Vaccine‐Like Immunity against Malaria by Repeated Causal‐Prophylactic Treatment of Liver‐StagePlasmodiumParasites

Abstract

Liver-stage development of Plasmodium parasites represents a dramatic expansion phase for the malarial parasite between vector transmission and onset of the pathogenic blood-stage cycle. Here, we report that repeated causal-prophylactic primaquine treatment of liver-stage Plasmodium parasites in rodents elicits vaccine-like protective immunity against sporozoite-induced malaria. This regimen differs fundamentally from those involving radiation- or genetically attenuated parasites, in which long-lasting immune responses are dependent on persistence of metabolically active parasites. Pharmacological inhibition of liver-stage parasites in the rodent malaria model offers a potential fast track toward development of a vaccine that targets parasites in preerythrocytic stages.

Induction of Antimalaria Immunity by Pyrimethamine Prophylaxis during Exposure to Sporozoites Is Curtailed by Parasite Resistance

“…The drugs tested so far in studies of immunoprophylaxis act at different points in the Plasmodium preerythrocytic cycle: primaquine kills intrahepatic parasites (32); antibiotics, such as azithromycin, lead to delayed death inside the infected hepatocyte, resulting in the emergence of noninfectious liver-stage merozoites (16); and chloroquine cover results in the suppression of emerging blood-stage infections (6,7). These experimental findings were validated by a recent proof-of-concept study with human volunteers.…”

“…Experimental studies in the rodent malaria model demonstrated the potential of inoculation with live sporozoites during prophylactic antimalarial administration for the induction of lasting protection against reinfection (6,7,16,32). The drugs tested so far in studies of immunoprophylaxis act at different points in the Plasmodium preerythrocytic cycle: primaquine kills intrahepatic parasites (32); antibiotics, such as azithromycin, lead to delayed death inside the infected hepatocyte, resulting in the emergence of noninfectious liver-stage merozoites (16); and chloroquine cover results in the suppression of emerging blood-stage infections (6,7).…”

Purification of Plasmodium Sporozoites Enhances Parasite-Specific CD8 + T Cell Responses

“…RTS,S achieves partial protection (1) through antibody and CD4 ϩ T cell responses (2) but does not trigger strong cytotoxic T lymphocyte (CTL) responses (3,4). The RTS,S vaccine does not induce sterile protection against challenge, a benchmark that is only routinely achieved through repeated immunizations with either attenuated whole sporozoites (5-7) or wild-type (WT) sporozoites with concurrent prophylactic drug coverage (8,9). These whole-sporozoite approaches induce protective humoral and cellular responses, and animal models suggest that protection relies on CD8 ϩ CTL (10).…”

Artesunate versus Chloroquine Infection–Treatment–Vaccination Defines Stage-Specific Immune Responses Associated with Prolonged Sterile Protection against Both Pre-erythrocytic and Erythrocytic Plasmodium yoelii Infection

“…For example, sterile protection in human volunteers can be achieved by exposure to ∼1,000 bites of irradiated (irr) mosquitoes infected with Plasmodium falciparum spz (4-6) or by i. v. administration of ∼450,000 irr-spz (7). In comparison, the alternative infection-treatment-vaccination (ITV) strategy, which involves administration of wild type (wt) malaria parasites under drug treatment, requires significantly less spz to elicit protection (8)(9)(10), suggesting that irr-spz are not as immunogenic as wt spz under drug coverage. For example, infection of naive individuals via 3 doses of 15 bites each of mosquitoes infected with wt P. falciparum under chloroquine (CQ) coverage induces long-term protection against challenge (11,12).…”