A Vaccine for the Next Pandemic

A new variant of Covid-19 has been popping up every few months, each time adding a new letter to the Greek alphabet soup: alpha, delta, and omicron are just the latest. With every variant comes a rise in cases and a delay to returning to normal life.

Researchers, too, are having a hard time keeping up. “You’re always waiting for the variant to appear and then pushing as quickly as possible to try to catch up,” says Dr. David E. Anderson, former professor of neurobiology at Harvard Medical School and the current chief scientific officer of Variation Biotechnologies Inc., a biopharmaceutical company headquartered in Cambridge.

Biotech giants like Moderna and Pfizer-BioNTech were able to make potent mRNA vaccines within six months of the outbreak in the United States — a feat Anderson says is “the equivalent of when we put a man on the moon.”

However, these vaccines won’t last in the long term. Current Covid-19 mRNA-based vaccines rely on recognizing a specific spike protein — the more a vaccine looks like the virus it aims to target, the more potent it will be. While this specificity has made vaccines incredibly effective against current strains, they cannot keep up with the quickly-evolving virus as it develops increasingly unrecognizable spike proteins.

As a result, many researchers are trying to develop an entirely different type of vaccine — a universal one. A pan-coronavirus vaccine would protect against strains of Covid-19, a future strain of SARS-CoV-3, or even a new coronavirus that might not yet have jumped from animals to humans. The idea has been endorsed by Anthony S. Fauci, chief medical advisor to the president and director of the National Institute of Allergy and Infectious Disease. In a January 2022 New England Journal of Medicine op-ed, Fauci wrote: “our ongoing experience with the current Covid-19 pandemic, together with the ever-present threat of the emergence of other potentially pandemic coronaviruses, necessitates the expeditious development of safe and broadly protective coronavirus vaccines.”

Moderna and Pfizer’s approach “is a game where you’re playing catch up constantly,” Anderson says. “This pan-coronavirus candidate is to stop chasing the variance and get ahead of it.”

VBI’s team of 35 scientists are working on a pan-coronavirus vaccine that exposes the immune system to multiple variants at the same time, to “educate it.”

“We thought we could teach the immune system to be more broadly reactive,” Anderson says.

Human immune systems have two strategies for addressing threats — one is hardwired from birth to sense and respond to infections, while the other is made of T and B cells that respond adaptively to foreign invaders, including vaccines, by secreting customized antibodies.

As an analogy, Anderson says you can imagine the spike proteins from three virus variants — MERS-CoV, SARS-CoV-1, and Covid-19 — are red, yellow, and blue. The VBI team hypothesizes that after being exposed to different variants, the immune system could learn to recognize mixtures of these colors.

“If a B cell or an antibody saw the red, and then it saw the yellow, it might start seeing a shade of orange somewhere in between,” he says. “Or if it saw the yellow spike, and then the blue spike, it might actually see … a shade of green.” After seeing these mixed shades, antibodies would be able to target a greater variety of viruses for destruction by the immune system.

While the VBI team studies how the immune system might better identify these spike proteins, researchers at HMS are studying how to make it harder for the proteins to escape from the immune system.

Duane R. Wesemann, an immunologist at Brigham and Women’s Hospital and professor at Harvard Medical School, is leading this research. In September, his group received one of just three NIAID grants issued to search for a pan-coronavirus vaccine.

Wesemann’s team is interested in the maximal immune response that a vaccine could muster to protect against multiple strains of Covid-19 and potentially even multiple coronaviruses — though he notes that its potency against an unknown strain, whose spike proteins have not yet been characterized, would be much lower.

Immune responses are driven by neutralizing antibodies, which can block the entry of a virus into healthy cells. Wesemann’s team is manipulating several variables, including vaccine delivery methods, vaccine dosage, target regions of spike proteins from different variants, and the timing of spike protein delivery, with the aim of making these neutralizing antibodies as strong as possible.

Early results from both VBI and HMS are promising, suggesting that it is possible to optimize the immune system to recognize multiple variants. But only time will tell if a pan-coronavirus vaccine can prevent the next pandemic.

“You don’t want to over-promise when you have pretty early stage clinical development ongoing,” says Nicole E. Anderson, the Director of Corporate Communications & Investor Relations at VBI. “It’s encouraging, but it’s also early days, and we have to see it bear out in the clinic and see it put into humans, hopefully in the middle of this year.”

The approaches to developing a pan-coronavirus vaccine are just as diverse as the viruses they are targeting — and the process has revealed many gaps in our fundamental understanding of the immune system.

“We’re not quite masters of understanding our own immune system in terms of predicting what happens with a vaccine or how to make a proper response to a pathogen,” Wesemann says. “So is it possible to make a universal HIV vaccine or universal flu vaccine? Is it possible to make a pan-coronavirus vaccine that really is highly potent? We don’t know.”

– Akila V. Muthukumar can be reached at akila.muthukumar@thecrimson.com. Follow her on Twitter @akila29m.