Are Anti-Malaria Vaccines Doing More Harm Than Good?

A long-held belief regarding the way in which vaccinations work to protect hosts from pathogens may be inaccurate.

A long-held belief regarding the way in which vaccinations work to protect hosts from pathogens may be inaccurate, according to the results of a study published recently in EBioMedicine.1

Malaria is a potentially lethal disease that kills almost one million people worldwide every year, most of whom are children under the age of five years.2,3. It is attributable to infection with any of the five species of Plasmodium that can infect humans, with the Plasmodium falciparum species accounting for the majority of malaria-related deaths. Blocking red blood cell invasion by Plasmodium falciparum via vaccination-induced compliment activation should theoretically provide protection against malaria; however, efforts to develop vaccines that can do this effectively have not been successful.

In general, vaccinations are thought to confer protection from pathogens through the complement system, a part of the innate immune response that plays an essential role in the humoral immune response mediated by antibody molecules secreted by plasma cells. One hypothesis for the lack of success in developing an anti-malaria vaccine is that complement activation may serve to enhance, rather than block, the entrance of Plasmodium falciparum into red blood cells.

Senior author José A. Stoute, MD, FACP, FIDSA, a professor of Medicine, and Microbiology and Immunology in the Department of Medicine, Division of Infectious Diseases and Epidemiology, at the Penn State University College of Medicine in Hershey, Pennsylvania, told Contagion that, "We knew from previous studies that we and others had done that the malaria parasite uses complement receptors to enter the red cell."

Dr. Stoute and his colleagues conducted both in vitro and in vivo experiments using a variety of methodologies in order to determine the role of complement system activation in malaria parasite red blood cell invasion. In describing his team's results, Dr. Stoute told Contagion, "We found [that], in vitro (in the test tube) and in vivo in mice using a mouse malaria strain, complement activation can enhance the entrance of the parasite into red cells. In vitro we found that the presence of complement always made red cell invasion higher especially when we added antibodies that target the merozoite, the invading stage of the parasite. We used a monoclonal antibody as well as antibodies from volunteers who had received an experimental vaccine. In mice, we observed that mice that were deficient in a critical complement protein C3, always had lower parasitemia than mice that were able to make this protein. In addition, whenever we gave mice antibodies that targeted the parasite, the usual result was that the parasitemia was enhanced."

Collectively, the study results demonstrated the ability of merozoites to invade red blood cells by exploiting both anti-malaria antibodies and activation of the complement-mediated pathway. Such results strongly suggest that the anti-malaria vaccines developed and tested to date have failed and may do more harm than good by paradoxically enhancing red blood cell infiltration by merozoites.

In order to place his team's study results into context, Dr. Stoute told Contagion that, "These results go against the dogma that complement activation always protects the host and hinders the pathogen." He also noted that although activation of the complement system has been shown to aid other pathogens in gaining access to the interior of red blood cells, the study conducted by his team was the first time to demonstrate this phenomenon in malaria. Regarding the broader significance of his team's findings, Dr. Stoute told Contagion that, "The results have important implications for malaria vaccine development because most vaccines rely on stimulating antibodies and complement activation to kill the pathogen. If malaria can indeed use complement activation for its own advantage, we may need to think of new strategies to develop a vaccine that blocks red cell invasion."

William Perlman, PhD, CMPP is a former research scientist currently working as a medical/scientific content development specialist. He earned his BA in Psychology from Johns Hopkins University, his PhD in Neuroscience at UCLA, and completed three years of postdoctoral fellowship in the Neuropathology Section of the Clinical Brain Disorders Branch of the National Institute of Mental Health.


  1. Biryukov S, Angov E, Landmesser ME, Spring MD, Ockenhouse CF, Stoute JA. Complement and Antibody-mediated Enhancement of Red Blood Cell Invasion and Growth of Malaria Parasites, EBioMedicine (2016),
  2. Murray CJ, Rosenfeld LC, Lim SS, et al. Global malaria mortality between 1980 and 2010: a systematic analysis. Lancet 2012;379,413—431.
  3. World Health Organization, 2013. World Malaria Report 2013 (Geneva).