Covid Just Messed with the Wrong Team

Sharpening our swords

I bet Covid wishes it could have given me serious brain damage. As I’ve outlined in the last few posts, seeing the strange and interesting dynamics of Covid infection firsthand has been sparking my creative imagination about how to kill the little bastards. One strategic victory a personified Covid might have thought it scored was when its multiple rebounds prevented me from flying to Italy for the annual Small DNA Tumor Virus Meeting - where I was slated to give a talk about a new vaccine approach being developed by two brilliant postdocs in our group, Safoura Soleymani and Amin Tavassoli. I’m increasingly imagining the new vaccine approach could be retooled for next-generation Covid vaccines. But the joke’s on Covid. My scientific partner Diana Pastrana delivered the talk in my place and colleagues report she knocked it out of the park. Sorry, Covid. We are still coming for you¹.

The basic idea behind Amin and Safoura’s work is that if you don’t have to inject a vaccine using a needle then the usual time-consuming industrial-scale purification processes that require expensive equipment suddenly become unnecessary. If we could kick the expensive habit of using needles, we could theoretically have cheap food-grade vaccines. In a sense, the idea is simply harking back to older vaccines - such as early smallpox vaccines that were delivered intranasally or scratched into the skin - or oral polio vaccines that were sometimes delivered on a tasty sugar cube. In grad school I was taught that needle-free approaches only work because they use a live virus that’s capable of replicating and spreading to other tissues. That dogma has since been disproven by modern cholera vaccines, which consist of drinking some fluid that contains a harmless subunit of the cholera’s major toxin. Food-grade vaccines don’t have to be replication-competent.

Although we’ve been working to develop a traditional injection vaccine against polyomaviruses (disclosure: I receive commercial licensing royalties for that vaccine project), I still have residual intellectual trauma from the fact that it took us several years to convince investors to commit millions of dollars to producing purified polyomavirus-like particles in an expensive state of the art facility. And by “us” I actually mean Diana. She and I are both skilled in the art of talking to fellow scientists, but our licensing efforts revealed that I’m remarkably bad at convincing any investors to do anything - whereas Diana has some type of superpower. Diverse teams are stronger teams, as the saying goes.

In her talk at the Tumor Virus Meeting, Diana presented Safoura and Amin’s exciting emerging data showing that purified replication-incompetent polyomavirus-like particles (VLPs) give good vaccine responses when delivered intranasally or when applied to the skin with a cosmetic derma-roller. We’ve also been finding that brewer’s yeast engineered to express VLPs give pretty good immune responses when delivered intranasally or intradermally.

NASA has the famous motto “faster better cheaper.” Immune responses against the new food-grade vaccines aren’t necessarily “better” than traditional injection vaccines, but they’re definitely opening the door to an approach we’re calling “faster easier cheaper.” We can probably also add “safer” to our motto. Not to mention, “people like it more than getting jabbed with a needle.”

We initially chose brewer’s yeast because our collaborators Alma Gedvilaitė and Emilija Vasilliūnaitė had already developed robust yeast-based VLP expression systems. In parallel, we’re developing bacteriophages that can express polyomavirus VLPs in the types of bacteria that are used to ferment yogurt.

The new thinking my Covid infection inspired has suddenly expanded my view of which microbes we might want to use for food-grade vaccine approaches. The ideal vehicle would be something people routinely use as a food or probiotic and - importantly - the vehicle should be known to induce an effective Th1 response without the type of ineffectual IL-4/histamine/mast cell/allergic/worm-fighting/Th2 responses I hypothesize are flummoxing the immune system during Covid infections (see: “Bullfighting Covid”). Two examples of the ideal vehicle might be the Th1-skewed probiotics Saccharomyces boulardii and Latilactobacillus sakei. If anybody has any favorite organisms to suggest, we’re all ears².

It’s conceivable the food-grade vaccine approach could be used to experimentally test the hypotheses presented in “Latency, Long Covid, and the Dreaded Rererebound.” The basic idea would be to load SARS-CoV-2 early proteins, such as defanged NSP3, into a VLP by fusing it to a minor capsid protein. The NSP3-bearing VLP could then be expressed in yeast or bacteria and we could see whether nasal or dermal exposure to the food-grade VLP preparation reduces the odds of having the type of Covid rebounds my husband and I just unhappily experienced. To the extent that latent infections are a primary driver of long Covid, it could also be interesting to see whether a food-grade NSP3 vaccine might make long Covid sufferers feel better by eradicating latently infected cells.

Our team is small - consisting of Diana, Amin, Safoura, and a fifth team member, Claive Asiedu, who has been helping Safoura and Amin wrangle VLP production in yeast. I would love to see a thousand times more people independently working on food-grade vaccines. The most powerful aspect of the idea is that you don’t have to convince investors to give you millions of dollars for fancy equipment. The approach is simple enough that it could conceivably be within reach of a Science House kitchen. Are your ears burning yet,

Adam Mastroianni

?

Covid. Must. Die.

1. Song of the day: “Iron” by Woodkid

2. I’m increasingly a fan of a new AI search engine called Perplexity.ai. Asking it, “does [my favorite probiotic organism] induce a Th1 or a Th2 immune response” could be a fun way of taking it for a quick spin.