A Vaccine Composed of Antigen Fused to a Ligand for a Receptor on Immature Dendritic Cells Elicits Protective Antibody Responses to Malaria Sporozoites in Infant …

Infants and young children are the groups at greatest risk for severe disease and mortality following acquisition of Plasmodium falciparum infection. Recent large clinical trials with a candidate malaria vaccine have demonstrated very limited protection of only short duration. We have previously demonstrated in mice that a protein vaccine in which the chemokine macrophage inflammatory protein 3α is genetically fused to the minimally truncated circumsporozoite protein of P. falciparum (MCSP) elicits extended high level protection against sporozoite challenge in a mouse model system. In the current study we determined that the research grade formulation of a clinically approved vaccine adjuvant, MF59, elicited greater antibody responses in mice than the previously employed adjuvant, poly(I:C). Use of the MF59 vaccine also expanded the range of IgG subtypes elicited by vaccination. Two immunizations of infant rhesus macaques at one and two months of age with the MCSP/MF59 regimen elicited antibody concentrations that were sustained for 18 weeks at levels that provided passive protection of mice challenged with large sporozoite inocula. The efficacy of this vaccine in a relevant non-human primate model indicates its potential usefulness for the analogous high risk human population. The World Health Organization reported in 2017 that after many years of decline in malaria incidence, the number of estimated cases increased from 211 million in 2015 to 216 million in 2016 1. This increase, and emerging evidence of increased resistance to antimalarial drugs 2,3, indicate the continued need for cost-effective strategies to control the epidemic. The development of an effective malaria vaccine would obviously address this need. However, despite clear evidence from animal model systems that sufficient concentrations of specific antibody can protect against malaria infection, candidate vaccines tested in human populations have failed to achieve and sustain the levels of protection expected from an effective vaccine. The inadequacy of the observed protection has been particularly apparent in the infants and young children who are at greatest risk of severe malaria infection 4. We have previously reported that combining the experimental adjuvant polyinosine-polycytidylic acid (poly (I:C)) with a vaccine platform targeting the circumsporozoite protein of the Plasmodium falciparum parasite (PfCSP) yielded a protective response that, in a mouse challenge model system, was sustained for 22 weeks following the final immunization, which was the latest time point tested. Protection sustained over that period of time had not previously been reported in malaria mouse challenge models. Our vaccine platform consists of a protein in which the chemokine Macrophage Inflammatory Protein 3 Alpha (MIP3α), also known as Chemokine (C-C Motif) Ligand 20 (CCL20) has been genetically fused to the PfCSP antigen. This fusion product has two functions: 1) To target the vaccine antigen to the C-C Motif Chemokine Receptor 6 (CCR6) protein present on the surface of the immature dendritic cells (iDC) that initiate the adaptive immune response 5,6 and 2) To attract immune cells to the site of immunization 7,8. Previous studies demonstrated marked enhancement of the antibody response compared to that observed with vaccine constructs not employing the chemokine component Luo, 2014 #2978;Luo, 2017 #3226]. In the current study we have compared in the mouse model system the immune responses and protection observed using clinically approved adjuvants in addition to the the poly (I:C) adjuvant previously demonstrated to be effective. These studies indicated that the clinically approved adjuvants elicited more profound antibody responses than poly (I:C). We then examined in a pilot study the ability of this vaccine construct used with a clinically approved adjuvant to elicit protective immune responses in one and six month old macaques, representing the age groups in humans most vulnerable to severe malaria infection. Our studies indicate that this vaccine construct is highly immunogenic in infant and juvenile macaques.