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Going beyond B cells in the search for a more multi-targeted vaccine

The ultimate goal: a vaccine with coverage so broad it can protect against viruses never before encountered.

Part 3: This is the last of a three-part series on how Stanford Medicine researchers are designing vaccines that protect people from not merely individual viral strains but broad ranges of them. The ultimate goal: a vaccine with coverage so broad it can protect against viruses never before encountered.

Until now, vaccine efforts have mainly focused on stimulating B cells, described and discussed in Part 1 and Part 2. These antibody-producing immune cells' virtue of being highly specific in what they target is also a vice. An antibody against influenza is unlikely to ever bind to, say, a coronavirus or a rabies virus.

Even when a virus mutates in some small way that distorts or disguises one of its biochemical bull's-eyes, antibodies that worked before (because they aimed at that particular bull's-eye) are now unemployed.

The adaptive immune system is supported by a far more evolutionarily ancient consortium of cells and sensors called the innate immune system. While the adaptive immune system takes a week or two to fire up its carefully tailored response to a detected pathogen, the innate system leaps into action almost immediately. It can do this because it's far less fastidious -- it operates via simple pattern recognition.

Many types of cells have sensors that can detect telltale markers of infection such as, for example, materials found exclusively in cell walls (which bacteria have, but animals never do), certain DNA patterns abounding much more in viruses than in our genomes, or double-stranded RNA molecules (which form some virus's genomes but never ours).

Cells whose sensors detect such internal infection markers quickly send out signals calling in all-purpose warrior cells that don't care what specific bacterial or viral species deposited one of these generic calling cards. These warrior cells simply head to the area where the pathogenic marker was detected and wreak inflammatory mayhem on the tissue there. This occurs within hours of an infection or a vaccination (it's what makes our arms sore after a shot) and typically fades away quickly -- it's pretty much clinically undetectable within a few days.

Infected cells have an additional way of defeating viral infections: Given the right chemical cues, they can shut down their protein-production systems selectively, depriving viruses of the ability to replicate, which they do by hijacking those systems.

Bali Pulendran, PhD, a professor of pathology and of microbiology and immunology and the Violetta L. Horton Professor, thinks it's possible to rev up the innate immune system for longer in advance of a suspected impending new microbial threat. He envisions a new class of vaccines that will work immediately and broadly, without needing to wait a year or more for a bespoke vaccine.

"This represents a new way of immunizing people against any virus that can emerge in the future," he said. 

Pulendran has been studying a vaccine composed of a live, but much-weakened, bacterial strain known as Bacille Calmette-Guerin, or BCG, derived from the microorganism that causes tuberculosis. BCG, administered to 4 billion people since its first use in 1921 and still in use a century later, is the world's only vaccine against TB.

"It's routinely given to 100 million people annually, including infants on the day of their birth," Pulendran said.

Old bacteria, new clues

There's epidemiological evidence that BCG protects against other microbial pathogens besides TB. Pulendran and his colleagues have identified a multistep mechanism that explains this broad protection against multiple microbial species.

In a study published in Nature Immunology in November 2023, Pulendran and his colleagues peeled back the layers of consecutive steps taken in a collaboration between the adaptive and innate immune systems. Experimenting in mice, they discovered that innate immunity's starting pistol, in response to vaccination with BCG, fires not once but twice: early on, as with most vaccines, then again about three weeks post-vaccination. The innate immune system remains strongly activated for at least three months after the day of vaccination.

Throughout that period, BCG-vaccinated mice were infected with otherwise-lethal doses of various viruses -- an influenza A virus; both the early "beta" strain and the newer omicron variant of SARS-CoV-2, SARS1; and another coronavirus called SHC014 that, according to Pulendran, is harmless at the moment but might be a mere couple of mutations away from posing a major danger to us. Yet these mice were protected from death or even significant weight loss, a marker of infection-induced malaise. And vaccinated mice's lungs contained far less viral material compared with those of unvaccinated mice given the same dose of pathogenic virus.

"There's a feedback loop keeping innate immunity in a heightened state of activation for months at a time," Pulendran said.

The mechanism: BCG enters the body and is taken up by antigen-presenting cells, which show BCG antigens to helper T cells. BCG-specific helper T cells get activated, enter circulation and home in on tissues displaying BCG antigens, which signify BCG's presence there. That includes the lungs, the major target of not only the TB microbe (and BCG) but also myriad other respiratory pathogens such as those that cause COVID-19 and flu. These helper T cells remain active for at least three months, releasing substances into these tissues. That reminds the tissues' constituent cells to restrain their viral-protein production, putting an infecting virus out of business.

"These cells become resistant to infection -- any viral infection," Pulendran said.

Pulendran thinks a vaccine designed to similarly stimulate lung and airway innate immunity and keep these tissues on guard might be effective against a broad range of respiratory viral and, possibly, bacterial threats.

BCG is special, Pulendran said. "It grows very slowly, and not dangerously, in the lungs. There's plenty of time for the adaptive immune system to catch up to it, overwhelm it and develop a very strong memory of the encounter."

"For us," Pulendran said, "BCG has been our entry port into a bigger question: Can we develop a 'universal vaccine' that can protect us from virtually any virus that could emerge in the future?"

That's the kind of question David Relman, MD, a professor of microbiology and immunology and of infectious diseases, and the Thomas C. and Joan M. Merigan Professor, whose additional role as the Center for International Security and Cooperation's co-director is all about foresight and preparation, has been asking.

"Getting ahead of the threat gives you a much better chance of deploying measures to defeat or defang it," he said.

Part 1: The hunt for a vaccine that fends off not just a single viral strain, but a multitude

Part 2: Searching for vaccine variability in the land of the flu

Photo: gopixa

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