Whole-Killed Blood-Stage Vaccine-Induced Immunity Suppresses the Development of Malaria Parasites in Mosquitoes

Abstract

As a malaria transmission-blocking vaccine alone does not confer a direct benefit to the recipient, it is necessary to develop a vaccine that not only blocks malaria transmission but also protects vaccinated individuals. In this study we observed that a whole-killed blood-stage vaccine (WKV) not only conferred protection against the blood-stage challenge but also markedly inhibited the transmission of different strains of the malaria parasite. Although the parasitemia is much lower in WKV-immunized mice challenged with malaria parasites, the gametocytemia is comparable between control and immunized mice during the early stages of infection. The depletion of CD4 T cells prior to the adoptive transfer of parasites into WKV-immunized mice has no effect on the development of the malaria parasite in the mosquito, but the adoptive transfer of the serum from the immunized mice into the parasite-inoculated mice remarkably suppresses the development of malaria parasites in mosquitoes. Furthermore, immunized mice challenged with the malaria parasite generate higher levels of parasite-specific Abs and the inflammatory cytokines MCP-1 and IFN-γ. However, the adoptive transfer of parasite-specific IgG or the depletion of MCP-1, but not IFN-γ, to some extent is closely associated with the suppression of malaria parasite development in mosquitoes. These data strongly suggest that WKV-induced immune responses confer protection against the mosquito stage, which is largely dependent on malaria parasite-specific Abs and MCP-1. This finding sheds new light on blocking malaria transmission through the immunization of individuals with the WKV.

Improving the immunogenicity and protective efficacy of a whole‐killed malaria blood‐stage vaccine by chloroquine

“…The pRBC lysate preparation and vaccine immunization schedule were carried out as previously described . Briefly, when the parasitemia of P yoelii NSM‐infected mice reached 30%‐40%, blood was collected into heparinized tubes and washed with sterile PBS (1000 g for 10 minutes).…”

“…The pRBC lysate preparation and vaccine immunization schedule were carried out as previously described. 9,13 Briefly, when the parasitemia of P yoelii NSM-infected mice reached 30%-40%, blood was collected into heparinized tubes and washed with sterile PBS (1000 g for 10 minutes). Total RBC counts and parasitemias were determined, and the parasites were adjusted to the desired concentrations with the sterile PBS.…”

“…However, the culturing of the blood stage of Plasmodium falciparum has been well established, and a whole blood‐stage vaccine has been easily manufactured. Our previous studies have shown that immunization with WKV could induce protective immunity against the blood stage, liver stage and mosquito stage . However, because the immunogenicity of pRBC lysate is low, a high dose of pRBC lysate is needed for vaccination, and the protection efficacy induced by the WKV still needs to be improved …”

Whole-Killed Blood-Stage Vaccine: Is It Worthwhile to Further Develop It to Control Malaria?

“…In contrast, wholeparasite vaccines against the pre-erythrocytic stage, such as chemically and genetically attenuated sporozoites, have been shown to induce cross-stage protection against the blood stage (Nahrendorf et al, 2015b;Sack et al, 2015). Although the protection induced by chemically attenuated blood-stage P. yoelii parasites was stage specific as immunized mice were not protected against intravenous or mosquito bite sporozoite challenges (Raja et al, 2016), our study showed that the WKV not only conferred the cross-stage immunity against sporozoite challenge but also blocked parasite development in mosquitoes (Figure 2; Lu et al, 2017;Zhu et al, 2017). Therefore, the WKV not only prevents malarial infection and reduces mortality and morbidity among malaria patients but also blocks malaria transmission.…”

Transmission-Blocking Vaccines: Old Friends and New Prospects

“…Effector CD4 ϩ T cells are also important sources of cytokines that activate macrophages and other immune effector cells. Although the role of CD4 ϩ T cells in the induction of antibodies against asexualstage P. falciparum parasites has been studied extensively (56), their role in inducing gametocyte-specific antibodies is not well established (57)(58)(59). In general, antibody responses against gametocyte antigens tend to be lower than anti-asexual-antigen responses, but the intensity and breadth of the response increases over the season, suggesting boosting during reexposure (60).…”