Biological strategies and political hurdles in developing malaria vaccines

Abstract

Malaria is a devastating parasitic disease for which a vaccine is urgently needed. Seminal studies in the 1940s demonstrated that a whole parasite malaria vaccine could induce protective immunity in ducks and monkeys [1,2]. Nearly 80 years later, only one malaria vaccine (MosquirixTM), albeit one with moderate efficacy, has progressed into Phase III trials and has subsequently been licensed. There are many reasons for why we still do not have a highly effective malaria vaccine including unique aspects of the malaria parasite’s biology and our incomplete understanding of host–pathogen interactions, although our knowledge in this latter area has greatly improved in recent decades and this will facilitate the rational design of vaccine candidates. This special issue of Expert Review of Vaccines devoted to malaria includes reviews of many current, frontline approaches to vaccine development, with expert opinions on sporozoite/liver-stage, blood-stage, and sexual-stage vaccines as well as a review devoted to the special case of pregnancy-associated malaria (PAM). Historically, malaria vaccine development has focused on P. falciparum, due to its associated morbidity and mortality; however, the need for a vaccine for the most geographically wide-spread human malaria parasite, P. vivax, is well recognized and De et al. [3] discuss some of the unique challenges associated with developing a P. vivax vaccine. The complexity of the multi-stage malaria parasite life-cycle has been challenging for vaccine development as immunity to malaria is stage-specific. The majority of malaria vaccines that are currently in development target a single life-cycle stage. Immunity that has developed against one life-cycle stage will not lead to immunity against another life-cycle stage, e.g., immunity against blood-stage parasites will not protect against infection with sporozoites. For sporozoite-liver-stage immunity, this means that a vaccine-induced immune response must induce sterilizing immunity. If just a single sporozoite or infected hepatocyte evades the vaccineinduced immune response, then a blood-stage infection and transmission of the malaria parasite will follow. The leading malaria vaccine, MosquirixTM (RTS,S), targets the sporozoite/ liver-stage of the parasite and although it is now being further evaluated in pilot implementation studies in Africa, in its current formulation it offers only moderate, short-term protective immunity [4]. Further optimization of the vaccine formulation or regimen will be required to improve the protective efficacy of this vaccine. By using a structure-guided vaccine approach it may also be possible to identify other regions of the vaccine antigen, the circumsporozoite protein (CSP), to yield a more effective second-generation CSP-based vaccine [5]. Different types of immune responses are also required for protective immunity against the different life-cycle stages; understanding this will facilitate the rational design of vaccine candidates. Recent studies have shown that Plasmodiumspecific CD8 tissue-resident memory (TRM) cells in the liver contribute to protective immunity against malaria [6], resulting in a focus on the development of novel vaccination strategies to maximize TRM generation in the liver for a more effective malaria vaccine. A clear understanding of what constitutes a protective immune response against the different life-cycle stages will also enable the identification of immunological correlates of vaccine efficacy which may help to accelerate clinical vaccine development [7]. Recent studies [7] suggest that functional assays that represent in vivo antiparasite effector mechanisms, may be a better predictor of protective immunity than many of the simple quantitative assays that have been employed to date. The malaria parasite is adept at evading the human immune response, whether it be by varying critical target antigens or by modulating the immune response. The former has major implications for the selection of vaccine antigens. The efficacy of sub-unit vaccine candidates tested in the field so far has suffered in part from the impact of polymorphisms in target vaccine antigens [8–12]. This has reignited enthusiasm for the whole parasite vaccine approach, which is currently being developed for both sporozoite and blood-stage parasites [13]. The whole parasite approach has the advantage of presenting a broad repertoire of antigens to the immune system and limiting the impact of antigen polymorphism and immunological non-responsiveness to individual antigens. A further unique issue for malaria vaccine development applies to immunity to the sexual-stages of the parasite. This immunity, referred to as ‘transmission-blocking’ immunity, aims to kill the gametes or zygotes in the mosquito mid-gut via antibodies taken up by the feeding mosquito. Thus, unlike sporozoite/liver-stage and blood-stage vaccines, a sexualstage vaccine will not directly protect the vaccinated individual from contracting malaria but will prevent the vaccinee from passing the malaria parasite to another person. All malaria vaccines have the ability to have an impact on the