Why did it take 35 years to get a malaria vaccine?

Why did it take 35 years to get a malaria vaccine? thumbnail

This article was originally featured on Undark.

When the World Health Organization approved a malaria vaccine for the first time in October 2021, it was widely hailed as a milestone. “This is a historic moment,” said WHO director-general Tedros Adhanom Ghebreyesus in a statement that month.

The vaccine–dubbed RTS,S–promises a 30 percent reduction in severe malaria in fully vaccinated children. In 2020, a research team estimated that each year, the vaccine could prevent between 3 and 10 million malaria cases, and save the lives of 14,000 to 51,000 small children, depending on how it’s implemented.

What those plaudits often failed to note, though, was that the core ingredient of the path-breaking vaccine was actually almost 35 years old–and that researchers have known since the late 1990s that the formula was probably somewhat effective at protecting against malaria.

At a time when Covid-19 vaccines were developed and authorized in less than one year, the delay for malaria raises a question: Why did a vaccine for a leading global killer take so long to arrive? Researchers involved in the development and approval of RTS,S believe the reason lies in the difficulties of developing a vaccine against a vexing parasite, as well as the lack of funding and urgency behind malaria research. This stifled the logistics of the research trials at each step.

The people who are affected with malaria are not Europeans, Australians or Africans,” said Ashley Birkett (director of the malaria vaccine initiative at PATH), a non-profit global healthcare organization. “Unfortunately, I believe we must accept that that is part the reason for the lackluster urgency in the community

Researchers had been searching for a malaria vaccine since the late 1960s. In 1980, they identified a protein that is abundant on the parasite’s surface, called circumsporozoite protein, and realized that a vaccine directed against this protein might grant immunity. After U.S. government researchers sequenced the gene for the protein in 1984, the military asked them to develop a malaria vaccine to protect troops overseas. The government then asked Smith, Kline & French, a precursor to GlaxoSmithKline, for assistance.

Experts recall that the work was difficult. Experts recall that the malaria parasite has a complex life cycle. It can go through at least three stages once it’s infected. A vaccine that is developed to combat a specific stage of the disease must be effective. It will not work if the parasite moves on to the next stage. It is not possible to use the basic tools that scientists have today to accelerate vaccine development.

More than a dozen vaccines based upon the circumsporozoite proteins failed. RTS,S was the exception. In the late 1980s and early 1990s, the team figured out various technical details, and a 1998 trial in Gambia, involving 250 men, found that the vaccine prevented 34 percent of infections.

” That was really the beginning of RTS,S,” said Brian Greenwood (infectious disease expert at London School of Hygiene and Tropical Medicine) who was involved with the Gambia trial.

Greenwood said that attention to the vaccine was driven more by intellectual curiosity than a sense medical urgency, at least for the wider public and not just the troops. “I don’t believe there was any kind of push. He said that it was done by people who were more interested in immunology and academics. It wasn’t a public health problem .”


People involved in the development of the vaccine told Undark that the promising shot was about run into a whole new set problems: the myriad tribulations that can come with testing a vaccine without a commercial market.

In 1999, Ripley Ballou, a vaccinologist who then worked at the Walter Reed Army Institute of Research, flew to Europe to meet with GSK executives. He recalled that he was still in the Army at that time and that he and his colleagues from GSK sat down to present their findings from the Gambia trial. “We had this glimmering of hope that came out of this study that said, ‘you know what, something’ and we think it was time to take it to a higher level,'” he said. The next step would be to test the vaccine in children, the group that would most benefit.

GSK was willing to move forward, provided that Ballou and his colleagues could raise additional funding from a partner organisation. GSK could not expect financial rewards if the project failed. The U.S. military was not interested in RTS.S because it wasn’t convinced that its effectiveness would be sufficient to protect troops.

Instead, the partner organization that funded this work was the Malaria Vaccine Initiative at PATH, which was established a year prior through a grant from Bill and Melinda Gates Foundation.

“Given the attitude towards vaccines globally, it was important to make sure that we ruled out any potential safety issues,” said Wongani Nyangulu.

As vaccine makers began to launch trials in Africa, they quickly realized that testing the vaccine would be difficult. Ballou said that there were many logistical problems. He recalled that he had to go to find a building without any interior, just a concrete shell. Then, he said, “We had to go and it would have to be turned into a laboratory.” “That took time, and that took money

These trials were also intended for young infants and small kids. Therefore, the Phase I and 2 trials, which looked at the shot’s safety, efficacy and safety, had to first be conducted in adults, then in children aged over 10, and finally in children under 10. Each age group was responsible for optimizing the dosage against side effects before moving on. “All that process took about 10 years,” said Greenwood.

The promising results from Phase II trials–in which infants saw a 65.9 percent reduction in the rate of infection compared to the control group in the months after the third dose–led to a large-scale Phase III trial, which did not begin until 2009. The trial design was difficult. Ballou stated that “Nobody had ever done an malaria vaccine trial at this size “.

The Phase III trials ran from 2009 to 2014 in seven sub-Saharan African countries. They enrolled over 15,000 children. Schuerman said that the results were encouraging and that GSK was preparing a manufacturing plant for the shot.

But in October 2015, a WHO review of the Phase III trial data found that the rate of meningitis was higher in the vaccinated group than the control and death was higher among girls who had received a vaccine, although whether it was linked to the shot wasn’t clear. The WHO requested a larger trial to address these issues and test the vaccine in a wider real-life setting. This announcement came out of the blue, said multiple scientists. Schuerman stated that the manufacturing side had to be shut down. He said that the vaccine team was again responsible for setting up clinical trials. This included funding, selecting countries to implement the trial, and hiring people to do it.

Today, most researchers agree that additional research was necessary. “Given the global attitude to vaccines, it was important that we ruled out potential safety issues,” stated Wongani Nyangulu (a Southern Malawian physician who oversees a phase IV study).

It took four years for the trial to be launched. Eventually, 900,000 children in Ghana, Malawi, and Kenya received the vaccine. After reviewing the results, the WHO recommended the vaccine for widespread use in areas of moderate to high malaria transmission in October 2021. In December, GAVI, the global agency that funds and distributes vaccines in poor countries, announced it would invest $155.7 million in an RTS,S rollout.

More than 20 years after the first promising trials, RTS,S was ready for widespread use.

By the time RTS,S was approved, vaccines for another global killer, Covid-19, had already been developed and authorized around the world–less than two years after the virus emerged.

Some researchers in sub-Saharan Africa have been frustrated by these apparent disparities. “If the same energy and resources were directed towards malaria vaccine development as has been the case for Covid-19, then malaria could be eradicated,” wrote Damaris Matoke-Muhia, a scientist at the Kenya Medical Research Institute, in an essay for the global development site SciDev.Net last August. (At the time, she noted, malaria was killing more people on the continent than Covid-19. )

Other African researchers have also noticed the discrepancy. Deus Ishengoma, a malaria expert at the National Institute for Medical Research in Tanzania, noted that, considering Covid, it would be “really bad if the world now closes their eyes for diseases like malaria.” The speed of development for the Covid-19 vaccine, he added, meant “we’ll never have a justification or excuse of not making a vaccine for malaria in the next 10 years.”

Other experts cautioned that comparing vaccines is not always fair. Birkett, the executive at PATH, stated that Covid is a much more suitable target for a vaccine. Birkett, the executive at PATH, stated that malaria was a much easier target for a vaccine. And antimalarial drugs and other tools have long helped offset the burden of malaria, said Birkett, so the vaccine wasn’t a priority in the same sense compared to Covid-19.

Experts said that the disparity is due to long-standing patterns of which deadly diseases get attention and which don’t. Ballou stated that this is the main problem when trying to develop a vaccine for which no one wants to pay.

Considering Covid, it would be “really bad if the world now closes their eyes for diseases like malaria,” said Deus Ishengoma.

Each step of development was plagued by funding problems, according to Birkett. Birkett stated that it was necessary to proceed sequentially, step-by-step, to generate data, raise money, and design the protocol. Experts worry that funding shortages could also hinder the rollout RTS,S. Ballou said that this is the greatest risk facing the vaccine program right now. Funds for malaria vaccine R&D–especially for clinical development–have been on a downward trend since 2017, and in 2020 dropped by $21 million, a 15 percent drop from the earlier year, according to Policy Cures Research, a global health think tank.

The development of RTS.S has opened the door to next-generation malaria vaccines. The University of Oxford’s R21 vaccine, which showed a promising 77 percent efficacy in Phase II trials, is probably next in line. Greenwood stated that they will be greatly benefited by the delivery system and regulators because everyone is familiar with it. Still, R21 might not be a game changer, as it’s based on the same underlying formula as RTS,S, said Birkett, and “all the data suggests, so far, it’s going to be very similar.”

In July 2021, BioNTech, a German biotech company which co-created the first mRNA Covid-19 vaccine, also announced plans to use the same technology to develop a malaria vaccine, with clinical trials planned for 2022.

The next round of vaccines, should they prove safe and more efficacious, should take far fewer than 35 years to come to market. Birkett stated, “I am very confident that we can go faster next “.

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