4. Discussion
RV infection, Rotavirus, IgA, infection, coinfections
VIRUS, INFECTION, DISEASE
Correlates of protection, which can act as a proxy measure of protection against clinical disease, can be used to enable noninferiority trials to support licensure of vaccines where placebo-controlled trials are no longer ethical or feasible due to low attack rates, to bridge the transition from first-generation to second-generation vaccines, to monitor the consistency of vaccine production, to study the susceptibility of a population after vaccination and to enable the licensure of combination vaccines [Anti-RV IgA seroresponse to whole RV lysate was low at the Day 84 time point (one month post-third P2-VP8-P[8] dose or placebo) among non-shedders in both vaccine (8.1%) and placebo (7.4%) recipients. None of the vaccine or placebo recipients who demonstrated RV shedding post-challenge showed any anti-RV IgA seroresponse at the Day 84 time point. This was expected as infants were unlikely to be have been naturally exposed to RV prior to this time point. In addition, in the vaccine group, the parenteral vaccine was unlikely to generate a robust response to the whole RV lysate. However, at the Day 224 time point, when all participants had also received three doses of Rotarix, anti-RV IgA seroresponse and GMTs were higher overall compared to Day 84, and significantly higher in placebo recipients shedding RV after the first Rotarix (challenge dose) compared to non-shedding placebo recipients. This suggests that those shedding RV after the first Rotarix dose demonstrated a robust anti-RV IgA response at around nine months of age. This provides further support to the potential to use shedding following the first dose of ORV as a predictor of vaccine response, with the added benefit of obtaining results earlier and with a noninvasive sample [One month after the third P2-VP8-P[8] dose in vaccine recipients, anti-P2-VP8-P[8] IgA seroresponse and titers were similar in RV shedders compared to non-shedders, suggesting no clear association between RV shedding and anti-P2-VP8-P[8] IgA as measures of immune response to a parenteral RV vaccine. At the Day 224 time point, after receipt of three doses of Rotarix, there were good anti-P2-VP8-P[8] IgA seroresponses in both shedders and non-shedders, although GMTs were significantly higher in shedders compared to non-shedders. This once again suggests that infants who shed RV following their first dose of ORV showed slightly better immune response measured at nine months of age.Several studies have shown that serum IgG was associated with protection against RV infection and illness [At the Day 224 time point, six months after the third P2-VP8-P[8] or placebo injection and having received three doses of Rotarix, RV shedders demonstrated higher immune responses than non-shedders. Those with higher immune responses to IgA anti-P[8], IgA anti-whole RV lysate, NAb to RV strain Wa and 89-12 at around nine months of age were more likely to have shed RV following the first dose of Rotarix (challenge). This shows that RV shedding after ORV challenge is reflective of vaccine response following ORV and is predictive of higher serum immune responses at this later time point. This finding requires further investigation to properly understand what this means for RV shedding as a potential correlate of protection. Infants in both the vaccine and placebo groups would all have received three doses of the ORV, Rotarix, by this time point. The relationships seen between RV shedding and serum immune responses at nine months of age may also possibly be influenced by the same factors that have been hypothesized to be responsible for the lower efficacy and immunogenicity observed in the clinical trials assessing ORVs [This analysis had several limitations. First, the study was powered for safety and immunogenicity endpoints for the primary study, and the lack of significance may have been due to the sample size available for this analysis. The separate analyses for vaccine recipients and placebos further reduced the power. A larger sample size is needed to further evaluate differences in serum immune responses by shedding status. Important confounders such as Lewis and secretor status, enteric coinfections and breastfeeding were not measured in the primary study and could not be adjusted for in the analysis. Rotavirus-specific copro-IgA and IgG antibodies were not measured, so their association with fecal RV shedding could not be assessed. Rotavirus shedding was due to an attenuated stain, not natural infection with a virulent virus, making it difficult to correlate the findings with protection against disease. Exposure to wild-type RV during the study may also have confounded our results and complicated the interpretation. The strain was confirmed as the Rotarix