Influence of the intestinal microbiota on the immunogenicity of oral rotavirus vaccine given to infants in south India

Abstract

Oral rotavirus vaccines have consistently proven to be less immunogenic among infants in developing countries. Discrepancies in the intestinal microbiota, including a greater burden of enteropathogens and an altered commensal community composition, may contribute to this trend by inhibiting the replication of vaccine viruses. To test this possibility, we performed a nested case–control study in Vellore, India, in which we compared the intestinal microbiota of infants who responded serologically or not after two doses of Rotarix delivered at 6 and 10 weeks of age as part of a clinical trial (CTRI/2012/05/002677). The prevalence of 40 bacterial, viral, and eukaryotic pathogen targets was assessed in pre-vaccination stool samples from 325 infants using singleplex real-time PCR on a Taqman array card (TAC). In a subset of 170 infants, we assessed bacterial microbiota composition by sequencing the 16S rRNA gene V4 region. Contrary to expectations, responders were more likely than non-responders to harbor ≥1 bacterial enteropathogen at dose 1 (26% [40/156] vs 13% [21/157] of infants with TAC results who completed the study per protocol; χ 2 , P = .006), although this was not apparent at dose 2 (24% [38/158] vs 23% [36/158]; P = .790). Rotavirus shedding after dose 1 was negatively correlated with the replication of co-administered oral poliovirus vaccine (OPV). We observed no consistent differences in composition or diversity of the 16S bacterial microbiota according to serological response, although rotavirus shedding was associated with slightly more bacterial taxa pre-vaccination. Overall, our findings demonstrate an inhibitory effect of co-administered OPV on the first dose of Rotarix, consistent with previous studies, but in the context of OPV co-administration we did not find a strong association between other components of the intestinal microbiota at the time of vaccination and Rotarix immunogenicity.

Causes of Impaired Oral Vaccine Efficacy in Developing Countries

“…In rural Ghana, Rotarix immunogenicity was associated with a lower abundance of Bacteroidetes and a greater abundance of Bacilli (specifically Streptococcus bovis) at 6 weeks of age, while infants who seroconverted exhibited an overall microbiota profile more similar to that of Dutch infants compared with nonresponders [156]. However, no comparable discrepancies in pre-vaccination microbiota composition were observed according to rotavirus or poliovirus seroconversion status among infants in India who received Rotarix and OPV at 6 and 10 weeks of age [157]. Thus, a consistent link between microbiota composition and oral vaccine performance has not yet been identified, and there is limited evidence to suggest that vaccine failure is associated with overt perturbations in the microbiota (or 'dysbiosis').…”

“…[65], [98], [108], [135], [171], [196] [67], [133][134][135], [198][199][200][201] [8], [181], [182], [201], [203], [204] [28], [92], [93], [128], [131], [137], [138], [140], [130], [131], [157], [202] [ [43][44][45], [49], [61][62][63][64][65][66][67][68][69][70], [197] [ [155][156][157] [28], [98], [170][171][172]…”

The interaction of intestinal microbiota and innate lymphoid cells in health and disease throughout life

“…Moreover, synergy between IL‐22 produced by ILC3s and IFN‐γ has been identified, further highlighting the strong interaction of ILCs and epithelial cells during infection. Data are limited on the link between rotavirus infection and microbiota; however, the efficacy of a rotavirus vaccine (Rotarix: live, attenuated human rotavirus vaccine used in infants) and microbiota has been noted . To which extend this is linked to ILC3 activity has not yet been addressed, but would be of great interest.…”

“…145 Moreover, synergy between IL-22 produced by ILC3s and IFN-c has been identified, 146 virus vaccine used in infants) and microbiota has been noted. 147 To which extend this is linked to ILC3 activity has not yet been addressed, but would be of great interest.…”

Rotavirus vaccine efficacy: current status and areas for improvement

“…Further, the pathogen burden in infants that failed to respond to vaccination was comparable to those that did. 10 Overall, as no single solution can entirely overcome EE, a holistic approach is generally advised. Experts have postulated that reduced levels of EE may prove critical for increasing oral vaccine efficacy.…”