A novel anti-malaria vaccine About half a million people every year die of malaria. The majority of vaccine candidates developed over the years have failed to achieve malaria control. Health © ANDREA DELBO, Shutterstock Malaria, caused by the protozoan parasite Plasmodium falciparum, is transmitted by infected female Anopheles mosquitoes. Invading parasites initially migrate to the liver and undergo a complex life cycle comprising four stages, namely the sporozoite, hepatic, blood and mosquito stages. So far, malaria vaccine development has proved difficult, mainly because of the differential gene expression of each life cycle stage and the substantial polymorphism of many parasite antigens. Vaccine clinical trials have demonstrated the importance of correct antigen conformation during vaccine production and underscored the need for exceptionally potent antibody and T cell responses to induce protective immunity. Development of whole parasite vaccines has been hampered by challenges in manufacture, deployment and delivery. There is no licenced vaccine to date against malaria, and the most advanced candidate (called RTS,S) targets a pre-erythrocyte stage protein which is required for parasite entry into the liver. Although a large part of the generated immune response is against the viral envelope protein of the hepatitis B virus included in the vaccine, it can produce up to 60 % protection on challenge. A multi-stage vaccine The EU-funded pan-European MULTIMALVAX project brought together leading European academic and industrial experts in the field. ‘The overarching aim of the MULTIMALVAX clinical development programme was to develop the concept of a highly effective multi-stage malaria vaccine.’ states project co-ordinator Prof Adrian Hill. The consortium exploited recent advances in vaccine design including a viral vector approach based on the chimpanzee adenovirus (ChAd63) and the modified vaccinia Ankara (MVA) vectors for prime and boost vaccination. The capacity of this vector combination to generate potent CD8+ T cell responses and high antibody titres against multiple malaria antigens make it a promising tool for malaria vaccines. Researchers combined the protective vaccine candidate R21, a next generation virus-like particle targeting sporozoites, alongside viral vectors targeting the liver-stage parasite, the blood-stage antigen RH5, and the transmission blocking vaccine candidate Pfs25. Vectors generated expressing the different-stage components were assessed individually before a recent combination trial. RH5 proved to be safe as a vaccine antigen in humans and capable of inducing cross-strain growth inhibition. Trial results of the vectored transmission blocking vaccine demonstrated safety and immunogenicity for both antibody and T cell induction. Advantages of a multi-hit approach Interrupting malaria transmission is an important goal of malaria vaccination. ‘The MULTIMALVAX vaccine approach takes advantage of the potential synergies between vaccine components acting at different stages of the life cycle.’ explains Prof Hill. ‘Another advantage’ he continues, ‘is that a parasite with a variant that allows escape from one immune response should still be susceptible to immunity against other vaccine components.’ Pre-clinical data of the MULTIMALVAX project showed that different mosquito-stage antigens can induce potent transmission blocking against African isolates of P. falciparum. Importantly, the combination of anti-sporozoite and anti-liver stage components provided synergistic effects. The MULTIMALVAX project has combined some of the most promising antigens and delivery systems for each stage of the P. falciparum life-cycle to address one of the major goals of global health research for several decades, a high efficacy malaria vaccine. Project partners anticipate that the proposed vaccine could be cost-effectively manufactured to meet the global annual need for tens of millions of vaccine courses in developing countries. The next step is to further optimise and evaluate the multi-stage vaccine for malaria-endemic regions in Africa under the new EU-funded programme, OPTIMALVAX. Keywords Malaria, vaccine, Plasmodium falciparum, life cycle, MULTIMALVAX
