After clean water, vaccines may have saved more lives than any other public health intervention. Eradication of malaria, a disease that may have killed more humans than any other single cause, likely requires a malaria vaccine. However, after nearly a century of research, today’s only candidate might not pack enough immunological punch to win deployment. Sadly, there are no obvious successors. Goals for vaccines set in 2006 are now approaching, but may not be possible to meet.

A quarter century of painstaking work has gone into the vaccine known as RTS,S, now in phase III clinical trials. But after numerous modifications and enhancements, RTS,S still protects only intermittently, 30 to 60 percent of the time. This protection wanes, although over how many years or months is still being studied. The vaccine reduces disease but, so far, not deaths.

The organism that causes malaria has made vaccine development a challenge. Malaria is caused by the parasite Plasmodium rather than bad or “mal” air as thought long ago. The human genome, particularly in sub-Saharan Africa, chronicles our lengthy and ongoing battle with Plasmodium. Strong selection pressure on humans has led to evolutionary gambits like the sickle cell trait—risking potentially lethal blood disorders to reduce susceptibility to malaria infection. But Plasmodium has kept the upper hand in many ways. The parasite continues to baffle the immune system with a complex genome reshuffled by sexual reproduction, a multi-stage life cycle that features antigenic shape-shifting, to avoid immune surveillance.

For pathogens like polio, the human immune system can develop durable, sterilizing immunity, which rids the body of the invader. Polio vaccines reliably trigger these natural mechanisms. For malaria, humans can acquire a kind of immunity and potentially even clear parasites completely. But the genetic diversity of Plasmodium falciparum allows it to often avoid such direct hits. Acquired immunity is often a détente in which the parasite survives and reproduces at low levels that cause neither disease nor death. A study in western Kenya, for example, found 90 percent of a cohort was infected with falciparum even though not one of the 93 people was ill. Vaccines like RTS,S prod the immune system toward this partial protection, but there is concern that it isn’t reducing severe malaria enough.

Transmission studies: jammed

Vaccines not only help protect those who are immunized but also slash disease by reducing the number of available hosts, an effect termed “herd immunity.” However, because RTS,S generally doesn't provide sterilizing immunity that kills all parasites, those that escape the liver will reach the blood, where they can differentiate into the gametocyte stage. Even submicroscopic quantities of gametocytes in human blood suffice to pass the parasite on to mosquitos. Consequently, even if it reduces malarial risk in those who receive it, RTS,S might be incapable of reducing transmission. Neither GlaxoSmithKline, maker of RTS,S, nor the Malaria Vaccine Initiative (MVI), a co-sponsor of RTS,S trials, would comment on this possibility.

RTS,S could conceivably increase malaria transmission. A vaccine that elicits immune responses might trigger increased numbers of gametocytes, a pattern seen with natural immune responses and antimalarial drugs. Remarkably, we aren’t currently certain whether carrying more gametocytes causes increased transmission. The question of how RTS,S affects gametocyte densities could be answered, but GlaxoSmithKline says it hasn’t yet looked at samples from the phase II trial, completed in 2010, or the ongoing phase III trials.

GSK spokesperson Sarah Alspach said that the company would explore gametocytemia, perhaps by the end of 2014. However, said Alspach, “Our goal remains licensure against malaria disease and that is what the trial is designed to do.” It is unclear if effects on transmission will be considered as part of the licensing and approval decision.

Ashley Birkett, director of research and development at the MVI, said, “there was never a strong rationale to look at gametocytes previously (not sure there still is really)…” MVI is a co-sponsor of the RTS,S trials. Birkett declined to comment on possible public health consequences of a vaccine that increases transmission.

Adding RTS,S to the current Extended Program for Immunization would mean vaccinating roughly 3 percent of the population in sub-Saharan Africa, according to Chris Drakeley at the London School of Hygiene & Tropical Medicine. “I would not expect RTS,S to have much of an effect on transmission,” Drakeley said, because such a small part of the population would be immunized. Drakeley said he was “advising GSK on assessing the effects of RTS,S on gametocyte carriage in the current phase 3 study and this is underway.” But any results coming out of the trial won’t be in print for a while; his recent paper in Clinical Microbiology Reviews (CMR), which examines gametocytes in relation to malaria control and elimination, makes no mention of RTS,S.

However, if eliminating malaria is the goal, progress will mean that eventually older children and adults in high transmission areas will lose their immunity. “They are likely to be included in an immunization scheme, in which case a transmission-boosting vaccine could become a problem," said Christopher Plowe of the University of Maryland. “It's a legitimate question to ask,” continued Plowe, “does a vaccine have an effect on transmission, in either direction?”

Vaccine resistance—and other impediments

Another concern is “vaccine resistance.” If a vaccine acts against a specific strain of malaria, it might drive selection of strains not addressed by the vaccine. This substitution effect has been seen with pneumonia vaccines, and may be appearing following the adoption of the HPV vaccine.. The Broad Institute has developed new methods to accurately sequence the small numbers of potentially different malaria strains in individual blood samples, which will allow them to determine whether those children vaccinated with RTS,S show a different distribution of strains than non-vaccinees.

RTS,S presents the immune system with a large piece of the protein that surrounds the parasite when it is first injected as a spore into humans by an infected mosquito. MVI has considered putting RTS,S together with a vaccine from Crucell, now part of Johns & Johnson. Crucell’s vaccine also dangles a parasite surface protein in front of the immune system, but uses an adenovirus to excite a response that’s hoped to be both more energetic and enduring. In animal models, however, Crucell’s vaccine failed to elicit the desired effect (specifically an increase in CD8+ T cells). Asked whether the vaccine might still work in humans, Adrian Hill at Oxford University said, “it will not,” and that vectored vaccines “have moved on.” (Hill is working on some of them).

Meanwhile, personnel changes may be slowing things down further. Both Crucell and the MVI have seen staff changes at senior levels. A vice president for clinical development working on malaria vaccines at Crucell departed unexpectedly. At MVI, Christian Loucq, who headed the organization for nearly five years, left last October. The trial of RTS,S and Crucell, which Loucq announced last June, was recently suspended. Spokespersons at MVI and Crucell declined to comment.

Waiting for Godot

Many have lost patience waiting for a vaccine. Richard Feachem, chair of the Malaria Elimination Group, has likened it to waiting for Godot. Some vaccine researchers believe that subunit vaccines like RTS,S which only present part of the parasite to the immune system, may be incapable of eliciting the sort of immunity generated by malaria infection.

Conceivably, only exposure to all of a parasite can draw out the full immune response that protects against malaria. According to Christopher Plowe, “it seems not unlikely that vaccines that target two, five, or even 15 of the [parasite’s] 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.”

Irradiating malaria-infected mosquitos sterilizes the parasites, rendering them incapable of causing disease. But when those mosquitos are allowed to bite humans, the attenuated parasites stimulate an incredibly potent immune response: 90 percent of subjects exposed to at least 1,000 bites were protected from subsequent infection by live parasites.

However, needle and syringe efforts to replicate the effect of 1,000 mosquito bites have failed. Subcutaneous injection of the same attenuated parasite differs in some unknown but important way from the prick of a mosquito bite. Intravenous injection appears to trigger a strong immunological response in animal models, and tests in humans are under way. But MVI dropped support for this approach. Finding a vein in very young children poses too great a risk. In addition, the irradiated parasites must be frozen in liquid nitrogen at -140 Celsius. To distribute a vaccine of this sort in Africa isn’t logistically practical.

The Malaria Vaccine Technology Roadmap envisioned a vaccine by 2015 “that has a protective efficacy of more than 50 percent against severe disease and death and lasts longer than one year.” Current trials will shed light on how much RTS,S impacts severe malaria among the very young, but the trials don’t directly measure mortality effects. There is already debate about whether RTS,S meets roadmap criteria.

Licensing and deployment are separate matters. Sign off is needed from both the European Medicines Agency and WHO. Although the final decision on deployment ultimately rests with individual countries, WHO’s recommendation and the financial terms, largely set by donor nations and international aid groups, will make deployment feasible or not.

The more important ambition of an 80 percent effective vaccine envisioned in the roadmap appears infeasible. There is no clear candidate in the research portfolio, and there likely isn’t enough time to both develop something new and conduct trials in order to license a vaccine by 2025, the roadmap deadline.

Looking back, as one review recently concluded, “All predictions of when a malaria vaccine will be available have been overly optimistic.” And absent a vaccine, the road to malaria eradication may be a bridge to nowhere.