RTS,S Vaccination Is Associated With Serologic Evidence of Decreased Exposure to XXXX Liver- and Blood-Stage Parasites.

@entity1 @entity311 @entity281 @entity3964
The leading @entity311 vaccine candidate, RTS,S, targets the sporozoite and liver stages of the @entity3964 life cycle, yet it provides partial protection against disease associated with the subsequent blood stage of @entity281 . Antibodies against the vaccine target, the circumsporozoite protein, have not shown sufficient correlation with risk of clinical @entity311 to serve as a surrogate for protection. The mechanism by which a vaccine that targets the asymptomatic sporozoite and liver stages protects against disease caused by blood-stage parasites remains unclear. We hypothesized that vaccination with RTS,S protects from blood-stage disease by reducing the number of parasites emerging from the liver, leading to prolonged exposure to subclinical levels of blood-stage parasites that go undetected and untreated, which in turn boosts pre-existing antibody-mediated blood-stage immunity. To test this hypothesis, we compared antibody responses to 824 P. falciparum antigens by protein array in Mozambican @entity1 6 months after receiving a full course of RTS,S (n = 291) versus comparator vaccine (n = 297) in a Phase IIb trial. Moreover, we used a nested case-control design to compare antibody responses of @entity1 who did or did not experience febrile @entity311 . Unexpectedly, we found that the breadth and magnitude of the antibody response to both liver and asexual blood-stage antigens was significantly lower in RTS,S vaccinees, with the exception of only four antigens, including the RTS,S circumsporozoite antigen. Contrary to our initial hypothesis, these findings suggest that RTS,S confers protection against clinical @entity311 by blocking sporozoite invasion of hepatocytes, thereby reducing exposure to the blood-stage parasites that cause disease. We also found that antibody profiles 6 months after vaccination did not distinguish protected and susceptible @entity1 during the subsequent 12-month follow-up period but were strongly associated with exposure. Together, these data provide insight into the mechanism by which RTS,S protects from @entity311 .
