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An end to malaria?

Yale Medicine Magazine, 2022 Issue 169 Rising Up
by Rhea Hirshman


Among other advances, new RNA treatments may hold the key to fighting one of the foremost scourges of warmer climates.

Malaria, the world’s second most deadly communicable disease (after tuberculosis) has coexisted with humanity for over 100,000 years. While the mosquito-borne illness was virtually wiped out in this country in the early 1950s, many more U.S. travelers in the recent past have been returning from parts of the world where the disease is endemic. According to the Centers for Disease Control, about 2,000 Americans are diagnosed with malaria each year, most of them frequent travelers or immigrants.

But malaria exacts its greatest toll in sub-Saharan Africa, where it kills over half a million people annually. Most are children who have not yet developed any immunity to the disease. Another highly vulnerable population is pregnant women; immunity to the disease is decreased by pregnancy.

In addition to the personal suffering that malaria causes, its social and economic burdens are enormous. According to the Johns Hopkins Bloomberg School of Public Health, “The economic impact of malaria is estimated to cost Africa $12 billion every year. This figure factors in costs of health care, absenteeism, days lost in education, decreased productivity due to brain damage from cerebral malaria, and loss of investment and tourism. Malaria (results in) sub-optimal agricultural production (and) reduces labor productivity…. (In) endemic areas, malaria may impair as much as 60% of schoolchildren’s learning.”

“Malaria is both a huge medical problem and a huge social problem,” says Richard Bucala, MD, PhD, the Waldemar Von Zedtwitz Professor of Medicine (Rheumatology), and professor of pathology and of epidemiology (microbial diseases). “A malaria vaccine has long been the holy grail, but development has suffered from a lack of understanding of the disease’s basic immunology.”

Increasing resistance to treatment

The quest for a malaria vaccine is made even more urgent by limited treatment options. After World War II, DDT was used to kill the mosquitoes that carry the malaria parasite. Chloroquine, a cheap and effective drug, was developed to treat patients. But DDT proved to be toxic to humans and animals, the mosquitoes developed resistance to it, and the malaria organism developed resistance to chloroquine. Now, only one antibiotic treatment remains— artemisinin, a drug derived from an ancient Chinese herbal remedy. And, says Bucala, “We are finding resistance to artemisinin on the Thai-Cambodian border, which is the first place chloroquine resistance developed in the 1950s. We are losing tools for malaria control.”

Malaria is caused by several species of Plasmodium parasites that are spread to humans through the bites of infected mosquitoes. The organism has evolved elaborate mechanisms to avoid destruction by the body’s immune system, including secreting a protein (PMIF) that kills our immunity-generating memory T cells. “It’s been so difficult to create an effective vaccine,” Bucala says, “because the infection is not associated with sterilizing immunity”—the ability of the immune system to stop pathogens from replicating within the body. “With malaria,” he explains, “once you are infected, you are always infected. Even if the infection responds to treatment, you remain at risk for reinfection because protective memory T cells do not form. Moreover, it’s not the organism itself that kills, but the body’s inflammatory response to the infection.”

In 2012, Bucala, whose research focuses on the relationship between protective immune responses and immunopathology, published a paper showing that the function of PMIF is to kill memory T cells. The next step was to develop a vaccine that would inhibit PMIF activity, allowing the body to attack the parasite and generate a natural immune response to the disease.

A former postdoctoral student in Bucala’s lab, Andrew Geall, PhD—previously RNA vaccine platform leader at Novartis Pharmaceuticals and now at Replicate Bioscience—suggested using a novel RNA technology as the vaccine platform.

Self-amplifying RNA to the rescue

The mRNA (messenger RNA) vaccines so prominent in the news during the COVID-19 pandemic work differently from traditional vaccines. Rather than introducing a small amount of pathogen (live attenuated or inactivated) or one of its proteins into the body to trigger immunity, mRNA teaches cells how to make a specific protein to create a protective immune response against infection. Bucala and Geall created their antimalarial vaccine on a second-generation RNA platform: self-amplifying RNA (saRNA).

Self-amplifying RNAs contain the “teaching” vaccine mRNA plus a code for an enzyme that allows the genetic material to self-replicate inside the vaccinated cell over several weeks. “Replication means that you can inject much smaller amounts of vaccine to achieve adequate immunization,” Bucala says, “making the vaccines cheaper and easier to distribute—much more accessible for the developing world.” The replication function of saRNA is also critical because it activates intracellular immune pathways necessary for the generation of long-term protective memory T cells.

To test their vaccine, Bucala’s group injected it into mice infected with a murine strain of malaria. In 2018, Bucala and Geall published the results in Nature Communications, showing that the saRNA-vaccinated rodents combatted a series of malaria infections better than those that received a control vaccine. “In the mouse models we used,” Bucala says, “we saw an unprecedented level of protection against malaria by using saRNA for the MIF antigen.”

While more research is needed—for instance, in determining the length of vaccine efficacy—Bucala is hopeful. Yale was granted a patent for this approach in 2021, paving the way for continued development and ultimate testing in human clinical trials. “We’ve been working on this vaccine for years,” he says, “but the entire landscape has changed.” He notes that one positive outcome of the COVID-19 pandemic has been widespread acceptance of the RNA vaccine platform with its potential for tremendous positive results, including the possibility of similar vaccines for other parasitic diseases. “What we have now is not just an improved iteration of something that already existed,” he adds, “but something that has never existed before, with the potential to save and improve millions of lives.” Currently, Bucala is working with Oxford’s Jenner Vaccine Institute to further test the PMIF saRNA vaccine. Planning also is underway for testing against infection by Plasmodium falciparum, which causes the most lethal form of human malaria, in a trial in non-human primates.