“The Effects of Increased Inoculum on Oral Rotavirus Vaccine Take and Immunogenicity”

Key Words: Rotavirus, Vaccine take, Fecal shedding, Immunogenicity, Correlates of protection

The long-term goal of this project is to identify strategies to improve oral rotavirus vaccine performance in low-income countries. The burden of rotavirus disease remains unacceptably high in low-income countries, where current vaccines show markedly diminished efficacy. The reason(s) for vaccine underperformance remain unclear.

One potential mechanism is rapid inhibition of the live-attenuated vaccine-strain virus in the infant gut due to gut inflammation from enteric coinfections and/or maternal antibodies, preventing establishment of replicating infection by the vaccine, or vaccine “take.” Vaccine take is an absolute requirement for immune recognition and subsequent protection (i.e. effective vaccination), and is identified by detection of fecal vaccine shedding or by host antibody response. Previous experiments with oral cholera vaccines have demonstrated that an increased inoculum of vaccine improves host immune responses, but this strategy remains unexplored for rotavirus. Furthermore, the currently accepted marker vaccine immunogenicity, rotavirusspecific serum IgA, correlates poorly with vaccine efficacy in low-income countries; improved markers are urgently needed to inform future vaccine trials.

Therefore, we will perform a randomized, controlled trial of standard versus high dose oral rotavirus vaccine among infants in Dhaka, Bangladesh. In Aim 1, we will evaluate the effects of increased vaccine inoculum on vaccine take as measured by fecal shedding and serum IgA seroconversion. In Aim 2, we will evaluate the performance of serum antibodies directed against the rotavirus outer capsid structural proteins VP4 and VP7 as alternate markers of immunogenicity as compared to serum IgA. If vaccine take and markers of immunogenicity can be improved using this approach, these strategies could be rapidly implemented in the field to improve rotavirus vaccine performance and inform next-generation vaccine trials design. Together, these findings have the potential to significantly decrease the burden of rotavirus disease and prevent thousands of deaths in children around the globe.