A vaccine for malaria elimination? A chance finding from 20 years ago may have the potential to transform vaccinology.

Posted 14 November 2016

by Dr. Ashley Birkett 

In a lab near Washington, DC, seven volunteers strapped paper cups filled with malaria-infected mosquitoes to their arms. They’d 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.

That was 20 years ago.

Now, data published in the Journal of Infectious Diseases appear to challenge our assumptions that the results of that trial were a chance finding. This new data could have the potential to impact not only malaria, but vaccine development.

A chance finding?

As vaccine developers, we’re always trying to develop 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 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, which is an important step for reducing childhood disease. But not the last.

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?

Adjustments in the dosing schedule

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 full 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 study received a green light from the US Food and Drug Administration to proceed, it was decided to 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, which was in line with the national immunizations already in place, was most appropriate to be used in the trials that followed. The study that showed 86 percent efficacy was never repeated—until now.

Repeat performance

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 may not have been a chance finding after all: 26 out of 30 study volunteers were protected from malaria by the delayed fractional dose regimen. 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 they received this fourth dose.

More is not always better

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.

Tackling a stubborn disease

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.

Elimination requires preventing everyone from becoming infected, including those who carry the parasite but 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 our findings can be replicated in larger field trials, this vaccine approach could have the potential to be an elimination accelerator.

Time and more studies will tell

The new results are exciting, but early, and the trial was small. 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 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 we achieved in a research institute in the United States can be replicated in adults and young children in Africa. Both these studies should begin in 2017.

However, it will be several years before we have results, and there is no guarantee of what those results will look like. We still need pilot implementation of the pediatric RTS,S to move forward. That program will involve nearly 750,000 children who face the risk of malaria every day. 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.