Whole sporozoite vaccines confer sterilizing immunity to malaria-naïve individuals by unknown mechanisms. In the first-ever PfSPZ Vaccine trial in a malaria endemic population, Vδ2 γδT cells were significantly elevated, and Vγ9/Vδ2 transcripts ranked as most-upregulated, in vaccinees that were protected from P. falciparum infection. In a mouse model, absence of γδ T cells during vaccination impaired protective CD8 T cell responses, and ablated sterile protection. γδ T cells were not required for CSP-specific antibody responses, and γδ T cell depletion before infectious challenge did not ablate protection. γδ T cells alone were insufficient to induce protection and required the presence of CD8α+ dendritic cells. In the absence of γδ T cells, CD8α+ DC did not accumulate in the livers of vaccinated mice. Altogether our results show that γδ T cells were essential for the induction of sterile immunity during whole organism vaccination.

No abstract

The Plasmodium falciparum protein, apical membrane antigen 1 forms a complex with another parasite protein, rhoptry neck protein 2, to initiate junction formation with the erythrocyte and is essential for merozoite invasion during the blood stage of infection. Consequently, apical membrane antigen 1 has been a target of vaccine development but vaccination with apical membrane antigen 1 alone in controlled human malaria infections failed to protect and showed limited efficacy in field trials. Here we show that vaccination with AMA1-RON2L complex in Freund's adjuvant protects Aotus monkeys against a virulent Plasmodium falciparum infection. Vaccination with AMA1 alone gave only partial protection, delaying infection in one of eight animals. However, the AMA1-RON2L complex vaccine completely protected four of eight monkeys and substantially delayed infection (>25 days) in three of the other four animals. Interestingly, antibodies from monkeys vaccinated with the AMA1-RON2L complex had significantly higher neutralizing activity than antibodies from monkeys vaccinated with AMA1 alone. Importantly, we show that antibodies from animals vaccinated with the complex have significantly higher neutralization activity against non-vaccine type parasites. We suggest that vaccination with the AMA1-RON2L complex induces functional antibodies that better recognize AMA1 as it appears complexed with RON2 during merozoite invasion. These data justify progression of this next generation AMA1 vaccine towards human trials.