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

Abstract

A whole‐killed malaria blood‐stage vaccine (WKV) is promising in reducing the morbidity and mortality of malaria patients, but its efficacy needs to be improved. We found that the antimalarial drug chloroquine could augment the protective efficacy of the WKV of Plasmodium yoelii. The direct antimalarial effect of chloroquine on parasites during immunization could be excluded, as the administration of chloroquine or chloroquine plus alum every two weeks had a slight effect on parasitemia, and an immunization with NP‐KLH (4‐hydroxy‐3‐nitrophenylacetyl Keyhole Limpet Hemocyanin) plus chloroquine could significantly promote the generation of NP‐specific antibodies. Additionally, alum was required for chloroquine to augment the immunogenicity of the pRBC lysate. Chloroquine did not promote the parasite‐specific CD4+ T‐cell responses, but significantly enhanced the WKV‐induced germinal centre B cell reactions, class‐switch recombination and secretion of functionally protective antibodies to plasmodium. The elevated parasite‐specific antibodies were demonstrated to largely contribute to the chloroquine‐enhanced protective immunity. Thus, we report that chloroquine could be used as an adjuvant to enhance the protective immunity of WKVs through promoting humoral responses.

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

“…Aluminum-containing adjuvants are the most widely used clinical adjuvants, which have been demonstrated not only to directly trigger the NALP3 inflammasome but also to indirectly activate the host innate immune response by inducing the release of the endogenous danger signal uric acid (Lambrecht et al, 2009). However, we found that alum only slightly improved the immunogenicity of pRBC lysate (Fu et al, 2020). Although CpG has been reported to be able to significantly enhance the malaria parasite-specific CD4 + T responses and reduce the vaccine dose from 10 8 to 10 3 (Pinzon-Charry et al, 2010), the use of CpG as an adjuvant in humans has not been approved.…”

“…However, chloroquine was found to greatly promote CD8 + T cell responses against soluble antigens in vivo, through inhibiting the degradation of internalized soluble antigen in endosomes by increasing the pH of the endosomes (Accapezzato et al, 2005). Interestingly, we found that low-dose antimalarial chloroquine along with alum synergistically improved the immunogenicity of pRBC lysates by enhancing the humoral response, although chloroquine alone only had a slight effect (Fu et al, 2020). As chloroquine has been approved as safe for humans, we strongly suggest that the use of low-dose chloroquine, along with alum, should be explored to enhance the immunogenicity of WKV.…”

The host targeting effect of chloroquine in malaria

“…In fact, chloroquine together with an adjuvant (i.e. alum) increases the protective efficacy of whole-killed blood-stage vaccines via humoral immune responses due to an expansion of GC B cells and class‐switch recombination [ 65 ]. A synthetic analog of malarial hemozoin has been proposed to be a universal adjuvant [ 66 ].…”