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WHAT'S NEW THIS SATURDAY: FOUR YEAR EFFICACY OF RTS,S AND ITS INTERACTION WITH MALARIA EXPOSURE

Monday, 18th of March 2013

• FOUR-YEAR EFFICACY OF RTS,S/AS01E AND ITS INTERACTION WITH MALARIA EXPOSURE

Ally Olotu, M.B., Ch.B., Gregory Fegan, Ph.D., Juliana Wambua, B.Sc., George Nyangweso, B.Sc., Ken O. Awuondo, H.N.D., Amanda Leach, M.R.C.P.C.H., Marc Lievens, M.Sc., Didier Leboulleux, M.D., Patricia Njuguna, M.B., Ch.B., Norbert Peshu, M.B., Ch.B., Kevin Marsh, F.R.C.P., and Philip Bejon, Ph.D.

N Engl J Med 2013; 368:1111-1120March 21, 2013DOI: 10.1056/NEJMoa1207564

Abstract below; full text, with tables, is athttp://www.nejm.org/doi/full/10.1056/NEJMoa1207564#t=article

Methods

For 4 years, we followed children who had been randomly assigned, at 5 to 17 months of age, to receive three doses of RTS,S/AS01E vaccine (223 children) or rabies vaccine (224 controls). The end point was clinical malaria (temperature of ≥37.5°C and Plasmodium falciparum parasitemia density of >2500 parasites per cubic millimeter). Each child's exposure to malaria was estimated with the use of the distance-weighted local prevalence of malaria.

Results

Over a period of 4 years, 118 of 223 children who received the RTS,S/AS01E vaccine and 138 of 224 of the controls had at least 1 episode of clinical malaria. Vaccine efficacies in the intention-to-treat and per-protocol analyses were 29.9% (95% confidence interval [CI], 10.3 to 45.3; P=0.005) and 32.1% (95% CI, 11.6 to 47.8; P=0.004), respectively, calculated by Cox regression. Multiple episodes were common, with 551 and 618 malarial episodes in the RTS,S/AS01E and control groups, respectively; vaccine efficacies in the intention-to-treat and per-protocol analyses were 16.8% (95% CI, −8.6 to 36.3; P=0.18) and 24.3% (95% CI, 1.9 to 41.6; P=0.04), respectively, calculated by the Andersen–Gill extension of the Cox model. For every 100 vaccinated children, 65 cases of clinical malaria were averted. Vaccine efficacy declined over time (P=0.004) and with increasing exposure to malaria (P=0.001) in the per-protocol analysis. Vaccine efficacy was 43.6% (95% CI, 15.5 to 62.3) in the first year but was −0.4% (95% CI, −32.1 to 45.3) in the fourth year. Among children with a malaria-exposure index that was average or lower than average, the vaccine efficacy was 45.1% (95% CI, 11.3 to 66.0), but among children with a malaria-exposure index that was higher than average it was 15.9% (95% CI, −11.0 to 36.4).

Conclusions

The efficacy of RTS,S/AS01E vaccine over the 4-year period was 16.8%. Efficacy declined over time and with increasing malaria exposure. (Funded by the PATH Malaria Vaccine Initiative and Wellcome Trust; ClinicalTrials.gov number, NCT00872963.)

 

•   PROTECTION OFFERED BY GSK MALARIA VACCINE FADES OVER TIME 

By Kate Kelland and Gene Emery

LONDON/NEW YORK | Wed Mar 20, 2013 5:03pm EDT

(Reuters) - The effectiveness of an experimental malaria vaccine developed by GlaxoSmithKline wanes over time, with the shot protecting only 16.8 percent of children over four years, according to trial data.

The disappointing results for RTS,S - the world's first potential malaria vaccine - raise further questions about whether it can make a difference in the fight against the disease, a major cause of illness and death among children in sub-Saharan Africa.

Results from a separate trial last year showed the vaccine was only 30 percent effective in babies.

"The results are kind of disappointing because we'd all like to see a malaria vaccine that has closer to 80 percent or 100 percent efficacy," said Christopher Plowe, a malaria researcher at the University of Maryland School of Medicine in the United States, who was not involved in the RTS,S trial.

Published in the New England Journal of Medicine on Wednesday, the new data found that although RTS,S initially had a protection rate as high as 53 percent, after an average of eight months that effectiveness faded swiftly.

"It was a bit surprising to see the efficacy waned so significantly over time. In the fourth year, the vaccine did not show any protection," said Ally Olotu of the Kenya Medical Research Institute (KEMRI) Wellcome Trust Research Programme in Kenya, who led the follow-up study.

There is currently no vaccine that offers complete protection against malaria.

The disease is caused by a parasite carried in the saliva of mosquitoes and is endemic in more than 100 countries worldwide. According to the World Health Organization, malaria infected around 219 million people in 2010, killing some 660,000 of them.

Control measures such as insecticide-treated bednets, indoor spraying and anti-malaria drugs have helped cut malaria cases and deaths significantly in recent years, but drug resistance is growing and experts say an effective vaccine could be a vital tool in eradicating the disease.

MOST ADVANCED CANDIDATE

GSK's RTS,S is the most advanced candidate malaria vaccine in development and full data from final-stage trials involving more than 15,000 children are expected by the end of next year.

A spokeswoman for GSK said since Wednesday's results were from a small, mid-stage trial, they did not "provide definitive answers about the duration of protection or how the vaccine candidate works in different malaria transmission settings".

The British drugmaker is developing RTS,S for children in Africa and has said it does not plan to make any significant profit on the project if the vaccine gains marketing approval.

The study involved 447 children in Kilifi, Kenya, who had been part of a mid-stage, or phase II, trial to assess the safety and efficacy of RTS,S. Of the 447 children, 320 were able to be followed up for four years.

Phillip Bejon, a researcher at the KEMRI-Wellcome Trust programme who also worked on the study, said despite the falling efficacy "there is still a clear benefit to the vaccine".

"Many of the children (in Africa) will experience multiple episodes of clinical malaria infection, but overall we found that 65 cases of malaria were averted over the four-year period for every 100 children vaccinated," he said.

"We now need to look at whether offering a vaccine booster can sustain efficacy for longer."

The researchers also found, however, that children exposed to more malaria tended to see their protection against the disease fade faster. Olotu said it was not clear why, but one possible explanation might be that children normally get natural immunity to malaria as they are exposed to it.

"But if you have a malaria vaccine that prevents exposure in the first place, the children might be acquiring natural immunity at a much slower rate compared to children who are not getting the vaccine," Olotu said.

(Reporting by Kate Kelland in London and Gene Emery in New York; Editing by John Stonestreet)