Have we already seen the best malaria vaccine prospects?

For half a century, scientists century have known one weird trick for eliciting immunity to malaria:  allow a person to be bitten 1,000 times by mosquitoes that have been irradiated. It works. In 1967, researchers reported sterilizing protection in mice from this approach. One thousand bites worked in later human experiments too, eliciting protection in 90% of the small group tested. Decades of malaria research has focused on bottling up the irradiation magic into a vaccine. But the most promising leads have been tried without success, raising the question: is the best yet to come? Or are we scraping the bottom of the barrel?

Malaria infection starts with the bite of a malaria-carrying mosquito which injects malaria spores (“sporozoites”) into humans. Radiation-damaged sporozoites, however, prompt a highly protective immune response while being too weak to survive and develop into disease.

A sporozoite consists of more than one thousand response-provoking, antibody generators or “antigens.” In the 1980s, scientists examined the successful antibody responses to the irradiated sporozoites. The winner, going away, was CSP or circumsporozoite protein. Other antigens were discovered too, with acronyms like TRAP and LSA-1. But none dominated the immune response like CSP, making it the clear favorite for a vaccine that only presented the parts of the parasite needed to elicit immunity, a “subunit” vaccine.

The CSP gene was sequenced, also way back in the 1980s, and optimism ran high that a vaccine was within reach. Much lengthy and laborious research eventually produced a candidate vaccine based on CSP called RTS,S. It was “the logical extension of more than a decade of research built on the hypothesis that a subunit vaccine based on the CS protein would protect humans from malaria infection,” as the vaccine’s co-inventor, W.R. Ballou, put it.

In 1997, RTS,S protected a remarkable 6 out of 7 people. However, fast forward years and hundreds of millions of dollars to 2014, and field trials now show the once-promising RTS,S protects only a disappointing 28% of children vaccinated. Although based on CSP, the champion of antigens, RTS,S delivered less than a third of the 90% benefit promised by the whole organism approach.

Many different approaches, combinations, formulations and technologies have been tried but none have produced a vaccine as good as even the mediocre RTS,S. Malaria researchers have helped pioneer a number of different technologies like the use of viruses and DNA as delivery vehicles. Adjuvants, used to amplify immune responses, have also been varied and are still being tested to see if they can improve the protective benefit of different vaccine candidates.

However, in recent years, little new ground has been broken. “A lot of people have been focused on various formulations with the currently available candidates,” said Lee Hall, Chief of the Parasitology & International Programs Branch at the National Institutes of Health. “There was some ramp up as people looked at a number of different ones. But if they didn’t pan out in the early studies then they weren’t moved forward.”

Among alternative to CSP, only one antigen, based on TRAP, is now in Phase IIb clinical trials. The vaccine protected only 13% of vaccinees in an earlier study. There is one other single-antigen candidate, FMP012, that has pending results from a Phase I trial. Mainly, however, vaccines aimed at protecting against malaria infection are overwhelmingly variations on CSP, both in the PATH Malaria Vaccine Initiative pipeline and the World Health Organization “Rainbow” table. Some projects combine RTS,S with other vaccines, in search of additive or synergistic effect. Also, scientists recently succeed in making a full-length CSP for study. (RTS,S only uses a portion of CSP.)

Many combinations are possible and the number of antigens could be increased, although technical and regulatory issues begin to arise. “Obviously people want to go for something is likely to be successful,” said Lee Hall. “They don’t want to embark on something that is so complex at the outset that the chances of it making it through the development process is low.” How many antigens a subunit vaccine could deliver is not known. According to Hall: “If it turns out that it’s two or five, that might [be] possible to do. If it turns out you need 50, then it turns out to be a lot more difficult.”

Some scientists see the failure of RTS,S as the undoing of the subunit approach. The success of the irradiated sporozoites served “as justification for the ensuing decades of research aimed at identifying the ‘right’ vaccine antigen,” or antigens wrote Mahamadou Thera and Christopher Plowe. “[I]t is reasonable to believe that it may be possible to construct a multistage, multi-antigen recombinant protein that improves on the efficacy of RTS,S,” they continue. But Plowe is skeptical that high levels of protection are possible. In a book chapter version of the article, Plowe added: “it seems not unlikely that vaccines that target 2, 5, or even 15 of the 5,000 gene products will still fall short of the high levels of protection seen with radiation-attenuated whole-organism vaccines when delivered through the bites of infected mosquitoes.”

According to Timothy Wells, Chief Scientific Officer at the Medicines for Malaria Venture, RTSS “even as a partial vaccine, is a massive triumph immunologically.” The human immune response to malaria is transient and requiring, on some estimates, 10 malaria infections, according to Wells. “This is why making a vaccine is close to impossible,” said Wells. Perhaps informed by this conclusion, the PATH Malaria Vaccine Initiative (MVI), funded by the Gates Foundation, has been quietly dropping candidate after candidate. Two projects testing multiple antigens have been dropped, one as long ago as December. However, that cancelation was only recently reflected in MVI’s portfolio which “was just updated last week,” the week of May 10, according to PATH spokesperson, Kelsey Mertes. One other canceled vaccine project “is still included on the portfolio because it hasn’t been closed out yet,” according to Mertes. Cancelled projects remain in the portfolio “until the contract is closed out and the last payment made,” Mertes explained. The portfolio still contains two studies of RTS,S given with another vaccine. Results are in for one but, perhaps suggesting the outcomes were not spectacular, Mertes did not reply to an email asking if it would move forward into the next phase of trials. The MVI portfolio looks increasingly barren as the sole remaining active trial for a protective pre-erythrocytic vaccine will report results later this year.

The search continues technically, although at the very earliest stage of the pipeline with any actual vaccine many years away. According to Mertes, MVI “is undertaking target validation work” on over 25 candidate antigens for a protective, pre-erythrocytic vaccine. However, science suggests that future discovery of a highly protective antigen or antigens is unlikely. Malaria has some 5,000 genes, but there are not 5,000 potential vaccine targets. Malaria genes produce just under 2,000 proteins. Vaccine targets are fewer still because not all the proteins are seen by the human immune system. Indeed, according to Stefan Kappe: “The number of surface and secreted proteins we identified is much lower, less than 100.” Kappe leads a group at Seattle Biomed that began assessing new antigen candidates in late 2012 for MVI. The project is expected to take six years or more. “Most of the novel targets are not published yet,” said Kappe.

It is not the first such effort but, because of its comprehensiveness, it could be the last.

In 2011, a group at New York University published results of efforts, supported by the Gates Foundation and others, to find new candidate antigens for a malaria vaccine. The researchers tested 34 new antigens, but concluded: “In summary, we failed in our attempt to discover powerful protective non-CS antigens…” Researchers saw no reason to look any further for other antigens. The study’s lead author, Satish Mishra, wrote in email: “We can’t rule out the possibilities in science but we as far as we understand it’s very unlikely” that there are important, yet to-be-discovered antigens. More bluntly, according to Mishra: “We have already checked the best candidates and already given up the new candidate search.”