient of the vaccine composition

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