Several countries have eliminated locally transmitted malaria in recent years, using a number of tools ranging from effective drug treatment to insecticides. But these tools are widely considered inadequate to eliminate malaria from the areas where it’s most deadly — namely sub-Saharan Africa, as well as parts of Asia. To reduce malaria transmission with the ultimate goal of eradicating the disease, many organizations have long supported the development of potential malaria vaccines. So far, a number of different approaches have shown promise in lab experiments and limited human trials. Here are some of the forms that such a vaccine might take — and why each one may be both promising and challenging.
How Is Malaria Different?
Unlike the classic examples of diseases that have been eradicated or widely eliminated through vaccines — such as smallpox, polio, and diphtheria — malaria isn’t caused by a virus or bacteria. Rather, it’s caused by parasitic protozoans — single-cell organisms that have proved to be adept at evading the human body’s immune response. Your immune system “may raise antibodies against one protein, and then [the parasite] will switch the protein, and then those antibodies don’t work anymore,” notes Elizabeth Ann Winzeler, PhD, a professor of pharmacology and drug discovery at the University of California in San Diego School of Medicine. This ability to constantly change is a key reason why developing a vaccine for malaria is so difficult, according to Dr. Winzeler. “There’s a limited number of genes in viruses, and a limited number of ways they can change,” she explains. Malaria is also unlike viral infections that confer natural immunity, which you can only get once. “You can get infected with malaria over and over again,” says Winzeler. “The parasite has developed ways to fool the immune system.” But unlike many other diseases, malaria isn’t spread directly through person-to-person contact — it’s spread only through mosquitoes. This distinction offers researchers an additional path in their efforts to develop an effective vaccine. (2)
Targeting Part of the Parasite
To date, the most successful approach in vaccine development has been to target a single part of the malaria parasite. This is the only vaccine approach, in fact, that has demonstrated success at reducing malaria transmission in phase 3 clinical trials — typically the final stage before a drug is approved for use in the “real world.” (3) The vaccine in question — known as RTS,S or by its trade name, Mosquirix — was shown in a five-year study, published in April 2015 in the journal The Lancet, to reduce malaria transmission in young children in seven African countries. This year, routine vaccination programs for children using RTS,S will begin in parts of Ghana, Kenya, and Malawi under a program organized by the WHO. (4) The RTS,S vaccine targets a molecule in the malaria parasite called circumsporozoite protein. Over four years of follow-up, it was shown to reduce malaria transmission by 39 percent — and severe malaria by 29 percent — in children 5 to 17 months old. (5) It’s possible that the success rate of the RTS,S vaccine could climb even higher if the size and scheduling of doses are optimized. Compared with the schedule tested in the main clinical trial, a delayed and smaller third dose was found in a separate study to result in greater efficacy. (6) But another follow-up study of RTS,S demonstrates its possible limitations. Seven years after the start of the clinical trial, the vaccine was found to reduce overall malaria transmission by only 4.4 percent, with the protective effect shrinking over time. (7) According to Winzeler, this waning effectiveness is what many researchers would predict. “If you’re only targeting one molecule, [the parasite] can mutate around that. It’s a pretty easy way for the parasite to escape,” she notes. Any vaccine that’s only partially effective, Winzeler says, can lead to the parasite becoming resistant to it — potentially rendering it useless over time. (2)
Targeting the Whole Parasite
An alternative to targeting just one molecule, or part of the malaria parasite, is to target the entire organism in a vaccine. This approach has been effective for vaccinating against viruses, Winzeler notes — but a parasite is much more complex. Some researchers have experimented with radiation-attenuated parasites, which are modified so that they’re not infectious. Others have used fully active parasites, paired with an antimalarial drug, to achieve a protective effect. In a study published in February 2017 in the journal Nature, researchers used non-irradiated parasites that were purified and frozen (known as PfSPZ-CVac) to test for protection against malaria in healthy adults taking the antimalarial drug chloroquine. In the group of participants who were given the highest dose of PfSPZ-CVac, all nine individuals failed to develop malaria when they were given a controlled infectious dose of the parasite 10 weeks after their last dose of PfSPZ-CVac. The researchers concluded that PfSPZ-CVac could be a promising vaccine candidate, when combined with an antimalarial drug. (8) But according to Winzeler, there are potential problems with this method. One is that it requires refrigeration and booster shots — which means it’s likely to be expensive and difficult to use in the areas where malaria poses the biggest problem. It’s also important, Winzeler says, to make sure that whole-organism vaccines are targeted toward — and tested with — more than just one specific malaria parasite. Some researchers don’t do this, she notes, because “they want their vaccine to look good” in the lab — but then it doesn’t work in field studies involving real-world parasites. (2) A review published in February 2017 in the journal The Lancet Infectious Diseases concludes that the lack of proven efficacy against multiple parasites remains a problem for PfSPZ-based vaccine candidates. (9)
Targeting Mosquitoes
An alternative approach to vaccines that directly target the malaria parasite is to interfere with mosquitoes’ ability to transmit it. The potential usefulness of this approach was demonstrated in a study published in April 2018 in the journal Cell Host & Microbe, in which researchers showed that a serum targeting a protein found in mosquito saliva could have a protective effect. The serum, which contained antibodies (proteins that target a specific substance) against a mosquito-produced saliva protein known as AgTRIO, was shown to reduce the malaria infection rate in mice that were bitten by infected mosquitoes, and it worked with different malaria parasite species. (10) “Our approach is unique in its potential to expand the current paradigm by considering mosquito proteins in malaria vaccine development,” says study author Tolulope A. Agunbiade, PhD, a postdoctoral fellow in infectious diseases at the Yale School of Medicine. Dr. Agunbiade cautions that the serum isn’t ready for use as a vaccine yet, and that further studies are necessary to confirm its safety and efficacy in humans. But the potential benefit from this approach is enormous, she says — not just in preventing malaria, but in reducing other diseases spread by mosquitoes. (11)
Drug-Based Approaches
A promising alternative to traditional vaccine approaches for malaria could be long-acting drugs, according to Winzeler. “Imagine a drug that keeps you from getting malaria,” she says. “We already have molecules like that. The only problem is, your body turns them over in 12 hours or so.” But researchers are exploring ways to formulate these drugs so that they’re active in the bloodstream for much longer. This can involve chemical modifications as well as experimentation with delivery methods, such as injections and patches worn on the skin. “If you could protect people for three to six months, and go in and vaccinate everyone in the village and follow up with insecticides … that might be the type of activity that could really push the disease into oblivion,” Winzeler imagines. Because it would involve a drug staying active in your bloodstream for months, safety is an important concern with such an approach, says Winzeler. But she notes that drugs have long been used to treat and help prevent malaria, with a good overall safety track record. “I think we can create molecules that are safe enough,” she says. “There are lots of different ways to kill malaria parasites, and … ways to prevent malaria from developing.” (2)
