RU2826110C2 - Compositions for use in preventing or treating otitis media or bronchitis in infants or younger children - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: present invention relates to a method for preventing and/or treating infections and/or inflammations of the lower respiratory tract and/or ear in an infant or a young child, wherein the method involves administering to an infant or young child a nutritional composition containing 2'-fucosylactose (2'-FL) as a single fucosylated oligosaccharide and lacto-N-neotetraose (LNnT) as the only N-acetylated oligosaccharide, wherein 2'-FL is present in a total amount of 0.75–1.65 g/l of the composition and/or in a total amount of 0.52–1.15 g/100 g of the composition in terms of dry weight; and LNnT is present in a total amount of 0.45–0.85 g/l of the composition and/or in a total amount of 0.31–0.59 g/100 g of the composition based on the dry weight; wherein composition does not contain sialylated oligosaccharide(s), and wherein infections and/or inflammations of the lower respiratory tract and/or ear are selected from the group consisting of pneumonia, bronchitis, bronchiolitis, otitis media, otitis media and combinations thereof.

EFFECT: present invention provides a synergetic effect of 2'-fucosyllactose and lacto-N-neotetraose when used to prevent and/or treat infections and/or inflammations of the lower respiratory tract and/or ear in an infant or a young child.

8 cl, 10 dwg, 1 tbl, 2 ex

Description

Field of technology to which the invention relates

The present invention relates to compositions for use in the prevention and/or treatment of infections and/or inflammation of the lower respiratory tract and/or ear, such as bronchitis or otitis, in infants or young children.

State of the art

Infections and/or inflammations of the respiratory tract are very common, especially in infants and young children, due to their physical weakness and immaturity of the immune defense elements (e.g. their respiratory tract is not yet sufficiently able to resist such infections and/or inflammations). For example, in the first year of life, an infant will often have three to six such infections. Such infections and/or inflammations may be of bacterial origin, viral origin, or the result of environmental influences.

Respiratory tract infections can affect different parts of the respiratory tract of infants and young children. Possible upper respiratory tract infections (also called URIs or URTIs) can be illnesses caused by an acute infection that affects the upper respiratory tract: the nose, paranasal sinuses, pharynx, and/or larynx. The most common examples of URIs are rhinitis, rhinosinusitis, nasopharyngitis, pharyngitis, epiglottitis, laryngitis, tonsillitis, laryngotracheitis, tracheitis, or a combination of these. URIs are often caused by viruses. More than 200 different viruses have been identified in patients with URIs. The most common virus is called rhinovirus. Other viruses include coronavirus, parainfluenza virus, adenovirus, enterovirus, and respiratory syncytial virus.

Another type of respiratory tract infection is called a lower respiratory tract infection (also called a LRT infection or LRTI). These are illnesses caused by an acute infection involving the lower respiratory tract (i.e., the lower airways): the trachea, bronchi, bronchioles, and/or lungs. Examples of lower respiratory tract infections include pneumonia, bronchitis, bronchiolitis.

URTI may sometimes be preceded by a common viral URTI.

LRT infections can be caused by bacteria or viruses. Some examples of bacteria that cause such infections are Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, Klebsiella pneumoniae, Enterobacteriaceae such as Escherichia coli, anaerobes. Some examples of viruses that cause such infections are Influenza A virus, Respiratory syncytial virus (RSV), Human metapneumovirus (HMPV), Varicella zoster virus.

The main symptoms of LRT infections are wheezing, feeding difficulties, increased irritability, poor sleep, coughing and/or tachypnea. LRT infections may also be accompanied by fever.

In the past, most LRT infections were fatal, but thanks to modern research and medications, they are now treatable. Bacterial infections are treated with antibiotics, while viral infections are more difficult to treat, but still curable. For lower respiratory tract infections, antibiotics are often considered first-line therapy; however, they are not indicated for viral infections. There are also concerns about increasing bacterial resistance to antibiotic treatment.

Certain environmental factors, such as inhalation of smoke, chemicals, air pollution (eg, fossil fuel particles (diesel, coal)) and sandstorms, can also cause lower respiratory tract inflammation, such as pneumonia.

Ear infections and/or inflammations are also common in infants and young children. They can be bacterial or viral in origin. Some examples of ear infections and/or inflammations include ear infections, ear inflammations, otitis media, otitis media, acute otitis media, otitis externa, mastoiditis, labyrinthitis. Otitis externa is inflammation of the outer ear, mastoiditis is inflammation of the mastoid process, and labyrinthitis is inflammation of the inner ear. The most common example of ear infections and/or inflammations is otitis media, such as otitis media, which is inflammation of the middle ear. Otitis media can include: acute otitis media, otitis media with effusion, intractable acute otitis media, recurrent acute otitis media, complicated otitis media, or chronic suppurative otitis media.

Otitis media may also be preceded by a URI and/or LRTI (so that an infant or young child may have both a lower respiratory tract infection/inflammation and an ear infection/inflammation). The main symptom of otitis media is ear pain, but it may also be accompanied by fever and/or increased irritability. It is a middle ear infection in which the eustachian tube, which connects the middle ear cavity to the outside environment through the mouth, becomes inflamed and then blocked, trapping bacteria in the middle ear. The middle ear cavity also becomes inflamed with a build-up of fluid, which causes pressure to build up, which is perceived by the patient as pain, due to the inability to equalize pressure between the middle ear and the outside environment through the eustachian tube as in healthy people. In severe cases, the eardrum may rupture under the pressure, allowing infected fluid to leak into the inner ear. This is a potentially serious condition that, if left untreated, can lead to permanent hearing loss. Up to 50% of children have at least one episode of acute otitis media in the first year of life (i.e., infancy), and up to 35% of children between the ages of one and three (i.e., younger) have recurrent episodes of acute otitis media. This, in turn, can lead to a condition called otitis media with effusion, in which fluid is not completely drained from the middle ear between episodes of infection. If this condition stabilizes, surgery may be needed.

Acute otitis media appears to be primarily associated with the activity of pathogenic bacteria that are commonly present in the natural microbiota of the nasopharynx. From a quantitative point of view, the most important pathogens are Streptococcus pneumoniae (35% of cases), non-typeable Haemophilus influenzae (30% of cases), and Moraxella catarrhalis (10% of cases). For this reason, acute otitis media is usually treated with antibiotics, especially in infants. Indeed, antibiotics are prescribed more often for otitis media than for any other condition in infants. This has also inevitably led to the development of resistance to commonly prescribed antibiotics in bacterial strains associated with otitis media. For example, at least 20% of S. pneumoniae strains are considered to be resistant to penicillins and cephalosporins. Similarly, at least 30% of H. influenzae strains and most M. catarrhalis strains have developed resistance to antibiotics. This high rate of antibiotic prescription is at least partly due to the pain experienced by infants and young children with otitis media, who respond to the pain with prolonged crying that parents and other caregivers try hard to soothe. Otitis media can also be caused by viruses, such as RSV and rhinovirus, which causes the common cold. In these cases, antibiotic treatment will be ineffective.

There is therefore a clear need for alternative ways to reduce the incidence of these painful and potentially serious illnesses in infants and young children.

There have been many attempts to develop alternative approaches to prevent/treat lower respiratory tract and ear infections and/or inflammations. In particular, probiotics have been studied. Probiotics are considered to be viable microorganism-based preparations that promote the health of an individual by preserving the natural microflora in the intestine. Probiotics are supposed to attach to the intestinal mucosa, colonize the intestine and in the same way prevent harmful microorganisms from attaching to it. The most important condition for their action is that they must reach the intestinal mucosa in a proper and viable form and must not be destroyed in the upper gastrointestinal tract, in particular under the influence of the low pH prevailing in the stomach.

For example, Danisco's WO2008042101 discloses methods for reducing the incidence of respiratory disease in children, comprising: providing a culture of L. acidophilus; identifying a child at risk of developing a respiratory disease; and administering the culture of L. acidophilus to the child at risk under conditions such that the risk of developing a respiratory disease is reduced. However, adding live probiotic bacteria to products so that they remain viable until consumption is not a trivial task. In particular, it is difficult to implement for products with a long shelf life and may require additional technical efforts.

The present invention is aimed at children, preferably between 3 and 5 years of age.

Other options other than probiotics are also being explored, such as the use of oligosaccharides, particularly human milk oligosaccharides (HMOs). Human milk oligosaccharides (HMOs) are collectively the third largest component (on a dry matter basis) in human milk after lactose and fat. HMOs typically consist of lactose at the reducing end with a carbohydrate core that often contains fucose or sialic acid at the non-reducing end. Over one hundred HMOs have been isolated and characterized from human milk.

Breast milk is recommended for all infants. However, in some cases breastfeeding is insufficient or unsuccessful for medical reasons, or the mother refuses to breastfeed. Infant formulas have been developed for these situations. Fortifiers have also been developed to fortify breast milk or infant formula with certain ingredients.

Thus, several compositions have been developed for various purposes using OGM ingredients such as fucosylated oligosaccharides, lacto-N-tetraose, lacto-N-neotetraose and/or sialylated oligosaccharides.

For example, patent WO2005055944 of the Children's hospital medical center describes a pharmaceutical composition comprising a molecule that contains a fucose group linked to a galactose group by an alpha-2 linkage, an alpha-3 linkage or an alpha-4 linkage, and a pharmaceutically acceptable carrier. Various molecules such as 2'-fucosyllactose are described. This application is quite general in nature, since the prevention or treatment of several infections, including respiratory or intestinal infections, in a large target group of patients (infants, children or adults) is possible.

Application WO2012092158 filed by Abbott relates to an infant formula containing a mixture of sialylated oligosaccharides in defined amounts for modulating inflammation caused by respiratory viruses.

Applications WO2009/059996 and WO2012/076323 filed by Nestec SA describe compositions with a mixture of OGMs, which necessarily contain sialylated oligosaccharides as components necessary for the prevention of secondary infections or acute respiratory infections (ARI).

Additional studies have focused on various associations of OGM with the probiotic strain or with other specific components.

For example, document WO2009/077352 by Nestec SA relates to a composition suitable for the prevention of opportunistic infections and comprising a specific synergistic combination of a Bifidobacterium probiotic with a fucosylated oligosaccharide. Among the opportunistic infections to be prevented are respiratory tract infections. The present invention is particularly aimed at immunocompromised individuals, such as premature infants, older children or adults with an incompletely effective immune system due to an existing pathological condition or disease (e.g. HIV) or due to therapy for an existing pathological condition, e.g. Crohn's disease or rheumatoid arthritis, or chemotherapy for the treatment of cancer).

Oligosaccharides in general are known to have a protective role when applied to the gastrointestinal, respiratory or urinary tract, see for example Wataru et al., 2003, and WO9843494. However, most of these studies describe different OSMs without linking the specific oligosaccharide type or synergistic combination to a specific benefit. They also describe different concentration examples and only report a general beneficial effect (i.e. without a focus on the lower respiratory tract and ear).

Abbott's WO2012/092154 relates to methods of using HMOs to improve airway health in infants, toddlers, and other children. However, this application provides an extensive list of HMOs, as well as several combinations of different HMOs. The composition is stated to be effective only when the HMOs are present together with a carotenoid.

Application WO2012092155 describes compositions containing OGM with another type of prebiotic, which is selected from the list of GOS or FOS, and designed to have a beneficial effect on the gastrointestinal tract.

A number of other studies also relate to the treatment/prevention of pathogenic URT infections, which differ from LRT because they affect or involve other tissues/organs of the body, as noted above. For example, patent WO2009/112361 of Nestec SA relates to another composition suitable for the prevention of opportunistic infections and comprising a specific synergistic combination of N-acetyl-lactosamine and/or an oligosaccharide containing N-acetyl-lactosamine with a probiotic Lactobacillus sp. Several pathological conditions are given as an example, such as upper respiratory tract infections caused by pathogenic microorganisms.

Thus, none of the previous studies describe the prevention and/or treatment of lower respiratory tract and ear infections/inflammations in infants or young children, although they are at higher risk of developing such infections/inflammations than average.

There is a clear need to develop acceptable ways to reduce the incidence of such diseases in infants and young children.

There is also a need to provide such health benefits in a way that is particularly suitable for young subjects (infants and young children), and the way should not involve classical pharmaceutical intervention, since these infants and young children are particularly vulnerable.

There is a need to provide these health benefits to these infants and young children in a manner that does not cause side effects and/or is easy to administer and acceptable to parents or health care professionals.

There is also a need to provide such benefits in a way that keeps the cost of such provision reasonable and affordable to the majority.

Thus, there is a clear need to develop alternatives to classical pharmaceutical interventions such as antibiotics, at least because of the above-mentioned problems of resistance development.

There is also a need to develop an alternative treatment approach that can be effective across a broad range of sources, i.e., independent of the cause of infection and/or inflammation (e.g. bacterial, viral or environmental origin).

Disclosure of invention

The inventors of the present invention have found that a composition comprising at least one fucosylated oligosaccharide and at least one N-acetylated oligosaccharide, both in certain amounts, can be advantageously used as a remedy for lower respiratory tract infections and/or inflammations, such as bronchitis, as well as ear infections and/or inflammations, such as otitis, in an infant or young child. Without being limited by theory, it is believed that such oligosaccharide(s) exhibit(s) a synergistic effect in the case of such specific diseases.

Accordingly, for this reason, the present invention provides a nutritional composition comprising at least one fucosylated oligosaccharide and at least one N-acetylated oligosaccharide for use in the prevention and/or treatment of lower respiratory tract and/or ear infections and/or inflammations in an infant or young child, wherein:

- the fucosylated oligosaccharide(s) is(are) present in a total amount of 0.75-1.65 g/l of the composition and/or in a total amount of 0.52-1.15 g/100 g of the composition, calculated on the dry matter weight; and

- N-acetylated oligosaccharide(s) is(are) present in a total amount of 0.45–0.85 g/l of the composition and/or in a total amount of 0.31–0.59 g/100 g of the composition, calculated on the dry matter weight.

In a particularly advantageous embodiment, the nutritional composition comprises 2'-fucosyllactose (2-FL) and lacto-N-neotetraose (LNnT), and in particular 2'-fucosyllactose (2-FL) in an amount of 1-1.5 g/l of the nutritional composition and LNnT in an amount of 0.5-0.7 g/l of the nutritional composition.

The inventors of the present invention have also found that a particular nutritional composition according to the invention is particularly effective in reducing fever and administering (i.e. administering) antibiotics and administering antipyretics to an infant or young child.

Brief description of the figures

Figure 1 shows the number of infants with at least one episode of bronchitis, and these infants received either standard infant formula (control group) or standard formula supplemented with 1.24 g/L 2'-fucosyllactose and 0.63 g/L lacto-N-neotetraose (FGM group). Among infants delivered by cesarean section, OR = 0.15, p = 0.02; among infants delivered vaginally, OR = 0.42, p = 0.095; among all infants, OR = 0.3, p = 0.004. In the control group, n = 87, and in the FGM group, n = 88.

Fig. 1A: Partial results (data were not available for all infants) during the first 12 months after birth.

Fig. 1B: Complete results (data on all infants were obtained) for 0–4, 0–6, and 0–12 months after birth.

Figure 2 shows the number of infants with at least one ear infection/inflammation during the first 12 months after birth, and these infants received either standard infant formula (control group) or standard formula supplemented with 1.24 g/L 2'-fucosyllactose and 0.63 g/L lacto-N-neotetraose (FGM group). Among all infants, OR = 0.3, p = 0.06. In the control group, n = 87, and in the FGM group, n = 88.

Fig. 2A: Partial results (data were not available for all infants) during the first 12 months after birth.

Fig. 2B: Complete results (data on all infants were obtained) for 0–4, 0–6, and 0–12 months after birth.

Figure 3 shows the number of infants who were given antibiotics at least once during the first 12 months after birth, and these infants received either standard infant formula (control group) or standard formula supplemented with 1.24 g/L 2'-fucosyllactose and 0.63 g/L lacto-N-neotetraose (FGM group). Among infants born by cesarean section, OR = 0.5, p = 0.2; among infants born vaginally, OR = 0.45, p = 0.068; among all infants, OR = 0.47, p = 0.025. In the control group, n = 87, and in the FGM group, n = 88.

Fig. 3A: Partial results (data were not available for all infants) during the first 12 months after birth.

Fig. 3B: Complete results (data on all infants were obtained) for 0–4, 0–6, and 0–12 months after birth.

Figure 4 shows the number of infants with at least one episode of fever during the first 12 months after birth, and these infants received either standard infant formula (control group) or standard formula supplemented with 1.24 g/L 2'-fucosyllactose and 0.63 g/L lacto-N-neotetraose (FGM group). Among infants delivered by cesarean section, OR = 0.3, p = 0.6; among infants delivered vaginally, OR = 0.4, p = 0.15; among all infants, OR = 0.4, p = 0.08. In the control group, n = 87, and in the FGM group, n = 88.

Fig. 4A: Partial results (data were not available for all infants) during the first 12 months after birth.

Fig. 4B: Complete results (data on all infants were obtained) for 0–4, 0–6, and 0–12 months after birth.

Figure 5 shows the total number of events per bronchitis group at 0–6 months postnatal (Figure 5A), ear infection/inflammation group at 0–12 months postnatal (Figure 5B), antibiotic use at 0–6 months postnatal (Figure 5C), and antipyretic use at 0–6 months postnatal (Figure 5D) in infants who received either standard formula (control group) or standard formula supplemented with 1.24 g/L 2'-fucosyllactose and 0.63 g/L lacto-N-neotetraose (FNM group) (partial results—data were not available for all infants). Antibiotics include all prescribed drugs that have the ability to inhibit the growth of or kill microorganisms. Antipyretics include all prescribed medications that have the ability and are intended to reduce temperature.

Figure 6 shows the total number of events per bronchitis group (Figure 6A), ear infection/inflammation group (Figure 6B), antibiotic group (Figure 6C), and antipyretic group (Figure 6D) during 0–12 months after birth in infants who received either standard formula (control group) or standard formula supplemented with 1.24 g/L 2’-fucosyllactose and 0.63 g/L lacto-N-neotetraose (FNM group). Full results (data available for all infants). The # symbol represents the number.

Implementation of the invention

In the context of this document, the following terms have the definitions below.

The term "infant" means a child under 12 months of age.

The term "toddler" means a child between the ages of one and three (also called a toddler).

"Infant or young child delivered by cesarean section" means an infant or young child delivered by cesarean section. This means that the infant or young child was not delivered vaginally.

"Infant or young child delivered vaginally" means an infant or young child who was delivered vaginally and not by cesarean section.

"Preterm" or "premature" means an infant or toddler who is born before the due date. Typically, the term refers to an infant or toddler born before 36 weeks of pregnancy.

The expression "nutritional composition" means a composition that is fed to a subject. This nutritional composition is usually intended for oral or intravenous use and usually includes a lipid or fat source and a protein source.

In a particular embodiment, the composition of the present invention is a hypoallergenic nutritional composition. The expression "hypoallergenic nutritional composition" means a nutritional composition that is unlikely to cause allergic reactions.

In a particular embodiment, the composition of the present invention is an "artificial nutritional composition". The expression "artificial nutritional composition" means a mixture obtained by chemical and/or biological means that may be chemically identical to the mixture of natural origin present in mammalian milk (i.e., the synthetic composition is not breast milk).

The expression "infant formula" in the context of this document refers to a food specifically intended for consumption by infants during the first months of life and which in itself satisfies the nutritional needs of this category of persons (Article 2(c) of Commission Directive 91/321/EEC 2006/141/EC of 22 December 2006 on infant formulae and complementary formulae). It also refers to a nutritional composition intended for infants as defined in the Codex Alimentarius (Codex STAN 72-1981) and the standard for "Special foods for infants" (including the article "Foods for special medical purposes"). The expression "infant formula" includes both "infant formula" and "complementary formula".

"Follow-on formula" or "weaning formula" is given starting from the 6th month. It is the main liquid element in the gradually increasing variety of the diet for people in this category.

The expression "infant food" means a food product specifically intended for use by infants or young children during the first years of life.

The expression "cereal-based infant formula" means a food product specifically intended for use by infants or young children during the first years of life.

The term "fortifier" refers to liquid or solid nutritional compositions suitable for mixing with breast milk or infant formula.

The term "weaning period" refers to the period during which breast milk is replaced by another food in the diet of an infant or young child.

The expressions "at the age of days/weeks/months/years" and "days/weeks/months/years after birth" can be used interchangeably.

The expression "prevention and/or treatment of infections and/or inflammations of the lower respiratory tract and/or ear" includes one or more of the following items:

- prevention of lower respiratory tract infections;

- prevention of ear infections;

- prevention of inflammation of the lower respiratory tract;

- prevention of ear inflammation;

- treatment of lower respiratory tract infections;

- treatment of ear infections;

- treatment of inflammation of the lower respiratory tract;

- treatment of ear inflammations.

The terms "lower respiratory tract infections", "LRTIs" and "LRTIs" can be used interchangeably. They are diseases caused by acute infection involving the lower respiratory tract (i.e. the lower airways): the trachea, bronchi, bronchioles and/or lungs. Examples of LRT infections are pneumonia, bronchitis, bronchiolitis or a combination of these. As detailed above, LRT infections can be bacterial in origin, viral in origin or result from environmental exposure.

The expressions "ear infections and/or inflammations" and "ear infections and/or inflammations" can be used interchangeably. They include ear infections, ear inflammations, otitis, otitis media, acute otitis media, otitis externa, mastoiditis, labyrinthitis. As detailed above, such infections and/or inflammations can be bacterial in origin, viral in origin, or result from environmental exposure.

The expressions “in the prevention of infections and/or inflammations”, “for the prevention of infections and/or inflammations”, “during the prevention of infections and/or inflammations” and “for the purpose of preventing infections and/or inflammations” may be used interchangeably.

Such expressions include preventing the occurrence of infections and/or inflammations of the LRTI/ear and/or reducing the frequency of occurrence of said infections and/or inflammations (reducing the frequency, i.e. the number of infections and/or inflammations of the LRTI/ear). In some embodiments, the prevention of infections and/or inflammations of the LRTI/ear occurs during treatment (i.e. during administration of the composition of the present invention, either immediately after the start of administration or some time after the start, such as several days or weeks). It may also include the prevention of infections and/or inflammations of the LRTI/ear in later life. The term "later life" includes the effect after the cessation of the intervention or treatment. The effect "later life" may last from 1 week to several months, such as from 2 to 4 weeks, from 2 to 6 weeks, from 2 to 8 weeks, from 1 to 6 months or from 2 to 12 months.

The expressions “in the treatment of infections and/or inflammations”, “for the treatment of infections and/or inflammations”, “during the treatment of infections and/or inflammations” and “for the treatment of infections and/or inflammations” may be used interchangeably.

These should be understood to include a reduction in the duration of LRT/ear infections and/or inflammations (the number of days/weeks/years that infants or young children will suffer from LRT/ear infections and/or inflammations), the severity of LRT/ear infections and/or inflammations (the consequences and/or severity of LRT/ear infections and/or inflammations). These expressions also include relief of symptoms such as wheezing, feeding difficulties, increased irritability, poor sleep, cough, tachypnea, ear pain, fever and combinations thereof, and/or reduction of complications caused by infections and/or inflammations of the LRTI/ear to the health of the infant or young child such as asthma, otitis exudative problems, need for surgery, and/or reduction of pain, and/or reduction of fatigue, and/or relief of sleep, and/or stabilization of activity in infants or young children suffering from infections and/or inflammations of the LRTI/ear.

By "mother's milk" we mean the mother's breast milk or colostrum.

An "oligosaccharide" is a saccharide polymer containing a small number (usually three to ten) of simple sugars (monosaccharides).

The term HMO refers to human milk oligosaccharide(s). These carbohydrates are highly resistant to enzymatic hydrolysis, indicating that they may have essential functions beyond their immediate caloric value. Most notably, they have been shown to play a vital role in the early development of infants and young children, such as the development of the immune system. Many different types of HMO have been found in human milk. Each individual oligosaccharide is based on a combination of glucose, galactose, sialic acid (N-acetylneuraminic acid), fucose and/or N-acetylglucosamine, with numerous and varied linkages between them, resulting in the presence of a huge number of different oligosaccharides in human milk – over 130 such structures have been identified to date. Almost all of them have a lactose group at their reducing end, while sialic acid and/or fucose (if present) occupy terminal positions at the non-reducing ends. The OGM can be acidic (e.g., an oligosaccharide containing a charged sialic acid) or neutral (e.g., a fucosylated oligosaccharide).

"Fucosylated oligosaccharide" is an oligosaccharide having a fucose residue. It has a neutral character. Some examples are 2-FL (2'-fucosyllactose), 3-FL (3-fucosyllactose), difucosyllactose, lacto-N-fucopentaose (e.g., lacto-N-fucopentaose I, lacto-N-fucopentaose II, lacto-N-fucopentaose III, lacto-N-fucopentaose V), lacto-N-fucohexaose, lacto-N-difucohexaose I, fucosyllacto-N-hexaose, fucosyllacto-N-neohexaose, difucosyllacto-N-hexaose I, difucosyllacto-N-neohexaose II, and any combination thereof. Although the authors do not wish to be bound by any theory, it is believed that the fucosyl epitope of fucosylated oligosaccharides may act as a "decoy" on the mucosal surface. Through a competitive effect, it may prevent and/or limit the action of pathogens causing infections (viral or bacterial origin) or their secreted components (e.g. toxins) by primarily preventing their binding to natural ligands, and, without being bound by any theory, it is believed that the risk of infections/inflammations, and in particular the risk of developing LRT/ear infections and/or inflammations, will be reduced. Additionally, it is believed that fucosylated oligosaccharides stimulate the growth and metabolic activity of specific commensal microbes, reducing the inflammatory response and creating an unfavorable environment for pathogens, thereby providing colonization resistance.

The expressions "fucosylated oligosaccharides containing a 2'-fucosyl epitope" and "2-fucosylated oligosaccharides" include fucosylated oligosaccharides with some homology in form because they contain a 2'-fucosyl epitope and therefore some homology in function can be expected. Although the authors do not wish to be bound by any theory, it is believed that the 2'-fucosyl epitope of these fucosylated oligosaccharides is particularly characteristic of pathogens (or their secreted components) that cause LRTI and/or ear infections.

The expression "N-acetylated oligosaccharide(s)" includes both "N-acetyllactosamine" and "oligosaccharide(s) containing N-acetyllactosamine". They are neutral oligosaccharides having an N-acetyllactosamine residue. Acceptable examples are LNT (lacto-N-tetraose), para-lacto-N-neohexaose (para-LNnH), LNnT (lacto-N-neotetraose) and any combinations thereof. Other examples are lacto-N-hexaose, lacto-N-neohexaose, para-lacto-N-hexaose, para-lacto-N-neohexaose, lacto-N-octaose, lacto-N-neooctaoses, iso-lacto-N-octaose, para-lacto-N-octaose and lacto-N-decaose.

The expressions “at least one fucosylated oligosaccharide” and “at least one N-acetylated oligosaccharide” mean “at least one type of fucosylated oligosaccharide” and “at least one type of N-acetylated oligosaccharide”.

An "OGM precursor" is a key compound that is involved in the production of OGM, such as sialic acid and/or fucose.

"Sialylated oligosaccharide" is an oligosaccharide containing a charged sialic acid, i.e. an oligosaccharide having a sialic acid residue. It has an acidic character. Some examples are 3-SL (3'-sialyllactose) and 6-SL (6'-sialyllactose).

The nutritional composition of the present invention may be in solid form (e.g. powder) or in liquid form. The amount of the various ingredients (e.g. oligosaccharides) may be expressed in g/100 g of the composition based on the weight of dry matter, if it is in solid form, e.g. powder, or as a concentration in g/l of the composition, if it is in liquid form (the latter case also includes a liquid composition that can be obtained from a powder after dissolution in a liquid, e.g. milk, water, ..., e.g. dissolved infant formulas, or formulas for complementary foods, or a cereal product for baby food, or any other formulation intended for feeding infants).

The term prebiotic refers to non-digestible carbohydrates that exert a beneficial effect on the host by selectively stimulating the growth and/or activity of health-promoting bacteria, such as bifidobacteria, in the human colon (Gibson GR, Roberfroid MB. Dietary modulation of the human colonic microbiota: introducing the concept of prebiotics. J Nutr. 1995; 125:1401–12).

The term "probiotic" refers to preparations of microbial cells or components of microbial cells that confer a beneficial effect on the health or well-being of the host organism. (Salminen S, Ouwehand A. Benno Y. et al. "Probiotics: how should they be defined" Trends Food Sci. Technol. 1999:10, 107–10). The microbial cells are usually bacteria or yeast.

The term "CFU" stands for colony-forming unit.

Unless otherwise stated, all percentages given are by weight.

Additionally, in the context of the invention, the terms "comprising" or "comprises" do not exclude other possible elements. The composition of the present invention, including many embodiments described herein, may comprise, consist of, or essentially consist of the essential elements and features of the invention described herein, as well as any additional or optional ingredients, components, or features of the invention described herein or otherwise as needed.

Any reference to prior art documents in this specification should not be construed as an admission that such prior art is commonly known or forms part of the general knowledge in the art.

The invention will now be described in more detail. It should be noted that the various aspects, features, examples and embodiments described in this application may be compatible and/or combined with each other.

Therefore, a first object of the present invention is a nutritional composition comprising at least one fucosylated oligosaccharide and at least one N-acetylated oligosaccharide, for use in the prevention and/or treatment of infections and/or inflammations of the lower respiratory tract and/or ear in an infant or young child, wherein:

- the fucosylated oligosaccharide(s) is(are) present in a total amount of 0.75-1.65 g/l of the composition and/or in a total amount of 0.52-1.15 g/100 g of the composition, calculated on the dry matter weight; and

- N-acetylated oligosaccharide(s) is(are) present in a total amount of 0.45–0.85 g/l of the composition and/or in a total amount of 0.31–0.59 g/100 g of the composition, calculated on the dry matter weight.

The composition of the present invention comprises at least one fucosylated oligosaccharide. One or more types of fucosylated oligosaccharide(s) may be present. The fucosylated oligosaccharide(s) can be selected from the list comprising 2'-fucosyllactose, 3'-fucosyllactose, difucosyllactose, lacto-N-fucopentaose (e.g. lacto-N-fucopentaose I, lacto-N-fucopentaose II, lacto-N-fucopentaose III, lacto-N-fucopentaose V), lacto-N-fucohexaose, lacto-N-difucohexaose I, fucosyllacto-N-hexaose, fucosyllacto-N-neohexaose (e.g. fucosyllacto-N-neohexaose I, fucosyllacto-N-neohexaose II), difucosyllacto-N-hexaose I, difuco-lacto-N-neohexaose, difucosyllacto-N-neohexaose I, difucosyllacto-N-neohexaose II, fucosyl-p-lacto-N-hexaose, tri-fuco-p-lacto-N-hexaose I and any combination thereof.

In some specific embodiments, the fucosylated oligosaccharide comprises a 2'-fucosyl epitope. It can be, for example, selected from the list comprising 2'-fucosyllactose, difucosyllactose, lacto-N-fucopentaose, lacto-N-fucohexaose, lacto-N-difucohexaose, fucosyllacto-N-hexaose, fucosyllacto-N-neohexaose, difucosyllacto-N-neohexaose, difucosyllacto-N-neohexaose, fucosyl-para-lacto-N-hexaose and any combination thereof.

In a preferred embodiment, the nutritional composition according to the invention comprises 2'-fucosyllactose (or 2FL, or 2'FL, or 2-FL, or 2'-FL). In a particular embodiment, no other type of fucosylated oligosaccharide is used except 2'-fucosyllactose, i.e., the nutritional composition of the present invention comprises only 2'-fucosyllactose as a fucosylated oligosaccharide.

The fucosylated oligosaccharide(s) may be isolated from a natural source such as animal milk by chromatography or filtration. Alternatively, it may be produced by biotechnological means using specific fucosyltransferases and/or fucosidases, or by using an enzyme-based fermentation method (recombinant or natural enzymes), or a microbiological fermentation method. In the latter case, either the microorganisms may express their natural enzymes and substrates, or it is possible to engineer microorganisms that produce the corresponding substrates and enzymes. Cultures of single-species microorganisms and/or mixed cultures may be used. The formation of the fucosylated oligosaccharide may be initiated by acceptor substrates starting from any degree of polymerization (DP) from DP = 1 onwards. Alternatively, the fucosylated oligosaccharides may be produced by chemical synthesis from lactose and free fucose. Fucosylated oligosaccharides are also commercially available, for example from Kyowa Hakko Kogyo, Japan.

The composition of the present invention also comprises at least one N-acetylated oligosaccharide. One or more types of N-acetylated oligosaccharide(s) may be present therein. The N-acetylated oligosaccharide(s) may be, for example, lacto-N-tetraose (LNT), lacto-N-neotetraose (LNnT), or any combination thereof. In some specific embodiments, the N-acetylated oligosaccharide is lacto-N-neotetraose (LNnT), para-lacto-N-neohexaose (para-LNnH), or any combination thereof. In some specific embodiments, the N-acetylated oligosaccharide is LNnT. In some specific embodiments, the N-acetylated oligosaccharide is LNT. In some other specific embodiments, the N-acetylated oligosaccharide is a mixture of LNT and LNnT. In some specific embodiments, the composition comprises both LNT and LNnT in a ratio of LNT:LNnT between 5:1 and 1:2, or from 2:1 to 1:1, or from 2:1.2 to 2:1.6.

In a preferred embodiment, the nutritional composition according to the invention comprises lacto-N-neotetraose (LNnT). In a particular embodiment, no other type of N-acetylated oligosaccharide is used except lacto-N-neotetraose (LNnT), i.e. the nutritional composition of the invention comprises only lacto-N-neotetraose (LNnT) as the N-acetylated oligosaccharide.

N-acetylated oligosaccharide(s) can be synthesized chemically by enzymatic transfer of saccharide units from donor moieties to acceptor moieties using glycosyltransferases as described, for example, in U.S. Patent No. 5,288,637 and WO 96/10086. In an alternative embodiment, LNT and LNnT can be prepared by chemically converting ketohexoses (e.g., fructose), either free or bound to an oligosaccharide (e.g., lactulose), to N-acetylhexosamine or N-acetylhexosamine-containing oligosaccharide as described in Wrodnigg, T. M.; Stutz, A. E. (1999) Angew. Chem. Int. Ed. 38:827–828. The N-acetyllactosamine obtained in this way can subsequently be transferred as an acceptor fragment to lactose.

In the most advantageous embodiment of the present invention, the nutritional composition comprises 2'-fucosyllactose (2FL) and lacto-N-neotetraose (LNnT).

In another specific embodiment, the nutritional composition of the present invention comprises a mixture of oligosaccharides, which consists of 2'-fucosyllactose (2FL) and lacto-N-neotetraose (LNnT). In other words, the nutritional composition of the invention comprises only 2'-fucosyllactose (2FL) as a fucosylated oligosaccharide and only lacto-N-neotetraose (LNnT) as an N-acetylated oligosaccharide.

In the present invention, the fucosylated oligosaccharide(s) and the N-acetylated oligosaccharide(s) are present in the nutritional composition in certain specified amounts. The term "amount", unless otherwise specified, refers to the total amount of each of such 2 components in the nutritional composition. Therefore, it does not refer to an individual amount, unless a single type of such components is referred to (in which case both the total and individual amounts will be the same). As an illustrative example, if only one fucosylated oligosaccharide (i.e., only one type thereof) is used in the composition (e.g., 2FL), its individual amount (and therefore the total amount of fucosylated oligosaccharides) will be in the range of 0.75-1.65 g/L. In case of several fucosylated oligosaccharides (i.e. several types) their individual amount will be less (e.g. in case of 2 different types of fucosylated oligosaccharides, e.g. 2FL + 3FL, each of them can be present in individual amount of 0.5 g/L), but the total amount of fucosylated oligosaccharides will be in the range of 0.75–1.65 g/L.

The fucosylated oligosaccharide(s) may be present in the nutritional composition of the present invention in a total amount of 0.75-1.65 g/L of the composition. In some embodiments, the fucosylated oligosaccharide(s) may be present in a total amount of 0.8-1.5 g/L of the composition, such as 0.85-1.3 g/L or 0.9-1.25 g/L or 0.9-1.1 g/L or 1-1.25 g/L or 1.05-1.25 g/L of the composition. In a particular embodiment, the fucosylated oligosaccharide(s) are present in a total amount of 1 g/L of the composition. In another embodiment, the fucosylated oligosaccharide(s) is(are) present in a total amount of 1.24 g/L of the composition.

The fucosylated oligosaccharide(s) may be present in the nutritional composition in a total amount of 0.52-1.15 g/100 g of the composition, calculated on a dry matter weight. The fucosylated oligosaccharide(s) may be present in a total amount of 0.55-1.05 g/100 g of the composition, such as 0.59-0.9 g/100 g, or 0.62-0.87 g/100 g, or 0.62-0.77 g/100 g, or 0.69-0.87 g/100 g, or 0.73-0.87 g/100 g of the composition. In a particular embodiment, the fucosylated oligosaccharide(s) is(are) present in a total amount of 0.69 g/100 g of the composition. In another particular embodiment, the fucosylated oligosaccharide(s) is(are) present in a total amount of 0.86 g/100 g of the composition.

The N-acetylated oligosaccharide(s) may be present in the nutritional composition according to the present invention in a total amount of 0.45-0.85 g/l of the composition.

In some embodiments, the N-acetylated oligosaccharide(s) may be present in a total amount of 0.5-0.8 g/L of the composition, such as 0.5-0.75 g/L or 0.5-0.7 g/L of the composition. In a particular embodiment, the N-acetylated oligosaccharide(s) is(are) present in a total amount of 0.5 g/L of the composition. In another particular embodiment, the N-acetylated oligosaccharide(s) is(are) present in a total amount of 0.63 g/L of the composition.

The N-acetylated oligosaccharide(s) may be present in the nutritional composition in a total amount of 0.31-0.59 g/100 g of the composition, based on dry matter weight. The N-acetylated oligosaccharide(s) may be present in a total amount of 0.35-0.56 g/100 g of the composition, such as 0.35-0.52 g/100 g or 0.35-0.49 g/100 g. In a particular embodiment, the N-acetylated oligosaccharide(s) is/are present in a total amount of 0.35 g/100 g of the composition. In another particular embodiment, the N-acetylated oligosaccharide(s) is/are present in a total amount of 0.44 g/100 g of the composition.

Therefore, in one embodiment of the present invention, the nutritional composition comprises at least one fucosylated oligosaccharide and at least one N-acetylated oligosaccharide, wherein:

- the fucosylated oligosaccharide(s) is(are) present in a total amount of 0.8-1.5 g/l of the composition and/or in a total amount of 0.55-1.05 g/100 g of the composition based on dry matter weight; and/or

- N-acetylated oligosaccharide(s) is(are) present in a total amount of 0.5–0.8 g/l of the composition and/or in a total amount of 0.35–0.56 g/100 g of the composition, calculated on the dry matter weight.

In another particular embodiment, the nutritional composition of the present invention comprises at least one fucosylated oligosaccharide and at least one N-acetylated oligosaccharide, wherein:

- the fucosylated oligosaccharide(s) is(are) present in a total amount of 0.85-1.3 g/l of the composition and/or in a total amount of 0.59-0.9 g/100 g of the composition based on dry matter weight; and/or

- N-acetylated oligosaccharide(s) is(are) present in a total amount of 0.5–0.75 g/l of the composition and/or in a total amount of 0.35–0.52 g/100 g of the composition, calculated on the dry matter weight.

In another particular embodiment, the nutritional composition of the present invention comprises at least one fucosylated oligosaccharide and at least one N-acetylated oligosaccharide, wherein:

- the fucosylated oligosaccharide(s) is(are) present in a total amount of 1-1.25 g/l of the composition and/or in a total amount of 0.69-0.87 g/100 g of the composition based on dry matter weight; and/or

- N-acetylated oligosaccharide(s) is(are) present in a total amount of 0.5–0.7 g/l of the composition and/or in a total amount of 0.35–0.49 g/100 g of the composition based on dry matter weight.

In another particular embodiment, the nutritional composition of the present invention comprises at least one fucosylated oligosaccharide and at least one N-acetylated oligosaccharide, wherein:

- the fucosylated oligosaccharide(s) is(are) present in a total amount of 1.05-1.25 g/l of the composition and/or in a total amount of 0.73-0.87 g/100 g of the composition based on dry matter weight; and/or

- N-acetylated oligosaccharide(s) is(are) present in a total amount of 0.5–0.7 g/l of the composition and/or in a total amount of 0.35–0.49 g/100 g of the composition based on dry matter weight.

In a particular embodiment, the nutritional composition according to the present invention comprises at least one fucosylated oligosaccharide and at least one N-acetylated oligosaccharide, wherein:

- the fucosylated oligosaccharide(s) is(are) present in a total amount of 1 g/l of the composition and/or in a total amount of 0.69 g/100 g of the composition based on dry matter weight; and/or

- N-acetylated oligosaccharide(s) is(are) present in a total amount of 0.5 g/l of the composition and/or in a total amount of 0.35 g/100 g of the composition, calculated on the dry matter weight.

In another particular embodiment, the nutritional composition according to the present invention comprises at least one fucosylated oligosaccharide and at least one N-acetylated oligosaccharide, wherein:

- the fucosylated oligosaccharide(s) is(are) present in a total amount of 1.24 g/l of the composition and/or in a total amount of 0.86 g/100 g of the composition based on dry matter weight; and/or

- N-acetylated oligosaccharide(s) is(are) present in a total amount of 0.63 g/l of the composition and/or in a total amount of 0.44 g/100 g of the composition, calculated on the dry matter weight.

The fucosylated oligosaccharide(s) and the N-acetylated oligosaccharide(s) in the nutritional composition according to the invention are typically present in a ratio of fucosylated oligosaccharide(s):N-acetylated oligosaccharide(s) of 2:0.54 to 2:2.26, such as 2:0.76 to 2:1.8 or 2:0.8 to 2:1.4. In a particularly advantageous embodiment, such a ratio is 2:1 or about 2:1.

The nutritional composition according to the present invention may also comprise at least another oligosaccharide(s) (i.e. different from the fucosylated oligosaccharide(s) and N-acetylated oligosaccharide(s), which are necessarily present in the composition) and/or at least fiber and/or at least its precursor(s). The other oligosaccharide and/or fiber and/or its precursor may be selected from the list comprising galactooligosaccharides (GOS), fructooligosaccharides (FOS), inulin, xylooligosaccharides (XOS), polydextrose, sialylated oligosaccharides, sialic acid, fucose and any combination thereof. They may be present in an amount of from 0 to 10% by weight of the composition. In a particular embodiment, the nutritional composition may also comprise at least one bovine milk oligosaccharide (BMO).

Suitable commercially available products that can be used in addition to the oligosaccharides contained in the oligosaccharide mixture to produce the nutritional compositions according to the invention include combinations of FOS with inulin, such as the products sold by BENEO under the trade name Orafti, or polydextrose sold by Tate & Lyle under the trade name STA-LITE®.

In a particular embodiment, the composition according to the invention may comprise sialylated oligosaccharide(s). One or more sialylated oligosaccharides may be present.

The sialylated oligosaccharide(s) may be selected from the group consisting of 3'-sialyllactose (3-SL), 6'-sialyllactose (6-SL), and any combination thereof. In some embodiments, the composition comprises 3-SL and 6-SL. In some specific embodiments, the ratio of 3'-sialyllactose (3-SL) to 6'-sialyllactose (6-SL) may be in the range between 5:1 and 1:10, or from 3:1 to 1:1, or from 1:1 to 1:10.

In some specific embodiments, the sialylated oligosaccharide of the composition is 6'-sialyllactose (6-SL).

The sialylated oligosaccharide(s) may be isolated from a natural source such as animal milk by chromatographic or filtration methods. Alternatively, they may be produced by biotechnological means using specific sialyltransferases or sialidases, neuraminidases, by enzyme-based fermentation methods (recombinant or natural enzymes), by chemical synthesis or by microbiological fermentation methods. In the latter case, either the microorganisms may express their natural enzymes and substrates or microorganisms may be engineered to produce the corresponding substrates and enzymes. Single-species or mixed cultures of microorganisms may be used. The formation of sialyloligosaccharide may be initiated by acceptor substrates starting from any degree of polymerization (DP) from DP = 1 onwards. In an alternative embodiment, sialyllactoses can be produced by chemical synthesis from lactose and free N'-acetylneuraminic acid (sialic acid). Sialyllactoses are also commercially available, for example from Kyowa Hakko Kogyo, Japan.

In particular examples, the composition may comprise from 0.05 to 5 g/L of sialylated oligosaccharide(s), or from 0.1 to 4 g/L, or from 0.3 to 2 g/L, or from 0.4 to 1.5 g/L, or from 0.4 to 1 g/L, such as 0.5 or 0.9 g/L of sialylated oligosaccharide(s). In some particular embodiments, the composition may comprise from 0.8 to 1.7 g/L of sialylated oligosaccharide(s).

The composition according to the invention may contain from 0.03 to 3.5 g of sialylated oligosaccharide(s) per 100 g of the composition, calculated on the dry matter weight, for example from 0.1 to 2 g or from 0.2 to 1 g, or from 0.3 to 0.6 g of sialylated oligosaccharide(s) per 100 g of the composition, calculated on the dry matter weight.

In some specific embodiments of the present invention, the nutritional composition comprises sialylated oligosaccharide(s) in an amount of less than 0.1 g/100 g of the composition on a dry matter weight basis.

In some specific embodiments of the present invention, the nutritional composition does not comprise sialylated oligosaccharide(s).

The composition according to the present invention may also optionally contain at least one oligosaccharide precursor. One or more oligosaccharide precursors may be present. For example, the human milk oligosaccharide precursor is sialic acid, fucose, or a mixture thereof. In some specific embodiments, the composition comprises sialic acid.

In specific examples, the composition comprises from 0 to 3 g/L of the oligosaccharide precursor(s), or from 0 to 2 g/L, or from 0 to 1 g/L, or from 0 to 0.7 g/L, or from 0 to 0.5 g/L, or from 0 to 0.3 g/L, or from 0 to 0.2 g/L of the oligosaccharide precursor(s).

The composition according to the invention may contain from 0 to 2.1 g of oligosaccharide precursor(s) per 100 g of composition based on dry matter weight, for example from 0 to 1.5 g, or from 0 to 0.8 g, or from 0 to 0.15 g of oligosaccharide precursor(s) per 100 g of composition based on dry matter weight.

The nutritional composition of the present invention may further comprise at least one probiotic (or probiotic strain), such as a probiotic bacterial strain.

The most commonly used probiotic microorganisms are mainly bacteria and yeasts of the following genera: Lactobacillus spp., Streptococcus spp., Enterococcus spp., Bifidobacterium spp. and Saccharomyces spp.

In some specific embodiments, the probiotic is a probiotic bacterial strain. In some specific embodiments, it is, in particular, Bifidobacteria and/or Lactobacilli.

Suitable probiotic bacterial strains include Lactobacillus rhamnosus ATCC 53103, commercially available from Valio Oy, Finland, under the trade name LGG; Lactobacillus rhamnosus CGMCC 1.3724, Lactobacillus paracasei CNCM I-2116, Lactobacillus johnsonii CNCM I-1225, Streptococcus salivarius DSM 13084, sold by BLIS Technologies Limited, New Zealand, under the trade name KI2; Bifidobacterium lactis CNCM 1-3446, sold among others by Christian Hansen, Denmark, under the trade name Bb 12; Bifidobacterium longum ATCC BAA-999, sold by Morinaga Milk Industry Co. Ltd., Japan, under the trade name BB536; Bifidobacterium breve, marketed by Danisco under the trade name Bb-03; Bifidobacterium breve, marketed by Morinaga under the trade name M-16V; Bifidobacterium infantis, marketed by Procter & Gamble Co. under the trade name Bifantis; and Bifidobacterium breve, marketed by Institut Rosell (Lallemand) under the trade name R0070.

The nutritional composition according to the invention may contain from 10e3 to 10e12 CFU of the probiotic strain, more preferably from 10e7 to 10e12 CFU, for example from 10e8 to 10e10 CFU of the probiotic strain per gram of the composition, calculated on the dry matter weight.

In one embodiment, the probiotics are viable. In another embodiment, the probiotics are non-replicating, or inactivated. In some other embodiments, both viable probiotics and inactivated probiotics may be used.

The nutritional composition of the invention may additionally contain at least one phage (bacteriophage) or a mixture of phages, preferably directed against the pathogenic microorganisms Streptococci, Haemophilus, Moraxella and Staphylococci.

The nutritional composition according to the invention may be, for example, an infant formula, a starter formula, a weaning formula or a follow-on formula, an infant food, a cereal-based infant formula, a fortifier such as a breast milk fortifier, or a supplement. In some specific embodiments, the composition of the invention is an infant formula, a fortifier or a supplement, which may be intended for the first 4 or 6 months of life. In a preferred embodiment, the nutritional composition of the invention is an infant formula.

In some other embodiments, the nutritional composition of the present invention is a fortifier. The fortifier may be a breast milk fortifier (e.g., a human breast milk fortifier) or a formula fortifier, such as an infant formula fortifier or a supplemental formula fortifier.

When the nutritional composition is a supplement, it may be provided in unit dose form.

The nutritional composition of the present invention may be presented in solid (eg powder), liquid or gel form.

The nutritional composition according to the invention essentially comprises a protein source. The protein may be present in an amount of 1.6 to 3 g per 100 kcal. In some embodiments, particularly when the composition is intended for premature infants, such an amount may be 2.4 to 4 g/100 kcal or more than 3.6 g/100 kcal. In some other embodiments, the amount of protein may be below 2.0 g per 100 kcal, such as 1.8 to 2 g/100 kcal, or in an amount below 1.8 g per 100 kcal.

The type of protein is not considered critical for the present invention, provided that the minimum requirements for essential amino acids are met and satisfactory growth is ensured. Thus, protein sources based on whey, casein and mixtures thereof, as well as protein sources based on soy, can be used. With respect to whey proteins, the protein source can be based on acid whey or sweet whey or mixtures thereof and can include alpha-lactalbumin and beta-lactalbumin in any desired ratios.

In some preferred embodiments, the protein source is predominantly whey (i.e., more than 50% of the proteins are derived from whey proteins, such as 60% or 70%).

The proteins may be intact or hydrolyzed, or may be a mixture of intact and hydrolyzed proteins. The term "intact" means that the majority of the proteins are intact, i.e. their molecular structure is not changed, for example at least 80% of the proteins are not changed, for example at least 85% of the proteins are not changed, preferably at least 90% of the proteins are not changed, even more preferably at least 95% of the proteins are not changed, for example at least 98% of the proteins are not changed. In a particular embodiment, 100% of the proteins are not changed.

The term "hydrolyzed" as used herein means a protein that has been hydrolyzed or broken down into its constituent amino acids.

The proteins may be fully or partially hydrolyzed. It may be desirable to administer partially hydrolyzed proteins (degree of hydrolysis from 2 to 20%), for example, to infants or young children suspected of being at risk of developing cow's milk allergy. When hydrolyzed proteins are to be used, the hydrolysis process may be carried out as desired and as is known in the art. For example, whey protein hydrolysates may be prepared by enzymatically hydrolyzing a whey fraction in one or more steps. If the whey fraction which is used as starting material is substantially lactose-free, it has been found that lysine blocking of the protein occurs to a much lesser extent during the hydrolysis process. This allows the degree of lysine blocking to be reduced from about 15 wt.% of total lysine to less than about 10 wt.% lysine; for example, about 7 wt.% lysine, which significantly improves the nutritional quality of the protein source.

In an embodiment of the invention, at least 70% of the proteins are hydrolyzed, preferably at least 80% of the proteins are hydrolyzed, such as at least 85% of the proteins are hydrolyzed, more preferably at least 90% of the proteins are hydrolyzed, such as at least 95% of the proteins are hydrolyzed, in particular at least 98% of the proteins are hydrolyzed. In a particular embodiment, 100% of the proteins are hydrolyzed.

In one particular embodiment, the proteins of the nutritional composition are hydrolyzed, fully hydrolyzed or partially hydrolyzed. The degree of hydrolysis (DH) of the protein can be from 8 to 40, or from 20 to 60, or from 20 to 80, or more than 10, 20, 40, 60, 80 or 90.

In a particular embodiment, the nutritional composition according to the invention is a hypoallergenic composition. In another particular embodiment, the composition according to the invention is a hypoallergenic nutritional composition.

The nutritional composition according to the present invention essentially comprises a carbohydrate source. This is particularly preferred when the nutritional composition of the invention is an infant formula. In this case, any carbohydrate source conventionally found in infant formulas can be used, such as lactose, sucrose, sucrose, maltodextrin, starch and mixtures thereof, although one of the preferred carbohydrate sources is lactose.

The nutritional composition according to the present invention typically comprises a lipid source. This is particularly important if the nutritional composition of the invention is an infant formula. In this case, the lipid source may be any lipid or fat that is acceptable for use in infant formula. Some acceptable fat sources include palm oil, high oleic sunflower oil and high oleic safflower oil. The essential fatty acids linolenic acid and α-linolenic acid may also be added, as well as small amounts of oils containing large amounts of arachidonic acid and docosahexaenoic acid in their final form, such as fish oils or microbial oils. The ratio of n-6 to n-3 fatty acids in the fat source may be from about 5:1 to about 15:1; for example from about 8:1 to about 10:1.

The nutritional composition of the invention may also contain all vitamins and minerals that are considered essential in the daily diet, in nutritionally significant amounts. For some vitamins and minerals, minimum requirements are established. Examples of minerals, vitamins and other nutrients optionally present in the composition of the invention include vitamin A, vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin E, vitamin K, vitamin C, vitamin D, folic acid, inositol, niacin, biotin, pantothenic acid, choline, calcium, phosphorus, iodine, iron, magnesium, copper, zinc, manganese, chlorine, potassium, sodium, selenium, chromium, molybdenum, taurine and L-carnitine. Minerals are usually added in the form of salt. The presence and amounts of specific minerals and other vitamins will vary depending on the target population.

If necessary, the nutritional composition of the invention may contain emulsifiers and stabilizers such as soy, lecithin, citric acid ester mono- and diglycerides, etc.

The nutritional composition of the invention may also contain other substances that may have a beneficial effect, such as lactoferrin, nucleotides, nucleosides, etc.

The nutritional composition of the invention may also contain carotenoid(s). In some specific embodiments, the nutritional composition of the invention does not contain carotenoids.

The nutritional composition according to the invention can be prepared in any suitable way. The composition will be described below using an example.

For example, a formula such as an infant formula can be prepared by mixing a protein source, a carbohydrate source, and a fat source in appropriate proportions. Emulsifiers, if used, can be included at this stage. Vitamins and minerals can be added at this stage, but are usually added later to prevent thermal degradation. Any lipophilic vitamins, emulsifiers, etc. can be dissolved in the fat source before mixing. Water, preferably reverse osmosis purified water, can then be mixed in to form a liquid mixture. The temperature of the water is conveniently in the range of about 50°C to about 80°C to facilitate dispersion of the ingredients. Commercially available diluents can be used to form a liquid mixture.

Fucosylated oligosaccharide(s) and N-acetylated oligosaccharide(s) may be added at this stage, particularly if the final product is to be in liquid form. If the final product is to be in powder form, they may also be added at this stage if required.

The liquid mixture is then homogenized, for example in two stages.

The liquid mixture can then be thermally treated to reduce the bacterial load by rapidly heating the liquid mixture, for example to a temperature in the range of about 80°C to about 150°C, for a period of time, for example, from about 5 seconds to about 5 minutes. This can be done by steam injection or by using an autoclave or a heat exchanger, such as a plate heat exchanger.

The liquid mixture may then be cooled to a temperature of about 60°C to about 85°C, for example by flash cooling. The liquid mixture may then be homogenized again, for example in two stages: under a pressure in the range of about 10 MPa to about 30 MPa in the first stage and from about 2 MPa to about 10 MPa in the second stage. The homogenized mixture may then be further cooled to add any temperature-sensitive components, such as vitamins and minerals. At this stage, the pH and solids content of the homogenized mixture are conveniently adjusted.

If the final product is to be a powder, the homogenized mixture is transferred to a suitable drying apparatus, such as a spray dryer or a freeze dryer, and converted into a powder. The moisture content of the powder should be less than about 5% by weight. Alternatively, the fucosylated oligosaccharide(s) and N-acetylated oligosaccharide(s) can also be added at this stage by dry mixing or by mixing them in the form of a crystal syrup together with the probiotic strain(s) (if used), and the mixture is spray dried or freeze dried.

If a liquid composition is preferred, the homogenized mixture may be sterilized and then aseptically filled into suitable containers, or may be first filled into containers and then sterilized in an autoclave.

In another embodiment, the composition of the invention may be an additive.

The additive may be, for example, in the form of tablets, capsules, lozenges or liquid. The additive may further comprise protective hydrocolloids (e.g. gums, proteins, modified starches), binders, film-forming agents, encapsulating agents/materials, wall/shell materials, matrix compounds, coatings, emulsifiers, surface-active agents, solubilizing agents (oils, fats, waxes, lecithins, etc.), adsorbents, carriers, fillers, auxiliary compounds, dispersing agents, wetting agents, processing aids (solvents), anti-caking agents, taste-masking agents, weighting agents, gelling agents and gel-forming agents. The supplement may also contain traditional pharmaceutical additives and adjuvants, excipients and diluents, including, without limitation, water, gelatin of any origin, vegetable gums, lignin sulfonate, talc, sugars, starch, gum arabic, vegetable oils, polyalkylene glycols, flavoring agents, preservatives, stabilizers, emulsifying agents, buffers, lubricants, colorants, wetting agents, fillers, etc.

Additionally, the supplement may contain organic or inorganic carrier material acceptable for oral or parenteral administration, as well as vitamins, minerals, trace elements and other trace elements in accordance with recommendations of government agencies, such as the Recommended Dietary Allowances (RDAs) in the United States.

The nutritional composition according to the invention is suitable for use in infants or young children. Infants or young children may be born at term or prematurely. In a particular embodiment, the nutritional composition of the invention is intended for use in infants or young children who were born prematurely. In a particular embodiment, the nutritional composition of the invention is intended for use in premature infants.

The nutritional composition of the present invention can also be used in infants or young children born by caesarean section or vaginal delivery. Indeed, as shown in the experimental part, the authors of the present invention were able to demonstrate good results when administering the nutritional composition of the present invention to each of the mentioned populations.

In some embodiments, the composition according to the invention may be intended for use before and/or during the weaning period.

The age for the introduction (use or feeding) of the nutritional composition, as well as the duration of such introduction, depends on the needs. The nutritional composition of the present invention can be used for the purposes of prevention or treatment of:

- in the prevention and/or treatment of infections and/or inflammations of the lower respiratory tract and/or ear in an infant or young child;

- to reduce the temperature of an infant or young child;

- to reduce the use of antibiotics in an infant or young child;

- to reduce the use of antipyretic drugs in an infant or young child; and/or

- in the prevention and/or treatment of diseases/conditions with elevated temperature and/or requiring the administration of antibiotics or antipyretics to an infant or young child.

In some embodiments, the nutritional composition is used for prophylactic purposes. The nutritional composition can, for example, be given to infants immediately after birth. The composition of the invention can also be given during the first week of life of an infant, or during the first 2 weeks of life, or during the first 3 weeks of life, or during the first month of life, or during the first 2 months of life, or during the first 3 months of life, or during the first 4 months of life, or during the first 6 months of life, or during the first 8 months of life, or during the first 10 months of life, or during the first year of life, or during the first two years of life, or even longer. In a number of particularly advantageous embodiments of the invention, the nutritional composition is given (or administered) to an infant during the first 4 to 6 months after the birth of said infant.

In some other embodiments, the nutritional composition of the invention is given several days (e.g., 1, 2, 3, 5, 10, 15, 20...) or several weeks (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10...), or several months (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10...) after birth. This may be especially relevant, but not necessarily, in the case where the infant was born prematurely.

In one embodiment, the composition of the invention is given to an infant or young child as a composition supplementary to human milk. In some embodiments, the infant or young child receives human milk for at least the first 2 weeks, the first 1, 2, 4 or 6 months. In one embodiment, the nutritional composition of the invention is given to the infant or young child after such a period of feeding with human milk or is given during such a period of feeding with human milk. In another embodiment, the composition is given to the infant or young child as the sole or main nutritional composition for at least one period of time, such as after the 1st, 2nd or 4th month of life, for at least 1, 2, 4 or 6 months.

In one embodiment, the nutritional composition of the invention is a complete nutritional composition (meeting all or most of the nutritional needs of a subject). In another embodiment, the nutritional composition is a supplement or fortifier intended, for example, to supplement breast milk or to supplement infant formula or formula for weaned infants.

In some other embodiments, the nutritional composition of the invention is given for medicinal purposes. This is most often observed in cases of using the composition to treat infections and/or inflammations of the lower respiratory tract and/or ear.

In such cases, the nutritional composition of the invention can be given for several days (1, 2, 3, 4, 5, 6...), or for several weeks (1, 2, 3, 4, 5, 6, 7, 8 or even more), or for several months (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or even more) depending on the needs. It can be given immediately after the onset of symptoms or after diagnosis of such diseases/conditions. It can be continued until the symptoms of the diseases/conditions against which the treatment is directed disappear, or after several days/weeks/months after said disappearance.

The nutritional composition according to the invention can be used in the prevention and/or treatment of infections and/or inflammations of the lower respiratory tract and/or ear. As detailed above, infections and/or inflammations of the lower respiratory tract and/or ear can be of bacterial origin, viral origin or be the result of environmental influences. In some embodiments, such infections and/or inflammations are of bacterial origin. In some other embodiments, they are of viral origin.

Examples of lower respiratory tract infections and/or inflammations may be pneumonia, bronchitis and/or bronchiolitis. They may be localized in at least one of the following sections of the lower respiratory tract: in the trachea, bronchi, bronchioles and/or lungs. In a specific example, the nutritional composition according to the invention is used in the prevention and/or treatment of bronchitis.

Ear infections and/or inflammations may be ear infections, ear inflammations, otitis, otitis media, acute otitis media. They may be localized in the middle ear. In a specific example, the nutritional composition according to the invention is used in the prevention and/or treatment of otitis or otitis media.

The present inventors have also found that a particular nutritional composition according to the invention is particularly effective in reducing fever and reducing the use (i.e. administration) of antibiotics and antipyretics to an infant or young child.

The nutritional composition according to the invention can also be used to reduce fever and/or reduce the use of antibiotics and antipyretics in an infant or young child in addition to the prevention and/or treatment of infections and/or inflammations of the lower respiratory tract and/or ear.

In a particular aspect, the present invention also relates to a nutritional composition comprising at least one fucosylated oligosaccharide and at least one N-acetylated oligosaccharide, for use in reducing fever and/or reducing the administration of antibiotics and/or reducing the use of antipyretics in an infant or young child, wherein:

- the fucosylated oligosaccharide(s) is(are) present in a total amount of 0.75-1.65 g/l of the composition and/or in a total amount of 0.52-1.15 g/100 g of the composition, calculated on the dry matter weight; and

- N-acetylated oligosaccharide(s) is(are) present in a total amount of 0.45–0.85 g/l of the composition and/or in a total amount of 0.31–0.59 g/100 g of the composition, calculated on the dry matter weight.

The previously noted embodiments and examples (e.g., relating to types and amounts of oligosaccharide, nutritional composition, administration, target population, ...) also apply to the present aspect.

In another particular aspect, the present invention also relates to a nutritional composition comprising at least one fucosylated oligosaccharide and at least one N-acetylated oligosaccharide for use in the prevention and/or treatment of diseases/conditions (e.g. infections, inflammations...) associated with fever and/or the administration of antibiotics or antipyretics to an infant or young child, wherein:

- the fucosylated oligosaccharide(s) is(are) present in a total amount of 0.75-1.65 g/l of the composition and/or in a total amount of 0.52-1.15 g/100 g of the composition, calculated on the dry matter weight; and

- N-acetylated oligosaccharide(s) is(are) present in a total amount of 0.45–0.85 g/l of the composition and/or in a total amount of 0.31–0.59 g/100 g of the composition, calculated on the dry matter weight.

The previously noted embodiments and examples (e.g., relating to types and amounts of oligosaccharide, nutritional composition, administration, target population, ...) also apply to the present aspect.

Other goals

Another object of the present invention is the use of at least one fucosylated oligosaccharide and at least one N-acetylated oligosaccharide for the preparation of a nutritional composition for the prevention and/or treatment of infections and/or inflammations of the lower respiratory tract and/or ear in an infant or young child, in which:

- the fucosylated oligosaccharide(s) is(are) present in a total amount of 0.75-1.65 g/l of the nutritional composition and/or in a total amount of 0.52-1.15 g/100 g of the nutritional composition, calculated on the dry matter weight; and

- N-acetylated oligosaccharide(s) is(are) present in a total amount of 0.45–0.85 g/l of the nutritional composition and/or in a total amount of 0.31–0.59 g/100 g of the nutritional composition, calculated on the dry matter weight.

Another object of the present invention is the use of at least one fucosylated oligosaccharide and at least one N-acetylated oligosaccharide for the preparation of a nutritional composition for reducing fever and/or reducing the administration of antibiotics and/or reducing the administration of antipyretics and/or preventing and/or treating diseases/conditions (e.g. infections, inflammations...) associated with fever and/or the administration of antibiotics or antipyretics in an infant or young child, in which:

- the fucosylated oligosaccharide(s) is(are) present in a total amount of 0.75-1.65 g/l of the composition and/or in a total amount of 0.52-1.15 g/100 g of the composition, calculated on the dry matter weight; and

- N-acetylated oligosaccharide(s) is(are) present in a total amount of 0.45–0.85 g/l of the composition and/or in a total amount of 0.31–0.59 g/100 g of the composition, calculated on the dry matter weight.

Another object of the present invention relates to the use of a nutritional composition comprising at least one fucosylated oligosaccharide and at least one N-acetylated oligosaccharide for reducing fever and/or reducing the administration of antibiotics or antipyretics in an infant or young child, wherein:

- the fucosylated oligosaccharide(s) is(are) present in a total amount of 0.75-1.65 g/l of the composition and/or in a total amount of 0.52-1.15 g/100 g of the composition, calculated on the dry matter weight; and

- N-acetylated oligosaccharide(s) is(are) present in a total amount of 0.45–0.85 g/l of the composition and/or in a total amount of 0.31–0.59 g/100 g of the composition, calculated on the dry matter weight.

The previously noted embodiments and examples (e.g., relating to types and amounts of oligosaccharide, nutritional composition, use, target population, ...) also apply to the listed purposes (i.e., aspects of use).

Another object of the present invention is a pharmaceutical composition comprising at least one fucosylated oligosaccharide and at least one N-acetylated oligosaccharide for the prevention and/or treatment of infections and/or inflammations of the lower respiratory tract and/or ear in an infant or young child, wherein:

- the fucosylated oligosaccharide(s) is(are) present in a total amount of 0.75-1.65 g/l of the nutritional composition and/or in a total amount of 0.52-1.15 g/100 g of the nutritional composition, calculated on the dry matter weight; and

- N-acetylated oligosaccharide(s) is(are) present in a total amount of 0.45–0.85 g/l of the nutritional composition and/or in a total amount of 0.31–0.59 g/100 g of the nutritional composition, calculated on the dry matter weight.

Another object of the present invention is a pharmaceutical composition comprising at least one fucosylated oligosaccharide and at least one N-acetylated oligosaccharide, for use in reducing fever and/or reducing the administration of antibiotics and/or reducing the administration of antipyretics in an infant or young child, wherein:

- the fucosylated oligosaccharide(s) is(are) present in a total amount of 0.75-1.65 g/l of the composition and/or in a total amount of 0.52-1.15 g/100 g of the composition, calculated on the dry matter weight; and

- N-acetylated oligosaccharide(s) is(are) present in a total amount of 0.45–0.85 g/l of the composition and/or in a total amount of 0.31–0.59 g/100 g of the composition, calculated on the dry matter weight.

In another particular aspect, the present invention also relates to a pharmaceutical composition comprising at least one fucosylated oligosaccharide and at least one N-acetylated oligosaccharide for use in the prevention and/or treatment of diseases/conditions (e.g. infections, inflammations...) associated with fever and/or antibiotic administration and/or antipyretic administration in an infant or young child, wherein:

- the fucosylated oligosaccharide(s) is(are) present in a total amount of 0.75-1.65 g/l of the composition and/or in a total amount of 0.52-1.15 g/100 g of the composition, calculated on the dry matter weight; and

- N-acetylated oligosaccharide(s) is(are) present in a total amount of 0.45–0.85 g/l of the composition and/or in a total amount of 0.31–0.59 g/100 g of the composition, calculated on the dry matter weight.

The previously noted embodiments and examples (e.g., relating to types and amounts of oligosaccharide, nutritional composition, administration, target population, ...) also apply to the listed purposes (i.e., to the pharmaceutical composition).

Another object of the present invention relates to a method for the prevention and/or treatment of lower respiratory tract and/or ear infections and/or inflammations in an infant or young child, said method comprising administering to said infant or young child a nutritional composition comprising at least one fucosylated oligosaccharide and at least one N-acetylated oligosaccharide, wherein:

- the fucosylated oligosaccharide(s) is(are) present in a total amount of 0.75-1.65 g/l of the nutritional composition and/or in a total amount of 0.52-1.15 g/100 g of the nutritional composition, calculated on the dry matter weight; and

- N-acetylated oligosaccharide(s) is(are) present in a total amount of 0.45–0.85 g/l of the nutritional composition and/or in a total amount of 0.31–0.59 g/100 g of the nutritional composition, calculated on the dry matter weight.

Another object of the present invention is a method for reducing fever and/or reducing the administration of antibiotics and/or reducing the administration of antipyretics and/or preventing and/or treating diseases/conditions (e.g. infections, inflammations...) associated with fever and/or antibiotic administration in an infant or young child, said method comprising administering to said infant or young child a nutritional composition comprising at least one fucosylated oligosaccharide and at least one N-acetylated oligosaccharide, wherein:

- the fucosylated oligosaccharide(s) is(are) present in a total amount of 0.75-1.65 g/l of the nutritional composition and/or in a total amount of 0.52-1.15 g/100 g of the nutritional composition, calculated on the dry matter weight; and

- N-acetylated oligosaccharide(s) is(are) present in a total amount of 0.45–0.85 g/l of the nutritional composition and/or in a total amount of 0.31–0.59 g/100 g of the nutritional composition, calculated on the dry matter weight.

The various embodiments, details and examples previously described in the specification (e.g. relating to types and amounts of oligosaccharide, nutritional composition, administration, target population...) also apply to the listed purposes (i.e. methods).

Examples

The following examples demonstrate some specific embodiments of the composition for use in accordance with the present invention. The examples are provided for illustrative purposes only and should not be considered as limitations of the present invention.

Example 1

An example of the composition of a nutritional composition (e.g., infant formula) according to the present invention is given in Table 1 below. This composition is given solely for illustrative purposes.

Table 1. Example of the composition of a nutritional composition (e.g., infant formula) according to the present invention

Nutrients Per 100 kcal Per liter Energy value (kcal) 100 670 Protein (g) 1.83 12.3 Fat (g) 5.3 35.7 Linoleic acid (g) 0.79 5.3 α-Linolenic acid (mg) 101 675 Lactose (g) 11.2 74.7 Minerals (g) 0.37 2.5 Na (mg) 23 150 K (mg) 89 590 Cl (mg) 64 430 Ca (mg) 62 410 P (mg) 31 210 Mg (mg) 7 50 Mn (mcg) 8 50 Se (mcg) 2 13 Vitamin A (mcg retinol equivalent (RE)) 105 700 Vitamin D (mcg) 1.5 10 Vitamin E (mg tocopherol equivalent (TE)) 0.8 5.4 Vitamin K1 (mcg) 8 54 Vitamin C (mg) 10 67 Vitamin B1 (mg) 0.07 0.47 Vitamin B2 (mg) 0.15 1.0 Niacin (mg) 1 6.7 Vitamin B6 (mg) 0.075 0.50 Folic acid (mcg) 9 60 Pantothenic acid (mg) 0.45 3 Vitamin B12 (mcg) 0.3 2 Biotin (mcg) 2,2 15 Choline (mg) 10 67 Fe (mg) 1,2 8 I (mcg) 15 100 Cu (mg) 0.06 0.4 Zn (mg) 0.75 5 Oligosaccharides (OS) 2FL (g) 0.15 1 LNnT (g) 0.075 0.5

Example 2

Description of the study

A controlled, single-blind, randomized, multicenter, parallel-group, interventional clinical trial was conducted. Infants were recruited and randomized to one of the 2 study groups within 14 days of birth. Study groups included the use of a classic infant formula without HM [control] or the same classic infant formula supplemented with 2 HM [HM].

The composition of the tested infant formula with or without added OGM was identical to the composition given in Table 1, except that:

- the control infant formula did not contain oligosaccharides/OGM (i.e. did not contain 2’-fucosyllactose and lacto-N-neotetraose);

- the tested infant formula with OGM contained 2’-fucosyllactose, but in an amount of 1.24 g/l (which corresponded to an amount of 0.86 g/100 g of powder before dissolution; 129.18 g of powder/900 ml were used for dissolution), as well as lacto-N-neotetraose, but in an amount of 0.63 g/l (which corresponded to 0.44 g/100 g of powder before dissolution; 129.18 g of powder/900 ml were used for dissolution).

The introduction of weaning food began at 4 months of age.

The study included a treatment period of 6 months ± 7 days using one of the two treatment options, followed by an observation period of 6 months without treatment.

Results

The inventors unexpectedly found that infants in the HMW group (i.e., those receiving the classic formula supplemented with 1.24 g/L 2'-fucosyllactose and 0.63 g/L lacto-N-neotetraose) had a lower incidence of bronchitis (Fig. 1). The number of infants with at least one case of bronchitis is given.

The inventors also unexpectedly found that the infants in the OHM group tended to suffer less from ear infections/inflammation (Fig. 2). The number of infants with at least one ear infection/inflammation is reported. Recordable examples of ear infections and/or inflammations include any ear infection, ear inflammation, otitis, otitis media, acute otitis media, otitis externa, mastoiditis, or labyrinthitis diagnosed by a physician or health care professional.

The authors also unexpectedly found that infants in the GM group required fewer antibiotics (Figure 3) and had lower temperatures (Figure 4).

These effects were observed regardless of the route of administration.

The incidence rate per group confirms the results described above (Figs. 5 and 6). Specifically, infants receiving the HMW test formula had fewer cases of (i) bronchitis (Figs. 5A and 6A), (ii) ear infections/inflammation (Figs. 5B and 6B), (iii) antibiotic use (Figs. 5C and 6C), and (iv) antipyretic use (Figs. 5D and 6D).

All of the above results were observed throughout the entire experimental period (12-month period), i.e. from 0 to 4 months, from 0 to 6 months, and from 0 to 12 months.

Thus, a composition containing at least one fucosylated oligosaccharide and at least one N-acetylated oligosaccharide in the stated amounts is highly effective for infants for use in the prevention and/or treatment of infections and/or inflammations of the lower respiratory tract and ear, as well as for reducing temperature and reducing the administration of antibiotics and antipyretics in said infants.

Claims (17)

1. A method for the prevention and/or treatment of lower respiratory tract and/or ear infections and/or inflammations in an infant or young child, the method comprising administering to the infant or young child a nutritional composition comprising 2'-fucosyllactose (2'-FL) as the only fucosylated oligosaccharide and lacto-N-neotetraose (LNnT) as the only N-acetylated oligosaccharide, wherein 2’-FL is present in a total amount of 0.75–1.65 g/L of the composition and/or in a total amount of 0.52–1.15 g/100 g of the composition, calculated on the dry matter weight; and LNnT is present in a total amount of 0.45–0.85 g/l of the composition and/or in a total amount of 0.31–0.59 g/100 g of the composition based on the dry matter weight; wherein the composition does not contain sialylated oligosaccharide(s), and wherein the infections and/or inflammations of the lower respiratory tract and/or ear are selected from the group consisting of pneumonia, bronchitis, bronchiolitis, otitis, otitis media and combinations thereof. 2. The method according to item 1, wherein 2’-FL is present in a total amount of 0.8–1.5 g/L of the composition and/or in a total amount of 0.55–1.05 g/100 g of the composition based on dry matter weight; and/or LNnT is present in a total amount of 0.5–0.8 g/l of the composition and/or in a total amount of 0.35–0.56 g/100 g of the composition based on the dry matter weight. 3. The method according to item 1 or 2, wherein 2’-FL is present in a total amount of 0.85–1.3 g/L of the composition and/or in a total amount of 0.59–0.9 g/100 g of the composition based on dry matter weight; and/or LNnT is present in a total amount of 0.5–0.75 g/l of the composition and/or in a total amount of 0.35–0.52 g/100 g of the composition, based on the dry matter weight. 4. A method according to any of the preceding paragraphs, wherein 2’-FL is present in a total amount of 1–1.25 g/L of the composition and/or in a total amount of 0.69–0.87 g/100 g of the composition based on dry matter weight; and/or LNnT is present in a total amount of 0.5–0.7 g/l of the composition and/or in a total amount of 0.35–0.49 g/100 g of the composition based on the dry matter weight. 5. The method according to any of the preceding claims, wherein said nutritional composition comprises at least other oligosaccharide(s) and/or fibre and/or its precursor(s) that are selected from the list containing galactooligosaccharides, fructooligosaccharides, xylooligosaccharides, inulin, polydextrose, sialic acid, fucose and any combinations thereof. 6. The method according to any of the preceding claims, wherein said nutritional composition further comprises at least one probiotic in an amount of from ¹⁰³ to ¹⁰¹² CFU/g of said composition, calculated on dry matter weight. 7. The method according to any one of the preceding claims, wherein said nutritional composition is an infant formula, a starter formula, a complementary or follow-on formula, an infant food, a cereal-based infant formula, a fortifier or a supplement. 8. The method of any of the preceding claims, which is also intended to reduce fever and/or reduce the use of antibiotics and/or reduce the use of antipyretics in an infant or young child.

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