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 circumsporo-
zoite protein, have not shown sufficient correlation with
risk of clinical malaria to serve as a surrogate for protec-
tion. 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 num-
ber of parasites emerging from the liver, leading to pro-
longed exposure to subclinical levels of blood-stage par-
asites that go undetected and untreated, which in turn
boosts pre-existing antibody-mediated blood-stage im-
munity. 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 ⴝ 291) versus comparator vaccine (n ⴝ
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 vaccin-
ees, 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. Together, these data provide
insight into the mechanism by which RTS,S protects from
malaria. Molecular & Cellular Proteomics 14: 10.1074/
mcp.M114.044677, 519–531, 2015
