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SEATTLE -- A much-anticipated malaria vaccine candidate demonstrated an overall efficacy of 75% in young children, and with no serious safety concerns, results from a phase III trial spanning four African nations showed.

In modified per-protocol analyses, the R21/Matrix-M vaccine had an adjusted efficacy against a first clinical malaria episode of 75% (95% CI 71-79, P<0.001) when administered in regions where transmission of the mosquito-borne disease is highly seasonal and 73% (95% CI 65-80, P<0.001) at so-called standard sites, where transmission patterns are spread out during the year, reported Adrian Hill, FRS, of the University of Oxford in England.

"This is what people were really interested in: Would we see as good efficacy at the standard sites as we did in the seasonal sites?" said Hill during his presentation at the annual American Society of Tropical Medicine & Hygiene (ASTMH) meeting.

"The reason you might expect seasonal to be better, of course, is that the malaria comes very, very soon after you're vaccinated, when the antibody titers are at their peak," he explained.

Across all sites, the vaccine efficacy against a severe malaria episode was 74% (95% CI 11-92, P=0.032) versus the placebo shot.

When stratified by age, younger children in the trial seemed to get better efficacy, said Hill: 80% for kids ages 5 to 17 months and 71% for those ages 18 to 36 months (P=0.23 for interaction). "Lots of vaccines seem to perform well in people about 1 year of age," he said.

R21 and the RTS,S/AS01 vaccine approved by the World Health Organization (WHO) last year both have a similar immunogen that targets Plasmodium falciparum, the parasite that causes malaria in humans. But R21 is adjuvanted with Matrix-M in order to enhance the immune response. Another difference is R21/Matrix-M was tested in older children as well, those ages 18 to 36 months.

"We broadly thought it might be valuable to get a license for a vaccine to give to kids older in age," said Hill.

During a Q&A session discussing the findings, Hill pointed out that R21/Matrix-M's efficacy for children 5 to 17 months of age appeared superior in non-seasonal sites when compared with the phase III trial data of RTS,S/AS01 (83% vs 51%). In seasonal sites, differences were less apparent (89% vs 73%, respectively).

While Hill said he was eager to see the R21/Matrix-M vaccine get to where it's needed, he expects delays. "We're up against a track record of vaccine pre-qualification that takes years," he said, but for every quarter of year the vaccine is delayed "that's 200,000 lives," he said.

In a previous session at ASTMH, Eliane Furrer, of the WHO, explained that over the next 3 years, about 18 million doses of RTS,S/AS01 are going to be available for the 25 million children born each year across more than two dozen African countries where malaria poses a threat.

The WHO has been tasked with coming up with a plan on how to dole out the limited doses, which is only enough supply for about three to four medium-sized countries, said Furrer. "I'd like to invite you, just for 5 seconds, to think about how you would do this."

Many attending the R21/Matrix-M presentation were excited by the prospects of a second vaccine in the arsenal. Irene Yameogo Ngendakumana, MD, of the U.S. President's Malaria Initiative in Burkina Faso, told MedPage Today "the results are impressive, it would be wonderful to have another vaccine in the pipeline."

In Burkina Faso, "we have more than 4,000 children dying of malaria every year," she said. "Having another vaccine would increase the supply. The demand is here -- we are hopeful."

Hill suggested that within a year of licensure, suppliers of R21/Matrix-M could scale up production to 180 million doses per year.

Others were more skeptical.

"R21 is an incremental improvement to RTS,S," said Stefan Kappe, PhD, of the University of Washington in Seattle. "Neither are proven to protect against clinical malaria -- it all remains to be seen."

Study Details

To evaluate the vaccine, researchers enrolled 4,800 children ages 5 to 36 months across Kenya, Tanzania, Mali, and Burkina Faso, including 2,400 participants at three standard sites with perennial malaria transmission and 2,400 participants at two sites with seasonal transmission.

Participants were randomized in a 2:1 fashion. In the study arm, children received three primary doses of R21/Matrix-M (5 µg of R21 with 50 µg of Matrix-M adjuvant), with each dose given 1 month apart, and then a booster at 1 year. The control group received a rabies vaccine as placebo. All standard malaria preventions remained in place.

The primary endpoint was efficacy at 12 months following the initial series of primary vaccinations. The researchers reported that the modified per-protocol analysis population had a 3- to 6-week interval between dose one and two, and a 3- to 12-week interval between dose two and three.

Given the duration of follow-up for the standard sites (298 days), Hill noted that the data should be considered preliminary, though the numbers are "unlikely" to change significantly, he said. The data from the seasonal sites included 344 days of follow-up.

Common adverse events between the treatment and control groups, respectively, included pain (15% vs 7.8%) and fever (44.9% vs 20.7%). Pain (11.9%) and fever (26.8%) were less frequent with the R21/Matrix-M booster shots.

There were 107 serious adverse events in 101 participants, but none were deemed related to vaccine. Adverse events of special interest included 10 febrile convulsions (three within a week of vaccination), two cases of bacterial meningitis, and one case of cerebral malaria.

All data were adjusted for sex, age, and chemoprevention, and also factored in the use of malaria nets at day 70, which was 2 weeks following primary vaccination.

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