Infant formula

Abstract

An infant formula for use in preventing or reducing the occurrence of allergic sensitisation in an infant, wherein the infant formula comprises 0.8-2.5 g / L 2'-fucosyllactose (2'FL) and / or 0.05-0.2 g / L lacto-N-neotetraose (LNnT).

Description

(19) *EP004649837A2* (11) EP 4 649 837 A2 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: 19.11.2025 Bulletin 2025 / 47 (21) Application number: 25198278.1 (22) Date of filing: 28.12.2020 (51) International Patent Classification (IPC): A23L 33 / 00 (2016.01) (52) Cooperative Patent Classification (CPC): A23L 33 / 40 (84) Designated Contracting States: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR (30) Priority: 30.12.2019 EP 19219957 (62) Document number(s) of the earlier application(s) in accordance with Art. 76 EPC: 20841726.1 / 4 084 628 (71) Applicant: Société des Produits Nestlé S.A. 1800 Vevey (CH) (72) Inventors: • BLANCHARD, Carine Le Mont-sur-Lausanne (CH) • HOLVOET, Sébastien Montpreveyres (CH) (74) Representative: Elkington and Fife LLP Prospect House 8 Pembroke Road Sevenoaks, Kent TN13 1XR (GB) Remarks: This application was filed on 26‑08‑2025 as a divisional application to the application mentioned under INID code 62. (54) INFANT FORMULA (57) An infant formula for use in preventing or redu- cing the occurrence of allergic sensitisation in an infant, wherein the infant formula comprises 0.8‑2.5 g / L 2’-fu- cosyllactose (2’FL) and / or 0.05‑0.2 g / L lacto-N-neote- traose (LNnT). EP 4 64 9 83 7 A 2 Processed by Luminess, 75001 PARIS (FR) Description FIELD OF THE INVENTION

[0001] The present invention relates to infant formulas for use in preventing or reducing the occurrence of allergic sensitisation in an infant. In particular, the invention relates to infant formulas comprising 2’-fucosyllactose (2’FL) and / or lacto-N-neotetraose (LNnT). BACKGROUND TO THE INVENTION

[0002] The incidence of allergic diseases such as atopic dermatitis, food allergy and asthma is increasing globally. For example, 300 million people worldwide suffer from asthma, and in the European Union 11‑26 million people have a food allergy (Martins, T.B. et al. (2014) J Allergy Clin Immunol 133: 589‑91).

[0003] There is growing evidence regarding the role of infant gut microbial composition in the immune trajectory and allergy development of the infant host (Quante M. et al. (2012) BMC Public Health 12: 1021). As such, environmental factors such as diet, pollution, urban lifestyle, cleanliness and birthmethod have been associatedwith the development of the immune system and allergic diseases (Seppo, A.E. et al. (2017) J Allergy Clin Immunol 139: 708‑11 e5; Azad, M.B. et al. (2018) J Nutr 148: 1733‑42).

[0004] Breast milk is an immunologically active fluid, which contains a host of components that may modulate the development of the immune system and, in turn, the development of allergic disease. The influence of human milk oligosaccharides (HMOs), the third most abundant component in breast milk, in the development of allergic disease has been of particular interest. HMOsare structurally varied lactose-based complex glycans that include both short‑ and long- chain oligosaccharides. The number (over 200 HMOs have been identified) and structural diversity of HMOs in human breastmilk arenot observed inothermammalianmilks.HMOcomposition is influencedbybothenvironmental andgenetic influences and varies greatly across maternal populations. Synthesised in the mammary glands, HMO quantity in breast milk ranges from about 20.9 g / L in colostrum to 12.9 g / L in mature milk.

[0005] There is some in vitro evidence suggesting that HMOs may modulate the allergic response, and certain HMOs (e.g. 2’-fucosyllactose, 2’FL) have been suggested to decrease allergic response in a food allergy animal model. In addition, association studies have led to the identification of some breast milk levels of HMOs that correlate with milk or food allergy in infants. However, synthetic food gradeHMOs have until recently been unavailable, which has rendered the testing of HMOs on infants in intervention studies impossible.

[0006] In addition, there has remained uncertainty over the identity of particular HMOs that may be beneficial in modulating allergy, and also the levels of the HMOs that may provide for a beneficial effect.

[0007] Humanbreastmilk and breast feeding are considered to be the optimal formof nutrition for healthy infants during the first months of life. However, there is a need for nutritional sources that can be used in addition to breast milk. Furthermore, not all infants can bebreast fed and theneeds ofmore vulnerable infants, such aspreterm infants, cannot be achieved by their mother’s milk, so there is also a need for alternatives to breast milk. Nutritional compositions, such as infant formulas, that satisfy the nutritional requirements of infantsmaybe usedas a substitute for or complement to human breast milk. However, the composition of infant formulas must be carefully controlled to satisfy nutritional requirements, provideacceptable tasteand further aid thedevelopmentof infants, particularlywhen targeted to infantswhoareallergicor at risk of allergy.

[0008] Accordingly, there remains a significant need for nutritional compositions, such as infant formulas, that may be used to prevent or reduce the development of allergies in infants, in particular infant formulas that are effective in the prevention or reduction of allergic sensitisation in infants. SUMMARY OF THE INVENTION

[0009] The present inventors have surprisingly found that intermediate levels of the HMOs 2’-fucosyllactose (2’FL) and lacto-N-neotetraose (LNnT) are most efficacious in the prevention of allergic sensitisation. The inventors have found that levels that are lower or higher than an optimal intermediate dose may be less beneficial.

[0010] The inventorsanalysedHMO levels in thebreastmilk fromacohort ofmothersand identified twoHMOs, 2’FLand LNnT, as associatedwith skin sensitisation or skin rash. In addition, from analysis of the distribution of theHMO levels in a clinically diagnosed population, the inventors found a non-lineal distribution suggesting a beneficial effect of intermediate dosing levels. The inventors then carried out animal model studies, which confirmed that intermediate levels of the HMOs indeed exhibit a more beneficial effect in the prevention of allergic sensitisation when compared to lower or higher doses.

[0011] Accordingly, in one aspect, the invention provides infant formula for use in preventing or reducing the occurrence of allergic sensitisation in an infant, wherein the infant formula comprises 0.8‑2.5 g / L 2’-fucosyllactose (2’FL) and / or 0.05‑0.2 g / L lacto-N-neotetraose (LNnT). 2 EP 4 649 837 A2 5 10 15 20 25 30 35 40 45 50 55

[0012] In another aspect, the invention provides a method for preventing or reducing the occurrence of allergic sensitisation in an infant, wherein the method comprises administering to the infant an infant formula, wherein the infant formula comprises 0.8‑2.5 g / L 2’-fucosyllactose (2’FL) and / or 0.05‑0.2 g / L lacto-N-neotetraose (LNnT).

[0013] In some embodiments, the infant formula comprises 0.8‑1.5 g / L, 0.8‑1.4 g / L, 0.8‑1.3 g / L, 0.8‑1.2 g / L, 0.8‑1.1 g / L, 0.9‑1.1 g / L, or about 1 g / L 2’FL. In some embodiments, the infant formula comprises 0.8‑1.2 g / L 2’FL. In some embodiments, the infant formula comprises 0.9‑1.1 g / L 2’FL.

[0014] In someembodiments, the infant formula comprises1‑1.5 g / L, 1‑1.4 g / L, 1‑1.3 g / L, 1‑1.2g / L, 1‑1.1 g / L, or about 1 g / L 2’FL. In some embodiments, the infant formula comprises 1‑1.1 g / L 2’FL.

[0015] In preferred embodiments, the infant formula comprises about 1 g / L 2’FL.

[0016] In some embodiments, the infant formula comprises 1.5‑2.5 g / L, 1.5‑2.4 g / L, 1.5‑2.3 g / L, 1.5‑2.2 g / L, 1.5‑2.1 g / L, 1.5‑2 g / L, 1.6‑2 g / L, 1.7‑1.9 g / L, or about 1.8 g / L 2’FL. In some embodiments, the infant formula comprises 1.5‑2 g / L 2’FL. In some embodiments, the infant formula comprises 1.7‑1.9 g / L 2’FL.

[0017] In preferred embodiments, the infant formula comprises about 1.8 g / L 2’FL.

[0018] In some embodiments, the infant formula comprises 0.05‑0.15 g / L, 0.06‑0.14 g / L, 0.07‑0.13 g / L, 0.08‑0.12 g / L, 0.09‑0.11 g / L or about 0.1 g / L LNnT. In some embodiments, the infant formula comprises 0.08‑0.12 g / L LNnT. In some embodiments, the infant formula comprises 0.09‑0.11 g / L LNnT.

[0019] In preferred embodiments, the infant formula comprises about 0.1 g / L LNnT.

[0020] In preferred embodiments, the infant formula comprises 2’FL and LNnT.

[0021] In someembodiments, the infant formula comprises about 1.5‑2 g / L 2’FL and about 0.08‑0.12 g / L LNnT. In some embodiments, the infant formula comprises about 1.7‑1.9 g / L 2’FL and about 0.09‑0.11 g / L LNnT. In some embodiments, the infant formula comprises about 1.8 g / L 2’FL and about 0.1 g / L LNnT.

[0022] In some embodiments, the infant formula is an extensively hydrolysed infant formula (eHF). In some embodi- ments, the infant formula is an amino acid-based infant formula (AAF).

[0023] In preferred embodiments, the infant formula comprises protein, carbohydrate and fat.

[0024] In some embodiments, the infant formula comprises: (a) 1.8‑3.2 g protein per 100 kcal; (b) 9‑14 g carbohydrate per 100 kcal; and / or (c) 4.0‑6.0 g fat per 100 kcal.

[0025] In some embodiments, the infant formula comprises about 2.4 g or less protein per 100 kcal.

[0026] In someembodiments, the infant formula comprises 1.8‑2.4 g protein per 100 kcal, 2.1‑2.3 gprotein per 100 kcal, or 2.15‑2.25 g protein per 100 kcal. In preferred embodiments, the infant formula comprises about 2.2 g protein per 100 kcal.

[0027] In some embodiments, about 30% or less by weight of the fat is medium chain triglycerides (MCTs).

[0028] In someembodiments, about 25%or lessbyweight, 20%or less byweight, 15%or less byweight, 10%or lessby weight, 5% or less by weight, or 1% or less by weight of the fat in the infant formula is medium chain triglycerides (MCTs).

[0029] In some embodiments, the infant formula comprises no added MCTs.

[0030] In another aspect, the inventionprovidesan infant formula comprising0.05‑0.2g / L, 0.05‑0.15g / L, 0.05‑0.1g / Lor about 0.1 g / L LNnT, preferably wherein the infant formula comprises about 0.1 g / L LNnT. DESCRIPTION OF THE DRAWINGS

[0031] FIGURE 1 Human milk oligosaccharide (HMO) levels in breast milk of mothers from non-allergic (N=40) and medically diagnosed allergic / atopic infants (N=29). Milk samples were taken at 3 months. The box plots show the median (horizontal line) within the box indicating the 25th and 75th percentiles, the whiskers indicate the 10th and 90th percentile, and circles represent upper and lower 10%. No statistical differences (Q or corrected p>0.05) between HMOs from themilkof thenon-allergic andallergicgroupswere found (non-parametricMann-Whitney-Wilcoxon test). FIGURE 2 Quartile analysis of (A) 2’-fucosyllactose (2’FL) levels (mg / L); and (B) lacto-N-neotetraose (LNnT) (µg / mL) in human breast milk showing differences in distributions between population sub-groups: percent values in green (highlighted withanoval) showstatistically significantpositive results; andpercent values in red (highlightedwitha rectangle) show 3 EP 4 649 837 A2 5 10 15 20 25 30 35 40 45 50 55 negative results. FIGURE 3 Optimal intermediate dosing at 1% of a 2:1 mix of the 2’FL and LNnT (HMO) in the prevention of allergic sensitisation as shown by reduced specific IgG concentrations observed in a mouse model of skin sensitisation.. DETAILED DESCRIPTION OF THE INVENTION

[0032] The terms "comprising", "comprises" and "comprised of" as used herein are synonymous with "including" or "includes":, or "containing" or "contains", and are inclusive or open-ended and do not exclude additional, non-recited members, elementsor steps.The terms "comprising’, "comprises"and "comprisedof"also include the term"consistingof". INFANT FORMULA

[0033] The term "infant formula" may refer to a foodstuff intended for particular nutritional use by infants during the first year of life and satisfying by itself the nutritional requirements of this category of person, as defined in European Commission Regulation (EU) 2016 / 127 of 25 September 2015.

[0034] In some embodiments, the infant formula is an extensively hydrolysed infant formula (eHF).

[0035] In some embodiment the infant formula is a 100% whey based partially hydrolysed formula (pHF),

[0036] In some embodiments, the infant formula is an amino acid-based infant formula (AAF).

[0037] In someembodiments, the formulation is a supplement, that canbemixed intoe.g. an infant formula, ormeal, that does not contain HMOs.

[0038] The term "extensively hydrolysed infant formula" or "eHF" may refer to an infant formula comprising extensively hydrolysed protein. The eHF may be a hypoallergenic infant formula which provides complete nutrition for infants who cannot digest intact cow’s milk protein (CMP) or who are intolerant or allergic to CMP.

[0039] The term "amino acid-based infant formula" or "AAF" may refer to an infant formula comprising only free amino acids as a protein source. The AAFmay contain no detectable peptides. The AAFmay be a hypoallergenic infant formula which provides complete nutrition for infants with food protein allergy and / or food protein intolerance. For example, the AAFmay be a hypoallergenic infant formulawhich provides complete nutrition for infants who cannot digest intact CMPor who are intolerant or allergic to CMP, and who may have extremely severe or life-threatening symptoms and / or sensitisation against multiple foods.

[0040] A "hypoallergenic" composition is a composition which is unlikely to cause allergic reactions. Suitably, the infant formula of the invention is tolerated bymore than 90%of infants with cow’smilk protein allergy (CMPA). This is in line with the guidance provided by the American Academy of Pediatrics (Committee on Nutrition (2000) Pediatrics 106(2): 346‑349). Suitably, the infant formula of the invention may not contain peptides which are recognised by CMP-specific IgE, e.g. IgE from subjects with CMPA.

[0041] ApHFcomposition is a compositionwhich is hydrolysed to reduce exposure the the intactmilk allergen. Suitably, the infant formula of the invention is intended for general infant population for the prevention of allergic diseases.

[0042] Infants can be fed solelywith the infant formula or the infant formula can beusedasa complement of humanmilk.

[0043] The infant formula of the invention may be in the form of a powder or liquid.

[0044] The liquidmay be, for example, a concentrated liquid infant formula or a ready-to-feed infant formula. The infant formula may be in the form of a reconstituted infant formula (i.e. a liquid infant formula that has been reconstituted from a powdered form). The concentrated liquid infant formula is preferably capable of being diluted into a liquid composition suitable for feeding an infant, for example by the addition of water.

[0045] In someembodiments, the infant formula is inapowdered form.Thepowder is capableof being reconstituted into a liquid composition suitable for feeding an infant, for example by the addition of water.

[0046] The infant formula may have an energy density of about 60‑72 kcal per 100 mL, when formulated as instructed. Suitably, the infant formula may have an energy density of about 60‑70 kcal per 100 mL, when formulated as instructed. HUMAN MILK OLIGOSACCHARIDES

[0047] The infant formula of the invention contains at least one of the human milk oligosaccharides (HMOs) 2’- fucosyllactose (2’FL) and / or lacto-N-neotetraose (LNnT).

[0048] Many different kinds of HMOs are found in the human milk. Each individual oligosaccharide is based on a combination of glucose, galactose, sialic acid (N-acetylneuraminic acid), fucose and / or N-acetylglucosamine with many and varied linkages between them, thus accounting for the enormous number of different oligosaccharides in humanmilk. AlmostallHMOshavea lactosemoietyat their reducingendwhile sialicacidand / or fucose (whenpresent) occupy terminal positions at the non-reducing ends. HMOs can be acidic (e.g. charged sialic acid containing oligosaccharides) or neutral 4 EP 4 649 837 A2 5 10 15 20 25 30 35 40 45 50 55 (e.g. fucosylated oligosaccharides).

[0049] The infant formula of the invention comprises 2’-fucosyllactose (2’FL) and / or lacto-N-neotetraose (LNnT).

[0050] In some embodiments, the infant formula comprises 2’FL. In some embodiments, there is no other type of fucosylated oligosaccharide than 2’FL, i.e. the infant formula of the invention comprises only 2’FL as fucosylated oligosaccharide.

[0051] The 2’FL may be produced by biotechnological means using specific fucosyltransferases and / or fucosidases either through the use of enzyme-based fermentation technology (recombinant or natural enzymes) or microbial fermentation technology. In the latter case, microbes may either express their natural enzymes and substrates or may beengineered toproduce respective substratesandenzymes.Alternatively, 2’FLmaybeproducedbychemical synthesis from lactose and free fucose.

[0052] In some embodiments, the infant formula comprises LNnT. In some embodiments, there is no other type of N- acetylated oligosaccharide than LNnT, i.e. the infant formula of the invention comprises only LNnT as N-acetylated oligosaccharide.

[0053] The LNnT may be synthesised chemically by enzymatic transfer of saccharide units from donor moieties to acceptor moieties using glycosyltransferases as described, for example, in US Patent No. 5,288,637 and WO 1996 / 010086. Alternatively, LNnT may be prepared by chemical conversion of Keto-hexoses (e.g. fructose) either free or bound to an oligosaccharide (e.g. lactulose) into N-acetylhexosamine or an N-acetylhexosamine-containing oligo- saccharide as described in Wrodnigg, T.M. and Stutz, A.E. (1999) Angew. Chem. Int. Ed. 38: 827‑828. N-acetyl- lactosamine produced in this way may then be transferred to lactose as the acceptor moiety.

[0054] In some embodiments, the infant formula comprises an oligosaccharide mixture that comprises 2’FL and / or LNnT. In preferred embodiments, the infant formula comprises an oligosaccharidemixture that consists of 2’FL and LNnT. The infant formula of the inventionmay, for example, comprise only 2’FL as fucosylated oligosaccharide and only LNnTas N-acetylated oligosaccharide.

[0055] 2’FLmay, for example, be present in the infant formula in a total amount of 0.8‑2.5 g / L of the infant formula (when formulated as instructed).

[0056] In some embodiments, the infant formula comprises (when formulated as instructed) 0.8‑1.5 g / L, 0.8‑1.4 g / L, 0.8‑1.3 g / L, 0.8‑1.2 g / L, 0.8‑1.1 g / L, 0.9‑1.1 g / L, or about 1 g / L 2’FL. In some embodiments, the infant formula comprises (when formulatedas instructed)0.8‑1.2g / L2’FL. In someembodiments, the infant formulacomprises (when formulatedas instructed) 0.9‑1.1 g / L 2’FL.

[0057] In some embodiments, the infant formula comprises (when formulated as instructed) 1‑1.5 g / L, 1‑1.4 g / L, 1‑1.3 g / L, 1‑1.2 g / L, 1‑1.1 g / L, or about 1 g / L 2’FL. In some embodiments, the infant formula comprises (when formulated as instructed) 1‑1.1 g / L 2’FL.

[0058] In preferred embodiments, the infant formula comprises (when formulated as instructed) about 1 g / L 2’FL.

[0059] In some embodiments, the infant formula comprises (when formulated as instructed) 1.5‑2.5 g / L, 1.5‑2.4 g / L, 1.5‑2.3g / L, 1.5‑2.2g / L, 1.5‑2.1g / L, 1.5‑2g / L, 1.6‑2g / L, 1.7‑1.9g / L, or about 1.8g / L2’FL. In someembodiments, the infant formula comprises (when formulated as instructed) 1.5‑2 g / L 2’FL. In some embodiments, the infant formula comprises (when formulated as instructed) 1.7‑1.9 g / L 2’FL.

[0060] In preferred embodiments, the infant formula comprises (when formulated as instructed) about 1.8 g / L 2’FL.

[0061] LNnT may, for example, be present in the infant formula in a total amount of 0.05‑0.2 g / L of the infant formula (when formulated as instructed).

[0062] In some embodiments, the infant formula comprises (when formulated as instructed) 0.05‑0.15 g / L, 0.06‑0.14 g / L, 0.07‑0.13 g / L, 0.08‑0.12g / L, 0.09‑0.11g / L or about 0.1 g / L LNnT. In someembodiments, the infant formula comprises (when formulated as instructed) 0.08‑0.12 g / L LNnT. In some embodiments, the infant formula comprises (when formulated as instructed) 0.09‑0.11 g / L LNnT.

[0063] In preferred embodiments, the infant formula comprises (when formulated as instructed) about 0.1 g / L LNnT.

[0064] In preferred embodiments, the infant formula comprises 2’FL and LNnT.

[0065] In some embodiments, the infant formula comprises (when formulated as instructed) about 0.8‑1.2 g / L 2’FL and about 0.08‑0.12 g / L LNnT.

[0066] In some embodiments, the infant formula comprises (when formulated as instructed) about 0.9‑1.1 g / L 2’FL and about 0.09‑0.11 g / L LNnT.

[0067] In some embodiments, the infant formula (when formulated as instructed) comprises about 1.8 g / L 2’FL and about 0.1 g / L LNnT.

[0068] In some embodiments, the infant formula comprises (when formulated as instructed) about 1.5‑2 g / L 2’FL and about 0.08‑0.12 g / L LNnT.

[0069] In some embodiments, the infant formula comprises (when formulated as instructed) about 1.7‑1.9 g / L 2’FL and about 0.09‑0.11 g / L LNnT.

[0070] In some embodiments, the infant formula (when formulated as instructed) comprises about 1.8 g / L 2’FL and about 0.1 g / L LNnT. 5 EP 4 649 837 A2 5 10 15 20 25 30 35 40 45 50 55

[0071] In some embodiments, the infant formula comprises (when formulated as instructed) 0.12‑0.225 g / 100 kcal, 0.12‑0.21g / 100kcal, 0.12‑0.195g / 100kcal, 0.12‑0.18g / 100kcal, 0.12‑0.165g / 100 kcal, 0.135‑0.165g / 100kcal, or about 0.15g / 100kcal 2’FL. In someembodiments, the infant formula comprises (when formulatedas instructed)0.12‑0.18g / 100 kcal 2’FL. In some embodiments, the infant formula comprises (when formulated as instructed) 0.135‑0.165 g / 100 kcal 2’FL.

[0072] In some embodiments, the infant formula comprises (when formulated as instructed) 0.15‑0.225 g / 100 kcal, 0.15‑0.21 g / 100 kcal, 0.15‑0.195 g / 100 kcal, 0.15‑0.18 g / 100 kcal, 0.15‑0.165 g / 100 kcal, or about 0.15 g / 100 kcal 2’FL. In some embodiments, the infant formula comprises (when formulated as instructed) 0.15‑0.165 g / 100 kcal 2’FL.

[0073] In preferred embodiments, the infant formula comprises (when formulated as instructed) about 0.15 g / 100 kcal 2’FL.

[0074] In some embodiments, the infant formula comprises (when formulated as instructed) 0.225‑0.375 g / 100 kcal, 0.225‑0.36 g / 100 kcal, 0.225‑0.345 g / 100 kcal, 0.225‑0.33 g / 100 kcal, 0.225‑0.315 g / 100 kcal, 0.225‑0.3 g / 100 kcal, 0.24‑0.3 g / 100 kcal, 0.255‑0.285 g / 100 kcal, or about 0.27 g / 100 kcal 2’FL. In some embodiments, the infant formula comprises (when formulated as instructed) 0.225‑2 g / 100 kcal 2’FL. In some embodiments, the infant formula comprises (when formulated as instructed) 0.255‑0.285 g / 100 kcal 2’FL.

[0075] In preferred embodiments, the infant formula comprises (when formulated as instructed) about 0.27 g / 100 kcal 2’FL.

[0076] LNnTmay, for example, be present in the infant formula in a total amount of 0.0075‑0.03 g / 100 kcal of the infant formula (when formulated as instructed).

[0077] In some embodiments, the infant formula comprises (when formulated as instructed) 0.0075‑0.0225 g / 100 kcal, 0.009‑0.021 g / 100 kcal, 0.0105‑0.0195 g / 100 kcal, 0.012‑0.018 g / 100 kcal, 0.0135‑0.0165 g / 100 kcal or about 0.015 g / 100 kcal LNnT. In some embodiments, the infant formula comprises (when formulated as instructed) 0.012‑0.018 g / 100 kcal LNnT. In someembodiments, the infant formula comprises (when formulatedas instructed) 0.0135‑0.0165g / 100 kcal LNnT.

[0078] In preferred embodiments, the infant formula comprises (when formulated as instructed) about 0.015 g / 100 kcal LNnT. PROTEIN

[0079] The term "protein" includes peptides and free amino acids. The protein content of the infant formula may be calculatedbyanymethodknown to thoseof skill in theart.Suitably, theprotein contentmaybedeterminedbyanitrogen-to- protein conversionmethod.For example, asdescribed inMaubois, J.L. andLorient,D. (2016)DairyScience&Technology 96(1): 15‑25. Preferably the protein content is calculated as nitrogen content× 6.25, as defined in EuropeanCommission Regulation (EU) 2016 / 127of 25September 2015. Thenitrogen contentmaybedeterminedbyanymethod known to those of skill in the art. For example, nitrogen content may be measured by the Kjeldahl method. Protein concentration

[0080] The protein content of the infant formula is preferably in the range 1.8‑3.2 g protein per 100 kcal. In some embodiments, the protein content of the infant formula is in the range 1.8‑2.8 g protein per 100 kcal.

[0081] eHFs typically contain 2.6‑2.8 g protein per 100 kcal andAAFs typically contain 2.8‑3.1 g protein per 100 kcal, for example to cover the needs of infants suffering gastrointestinal pathologieswith severemalabsorption or infants requiring more proteins and calories to cover a higher metabolic rate.

[0082] Infant formulas, such as an eHF or an AAF, with a lower protein content may support appropriate growth and development of allergic infants, as well as being safe and well-tolerated.

[0083] Accordingly, in some embodiments, the infant formulamay comprise about 2.4 g or less protein per 100 kcal. For example, the infant formulamay comprise about 2.3 gor less protein per 100 kcal, 2.25gor lessprotein per 100 kcal, or 2.2 g or less protein per 100 kcal.

[0084] Suitably, the infant formula comprises about 1.8 g or more protein per 100 kcal. For example, the infant formula may comprise about 1.86 g or more protein per 100 kcal, 1.9 g or more protein per 100 kcal, 2.0 g or more protein per 100 kcal, or 2.1 g or more protein per 100 kcal. Preferably, the infant formula comprises about 1.86 g or more protein per 100 kcal, in line with present EU regulations (EFSA NDA Panel (2014) EFSA journal 12(7): 3760).

[0085] In some embodiments, the infant formulamay comprise 1.8‑2.4 g protein per 100 kcal, 1.86‑2.4g protein per 100 kcal, 1.9‑2.4 g protein per 100 kcal, 2.0‑2.4 g protein per 100 kcal, 2.0‑2.3 g protein per 100 kcal, 2.1‑2.3 g protein per 100 kcal, or 2.15‑2.25 g protein per 100 kcal.

[0086] Preferably, the infant formula comprises about 2.2 g protein per 100 kcal. 6 EP 4 649 837 A2 5 10 15 20 25 30 35 40 45 50 55 Protein source

[0087] The source of protein may be any source suitable for use in an infant formula. Suitably, the protein is cow’s milk protein.

[0088] In some embodiments, the infant formula does not comprise dairy protein. In some embodiments, the infant formula does not comprise cow’s milk protein. Accordingly, in some embodiments 100% by weight of the total protein is non-dairy protein.

[0089] In some embodiments, the infant formula comprises plant protein. Example plant proteins thatmay optionally be used in the infant formula of the invention, include potato, pea, rice, quinoa, oat, sunflower or coconut proteins, or combinations thereof. Further example non-dairy proteins for use in the infant formula include algal protein or leaf protein.

[0090] An extensively hydrolysed / hydrolysed whey-based formula may be more palatable than an extensively hydro- lysed / hydrolysed casein-based formula and / or the subject may only be sensitised to casein protein. Suitably, therefore, more than about 50%,more than about 60%,more than about 70%,more than about 80%,more than about 90%, or about 100% of the protein is whey protein. Preferably, the protein source is whey protein.

[0091] The whey protein may be a whey from cheesemaking, particularly a sweet whey such as that resulting from the coagulation of casein by rennet, an acidic whey from the coagulation of casein by an acid, or the acidifying ferments, or even amixedwhey resulting from coagulation by an acid and by rennet. This startingmaterial may bewhey that has been demineralised by ion exchange and / or by electrodialysis and is known as demineralised whey protein (DWP).

[0092] The source of the whey protein may be sweet whey from which the caseino-glycomacropeptide (CGMP) has been totally or partially removed. This is called modified sweet whey (MSW). Removal of the CGMP from sweet whey results in a protein material with threonine and trytophan contents that are closer to those of human milk. A process for removing CGMP from sweet whey is described in EP880902.

[0093] The whey protein may be a mix of DWP and MSW.

[0094] In some embodiments, the amount of casein in the infant formula is undetectable, for example less than 0.2 mg / kg. The amount of casein may be determined by any method known to those of skill in the art. Degree of hydrolysis

[0095] In eHFs, the protein is "extensively hydrolysed", such that the eHFsmaybe toleratedbymore than90%of infants with CMPA.

[0096] Protein hydrolysates may have an extent of hydrolysis that is characterised by NPN / TN%, which refers to the non-protein nitrogen divided by the total nitrogen× 100. The non-protein nitrogen refers to amino nitrogen that is free to react with a reagent such as trinitrobenzenesulfonic acid (TNBS). NPN / TN%may be determined by anymethod known to thoseof skill in the art. For example,NPN / TN%maybemeasured as described inAdler-Nissen (Adler-Nissen, J. (1979) J. Agric. Food Chem. 27: 1256‑1262). Suitably, the protein may have an NPN / TN% greater than 90%, greater than 95% or greater than 98%.

[0097] The extent of hydrolysis may also be determined by the degree of hydrolysis. The "degree of hydrolysis" (DH) is defined as the proportion of cleaved peptide bonds in a protein hydrolysate andmay be determined by anymethod known to those of skill in the art. Suitably the degree of hydrolysis is determined by pH-stat, trinitrobenzenesulfonic acid (TNBS), o-phthaldialdehyde (OPA), trichloroacetic acid soluble nitrogen (SN-TCA), or formol titration degree of hydrolysis (DH) of the protein can, for example, be more than 90, more than 95 or more than 98.

[0098] The extent of hydrolysis may also be determined by the peptide molecular mass distribution. The peptide molecular mass distribution may be determined by high performance size exclusion chromatography, optionally with UV detection (HPSEC / UV) (Johns, P.W. et al. (2011) Food chemistry 125(3): 1041‑1050). For example, the peptidemolecular massdistributionmaybeaHPSECpeakarea-basedestimatedeterminedat205nm,214nmor220nm.Suitablywhen the peptide molecular mass distribution is determined by HPSEC / UV, the "percentage of peptides by weight" that have a certain molecular mass may be estimated by the "fraction of peak area as a percentage of total peak area", that have the molecular mass, determined at 205 nm, 214 nm or 220 nm. Suitably, the extent of hydrolysis may be determined by the methods described inWO2016 / 156077. Alternatively, the peptidemolecularmass distributionmay be determined by any method known to those of skill in the art, for example by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) (Chauveau, A. et al. (2016) Pediatric Allergy and Immunology 27(5): 541‑543).

[0099] Theoretically, to bind with cell membrane-bound IgE, peptides should be greater than about 1500 Dain size (approximately 15 amino acids) and to crosslink IgEmolecules and to induce an immune response, they must be greater than about 3000 Da in size (approximately 30 amino acids) (Nutten (2018) EMJ Allergy Immunol 3(1): 50‑59).

[0100] Suitably, therefore, at least about 95%, at least about 98%, at least about 99% or about 100% of the peptides by weight in the eHF have amolecular mass of less than about 3000 Da. There may, for example, be no detectable peptides about 3000 Da or greater in size in the eHF.

[0101] Suitably, therefore, at least about 95%, at least about 98%, at least about 99% or about 100% of the peptides by 7 EP 4 649 837 A2 5 10 15 20 25 30 35 40 45 50 55 weight in the eHF have a molecular mass of less than about 1500 Da. Preferably, at least 99% of the peptides by weight have amolecular mass of less than about 1500 Da. There may, for example, be no detectable peptides about 1500 Da or greater in size in the eHF.

[0102] Preferably, at least about 85%, at least about 90%, at least about 95%, at least about 98%or at least about 99%of thepeptides byweight in the eHFhaveamolecularmass of less than about 1200Da.Morepreferably, at least 95%or 98% of the peptides by weight in the eHF have a molecular mass of less than about 1200 Da.

[0103] Suitably, at least about 80%, at least about 85%, at least about 90%, or at least about 95% of the peptides by weight in the eHF have a molecular mass of less than about 1000 Da.

[0104] Preferably, at least about95%of thepeptidesbyweight in theeHFhaveamolecularmassof less thanabout1000 Da.

[0105] Preferably, the eHF has no detectable peptides about 3000 Da or greater in size; and at least about 95% of the peptides by weight have a molecular mass of less than about 1200 Da.

[0106] Having a high proportion of di‑ and tri-peptides may improve nitrogen (protein) absorption, even in patients with gut impairment. PEPT1 is a dedicated facilitator transport route for small peptide absorption (e.g. di‑ and tri-peptides). In the first weeks of life, intestinal PEPT1 is important for nutritional intake, and later for diet transition following weaning.

[0107] Thus, at least about 30%, at least about 40%, or at least about 50% of the peptides by weight in the eHFmay, for example, be di‑ and tri-peptides. Preferably, at least about 45%, at least about 50%, 45‑55%, or 50‑54%of the peptides by weight in the eHFaredi‑and tri-peptides.Morepreferably, about 51‑53%,ormost preferably, about 52%of thepeptidesby weight in the eHF are di‑ and tri-peptides.

[0108] Suitably, at least about 30%, at least about 40%, or at least about 50%of thepeptidesbyweight in the eHFhavea molecularmass of between 240 and600Da. Preferably, at least about 45%, at least about 50%, 45‑55%, or 50‑54%of the peptidesbyweight in the eHFhaveamolecularmass of between240and600Da.Morepreferably, about 51‑53%, ormost preferably, about 52% of the peptides by weight in the eHF have a molecular mass of between 240 and 600 Da.

[0109] Thepeptides in theeHFmay, for example, haveamedianmolecularweight of 300Da to370Da,preferably320Da to 360Da.

[0110] The principal recognised cow’smilk allergens are alpha-lactalbumin (aLA), beta-lactoglobulin (bLG) and bovine serum albumin (BSA).

[0111] Suitably, therefore, the eHFmay have non-detectable aLA content, for example about 0.010 mg / kg aLA or less; theeHFmayhavenon-detectablebLGcontent, for exampleabout0.010mg / kgbLGor less; and / or theeHFmayhavenon- detectable BSA content, for example about 0.010 mg / kg BSA or less. Preferably, the eHF comprises no detectable amountsofaLA,bLGandBSA.Thecontentof aLA,bLGandBSAmaybedeterminedbyanymethodknown to thoseof skill in the art, for example ELISA.

[0112] In preferredembodiments, theeHFof thepresent invention: hasnodetectablepeptidesabout 3000Daorgreater in size; at least about 95% of the peptides byweight have amolecular mass of less than about 1200Da; optionally at least about 45%, at least about 50%, or 45‑55% of the peptides by weight have a molecular mass of between 240 and 600 Da and / or are di- or tri-peptides; and the eHF comprises no added MCT. Method of hydrolysis

[0113] Proteins for use in the infant formula of the inventionmay be hydrolysed by any suitablemethod known in the art. For example, proteins may be enzymatically hydrolysed, for example using a protease. For example, protein may be hydrolysed using alcalase (e.g. at an enzyme:substrate ratio of about 1‑15% by weight and for a duration of about 1‑10 hours). The temperature may range from about 40°C to 60°C, for example about 55°C. The reaction time may be, for example, from 1 to 10 hours and pH values before starting hydrolysis may, for example, fall within the range 6 to 9, preferably 6.5 to 8.5, more preferably 7.0 to 8.0.

[0114] Porcine enzymes, in particular porcine pancreatic enzymesmaybeused in thehydrolysis process. For example, WO1993004593A1 discloses a hydrolysis process using trypsin and chymotrypsin, which includes a two-step hydrolysis reactionwithaheatdenaturationstep inbetween toensure that thefinal hydrolysate is substantially freeof intact allergenic proteins. The trypsin and chymotrypsin used in these methods are preparations produced by extraction of porcine pancreas.

[0115] WO2016156077A1 discloses a process for preparing a milk protein hydrolysate comprising hydrolysing a milk- based proteinaceous material with a microbial alkaline serine protease in combination with bromelain, a protease from Aspergillus and a protease from Bacillus. Free amino acids

[0116] The infant formula of the invention may comprise free amino acids.

[0117] The levels of free amino acidsmay be chosen to provide an amino acid profile that is sufficient for infant nutrition, 8 EP 4 649 837 A2 5 10 15 20 25 30 35 40 45 50 55 inparticular anaminoacidprofile that satisfiesnutritional regulations (e.g.EuropeanCommissionDirective2006 / 141 / EC).

[0118] Free amino acids may, for example, be incorporated in the eHF of the invention to supplement the amino acids comprised in the peptides.

[0119] Example free amino acids for use in the infant formula of the invention include histidine, isoleucine, leucine, lysine, methionine, cysteine, phenylalanine, tyrosine, threonine, tryptophan, valine, alanine, arginine, asparagine, aspartic acid, glutamic acid, glutamine, glycine, proline, serine, carnitine, taurine and mixtures thereof.

[0120] Free amino acids provide a protein equivalent source (i.e. contribute to the nitrogen content). As described above, having a high proportion of di‑ and tri-peptidesmay improve nitrogen (protein) absorption, even in patients with gut impairment. Accordingly, havinga lowproportion of freeaminoacidsmayalso improvenitrogen (protein) absorption, even in patients with gut impairment.

[0121] Suitably, therefore, the free aminoacids in theeHFmaybepresent in a concentration of 50%or less, 40%or less, 30%or less, or 25%or less byweight based on the total weight of amino acids. Preferably, the eHF comprises 25%or less byweight of freeaminoacidsbasedon the total weight of aminoacids.More preferably, the free aminoacids in theeHFare present in a concentration of 20‑25%, 21‑23%, or about 22% by weight based on the total weight of amino acids.

[0122] The free amino acids contentmay be determined by anymethod known of skill in the art. Suitably, the free amino acids content may be obtained by separation of the free amino acids present in an aqueous sample extract by ion exchangechromatographyandphotometricdetectionafter post-columnderivatisationwithninhydrin reagent. Total amino acids content may be obtained by hydrolysis of the test portion in 6 mol / L HCl under nitrogen and separation of individual amino acids by ion-exchange chromatography, as describe above.

[0123] In preferredembodiments, theeHFof thepresent invention: hasnodetectablepeptidesabout 3000Daorgreater in size; at least about 95% of the peptides byweight have amolecular mass of less than about 1200Da; optionally at least about 45%, at least about 50%, or 45‑55% of the peptides by weight have a molecular mass of between 240 and 600 Da and / oraredi‑or tri-peptides, and / or20‑25%,21‑23%,orabout22%byweightbasedon the totalweight of aminoacids; and the eHF comprises no added MCT. CARBOHYDRATE

[0124] The carbohydrate content of the infant formula of the invention is preferably in the range 9‑14 g carbohydrate per 100 kcal.

[0125] The carbohydrate may be any carbohydrate which is suitable for use in an infant formula.

[0126] Example carbohydrates for use in the infant formula of the invention include lactose, saccharose, maltodextrin and starch. Mixtures of carbohydrates may be used.

[0127] In some embodiments, the carbohydrate content comprises maltodextrin. In some embodiments, at least about 20%,at least about 25%,at least about 30%,at least about 35%,at least about 40%,at least about 50%,at least about 60% or at least about 70% by weight of the total carbohydrate content is maltodextrin.

[0128] In some embodiments, the carbohydrate content comprises lactose. In some embodiments, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 50%, at least about 60%or at least about 70% by weight of the total carbohydrate content is lactose.

[0129] In some embodiments, the carbohydrate comprises lactose and maltodextrin. FAT

[0130] The fat content of the infant formula of the invention is preferably in the range 4.0‑6.0 g fat per 100 kcal.

[0131] The fat may be any lipid or fat which is suitable for use in an infant formula.

[0132] Example fats for use in the infant formula of the invention include sunflower oil, low erucic acid rapeseed oil, safflower oil, canola oil, olive oil, coconut oil, palm kernel oil, soybean oil, fish oil, palm oleic, high oleic sunflower oil and high oleic safflower oil, and microbial fermentation oil containing long chain, polyunsaturated fatty acids.

[0133] The fatmayalsobe in the formof fractionsderived from theseoils, suchaspalmolein,mediumchain triglycerides (MCT) and esters of fatty acids such as arachidonic acid, linoleic acid, palmitic acid, stearic acid, docosahexaeonic acid, linolenic acid, oleic acid, lauric acid, capric acid, caprylic acid, caproic acid, and the like.

[0134] Further example fats include structured lipids (i.e. lipids that are modified chemically or enzymatically in order to change their structure). Preferably, the structured lipids are sn2 structured lipids, for example comprising triglycerides having an elevated level of palmitic acid at the sn2 position of the triglyceride. Structured lipids may be added or may be omitted.

[0135] Oils containing high quantities of preformed arachidonic acid (ARA) and / or docosahexaenoic acid (DHA), such as fish oils or microbial oils, may be added.

[0136] Long chain polyunsaturated fatty acids, such as dihomo-y-linolenic acid, arachidonic acid (ARA), eicosapen- taenoic acid and docosahexaenoic acid (DHA), may also be added. 9 EP 4 649 837 A2 5 10 15 20 25 30 35 40 45 50 55

[0137] The infant formulamay comprise 2‑20mgARAper 100 kcal, 5‑15ARAper 100 kcal, or about 10mgARAper 100 kcal and / or 2‑20 mg DHA per 100 kcal, 5‑15 DHA per 100 kcal, or about 10 mg DHA per 100 kcal. Preferably, the infant formula comprises about 10 mg ARA per 100 kcal and about 10 mg DHA per 100 kcal. Medium chain triglycerides (MCTs)

[0138] A high concentration of MCT may impair early weight gain. MCT is not stored and does not support fat storage. For instance, Borschel et al. have reported that infants fed formulawithoutMCTgained significantlymoreweight between 1‑56 days than infants fed formulas containing 50% of the fat from MCT (Borschel, M. et al. (2018) Nutrients 10(3): 289).

[0139] Thus, about 30%or less byweight of the fatmay, for example, bemediumchain triglycerides (MCTs) in the infant formula of the present invention.

[0140] In someembodiments, about 25%or lessbyweight, 20%or less byweight, 15%or less byweight, 10%or lessby weight, 5%or lessbyweight, 4%or lessbyweight, 3%or lessbyweight, 2%or lessbyweight, 1%or lessbyweight, 0.5%or less by weight, or 0.1% or less by weight of the fat is medium chain triglycerides (MCTs).

[0141] In someembodiments, 0‑30%byweight, 0‑25%byweight, 0‑20%byweight, 0‑15%byweight, 0‑10%byweight, 0‑5%byweight, 0‑4%byweight, 0‑3%byweight, 0‑2%byweight, 0‑1%byweight, 0‑0.5%byweight, or 0‑0.1%byweight of the fat is medium chain triglycerides (MCTs).

[0142] Preferably, the infant formula comprises no addedMCTs. Suitably, about 0% by weight of the fat is MCTs and / or the infant formula comprises no detectable MCTs. Suitably, the infant formula comprises no MCTs.

[0143] In preferredembodiments, theeHFof thepresent invention: hasnodetectablepeptidesabout 3000Daorgreater in size; at least about 95% of the peptides by weight have a molecular mass of less than about 1200 Da; 45‑55% of the peptides byweight have amolecular mass of between 240 and 600Da; free amino acids are present in a concentration of 20‑25% by weight based on the total weight of amino acid; and the eHF comprises no added MCT. FURTHER INGREDIENTS

[0144] The infant formulaof the inventionpreferablyalsocontainsall vitaminsandmineralsunderstood tobeessential in the daily diet in nutritionally significant amounts. Minimum requirements have been established for certain vitamins and minerals.

[0145] Example vitamins, minerals and other nutrients for use in the infant formula of the invention include vitamin A, vitaminB1, vitaminB2, vitaminB6, vitaminB12, vitaminE, vitaminK, vitaminC, vitaminD, folic acid, inositol, niacin, biotin, pantothenicacid, choline, calcium,phosphorous, iodine, iron,magnesium,copper, zinc,manganese, chlorine,potassium, sodium, selenium, chromium, molybdenum, taurine and L-carnitine. Minerals are usually added in their salt form.

[0146] The infant formula of the invention may comprise one or more carotenoids.

[0147] The infant formula of the invention may also comprise at least one probiotic. The term "probiotic" refers to microbial cell preparationsor components ofmicrobial cellswith beneficial effects on thehealth orwell-beingof the host. In particular, probiotics may improve gut barrier function.

[0148] Preferred probiotics are those which as a whole are safe, are L(+) lactic acid producing cultures and have acceptable shelf-life for products that are required to remain stable and effective for up to 24 months.

[0149] Examples of probiotic micro-organisms for use in the infant formula of the invention include yeasts, such as Saccharomyces, Debaromyces, Candida, Pichia and Torulopsis; and bacteria, such as the genera Bifidobacterium, Bacteroides, Clostridium, Fusobacterium, Melissococcus, Propionibacterium, Streptococcus, Enterococcus, Lactococ- cus, Staphylococcus, Peptostrepococcus, Bacillus, Pediococcus, Micrococcus, Leuconostoc, Weissella, Aerococcus, Denococcus and Lactobacillus.

[0150] Specific examples of suitable probiotic microorganisms are: Saccharomyces cereviseae, Bacillus coagulans, Bacillus licheniformis, Bacillus subtilis, Bifidobacterium bifidum, Bifidobacterium infantis, Bifidobacterium longum, En- terococcus fiaecium, Enterococcus faecalis, Lactobacillus acidophilus, Lactobacillus alimentarius, Lactobacillus casei subsp. casei, Lactobacillus casei Shirota, Lactobacillus curvatus, Lactobacillus delbruckii subsp. lactis, Lactobacillus farciminus, Lactobacillus gasseri, Lactobacillus helveticus, Lactobacillus johnsonii, Lactobacillus rhamnosus (Lactoba- cillus GG), Lactobacillus sake, Lactococcus lactis, Micrococcus varians, Pediococcus acidilactici, Pediococcus pento- saceus, Pediococcus acidilactici, Pediococcus halophilus, Streptococcus fiaecalis, Streptococcus thermophilus, Sta- phylococcus carnosus and Staphylococcus xylosus.

[0151] The infant formula of the inventionmayalso contain other substanceswhichmayhavea beneficial effect suchas prebiotics, lactoferrin, fibres, nucleotides, nucleosides, short chain fatty acids, e.g butyrate, and / or postbiotics and the like. REDUCED OCCURRENCE AND PREVENTION OF ALLERGIC SENSITISATION

[0152] The term"allergy" refers toahypersensitivity of the immunesystem toasubstancewhich isnormally tolerated (an 10 EP 4 649 837 A2 5 10 15 20 25 30 35 40 45 50 55 allergen). The allergy may be an allergy detected by a medical doctor. Examples of allergic diseases include atopic dermatitis, eczema, food allergy, asthma and rhinitis

[0153] Immunisation is part of the normal immune response, which in healthy individuals occurs when the immune system registers a substance as a threat. As a consequence, for example, B cells may then produce antibodies that bind that substance.

[0154] The term "allergic sensitisation" refers to sensitisationof the immunesystem toagents that arenormally tolerated andwhichwould typically beharmless in theabsenceofanallergic response (knownasallergens, for examplesubstances in food or pollen).

[0155] While not wishing to be bound by theory, when allergens enter a body, they may be captured and presented by antigen presenting cells to other cells of the immune system, in particular Tcells. Following interaction betweenTcells and B cells, B cells may then produce allergen-specific antibodies (IgE). Subsequently, once released into the blood, IgE antibodies may bind to mast cells, as well as other immune cells such as basophils. Individuals who are sensitised may then develop an allergic reaction on re-exposure to the allergen.

[0156] Thus, allergic sensitisation may refer to a priming of the immune system to recognise allergens. Individuals who are sensitised in this way may then develop an allergic reaction on re-exposure to the allergen.

[0157] In some embodiments, allergic sensitisation in an infant may be characterised by a total IgE concentration greater than 35 kU / L at 6 months of age and / or 53 kU / L at 12 months of age (Martins, T.B. et al. (2014) J Allergy Clin Immunol 133(2): 589‑91). In some embodiments, allergic sensitisation in an adult may be characterised a total IgE level greater than 127 KU / L. The skilled person is readily able to determine IgE concentrations in a sample from a subject, for example using ImmunoCAP Phadia technology as disclosed in the Examples.

[0158] The infant formula of the invention may be used to reduce the occurrence of allergic sensitisation in an infant and / or prevent allergic sensitisation in an infant.

[0159] As used herein, "reduce the occurrence" of allergic sensitisation means that the infant formula reduces the likelihood of allergic sensitisation.

[0160] As used herein, "prevent" allergic sensitisation means that the infant has not yet been sensitised, and the infant formula prevents allergic sensitisation.

[0161] The term "infant" refers to a child under the ageof 12months, for example a child between 0and6months of age.

[0162] In someembodiments, the infant isat riskof developingoneormoreallergies.Forexample, the infantmaybelong to a family with a history of one or more allergies.

[0163] In oneaspect the inventionprovidesamethodof preventingor reducing theoccurrenceof allergic sensitisation in an infant, comprising administering to the infant an infant formula of the invention. METHOD OF MANUFACTURE

[0164] The infant formula of the invention may be prepared in any suitable manner.

[0165] For example, the infant formula may be prepared by blending together the protein source, the carbohydrate source and the fat source in appropriate proportions. If used, the further emulsifiers may be included at this point. The vitamins and minerals may be added at this point but vitamins are usually added later to avoid thermal degradation. Any lipophilic vitamins, emulsifiers and the like may be dissolved in the fat source prior to blending. Water, preferably water which has been subjected to reverse osmosis, may then be mixed in to form a liquid mixture. Commercially available liquefiers may be used to form the liquid mixture. The liquid mixture may then be homogenised.

[0166] The liquidmixturemay then be thermally treated to reduce bacterial loads. Thismay be carried out, for example, by means of steam injection, or using an autoclave or heat exchanger, for example a plate heat exchanger.

[0167] The liquid mixture may then be cooled and / or homogenised. The pH and solid content of the homogenised mixture may be adjusted at this point.

[0168] Thehomogenisedmixturemay then be transferred to a suitable drying apparatus such as a spray dryer or freeze dryer and converted to powder. If a liquid infant formula is preferred, the homogenised mixture may be sterilised, then aseptically filled into a suitable container or may be first filled into a container and then retorted.

[0169] The skilled person will understand that they can combine all features of the invention disclosed herein without departing from the scope of the invention as disclosed.

[0170] Preferred features and embodiments of the invention will now be described by way of nonlimiting examples. EXAMPLES

[0171] Some studies have shown that specific components of breast milk, considered separately, are associated with disease status in the mother or the child using univariate analyses. However, recent analysis approaches to evaluate the relationship between breast milk HMO components independently have shown not association with allergy. Example 1 identify the specific doses of 2FL and LNnt necessary for allergic sensitization protection. Example 2 confirms in animals 11 EP 4 649 837 A2 5 10 15 20 25 30 35 40 45 50 55 the need for a specific dose to protect against allergic sensitization. EXAMPLE 1

[0172] In the present study, we aimed to understand the association between human milk oligosaccharides (HMOs) level and allergic sensitization in humans

[0173] While we confirmed a non-significant association when doing univariate analysis, suggesting no linear associa- tion between the level of HMOs and the risk of allergic sensitization; we found that the HMOs 2’-fucosyllactose (2’FL) and lacto-N-neotetraose (LNnT) protect against allergic sensitisation, and that a bell-shaped effect is observed showing optimum protection at intermediate doses, while lower and higher doses may be less effective. MATERIALS AND METHODS Breast milk analysis (German cohort)

[0174] A cohort of 156 mother / infant pairs was sub-selected from samples from the Life Child study (Seppo, A.E. et al. (2017) J Allergy Clin Immunol 139(2): 708‑11 e5). The selection of samples was based on the availability of breast milk samplesat threemonthsalongwith thecompletionofallergyquestionnairesbymothersatany timeduring thestudyand / or for infants in the first year of life of the infant.

[0175] For the purpose of the study, maternal allergic sensitisation was defined by the total IgE level greater than 127 KU / L (Martins, T.B. et al. (2014) J Allergy Clin Immunol 133(2): 589‑91) and allergy was defined as self-reported asthma, rhinitis, atopic dermatitis, eczema and / or allergic reactions to specific food (with vomit, nausea, diarrhea, exacerbation of eczema or asthma symptoms) in the mother. For the purpose of this study, infant allergic sensitisation was defined as a total IgE greater than 35 kU / L and 53 kU / L, at 6 and 12 months, respectively (Martins, T.B. et al. (2014) J Allergy Clin Immunol 133(2): 589‑91), and allergy risk as a positive answer to the questions "did a doctor ever diagnose food allergy in your child", "did your child ever have eczema / atopic dermatitis" or "did your child suffer from recurrent rashes associated with pruritus during more than 15 days" at 3, 6 months or at one year. Mother and child total IgE was quantified using ImmunoCAP Phadia technology.

[0176] In this cohort, allergy and confounders such as socio-economic statuswere obtained via various questionnaires. Confounders were identified based on available literature associating allergy and breast milk components and were chosen based on available data (deliverymode (delivery), child gender (gender), child weight at birth (weight), exclusively breastfeeding at 3months (Breastfeed), socioeconomic status (ecoStatus) and number of siblings (siblings)). This cohort was used as an exploratory cohort. Breastmilkwas expressed, collected and stored at ‑80°C from lactatingmothers in the thirdmonth postpartum (Quante,M. et al. (2012)BMCPublicHealth 12: 1021).Onemother / child pair was excluded due to too many missing values for the breast milk component levels (>50%). The study was designed in accordance with the Declaration of Helsinki and under the supervision of the Ethics Committee of the University of Leipzig (Reg. No. 264‑10‑19042010). The LIFE Child study is registered in ClinicalTrials.gov under the clinical trial number: NCT02550236 (Poulain, T. et al. (2017) European Journal of Epidemiology 32(2): 145‑58). Component level assessment

[0177] Liquid chromatography analysis was carried out, for which sampleswere centrifuged for 5minutes at 10,000 x g. Sampleswere subsequently analysedusing anUltimate 3000-RDUHPLCsystemwhich containedanRF‑200fluorimeter and a 2-way ten port high-pressure switching valve (ThermoFisher Scientific,Waltham,USA). Sampleswere loaded onto AcquityBEHGlycanandVanGuardBEHamidecolumns (WatersCorporation,Milford,USA)withaguardcolumnbetween the injector and ten port valve. The temperature of the columnswas 55°C, and the flow ratewas 0.5mL / min. The reliability of themethod was validated by spike reliability assessments with calibration curves being validated using the standard of the oligosaccharide in question and a maltotriose control.

[0178] In total, absolute concentrations of 21HMOsweremeasured: 2’-Fucosyllactose (2’FL), 3-Fucosyllactose (3’FL), 3’-Sialyllactose (3’SL), 6’-Sialyllactose (6’SL), 3’-Galactosyllactose (3’GL), 6’-Galactosyllactose (6’GL), Lacto-N-tetrose (LNT), Lacto-N-neotetraose (LNnT), Lacto-N-fucopentaose I (LNFP I), Lacto-N-fucopentaose II (LNFP II), Lacto-N- fucopentaose III (LNFP III), Lacto-N-fucopentaose V (LNFPV), Lacto-N-neofucopentaose (LNnFP), Lactodifucotetraose (LDF), Lacto-N-tetraose b (LST b), Lacto-N-tetraose(LST c), difucosyllacto-N-hexaose a (DFLNHa), disialyllacto-N- tetraose (DSLNT), monofucosyllacto-N-hexaose (MFLNH III), Lacto-N-neodifucohexaose (LNnDFH) and Lacto-N-difu- cohexaose (LNDFH 1). 12 EP 4 649 837 A2 5 10 15 20 25 30 35 40 45 50 55 Univariate analysis

[0179] To test for association between HMOs and allergic sensitization or allergy, logistic regression and Chi-squared testing was completed comparing individual HMO levels against the incidence of atopic dermatitis. The sum of the 21 HMOs was also included in statistical analysis and classified as ’Total HMOs’.

[0180] For the statistical analysis, the following confounding variables were included in the model: gender, delivery mode, parental allergy, breast milk Se and Le status and pets in the home.. The non-parametric Mann-Whitney-Wilcoxon test was used to compare the differences in the levels of individual HMOs between the allergic and non-allergic infants. RESULTS Association between HMO and allergy in the German cohort

[0181] Demographics of the study population at baseline are shown in Table 1. Table 1. Discovery Cohort Summary Demographic Data Variable Number of infants N=121 % of Total Population Sensitisation and or Allergy 31 25.6% Atopic Dermatitis / Eczema 20 16.5% IgE mediated Food Allergy 8 6.6% IgE Sensitisation 11 9% Female 59 48.8% Male 62 51.2% Age (Months) 3 Gestational Age (mean number of weeks) 39.4 C Section Delivery 18 14.9% Vaginal Delivery 102 84.3% Allergic Parent 71 58.7% Has Siblings 57 47.1% Allergic Nuclear Family Member 65 53.7% Pets in Household 39 32.2% Se+, Le+ 92 76.0% Se+, Le- 12 9.9% Se‑, Le+ 15 12.4% Se‑, Le- 2 1.7% Table 2. Discovery Cohort Summary Demographic Data by SA Status. Variable SA (n=31) NSA (n=90) Number of infants %of SA Population Number of infants % of NSA Population Female 13 41.9% 46 51.1% Male 18 58.1% 44 48.9% Age (months) 3 Gestational Age (mean number of weeks) 39.7 39.2 C Section Delivery 2 6.5% 16 17.8% Vaginal Delivery 29 93.5% 73 81.1% Allergic Parent 19 61.3% 52 57.8% Has Siblings 13 41.9% 44 48.9% Allergic Nuclear Family Member 17 54.8% 48 53.3% Pets in Household 14 45.2% 25 27.8% Se+, Le+ 23 74.2% 69 76.7% Se+, Le- 5 16.1% 7 7.78% Se‑, Le+ 2 6.45% 12 13.3% 13 EP 4 649 837 A2 5 10 15 20 25 30 35 40 45 50 55 (continued) Variable SA (n=31) NSA (n=90) Number of infants %of SA Population Number of infants % of NSA Population Se‑, Le- 0 0.0% 2 2.22%

[0182] A total of 21 HMO levels were measured and are presented in Figure 1. Using only medically diagnosed and or sensitized infants, no significant associationwas found between anyHMO levels andmedically diagnosed allergic infants versus non-allergic infants. Q-values or corrected p-values for multiple testing were all above 0.05. HMO levels and association with the risk of allergic sensitisation and skin rash

[0183] We then assessed the possibility that HMOsmay be linkedwith allergic sensitisation. Since less than 30%of the population was analysed for sensitisation in our cohort, we expanded the analysis to include the infants with a positive sensitisation as well as those with an increased risk of sensitisation based on prolonged skin rash or eczema. When lookingat thedistributionof2’FLandLNnT levels in thisextendedpopulation,we foundanon-lineal distributionsuggesting that only specific doses of 2FL, LNnTmay be associated with a decreased risk for for allergic sensitisation (Figure 2) and higher dose are not protective.

[0184] Quartile analysis of the population as shown in Figure 2 identified levels of 2’FL and LNnT in breast milk that are associated with reducing allergic sensitisation: 2’FL levels in breast milk below 2.5 mg / L; and LNnT levels below 0.2 g / L appear to be associated with a particularly beneficial effect. Example 2

[0185] In the present example, we aimed at confirming a bell shape effect of the protective effect of human milk oligosaccharides (HMOs) on allergy prevention in mice. Preclinical assays

[0186] The animal study protocol was approved by the Service Vétérinaire du Canton de Vaud, Switzerland. Briefly, 5 week-old female BALB / c mice were fed a diet supplemented with a HMO mixture of 2’FL and LNnT (2:1 weight ratio) at either 0%, 0.2%, 1%, 5% or 10% (by weight) starting at week 0 of the protocol. The backs of the mice were shaved and cleaned with 70% isopropanol solution (VWR; Nyon, Switzerland) and transepidermal water loss (TEWL) wasmeasured as described below. During week 3, 100µL ofAspergillus flumigatus (Af) protein extract (Greer Laboratories; Lenoir, NC, USA) at 2 mg / mL (Sensitized group (S.)) or 100 µL of a 0.9 % NaCl solution (non-sensitized group (N.S.); Merck: Zoug, Switzerland) was applied to a 1x1 cm patch of sterile gauze (Hartmann; Dermaplast, Chatenois, France) and secured to the skin with a bio-occlusive transparent dressing (Systagenix; Bioclusive, San Antonio, Texas, USA, Switzerland) and a Band-Aid (Mefix; Wasquehal, France). Subsequently, TEWL was again measured. After a 2-week resting period, a second, identical patch was applied for a further week and subsequently TEWL was again measured. Mice were then challenged intranasally with Af diluted in 0.9% NaCl. Mice were subsequently anaesthetised using isoflurane and euthanised after collecting blood from the abdominal aorta. Specific IgG1 quantification

[0187] Ninety-six well plates (Nunc Maxisorp; VWR) were coated overnight at 4°C with Af protein extract (Greer Laboratories) at 50 µg / ml in carbonate buffer. Plates were then washed with PBS‑0.05% Tween (Biorad, Reinach, Switzerland) and blocked with PBS‑1 % BSA (Sigma) for 1 h at 37°C. Diluted sera were incubated for 2 hat 37°C. After washing, plates were incubated 2 hat 37°C with horseradish peroxidase (HRP)‑conjugated goat anti-mouse IgG1‑ (Southern Biotech, Bioconcept Allschwil, Switzerland), and then with the HRP substrate tetramethylbenzidine (TMB) (KPL, Socochim, Lausanne, Switzerland). The reaction was stopped using 1 N hydrochloric acid (HCl, Merck). Absor- bance was measured at 450 nm and the results expressed as optical density (OD) values. Statistical analysis

[0188] Statistical analysis was performed using JMP Pro 14 (SAS Software, Cary, USA). Figures were drawn with GraphPad Prism 6 (GraphPad Software, San Diego, USA). For all tests, a p-value of >0.05 was considered significant for 14 EP 4 649 837 A2 5 10 15 20 25 30 35 40 45 50 55 the association.

[0189] For animal experimentation, the exact Wilcoxon non-parametric statistical test was used to compare groups. Statistical analyses were performed using the software R 2.14.1. Results with a p-value ≤0.05 were considered as significant. Data are expressed as median± standard error (SE) of the median. Beneficial effects of HMOs on allergic sensitisation

[0190] To confirm that 2’FL andLnNTare able to protect against allergic sensitisation, weused an animalmodel to study theefficacyof a2’FL:LNnTmix.Sensitisationof animals in askin sensitisationmousemodelwasachievedepicutaneously using Aspergillus fumigatus.

[0191] The variations in specific IgGwith HMO level observed from these studies confirmed that the 2’FL and LNnTare particularly efficacious in preventing allergic sensitisation at the doses of 1% (in the mouse model of skin sensitisation, Figure 3), while less efficacious at a lower or higher doses as shown by the bell-shaped curve. DISCUSSION

[0192] Wehaveshown that 2’FLandLNnTprotect againstallergic sensitisationand that abell-shapedeffect isobserved showing improved protection at intermediate doses.

[0193] All publicationsmentioned in theabovespecificationareherein incorporatedby reference.Variousmodifications and variations of the disclosed uses and methods of the invention will be apparent to the skilled person without departing from the scope and spirit of the invention. Although the invention has been disclosed in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, variousmodificationsof thedisclosedmodes for carryingout the invention,whichareobvious to the skilled person are intended to be within the scope of the following claims. The invention also relates to the following embodiments:

[0194] 1. An infant formula for use in preventing or reducing the occurrence of allergic sensitisation in an infant, wherein the infant formula comprises 0.8‑2.5 g / L 2’-fucosyllactose (2’FL) and / or 0.05‑0.2 g / L lacto-N-neotetraose (LNnT). 2. The infant formula for use according to embodiment 1, wherein the infant formula comprises 0.8‑1.5 g / L, 1‑1.5 g / L, or about 1 g / L 2’FL, preferably wherein the infant formula comprises about 1 g / L 2’FL. 3. The infant formula for use according to embodiment 1, wherein the infant formula comprises 1.5‑2.5 g / L, 1.5‑2 g / L, 1.6‑2 g / L, or about 1.8 g / L 2’FL, preferably wherein the infant formula comprises about 1.8 g / L 2’FL. 4. The infant formula for use according to anypreceding embodiment,wherein the infant formula comprises0.05‑0.15 g / L or about 0.1 g / L LNnT, preferably wherein the infant formula comprises about 0.1 g / L LNnT. 5. The infant formula for use according to any preceding embodiment, wherein the infant formula comprises 2’FL and LNnT. 6. The infant formula for use according to embodiment 5, wherein the infant formula comprises about 1.8 g / L 2’FL and about 0.1 g / L LNnT. 7. The infant formula for use according to any preceding embodiment, wherein the infant formula is an extensively hydrolysed infant formula (eHF) or an amino acid-based infant formula (AAF). 8. The infant formula for use according to any preceding embodiment, wherein the infant formula comprises protein, carbohydrate and fat. 9. The infant formula for use according to any preceding embodiment, wherein the infant formula comprises: (a) 1.8‑3.2 g protein per 100 kcal; (b) 9‑14 g carbohydrate per 100 kcal; and / or 15 EP 4 649 837 A2 5 10 15 20 25 30 35 40 45 50 55 (c) 4.0‑6.0 g fat per 100 kcal. 10. The infant formula for use according to any preceding embodiment, wherein the infant formula comprises about 2.4 g or less protein per 100 kcal. 11. The infant formula for useaccording to anyprecedingembodiment,wherein the infant formula comprises1.8‑2.4g protein per 100 kcal, 2.1‑2.3 g protein per 100 kcal, or2.15‑2.25 g protein per 100 kcal, preferably wherein the infant formula comprises about 2.2 g protein per 100 kcal. 12. The infant formula for use according to any preceding embodiment, wherein about 30%or less byweight of the fat is medium chain triglycerides (MCTs). 13. The infant formula for use according to any preceding embodiment, wherein about 25% or less by weight, 20% or less byweight, 15%or less byweight, 10%or less byweight, 5%or less by weight, or 1% or less byweight of the fat in the infant formula is medium chain triglycerides (MCTs). 14. The infant formula for use according to any preceding embodiment, wherein the infant formula comprises no added MCTs. 15. A method for preventing or reducing the occurrence of allergic sensitisation in an infant, wherein the method comprises administering to the infant an infant formula, wherein the infant formula comprises 0.8‑2.5 g / L 2’- fucosyllactose (2’FL) and / or 0.05‑0.2 g / L lacto-N-neotetraose (LNnT). Claims 1. An infant formula for use in preventing or reducing the occurrence of allergic sensitisation in an infant, wherein the infant formula comprises 0.8‑2.5 g / L 2’-fucosyllactose (2’FL) and / or 0.05‑0.2 g / L lacto-N-neotetraose (LNnT). 2. The infant formula for use according to claim 1, wherein the infant formula comprises 0.8‑1.5 g / L, 1‑1.5 g / L, or about 1 g / L 2’FL, preferably wherein the infant formula comprises about 1 g / L 2’FL. 3. The infant formula for use according to claim 1, wherein the infant formula comprises 1.5‑2.5 g / L, 1.5‑2 g / L, 1.6‑2 g / L, or about 1.8 g / L 2’FL, preferably wherein the infant formula comprises about 1.8 g / L 2’FL. 4. The infant formula for use according to any preceding claim, wherein the infant formula comprises 0.05‑0.15 g / L or about 0.1 g / L LNnT, preferably wherein the infant formula comprises about 0.1 g / L LNnT. 5. The infant formula for use according to any preceding claim, wherein the infant formula comprises 2’FL and LNnT. 6. The infant formula for use according to claim 5, wherein the infant formula comprises about 1.8 g / L 2’FL and about 0.1 g / L LNnT. 7. The infant formula for use according to any preceding claim, wherein the infant formula is an extensively hydrolysed infant formula (eHF) or an amino acid-based infant formula (AAF). 8. The infant formula for use according to any preceding claim, wherein the infant formula comprises protein, carbohydrate and fat. 9. The infant formula for use according to any preceding claim, wherein the infant formula comprises: (a) 1.8‑3.2 g protein per 100 kcal; (b) 9‑14 g carbohydrate per 100 kcal; and / or (c) 4.0‑6.0 g fat per 100 kcal. 10. The infant formula for use according to any preceding claim, wherein the infant formula comprises about 2.4 g or less protein per 100 kcal. 16 EP 4 649 837 A2 5 10 15 20 25 30 35 40 45 50 55 11. The infant formula for useaccording toanyprecedingclaim,wherein the infant formulacomprises1.8‑2.4gproteinper 100 kcal, 2.1‑2.3 g protein per 100 kcal, or 2.15‑2.25 g protein per 100 kcal, preferably wherein the infant formula comprises about 2.2 g protein per 100 kcal. 12. The infant formula for use according to any preceding claim, wherein about 30%or less by weight of the fat ismedium chain triglycerides (MCTs). 13. The infant formula for use according to any preceding claim, wherein about 25% or less by weight, 20% or less by weight, 15%or lessbyweight, 10%or lessbyweight, 5%or lessbyweight, or 1%or lessbyweight of the fat in the infant formula is medium chain triglycerides (MCTs). 14. The infant formula for use according to any preceding claim, wherein the infant formula comprises no added MCTs. 17 EP 4 649 837 A2 5 10 15 20 25 30 35 40 45 50 55 18 EP 4 649 837 A2 19 EP 4 649 837 A2 20 EP 4 649 837 A2 21 EP 4 649 837 A2 REFERENCES CITED IN THE DESCRIPTION This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard. Patent documents cited in the description • US 5288637 A

[0053] • WO 1996010086 A

[0053] • EP 880902 A

[0092] • WO 2016156077 A

[0098] • WO 1993004593 A1

[0114] • WO 2016156077 A1

[0115] Non-patent literature cited in the description • MARTINS, T.B. et al. J Allergy Clin Immunol, 2014, vol. 133, 589-91

[0002] • QUANTEM. et al. BMC Public Health, 2012, vol. 12, 1021

[0003] • SEPPO, A.E. et al. J Allergy Clin Immunol, 2017, vol. 139, 708-11

[0003] • AZAD, M.B. et al. J Nutr, 2018, vol. 148, 1733-42

[0003] • Pediatrics. American Academy of Pediatrics, 2000, vol. 106, 346-349

[0040] • WRODNIGG, T.M. ; STUTZ, A.E. Angew. Chem. Int. Ed., 1999, vol. 38, 827-828

[0053] • MAUBOIS, J.L. ; LORIENT, D. Dairy Science & Technology, 2016, vol. 96 (1), 15-25

[0079] • EFSA NDA Panel. EFSA journal, 2014, vol. 12 (7), 3760

[0084] • ADLER-NISSEN, J. J. Agric. Food Chem., 1979, vol. 27, 1256-1262

[0096] • JOHNS, P.W. et al. Food chemistry, 2011, vol. 125 (3), 1041-1050

[0098] • CHAUVEAU, A. et al. Pediatric Allergy and Immu- nology, 2016, vol. 27 (5), 541-543

[0098] • NUTTEN. EMJ Allergy Immunol, 2018, vol. 3 (1), 50- 59

[0099] • BORSCHEL, M. et al. Nutrients, 2018, vol. 10 (3), 289

[0138] • MARTINS, T.B. et al. J Allergy Clin Immunol, 2014, vol. 133 (2), 589-91

[0157]

[0175] • SEPPO, A.E. et al. J Allergy Clin Immunol, 2017, vol. 139 (2), 708-11

[0174] • QUANTE,M. et al.BMCPublic Health, 2012, vol. 12, 1021

[0176] • POULAIN, T. et al. European Journal of Epidemiol- ogy, 2017, vol. 32 (2), 145-58

[0176] (19) *EP004649837A3* (11) EP 4 649 837 A3 (12) EUROPEAN PATENT APPLICATION (88) Date of publication A3: 21.01.2026 Bulletin 2026 / 04 (43) Date of publication A2: 19.11.2025 Bulletin 2025 / 47 (21) Application number: 25198278.1 (22) Date of filing: 28.12.2020 (51) International Patent Classification (IPC): A23L 33 / 00 (2016.01) (52) Cooperative Patent Classification (CPC): A23L 33 / 40 (84) Designated Contracting States: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR (30) Priority: 30.12.2019 EP 19219957 (62) Document number(s) of the earlier application(s) in accordance with Art. 76 EPC: 20841726.1 / 4 084 628 (71) Applicant: Société des Produits Nestlé S.A. 1800 Vevey (CH) (72) Inventors: • BLANCHARD, Carine Le Mont-sur-Lausanne (CH) • HOLVOET, Sébastien Montpreveyres (CH) (74) Representative: Elkington and Fife LLP Prospect House 8 Pembroke Road Sevenoaks, Kent TN13 1XR (GB) (54) INFANT FORMULA (57) An infant formula for use in preventing or redu- cing the occurrence of allergic sensitisation in an infant, wherein the infant formula comprises 0.8‑2.5 g / L 2’-fu- cosyllactose (2’FL) and / or 0.05‑0.2 g / L lacto-N-neote- traose (LNnT). EP 4 64 9 83 7 A 3 Processed by Luminess, 75001 PARIS (FR) 2 EP 4 649 837 A3 5 10 15 20 25 30 35 40 45 50 55 3 EP 4 649 837 A3 5 10 15 20 25 30 35 40 45 50 55 4 EP 4 649 837 A3 5 10 15 20 25 30 35 40 45 50 55 5 EP 4 649 837 A3 5 10 15 20 25 30 35 40 45 50 55 6 EP 4 649 837 A3 5 10 15 20 25 30 35 40 45 50 55 7 EP 4 649 837 A3 5 10 15 20 25 30 35 40 45 50 55 8 EP 4 649 837 A3 5 10 15 20 25 30 35 40 45 50 55 PH 260175 EP 25198278.1 PH 260175 Title: INFANT FORMULA 发明名称: 婴儿配方食品 Abstract / 摘要 An infant formula for use in preventing or reducing the occurrence of allergic sensitisation in an infant, wherein the infant formula comprises 0.8-2.5 g / L 2'-fucosyllactose (2'FL) and / or 0.05-0.2 g / L lacto-N-neotetraose (LNnT). 本发明提供了用于在预防或减少婴儿的变应性致敏的发生中使用的婴儿配方食品，其 中所述婴儿配方食品包含 0.8‑2.5g / L 2'‑岩藻糖基乳糖(2'FL)和 / 或 0.05‑0.2g / L 乳糖‑N‑新 四糖(LNnT)。 摘 要

Claims

1. An infant formula for use in preventing or reducing the occurrence of allergic sensitisation in an infant, wherein the infant formula comprises 0.8-2.5 g / L 2'-fucosyllactose (2'FL) and / or 0.05-0.2 g / L lacto-N-neotetraose (LNnT).

2. The infant formula for use according to claim 1, wherein the infant formula comprises 0.8-1.5 g / L, 1-1.5 g / L, or about 1 g / L 2'FL, preferably wherein the infant formula comprises about 1 g / L 2'FL.

3. The infant formula for use according to claim 1, wherein the infant formula comprises 1.5-2.5 g / L, 1.5-2 g / L, 1.6-2 g / L, or about 1.8 g / L 2'FL, preferably wherein the infant formula comprises about 1.8 g / L 2'FL.

4. The infant formula for use according to any preceding claim, wherein the infant formula comprises 0.05-0.15 g / L or about 0.1 g / L LNnT, preferably wherein the infant formula comprises about 0.1 g / L LNnT.

5. The infant formula for use according to any preceding claim, wherein the infant formula comprises 2'FL and LNnT.

6. The infant formula for use according to claim 5, wherein the infant formula comprises about 1.8 g / L 2'FL and about 0.1 g / L LNnT.

7. The infant formula for use according to any preceding claim, wherein the infant formula is an extensively hydrolysed infant formula (eHF) or an amino acid-based infant formula (AAF).

8. The infant formula for use according to any preceding claim, wherein the infant formula comprises protein, carbohydrate and fat.

9. The infant formula for use according to any preceding claim, wherein the infant formula comprises: (a) 1.8-3.2 g protein per 100 kcal; (b) 9-14 g carbohydrate per 100 kcal; and / or (c) 4.0-6.0 g fat per 100 kcal.

10. The infant formula for use according to any preceding claim, wherein the infant formula comprises about 2.4 g or less protein per 100 kcal.

11. The infant formula for use according to any preceding claim, wherein the infant formula comprises 1.8-2.4 g protein per 100 kcal, 2.1-2.3 g protein per 100 kcal, or 2.15-2.25 g protein per 100 kcal, preferably wherein the infant formula comprises about 2.2 g protein per 100 kcal.

12. The infant formula for use according to any preceding claim, wherein about 30% or less by weight of the fat is medium chain triglycerides (MCTs).

13. The infant formula for use according to any preceding claim, wherein about 25% or less by weight, 20% or less by weight, 15% or less by weight, 10% or less by weight, 5% or less by weight, or 1% or less by weight of the fat in the infant formula is medium chain triglycerides (MCTs).

14. The infant formula for use according to any preceding claim, wherein the infant formula comprises no added MCTs.

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