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COVID-19 reshapes work on vaccines for a variety of diseases

Medicine@Yale, 2022 - May June
by Isabella Backman

Contents

New insights have been gained from the COVID-19 experience.

At the height of the COVID-19 pandemic, Yale scientists were at the forefront of vaccine development—and their efforts have helped save lives worldwide. Some of these researchers had already worked for years in other vaccine development efforts focused on conquering some the world’s most malicious and deadly diseases. Those efforts continue on trajectories that may be reshaped by knowledge gained from the COVID-19 experience.

Developing a vaccine for malaria

Richard Bucala, MD, PhD, Waldemar Von Zedtwitz Professor of Medicine and professor of pathology and of epidemiology, sees a silver lining to the pandemic despite its tragic cost in human lives. Bucala has been conducting research on malaria for 25 years. The disease is one of the leading causes of death in low-income countries. In 2019, malaria infected approximately 229 million people and was responsible for 409,000 deaths, according to the World Health Organization.

Part of the reason the disease is hard to control is that the parasite that infected mosquitoes transmit alters the human body’s immune response so that no immunologic memory is retained. That makes infected individuals continually vulnerable to reinfection. Because of that problem, when Bucala decided he wanted to pursue malaria vaccine research, experts told him that scientists had been trying but failing for two generations.

“The host never makes an effective immune response,” says Bucala. “It’s been a huge impediment to making a vaccine.”

Bucala has worked for years on a self-amplifying RNA (saRNA) vaccine for malaria. In 2018, his team published proof in mouse models that an saRNA malaria vaccine targeting the parasite’s immune escape mecha- nism provided unprecedented levels of protection. Despite this success, he found it difficult to interest funders in RNA as a platform. At the time it wasn’t accepted or under- stood. Due to the unexpected success of the Pfizer and Moderna mRNA vaccines for COVID-19, he says that regulatory agencies are now all primed for RNA technologies.

“In some ways, the RNA vaccine idea is an unforeseen benefit of the COVID-19 tragedy,” says Bucala. “The rug wasn’t pulled out from under malaria research. If anything, it’s the other way around because the RNA has become accepted and even favored now.”

The COVID-19 vaccines use mRNA technology, in which the RNA molecule encodes the antigen protein that trains an individual’s immune system to fight the virus. The saRNA vaccine Bucala’s team is working on is in many ways superior to the mRNA shot, he says. In front of the RNA molecule in Bucala’s vac- cine, there is another gene that causes the molecule to replicate. When the saRNA is injected into a muscle, it replicates over six to eight weeks, producing antigens over that time period. As a result, a robust immune response can occur with just a small quantity of the RNA. The vaccine would allow for lower dosing— making it more cost effective, have fewer side effects, and be easier to produce and distribute worldwide. Bucala is hopeful about the potential benefits of an saRNA vaccine not only on malaria, but also on all kinds of parasitic illnesses that scourge tropical medicine.

Vaccine for Lyme and other tick-borne diseases

Erol Fikrig, MD, Waldemar Von Zedtwitz Professor of Medicine, and professor of epidemiology and of microbial pathogenesis, and section chief of infectious diseases, feels similarly hopeful about the increased awareness. He and his team want to develop a vaccine that can prevent ticks from biting and feeding on humans, solving many tick-borne conditions including Lyme disease. When a tick reaches its host, the tiny parasite sips blood through a feeding tube while a numbing substance in its saliva leaves the source of its meal unsuspecting. This process quietly transmits pathogens into the bloodstream, which can lead to illness.

Instead of attacking the pathogens, however, Fikrig is interested in developing a vaccine that targets the tick proteins that help pathogens reach their target. A major advantage to this approach is that the same proteins that enable ticks to transmit infection are involved in spreading multiple diseases. “Ticks transmit many different infections, including Lyme disease, anaplasmosis, Powassan virus, and babesiosis,” Fikrig says.

Rather than use a different vaccine against each pathogen, Fikrig hopes that a single vaccine that targets important proteins can neutralize a wide variety of tick-borne diseases. An mRNA approach is one of several ways his lab is trying to deliver tick targets into animal subjects.

Thanks to the triumph of the Pfizer and Moderna vaccines, experts have realized that mRNA-based vaccines are safe and effective for humans, and Fikrig expects a boom in this technology.

“There will likely be many other mRNA vaccines for humans in the future,” he says. “An anti-tick vaccine could be one example of many.”

Vaccinating against the respiratory illness RSV

Carlos Oliveira, MD, PhD, assistant professor of pediatrics (infectious disease), is a physician-scientist and vaccinologist who is studying RSV, or respiratory syncytial virus. RSV is a common, highly contagious respiratory illness, and while symptoms are usually mild, the virus can be dangerous in newborns. Accord- ing to the CDC, approximately 58,000 children under age five are hospitalized annually in the United States due to severe infection.

Delayed for a year by the pandemic, Oliveira is now enrolling women in a Pfizer study of a vaccine for RSV, which will involve immunizing pregnant mothers in their third trimester to protect their babies from infection. Oliveira also believes that experience with COVID-19 has revolutionized the field of vaccine development.

“There are now people developing vaccines for infectious diseases that weren’t possible before COVID,” he says.

Vaccinating against leptospirosis

Yale researchers in other disease areas are also hopeful that the pandemic will boost momentum for their efforts. Elsio Wunder Jr., PhD, DVM, MS, research scientist in epidemiology at Yale School of Public Health, is a veterinarian-turned-epidemiology researcher from Brazil who is working on a vaccine for leptospirosis—a zoonotic bacterial disease that often affects individuals in tropical climates living in unsanitary conditions. Endemic outbreaks are often caused by environmental contamination from live animals. His longstanding research involves trying to develop a live attenuative vaccine. By deleting an important protein for motility of the bacteria, this type of vaccine stimulates an immune response in the body by injecting a less pathogenic form of the bacteria. However, because leptospirosis mainly impacts people from poor socioeconomic backgrounds, there is little economic incentive for companies to develop vaccines for the disease. Now, Wunder is hopeful that the pandemic has increased awareness of the significance of preventing disease in general.

“One of the positive things about this pandemic is that people saw that investing money in vaccine development and prevention methods is a good thing,” he says.