RTS,S Vaccination Is Associated With Serologic Evidence of Decreased Exposure to Plasmodium falciparum Liver- and Blood-Stage Parasites*

Abstract

The leading malaria vaccine candidate, RTS,S, targets the sporozoite and liver stages of the Plasmodium falciparum life cycle, yet it provides partial protection against disease associated with the subsequent blood stage of infection. Antibodies against the vaccine target, the circumsporozoite protein, have not shown sufficient correlation with risk of clinical malaria 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 children 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 children who did or did not experience febrile malaria. Unexpectedly, we found that the breadth and magnitude of the antibody response to both liver and asexual bloodstage 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 malaria 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 children during the subsequent 12-month follow-up period but were strongly associated with exposure.

T cell subtypes and reciprocal inflammatory mediator expression differentiate P. falciparum memory recall responses in asymptomatic and symptomatic malaria patients in southeastern Haiti

“…In addition, there was no overlap in the top twenty antigens with regards to IgG and IgM reactivity with the exception of LSA-1, which was bound by both IgG and IgM antibodies. The results corroborate previous investigations in low endemic settings, in that there are numerous Pf antigens that elicit humoral responses [25, 26]; however, there was no demonstrable evidence that any of these Pf antigens were diagnostic in separating asymptomatic from symptomatic malaria patients in Haiti.…”

Evaluating antidisease immunity to malaria and implications for vaccine design

“…These observations have important implications for vaccine efficacy studies and future vaccine designs, particularly vaccines that prevent exposure to blood stage parasites altogether. For instance, RTS,S, the most advanced malaria vaccine, was associated with serological evidence of reduced exposure (reduced breadth and magnitude of antibodies), 150 suggesting a scenario where exposure to blood-stage parasites was 'knocked-down' among the vaccinated cohort. Considering that vaccinated children were shown to be at higher risk of clinical malaria at the end of the study compared to unvaccinated 'wild-type' children, 24 it is possible that vaccine-induced loss of exposure to blood stage parasites resulted in a loss of immune tolerance.…”

Genetic Diversity and Protective Efficacy of the RTS,S/AS01 Malaria Vaccine

“…14-17 The circumsporozoite protein is expressed on the surface of the parasite during the infective sporozoite stage and contains a conserved NANP–NVDP tandem repeat with a length polymorphism ranging from 37 to 44 repeat units, 18 which is thought to represent the dominant B-cell epitope. 19 There are numerous polymorphisms within the C-terminal region of circumsporozoite protein, 18,20-22 some of which reside within described T-cell epitopes (Th2R and Th3R) 23 that may also function as B-cell epitopes.…”