A study published in Nature Communications looks at mode of delivery, intestinal microbiota and response to vaccination in children.
Prof Kim Barrett, Vice Dean for Research and Distinguished Professor of Physiology and Membrane Biology, UC Davis School of Medicine, said:
“While it was known that the mode of delivery impacts the gut microbiome of neonatal humans, the present study extends that work of the authors and others to show an associated impact on the response of babies to early life vaccines. The conclusions are drawn from a large cohort of healthy infants, and imply that birth by caesarian section may render some vaccines less protective. The study design, of necessity, was correlative and cannot necessarily assign a beneficial effect for the bacterial types that were increased following vaginal delivery. Further work will be needed to uncover if and how manipulation of the human microbiome following C-section births might improve vaccine efficacy. On the other hand, the work should at least lead to prompt additional consideration about an unintended consequence of the ever-increasing use of C-sections that may not be medically-necessary.”
Prof Sheena Cruickshank, Immunologist and Professor in Biomedical Sciences, University of Manchester, said:
“It is now well established that the microbiome is important in immune development. In turn the mode of delivery and initial method of feeding is important in how the microbiome is first seeded in the baby. However, other factors such as exposure to antibiotics and subsequent diet also play a role in how it then develops making understanding the way the microbiome develops and changes quite complex. Microbes works as communities and it can be difficult to determine whether changes in single species are important functionally. Breastmilk also plays an important role in protecting the baby via transfer of maternal immunoglobulins which will wane over a period of 6-12 months in the baby, thus ascertaining whether it’s the baby’s Ig is challenging.
“Given the complexity of the multitude of interactions, it is important that this is accounted for and group sizes are larger enough to ensure data is robust. Whilst this is an interesting study that adds to our knowledge of how the microbiome develops and the possible implications for immune development, it is still very preliminary and the small groups sizes warrant a need for further studies to verify this in larger groups. The data is observational and we can’t be sure of cause and effect. Critically, if reproduced, we will need to understand whether possible impacts of maternal delivery and feeding on immune development or vaccine responses can be restored by for example manipulating the microbiome.”
Dr Marie Lewis, researcher in gut microbiota at the University of Reading, said:
“This is an interesting study that provides new evidence to add to our growing understanding of the links between gut bacteria and immune response in the crucial early years of life. This paper describes a well-designed study that fits in well with the current understanding of how babies develop their microbiome. What is new here is good quality data showing the extent to which babies born vaginally have an advantage in their immune response to routine immunisations, compared to babies born by caesarean.
“We have known for quite some time that the mode of delivery is incredibly important when it comes to the type of bacteria which colonise our guts. We also know that our gut bacteria in early life drive the development of our immune system, and natural births are linked with reduced risks of developing inflammatory conditions, such as asthma. It is therefore perhaps not really surprising that mode of delivery is also linked to responses to vaccinations.
“The really interesting part here is the extent to which our gut microbiotas are accessible and changeable, and this important work could pave the way for administration of probiotics and prebiotics – food supplements that add new bacteria or feed existing bacteria – to improve vaccine responses in caesarean-born children.”
Prof Neil Mabbott, Personal Chair in Immunopathology, The Roslin Institute, University of Edinburgh, said:
“This is a very interesting and important study.
“The authors show that infants delivered by a vaginal birth had higher responses to the two different types of vaccines against bacterial diseases, and this was associated with higher abundances of the potentially beneficial bacteria known as Bifidobacterium and E. coli in their intestines. Their study helps us to begin to understand how early-life experiences such as vaginal delivery could impact on the infant’s immune system when vaccinated several months later.
“These are interesting observational data, but it is uncertain whether the changes to the microbiota are directly responsible for the increased antibody responses.
“Many factors can influence the composition of the gut microbiota, so it will be important to see if similar associations can be replicated in groups of infants from different populations and regions.
“This study raises the possibility that it may be possible to treat infants, especially caesarean-delivered infants, with a bacterial supplement or even a product produced by these beneficial bacteria to help improve their immune systems, enhance their responses to certain vaccines and reduce their susceptibility to infections.
“The study does raise lots of important questions, and further work will be necessary to address them:
– The authors showed that the production of a particular type of antibody molecules known as IgG was increased in the infants that were vaginally delivered. It will also be important to determine whether IgA antibody molecules that help to protect the wet body surfaces such as those in the mouth, gut and lung are also enhanced.
– Although birth by vaginal delivery was associated with increased antibody levels after pneumococcal and meningococcal vaccinations, further research is needed to determine whether this also leads to the increased protection of the infants against infection or serious disease. Similarly, it also remains to be determined whether birth by vaginal delivery is associated with the enhanced responses to vaccination against viral diseases.
– Research is now needed to determine how the association of the mode of delivery with the microbiota in the infant gut affect their ability to make antibody responses after vaccination. Identifying this mechanism could lead to the development of new treatments to improve vaccine responses and immunity infants and reduce their susceptibility to bacterial infections.”
Dr George Savva, Institute Statistician, Quadram Institute Bioscience, said:
“This paper is important in beginning to understanding the factors that contribute to vaccine response in infants and the role of the microbiome. However this is a relatively small exploratory study including 101 infants with many factors tested – the association with caesarean section is moderate compared to the wide variation seen in vaccination response and the differences are barely statistically significant. This means that we should not rule out the possibility that this was a chance finding and it will be important to validate this finding in other independent birth cohorts.”
Comments from our friends at the German SMC:
Prof Dr Maria Vehreschild, Head of the Infectious Diseases Unit at the Medical Clinic II, University Hospital Frankfurt, said:
“This is a study with potentially important clinical implications. In contrast to other studies, a very early time window – well before the vaccinations were administered – was chosen as the basis for the microbiome analyses. This time window of approximately 100 days is when the maturation of the early childhood immune system occurs. The time when the microbiome influences B-cell maturation is therefore clearly before vaccination and the subsequently measurable vaccination response. Nevertheless, making this connection is a great strength of the analysis. It would have been very interesting to collect additional samples that could provide information about the exact functional relationships. Because, of course, the precise signaling cascades also contain the therapeutic starting points.
When asked to what extent the finding that the mode of birth influences the gut microbiome – and thus the antibody response to routine childhood vaccines – is relevant for further research or clinical application:
“This finding is very relevant because the number of cesarean sections in industrialized nations is very high. If this finding can be confirmed by further analyses, microbiota-based supplementation approaches could be promising.
When asked about how to evaluate the determination of IgG levels in saliva rather than in infants’ blood serum:
“Certainly, the measurement of IgG antibody levels from serum is of higher quality. However, these are infants and you might not want to make them undergo blood sampling in the context of a study. So I think it’s the best possible method for this situation.
“I don’t think changing the vaccines themselves will be the consequence of this study. Rather, I see potential here for the development of microbiota-based therapies that can be given during the neonatal immune maturation phase to achieve optimal vaccine outcomes later.”
Prof Dr Michael Zemlin, Director of the Department of General Paediatrics and Neonatology, Saarland University Hospital, Homburg, said:
“Once again, a neatly conducted study confirms that the first weeks of life represent a window of opportunity in which a long-term imprinting of the immune system occurs.
“The authors elegantly demonstrate that the strength of vaccine responses against two dangerous pathogens is related to the composition of the gut microbiome in the first week after birth.
“An important factor influencing the composition of the microbiome is the birth mode. After vaginal birth, the vaccine responses studied are stronger than after a C-section. This suggests that the birth mode may also directly or indirectly affect many other protective immune responses.
“The study cohort was very thoroughly characterized microbiologically and immunologically. This is necessary to understand, at least approximately, the complex interactions that operate during maturation of the immune system.
“The longitudinal study after 12 and 18 months, respectively, shows that the effects of the first weeks of life are indeed long-lasting and affect medically highly significant protective functions of the immune system. The microbiome plays a central role, which in turn depends on numerous internal and external factors.
“The decision to have a cesarean delivery always has reasons. Therefore, children with and without cesarean delivery differ in many ways, not only in terms of their mode of delivery. For example, in the current study, compared to children born vaginally, those delivered by c-section were born earlier, hospitalized longer, and breastfed for a significantly shorter time – all factors that can have a significant impact on the microbiome. This important information comes from another publication on the same cohort  and should have been discussed in more detail in the current publication. To clarify the role of the many influencing factors independently, the study would need to be designed many times larger.
“The wish to have a C-section has been ‘out of fashion’ for a long time. The influence on the development of the microbiome and the associated long-term imprinting of the immune system are an argument against having a C-section.
“Other important questions for future studies arise from the current study: can the negative effects of cesarean delivery on the infant microbiome be avoided? Does so-called ‘vaginal seeding’ – for instance by brushing the baby with compresses that were previously in the mother’s vagina – have long-term benefits? Can the development of the infant microbiome be positively influenced by probiotic administration or other factors after a cesarean delivery,?
When asked about how to evaluate the determination of IgG levels in saliva instead of blood serum of the children:
“The determination of IgG antibodies in saliva is reasonable for ethical reasons to avoid blood sampling from the children for study purposes. However, the examination of saliva is not a significant disadvantage because, after all, the two bacteria examined are predominantly absorbed via the mucosa, so that the IgG antibodies in saliva have an important defense function. In this respect, the salivary antibodies can be used to measure an important protective function of the vaccination. However, salivary antibodies reflect only one aspect of immune protection, because vaccine protection is additionally mediated by T cells and other mechanisms that are much more difficult to measure even in blood samples. So we’re used to having limited ability to assess vaccine protection in studies.
“In vaccine development, enhancer substances, known as adjuvants, play a major role. As we better understand the relationship between the microbiome and vaccine response, important clues may emerge about new biological adjuvants that make vaccines even more effective.
“However, it is at least as important to set the course long before vaccination by optimizing the microbiome in such a way that a strong protective immune response is established. After all, what matters is not the vaccine response, but the immune response to all sorts of pathogens we encounter in life.
“We hope that we can optimize the microbiome in the newborn after C-section, antibiotic administration or other potentially harmful influences in a way that promotes protective immune responses and prevents harmful immune responses – for example, allergies and autoimmune diseases.”
 Reyman M et al. (2019): Impact of delivery mode-associated gut microbiota dynamics on health in the first year of life. Nature Communications. DOI: 10.1038/s41467-019-13014-7.
Dr Claudius Meyer, Head of the Paediatric Immunology Group at the Centre for Paediatrics and Adolescent Medicine, University Medical Center Mainz, said:
“The authors report their findings of a monocentric, nonblinded study that focusses on the association between the gut microbiome, the level of humoral response against vaccine antigens in infants at 12 and 18 months of age and physiological as well as environmental parameters.
“Using a substantial number of bioinformatic tools, the authors examine the development of the gut microbiome of newborn infants. Depending on whether the children were born by C-section or naturally, it can be determined at 12 or 18 months of age that the effect of normal childhood vaccinations against meningococcal and pneumococcal was attenuated after C-section. A positive effect is shown especially for spontaneous birth, but other factors with less influence are evident as well, such as breast milk instead of bottled milk, the sex of the newborn, not taking antibiotics and, interestingly, the absence of pets. The paper focuses on the unfavorable effect of a ce-section on the vaccination success. According to the authors, the coincidence of basic immunization of children with a critical developmental phase of the microbiome in the first two months of life is unfavorable. On the other hand, however, this observation could provide a strategic window of opportunity in which to generate positive therapeutic effects in the future.
“The single observation in the present publication is interesting and new in its own right, but a large number of similar observations have now been published in this subject area. Thus, the present publication may be seen as another puzzle piece on the way to controlled therapeutic influence on the microbiome.
“The rather small number of study participants is also typical of current research on the microbiome. This severely limits the power of the evidence, especially in light of the tremendous complexity of the microbiome. The methods are still expensive; in particular, considerable bioinformatics expertise is required to calculate valid data. Often, the validity of individual methods is questioned – for example, the method of bacterial species recognition, OTU (Operational Taxonomic Unit; editor’s note) or ASV (Amplicon Sequence Variant; editor’s note).”
“Currently our view of the microbiome is quite one-sided, which is also the case in this study, looking exclusively at the bacteriome, i.e., bacteria. Viruses, fungi and other microorganisms are left out, without knowing what influence these disregarded members of the microbiome have on the microbiome itself or on the host, i.e. humans. Therefore, every piece of the puzzle is helpful in the long run.”
‘Mode of delivery modulates the intestinal microbiota and impacts the response to vaccination’ by Emma M. de Koff et al. was published in Nature Communications at 16:00 UK time on Tuesday 15 November 2022.
Prof Kim Barrett: “I have no conflict of interest regarding the paper.”
Prof Sheena Cruickshank: “No conflicts.”
Prof Neil Mabbott: “I have no commercial conflicts of interest to declare. I am a professor of immunopathology at the University of Edinburgh.”
Dr George Savva: “No conflicts.”
Prof Dr Maria Vehreschild: “I have no conflicts of interest in this regard.”
Prof Dr Michael Zemlin: “There is no conflict of interest, personal acquaintance or cooperation with the authors of the manuscript. Dr Zemlin is leading a sub-project on the relationship between gut microbiome, probiotic administration and vaccination response in preterm infants as part of the BMBF-funded PRIMAL consortium (‘Imprinting the Immune System at the Beginning of Life’). Dr Zemlin is vice-president of the Society for Neonatology and Paediatric Intensive Care Medicine.”
Dr Claudius Meyer: “Regarding the statement given above, I declare that I have no conflict of interest with either the Science Media Center gGmbH, the authors of the publication, the publisher or the equipment manufacturers or reagent suppliers named in the publication.”