Abstract
Apical Membrane Antigen 1 (AMA1) is a leading malaria vaccine candidate and a target of naturally-acquired human immunity. Plasmodium falciparum AMA1 is polymorphic and in vaccine trials it induces strain-specific protection. This antigenic diversity is a major roadblock to development of AMA1 as a malaria vaccine and understanding how to overcome it is essential. To assess how AMA1 antigenic diversity limits cross-strain growth inhibition, we assembled a panel of 18 different P. falciparum isolates which are broadly representative of global AMA1 sequence diversity. Antibodies raised against four well studied AMA1 alleles (W2Mef, 3D7, HB3 and FVO) were tested for growth inhibition of the 18 different P. falciparum isolates in growth inhibition assays (GIA). All antibodies demonstrated substantial cross-inhibitory activity against different isolates and a mixture of the four different AMA1 antibodies inhibited all 18 isolates tested, suggesting significant antigenic overlap between AMA1 alleles and limited antigenic diversity of AMA1. Cross-strain inhibition by antibodies was only moderately and inconsistently correlated with the level of sequence diversity between AMA1 alleles, suggesting that sequence differences are not a strong predictor of antigenic differences or the cross-inhibitory activity of anti-allele antibodies. The importance of the highly polymorphic C1-L region for inhibitory antibodies and potential vaccine escape was assessed by generating novel transgenic P. falciparum lines for testing in GIA. While the polymorphic C1-L epitope was identified as a significant target of some growth-inhibitory antibodies, these antibodies only constituted a minor proportion of the total inhibitory antibody repertoire, suggesting that the antigenic diversity of inhibitory epitopes is limited. Our findings support the concept that a multi-allele AMA1 vaccine would give broad coverage against the diversity of AMA1 alleles and establish new tools to define polymorphisms important for vaccine escape.
Highlights
There is strong need for vaccines against malaria to combat the global burden of disease, in light of increasing drug resistance [1] and the declining efficacy of vector control interventions [2]
To understand the antigenic diversity of inhibitory epitopes of Apical Membrane Antigen 1 (AMA1) and the cross-inhibitory activity of antibodies, we generated a panel of 18 different P. falciparum isolates that would broadly represent AMA1 global diversity (Table 2)
The four alleles used for antibody generation were selected on the basis that i) they broadly represent global AMA1 diversity based on phyologenetic analysis (Figure 1), ii) they have a varied distribution of polymorphic sites, iii) there is a high level of sequence diversity between the alleles and iv) an isolate corresponding to each allele could be cultured in vitro
Summary
There is strong need for vaccines against malaria to combat the global burden of disease, in light of increasing drug resistance [1] and the declining efficacy of vector control interventions [2]. The capacity of AMA1 to elicit protective immunity in humans was recently demonstrated by a phase 2b vaccine trial of 1–6 year old children in Mali [15]. This trial, using a vaccine based on a single AMA1 allele, reported 64% protective efficacy against malaria episodes caused by vaccine-like alleles, but no significant efficacy against episodes due to other alleles. These findings demonstrate the potential of AMA1-based malaria vaccines, but highlight the need for strategies to overcome antigenic diversity and prevent vaccine escape
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