Colorized electron micrograph showing malaria parasite (right, blue) attaching to a human red blood cell. The inset shows a detail of the attachment point at higher magnification. [NIAID]
Colorized electron micrograph showing malaria parasite (right, blue) attaching to a human red blood cell. The inset shows a detail of the attachment point at higher magnification. [NIAID]

Infections from malaria have persisted within humans for so long that the parasite has shaped the course of human evolution and is an example of how natural selection works in our species. This parasitic disease—particularly from the virulent Plasmodium falciparum strain—is still one of the leading causes of death worldwide. Vaccines to P. falciparum and other parasite strains infecting humans have been notoriously difficult to develop and have seen very limited success. However, now, investigators at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), have modified a previously unsuccessful experimental malaria vaccine. It is successful at completely protecting 50% of monkeys against a challenge from P. falciparum and delayed when parasites first appeared in the blood by more than 25 days in 75% of the remaining primates.

The findings from this study were published recetnly in npj Vaccines in an article entitled “A Malaria Vaccine Protects Aotus Monkeys against Virulent Plasmodium falciparum Infection.”

Classic symptoms of malaria, such as extremely high fever, malaise, and chills, occur once the parasites reach the systemic circulation and begin to replicate inside red blood cells—causing them to burst. To enter blood cells, parasites first secrete their own receptor protein, RON2, onto the cell's surface. Another parasite surface protein, AMA1, then binds to a specific portion of RON2, called RON2L, and the resulting complex initiates attachment to the outer membrane of the red blood cell.  

“We show that vaccination with AMA1–RON2L complex in Freund’s adjuvant protects Aotus monkeys against a virulent Plasmodium falciparum infection,” the authors wrote. “Vaccination with AMA1 alone gave only partial protection, delaying infection in one of eight animals. However, the AMA1–RON2L complex vaccine completely protected four of eight monkeys and substantially delayed infection (>25 days) in three of the other four animals. Interestingly, antibodies from monkeys vaccinated with the AMA1–RON2L complex had significantly higher neutralizing activity than antibodies from monkeys vaccinated with AMA1 alone.”

Several experimental malaria vaccines previously tested in people were designed to elicit antibodies against AMA1 and thus prevent parasites from entering blood cells. Although AMA1 vaccines did generate elevated levels of antibodies in humans, they have shown limited efficacy in field trials in malaria-endemic settings.

To improve vaccine efficacy, the NIAID scientists modified an AMA1 vaccine to include RON2L so that it more closely mimicked the protein complex used by the parasite. Monkeys were vaccinated with either AMA1 alone or with the AMA1–RON2L complex vaccine. Although the overall levels of antibodies generated did not differ between the two groups, animals vaccinated with the complex vaccine produced much more neutralizing antibodies, indicating a higher-quality antibody response with AMA1–RON2L vaccination. Moreover, antibodies taken from AMA1–RON2L-vaccinated monkeys neutralized parasite strains that differed from those used to create the vaccine.

“Importantly, we show that antibodies from animals vaccinated with the complex have significantly higher neutralization activity against non-vaccine type parasites,” the authors concluded. “We suggest that vaccination with the AMA1–RON2L complex induces functional antibodies that better recognize AMA1 as it appears complexed with RON2 during merozoite invasion. These data justify progression of this next generation AMA1 vaccine towards human trials.”