‘The worst version’ of COVID is spreading. Can we update our vaccines on time?

For the past 18 months, the original COVID-19 vaccines — first as a two-dose series, then as boosters — have done an extraordinary job of protecting us from illness, hospitalization and death. Worldwide, they saved an estimated 20 million lives in 2021 alone. Even today, unvaccinated Americans are twice as likely as vaccinated Americans to test positive for COVID — and six times as likely to die from the disease.

But viruses evolve, and vaccines should too.

That was the big conclusion of a pivotal meeting this week of the US Food and Drug Administration’s expert advisory panel. The question before them was simple: in anticipation of an expected winter surge, should vaccine manufacturers adjust their upcoming booster shots to target Omicron — the ultra-infectious variant that has been on the rise in one form or another around the world for the past seven months — or should they stick to the tried and true recipe for 2020?

The panel voted 19-2 in favor of Omicron boosters on Tuesday. Now the question is which one? version of Omicron should target the next round of shots.

A health professional administers a dose of a Moderna COVID-19 vaccine.

A health worker administers a dose of a Moderna COVID-19 vaccine in Norristown, Pennsylvania, in 2021. (Matt Rourke/AP)

For anyone who hasn’t been paying attention, the Omicron strain that caused last winter’s massive COVID (BA.1) wave is now extinct. In March, it was supplanted by the even more transferable BA.2… which was replaced in May by the even more transferable BA.2.12.1… which is now being replaced by the (you guessed it) even more transferable BA.4 and BA .5.

Experts say BA.5 is the one to worry about: “The worst version of the virus we’ve seen,” as Dr. Eric Topol, the founder of Scripps Research Translational Institute, put it recently. Together, the closely related BA.4 and BA.5 now account for the majority of new US COVID cases, according to the latest data from the Centers for Disease Control and Prevention — but BA.5 (36.6%) is spreading much faster than BA.4 (15.7%). In early July it will be the dominant strain in the US

That is difficult for several reasons. For our immune system, the distance from BA.1 to heavily mutated BA.4 and BA.5 is “much greater,” writes Topol, than the distance from the original BA.1 virus to previous blockbuster variants such as Alpha and Delta, making them harder to spot and answer. According to the latest research, that could mean:

None of this will bring the US back to square one. Despite the increased number of cases, there are now fewer U.S. COVID patients in intensive care units than during earlier phases of the pandemic, and the national death rate (about 300-400 per day) is near its lowest ever. Acquired immunity, multiple rounds of vaccinations and improved treatment options help – a lot.

But coupled with declining vaccine protection and disappointing booster uptake in the elderly, the virus’s accelerating evolution and aggressive new pathway — toward greater transmissibility, evasion and potentially pathogenicity — could cause significant reinfections and disruptions if not addressed.

It could also endanger vulnerable Americans in the coming months.

A person wearing a mask walks past a sign in New York City listing the CDC's guidelines for controlling the spread of COVID.

A sign spotted in New York City in March stating the CDC’s guidelines for controlling the spread of COVID. (John Minchillo/AP)

At the end of April, BA.5 hit Portugal; in June, more Portuguese died from COVID every day than during the country’s winter Omicron peak. Portugal has a larger senior population (23%) than the US (16%), but not much. And the vaccination rate there is 87%, compared to just 67% in America. Portugal’s booster percentage is now almost twice as high as ours. The number of infections and hospital admissions is now rising also in much of the rest of Europe

At Tuesday’s FDA advisory meeting, Justin Lessler, an epidemiologist at the University of North Carolina at Chapel Hill, presented a series of forecasts for how the virus could affect the US in the coming months. The most optimistic scenario? About 95,000 new deaths between March 2022 and March 2023. The most pessimistic? Over 200,000.

So given that BA.5 — again surpassing its cousin BA.4 — will soon be everywhere, it seems logical that the next version of the vaccine would have to be modified to combat it.

However, that was not necessarily the plan. Both Pfizer and Moderna have already launched clinical trials for redesigned fall boosters… but those boosters have been optimized to counteract the now-nonexistent BA.1 rather than the soon-to-be dominant BA.5. According to data presented by Pfizer on Tuesday, their existing BA.1 booster generated significantly lower levels of neutralizing antibodies against BA.4 and BA.5 than against BA.1.

Vials of the Pfizer-BioNTech COVID-19 vaccine are being prepared for packaging.

Vials of the Pfizer-BioNTech COVID-19 vaccine will be ready for packaging in 2021. (Pfizer via AP)

But in mice, a booster containing BA.4 and BA.5 produced at least a higher neutralizing response to all Omicron variants (including BA.4 and BA.5) than the parent vaccine.

Despite concerns about “scarce” data; on whether bivalent boosters (equal parts original strain and Omicron) work better than monovalent boosters (100% Omicron); and on whether it’s worth waiting for Novavax’s promising non-mRNA vaccine to hit the market, the panel largely agreed that BA.4/5 boosters make sense. The FDA is also leaning in that direction. Pfizer said it was “ready” to ship the new boosters in the first week of October; Moderna, by the last week of October or early November – “assuming no clinical data is required.”

That means no human trials — just animal experiments and lab tests. That may sound scary to some, but regulators are already using the same accelerated process to update the flu vaccine every year — and there’s no mechanism by which small mRNA changes will make revised Pfizer and Moderna injections less safe than the billions of doses so are administered worldwide. Otherwise, the US will miss the fall-winter deadline and the rapidly developing virus will continue to evade vaccines.

The FDA itself will decide “very quickly” what to recommend; manufacturers will follow suit.

A syringe is being prepared containing the Pfizer COVID-19 vaccine.

In Chester, Pa., a syringe containing the Pfizer COVID-19 vaccine will be prepared in 2021. (Matt Rourke/AP)

In the future, variant chasing may not prove to be the most effective or efficient approach to COVID vaccination. As Topol put it, “who knows what will be the predominant strain by the time a BA.5 vaccine booster may be available… the predominant strain”? That’s why it was welcome news on Wednesday when Pfizer and BioNTech announced they plan to “start human trials in the second half of the year with next-generation shots that protect against a wide variety of coronaviruses,” according to a report from Reuters.

These include “T-cell-boosting shots, designed to protect primarily against serious illness as the virus becomes more dangerous,” and “pan-coronavirus shots that protect against the broader family of viruses and its mutations.” Nasal vaccines intended to stop the infection before it starts also show promise.

But these are all proposals for the longer term. In any case, this year a BA.5 booster is probably our best bet to minimize infection, illness and death during another likely winter wave.

“I fully expect that there will be further evolution in the coming months, but that this evolution will most likely come on top of BA.4/BA.5 – and thus [it] should not discourage vaccine updates,” virologist Trevor Bedford of the Fred Hutchinson Cancer Research Center in Seattle wrote earlier this week† “I believe that the decision-making process can be reduced to: from vaccine formulations that can be produced in time for fall distribution, which we expect to have the highest [protection] against BA.4/BA.5?”

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