The hunt for a vaccine that fends off not just a single viral strain, but a multitude – Scope

Part 1: This is the first of a three-part series on how Stanford Medicine researchers are designing vaccines that might 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.

There were germs way before there were people. Fortunately, we've made friends or at least signed peace treaties with many of them. But others remain our enemies. Still others are a mutation or two away from slipping from one category into another.

The annual sniffling season is upon us, as cases of COVID-19, respiratory syncytial virus and perennial old-timer influenza pile up. Lurking in the background: wild cards such as a killer avian influenza virus that is, as yet, not easily transmitted from one human to another.

"During a wave of infections back in the 1990s, certain bird flu strains were killing half of the people who were getting them," said David Relman, MD, a professor of microbiology and immunology and of infectious diseases, and the Thomas C. and Joan M. Merigan Professor. "Fortunately, that wave petered out -- but what if that virus had mutated to become more transmissible among human beings?"

Relman, co-director of the Center for International Security and Cooperation, thinks a lot about potential, emergent and present microbial threats. (CISAC brings together natural and social scientists to take on the world's most critical security issues.)

"Thousands of potential threats fall into these categories," Relman said.

Respiratory viruses endanger entire populations. A single sneeze, cough or shout can spew billions of infectious viral particles into the air to lounge for hours before lodging in innocent passersby's airways, spreading from there to points unknown. All you have to do is walk into the wrong restaurant or office.

Respiratory virus transmission typically peaks in winter, when people congregate in closer quarters indoors.

Our immune systems, built over evolutionary time to fight off microbial pathogens, usually do better the second time around, assuming they survive the first pass.

That's where vaccines come in. Vaccination is a dress rehearsal for an infection. A classical vaccine displays, in a non-threatening way, one or more of a pathogen's defining biochemical features, or antigens, to various cells of the adaptive immune system, whose job is to carefully note and memorize particular antigens belonging to the pathogen of interest. When the real thing comes along, that memory will rouse those normally dormant immune cells to jump up, pump up and punch out that pest's lights -- preferably before it can invade any cells.

When antibody-producing immune cells called B cells sense a microbial invader's presence, they become prolific and productive. Each activated B cell produces large amounts of a distinctly shaped antigen-grabbing antibody, which clings more or less exclusively to a single antigenic section of the germ.

In their own way, germs have studied Darwin's law more carefully -- certainly for far longer -- than we have. They've learned to survive and thrive through trial and error. They are especially prone to mutation. This results in some bugs' antigens undergoing some nanoscale shape shifting, enabling them to shake off the antibodies B cells have dispatched to fight them off. Antibody-resistant microbes are free to proliferate, giving rise to new strains.

Influenza viruses and coronaviruses are particularly prone to mutation and consequent immune evasion. With all this shifting, there's typically more than one strain circulating at a time, forcing vaccinologists to guess which of these strains they should immunize against.

In the case of SARS-CoV-2, the virus that causes COVID-19, it took a mere 326 days from identification of gene sequence to the emergence of a vaccine, said Bali Pulendran, PhD, a professor of pathology and of microbiology and immunology and the Violetta L. Horton Professor. "But we were lucky: We already knew about SARS1 -- a somewhat related coronavirus that emerged in 2003 in Asia which, although highly lethal, was fortunately not highly contagious. And we knew about other coronaviruses. We may not be so lucky next time."

"It would be wonderful if you didn't have to be so granular in deciding what to cover," Relman said. "You wouldn't have to be as lucky or savvy or insightful."

With this in mind, Stanford Medicine researchers are coming up with more-inclusive vaccines designed to protect people from not just single viral strains but broad ranges of them, including some not yet encountered.

The best-known SARS-CoV-2 antigen is "Big Spike," aka the infamous spike protein, which pokes out of the viral particle's surface and is essential for locking onto and penetrating the target cell's outer membrane. The spike protein is very immunogenic -- visible to the immune system -- and antibodies targeting it can prevent SARS-CoV-2 from infecting a cell.

In real life, the virus's spike proteins come in threes. Peter Kim, PhD, the Virginia and D.K. Ludwig Professor of Biochemistry, and his lab mates have shown that bunching up a lot of these spike-protein threesomes on the surface of a nanoparticle can make that nanoparticle look a lot more like a SARS-CoV-2 viral particle than scattered lone spike proteins do to antigen-presenting cells. These are immune cells that, on crossing paths with foreign objects such as viruses, suck them in, chew them up and display bits of their prey on their surfaces in a way that's ideal for enhancing the chances that other immune cells will notice and, among other things, fire up the production of antibodies targeting the appropriate microbial menace.

Kim's team also increased the spike protein's immunogenicity and stabilized it by, respectively, chopping off a chunk of it and making a couple of chemical substitutions in the molecule.

"The practice in the United States and elsewhere has been to chase each new SARS-CoV-2 variant by continually updating a vaccine to reflect whatever recent dominant strain happens to be trending," Kim said. "Our construct is the opposite. We're using spike proteins identical to the ones found on the surface of the original strain that emerged from China in late 2019. Yet this vaccine is effective against all the variants we've tested it against, including omicron."

It even worked against SARS1, Kim said.

"We're getting a very durable response in monkeys," he said. "Now we're going to see what happens in humans."

Coming Wednesday: Part 2: A Cure for the Flus?

Photo: Numstocker

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The hunt for a vaccine that fends off not just a single viral strain, but a multitude - Scope