Yale School of Medicine Awarded $1.69 Million Gift to Advance Development of Novel Immunoregulatory Parasite Vaccines

Yale School of Medicine (YSM) was awarded a $1.69 million gift from Coefficient Giving to advance the development of an effective parasite vaccine led by Richard “Rick” Bucala, YC ’79, MS ’79, MD, PhD, chief of the Section of Rheumatology, Allergy, and Immunology, Waldemar Von Zedtwitz Professor of Medicine (Rheumatology), and professor of pathology and of epidemiology (microbial diseases).

This latest award from Coefficient Giving builds on three previous gifts in support of Bucala’s research on vaccine immunology, for a funding total of nearly $2.8 million.

“We are enormously grateful for this additional gift and Coefficient Giving’s continued commitment, as well as for their generous funding over the past five years,” says Bucala. “Their support enables critically important research to be conducted at Yale and elsewhere—some of it high-risk and for which there is no market interest—focused on eliminating parasitic infections in developing countries that have never received adequate attention or funding. Despite advances in our understanding of immunology and parasite biology, these diseases remain a scourge for humanity. Over 2 billion people suffer from parasitic infections, causing untold suffering and a societal cost that hinders the economic development of many countries.”

Malaria, for example, is the world’s second leading cause of death from infectious disease. According to the World Health Organization, in 2024, there were an estimated 282 million malaria cases and 610,000 malaria deaths in 80 countries. Most deaths are in young children, and there is no completely effective vaccine.

Building on its prior support of Bucala’s malaria research, Coefficient Giving will fund a clinical trial of a potentially universal vaccine for sheep that targets a parasitic worm called a helminth. The trial will be conducted in collaboration with Rick Maizels, PhD, professor of parasitology at the University of Glasgow’s School of Infection and Immunity, and Alasdair Nisbet, PhD, deputy director at the Moredun Research Institute in Edinburgh.

The vaccine targets a protein in parasites that prevents the generation of immune cells that protect against infection. By neutralizing the mechanism that parasites use to escape destruction, this approach could overcome a hurdle that has frustrated immunologists for decades: immune suppression that blunts the strength and durability of a vaccine response.

Bucala explains that the trial is being conducted in Scotland because Maizels—widely regarded as the world’s leading expert in helminth infection—is based at the University of Glasgow.

For decades, malaria researchers have faced an immunologic barrier: recovery from infection does not produce long-lasting, protective immune memory. As Bucala explains, many infections—such as seasonal influenza—leave in their wake immune “memory” that protects the person from reinfection years later. In malaria, that memory response never forms, leaving people vulnerable to reinfection.

“People are infected, treated, and then infected again—repeatedly and over a lifetime,” says Bucala. “If children are lucky enough to survive the first infection, they remain susceptible to reinfection and, in most cases, remain chronically infected. They can never clear the infection, and if cured by antibiotics, they are simply reinfected by the next mosquito bite.”

This challenge has real-world consequences. The first malaria vaccine approved for human use in 2015 provided protection for about half of vaccinated individuals and diminished over time. Newer vaccine candidates have achieved better protection, but the field continues to seek vaccines that are both potent and long-lasting as well as effective against new strains, which evolve quickly and arrive with each rainy season.

Bucala’s team is pursuing a strategy grounded in parasite immunology. Humans have a protein called macrophage migration inhibitory factor, or MIF, that helps regulate the immune system. In the early 2000s, genomics researchers discovered that malaria parasites have their own version of MIF (known as PMIF)—a unique occurrence among the more than 20,000 human genes. In experimental models, Bucala’s team found that a malaria strain engineered without PMIF triggered a completely different immune response: Infected mice developed effective immunity and immunological memory while mice infected with parasites that had PMIF did not.

The mechanism discovered by the Yale laboratory is that PMIF exploits a host inflammatory pathway to eliminate the formation of T cells, immune cells that are essential for long-term immune memory. “Malaria kills because of this subversion of the inflammatory response,” says Bucala.

That insight created the team’s vaccine strategy: Rather than focusing on a pathogen’s structural proteins—the basis for prior vaccine strategies—the new approach targets the immunologic pathway that the parasite evolved over millions of years in order to co-exist with its human host. It is precisely this evolutionarily conserved mechanism that has made it so difficult to achieve protective vaccination against malaria and other parasitic infections.

“We are targeting the mechanism the parasite uses to redirect the immune response for its own survival,” says Bucala. In animal models, the strategy has been compelling: when PMIF is neutralized, “the infected host mounts a fully protective and long-lasting immune response that both eliminates the parasite and prevents reinfection.

“Because PMIF is so necessary for parasites’ survival, they cannot mutate or evolve away from its function, raising hope for long-term protection against the evolution of future strains,” says Bucala.

And evidence suggests PMIF vaccination may protect against infection by entire groups of parasites, either on its own or in combination with current vaccines whose efficacy wanes quickly. This is why the research team will be testing this approach against a different parasite—helminths—in sheep.

“The vaccine target and the conceptual approach are the same as what we’ve been developing for malaria,” says Bucala. “We’re now extending it to helminths.”

A parasite vaccine must be feasible to manufacture and distribute widely, particularly in regions where resources are constrained and disease burden is highest.

To that end, Bucala reconnected in 2011 with a former trainee in the pharmaceutical industry to pursue an RNA-based platform, a technology related to—but distinct from—current mRNA vaccines. The vaccine antigen is encoded by self-amplifying RNA (saRNA), which includes genetic instructions that allow the RNA to replicate inside cells once delivered.

Because saRNA can amplify itself, far less RNA is needed per dose compared to conventional mRNA approaches, which greatly reduces production costs—an important consideration, especially since malaria is most prevalent in less-developed nations where resources are scarce.

Importantly, the self-amplifying RNA activates intracellular pathways that ensure robust T cell responses, which are the most effective in protecting against malaria. In mouse models, pairing saRNA delivery with the gene for the PMIF antigen has demonstrated full protection, helping drive the next phase of clinical development.

“As a physician-scientist, I’m fortunate to be at Yale School of Medicine, where the environment is one of such a productive apposition of training and research that accelerates discovery,” says Bucala. “It’s the main reason I returned here in 2002. I was beginning genetic epidemiology investigations in Zambia at the time, and our School of Public Health made it easy for me to expand these studies into other countries.”

Bucala and his team of Yale students were soon conducting clinical studies in sub-Saharan Africa to examine the frequency of common polymorphisms in the human MIF gene to understand why lethal malaria develops in some children but not others.

“When our work moved toward translating our findings toward better vaccine approaches, Coefficient Giving stepped in with philanthropic support to make that possible,” says Bucala.

“Malaria has been with us since the origin of humanity, but it can be prevented. Having an effective, low-cost vaccine is critical to alleviating the suffering from parasitic infections and perhaps even eliminating them. That is why donor support is so vital. I’m grateful for Coefficient Giving’s vision and their mission to have a meaningful impact on humanity.”