Recombinant Viral Vaccines Expressing Merozoite Surface Protein-1 Induce Antibody- and T Cell-Mediated Multistage Protection against Malaria

Abstract

SummaryProtecting against both liver and blood stages of infection is a long-sought goal of malaria vaccine design. Recently, we described the use of replication-defective viral vaccine vectors expressing the malaria antigen merozoite surface protein-1 (MSP-1) as an antimalarial vaccine strategy that elicits potent and protective antibody responses against blood-stage parasites. Here, we show that vaccine-induced MSP-1-specific CD4+ T cells provide essential help for protective B cell responses, and CD8+ T cells mediate significant antiparasitic activity against liver-stage parasites. Enhanced survival is subsequently seen in immunized mice following challenge with sporozoites, which mimics the natural route of infection more closely than when using infected red blood cells. This effect is evident both in the presence and absence of protective antibodies and is associated with decreased parasite burden in the liver followed by enhanced induction of the cytokine IFN-γ in the serum. Multistage immunity against malaria can thus be achieved by using viral vectors recombinant for MSP-1.

Assessment of Immune Interference, Antagonism, and Diversion following Human Immunization with Biallelic Blood-Stage Malaria Viral-Vectored Vaccines and Controlled Malaria Infection

“…However, the data clearly establish that strong and detectable IFN-g T cell responses can be primed and boosted by immunization against both component alleles, and this was independently observed in two clinical trials of the same vaccines. The observation of strong cellular responses against the MSP1 33 region (in comparison with MSP1 19 ) is in good agreement with many previous studies that have assessed T cell recognition within MSP1 42 in both animal models (20,45) and humans (46)(47)(48)(49). Note also that future studies could further assess such phenomena in the context of other T cell phenotype readouts, including different cytokine production.…”

“…CD8 + T cells have been shown to be protective in the Plasmodium yoelii mouse model at both the liver stage (19,20) and blood stage of malaria infection (21). CD8 + T cells specific for blood-stage Ags potentially target merozoite-derived Ags during the late stages of preerythrocytic parasite development within infected hepatocytes (20).…”

“…Although infected erythrocytes lack MHC molecules with which to present parasite-derived peptides, it is thought that effector CD4 + T cells can enhance clearance of opsonized parasitized RBCs by macrophages in the spleen, orchestrate the induction of parasiticidal proinflammatory serum cytokine responses, and/or provide polarizing help for B cells leading to the induction of protective cytophilic IgG subclasses that may better interact with innate cellular effectors such as monocytes or neutrophils (17,18). CD8 + T cells have been shown to be protective in the Plasmodium yoelii mouse model at both the liver stage (19,20) and blood stage of malaria infection (21). CD8 + T cells specific for blood-stage Ags potentially target merozoite-derived Ags during the late stages of preerythrocytic parasite development within infected hepatocytes (20).…”

The Impact of Immune Responses on the Asexual Erythrocytic Stages of Plasmodium and the Implication for Vaccine Development

“…Such particle presentation could be achieved by using either recombinantly expressed antigen on whole-killed bacteria or viruses. For example, mouse studies using recombinant adenovirus encoding MSP-1 demonstrated "protection" (defined by the authors as delayed and lower parasitemia) (Draper et al, 2009).…”

Evaluation of Recombinant Plasmodium knowlesi Merozoite Surface Protein-133 for Detection of Human Malaria

“…23 For example, P. yoelii MSP-1 33 induces effector T cells that could assist in protective B cells response and mediate significant antiparasitic activity against P. yoelii. 24,25 Plasmodium falciparum MSP-1 33 is naturally immunogenic because antibodies against this antigen could be detected in serum of P. falciparum-exposed blood donors. 26 It was further shown that that T cell response and antibodies against MSP1 were induced in human clinical trials by using P. falciparum MSP-1, in which epitopes responsible for cytokine production and memory response development were localized to the 33-kDa region of MSP-1 42 .…”