A vaccine for malaria elimination?

Editor’s note: This blog post was recently revised and includes updates from its original posting in September 2016.

In a lab near Washington, DC, 160 volunteers are preparing to be bitten by malaria-infected mosquitoes in a follow-up to an intriguing study done 20 years ago.

In 1996, seven volunteers strapped paper cups filled with mosquitoes to their arms after they received three doses of one of the first attempts at a malaria vaccine. The result was thrilling—six out of seven were protected. That’s 86 percent efficacy.

At the time, we assumed it was a chance finding; however, data recently published in the Journal of Infectious Diseases (JID) suggest otherwise. This new human challenge trial—held at the same location as the first—and another study just launched in Thailand, will help us answer important questions about whether and how the vaccine, with its unconventional regimen, could accelerate malaria elimination.

As vaccine developers, we’re always trying to create a better vaccine that protects children and communities from disease. It took PATH, GSK, and our other partners 30 years to develop RTS,S, the first malaria vaccine candidate to receive a positive scientific opinion from regulators, as well as a recommendation from the World Health Organization (WHO) for pilot implementation.

Young children in sub-Saharan Africa bear the greatest burden of this disease, which kills more than 400,000 people annually. The current regimen of RTS,S has been recommended for pediatric use in children ages 5 to 17 months at first vaccination, which is an important first step for reducing childhood disease. RTS,S will be administered in selected areas of three countries in Africa—Ghana, Kenya, and Malawi—starting in 2018.

We continue to learn from and improve this vaccine. And the data from that initial RTS,S challenge study held at the Walter Reed Army Institute of Research (WRAIR) two decades ago intrigued us. At the time, the very high level of protection observed was assumed to be a chance finding associated with the small size of the study.

But was it?

There were two significant differences between that first study and the ones that followed. The vaccination regimen that was advanced to later-stage testing better fit within the standard immunization schedule for children in sub-Saharan Africa: three identical doses of the vaccine were given according to a 0-, 1-, 2-month schedule.

In the 1995 trial, two volunteers experienced local reactions following vaccination that required more detailed review by the scientists conducting the study. By the time these reactions were fully assessed and the US Food and Drug Administration gave the study a green light, researchers decided to proceed cautiously and reduce the third vaccine dose to one-fifth of the initial dose and to give it six months (instead of one month) after the second dose.

Afterward, the researchers determined that the standard schedule of three full doses given at one-month intervals, in line with the national immunizations already in place, was most appropriate to use in subsequent trials. The study that showed 86 percent efficacy was never repeated—until recently.

In 2014, WRAIR repeated the study from 20 years ago with support from PATH’s Malaria Vaccine Initiative and GSK. In this small trial, one group of adults received three doses of RTS,S using the standard 0-, 1-, 2-month regimen, while another received the alternate regimen from the 1995 trial, which included a third, fractional dose given seven months after the first dose.

It showed that the result in 1995 might not have been a chance finding after all: the delayed fractional dose regimen protected 26 out of 30 study volunteers from malaria. That’s 87 percent efficacy.

While the effect declined to 40 percent after seven months, a fractional fourth dose boosted the efficacy back up to 90 percent. Further, people who weren’t protected by the first round of vaccination were protected after given this fourth dose.

The finding is exciting on two levels: its implications for vaccine development in general and its potential to both help prevent and eliminate malaria so more children can grow up healthy and achieve their full potential.

“Fractional dosing,” also known as “dose sparing,” has been used to make vaccines go further when they’re in short supply. This is potentially promising evidence that less vaccine may actually be more effective. The finding makes sense when you consider newer understandings of the human immune system; by reducing the dose, we may be creating a greater level of “competition” among the cells that respond to the vaccine, thereby preferentially activating the most potent ones.

We are confident that if these results can be replicated in the field, this modified regimen of RTS,S could both protect children from the disease and help drive down transmission of the malaria parasite to accelerate elimination efforts.

Fighting the resourceful, adaptable malaria parasite requires an innovative arsenal of tools. Find out how PATH is accelerating progress against malaria in The PATH Innovation Pipeline for Malaria report.

Elimination requires preventing everyone from becoming infected, including those who don’t show symptoms. To use a vaccine for elimination, it needs to provide a relatively high level of protection and be used in mass immunization campaigns, similar to the Meningitis A campaigns in sub-Saharan Africa.

Our goal is to advance the most promising methods to tackle this stubborn disease. Any malaria vaccine will have to be used as part of a suite of interventions. But if we can replicate the findings in larger field trials, this vaccine approach could have the potential to be an elimination accelerator.

The results published in JID are exciting, but early, and the trial involved relatively small numbers of subjects. There are still many questions to answer.

Will the findings hold up in the real world? Was it the fractional dose, the delay in the third dose, or both that made the difference? There’s good evidence pointing to the fractional dose being the key factor, but we need more proof. And while a fractional dose will lower costs, the unusual immunization schedule will be challenging, logistically. Is it possible to simplify the regimen?

To answer these questions, we’re partnering with GSK and WRAIR on the largest malaria challenge study ever, in order to further refine the fractional dose approach. In parallel, we’re planning field studies in two African countries to see if the results achieved in a research institute in the United States can be replicated in adults and young children in African countries where malaria is endemic.

Finally, we’re exploring the possibility of using this modified RTS,S regimen to help eliminate malaria in Southeast Asia, where drug-resistant malaria parasites are emerging. In partnership with the Mahidol Oxford Tropical Medicine Research Unit, we have initiated the first-ever study of RTS,S in Asia, to determine whether administering the vaccine with antimalarial drugs will affect its ability to create an immune response.

It will be several years before we have results. Meanwhile, the WHO; ministries of health in Kenya, Ghana, and Malawi; GSK; and PATH are planning pilot implementation of the pediatric version of RTS,S. At least 360,000 children—who face the risk of malaria every day—will receive the vaccine through this program. Unquestionably we need to protect as many children as we can, as soon as we can, while we continue to pursue our long-term goal of a world without malaria.