Abstract
Group A rotaviruses (RVA) remain a leading cause of pediatric diarrhea worldwide, in part due to underperformance of currently approved live-attenuated, oral vaccines in low-and-middle income countries. Improved immune correlates of protection (CoP) for existing oral vaccines and novel strategies to evaluate the performance of next-generation vaccines are needed. Use of oral vaccines as challenge agents in controlled human infection models is a potential approach to CoP discovery that remains underexplored. In a live-attenuated, oral rotavirus vaccine (Rotarix, GlaxoSmithKline) efficacy trial conducted among infants in Dhaka, Bangladesh, we explored the potential for the second dose of the two-dose series to be considered a challenge agent through which RVA immunity could be explored, using fecal virus shedding post-dose 2 as a marker of mucosal immunity. Among 180 vaccinated infants who completed the parent study per protocol, the absence of fecal vaccine shedding following the second dose of Rotarix suggested intestinal mucosal immunity generated by the first dose and a decreased risk of RVA diarrhea through 2 years of life (RR 0.616, 95% CI 0.392–0.968). Further development of controlled human infection models for group A rotaviruses, especially in prospective studies with larger sample sizes, may be a promising tool to assess rotavirus vaccine efficacy and CoPs.
Highlights
Group A rotaviruses (RVA) remain a leading cause of pediatric diarrhea worldwide, in part due to underperformance of currently approved live-attenuated, oral vaccines in low-and-middle income countries
A smaller proportion of children without fecal RVA shedding following the second Rotarix dose subsequently experienced an episode of RVA diarrhea (26%) compared to children who shed RVA in the stool (39%; Relative risk (RR) 0.679, 95% confidence intervals (CI) 0.415–1.110; Table 1), this did not reach statistical significance
In sensitivity analysis utilizing a slightly higher quantitative reverse transcription polymerase chain reaction (qPCR) cut-off of cycle threshold (Ct) < 36, a significantly smaller proportion of children without fecal RVA shedding following the second Rotarix dose subsequently experienced an episode of RVA diarrhea (24%) compared to children who shed RVA in the stool (40%; RR 0.616, 95% CI 0.392–0.968; Table 1)
Summary
Group A rotaviruses (RVA) remain a leading cause of pediatric diarrhea worldwide, in part due to underperformance of currently approved live-attenuated, oral vaccines in low-and-middle income countries. In a live-attenuated, oral rotavirus vaccine (Rotarix, GlaxoSmithKline) efficacy trial conducted among infants in Dhaka, Bangladesh, we explored the potential for the second dose of the two-dose series to be considered a challenge agent through which RVA immunity could be explored, using fecal virus shedding post-dose 2 as a marker of mucosal immunity. CHIMs are often not ethical to perform in children, but use of approved oral vaccines as challenge agents, as have been used extensively in the poliovirus field[5,6,7,8,9,10], shows promise but remains underexplored in the evaluation of mucosal immunity to RVA and rotavirus CoPs. Globally, the most widely used rotavirus vaccine is Rotarix (GlaxoSmithKline), which consists of live-attenuated, monovalent (G1P[8]) human rotavirus strain RIX4114 administered in a two-dose oral series. RVA shedding Ct cut-off < 34 No shedding Shedding RVA shedding Ct cut-off < 36 No shedding Shedding RVA-IgA Seropositive Seronegative Shedding plus RVA-IgA No shedding OR seropositive Shedding AND seronegative No shedding AND seropositive Shedding OR seronegative
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