Human live-attenuated rotavirus to assess next-genchallenge with eration rotavirus vaccines in Africa

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Rotavirus infection causes severe diarrhoea and is responsible for about 130,000 child deaths every year in low-income countries in Africa and Asia. Two vaccines have recently been introduced worldwide and have started to reduce the burden of rotavirus disease. Unfortunately, these orally administered vaccines are less effective in the low-income countries where they are needed compared with high-income countries. This means rotavirus remains the main cause of hospitalisation for diarrhoea even after their introduction. To tackle this challenge, we need a next-generation of rotavirus vaccines that overcome the barrier to effective oral vaccines in low-income countries. These vaccines are in the development pipeline. However, their assessment in clinical trials is challenging because comparison with placebo is no longer considered ethical and immune correlates of protection (CoP) that could be used as alternative trial endpoints have not been identified.Controlled human infection studies, where participants are deliberately exposed to wild-type or attenuated infections, are increasingly playing a role in the clinical development of new vaccines and global recommendations concerning their use. We propose to use a licensed live-attenuated oral rotavirus vaccine (Rotarix) as a controlled human infection challenge in infants in Zambia to investigate a novel injectable rotavirus vaccine used alone or in combination with oral vaccination. This is an exciting opportunity to see whether this injectable VP8 subunit vaccine can overcome the barrier to oral immunisation and whether its effectiveness is improved through combined use with oral vaccine.Use of a live-attenuated vaccine as a challenge agent has many advantages compared with wild-type infection, including its established safety profile, highly regulated (GMP) manufacture and its suitability for use in children. The relevance of this infection model (rather than clinical disease) is supported by recent findings showing acquired immunity to rotavirus acts primarily by preventing infection rather than reducing the risk of disease following infection and will be further validated by comparison with results from an ongoing phase 3 clinical trial of the efficacy of this vaccine.This human infection model will also allow us to investigate the development of intestinal (mucosal) immunity following oral and parenteral immunisation and to efficiently explore potential immune correlates of protection (CoP) against infection that can be measured in blood or saliva samples taken from infants after vaccination. These will be based on recent advances in our understanding of rotavirus immunology and focus on systemic and mucosal antibodies targeting different rotavirus antigens.If we find that combined use of an oral and injectable vaccine is more effective than current schedules, this will support further studies and programmatic evaluation that could ultimately lead to a greater impact of vaccination in Africa and Asia on rotavirus disease and mortality. At the end of this project, we will also have improved our understanding of vaccine-induced rotavirus immunity and established a live-attenuated rotavirus infection model in African infants that can be used to assess new rotavirus vaccines under development.