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COVID is not a "one and done" thing—far from it.

Those who are unvaccinated and don't mask can expect to come down with COVID once a year or so—once every other year for the unvaccinated who regularly use a "good quality" mask in public, according to modeling by drug developer Fractal Therapeutics.

As for the vaccinated, both masked and unmasked, they can expect to get COVID "a lot less frequently," though it's impossible to say just how often, said Arijit Chakravarty, a COVID researcher and Fractal Therapeutics CEO.

"The bottom line is if you are planning not to use a mask and live your life as usual, expect to get infected at least once a year, if not more," he said. "If you're planning to mask everywhere but at home, that probably cuts the risk in half."

The team's latest models accounts for waning immunity from vaccines and prior infection, and a certain degree of immune evasion, as has been increasingly seen in Omicron subvariants. It also assumes that with each round of infection, a person gains some measure of protection against the sometimes deadly virus, albeit temporary.

It does not account for the possible evolution of a variant that completely evades immunity, he cautioned.

The modeling focuses on the unvaccinated because "vaccines are not currently providing protection against infection" for the majority of the U.S. population, though they are providing protection against severe illness and death, Chakravarty said.

The percentage of Americans who've received one booster is small—46.5%, according to the CDC—and smaller yet for a second booster: 19.7%. Regardless, "boosters only provide a short duration of protection against infection," he said. Immunity, whether from vaccine or prior infection, is thought to wane after three or four months, though it varies by person.

The case for a nasal vaccine

Chakravarty's team also ran simulations in which the vaccine is still undermined by immune evasion, but the public is able to "dose over and over again" with current vaccines.

"If we assume that each new round of vaccine gives you a 15-fold jump in antibody titers—yes, in fact, if you vaccinate very often, you can probably massively reduce the risk of being infected," he said.

The hypothesis "might well be worth testing in the real world," he said. While few would want to deal with a jab and current vaccine side effects every eight weeks or so, more might be willing to take a readily available nasal-mist vaccine, which may cause fewer side effects.

Variants are outpacing current vaccine technology, potentially rendering it completely ineffective in the future. But "we haven't fully explored the range" of what that technology can provide in the way of protection, Chakravarty said—not yet.

"More research needs to be done on this—in addition to coming up with vaccines that work better against the current viral variants, vaccines that can be used nasally—exploring how often vaccines can be given, and how much of a boost to our neutralizing antibodies we could get from frequent administration.”

Such research might not require full clinical trials, but could start by looking at neutralizing antibody titers and asking the question, "What course of vaccine doses provide higher titers while still being acceptable from a safety standpoint?" Chakravarty said.

"It's a relatively low-cost thing to fund and could yield benefit, even as we're exploring next-generation vaccines."