Mosquito Bite-Induced Controlled Human Malaria Infection with Plasmodium vivax or P. falciparum Generates Immune Responses to Homologous and Heterologous Preerythrocytic and Erythrocytic Antigens

Abstract

Seroepidemiological studies on the prevalence of antibodies to malaria antigens are primarily conducted on individuals from regions of endemicity. It is therefore difficult to accurately correlate the antibody responses to the timing and number of prior malaria infections. This study was undertaken to assess the evolution of antibodies to the dominant surface antigens of Plasmodium vivax and P. falciparum following controlled human malaria infection (CHMI) in malaria-naive individuals. Serum samples from malaria-naive adults, collected before and after CHMI with either P. vivax (n = 18) or P. falciparum (n = 18), were tested for the presence of antibodies to the circumsporozoite protein (CSP) and the 42-kDa fragment of merozoite surface protein 1 (MSP-142) of P. vivax and P. falciparum using an enzyme-linked immunosorbent assay (ELISA). Approximately 1 month following CHMI with either P. vivax or P. falciparum, >60% of subjects seroconverted to homologous CSP and MSP-1. More than 50% of the subjects demonstrated reactivity to heterologous CSP and MSP-142, and a similar proportion of subjects remained seropositive to homologous MSP-142 >5 months after CHMI. Computational analysis provides insight into the presence of cross-reactive responses. The presence of long-lived and heterologous reactivity and its functional significance, if any, need to be taken into account while evaluating malaria exposure in field settings.

The Case for Exploiting Cross-Species Epitopes in Malaria Vaccine Design

“…MSP-1 is another viable blood stage candidate. In the CHMI study described earlier (56), 50% of volunteers infected with P. vivax had antibodies to PfMSP-1 while 67% of those infected with P. falciparum recognized PvMSP-1 on day 28 after infection. Far lower frequencies of cross-reactivity were observed in other studies.…”

“…These findings suggested that PvCSP and PfCSP might share cross-reactive T-cell epitopes, while there was no evidence of heterologous antibody responses. In contrast, deliberate infection of naïve volunteers with either P. falciparum or P. vivax by mosquito bite gave rise to heterologous antibody responses to CSP from each species (56). In both groups, 61% of volunteers had antibodies that cross-reacted with the heterologous CSP antigen.…”

“…The focus of immunity to sporozoite/liver stage infection is largely on CSP. Cross-reactive immune responses between CSP from P. vivax and P. falciparum have been reported in both naturally exposed populations (55) and in controlled human malaria infections (CHMI) (56). In populations from a region in Brazil endemic for both species, peripheral blood mononuclear cells (PBMCs) were highly responsive to stimulation with either PfCSP or PvCSP (55).…”

“…In parallel, computational approaches can be applied to protein databases to predict conserved epitopes. This technique was recently adopted to predict conserved linear and discontinuous epitopes in CSP and MSP-1 shared between the P. falciparum and P. vivax orthologs (56). Computational modeling can also guide the formulation of vaccines to enhance immunogenicity and to elicit broadly neutralizing antibodies.…”

The consequences of mixed-species malaria parasite co-infections in mice and mosquitoes for disease severity, parasite fitness, and transmission success

“…Compelling evidence suggests cross-protection between malaria parasite species due to species-transcending immunity [41,42]. We wondered whether the lack of ability to control the P. vinckei parasitaemia towards the end of the mixed infection of P. vinckei and P. yoelii may be due to the phenomenon of "original antigenic sin" [43] rendering the acquisition of antibodies specific to P. vinckei sub-optimal due to the larger quantity of P. yoelii antigen present in the early stages of the infection.…”