A pivotal test of malaria vaccine is set to begin. Can it live up to its promise?

Researchers are preparing to launch a pivotal test of an important malaria vaccine this month — one that global health leaders believe could eventually lead to big reductions in the number of cases and deaths worldwide.

Despite those high hopes, there are also concerns that the theoretical benefits of the vaccine, made by GSK, might not translate into the real world.

To see whether the vaccine lives up to its promise, the World Health Organization and partners have designed a sort of beta rollout of the vaccine, called RTS,S. Beginning April 23, Malawi is expected to start using the vaccine in its routine immunization programs for children. Ghana and Kenya will later do the same.

Over the next four years, the experiences of these countries will help the WHO determine if RTS,S can be effectively used, and whether it will deliver the nearly 40 percent decrease in malaria infections seen in an earlier Phase 3 clinical trial.

Gavi, a public-private partnership that subsidizes vaccine purchases for low income countries, is one of the funders of these pilot projects. CEO Dr. Seth Berkley said the fundamental question the work will ask is simple: “Is this vaccine practical for real-world use?”

A vaccine that resulted in a 40 percent reduction in infections would not be considered effective enough for a vaccine meant to protect against measles or chickenpox. But because malaria is such a huge health problem — there are roughly 200 million infections a year and about 445,000 deaths — and because existing tools to protect against it are both limited and imperfect, such a decline in infections would mark a big gain in the fight against the disease.

“This vaccine, which has pretty modest efficacy, could have quite a high impact, because children get malaria over and over,” explained Dr. Mary Hamel, who heads the WHO’s malaria vaccine implementation program.

Malaria is caused by a parasite transmitted through the bite of Anopheles mosquitoes. The problem is most acute in sub-Saharan Africa, though malaria is also present in some parts of South America and Asia.

Unlike measles, malaria is not a one-and-done disease. People can and are infected multiple times over a lifetime. A study in western Kenya found children there had an average of six bouts of malaria a year, Hamel said. “It’s a bad illness. The child is extremely sick.”

Some children who are infected go on to develop severe malaria, which can be fatal. Over time and many infections, people begin to develop some immunity to the parasites and the risk of severe infection falls.

Distribution of insecticide-treated bed nets, spraying of homes with long-lasting insecticides, and use of antimalarial drugs for years helped drive down the number of annual cases. But in the past couple of years the declines in malaria deaths have stalled, and the numbers of cases are actually rebounding, Hamel said.

“We’re also seeing the limit of where we can get with the tools we have. This is why another tool for malaria control is so important,” she said.

Enter RTS,S, which has been developed over 30 years and which is the first vaccine to offer even partial protection against malaria. It is also the first vaccine to protect against a parasite; most protect against bacteria or viruses.

The vaccine must be given in four doses; research has shown that if only three doses are given protection wanes very quickly. Ensuring that children are given all four doses could be challenging, in part because the timing of some of the doses — the exact schedule varies by country — do not coincide with when children typically get other immunizations or medical interventions. The worry is this: In remote and rural areas, will parents make extra trips to doctors to ensure their children are fully vaccinated?

(All of the proposed schedules require three doses at monthly intervals starting at about 5 or 6 months of age, with the last given 18 months or so after the first — around a child’s second birthday.)

Based on those concerns, two WHO expert panels — the Strategic Advisory Group of Experts on Immunization and the Malaria Policy Advisory Committee — jointly recommended the pilot implementation approach. That recommendation was made in the fall of 2015; it has taken the time since to select the pilot countries and have them take the steps needed to add a new vaccine to their immunization programs.

Gavi, the Global Fund to Fight AIDS, Tuberculosis and Malaria, and Unitaid are jointly funding the first phases of these pilot implementation projects, providing just under $50 million. In a recent news conference, Berkley said the aim is to vaccinate roughly 360,000 children a year in the three countries.

Modeling work estimates that if the vaccine works as well in the field as it did in the Phase 3 trial, one malaria death will be averted for every 200 children vaccinated, Berkley said.

Data amassed over the next two years may give an indication of where policy decisions could head, Hamel said.

The vaccine has not yet been licensed but has been authorized for use based on an evaluation by the European Medicines Agency — Europe’s equivalent of the Food and Drug Administration, she said. If asked, the EMA will at times study drugs and vaccines not destined for the European market, rending a positive or negative scientific opinion.

The pilot implementation programs have been designed to answer three critical questions: Is use of RTS,S feasible? Are there any safety concerns? What impact does it have on severe illness and mortality from malaria?

The safety question relates to the fact that there were more cases of meningitis and cerebral malaria in children who received the vaccine in the Phase 3 clinical trial than in children who were in the control arm and got another vaccination.

There is reason to think the finding isn’t real — that RTS,S did not cause these additional outcomes. But wider-scale use of the vaccine should answer this important question, said Dr. Pedro Alonso, director of WHO’s global malaria program.

“I think there’s a broad belief that these are chance findings, but of course we must take them seriously and be sure,” Alonso told STAT. “We need to be sure of the safety of the product.”

An earlier version of this story incorrectly described the malaria vaccine as “experimental.” It also incorrectly stated that Ghana would begin the test first.