Still searching for an effective malaria vaccine

Posted by Jamie Colbert • December 14th, 2012

In May, 1796, British physician Edward Jenner inoculated his gardener’s eight year-old son with fluid from a cowpox blister that he had extracted from the hand of a local milkmaid. Jenner hypothesized that exposure to cowpox would protect the child against the related disease of smallpox. He later injected the boy with smallpox and the boy did not develop any evidence of infection. Thus was born one of the first human vaccines.

By the late 19th century Louis Pasteur further perfected the technique of vaccination by modifying inoculums prior to vaccination so as to kill the infectious agent and prevent the possibility of transmitting live disease during the vaccination process.  Today we have vaccines for hepatitis, meningitis, influenza, pneumonia, measles, mumps, rubella, polio, rotavirus, and many more. Vaccination has prevented millions of human deaths from viral and bacterial infections over the past two centuries. However, until now there has never been a successful vaccine to prevent parasitic disease.

Malaria is an ideal target for the first parasitic disease vaccine. Despite years of medical progress, the global burden of malaria is staggering, with more than 200 million new cases and 600,000 deaths each year. Furthermore, we have evidence that the creation of a malaria vaccine may be scientifically feasible. Children living in malaria-endemic regions who are exposed repeatedly to the malaria parasite will generally develop immunity to severe infection. Furthermore, immunoglobulins harvested from such a malaria-immune individual can be transferred to a second malaria-naive person who will then display immunity as well.

Vaccine strategies have targeted three different stages of the malaria lifecycle. One approach is to target the sporozoites immediately upon entering the human host to prevent the parasite from establishing itself in the liver. A second strategy is to target the red blood cells which contain merozoites and to prevent the parasite from further multiplying within the human blood stream.  Finally, a vaccine that targeted the sexual gametocyte would not directly prevent infection of vaccinated hosts, but would reduce transmission to others by preventing the parasite from reproducing sexually within mosquitos.

This week’s NEJM contains a report of a phase 3 trial of a malaria vaccine that targets a malaria protein responsible for entry into the liver.  The RTS,S/AS01 vaccine, which was developed by GlaxoSmithKline and the PATH Malaria Vaccine Initiative with support from the Bill and Melinda Gates Foundation,  has been previously shown to have an effectiveness of 56% in preventing clinical malaria and an effectiveness of 47% in preventing severe malaria amongst children 5 to 17 months of age.  The new data published this week reports on the efficacy of this vaccine in preventing malaria amongst younger children aged 6 to 12 weeks at time of vaccination.

More than 6000 infants residing in seven countries in sub-Sarahan Africa participated in the trial. The infants were randomly assigned to receive the malaria vaccine or placebo along with their regular medical care and vaccinations. After 12 months of follow up, the incidence of clinical malaria was about 1 case for every three person years in the vaccine group while in the control group it was about one case for every two person years; this represents a calculated vaccine efficacy of just over 30%. Similar relative reductions occurred in preventing cases of severe malaria for a vaccine efficacy of just over 35%.

The lower vaccine efficacy against infants compared with older children is a disappointment not only to the drug developers but to public health officials throughout the regions where malaria is endemic.  Proposed explanations for the lower efficacy in infants include interference from maternal antibodies, inability of the newborn immune system to respond to the vaccine, and lack of prior exposure to malaria (one hypothesis suggests that older children benefited more from the vaccine because they were already primed through exposure to mosquito-borne malaria prior to receiving the vaccine).

According to NEJM Deputy Editor Lindsey Baden, M.D., “Malaria continues to be a major global public health challenge. We need to redouble our efforts to develop durable, scalable control efforts and the quest for an effective vaccine remains a critical element.”

While the results of this trial suggest that the RTS,S/AS01 malaria vaccine is not ready for primetime, the good news is that many more vaccines are currently under development and will be ready for experimental testing in the near future. Researchers remain hopeful that it is only a matter of time before the infectious disease community will conquer another milestone – the first vaccine to halt the spread of a pesky protozoan.

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