RTS,S Has a Fighting Chance to Become Malaria Vaccine

Underlying Factors

 Malaria is a complex disease, and therefore poses several challenges for the development of a vaccine. It is important to note that the most prevalent species of the parasite (there are four known to cause malaria in humans), Plasmodium falciparum is the main focus of vaccine efforts at this point. The malaria parasite is a protozoan, which is more biologically complex than bacteria or viruses. It also creates a complicated array of potential vaccine targets. The three most promising vaccines and their modes of action are detailed below, including an analysis of which of the three is has the highest potential to become a widely used vaccine to prevent malaria from P. falciparum. A malaria vaccine would reduce the number of severe malaria cases and deaths, and by ensuring preventability would be an important step towards eradication of the disease. There are currently three vaccines in various stages of development, and, based on efficacy testing and other supporting evidence, it has been determined that RTS,S is the vaccine that will succeed over other candidates.

Parasite Evolution

To make a vaccine, it is necessary not only to determine a mode of action against the parasite, but also to combat the development of resistance. This is especially difficult in P. falciparum, which it has an excessively high replication rate, meaning that drugs aimed at reducing reproduction rate will exert high selection pressure on the organism, leading to resistance through natural selection.

Possible Mechanisms of Defense

The following presents the mechanisms by which vaccines could target the parasite, based on the stages of development in its life cycle.

•       Antibodies target gametocytes or gametes to prevent the development of sporozoites
•       Antibodies target sporozoites to block invasion and infection of hepatocytes (liver cells)
•       Target infected hepatocytes for lysis before merozoite stage
•       Antibodies target merozoites to prevent invasion of red blood cells
•       Destroy infected red blood cells and disable gametocytes

The Three Vaccines and their Modes of Action
 RTS,S/AS01-Mosquirix: This vaccine shows at best 27% efficacy (the highest among current vaccines) after four successive doses. Therefore, it is considered “complimentary” along with other preventative measures and treatments. RTS,S arms the immune system to defend against P. falciparum at its entry to the bloodstream. It aims to prevent infection of hepatocytes and, as it would prevent the stage involving red blood cells, would likely negate the occurrence of noticeable symptoms. This is the first vaccine to complete multiple phases of clinical trials.
RTS,S-AS01/ChAd63/MVA-TRAP This vaccine showed repeatable but moderate efficacy and targets the parasite before it enters the red blood cells. It is a kind of combined drug, with each component performing a specific defense against the parasite. 
Pfs25-VLP-Alhydrogel: This vaccine aims to prevent the transmission of the malaria parasite from human to mosquito in the gametocyte stage by inhibiting development of the parasite inside the mosquito. This approach would lower transmission rates and reduce the number of new cases.

RTS,S/AS01 Stands Out as Best Candidate

Based on its relatively high efficacy, considerable progress in clinical trials and in phase 3 testing, and administration in young children in several Sub-Saharan African countries, Mosquirix shows great promise for a malaria vaccine. It will likely to move forward to reach a larger group of individuals in testing, and, with sufficient funding, can be implemented in African countries. The other main vaccines, though sophisticated and functional in theory and in cell exposure tests, lack the clinical efficacy of RTS,S/AS01 and therefore require further modification to achieve a similar level of promise. Further, the research and development of this vaccine is funded by the Bill and Melinda Gates Foundation. This provides great leverage due for the success of this drug over its lagging contenders. 

For a more extensive list of malaria vaccines, see the malaria vaccine initiative website. Over the past ten years, about 40 vaccines have undergone testing at the initial clinical trial level.