## 4 Interactions between Vaccine Administration and Gut Microbiome Status
### Gut Dysbiosis and Its Influence on Vaccine Efficacy in Human Medicine  
As vaccines targeting viral and bacterial diseases in humans continue to be developed, researchers have noticed differences in vaccine immunogenicity among various human populations. This has led to an extensive catalog of human case studies that have investigated vaccine efficacy among various human populations. Although the mechanisms are yet to be understood, many studies have discovered that children raised in regions with high incidences of enteric disease and environmental enteropathy display much lower antigen-specific immunological memory to viral or bacterial oral vaccines when compared to children raised in developed countries [8; 48; 50; 52]. For example, [PERSON] et al. [52] observed that children raised in Sweden had higher antibody responses and lower enteric disease incidence after oral administration of a killed cholera vaccine than those raised in Nicaragua. Similar results were observed in infants who received an oral rotavirus vaccine, where infants from the United Kingdom had greater antigen-specific antibody production than those raised in Malawi or India [8]. Because of vaccine hyporesponsiveness (reduced vaccine response) among children with a greater incidence of enteric inflammation, it is hypothesized that dysbiosis of the gut microbiota may contribute to the dampened vaccine responses [6; 7]. Although it is assumed that a host with a rich and diverse microbial community would inherently develop stronger vaccine responses, because commensal microbes drive maturation of the gastrointestinal lymphoid tissue [53; 54], the current evidence suggests that low vaccine immunogenicity in human populations may be correlated with a high enteric pathogen load [48]. For example, Bangladeshi infants with high microbial diversity in stool samples exhibited greater gastrointestinal inflammation and lower antigen-specific responses to the tetanus toxin vaccine [55]. Similarly, Indian, and Malawian infants had higher microbial diversity in their stools when compared to infants born in the United Kingdom, but Indian and Malawian infants had lower antigen-specific antibody production after oral rotavirus vaccination than the United Kingdom infants [8]. However, the infants' stool samples from each of these three nations contained different enriched genera with potentially pathogenic attributes (_Prevotella_ in Malawian infants, _Enterococcus_ in Indian infants, and _Citrobacter_ in U.K. infants), indicating that region and diet influence gut microbiota which makes it difficult to link improved or dampened vaccine responses to specific genera [8]. Moreover, the fecal-oral transmission of enteric pathogens and subsequent high endotoxin (lipopolysaccharide) load in the gut can lead to chronic inflammation which could limit the host's ability to respond to orally administered bacterial or viral vaccines. The overabundance of enteric pathogens may drive vaccine hyporesponsiveness either through chronic enteric inflammation or through elevated oral tolerance to the environmental pathogens, but a lack of microbes can also reduce vaccine efficacy. More specifically, studies investigating the influence of antibiotic exposure on vaccine responses have provide insights into the importance of a balanced gut microbiota in the host. One clear example of this is in chicken pox vaccination regimens in China. [PERSON] et al. [56] discovered that antibiotic exposure for at least seven days during the first two years of a child's life was positively correlated (\(p<0.01\)) with chicken pox disease incidence, regardless of chicken pox vaccination status. Similar results were emulated in the murine model, where various types of antibiotic treatment and durations of exposure lead to decreased vaccine immunogenicity along with decreased gut microbiota diversity [57; 58; 59; 60].