The 2016 World Malaria Report estimates that there were approximately 215 million cases of malaria and 438,000 deaths in 2015. The majority of deaths occur in sub-Saharan Africa and among young children, and malaria remains endemic in around 100 countries with over three billion people at risk. Over the past 15 years there have been major gains in reducing the global burden of malaria; however, it continues to be a major cause of mortality and morbidity globally. The 25th of April marks World Malaria Day, highlighting key issues in the fight against this major disease. Plasmodium falciparum causes the bulk of malaria, with P. vivax being a second major cause. World Malaria Day 2016 highlights the need for innovation to develop effective vaccines, new drugs, and better diagnostics to ensure continued success towards malaria elimination.
An effective vaccine has long been a goal of the global community, and the tremendous benefits of low cost, safe, and highly effective vaccines have been demonstrated with other infectious pathogens. The WHO Malaria Technology Roadmap sets out the goals for malaria vaccine development with the aim of achieving a licensed vaccine with >75% efficacy by 2030 (vaccine efficacy is usually expressed as the proportion of malaria episodes prevented), and vaccines that reduce malaria transmission to facilitate malaria elimination. However, achieving highly efficacious vaccines has proved exceptionally challenging.
The most advanced vaccine, known as RTS,S, and the only malaria vaccine to have progressed through formal phase III trials, showed significant, but modest, efficacy of 26-36% among infants and young children even with a booster dose (efficacy varied by age group). RTS,S is based on using a single antigen of P. falciparum. One strategy to develop more efficacious malaria vaccines is to incorporate multiple antigens across different life stages of the parasite. The infection commences with the bite of an infected mosquito (Anopheles spp only), which inoculates the sporozoite stage; this is the stage targeted by the RTS,S vaccine. Sporozoites travel to the liver where they infect hepatocytes and replicate inside them for seven to ten days, before daughter parasites are released to enter the blood stream to commence the blood-stage of infection. It is during this stage that malaria disease develops as Plasmodium spp infect red blood cells and replicate inside them.
The majority of deaths occur in sub-Saharan Africa and among young children, and malaria remains endemic in around 100 countries with over three billion people at risk.
Developing vaccines that target the merozoite to block infection of red blood cells is an attractive approach to preventing blood-stage replication and clinical disease. The merozoite is highly complex and the process of red blood cell infection involves multiple proteins and interactions. This complexity has proved challenging to our efforts to understand merozoite invasion and malaria immunity, as well as to developing merozoite antigens as malaria vaccines.
Over recent years, major progress has been made in understanding red blood cell invasion by merozoites, as well as the nature and targets of immune responses that block infection. This has enabled the identification of several promising vaccine candidates. A number of candidate vaccine antigens have shown significant promise in animal and in vitro models and a few have shown efficacy in clinical trials establishing a proof-of-concept for this strategy. Effective immunity appears to involve multiple different immune mechanisms, including the ability of antibodies produced by the immune system to directly block merozoite function, recruit complement proteins from the blood to kill or inactivate merozoites, and interact with leukocytes to clear infection. Through this expanding understanding of infection and immunity, developing vaccines that target both the merozoite and sporozoite forms might help achieve the goal of high efficacious vaccines in the future.
The persisting challenges faced in malaria control and elimination, including escalating drug resistance, insecticide resistance, and insufficient funding further strengthen the importance of the long term goal of developing highly effective malaria vaccines to protect humanity from one its greatest foes.
Featured image credit: ‘Mosquito’ by Tom. CC BY 2.0 via Flickr.