Low doses of killed parasite in CpG elicit vigorous CD4+ T cell responses against blood-stage malaria in mice

Abstract

Development of a vaccine that targets blood-stage malaria parasites is imperative if we are to sustainably reduce the morbidity and mortality caused by this infection. Such a vaccine should elicit long-lasting immune responses against conserved determinants in the parasite population. Most blood-stage vaccines, however, induce protective antibodies against surface antigens, which tend to be polymorphic. Cell-mediated responses, on the other hand, offer the theoretical advantage of targeting internal antigens that are more likely to be conserved. Nonetheless, few of the current blood-stage vaccine candidates are able to harness vigorous T cell immunity. Here, we present what we believe to be a novel blood-stage whole-organism vaccine that, by combining low doses of killed parasite with CpG-oligodeoxynucleotide (CpG-ODN) adjuvant, was able to elicit strong and cross-reactive T cell responses in mice. Our data demonstrate that immunization of mice with 1,000 killed parasites in CpG-ODN engendered durable and cross-strain protection by inducing a vigorous response that was dependent on CD4 + T cells, IFN-γ, and nitric oxide. If applicable to humans, this approach should facilitate the generation of robust, cross-reactive T cell responses against malaria as well as antigen availability for vaccine manufacture.

Induction of immunity following vaccination with a chemically attenuated malaria vaccine correlates with persistent antigenic stimulation

“…Parasite DNA was detectable in the blood of some of the recipient mice after second transfer and third transfer; however, it seems very unlikely that transferred DNA, per se , was responsible for inducing protection in recipient mice. We previously showed that large numbers of killed parasites (without adjuvant) are unable to induce immunity 26. It thus seems most likely that persisting antigen in the blood of mice, and still within RBCs,11 has induced both a cellular immune response and protection.…”

An Essential Role for C5aR Signaling in the Optimal Induction of a Malaria-Specific CD4+ T Cell Response by a Whole-Killed Blood-Stage Vaccine

“…Detection of malaria-specific IgG in serum P. yoelii 17XL crude parasite Ag was prepared, as described previously (10,24). Briefly, P. yoelii 17XL-infected mouse blood was collected, washed in PBS, and lysed with 0.01% saponin (Sigma-Aldrich) at 37˚C for 20 min.…”

“…Because of the failure of subunit malaria vaccines, a variety of whole-malaria parasite vaccines, including infection treatment vaccine (9), killed malaria parasite vaccine (10), and genetically attenuated blood-stage malaria vaccine (11,12), have garnered more attention from researchers in recent years. Evidence has shown that the whole-killed parasite vaccine could induce the host to generate protective immunity against blood-stage malaria parasites in both human and animal models (10,13).…”

“…Evidence has shown that the whole-killed parasite vaccine could induce the host to generate protective immunity against blood-stage malaria parasites in both human and animal models (10,13). In contrast to subunit vaccines, the protective immunity induced by the wholekilled blood-stage vaccine was dependent on malaria-specific CD4 + T cells, IFN-g, and NO (10). In addition, the CD4 + T cell response induced by the whole-killed blood-stage vaccine has the theoretical advantage of targeting internal Ags.…”

“…In addition, the CD4 + T cell response induced by the whole-killed blood-stage vaccine has the theoretical advantage of targeting internal Ags. These Ags are more likely to be conserved, and may provide cross-strain protection (10). Therefore, the induction of a robust malaria-specific CD4 + T cell response was regarded as a promising new vaccine development strategy (14).…”