Vaccines are among the most successful advancements in modern medicine, with several successfully protecting against polio, tetanus, diphtheria, whooping cough, measles, mumps, and rubella. However, vaccines have varying efficacy depending on the population being covered.
The failure to recognize this variability has led to poor vaccine efficacy in some groups. A new The Lancet Microbe study reports the effect of the infant gut microbiome on vaccine efficacy.
Study: The Early-Life Gut Microbiome and Vaccine Efficacy. Image Credit: Dmitry Naumov / Shutterstock.com
The most vulnerable segment of the population for most infectious diseases is young babies, particularly those less than five months of age, and those residing in low- and middle-income countries (LMICs). Unfortunately, these regions have low immunization rates and often report low vaccine efficacy, as has been observed with oral rotavirus vaccines, for instance.
While these vaccines have protected almost 100% of young children in Finland, the same was true for less than 60% and 50% of Nicaraguan and Bangladeshi children, respectively. The same decline in protection has been observed with the bacille Calmette-Guérin (BCG) vaccine used to prevent tuberculosis, with rates of up to 100% reported in Europe, as compared to the 0-50% protective efficacy reported in Africa.
Among the factors influencing vaccine responses, age, genotype, sex, and anemia are particularly important. Genetics may contribute up to 40% of the variance between vaccine responses.
Apart from these internal factors, external factors such as the vaccine composition, storage factors, history of prior exposure to the pathogen, chronic inflammation, and nutritional status also play an important role in the vaccine response.
The current study examines the role of the early life gut microbiome in immunologic maturation and function in infants. This is affected by the level of hygiene, diet, and other environmental factors of both mothers and children. Thus, infants in African communities, for example, show a distinctive microbial profile compared to those from westernized societies.
Significantly, these differences are associated with reduced vaccine responses, which may account, in part, for the difference in efficacy with geographical areas and between individuals. Understanding and overcoming these limitations could help avoid using adjuvants to improve vaccine immunogenicity since adjuvants are often unsafe, cause additional adverse effects, and contribute to increased costs of vaccine research and the vaccine itself.
The gut microbiome
The human gastrointestinal (GI) tract consists of human tissues and bacteria, viruses, fungi, and other microorganisms. The composition of the gut microbiome varies from site to site and with age, as well as with the individual’s state of health.
The gut is first inoculated during birth, with the first thousand days of life being the most critical period for establishing a healthy ecosystem structure. This microbiome helps the human to digest nutrients better, contributes to immunologic and other factors, induces and maintains immune tolerance, prevents the overgrowth of pathogenic bacteria, and produces beneficial metabolites that foster human health.
Abnormalities of the gut microbiome are linked to several immunologic, metabolic, neurodegenerative, malignant, or allergic conditions.
Gut microbiome and vaccine response
Both the gut microbiome and immunologic response to vaccination are affected by similar factors, thus pointing to their strong interdependence on each other. These include the mode of delivery, preterm birth, breastfeeding compared to formula feeding, antibiotic or probiotic use, and hygiene.
For example, vaginally delivered babies are inoculated with maternal and fecal microbes, predominantly Escherichia, Lactobacillus, Bacteroides, and Bifidobacterium species that colonize the infant gut, among others. Cesarean delivery is followed by gut colonization with skin and hospital-associated microbes and, as a result, is dominated by Streptococcus, Staphylococcus, and Enterococcus species. Antibiotics inhibit this process, thus increasing the risk of aberrant immunologic maturation and autoimmune or atopic conditions.
Breastfeeding also provides numerous nutritional, immunologic, and antimicrobial factors that support the development of the infant gut microbiome. For example, some milk sugars in human milk promote the colonization of Bifidobacterium. This causes about 80% of the gut microbiome of breastfed babies to consist of Bifidobacterium, compared to 5-30% in formula-fed infants. Additionally, these sugars are digested to yield short-chain fatty acids (SCFAs) that are vital for the development of immune tolerance.
Breastmilk also inoculates the gut with other microbes from its microbiome. When babies are weaned off breastmilk, other species such as Akkermansia and Ruminococcus may enter the infant gut microbiome.
SCFAs have several benefits, as they provide a source of energy for intestinal epithelial cells, support the mucosal epithelial barrier, modulate gut cell metabolism, prevent pathogen overgrowth, and act as signals within regulatory pathways in the gut and systemic immune pathways. Acetate, propionate, and butyrate are the most abundant SCFAs within the infant gut microbiome.
These SCFAs stimulate immune cells, both innate and adaptive, enhance the number of regulatory T-cells (Tregs) in the mucosa, and reduce autoimmune activity. Moreover, these fatty acids promote class-switching of the antibody response with the maturation of antigen-responsive B-cells and stimulate the differentiation of plasma cells by their effect on the signaling pathways in dendritic cells.
Another mechanism in influenza A protection might be through SCFA binding of the G-protein-coupled receptor 43 (GPR43), which inhibits virus entry by blocking its coreceptor.
The gut microbiome also provides bacterial extracellular vesicles (BEVs) and exopolysaccharides (clusters of sugar molecules), which produce their unique effects on host immunity or offer novel approaches to vaccination.
BEVs can activate immune cells and prime them for immune responses to the cells that produced them. BEVs can also be used to directly carry vaccine particles into the mucosal cells without the need for injections, as they do not replicate in the host, are stable to body temperature, and resist breakdown in the presence of many enzymes and an acidic pH.
The use of BEVs could reduce the cost of producing and administering vaccines and their adverse effects, all the while providing a natural adjuvant effect that would improve vaccine efficacy.
The success of the already established BEV vaccine against cholera and type B meningitis, and the promising results with commensal BEV antigen carriers against plague and influenza, could give rise to a novel vaccine generation based on immunomodulatory BEVs of commensal origin with high efficacy and biosafety standards on a global scale.”
How does this affect vaccine responses?
The gut microbiota increases the adaptive immune response to vaccines by stimulating the development and maturation of B- and T-cells. This ultimately promotes the formation of lymphoid-rich Peyer’s patches in the small intestine, type I interferon production, and antigen-specific T-cell responses.
Animal experiments have shown that perturbation of the normal infant gut microbiome impairs antibody responses to both adjuvant-containing and live attenuated vaccines. However, this could be reversed by introducing certain Escherichia coli strains or fecal microbiota transfer.
The composition of the gut microbiome is associated with differential responses to vaccines, with different microbes acting differently depending on the level of abundance. For example, an early abundance of Bifidobacteria enhanced early and late responses to tetanus, BCG, and polio vaccines in Bangladeshi babies for up to two years.
Infants from low- and high-income countries who responded similarly to vaccines had similar gut microbiome profiles, such as lower Bacteriodetes and higher Clostridium cluster XI or Proteobacteria.
Optimizing gut microbiota for immunity
Probiotics and prebiotics, which consist of live microbes and substances, respectively, promote the health of the host through their effects on the microbiome.
These supplements may also enhance the growth of beneficial species such as Bifidobacterium and Lactobacillus, thus resulting in higher SCFA production.
In infants less than four months of age, both pre- and probiotics successfully increased the humoral response to a number of vaccines, including polio, diphtheria, rotavirus, and influenza, as compared to adults.
Conversely, adult trials have shown that vaccine responses reduced or failed to improve following antibiotic-induced depletion of these microbes.
In rats, specific Bifidobacterium species produce specific immunomodulatory effects, such as restoring the function of Tregs with a subsequent drop in inflammatory cytokines, inducing a favorable T-cell profile, promoting Treg differentiation, enhancing cytotoxic CD8 T-cell activity while keeping CD4 T cell activity intact, as well as improving both B-cell and antiviral immune responses,
In fact, one such metabolite, serpin, defuses inflammatory proteases. Bifidobacterium abundance is linked to Actinobacteria levels which, as a result, affects vaccine-induced immune responses.
Other important bacteria that modulate vaccine responses include Bacteroides, which is dominant in the adult gut, with one specific strain expressing a natural lipooligosaccharide adjuvant that is safer than the E. coli adjuvant.
A greater understanding and characterization of key strains from the healthy infant microbiome could give rise to a new generation of safe, needle-free, and economical vaccine-boosting therapies, ideally suited to use in low-income and middle-income countries.”
These alternative approaches to vaccination could also be manipulated to enhance responses to immunogenic particles, considering their safety profile, which could accelerate vaccine research and reduce costs. Furthermore, such vaccines could also support the development of new and improved immunization methods.