Why we didn’t get a malaria vaccine sooner

It’s a long history, but here are a few quotes from the article:

Even today, parasites are seen as bad luck in vaccinology. No other vaccine has yet been developed for a parasite that causes disease in humans – although several have been made for parasitic diseases that affect livestock and pets.

This is because the complexity of parasites leads to several difficult, though not insurmountable, challenges for scientists: finding a suitable animal model, culturing the parasite in the lab, and identifying and refining the ingredients needed for a vaccine.

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Only in 1948 was a rodent model for malaria finally discovered.

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Unfortunately it was not a perfect model, because the Anopheles dureni mosquito was fragile and difficult to breed in the lab. Other researchers abroad were unable to see it transmit the Plasmodium parasite and were limited to studying only the initial stages of the parasite – until 1964, 16 years later.

In the meantime, a major breakthrough had shaken up the field: the pesticide DDT.

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A major premise of the WHO’s program was that existing tools were sufficient, and success depended primarily on execution. So field scientists were recruited to become its operators and managers, and largely withdrew from their research. All countries were instructed to strictly follow detailed, standardized manuals of operation. Research funding by the WHO was limited; in the US, now free of malaria, research funding also contracted swiftly.

In 1956, the year after the eradication program’s launch, the United States became its biggest funder. The ‘conquest against tropical diseases’, it was argued by the US Secretary of State George Marshall and other officials, would have great economic benefits for agricultural productivity and international trade.

The global eradication program led to a great decline in malaria prevalence, to the point of elimination in several countries including Cyprus, Hungary, Spain, Taiwan, and Jamaica.

But the program’s greatest weapon – DDT – was gradually losing its strength, as insect resistance to it continued to evolve and spread further.

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In 1963, America ended its contributions to the WHO’s Malaria Special Account, which had made up more than 85 percent of the total funding. Part of the WHO’s general budget was reallocated to bridge the gap, but the challenges of eradication continued to grow.

Local malaria control measures faced funding shortages, disruptions, withdrawals, and in several cases just complacency. The disease remained a large burden in much of the world.

It was around this time, in the early 1960s, that the answer to a more practical rodent model finally emerged – which would allow researchers to carefully test new drugs and vaccines.

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[T]he same step could have been sped up in multiple ways: through closer attention to the early findings; or with more resources and researchers working on the problem; or through pure chance, by stumbling upon a more practical wild parasite first.

Nevertheless, work on a vaccine could now really get going.

By this time, the US government was eager to renew malaria research, in order to protect troops fighting in the Vietnam War, who encountered drug-resistant malaria. The US army set up major research programs on new antimalarial treatments and potential vaccines.

And in 1967, the WHO called for a re-examination to the eradication strategy, switching focus from eradication to control. Across the 1970s, massive malaria epidemics affected South Asia and Turkey, and threatened resurgences elsewhere.

Altogether, organizations turned again to funding malaria control and R&D that could pay off in the long-term.

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In a 1997 human challenge trial, this RTS,S vaccine protected six out of seven of the volunteers. Although it was only a small pilot trial, it appeared to be far more effective than any other formulation so far.

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The results were promising. The researchers found it was broadly safe and reduced the chances of infection by 34 percent over four months.

Brian Greenwood, one of the researchers who led the trial, described the results to Undark magazine. ‘That was really the start of RTS,S’ he explained. But in his view, people’s interest in the vaccine was primarily about intellectual curiosity. ‘I don’t think there was any sort of push. It was done by people who were more academics and interested in the immunology,’ he said. ‘It wasn’t seen as a public health issue.’

But while the RTS,S vaccine showed promise, it was also far from ideal. Its efficacy began high but appeared to decline after a few months. Even after three doses, its efficacy was only 30–40 percent, averaged over the next four months.

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That next step would be trials in children, who make up the majority of deaths from the disease. The situation for GSK wasn’t expected to be financially rewarding: they would eventually invest hundreds of millions of dollars in funding clinical trials for it – but even if it was approved, the market would be poor countries, and GSK committed to offer it at a not-for-profit price.

Despite the risks, GSK gave the green light to the vaccine – but only if Ballou and his colleagues could find additional funding for the project. By this time, long after the end of the Vietnam War, the US army was no longer interested in funding the vaccine – not believing it would be worthwhile or effective enough to protect military personnel.

Eventually, the team found their additional funding from the new Malaria Vaccine Initiative at PATH, which had been recently established after a grant from the Gates Foundation.

Yet, because no strong ‘correlate of protection’ had been found (that is, there was no immunological signal that predicted who had developed protection), it was difficult to demonstrate that the findings could be extrapolated from a single trial.14 So, to gather evidence that it was broadly effective, the researchers were to run field trials in different regions, and at a range of different dosings.

And because of worries of potential side effects, the trials ran sequentially down age groups: the vaccine was first tested in the oldest children (6–11 year olds), then in younger children (1–4 year olds), and finally in infants under one year old.

All in all, this meant the trials were much longer and more expensive than typical vaccine trials – and each part of the logistic process was hampered by funding struggles and shortfalls.

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In July of 2015, the European Medicines Agency gave the malaria vaccine the green light, stating its safety profile was acceptable – which was a prerequisite for it to be approved by the WHO, whose decisions are used to support countries without strong regulatory bodies and recommend it for international funding.17

But when the results reached the WHO, the vaccine was unexpectedly held back. The WHO recommended it only for children aged 5 to 17 months of age, and asked for further testing, pilot studies and follow-ups before it could be rolled out more widely.

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The WHO explained that these cases were not actually believed to be related to the vaccine itself: they weren’t related to the timing of the doses, only occurred in patients in two of the trial sites, and included different types of meningitis. Nevertheless, they argued, the disease needed to be ruled out as a potential side effect with more pilot studies.

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The vaccine was finally endorsed by the WHO in October 2021 for broad use in children.

In sum, the RTS,S vaccine spent 23 years in 25 trials and pilot studies, before it was licensed.

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The development of malaria vaccines was stalled over and over again: by the focus on the eradication campaign and suspension of research; then by the lack of funding and urgency to address what had become a distant problem for the West; then by the complexity, length and cost of running the clinical trials; and then by the heightened and shifting regulatory requirements that added years of additional funding struggles and studies.