Introduction

The development of highly effective and durable vaccines against the human malaria parasites Plasmodium falciparum and P.vivax remains a key priority. Decades of endeavor have taught that achieving this goal will be challenging; however, recent innovation in malaria vaccine research and a diverse pipeline of novel vaccine candidates for clinical assessment provides optimism. With first-generation pre-erythrocytic vaccines aiming for licensure in the coming years, it is important to reflect on how next-generation approaches can improve on their success. Here we review the latest vaccine approaches that seek to prevent malaria infection, disease, and transmission and highlight some of the major underlying immunological and molecular mechanisms of protection. The synthesis of rational antigen selection, immunogen design, and immunization strategies to induce quantitatively and qualitatively improved immune effector mechanisms offers promise for achieving sustained high-level protection.

History of malaria vaccine

Modern malaria vaccine development stems from immunization studies of mice with irradiated sporozoites, conducted in the 1960s, and subsequent analyses of the mechanisms of immunity in this model. Key challenge studies by Clyde in humans demonstrated that a high level of protection could be induced in volunteers but required large numbers of bites by irradiated infectious mosquitoes. The identification of the circumsporozoite protein as the major component of the sporozoite coat led to the cloning and sequencing of this gene in the early 1980s and optimistic predictions that a sporozoite vaccine was within reach. About this time, excellent progress was made in identifying and expressing a range of blood-stage antigens also raising hopes for a blood-stage vaccine. However, initial clinical trials revealed only modest immunogenicity of candidate antigens and no statistically significant efficacy on sporozoite challenge.

Modern methods for malaria vaccines

Modern malaria vaccine development began with seminal studies in mice using irradiated sporozoites. Although there is still no licensed product over 50 years later, it is important to remember the scale of the scientific and technical challenges facing those who develop vaccines against such a complex eukaryotic parasite. Moreover, steady progress is being made, especially with regard to breakthroughs in our understanding of the cellular and molecular mechanisms mediating protection in animal models and humans. The revised Malaria Vaccine Technology Roadmap to 2030 now calls for a next-generation vaccine to achieve 75% efficacy over 2 years against P. falciparum and/or P. vivax (in an era of renewed global interest toward malaria elimination and eradication), while also retaining its original 2015 “landmark” goal of a first-generation vaccine with protective efficacy of >50% lasting more than 1 year. Achieving this next-generation vaccine goal will necessitate building on the success of current pre-erythrocytic subunit and whole sporozoite-based vaccines, as well as new strategies to add blood-stage or transmission-blocking immunity. Here we review the progress and prospects for a diverse range of approaches targeting different stages of the P. falciparum parasite’s complex life cycle, before discussing those in development for P. vivax.

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