How the first malaria vaccine cleared the way for a second

“Advances in science are usually incremental,” says Sir Brian Greenwood, a renowned malaria researcher at the London School of Hygiene & Tropical Medicine. “As scientists, we stand on the shoulders of those who have come before us.”

The story of the world’s first two malaria vaccines—RTS,S and R21—follows in this tradition. RTS,S, the first malaria vaccine, was created in 1987 after more than a decade of research and development. R21, the second malaria vaccine, was created in 2012. The RTS,S vaccine received World Health Organization (WHO) recommendation in 2021 and the R21 vaccine received WHO recommendation in 2023.

Efforts to develop a malaria vaccine bore fruit in the early 1970s, with the work of Ruth and Victor Nussenzweig, who identified the protein that is the basis of the RTS,S and R21 vaccines. Both vaccines also use powerful adjuvants that include an ingredient—QS-21—derived from the bark of the Quillaja saponaria Molina tree.

WHO summarized the similarities between the two vaccines in its updated recommendation of malaria vaccines in October 2023, stating that they were “similar in construct, mechanism of action, target population, and delivery strategy.”

These factors were among the evidence that supported the inclusion of R21 in WHO’s recommendation of vaccines against malaria for use in children.

But what else made it possible for the R21 vaccine to advance through clinical development and policy review in a fraction of the time it took for RTS,S?

The R21 clinical trials relied on the physical infrastructure and scientific and operational capacity that were strengthened during the clinical development of RTS,S, as well as the experience of the scientists involved.

“Thanks to the RTS,S trial, we were able to set up the facility we have now,” notes Prof. Halidou Tinto, who established the Clinical Research Unit of Nanoro at the Institut de Recherche en Sciences de la Santé in Burkina Faso. Prof. Tinto also served as one of the principal investigators (PIs) for the RTS,S Phase 3 trial and plays a similar role for R21.

“Thanks to the RTS,S experience,” Prof. Tinto explains, “we learned how to set up a Phase 3 trial and to assemble the team to conduct the trial. This made it easy to conduct the R21 trials, as we had the necessary scientific and operational capacity.”

This was also true for other research centers.

“The RTS,S Phase 3 trial design included methodology and operating procedures that established a new level of competency and rigor in the laboratory, with both internal and external quality assurance, continuous monitoring of individuals’ expertise, and retraining exercises if expertise waned. This rigor became expected for all subsequent trials,” says Dr. Mary Hamel, who was the PI at the trial site in Siaya, Kenya, which was then part of the Kenya Medical Research Institute and US Centers for Disease Control and Prevention (CDC) Public Health and Research Collaboration.

Dr. Hamel, who now leads the malaria vaccines program at WHO, continues, “As part of the trial, infrastructure at the district hospital was improved, with [the] delivery of an X-ray machine, laboratory equipment, and associated supplies, as well as ongoing training on how to use the equipment and interpret the results, so that children could be diagnosed correctly and treated appropriately. The changes were so impactful that the Hospital Medical Superintendent, seizing the opportunity to build lasting capacity, initiated a medical internship program that continues to this day.”

In addition to physical infrastructure, PATH, GSK, and scientists at the research centers developed a successful and collaborative process for advancing a vaccine through a Phase 3 program in Africa.

“Together, we built up the infrastructure and know-how to perform solid regulatory trials,” says Joe Cohen, co-inventor of the RTS,S vaccine and former head of the malaria vaccine program at GSK.

These trials needed to generate results of sufficient quality to pass muster with the most stringent regulatory authorities. When it came time to advance a second malaria vaccine, the R21 vaccine could leverage both the infrastructure and the design of the existing clinical development plan.

“We paved the way for a second malaria vaccine—which I’m very happy to see, given the tremendous demand,” says Cohen.

Throughout the RTS,S research and development process, participating scientists prioritized collaboration and knowledge sharing. This strengthened their capacity to conduct high-quality clinical research and set a helpful precedent for ongoing, high-quality research for R21.

“While the major funding decisions were made by PATH and GSK, the running of the trial, as well as the design, standardization of clinical protocols, etcetera, was led by the Clinical Trials Partnership Committee, or CTPC,” said Prof. Greenwood. “This was unique and unlike what was usually done by pharmaceutical companies. This was a partnership.”

At its height, the CTPC involved around 140 clinicians and other scientists.

“The CTPC was a model for cross-institutional cooperation,” says Dr. Larry Slutsker, who was the director of the US CDC malaria program when RTS,S was in clinical development. Dr. Slutsker later served as the director of PATH’s malaria program and is now an independent consultant. “We were able to share lessons, and there was an excitement born of knowing that this would help all of us develop expertise and know-how,” he says.

Ashley Birkett, who leads malaria vaccine development at PATH, notes that the simplified design of the Phase 3 trial of R21 was made possible by what had been learned through—and since—the Phase 3 trial of RTS,S.

Indeed, thanks to these learnings, the R21 team was able to design “swift, very trim studies,” according to Dr. Patricia Njuguna, who served as a co-PI on the RTS,S Phase 3 trial at the Kilifi, Kenya, research center and, following several years at WHO, now serves as a Senior Medical Officer at PATH.

For example, data on severe malaria can be collected in post-approval studies rather than during Phase 3 trials.

“Requiring a malaria vaccine to show efficacy against severe malaria increases the size of the trial dramatically, and thus the cost,” says Dr. Hamel.

R21 also followed the policy pathway for malaria vaccines that was established for RTS,S.

“The process for how a malaria vaccine would be reviewed at WHO—the advisory bodies to involve, the communication process along the way—was less clear at the beginning,” says Dr. Slutsker, referring to WHO’s first review of RTS,S in 2015, which resulted in the recommendation for large-scale pilot implementation. “By the end of the process, following the review of RTS,S in 2021, the process for R21 was both clear and straightforward.”

Over many years of clinical trials and pilot evaluations, RTS,S generated a significant and comprehensive body of evidence. When it came time for WHO to review R21, the committee was able to leverage this existing evidence rather than requiring R21 trials to answer all the same questions that RTS,S trials had already addressed. The many similarities between the two vaccines meant that evidence from RTS,S could be used in place of direct evidence for R21 trials.

“If RTS,S had not been recommended, it could have been that R21 would not have gone forward,” says Dr. Hamel. “Instead, R21 has been able to benefit from the enthusiasm for malaria vaccination generated by the RTS,S pilots, as well as from the financial commitments made by the international community. So now we have two vaccines to help protect young children against malaria!”

Returning to the science behind the invention, Prof. Tinto says, “RTS,S demonstrated for the first time that it was possible to make a vaccine against a parasite.” He continues, “You might call it the ‘grandfather vaccine.’ R21 built on RTS,S by changing how the protein is synthesized. R21 and vaccine candidates still in development have all benefited from the investments in physical, human, and health systems infrastructure made for RTS,S.”

Dr. Slutsker states, “With RTS,S, we see the impact of a strong partnership among the public health community, private sector, and nonprofits that delivered the world’s first malaria vaccine—and helped make it possible to deliver a second.”