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Introduction: As the quest for an effective blood stage malaria vaccine continues, there is increasing reliance on the use of controlled human malaria infections (CHMI) in non-endemic settings to test vaccine efficacy at the earliest possible time. This is seen as a way to accelerate vaccine research and quickly eliminate candidates with poor efficacy.Areas covered: The data from these studies need to be carefully examined and interpreted in light of the very different roles that antibody and cellular immunity play in protection and within the context of the distinct clinical sensitivities of volunteers living in malaria-non-endemic countries compared to those living in endemic countries. With current strategies, it is likely that vaccines with protective immunological ‘signatures’ will be missed and potentially good candidates discarded.Expert commentary: Efficacy data from early phase vaccine trials in non-endemic countries should not be used to decide whether or not to proceed to vaccine trials...

There have been significant decreases in malaria mortality and morbidity in the last 10-15 years, and the most advanced pre-erythrocytic malaria vaccine, RTS,S, received a positive opinion from European regulators in July 2015. However, no blood-stage vaccine has reached a phase III trial. The first part of this review summarizes the pros and cons of various assays and models that have been and will be used to predict the efficacy of blood-stage vaccines. In the second part, blood-stage vaccine candidates that showed some efficacy in human clinical trials or controlled human malaria infection models are discussed. Then, candidates under clinical investigation are described in the third part, and other novel candidates and strategies are reviewed in the last part.

Malaria is a global health problem and the need for a vaccine that could prevent millions of deaths annually cannot be further justified. A number of strategies have been adopted in the pursuit of making a successful malaria vaccine including the use of blood stage antigens which would primarily target the merozoite and prevent its replication through the asexual blood cycle of the parasite. In this regard, merozoite surface proteins have gained a lot of attention by the malaria vaccine fraternity for development as subunit vaccines. In spite of concentrated efforts spanning a long number of years, we are not close on producing a successful blood stage vaccine, especially one based on merozoite surface proteins (MSP). However, a recent systematic review with meta-analysis of 33 different studies has reported that antibodies against MSP proteins (MSP-1(19) and MSP-3) exhibit the strongest association with lower incidence of malaria and protection. Also the efficacy of an MSP based vaccine, Combination B, in significantly reducing parasite density among infected children in Papua New Guinea supports the development of MSP based malaria vaccines. In light of these developments, in this commentary, we address different aspects and concerns about MSP based vaccines-the need to develop MSP based blood stage malaria vaccines, our successes and failures from the current and past MSP vaccine trails, the lessons learnt from these studies, the future directions and challenges that still face us.

Plasmodium falciparum malaria is a major global health problem, responsible for up to 1 million deaths each year. Major efforts have been made to develop an effective vaccine against this disease, to reduce the associated morbidity and mortality. There has already been considerable progress, with the first vaccine against the pre-erythrocytic stages of P. falciparum now en route to licensure. There remains, however, a strong scientific rationale for the development of a highly effective additional vaccine component against the blood stages of the parasite, which could be deployed in conjunction with partially effective control measures against the pre-erythrocytic stages. Here, recent progress in the clinical development of blood-stage vaccines is reviewed, including methods of antigen selection, the limitations of in-vitro assays for selecting vaccines for clinical development, and the results of recently published clinical trials. This review seeks to summarize recent developments in our understanding of immunity to blood-stage parasites, as well as the relevant key advances made in vaccine technologies over the last decade. The future challenges that face this field of vaccine research are also described.