International Journal of Nutrition

International Journal of Nutrition

International Journal of Nutrition

Current Issue Volume No: 8 Issue No: 1

Review Article Open Access Available online freely Peer Reviewed Citation

The Effects of Dairy Consumption on Vaccine Immune Response and Immunoglobulins: A Systematic Literature Review

Mina Suh 1,   Meghan Mitchell 1,   Naushin Hooda 1,   Lauren C. Bylsma 1,   Sarah S. Cohen 2  

1EpidStrategies, a division of ToxStrategies, LLC, 23501 Cinco Ranch Blvd, Suite B226, Katy, TX 77494.

2Independent contractor to ToxStrategies, LLC, Durham, NC, USA.

Abstract

Public health interest in vaccinations and immune protection has increased with the COVID-19 pandemic. Dairy products are an important source of protein and other nutrients, and there are unresolved research questions regarding the potential health impact of dairy products on the enhancement of immune response. A systematic literature review was conducted to synthesize the published literature reporting the effects of dairy interventions on: 1) the vaccine-specific immune response and 2) immunoglobulins in the absence of vaccination. To assess study validity and quality, we used the Academy of Nutrition and Dietetics Quality Criteria Checklist. Sixty-one studies (59 clinical trials, 1 cohort, 1 cross-sectional survey) were included, spanning 1983-2017. Ten trials evaluated the effect of dairy intervention on vaccine-specific IgG, IgA, IgM, vaccine-specific antibody titers, seroprotection rates, or seroconversion rates. Of these, 7 reported significant increases with dairy interventions for post-vaccine tetanus antibodies, mean change in tetanus antibody level, total antibody titers to flagellin from Salmonella Adelaide, mean antibody titers to influenza B, influenza-specific IgA and IgG levels, and seroconversion or seroprotection rates for influenza A and B. Fifty-six studies evaluated dairy’s effects on immunoglobulins without vaccinations. The results were heterogenous, with some studies reporting significant enhancement of immunoglobulins (IgA, IgE, or IgG), while others observed no differences between groups. Clinical relevance of the immunoglobulin changes was not investigated in these studies. Dairy products and their components could enhance the efficacy of vaccines. This review highlights the evidence gaps and provides a potential roadmap for additional research.

Author Contributions
Received 24 Jan 2024; Accepted 31 Jan 2024; Published 06 Feb 2024;

Academic Editor: Sasho Stoleski, Institute of Occupational Health of R. Macedonia, WHO CC and Ga2len CC.

Checked for plagiarism: Yes

Review by: Single-blind

Copyright © 2024 Mina Suh, et.al

License
Creative Commons License     This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Competing interests

The authors have declared that no competing interests exist.

Citation:

Mina Suh, Meghan Mitchell, Naushin Hooda, Lauren C. Bylsma, Sarah S. Cohen (2024) The Effects of Dairy Consumption on Vaccine Immune Response and Immunoglobulins: A Systematic Literature Review. International Journal of Nutrition - 8(1):1-25. https://doi.org/10.14302/issn.2379-7835.ijn-24-4938

Download as RIS, BibTeX, Text (Include abstract )

DOI 10.14302/issn.2379-7835.ijn-24-4938

Introduction

The potential benefits of dietary patterns and specific foods are of great interest to researchers, including nutritional intervention for overall health improvement, disease prevention, and symptom management 1, 2, 3. In various dietary guidelines, dairy products are considered as an important source of protein and other nutrients including vitamin D and calcium 4, 5. The ability of dairy products and/or their components to enhance immune response may be an important aspect of dairy’s influences on health 6, 7, 8.

The potential immune-modulating effects of dairy products and their components have been considered in in vivo and in vitro models, including the role of probiotics 9, 10, 11. The findings in these models suggest a beneficial role of probiotics on immunity through various proposed mechanisms, including a direct impact on pathogens by competing for colonization of the gut’s epithelium and the stimulation of the innate immune response in the gut (e.g., modulating the release of cytokines to promote defense) 10. Likewise, the whey protein lactoferrin may provide beneficial impacts with improved immunity, resistance to infection, and stimulation of the anti-inflammatory immune response 12. With regard to epidemiologic research on dairy products/components, recent systematic reviews and meta-analyses have concluded that there may be a neutral to positive benefit of whole dairy products, probiotics and proteins on biomarkers of inflammation 8, 13, 14, 15.

While there is a notable body of work regarding the impact of dairy products/components on immune functions, overall conclusions are not clear. As such, we conducted a systematic literature review to identify and synthesize existing literature on the effects of dairy products and their components on immune-related outcomes, excluding biomarkers of inflammation (PROSPERO: CRD42022333780). During our assessment of the available outcome data, vaccine response was identified as an outcome with available evidence. Given the increased focus on vaccinations with the onset of the COVID-19 pandemic, this systematic literature review examined the available evidence on the potential for whole dairy products/components to enhance the antibody response after vaccination. To complement this assessment, we also systematically evaluated the evidence for the effects of dairy products and their components on immunoglobulins in the absence of vaccination.

Methods

We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines during the conduct and reporting of this review 16. PRISMA checklist was submitted (Supplemental Material). Our protocol was registered prior to study conduct at the International Prospective Register of Systematic Reviews (PROSPERO: CRD42022333780). The registered protocol described a comprehensive literature search strategy, with search terms for dairy exposures and outcomes relevant to non-inflammatory immune outcomes. This review was conducted to identify the available evidence and rank the sufficiency of the evidence on the available outcomes. Herein, we summarize the evidence related to nutritional interventions with dairy products/components and 1) the immune response to vaccination and 2) the immunoglobulin response in general. Following PRISMA procedures and as specified in the registered protocol, other outcomes related to non-inflammatory immune function will be presented in future publications.

Eligibility Criteria

The eligibility criteria were developed based on the population, interventions, comparator, outcomes, and study design (PICOS) elements.

Population

This review included epidemiologic studies of all populations, excluding studies investigating persons with dairy sensitivity. There were no restrictions on geographical location, sex, age, or health status.

Interventions

We included studies of exposure or dietary intervention involving whole dairy products, dairy proteins, or other components of dairy. Whole dairy products of interest included cow’s milk, yogurt, and cheese (both standard products and those fermented with additional probiotics). Yogurts using the traditional starter cultures Lactobacillus (L.) bulgaricus and Streptococcus (S.) thermophilus were referred to as traditional yogurt, while probiotic yogurts were those with additional probiotics added. Dairy proteins included whey (soluble milk protein) and casein (insoluble milk protein). Other dairy components of relevance were the fat components of milk (i.e., milk phospholipids and the milk fat globular membrane). Milk powders, milk peptides/proteins, and dairy products fermented with experimental/ non-traditional bacterial strains were considered relevant. Studies assessing dietary patterns, including prenatal and maternal exposures, were included. Studies where dairy products or components were administered through a feeding tube were included. Studies of bovine colostrum, non-bovine milks, hyperimmunized milk, and raw/unpasteurized milk were excluded. Studies that administered probiotics alone or in a vehicle other than a dairy product were also excluded. Studies that did not calculate an effect estimate or conduct any statistical comparisons were excluded.

Comparator

Studies were required to have comparison group(s) of low or no dairy product/component consumption or pre- and post-intervention outcomes.

Outcomes

The registered protocol for the systematic literature review specified all outcomes related to immune function, excluding biomarkers of inflammation (which have been reviewed previously 8, 14) and outcomes related to milk allergies/sensitivities. In this publication, we evaluated the following outcomes reported in the included studies: 1) immunoglobulin levels (IgA, IgD, IgE, IgG, and/or IgM) in the absence of vaccination; and/or 2) immunological responses to vaccines, specifically vaccine-specific immunoglobulins, vaccine-specific antibody titers, seroprotection rates, and/or seroconversion rates. Antibody titers are used to assess immunogenicity of various vaccines (e.g., the hemagglutinin inhibition HI titer for influenza) 17. The seroprotection rate refers to the proportion of individuals reaching an established protective antibody titer level (e.g., 1:40 for influenza, which is associated with a 50% reduction in the risk of acquiring laboratory-confirmed influenza), while the seroconversion rate describes the proportion of patients that reach a predefined increase in the HI titer that indicates a response (e.g., fourfold for influenza) 18.

Study Design

The publication start date was not restricted. This review included peer-reviewed publications with the following study designs: prospective or retrospective cohort studies, case-control studies, cross-sectional studies, and clinical trials. Reviews, meta-analyses, case series, and case reports were excluded. Conference abstracts and articles for which neither the abstract nor the full text were available in English were excluded.

If more than one article from the same study population were published, data from the publication with the longest follow-up or most relevant population and/or outcomes were evaluated. For studies with overlapping data, data from the publication with the larger population size or most relevant population and/or outcomes were considered.

Study Identification and Screening

The pre-determined literature search strategy was followed at all stages of the review. Searches were conducted in the PubMed and Embase databases on May 19, 2022, with the human and English language filters applied (Supplemental Table 1). Standard software to conduct systematic literature reviews, i.e., DistillerSR (Version 2023.4) 19, was used to deduplicate the literature search results from PubMed and Embase and to track the identified publications at each stage of review.

One reviewer examined the titles and abstracts of the deduplicated articles for inclusion based on the eligibility criteria. The articles considered to be relevant at the title and abstract level were independently evaluated at the full-text level by 2 reviewers; all conflicts were resolved by a senior reviewer. Following the PRISMA guidelines, bibliographies of relevant reviews were also assessed to identify any additional citations of interest meeting the PICOS elements.

Data Abstraction

In DistillerSR, data abstraction was conducted for all included studies. The following information was abstracted for each included study: study design; geographical location(s); study period; dairy product(s)/component(s) under evaluation; dosing and duration; population size; health status; age range; immunoglobulin levels measured (IgA, IgD, IgE, IgG, and/or IgM); and the vaccine administered and concurrent or subsequent effects on immunoglobulins, vaccine-specific antibody titers, seroprotection rates, and/or seroconversion rates. Any relevant effect estimates, confidence intervals, and statistical testing for these outcomes were abstracted.

One reviewer conducted data abstraction, while a second reviewer independently reviewed the entries for complete quality control. All conflicts were resolved by a senior reviewer.

Risk of Bias Assessments

Risk of bias (RoB) assessment was also conducted for all included studies. To assess study validity and quality, we used the Academy of Nutrition and Dietetics Quality Criteria Checklist 20. This tool examined several domains pertaining to relevance, validity, and bias due to funding source. RoB assessment was conducted by one reviewer; the results were reviewed independently by a second reviewer (100% quality control). A senior reviewer resolved any conflicts and finalized the RoB results. Study quality was determined as positive, neutral, or negative, depending upon the scoring results from the domains (Supplemental Table 2).

Data Synthesis

For each outcome, we systematically summarized the data by study quality, dairy exposure/intervention, and publication year. Qualitative synthesis was done, as meta-analysis could not be performed due to the heterogeneous nature of the dairy exposures and reported outcomes.

Results

The PRISMA flow diagram describes the inclusion and exclusion of studies at each step of the review; 6145 and 6828 records were identified in PubMed and Embase, respectively (Figure 1). Using de-duplication in DistillerSR, 9382 records were screened at the title and abstract level. At the full-text level, 405 (389 references identified from title and abstract screening and 16 references identified from evaluations of relevant review articles) publications were reviewed, with 189 total references determined to be eligible. Among the 189 studies, 61 publications described the impact of dairy exposure/components on the vaccine-specific immune response and immunoglobins without vaccinations; the remaining publications examined outcomes that will be reported in future publications.

Figure 1.PRISMA Flow Diagram
PRISMA Flow Diagram

*Four of the relevant review articles were not further searched for additional references as the exposures were not relevant (i.e., bovine colostrum and/or hyperimmune milk).

Source of flow diagram template: Page et al. 2021 (16).

Characteristics of Included Studies (N=61)

Table 1 presents the characteristics of the 61 studies: 27 (44.3%) were determined to have positive study quality, 33 (54.1%) were determined to have neutral quality, while one study (1.6%) 21 was determined to have negative quality. Except for one cross-sectional survey 22 and one cohort study 23, the remaining 59 studies were clinical trials. Four studies provided vaccine-specific immunological response data only 24, 25, 26, 27, 50 studies reported the effects of dairy on immunoglobulin levels without vaccinations only, and 6 presented results on both outcome types 28, 29, 30, 31, 32, 33. The period of study enrollment and follow-up was not reported in 32 studies; of those providing enrollment and follow-up data (n=29), the years ranged from 1983 to 2017. Fifty-nine studies reported geographical location, with 80% (n=47) conducted in European nations.

Effect of Dairy Intervention on the Immune Response to Vaccination (N=10)

Ten clinical trials evaluated dairy interventions in conjunction with vaccination and their effect on vaccine-specific IgG, IgA, IgM, and antibody titers, seroprotection rates, and/or seroconversion rates 24, 25, 26, 27, 28, 29, 30, 31, 32, 33 (Table 1). Among 5 trials specifying the study enrollment and follow-up period, the years ranged from 2005 to 2011 24, 25, 29, 30, 31 (Table 1). The vaccines studied included diphtheria 27, 30, 33, tetanus 27, 30, 33, pertussis 27, 30, polio 26, 30, 32, influenza 24, 25, 29, 31, hepatitis B 33, Haemophilus influenzae type B 30, 33, flagellin from Salmonella adelaide28, and Streptococcus pneumoniae or pneumococcus30, 32, with studies often administering combination or multiple vaccines (Table 2). Four trials were conducted in hospitalized elderly patients 24, 25, 27, 29, while 3 were in adults (healthy: N=2; allergy: N=1) 26, 31, 32 and 3 were in infants and children (healthy: N=2; stunted growth: N=1) 28, 30, 33 (Table 2).

In 3 trials, differences between treatment arms were not observed in any of the reported analyses 30, 32, 33 (Table 2). The remaining 7 trials reported differences between the treatment arms or between pre- and post-intervention periods for at least one outcome. These 7 studies are described in the upcoming sections by the dairy product/component intervention 24, 25, 26, 27, 28, 29, 31 (Table 2).

Overall, the evidence base indicated that whole dairy products enhanced vaccine-specific immune response to tetanus and Salmonella Adelaide, while probiotics added to whole dairy products amplified vaccine-specific immune response to influenza and polio.

Whole dairy products

Two trials evaluated changes in vaccine-specific antibody titers following milk powder consumption 27, 28; study years were not reported in either trial (Table 1 and Table 2).

Elderly patients in retirement centers and long-term care facilities in the United States were given 6 g milk powder (n=10) or isoflavone soy protein (n=11) twice daily for 8 weeks and administered the diphtheria, tetanus, and pertussis (DTaP) vaccine at week 4 27 (Table 2). Post-vaccine tetanus antibodies were higher in the milk powder intervention compared with the soy protein group at week 8 (p=0.034). The mean change in the tetanus antibody level was also higher in the milk powder group (p=0.029).

Prepubertal children in New Guinea with growth deficiencies were given skim milk powder (n=30) or no intervention (n=24) for 8 months and administered flagellin (i.e., protein) from Salmonella adelaide at month 7 28 (Table 2). Total antibody titers at 6-weeks post-vaccination were higher in the skim milk powder group compared with the untreated group (p=0.002).

Whole dairy products with added probiotics

Five trials evaluated whether probiotics added to dairy products altered the immune response to vaccination, including 4 studies administering an influenza vaccine 24, 25, 29, 31 and one administering the polio vaccine 26 (Table 2).

During the 2010-2011 season, enterally-fed elderly patients in Japan were given a milk-based formula with added prebiotics and probiotics (L. delbrueckiisubsp. bulgaricus and S. thermophilus)(n=12)or a standard milk-based formula (n=12)for 14 weeks, with H1N1/H3N2/B influenza vaccination at week 4 29 (Table 2). The antibody titer to the influenza B antigen was lower in the intervention group compared to the control group at weeks 6 and 8 (p<0.05).

During the 2006/2007 influenza vaccine campaign in Spain, study participants aged 65-85 years received trivalent influenza vaccines 25 (Table 2). Probiotic consumption was started 3-4 months after vaccination. Nineteen elderly patients were randomized to high-dose skim milk powder with L. plantarum CECT 7315/7316, 14 were randomized to low-dose skim milk powder with L. plantarum CECT 7315/7316, and 15 were randomized to skim milk powder without the probiotic; the milk powders were administered for 3 months. For each treatment arm, the investigators compared immunoglobulin levels in the post- vs. pre-intervention. An increase in influenza-specific IgG was observed only for the high-dose intervention arm, comparing the post- vs. pre-intervention levels (p=0.023). Influenza-specific IgA was increased in both the high- and low-dose intervention arms, comparing post- vs. pre-intervention levels (p=0.008 and p=0.039, respectively).

During the 2008-2009 influenza season, healthy adults in Italy were randomized to 4 intervention arms. Two treatment groups were relevant for this review with 56 receiving an acidified dairy drink containing L. paracaseissp. paracasei (L. casei 431) and 54 receiving a placebo acidified dairy drink for 6 weeks 31 (Table 2). The trial participants were also administered the A/H1N1/A/H3N2/B influenza vaccine 2 weeks after starting the dairy intervention. Change between post-intervention and baseline plasma levels of influenza vaccine-specific total IgG, IgG1 and IgG3 were higher in the intervention group compared with the placebo (p=0.01, p<0.01, and p<0.001, respectively). The plasma IgG1 and IgG3 seroconversion rates were higher in the intervention group, compared to the placebo (p<0.001 and p<0.001, respectively).

A trial was conducted in France during the 2005-2006 (pilot study) and 2006-2007 (confirmatory study) influenza seasons 24 (Table 2). Differences between groups were observed in the confirmatory study only. In the confirmatory study, 113 participants were given a traditionally fermented dairy drink containing L. casei DN-114 001 (along with the traditional ferments of S. thermophilus and L.bulgaricus) for 13 weeks, and 109 were given non-fermented dairy drink. The influenza vaccine (A/H1N1, A/H3N2, and B) was administered 4 weeks after starting the consumption of the study products. The geometric mean antibody titers for the B strain were higher at 3 weeks (p=0.029), 6 weeks (p=0.027), and 9 weeks (p=0.025) after vaccination in the intervention arm, compared with the placebo. The seroconversion rate at 5 months after vaccination was also higher in the intervention arm, compared with the placebo for the B and A/H3N2 strains only (p=0.016 and p=0.031, respectively). The seroprotection rate at 3 weeks after vaccination in a subgroup of participants who were non-seroprotected at baseline was increased in the intervention group, compared to the placebo, for the A/H1N1 strain only (p=0.045).

In Germany, 22 healthy adults were given 100 g acidified milk product containing L. rhamnosusGG(LGG)(intervention 1) daily, 21 were given the same milk product with L. acidophilus paracaseisubspeciesparacasei(CRL431)(intervention 2) daily, and 20 received placebo acidified milk product 26 (Table 2). The treatment period spanned over 5 weeks for both intervention arms; the study year was not reported. Oral polio vaccination occurred at day 8. The poliovirus-1 IgA titer was increased in intervention arm 1 (p=0.036) and the poliovirus-2 IgM titer was increased in intervention arm 2 (p=0.040), compared to the placebo. Increased neutralizing antibodies of poliovirus-1 and -2 were also found with intervention arm 1, compared with the placebo (p=0.048 and p =0.014, respectively). Increased neutralizing antibodies were observed for poliovirus-3 (p=0.011), with intervention arm 2 compared to the placebo.

Effects of Dairy Intervention on Immunoglobulins (N=55)

Fifty-six studies evaluated dairy’s effects on immunoglobulins without vaccinations. The results were heterogenous, with some studies reporting significant enhancement of immunoglobulins (IgA, IgE, or IgG), while others observed no differences between treatment groups. Supplemental Table 3 presents the immunoglobulin information reported in these 56 studies. Supplemental Materials provide detailed summaries of the evidence.

Table 1. Characteristics of Included Studies, Organized by Study Quality, Dairy Exposure, and Publication Year (N=61)
Author (Year) Study Design Geographical Location Study Period Dairy Product or Component Study Outcome Study Quality
Suzuki (2020) 37 Clinical trial Japan NR Whole dairy: probiotic yogurt IgE Positive
Schaefer (2018) 27 Clinical trial United States NR Whole dairy: milk powder Vaccine-specific response: Antibody titers to vaccines Positive
Pu (2017) 38 Clinical trial China Both enrollment and follow-up: 2013 Whole dairy: probiotic yogurt IgA, IgE, IgG, IgM Positive
Vaisberg (2019) 39 Clinical trial Brazil NR Probiotic added to whole dairy IgA Positive
Corsello (2017) 40 Clinical trial Italy Both enrollment and follow-up: 2014-2015 Probiotic added to whole dairy IgA Positive
Lee (2017) 41 Clinical trial Korea Enrollment: Mar and Dec 2016 Probiotic added to whole dairy IgG Positive
Nocerino (2017) 42 Clinical trial Italy Both enrollment and follow-up: 2012 Probiotic added to whole dairy IgA Positive
Shida (2017) 43 Clinical trial Japan Both enrollment and follow-up: 2012-2013 Probiotic added to whole dairy IgA Positive
Nagafuchi (2015) 29 Clinical trial Japan Both enrollment and follow-up: 2010-2011 Probiotic added to whole dairy Vaccine-specific response: Antibody titers, seroprotection ratesIgA, IgG, IgM Positive
Bosch (2012) 25 Clinical trial Spain Both enrollment and follow-up: 2006-2007 Probiotic added to whole dairy Vaccine-specific response: IgA, IgG Positive
Lahtinen (2012) 44 Clinical trial Finland NR Probiotic added to whole dairy IgA Positive
Rizzardini (2012) 31 Clinical trial Italy Enrollment: 2009 Follow-up: 2009 Probiotic added to whole dairy Vaccine-specific response: IgA, IgGIgA, IgG, IgMSeroconversion rates: IgG Positive
Snel (2011) 45 Clinical trial Netherlands Both enrollment and follow-up: 2008 Probiotic added to whole dairy IgE, IgG Positive
Wassenberg (2011) 46 Clinical trial Switzerland Enrollment: 2006-2007 Probiotic added to whole dairy IgE, IgG Positive
Koyama (2010) 47 Clinical trial Canada Both enrollment and follow-up: Grass study (spring 2007); ragweed pollen study (summer-fall 2007) Probiotic added to whole dairy IgE, IgG, IgM Positive
Perez (2010) 30 Clinical trial Argentina Both enrollment and follow-up: 2006-2007 Probiotic added to whole dairy Vaccine-specific response: Antibody titersIgA, IgD, IgG, IgM Positive
Boge (2009) 24 Clinical trial France Both enrollment and follow-up: Pilot study in 2005-2006; Confirmation study in 2006-2007 Probiotic added to whole dairy Vaccine-specific response: Antibody titers, seroconversion rate, seroprotection rate Positive
Kawase (2009) 48 Clinical trial Japan Both enrollment and follow-up: 2006 Probiotic added to whole dairy IgE Positive
Martínez-Cañavate (2009) 49 Clinical trial Spain NR Probiotic added to whole dairy IgA, IgE, IgG, IgM Positive
Giovannini (2007) 50 Clinical trial Italy Enrollment: 2003-2004Follow-up: 2003-2005 Probiotic added to whole dairy IgA, IgE, IgG, IgM Positive
Olivares (2006) 51 Clinical trial Spain NR Probiotic added to whole diary IgA, IgE, IgG Positive
Spanhaak (1998) 52 Clinical trial Netherlands NR Probiotic added to whole dairy IgA, IgD, IgE, IgG, IgM Positive
Bumrungpert (2018) 53 Clinical trial Thailand NR Whey IgG Positive
Biesiekierski (2013) 54 Clinical trial, cross-over Australia Enrollment: Jan 2010-Jan 2011 Whey IgA, IgG Positive
Katayama (2011) 55 Clinical trial Japan NR Whey IgA, IgG Positive
King (2007) 33 Clinical trial United States NR Whey Vaccine-specific response: Antibody titers Positive
Micke (2001) 56 Clinical trial Germany Both enrollment and follow-up: Aug 1998-Mar 1999 Whey IgA, IgE, IgG, IgM Positive
Wheeler (1997) 57 Clinical trial, cross-over United States NR Probiotic added to whole dairy IgE Positive
Shinohara (2020) 58 Clinical trial Japan NR Whole dairy: Milk IgA Neutral
Papacosta (2015) 59 Clinical trial, cross-over Cyprus NR Whole dairy: Milk IgA Neutral
Mangold (2012) 60 Clinical trial Austria NR Whole dairy: Fermented milk IgA, IgD, IgE, IgG, IgM Neutral
Yang (2012) 23 Cohort Taiwan NR Whole dairy: probiotic yogurt IgA, IgE Neutral
Morita (2006) 61 Clinical trial Japan NR Whole dairy: Fermented milk IgE Neutral
Siekmann (2003) 62 Clinical trial Kenya Both enrollment and follow-up: Aug 1998-Aug 1999 Whole dairy: Milk H. pylori IgA, IgG, IgM, tetanus IgG Neutral
Pujol (2000) 63 Clinical trial, cross-over NR NR Whole dairy: Fermented milk IgA, IgG, IgM Neutral
Wheeler (1997) 32 Clinical trial, cross-over United States NR Whole dairy: Yogurt Vaccine-specific response: Seroconversion rateIgA, IgE, IgG, IgM Neutral
Link-Amster (1994) 64 Clinical trial Switzerland NR Whole dairy: Fermented milk IgG Neutral
Falth-Magnusson (1987) 65 Clinical trial Sweden Enrollment: 1983-1984 Whole dairy: Milk IgE Neutral
Matthews (1974) 28 Clinical trial New Guinea NR Whole dairy: milk powder Vaccine-specific response: IgG, Antibody titersIgM Neutral
Zhang (2021) 66 Clinical trial China NR Probiotic added to whole diary IgA, IgG, IgM Neutral
Eden (2019) 67 Clinical trial Turkey NR Probiotic added to whole diary IgA Neutral
Yamamoto (2019) 68 Clinical trial Japan Both enrollment and follow-up: Oct and Dec 2014 Probiotic added to whole dairy IgA Neutral
Zhang (2018) 69 Clinical trial China NR Probiotic added to whole dairy IgA, IgG, IgM Neutral
Yamamoto (2017) 70 Clinical trial Japan Both enrollment and follow-up: 2013 Probiotic added to whole dairy IgA Neutral
Kabeerdoss (2011) 71 Clinical trial India NR Probiotic added to whole dairy IgA Neutral
Surono (2011) 72 Clinical trial Indonesia NR Probiotic added to whole dairy IgA Neutral
Hasegawa (2009) 73 Clinical trial Japan Both enrollment and follow-up: 2008 Probiotic added to whole diary IgE Neutral
Ivory (2008) 74 Clinical trial United Kingdom Both enrollment and follow-up: 2005-2006 Probiotic added to whole dairy IgE, IgG Neutral
Tiollier (2007) 75 Clinical trial France NR Probiotic added to whole dairy IgA Neutral
Xiao (2006) 76 Clinical trial Japan Both enrollment and follow-up: 2004 Probiotic added to whole dairy IgE Neutral
De Vrese (2005) 26 Clinical trial Germany NR Probiotic added to whole dairy Vaccine-specific response: IgA, IgG, antibody titers, seroprotection rate Neutral
Ishida (2005) 77 Clinical trial Japan Both enrollment and follow-up: 2002 and 2003 Probiotic added to whole dairy IgE Neutral
Ishida (2005) 78 Clinical trial Japan Both enrollment and follow-up: 2002-2003 Probiotic added to whole diary IgE Neutral
Marteau (1997) 79 Clinical trial France NR Probiotic added to whole dairy IgA, IgG, IgM Neutral
Kaila (1992) 80 Clinical trial Finland NR Probiotic added to whole dairy IgA, IgG, IgM Neutral
Oda (2021) 81 Clinical trial Japan Both enrollment and follow-up: 2017 Whey IgA Neutral
Lothian (2006) 82 Clinical trial Canada Enrollment: Jan 2000-Jan 2002 Whey IgE Neutral
Rohr (2012) 83 Clinical trial China NR Casein IgA, IgG, IgM Neutral
Milewska-Wróbel (2020) 22 Cross-sectional Poland NR Dietary patterns: Maternal intake of yogurt, milk or cheese IgE Neutral
Keller (2014) 84 Clinical trial Germany Both enrollment and follow-up: Mar and Oct 2011 Milk phospholipids IgE Neutral
Coman (2017) 21 Clinical trial Italy NR Probiotic added to whole dairy IgA Negative

Table 2. Consumption of Dairy Products/Components and Vaccine-Specific Immune Response After Vaccination (N=10)
Author (Year) Study Population Dairy Intervention Details Vaccine Type and Timing of Administration Vaccine-Specific IgG Vaccine-Specific IgA or IgM Antibody Titers Seroprotection Rates or Seroconversion Rates
N Age and Health Status
Whole Dairy Products
Schaefer (2018) 27 Intervention (milk powder): 10Control (low isoflavone soy protein): 11 Elderly, hospitalized patients in retired centers and long-term care facilities 6 g milk powder twice a day for 8 weeks Diphtheria, tetanus, and polio (DTaP) vaccine at week 4 NR NR Mean change in tetanus antibody level week 8-week 0: SS higher in intervention group (p=0.029) Mean post-vaccine tetanus antibody level at week 8:SS higher in intervention group (p=0.034) Diphtheria and pertussis antibody levels: NSS between groups NR
Wheeler (1997) 32 20(cross-over trial of traditional yogurt and 2% milk) Adults, atopic disease 8 oz traditional yogurt per day for 1 month (yogurt contained live, active L. bulgaricus and S. thermophilus at 2.5 to 3.0 x 108 per g and 3.5 to 4.1 x 108 per g)8 oz milk twice daily for 1 month1 month of one product, 2 weeks without dietary restrictions, 2-week washout period, 1 month of the other product Quadrivalent pneumococcal vaccine and the standard oral polio vaccine at study start (day 0) NR NR NR Mean number of patients with a response (ratio values of >3) to pneumococcal titers across 12 serotypes: NSS with the cross-over analysisMean number of patients with a response to polio vaccine (fold rise >2): NSS for polio 1, 2, or 3 with the cross-over analysis
Matthews (1974) 28 Intervention (skim milk powder): 30Control (no intervention): 24 Children, growth-retarded Skim milk powder (25 g protein) 5 days per week for 8 months Flagellin from Salmonella adelaideadministered at 7 months Total IgG antibody: Difference NSS between treatment groups at 2- or 6-weeks post-immunization NR Total antibody titers to flagellin: SS higher in the intervention group at 6 weeks post- immunization (p=0.002)NSS difference between groups at 2 weeks post-immunization (p=0.05) NR
Probiotics
Nagafuchi (2015) 29 Intervention (milk-based formula with prebiotics and probiotics): 12Control (standard milk-based formula): 12 Elderly, Hospitalized Formula administered enterally via percutaneous endoscopic gastrostomy for 14 weeks, no details on doseIntervention formula contains prebiotics bifidogenic growth stimulator (BGS) and galacto-oligosaccharides (GOS) and probioticsL.delbrueckiisubsp. bulgaricus and S. thermophilus Influenza A/H1N1, A/H3N2, and B at week 4 NR NR Antibody titersA/H1N1: NSS differences between treatment groups at weeks 0, 4 (time of vaccination), 6, 8 or 12 A/H3N2: NSS differences between treatment groups at weeks 0, 4, 6, 8 or 12B: SS lower in the intervention group vs. control at week 6 and 8 (p < 0.05); NSS difference at week 0,4, or 12 Differences NSS in seroprotection rates between treatment groups for A/H1N1, A/H3N2 and B at weeks 0, 4, 6, 8 or 12
Bosch (2012) 25 Intervention arm 1 (high-dose skim milk powder with probiotic): 19Intervention arm 2 (low-dose skim milk powder with probiotic): 14Control arm (placebo: skim milk powder): 15 Elderly, Hospitalized High-dose: 5 x 109 cfu/day of L. plantarum CECT7315/7316 in 20 g powdered skim milk for 3 monthsLow dose: 5 x 108 cfu/day of L. plantarum CECT7315/7316 in 20 g powdered skim milk for 3 months Influenza A/H1N1, A/H3N2, and B 3-4 months prior to the intervention Influenza-specific IgG:High-dose: SS increase post- vs. pre-intervention (p = 0.023)Low-dose and placebo: NSS difference pre- vs. post-intervention Influenza-specific IgA:High-dose: SS increasepost- vs pre-intervention (p = 0.008)Low dose: SS increase pre- vs. post-intervention (p = 0.039) Placebo: NSS difference pre- vs. post-interventionInfluenza-specific IgM: NSS pre- vs. post-intervention for all treatment groups NR NR
Rizzardini (2012) 31 4 intervention arms were evaluated with 2 treatment groups relevant to this reviewIntervention (probiotic drink): 56Control (placebo acidified dairy drink): 54 Adults, healthy One acidified dairy drink with L.paracaseissp.paracasei (L. casei 431) once daily for 6 weeks. Minimum 1x109 cfu/dose Influenza A/H1N1, A/H3N2, and B at week 2 Changes from baseline, plasma: SS greater change in the intervention group vs. placebo for total IgG (p=0.01), IgG1 (p<0.001) and IgG3 (p<0.001) Changes from baseline, salivary: Difference NSS between treatment groups for total IgG Rate of substantial increase (>2-fold increase), salivary: SS higher rate for IgA (p=0.035) Changes from baseline, plasma: NRChanges from baseline,salivary: Difference NSS between treatment groups for total IgA or IgMRate of substantial increase (>2-fold increase), salivary: Difference NSS between treatment groups for total IgG or IgM NR Rate of substantial increase (>2-fold increase), plasma: Difference NSS between treatment groups for total IgG SS higher rate in the intervention group vs. control for IgG1 (p<0.001) and IgG3 (p<0.001)
Perez (2010) 30 Intervention (Milk fermented with S. thermophilus, L. acidophilus CRL431, L. caseiCRL730): 70Control (Milk fermented with S. thermophilus): 70 Children, healthy 95 g milk bottle once daily for at least 4 months95 x 108 cfu of S. thermophilus, 95 x 106 cfu of L. acidophilus and 95 x 106cfu of L. casei Diphtheria/ tetanus/ pertussis andHaemophilusinfluenzae typeB (DTP-HiB) vaccine or 23-valent anti-pneumococcal vaccine, depending on age NR NR Tetanus antibodies: Differences NSS between treatment and control for pre- and post-vaccinationPneumococcal antibodies: Differences NSS between treatment and control for pre- and post-vaccination NR
Boge (2009) 24 Intervention arm (dairy drink with probiotic): 44 pilot and 113 confirmatoryControl arm (non-fermented dairy drink): 42 pilot and 109 confirmatory Elderly, hospitalized patients and nursing home residents 2 bottles of 100 g dairy drink with L. casei DN-114 001and traditional yogurt ferments per day for 7 weeks (pilot study) or 13 weeks (confirmatory study) Influenza A/H1N1, A/H3N2, and B at week 4 NR NR Confirmatory study:Geometric mean titers: Intervention group: SS increase for B at 3 weeks (p= 0.029), 6 weeks (p=0.027), and 9 weeks (p=0.025) after vaccinationDifferences NSS for A/H1N1 and A/H3N2 at 3, 6 and 9 weeks after vaccinationControl group: Differences NSS for all 3 strains at 3, 6, and 9 weeks after vaccinationPilot study: NSS for all 3 strains at 3 weeks after vaccination in all treatment groups Confirmatory study:Seroconversion rate at 5 months after vaccination: SS increases in the intervention group vs. control for B (p=0.016) and A/H3N2 (p=0.031); NSS between treatment groups for A/H1N1Seroprotection rate at 3 weeks after vaccination: SS increase in the intervention group vs. control for A/H1N1 strain (p=0.045); NSS between treatment grups for B and A/H3N1Pilot study: NSS for seroprotection or seroconversion rates at 3 weeks after vaccination in all treatment groups
De Vrese (2005) 26 Intervention arm 1 (L. rhamnosusGG): 22Intervention arm 2 (L. acidophilus CRL431): 21Control (placebo): 21 Adults, healthy Whole dairy acidified milk product with L.rhamnosusGGor L. acidophilus CRL431100 g/day (1010cfu/serving) for 5 weeks for both intervention arms Polio virus 1, 2 and 3 administered at day 8 Poliovirus serotype-specific IgG titer:Difference NSS between placebo and intervention groups for polio virus 1, 2 or 3 Poliovirus serotype-specific IgA titer:Polio 1=SS increase in intervention 1 vs. placebo (p=0.036); Difference NSS between intervention 2 and placeboPolio 2 and Polio 3=Difference NSS between placebo and intervention groups Poliovirus serotype-specific IgM titer:Polio 2=SS increase in intervention 2 vs. placebo (p=0.040); Difference NSS between intervention 1and placeboPolio 1 and Polio 3= Difference NSS between placebo and intervention groups ∆ Neutralizing antibodies titer:Polio 1=SS increase in intervention 1 vs. placebo (p=0.048); NSS difference between placebo and intervention 2Polio 2=SS increase in intervention 1 vs. placebo (p=0.014); NSS difference between placebo and intervention 2Polio 3=SS increase in intervention 2 vs. placebo (p=0.011); NSS difference between placebo and intervention 1∆ PoBI Titer:NSS difference between placebo and intervention groups for polio 1, 2, or 3 Differences NSS in seroprotection rates between placebo and intervention groups
Dairy Proteins
King (2007) 33 Intervention arm (Similac with Fe formula, 850 mg/L bovine lactoferrin): 26Control arm (Similac with Fe formula, 102 mg/L bovine lactoferrin): 26 Infants <4 weeks of age, healthy Similac iron formula with bovine lactoferrin Diphtheria and tetanus (DT), Haemophilus influenzaetype B (HiB), and hepatitis B, according to the standard schedule NR NR Mean antibody levels at 9 months:Diphtheria, tetanus, Haemophilus influenzaetype B, and hepatitis B: treatment vs. control NSSMean antibody levels at 12 months:Hepatitis B: treatment vs. control NSS NR

• SS: Statistically significant (p<0.05)
• NSS: Not statistically significant (p≥0.05)

Discussion

This review provides a systematic assessment of the epidemiologic literature regarding dairy products/components’ potential impacts on the immune response to vaccination. The potential impacts of dairy products/components on immunoglobulins are also described in this review. Among various populations, dairy interventions were observed to modify the adaptive immune response after vaccination with significantly increased levels of IgA and IgG, vaccine-specific antibody titers, seroconversion rates, and seroprotection rates. The evidence describing the benefits of dairy seems to be most consistent for probiotics added to whole dairy products. Three randomized, double-blind, placebo-controlled trials reported enhanced productions of influenza vaccine-specific antibodies with Lactobacillus probiotic supplementation in dairy drinks/milk powder 24, 25, 31. Significant increases in seroprotection/seroconversion were reported in 2 trials that collected this information 24, 31. Sporadic changes in polio-specific antibodies were also observed with Lactobacillus supplementation, although no differences in the number of patients with seroprotection were found 26. Vaccination is an important preventative measure to protect against infections and reduce the severity/duration of illness 34. Currently, the COVID-19 pandemic is on-going and overlaps with influenza and respiratory syncytial virus seasons. In this era of ‘tripledemic’, our study suggests that dairy products and their components could be an effective vehicle to enhance the efficacy of vaccines.

Our findings on the potential immune benefits from probiotics in dairy are consistent with clinical trials evaluating vaccine efficacy and probiotics given without dairy 35. Probiotics may be the bioactive component of dairy products that confer an immunological benefit. Research is ongoing on the physiological effects of probiotics; the mechanism may include the stimulation of the innate immune response in the gut and/or the interaction of probiotic bacteria with immune and intestinal epithelial cells 36. Dairy products may be an ideal vehicle to deliver probiotics, as they are a well-accepted food item and provide additional valuable nutrients such as vitamin D and calcium.

In this review, the critical appraisal of the included studies indicates that the evidence base is strong, with the inclusion of 60 positive or neutral quality studies. Another strength of this review is that we followed all standard PRISMA recommendations for systematic reviews throughout the entirety of study conduct. Additionally, as the scope of the review was broad, this review is comprehensive and has captured the totality of the published literature on dairy and non-inflammatory immune response with or without vaccinations.

While this review suggests a beneficial role for dairy in the immune response to vaccination, the interpretation of these findings is impacted by substantial heterogeneity in study features, including the exposure under study, exposure dose/duration, the probiotic strain under investigation, the vaccine type, the age and comorbidities of the study population, and the different biological matrices used to measure immunoglobulins (including serum, saliva, and fecal matter). Variability was also observed in the timing of the dairy intervention and vaccine administration, with vaccines being given at the beginning of the study period or during the dairy intervention. Probiotics evaluated in the included studies comprised various species and strains, both naturally occurring and experimental. It is possible that probiotics’ immune-modulating effect is strain-specific and, thus, the positive or negative findings may be related to strain-specific variation. Due to the heterogeneity in exposures and outcomes, quantitative synthesis was not advisable. Finally, the interpretation of immunoglobulin results remains challenging as clinical relevance was not evaluated in the included studies. Specifically, the evidence connecting enhanced antibody productions by dairy interventions to protections against disease incidence and/or severity of illness was not available in the included studies. In tandem to the current review, we identified another evidence base related to the influence of dairy products/components on infectious disease incidence and the duration/severity of disease. This topic will be evaluated in a separate publication, and the conclusions of that companion paper will inform the current review.

Notably, this review highlights the evidence gaps and provides a potential roadmap for additional research on dairy and immune response. Multicenter, randomized, placebo-controlled trials or prospective cohort studies may be beneficial. These studies should include a range of specified exposure durations/doses, focused probiotic strains/dairy proteins, and clinically relevant outcomes (i.e., disease incidence). Study design with longitudinal measures of immunoglobulins and vaccine-specific immune response are also needed to fill the evidence gaps. Studies should incorporate a period of follow-up to obtain disease incidence and measures of immune response. Additional studies may also consider probiotic supplementation in dairy among the pediatric populations, where vaccination is routine and dairy products are recommended in the dietary guidelines 4, 5.

Conclusions

The consumption of dairy products/components prior to and after vaccination could represent an effective intervention to improve the antibody response to vaccination. This intervention could potentially provide a public health benefit by enhancing vaccine efficacy and thereby increasing protections of individuals susceptible to severe illness from vaccine-preventable diseases.

Author Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by MS and MM. The first draft of the manuscript was written by MS and all authors commented on subsequent versions of the manuscript. All authors read and approved the final manuscript.

Affiliations

MS, MM, NH, and LCB are employees of EpidStrategies, A Division of ToxStrategies, LLC. SSC was an employee of EpidStrategies at the time this work was conducted.

Acknowledgements

This study was funded by the National Dairy Council. We thank Dr. Cara Frankenfeld for providing editorial review.

References

  1. 1.Neuhouser M L. (2019) The Importance of Healthy Dietary Patterns in Chronic Disease Prevention. Nutr Res. 70, 3-6.
  1. 2.Reinhardt S L, Boehm R, Blackstone N T. (2020) . Systematic Review of Dietary Patterns and Sustainability in the United States. Adv Nutr 11(4), 1016-1031.
  1. 3.Schulze M B, Martinez-Gonzalez M A, Fung T T. (2018) Food Based Dietary Patterns and Chronic Disease Prevention. , BMJ 361, 2396.
  1. 4.US Department (2020) . of Agriculture and US Department of Health and Human Services.Dietary Guidelines for Americans DietaryGuidelines.gov 2020-2025.
  1. 5.Comerford K B, Miller G D, Boileau A C. (2021) Global Review of Dairy Recommendations in Food-Based Dietary Guidelines. Front Nutr. 8, 671999.
  1. 6.Zanini B, Simonetto A, Zubani M. (2020) The Effects of Cow-Milk Protein Supplementation in Elderly Population: Systematic Review and Narrative Synthesis. , Nutrients 12(9), 2548.
  1. 7.Talaei M, Faustini S, Holt H. (2022) Determinants of Pre-Vaccination Antibody Responses to Sars-Cov-2: A Population-Based Longitudinal Study (Covidence Uk). , BMC Med 20(1), 87.
  1. 8.Nieman K M, Anderson B D, Cifelli C J. (2021) The Effects of Dairy Product and Dairy Protein Intake on Inflammation: A Systematic Review of the Literature. , J Am Coll Nutr 40(6), 571-582.
  1. 9.Plaza-Diaz J, Gomez-Llorente C, Fontana L. (2014) . Modulation of Immunity and Inflammatory Gene Expression in the Gut, in Inflammatory Diseases of the Gut and in the Liver by Probiotics. World 20(42), 15632-15649.
  1. 10.Wu D, Lewis E D, Pae M. (2018) Nutritional Modulation of Immune Function: Analysis of Evidence, Mechanisms, and Clinical Relevance. Front Immunol. 9, 3160.
  1. 11.Kume H, Okazaki K, Takahashi T. (2014) Protective Effect of an Immune-Modulating Diet Comprising Whey Peptides and Fermented Milk Products on Indomethacin-Induced Small-Bowel Disorders in Rats. , Clin Nutr 33(6), 1140-1146.
  1. 12.Superti F. (2020) Lactoferrin from Bovine Milk: A Protective Companion for Life. , Nutrients 12(9), 2562.
  1. 13.Labonté M, Couture P, Richard C. (2013) Impact of Dairy Products on Biomarkers of Inflammation: A Systematic Review of Randomized Controlled Nutritional Intervention Studies in Overweight and Obese Adults. , Am J Clin Nutr 97(4), 706-717.
  1. 14.Bordoni A, Danesi F, Dardevet D. (2017) Dairy Products and Inflammation: A Review of the Clinical Evidence. Crit Rev Food Sci Nutr. 57(12), 2497-2525.
  1. 15.Benatar Sidhu, Stewart K, RA. (2013) Effects of High and Low Fat Dairy Food on Cardio-Metabolic Risk Factors: A Meta-Analysis of Randomized Studies. , PLoS One 8(10), 76480.
  1. 16.Page M J, McKenzie J E, Bossuyt P M. (2021) The Prisma. , BMJ 372, 71.
  1. 17.M Van Tilbeurgh, Lemdani K, Beignon A S. (2021) Predictive Markers of Immunogenicity and Efficacy for Human Vaccines. Vaccines (Basel). 9(6), 579.
  1. 18.Domnich A, Manini I, Panatto D. (2020) Immunogenicity Measures of Influenza Vaccines: A Study of 1164 Registered Clinical Trials. Vaccines (Basel). 8(2), 325.
  1. 19.Distillersr. (2023) Version 2023.4. Distillersr Inc.;. Accessed
  1. 20. (2016) Academy of Nutrition and Dietetics.Evidence Analysis Manual: Steps in the Academy Evidence Analysis Process.
  1. 21.Coman M M, Verdenelli M C, Silvi S. (2017) Knowledge and Acceptance of Functional Foods: A Preliminary Study on Influence of a Synbiotic Fermented Milk on Athlete Health. , International Journal of Probiotics and Prebiotics 12(1), 33-41.
  1. 22.Milewska-Wróbel D, Lis-Święty A. (2020) Does Maternal Diet During Pregnancy Influence Clinical and Laboratory Characteristics of Infantile-Onset Atopic Dermatitis? Eur Ann Allergy Clin Immunol. 52(6), 277-279.
  1. 23.Yang Y J, Sheu B S. (2012) Probiotics-Containing Yogurts Suppress Helicobacter Pylori Load and Modify Immune Response and Intestinal Microbiota in the Helicobacter Pylori-Infected Children. , Helicobacter 17(4), 297-304.
  1. 24.Boge T, Rémigy M, Vaudaine S. (2009) A Probiotic Fermented Dairy Drink Improves Antibody Response to Influenza Vaccination in the Elderly in Two Randomised Controlled Trials. , Vaccine 27(41), 5677-5684.
  1. 25.Bosch M, Méndez M, Pérez M. (2012) . Lactobacillus Plantarum Cect7315 and Cect7316 Stimulate Immunoglobulin Production after Influenza Vaccination in Elderly. Nutrición hospitalaria : organo oficial de la Sociedad Española de Nutrición Parenteral y Enteral 27(2), 504-509.
  1. 26.M De Vrese, Rautenberg P, Laue C. (2005) Probiotic Bacteria Stimulate Virus-Specific Neutralizing Antibodies Following a Booster Polio Vaccination. , European Journal of Nutrition 44(7), 406-413.
  1. 27.Schaefer S, Hettinga K A, Cullor J. (2018) Use of Uv Treated Milk Powder to Increase Vaccine Efficacy in the Elderly. Front Immunol. 9, 2254.
  1. 28.Mathews J D, Mackay I R, Tucker L. (1974) . Interrelationships between Dietary Protein, Immunoglobulin Levels, Humoral Immune Responses and Growth in New Guinean Schoolchildren. Am J Clin Nutr 27(9), 908-915.
  1. 29.Nagafuchi S, Yamaji T, Kawashima A. (2015) Effects of a Formula Containing Two Types of Prebiotics. Bifidogenic Growth Stimulator and Galacto-Oligosaccharide, and Fermented Milk Products on Intestinal Microbiota and Antibody Response to Influenza Vaccine in Elderly Patients: A Randomized Controlled Trial. Pharmaceuticals 8(2), 351-365.
  1. 30.Pérez N, Iannicelli J C, Girard-Bosch C. (2010) Effect of Probiotic Supplementation on Immunoglobulins, Isoagglutinins and Antibody Response in Children of Low Socio-Economic Status. , European Journal of Nutrition 49(3), 173-179.
  1. 31.Rizzardini G, Eskesen D, Calder P C. (2012) Evaluation of the Immune Benefits of Two Probiotic Strains Bifidobacterium Animalis Ssp. Lactis, Bb-12® and Lactobacillus Paracasei Ssp. Paracasei, L. Casei 431® in an Influenza Vaccination Model: A Randomised, Double-Blind, Placebo-Controlled Study. , British Journal of Nutrition 107(6), 876-884.
  1. 32.Wheeler J G, Bogle M L, Shema S J. (1997) Impact of Dietary Yogurt on Immune Function. , American Journal of the Medical Sciences 313(2), 120-123.
  1. 33.King J C, Cummings G E, Guo N. (2007) A Double-Blind, Placebo-Controlled, Pilot Study of Bovine Lactoferrin Supplementation in Bottle-Fed Infants. , J Pediatr Gastroenterol Nutr 44(2), 245-251.
  1. 34.Bechini A, Boccalini S, Ninci A. (2019) Childhood Vaccination Coverage in Europe: Impact of Different Public Health Policies. Expert Rev Vaccines. 18(7), 693-701.
  1. 35.Kazemifard N, Dehkohneh A, Ghavami Baradaran, S. (2022) Probiotics and Probiotic-Based Vaccines: A Novel Approach for Improving Vaccine Efficacy. Front Med (Lausanne). 9, 940454.
  1. 36.Mazziotta C, Tognon M, Martini F. (2023) . Probiotics Mechanism of Action on Immune Cells and Beneficial Effects on Human Health. Cells 12(1), 184.
  1. 37.Suzuki T, Nishiyama K, Kawata K. (2020) . Effect of the Lactococcus Lactis 11/19-B1 Strain on Atopic Dermatitis in a Clinical Test 12(3), 763.
  1. 38.Pu F, Guo Y, Li M. (2017) Yogurt Supplemented with Probiotics Can Protect the Healthy Elderly from Respiratory Infections: A Randomized Controlled Open-Label Trial. Clinical Interventions in Aging. 12, 1223-1231.
  1. 39.Vaisberg M, Paixão V, Almeida E B. (2019) Daily Intake of Fermented Milk Containing Lactobacillus Casei Shirota (Lcs) Modulates Systemic and Upper Airways Immune/Inflammatory Responses in Marathon Runners. , Nutrients 11(7), 1678.
  1. 40.Corsello G, Carta M, Marinello R. (2017) Preventive Effect of Cow's Milk Fermented with Lactobacillus Paracasei Cba L74 on Common Infectious Diseases in Children: A Multicenter Randomized Controlled Trial. , Nutrients 9(7), 669.
  1. 41.Lee A, Lee Y J, Yoo H J. (2017) Consumption of Dairy Yogurt Containing Lactobacillus Paracasei Ssp. Paracasei, Bifidobacterium Animalis Ssp. Lactis and Heat-Treated Lactobacillus Plantarum Improves Immune Function Including Natural Killer Cell Activity. , Nutrients 9(6), 558.
  1. 42.Nocerino R, Paparo L, Terrin G. (2017) Cow's Milk and Rice Fermented with Lactobacillus Paracasei Cba L74 Prevent Infectious Diseases in Children: A Randomized Controlled Trial. Clinical Nutrition. 36(1), 118-125.
  1. 43.Shida K, Sato T, Iizuka R. (2017) Daily Intake of Fermented Milk with Lactobacillus Casei Strain Shirota Reduces the Incidence and Duration of Upper Respiratory Tract Infections in Healthy Middle-Aged Office Workers. , European Journal of Nutrition 56(1), 45-53.
  1. 44.Lahtinen S J, Forssten S, Aakko J. (2012) . Probiotic Cheese Containing Lactobacillus Rhamnosus Hn001 and Lactobacillus Acidophilus Ncfm® Modifies Subpopulations of Fecal Lactobacilli and Clostridium Difficile in the Elderly. Age 34(1), 133-143.
  1. 45.Snel J, Vissers Y M, Smit B A. (2011) Strain-Specific Immunomodulatory Effects of Lactobacillus Plantarum Strains on Birch-Pollen-Allergic Subjects out of Season. Clin Exp Allergy. 41(2), 232-242.
  1. 46.Wassenberg J, Nutten S, Audran R. (2011) . Effect of Lactobacillus Paracasei St11 on a Nasal Provocation Test with Grass Pollen in Allergic Rhinitis. Clinical and Experimental Allergy 41(4), 565-573.
  1. 47.Koyama T, Kirjavainen P V, Fisher C. (2010) Development and Pilot Evaluation of a Novel Probiotic Mixture for the Management of Seasonal Allergic Rhinitis. , Canadian Journal of Microbiology 56(9), 730-738.
  1. 48.Kawase M, He F, Kubota A. (2009) Effect of Fermented Milk Prepared with Two Probiotic Strains on Japanese Cedar Pollinosis in a Double-Blind Placebo-Controlled Clinical Study. , International Journal of Food Microbiology 128(3), 429-434.
  1. 49.Martínez-Cañavate A, Sierra S, Lara-Villoslada F. (2009) A Probiotic Dairy Product Containing L. Gasseri Cect5714 and L. Coryniformis Cect5711 Induces Immunological Changes in Children Suffering from Allergy. Pediatric Allergy and Immunology 20(6), 592-600.
  1. 50.Giovannini M, Agostoni C, Riva E. (2007) A Randomized Prospective Double Blind Controlled Trial on Effects of Long-Term Consumption of Fermented Milk Containing Lactobacillus Casei in Pre-School Children with Allergic Asthma and/or Rhinitis. Pediatric Research. 62(2), 215-220.
  1. 51.Olivares M, Díaz-Ropero M P, Gómez N. (2006) The Consumption of Two New Probiotic Strains. Lactobacillus Gasseri Cect 5714 and Lactobacillus Coryniformis Cect 5711, Boosts the Immune System of Healthy Humans. International Microbiology 9(1), 47-52.
  1. 52.Spanhaak S, Havenaar R, Schaafsma G. (1998) The Effect of Consumption of Milk Fermented by Lactobacillus Casei Strain Shirota on the Intestinal Microflora and Immune Parameters in Humans. , European Journal of Clinical Nutrition 52(12), 899-907.
  1. 53.Bumrungpert A, Pavadhgul P, Nunthanawanich P. (2018) Whey Protein Supplementation Improves Nutritional Status, Glutathione Levels, and Immune Function in Cancer Patients: A Randomized, Double-Blind Controlled Trial. , Journal of Medicinal Food 21(6), 612-616.
  1. 54.Biesiekierski Peters, Newnham S L, ED. (2013) No Effects of Gluten in Patients with Self-Reported Non-Celiac Gluten Sensitivity after Dietary Reduction of Fermentable, Poorly Absorbed, Short-Chain Carbohydrates. , Gastroenterology 145(2), 320-328.
  1. 55.Katayama K, Matsuno T, Waritani T. (2011) Supplemental Treatment of Rheumatoid Arthritis with Natural Milk Antibodies against Enteromicrobes and Their Toxins: Results of an Open-Labelled Pilot Study. , Nutr J 10, 2.
  1. 56.Micke P, Beeh K M, Schlaak J F. (2001) Oral Supplementation with Whey Proteins Increases Plasma Glutathione Levels of Hiv-Infected Patients. , European Journal of Clinical Investigation 31(2), 171-178.
  1. 57.Wheeler J G, Shema S J, Bogle M L. (1997) . Immune and Clinical Impact of Lactobacillus Acidophilus on Asthma. Annals of Allergy, Asthma and Immunology 79(3), 229-233.
  1. 58.Shinohara M, Kuroda Y, toMaBechi N. (2020) Effects of Milk Intake Combined with Exercise on Upper Respiratory Tract Infection in Older Adults During Winter. Gazzetta Medica Italiana Archivio per le Scienze Mediche. 179(6), 386-392.
  1. 59.Papacosta E, Nassis G P, Gleeson M. (2015) Effects of Acute Postexercise Chocolate Milk Consumption During Intensive Judo Training on the Recovery of Salivary Hormones, Salivary Siga, Mood State, Muscle Soreness, and Judo-Related Performance. Appl Physiol Nutr Metab. 40(11), 1116-1122.
  1. 60.Mangold A, Hercher D, Hlavin G. (2012) Anti-Alpha-Gal Antibody Titres Remain Unaffected by the Consumption of Fermented Milk Containing Lactobacillus Casei in Healthy Adults. , International Journal of Food Sciences and Nutrition 63(3), 278-282.
  1. 61.Morita H, He F, Kawase M. (2006) Preliminary Human Study for Possible Alteration of. Serum Immunoglobulin E Production in Perennial Allergic Rhinitis with Fermented Milk Prepared with Lactobacillus Gasseri Tmc0356. Microbiology and Immunology 50(9), 701-706.
  1. 62.Siekmann J H, Allen L H, Watnik M R. (2003) Titers of Antibody to Common Pathogens: Relation to Food-Based Interventions in Rural Kenyan Schoolchildren. , Am J Clin Nutr 77(1), 242-249.
  1. 63.Pujol P, Huguet J, Drobnic F. (2000) The Effect of Fermented Milk Containing Lactobacillus Casei on the Immune Response to Exercise. Sports Medicine, Training and Rehabilitation. 9(3), 209-223.
  1. 64.Link-Amster H, Rochat F, Saudan K Y. (1994) Modulation of a Specific Humoral Immune Response and Changes. in Intestinal Flora Mediated through Fermented Milk Intake. FEMS Immunology and Medical Microbiology 10(1), 55-63.
  1. 65.Falth-Magnusson K, Kjellman NIM. (1987) Development of Atopic Disease in Babies Whose Mothers Were Receiving Exclusion Diet During Pregnancy - a Randomized Study. , Journal of Allergy and Clinical Immunology 80(6), 868-875.
  1. 66.Zhang H, Miao J, Su M. (2021) Effect of Fermented Milk on Upper Respiratory Tract Infection in Adults Who Lived in the Haze Area of Northern China: A Randomized Clinical Trial. Pharmaceutical Biology. 59(1), 647-652.
  1. 67.Eden E, Topaloglu Asli, Ak Özgenç, F. (2019) Effect of Short-Term Probiotic Yogurt Consumption on Caries Risk Factors in Infants. , Journal of Pediatric Research 6(1), 12-17.
  1. 68.Yamamoto Y, Saruta J, Takahashi T. (2019) Effect of Ingesting Yogurt Fermented with Lactobacillus Delbrueckii Ssp. Bulgaricus Oll1073r-1 on Influenza Virus-Bound Salivary Iga in Elderly Residents of Nursing Homes: A Randomized Controlled Trial. Acta odontologica Scandinavica. 77(7), 517-524.
  1. 69.Zhang H, Yeh C, Jin Z. (2018) . Prospective Study of Probiotic Supplementation Results in Immune Stimulation and Improvement of Upper Respiratory Infection Rate. Synthetic and Systems Biotechnology 3(2), 113-120.
  1. 70.Yamamoto Y, Fujino K, Saruta J. (2017) Effects of Yogurt Fermented with Lactobacillus Delbrueckii Ssp. bulgaricus Oll1073r-1 on the Iga Flow Rate of Saliva in Elderly Persons Residing in a Nursing Home: A before-after Non-Randomised Intervention Study. , Gerodontology 34(4), 479-485.
  1. 71.Kabeerdoss J, Devi R S, Mary R R. (2011) Effect of Yoghurt Containing Bifidobacterium Lactis Bb12® on Faecal Excretion of Secretory Immunoglobulin a and Human Beta-Defensin 2 in Healthy Adult Volunteers. , Nutr J 10, 138.
  1. 72.Surono I S, Koestomo F P, Novitasari N. (2011) Novel Probiotic Enterococcus Faecium Is-27526 Supplementation Increased Total Salivary Siga Level and Bodyweight of Pre-School Children: A Pilot Study. , Anaerobe 17(6), 496-500.
  1. 73.Hasegawa T, Hirakawa K, Matsumoto T. (2009) . Efficacy of Lactobacillus Plantarum Strain Hsk201 in Relief from Japanese Cedar Pollinosis. Bioscience, Biotechnology and Biochemistry 73(12), 2626-2631.
  1. 74.Ivory K, Chambers S J, Pin C. (2008) Oral Delivery of Lactobacillus Casei Shirota Modifies Allergen-Induced Immune Responses in Allergic Rhinitis. Clinical and Experimental Allergy. 38(8), 1282-1289.
  1. 75.Tiollier E, Chennaoui M, Gomez-Merino D. (2007) Effect of a Probiotics Supplementation on Respiratory Infections and Immune and Hormonal Parameters During Intense Military Training. Military Medicine. 172(9), 1006-1011.
  1. 76.Xiao J Z, Kondo S, Yanagisawa N. (2006) Effect of Probiotic Bifidobacterium Longum Bbs36 in Relieving Clinical Symptoms and Modulating Plasma Cytokine Levels of Japanese Cedar Pollinosis During the Pollen Season. A Randomized Double-Blind, Placebo-Controlled Trial. , Journal of Investigational Allergology and Clinical Immunology 16(2), 86-93.
  1. 77.Ishida Y, Nakamura F, Kanzato H. (2005) Effect of Milk Fermented with Lactobacillus Acidophilus Strain L-92 on Symptoms of Japanese Cedar Pollen Allergy: A Randomized Placebo-Controlled Trial. , Bioscience, Biotechnology and Biochemistry 69(9), 1652-1660.
  1. 78.Ishida Y, Nakamura F, Kanzato H. (2005) Clinical Effects of Lactobacillus Acidophilus Strain L-92 on Perennial Allergic Rhinitis: A Double-Blind, Placebo-Controlled Study. , Journal of dairy science 88(2), 527-533.
  1. 79.Marteau P, Vaerman J P, Dehennin J P. (1997) . Effects of Intrajejunal Perfusion and Chronic Ingestion of Lactobacillus Johnsonii Strain La1 on Serum Concentrations and Jejunal Secretions of Immunoglobulins and Serum Proteins in Healthy Humans. Gastroenterologie Clinique et Biologique 21(4), 293-298.
  1. 80.Kaila M, Isolauri E, Soppi E. (1992) Enhancement of the Circulating Antibody Secreting Cell Response in Human Diarrhea by a Human Lactobacillus Strain. Pediatric Research. 32(2), 141-144.
  1. 81.Oda H, Wakabayashi H, Tanaka M. (2021) Effects of Lactoferrin on Infectious Diseases in Japanese Summer: A Randomized, Double-Blinded, Placebo-Controlled Trial. , Journal of Microbiology, Immunology and Infection 54(4), 566-574.
  1. 82.Lothian J B, Grey V, Lands L C. (2006) Effect of Whey Protein to Modulate Immune Response in Children with Atopic Asthma. , International Journal of Food Sciences and Nutrition 57, 3-4.
  1. 83.Rohr U D, Li W W, Ziqiang H. (2012) The Effect of Fermented Soy. (Fsww08) on Blood Hematology and Cachexia in Cancer Patients. Hormone Molecular Biology and Clinical Investigation 12(3), 407-418.
  1. 84.Keller S, Le H Y, Rödiger C. (2014) Supplementation of a Dairy Drink Enriched with Milk Phospholipids in Patients with Atopic Dermatitis - a Double-Blind, Placebo-Controlled, Randomized, Cross-over Study.