Abstract
Following the RTS,S malaria vaccine, which showed only partial protection with short-term memory, there is strong support to develop second-generation malaria vaccines that yield higher efficacy with longer duration. The use of replicating viral vectors to deliver subunit vaccines is of great interest due to their capacity to induce efficient cellular immune responses and long-term memory. The measles vaccine virus offers an efficient and safe live viral vector that could easily be implemented in the field. Here, we produced recombinant measles viruses (rMV) expressing malaria “gold standard” circumsporozoïte antigen (CS) of Plasmodium berghei (Pb) and Plasmodium falciparum (Pf) to test proof of concept of this delivery strategy. Immunization with rMV expressing PbCS or PfCS induced high antibody responses in mice that did not decrease for at least 22 weeks post-prime, as well as rapid development of cellular immune responses. The observed long-term memory response is key for development of second-generation malaria vaccines. Sterile protection was achieved in 33% of immunized mice, as usually observed with the CS antigen, and all other immunized animals were clinically protected from severe and lethal Pb ANKA-induced cerebral malaria. Further rMV-vectored malaria vaccine candidates expressing additional pre-erythrocytic and blood-stage antigens in combination with rMV expressing PfCS may provide a path to development of next generation malaria vaccines with higher efficacy.
Highlights
Despite decades of malaria vaccine research, only RTS,S/AS01 vaccine candidate reached Phase III clinical trial to eventually show moderate protection of short duration.[1]
Following the moderate protection and short memory response induced by RTS,S vaccine candidate in phase III clinical trial,[1] there is strong support for developing a second-generation malaria vaccine with higher efficacy and longer duration of protection
We report here the first use of measles-based vaccine platform to deliver circumsporozoïte antigen (CS) malaria antigen as a proof of concept of the feasibility and advantages of this vector, in a murine model
Summary
Despite decades of malaria vaccine research, only RTS,S/AS01 vaccine candidate reached Phase III clinical trial to eventually show moderate protection of short duration.[1]. The rationale for malaria vaccine development relies on several observations. Natural immunity is gradually acquired to severe, life-threatening malaria and to clinical disease after several years of natural exposure.[4] this immunity is not sterile and quickly wanes if an individual leaves the endemic area. Continued exposure to parasites is, required to maintain immunological memory.[5] Second, transfer of gammaglobulin fractions from semi-immune to naïve humans clears blood stage parasites and mitigates malaria disease.[6] inoculation of irradiated attenuated sporozoïtes can protect humans against infectious challenge, but requires high and frequent doses, and immunity wanes after 6 months.[7] the induction of long-term memory is critical for sustained vaccine efficacy
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