Genetically engineered, attenuated whole-cell vaccine approaches for malaria

Abstract

Malaria remains one of the most significant infectious diseases affecting human populations in developing countries. The quest for an efficacious malaria vaccine has been ongoing for nearly a century with limited success. The identification of malaria parasite antigens focused efforts on the development of subunit vaccines but has so far yielded only one partially efficacious vaccine candidate, RTS/S. The lack of high vaccine efficacy observed to date with subunit vaccine candidates raises doubts that the development of a single antigen or even a multi-antigen malaria subunit vaccine is possible. Fortunately, it has been demonstrated in animal studies and experimental clinical studies that immunizations with live-attenuated sporozoite stages of the malaria parasite confer long lasting, sterile protection against infection, providing a benchmark for vaccine development. These early successful vaccinations with live-attenuated malaria parasites did not however, promote a developmental path forward for such a vaccine approach. The discovery of genetically engineered parasite strains that are fully attenuated during the early asymptomatic liver infection and confer complete sterile protection in animal malaria models support the development of a live attenuated sporozoite vaccine for Plasmodium falciparum and its accelerated safety and efficacy testing in malaria challenge models and in malaria endemic areas.

Figure 1

Liver stage (LS) developmental arrest of genetically attenuated parasites (GAPs) in rodent malaria models. Wildtype sporozoites invade hepatocytes with the formation of a parasitophorous vacuole membrane (PVM), transform into LS trophozoites and mature as LS schizonts. Schizonts eventually form infectious exo-erythrocytic merozoites (wildtype). GAP sporozoites successfully invade hepatocytes but do not develop fully as LSs. The p52⁻/p36⁻ GAP arrests without the formation of a PV. The sap1⁻ GAP forms a PVM and then arrests. The uis3⁻ and uis4⁻ GAPs form a PV begin to develop but arrest soon after the transition to early schizogony. The fabb/f⁻ GAP develops furthest and enters into late schizogony but is unable to form infectious merozoites.