Investigating factors affecting responses to rotavirus vaccination in a randomised control trial in South Africa

Abstract

Introduction: A randomised, placebo-controlled trial (RCT) investigating the safety and immunogenicity of a parenteral monovalent P2-VP8-P[8] subunit rotavirus (RV) vaccine in South African toddlers and infants showed good immune responses to the vaccine antigen and P[8] rotavirus strains. In addition, there was reduced faecal shedding of Rotarix, an oral replicating vaccine, in vaccinees compared to placebo recipients following a challenge dose of Rotarix, suggesting that the P2-VP8 vaccine may suppress local gut multiplication of RV. This model may have the potential to predict vaccine efficacy of other RV vaccines but requires further investigation. We determined whether serum rotavirus-specific antibody responses correlated with rotavirus faecal shedding. Methods: Rotarix-induced shedding of RV in faecal samples was measured five, seven, and nine days after receiving one dose of Rotarix. Serum immune responses included IgA and IgG directed against P2-VP8-P[8] vaccine antigen (anti-P[8] IgA and IgG) and the whole rotavirus lysate (anti- RV IgA), as well as neutralising antibody (NAb) responses against P[8], P[6], and P[4] RV strains. T-tests or Wilcoxon rank sum tests were used to test whether the mean or median, respectively, of antibody titres differed significantly between dichotomous outcome variables. Pearson chi-squared tests were used to detect associations between categorical variables. Multivariate logistic and linear regression models were derived through manual backward stepwise selection and verified by postestimation goodness of fit tests. Results: Of 147 infants, 76.9% (n=113) did not shed RV after challenge with Rotarix, whereas 23.13% (n=34) shed RV on at least one day. RV-specific IgA, IgG, and NAb immune responses one month after receiving three doses of P2-VP8-P[8] vaccine or placebo were not significantly associated with RV shedding following Rotarix challenge. However, immune responses tended to be higher in non-shedders than shedders. In contrast, IgA titres (AOR=2.14; 95% CI: [1.53-2.99];p<0.001) and seroresponse (AOR=1.96; 95% CI: [1.37-2.82]; p<0.001) to P[8] vaccine antigen and IgA titers (AOR=1.96; 95% CI: [1.37-2.82]; p<0.001) and seroresponse (AOR=10.79; 95% CI [2.25-51.85]; p=0.003) to whole RV lysate six-months post-P2-VP8-P[8] were significantly positively associated with RV shedding following Rotarix challenge. Similarly, six-months post- P2-VP8, NAb titers (OR=1.93, 95% CI: [1.34-2.78]; p<0.001) and seroresponse (AOR=4.14; 95% CI: [1.69-15.65]; p=0.004) to RV strain Wa and NAb titers (AOR=2.085; 95% CI: [1.41-3.09];p<0.001) and seroresponse (AOR= 4.08; 95% CI: [1.36-12.23]; p=0.012) to RV strain 89-12 were also significantly positively associated with RV shedding following Rotarix challenge. Discussion and conclusion: RV faecal shedding following Rotarix challenge is a potential model to assess protection following vaccination, however, our study highlighted the need for additional research before it can be used in the field. Serum RV-specific immune responses measured onemonth post-P2-VP8 vaccination tended to be higher in infants that did not shed RV post-challenge than infants who shed. Conversely, RV-specific immune responses measured six months postvaccination were significantly higher in infants with RV shedding than non-shedders. Immunological endpoints are not sufficient to assess faecal shedding following Rotarix challenge and further studies are needed to assess clinical endpoints in relation to faecal RV shedding, while accounting for potential confounders such as Lewis secretor status and presence of enteric coinfections at vaccination.