Strong off-target antibody reactivity to malarial antigens induced by RTS,S/AS01E vaccination is associated with increased protection

The RTS,S/AS01E vaccine targets the circumsporozoite protein (CSP) of the Plasmodium falciparum parasite. Using protein microarrays, levels of IgG to 1,000 P. falciparum antigens were measured in 2,138 infants (age 6-12 weeks) and children (age 5-17 months) from 6 African sites of the phase 3 trial, sampled before and at four longitudinal visits after vaccination. One month post-vaccination, IgG responses to 17% of all probed antigens showed differences between RTS,S/AS01E and comparator vaccination groups, whereas no prevaccination differences were found. A small subset of antigens presented IgG levels reaching 4- to 8 fold increases in the RTS,S/AS01E group, comparable in magnitude to anti-CSP IgG levels (~11-fold increase). They were strongly cross-correlated and correlated with anti CSP levels, waning similarly over time and re-increasing with the booster dose. Such an intriguing phenomenon may be due to cross-reactivity of anti-CSP antibodies with these antigens. RTS,S/AS01E vaccinees with strong off target IgG responses had an estimated lower clinical malaria incidence after adjusting for age group, site and post-vaccination anti-CSP levels. RTS,S/AS01E-induced IgG may bind strongly not only to CSP, but to unrelated malaria antigens, and this seems to either confer, or at least be a marker of, increased protection from clinical malaria.