By Robert Fortner, special to Humanosphere

For this year’s World Malaria Day, April 25, the big news is mostly bad news.

An experimental malaria vaccine the Bill & Melinda Gates Foundation had long championed and that many had characterized as the ‘most promising’ such vaccine, a critical tool for moving us closer to Bill Gates’ goal of eradication, has shown disappointing results.

While the manufacturer, GlaxoSmithKline, and the Gates Foundation continue to argue that the test vaccine may still be useful, many say it’s time to go back to the drawing board – and, for now, to shift to an aggressive, new malaria-combatting strategy that doesn’t depend on having a highly effective vaccine.

The bad news comes in The Lancet, a final report on GSK’s vaccine known as the RTS,S vaccine confirming that its power to protect is insufficient to justify widespread use and that it declines fairly rapidly over time, dropping to just 28% in children and 18% in infants. The vaccine also was found to have protected against severe malaria less than previously reported.

Indeed, in one arm of the study, RTS,S actually increased the risk of severe malaria. Researchers conjectured that vaccination “might have reduced the natural acquisition of immunity obtained through repeated infections, making these children more susceptible when the vaccine effect waned.”

None of this should really come as a surprise (see our earlier reports here and here) except perhaps to those who chose to see essentially the same results found in several earlier clinical studies of RTS,S as ‘promising’ as opposed to, well, not very promising at all.

The Gates Foundation, which put the world on a course to eradicating malaria back in 2007, continues to see promise in RTS,S and recently invested more in vaccine research.

“The final data suggest that the vaccine could potentially have a public health benefit in higher-transmission settings,” the philanthropy said in a statement following the disappointing results reported in The Lancet.

“It is now the role of the European Medicines Agency and the World Health Organization to review the data and provide an opinion to GAVI, the Global Fund, and malaria-endemic countries on where and how the vaccine could be deployed as part of broader package of cost-effective treatment and prevention options.”

However, even before these sour findings were reported, the Gates Foundation had already switched to a new strategy that emphasizes drug-based eradication strategy

Five years ago, many in the malaria field believed eradication would be “impossible” without an effective vaccine. However, Bill Gates’ 2015 annual letter proposed dispatching malaria “within a generation,” not through vaccination but mass screening and drug administration. In it, Gates relegated vaccines from the front lines to a mop up role, less protecting people from malaria than preventing further transmission in the event of infection, “so that once an area is cleared of the parasite, it stays clear.” Vaccines are much fallen.

Let’s take a look at the entire landscape, beyond RTS,S.

Whole cell, sterilizing

Although RTS,S disappointed, the foundation also backed a different and remarkably efficacious vaccine. Unfortunately, it’s too hard to make at the scale needed to vaccinate perhaps billions of people. This vaccine reproduces, with a few injections, the effects of being bitten by 1,000 mosquito that have been irradiated. The radiation damages the malaria sporozoites that mosquitos transmit to humans, preventing an infection yet prompting the immune systems to mount a highly effective protective response.

To make the vaccine, Sanaria raises, kills and manually dissects mosquitos, removing microscopic sporozoites from tiny mosquito salivary glands. Irradiated sporozoites, stored in liquid nitrogen, are then injected intravenously.

However, the current vaccine cold chain struggles with mere refrigeration, making cryogenic storage daunting. Also, finding a vein in children under five presents a problem, although Sanaria CEO Steve Hoffman believes it is tractable. Some in the field are waiting to see if Sanaria’s vaccine provides the same level of protection in larger trials, whether the protection lasts long enough, and whether it works against multiple strains of malaria.

But of all the obstacles, “production is probably the biggest,” according to the Gates Foundation’s Janice Culpepper, who oversees malaria vaccines. To simulate 1,000 mosquito bites, “you need a lot of mosquitos per person,” Culpepper explained.

“You want to produce a 100,000 vials, which isn’t even very many when you talk about malaria? That’s a lot of mosquitos.” Sanaria has already overcome countless difficulties, and Steve Hoffman gets “ornery” when questioned about large scale production because it’s “really not a problem.” He says with billion-dollar production facilities created for other vaccines, the math will work out. The foundation disagrees.

“I’ve been through the Sanaria plan,” said Culpepper. “I was the program officer on point when they actually built their plant,” and the pilot plant would be “very hard to scale,” requiring instead multiple sites, what Culpepper described as a “vision of distributed manufacturing.” The foundation actually countenanced upgrading the cold chain in Africa with liquid nitrogen storage to store a malaria vaccine like Sanaria’s. But even the technologically ambitious foundation just doesn’t believe Hoffman’s production vision will work.

There’s a chance, though, that the production problem could be made ten times easier. Using genetic attenuation—gene knockouts, instead of radiation—would make each sporozoite equally potent in eliciting immune response. Irradiation is inefficient, producing “dead sporozoites, potent sporozoites, weak and wimpy sporozoites,” according to Culpepper. Rough estimates are that just 10% are potent and actually induce immune response. But inefficiency is “part of the deal,” said Culpepper. “You can’t back off too much” on the radiation, or the vaccine might cause rather than prevent malaria.

Genetic attenuation, however, faces a similar difficulty: knocking out too many genes debilitates parasites so much they don’t trigger the desired immune response. But if the knock outs leave parasites too strong, they will cause malaria. “Indeed it’s the balance,” said Stefan Kappe, scientist at Seattle Biomed. Kappe has been developing the genetic attenuation approach for years. Knocking out two genes wasn’t enough and actually resulted in malaria infections. He recently said that “three gene deletions are sufficient,” in animal models, “and we will find out soon if that’s also the case in humans.” But according to Culpepper: “A few of us think the triple knock out is going to be safe.” However, “We’re not convinced it’s going to go far enough in its life cycle,” she said. “It’s going to be too attenuated and you’re not going to necessarily get the immunity you want.”

The usually optimistic foundation does not believe either the genetic or irradiated vaccines will work. And no one expects any vaccine to come close to their highly impressive protective efficacy. After the earlier RTS,S debacle, the bar for efficacy was lowered from 80% to 75%. The schedule to meet this lower bar was longer, sliding from 2025 to 2030. Also, a new goal was added: a vaccine that only blocked transmission. It would provide no protection from infection, stretching the definition of “vaccine” and even creating regulatory approval problems. Nonetheless, in Gates’ plan, drugs would be used to get rid of infection and then transmission blocking vaccines employed “so that once an area is cleared of the parasite, it stays clear.” A highly protective vaccine, perhaps like irradiated sporozoites, would itself “block” transmission by stopping infection to begin with. But because no such sterilizing vaccine is expected, different biological agents have to be developed to operate specifically against later stages in the parasite life cycle as malaria makes its way back to mosquitos.

Transmission blocking vaccine

To block transmission, explained Culpepper, the vaccine “generate[s] antibodies in the human that’s actually primarily expressed in the mosquito.” The human antibody ideally prevents the mosquito from becoming infected. The mosquito doesn’t have to mount an immune response. “All it has to do, is that antibody that you’ve already pre-generated has to find that target,” in the mosquito, Culpepper said. In other words, blocking transmission attempts to make human blood into an antimalarial drug for mosquitos.

There is considerable proof of principle from the laboratory and animals models. However, “the challenge is in translating that into a human that has been bitten by a mosquito,” said Culpepper. In the lab, researchers can simply concentrate the antibody, which is “not so easy to do in a human.” Humans vary notoriously in their immune responses to malaria. Consequently, the dose delivered to mosquitos may vary and the effects of any given dose will hinge on multiple factors specific to the biting mosquito. In some instances, the transmission blocking vaccine could increase transmission: If the vaccine reduces but does not eliminate malaria in the mosquito, it might live longer and bite more, for example.

The science of these complicated human-mosquito interactions is mostly unknown although Culpepper described it as “study-able.” Meanwhile, the vaccine search could be described as a shot in the dark.

Highly empirical, shot-in-the-dark approach

The portfolio of the Gates-funded Malaria Vaccine Initiative (MVI) includes very few transmission blocking candidates, just four. (Most of the other eleven seek to surpass the mediocre 46% protection of RTS,S. There is no clear leader.) What few transmission blocking candidates there are mostly aim at a one target. It’s less a portfolio than a big bet on a malaria protein called PFS25, reminiscent of MVI’s disproportionate support for RTS,S.

Perhaps the largest obstacle to a PFS25 vaccine is that the human immune system isn’t much perturbed by it. When researchers tried to boost the immune response by including an adjuvant, toxic side effects resulted, and the clinical trial had to be stopped. Safety is of particular concern. For transmission blocking to succeed at actually stopping new infections, coverage will have to be very high: most everyone in an area of transmission will have to be vaccinated. Also, if the vaccine confers no protection to the vaccinee and offers only the prospect of “herd” immunity, who will risk getting it if it’s not incredibly safe?

Resistance looms as a problem, even for vaccines. Variability in the amount of antibody delivered by humans to mosquitos could accelerate selection of parasites that don’t rely on PFS25. It might be necessary to add another target besides PFS25, and there are candidates “we’re kind of keeping on the shelf,” said Culpepper, “in case we decide, maybe we need two or three together.” Some candidates are larger and more complicated proteins, presenting problems that have yet to be surmounted. A multi-component vaccine, of course, would be more difficult, costly and time-consuming to develop.

Not enough

Suppose the significant scientific obstacles to a transmission blocking vaccine are overcome. What role would it play in eradication? By itself, very little. In 2008, Gates-funded researchers modelling the effect of malaria vaccines didn’t bother to simulate how much transmission blocking by itself would beat back malaria. (Said Culpepper, “It’s really hard to model.”) Researchers said “the most realistic scenarios” for transmission blocking combined it with other vaccines, and the best was a vaccine that acted against the earlier, “pre-erythrocytic” stage of infection. This is the foundation’s actual strategy: “a big piece of the going forward strategy,” explained Culpepper, “is to think about how you put pre-erythrocytic with transmission [blocking].” She described this as “the ideal situation,” a new dream made of broken ones. “Maybe neither one of them is perfect, but two imperfects could add up to something that’s pretty powerful.”

Developing two vaccines that work together is much harder than succeeding with just one. Acknowledged Culpepper: “You would probably say, ‘Wow, that’s even a bigger hurdle,’ and it is.”

Against these high risks, the rewards of the backup promise are low, at best yielding a tool too weak to tackle malaria head-on. Foundation-funded modelling efforts found “the biggest improvement to effectiveness” of a combined vaccine occurred “at very low transmission settings…” Where malaria gets real, the best vaccine currently imaginable becomes a toy.

Conclusion

Smallpox eradication depended entirely on an effective vaccine. Vaccines for polio account for the 99% reduction and near-eradication of that disease. Sustained oral vaccine coverage over 90% guarantees victory over polio. At the Gates Foundation, not a vaccine but political will is invoked as the guarantor of victory over malaria. Said the foundation’s director of malaria, Alan Magill: “We all know that with political commitment and proper management and systems in place we could eliminate malaria in any place in the world today probably with the tools we have.”

However, when the foundation gave researchers the task of “achieving a theoretical foundation for malaria elimination,” they found instead that extinguishing malaria was not possible in many places: “Prospects for elimination in Myanmar and southern Thailand,” where drug-resistant malaria lurks ominously, “do not appear to be favorable.” Myanmar and Thailand are malaria lightweights compared to heavy transmission areas in Africa.

Tellingly, the foundation is leaning toward demonstrating the offensive prowess of malaria tools in Swaziland. The majority of Swaziland is already malaria-free. The choice of Swaziland as a model occasioned incredulity even at the Gates-funded Institute for Health Metrics (IHME). At a talk given by the foundation’s deputy director of malaria, Bruno Moonen, IHME’s Nancy Fullman challenged the representativeness of Swaziland. Moonen defended the choice but also said Bill Gates actually wanted to focus on Madagascar, which has much more malaria but, as an island nation, greatly reduced re-importation risk.

Moonen said current tools could not eradicate malaria globally. Bednets, he said “didn’t work very well.” Vaccines, much talked about a few years ago, are expected to contribute little and only at the end. Indeed, the current effort might dispense with them entirely.

According to Ashley Birkett, “A lot of the gains we’ve seen over the last 15 years have been done in the absence of a vaccine. So we shouldn’t take for granted that a vaccine is absolutely essential.” Birkett is director of the Gates-funded Malaria Vaccine Initiative. Within the Gates Foundation proper, according to Janice Culpepper: “Some people argue that unless you can get a sterilizing vaccine, you may not want a vaccine at all? Right? It’s kind of binary.”

The foundation does not expect a sterilizing vaccine and instead is assembling an intervention patchwork applied in what Moonen described as a “learning by doing” approach.

According to Bill Gates: “Just as important as any specific innovation, our team has converged on an eradication strategy that will make the whole greater than the sum of the parts.” For both vaccines and the overall eradication strategy, synergy among imperfect components will substitute for a specific innovation actually capable of slamming the door on malaria.

Robert Fortner, based in Portland, Ore., is a science writer whose work has appeared in Scientific American, Ars Technica, and the Columbia Journalism Review. He is working on a book about Bill Gates, science and technology.