The first round of results from a large-scale phase 3 clinical trial show that RTS,S/AS01, a vaccine targeted against Plasmodium falciparum, cut the overall incidence of malaria by half in 6,000 closely monitored toddlers. This finding confirms the efficacy of RTS,S/AS01 seen in earlier, smaller trials — not near the 90% of most viral and bacterial vaccines, but malaria parasites are far more complex pathogens and RTS,S/AS01 is a first-generation vaccine.
Joe Cohen, co-inventor of RTS,S/AS01 and for many years leader of the malaria vaccine project at GlaxoSmithKline (GSK) in Rixensart, Belgium, is understandably “thrilled” by the initial trial results, saying that they “show, for the first time, that a malaria vaccine can provide significant benefit to children living in malaria-infested regions in Africa, a real-world setting.” The entire study, underway at 11 sites in seven African countries, has enrolled 15,460 children in two age categories; 6 to 12 week infants and 5 to 17 month toddlers.
Malaria will not be vanquished by vaccine alone
The 56% protection provided by RTS,S/AS01 against all episodes of P. falciparum malaria at 12-month follow up in toddlers who had received all three immunizations was at the upper end of expectations. However a 35% reduction in severe malaria by RTS,S/AS01, among both infants and toddlers, was slightly less than anticipated. Thus, Nicholas J. White, a tropical medicine expert at Mahidol University in Bangkok Thailand, who was not part of the vaccine study team, cautions that “This partially effective vaccine is not the sole solution to the control and elimination of malaria,” and urges that, when deployed, it should be added to interventions such as insecticides and insecticide-treated bed nets as well as artemisinin-combination treatments. Nonetheless, he adds, “while we still need more information on how long protection lasts, we do seem to have the first effective vaccine against a parasitic disease in humans.”
Safety profile of RTS,S/AS01 good despite two surprises
The very good news is that the new malaria vaccine appears to be relatively safe. However, “trials often throw up unexpected findings,” according to White. “In this one there were significantly more instances of meningitis among children immunized with RTS,S/AS01,than those vaccinated with the rabies comparator vaccine. “This could be chance,” he says, “but it cannot be ignored.” On the other hand, the increased risk of fevers and seizures among recipients of the malaria vaccination looks real and might reflect the vaccine’s extreme immunogenicity.”
A hybrid construct that keeps P. falciparum from invading the liver
RTS,S/AS01 is a hybrid molecule constructed with engineered surface protein sequences from P. falciparum and fused to a surface antigen from a hepatitis B vaccine (HBsAg). The immune response it triggers keeps the parasite from colonizing the liver, where it would normally replicate for a week before invading the blood stream and entering red blood cells. GSK is currently collaborating with Crucell in Leiden, the Netherlands, on a second-generation version of RTS,S/AS01 using an adenoviral vector for more targeted antigen delivery.
WHO anticipates use of RTS,S/AS01 in some African countries by 2015
The World Health Organization (WHO) emphasizes that infants aged 5-12 weeks are the vaccine development partnership’s stated target population, and the efficacy in this age group is not yet known. White adds that “Critical efficacy results in this subgroup won’t be reported for another year and even then only short-term data will be available; this will be insufficient to assess the public health role of RTS,S/AS01.” Nonetheless, malaria is such a devastating disease that when the trial 3 data are in and efficacy verified in a larger population, WHO indicates it could recommend the vaccine for use in some African countries as early as 2015.
It takes time and money to develop a vaccine
In the GSK vaccine pipeline since 1987, RTS,S/AS01 was ultimately developed in partnership with the Program for Appropriate Technology in Health (PATH) Malaria Vaccine Initiative and the trials supported with a $200 million grant from Bill and Melinda Gates Foundation. Peter Hotez, President of the American Society of Tropical Medicine and Hygiene (ASTMH), calls RTS,S/AS01,“a true testimony to perseverance in public health, it doesn’t get any more important than this,” adding that progress on the malaria vaccine “underscores the importance of a long-term investment in research.”
Because price will be an issue, GSK, which has already invested more than $300 million in RTS,S/AS01, pledges to keep it as low as possible by just covering its manufacturing costs and adding a small return of about 5% which will be invested in future vaccine research.
Nicholas J. White, GlaxoSmithKline Press office.
NEJM. First Results of Phase 3 Trial of RTS, S/AS01. Malaria Vaccine in African Children. 10.1056/NEJMoa1102287. October 18, 2011. Accessed November 14, 2011.
White, Nicholas J. A. A Vaccine for Malaria. 10.1056/NEJMe1111777. October 18, 2011. Accessed November 14, 2o11.
Johns Hopkins scientists discuss their malaria research at the New York Academy of Sciences. November 16, 2011.
World Health Organization. Malaria Initiative for Vaccine Research. Accessed November 14, 2011.
Decoding Science. One article at a time.