US may default to annual Covid boosters without sufficient data

A number of vaccine experts are concerned the United States may be sleepwalking into a policy of recommending annual Covid-19 vaccine boosters – without having generated the evidence to show they are actually needed.

Already, the Food and Drug Administration has authorized second boosters – or fourth doses – for people aged 50 and older, even though neither that agency nor the Centers for Disease Control and Prevention has explicitly urged people to get them. Based on recent meetings of panels that advise the FDA and the CDC, many vaccine experts assume another booster will be recommended in the fall in anticipation of a possible surge in Covid activity during the cold and flu season next winter.

Meanwhile, several vaccine manufacturers have said annual boosters will be needed and are working on combined flu and Covid vaccines that could be deployed every autumn.

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The developments have some experts warning that the US may be headed towards a policy of annual boosters as a sort of default position, not one arrived at by careful scrutiny of the evidence on how well vaccine protection is holding up.

“It’s alarming that there has not been organization around these vital questions, so that we can actually answer them in a very enlightened and data-driven and knowledgeable manner,” said Luciana Borio, a former acting chief scientist at the FDA who is now a senior fellow for global health at the Council on Foreign Relations.

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“It’s so reactive,” Borio said during a briefing for journalists organized by Georgetown University Medical Center. “And we know that this is just snowballs. And we end up being stuck with decisions that do not really make sense. ”

Paul Offit, a pediatric infectious diseases clinician at Children’s Hospital of Philadelphia and a member of the FDA’s vaccine advisory panel, said there is enormous pressure mounting to move to a system of annual Covid boosters. He cited an April 6 meeting of the panel, the Vaccine and Related Biological Products Advisory Committee, or VRBPAC.

“The only question was what were we going to boost with, not whether we were going to boost,” said Offit, who has repeatedly questioned the need for additional booster doses at this point. “We did not define what the goal of this extra [shot was]. ”

A key part of the problem, experts say, is the heavy reliance in public policy discussions on measurements of antibody levels among the vaccinated. These easy-to-generate data are predictive of our risk of catching Covid – as they decline, the risk rises – but aren’t indicative of whether our risk of developing severe disease is increasing.

“I’m distressed by the paucity… of data other than antibody data that we really need to design better vaccines or use these vaccines better. Know when to boost – things like that, ”said Jesse Goodman, a former chief scientist at the FDA and a professor of medicine at Georgetown University.

Booster shots shore up that protection against mild infection, but only for short periods of time.

“Any protection we get against infection – mild infection, asymptomatic infection – is going to be time-limited. Likely very time-limited. The severe disease protection is more durable, ”said Kathleen Neuzil, director of the Center for Vaccine Development and Global Health at the University of Maryland School of Medicine.

Immunologists and vaccinologists have been pointing out for months that the current crop of Covid vaccines are not going to be able to fend off mild infections. But they also note that the protection the vaccines induce against severe disease and death is not waning in any significant way.

“The efficacy data that I’ve seen from the CDC meeting” – the CDC’s vaccine experts on the Advisory Committee on Immunization Policy met last week to discuss boosters – “and lots of other data really shows that our protection from severe disease is holding up pretty well, ”said John Wherry, director of the Institute of Immunology at the University of Pennsylvania’s Perelman School of Medicine.

“We’ve created this public perception that when antibodies are declining, everything’s gone. And that’s not correct, ”he said.

But predicting protection in the face of a looming wave of cases is hard to do without more data.

Last week Wherry and several dozens of experts signed a letter urging the FDA to put more emphasis on assessing additional parts of the immune response to Covid vaccines, arguing that measuring T cells is critical to fleshing out our understanding of how long-lasting vaccine protection is . They asked the FDA to revise its guidance to vaccine manufacturers to ask them to make a greater effort to measure T cell responses. Borio was one of the signatories.

“I think there are a lot of forces here that have had us almost myopically assessing antibodies as the guiding force in what immune measurements are most important,” Wherry told STAT in an interview. “The antibody trajectories do not explain the fact that nobody’s ending up in the hospital.”

T cells are a part of the adaptive immune system, the part that remembers previously encountered threats – through infection or vaccination – and fights them off if they reappear. They both kill cells that have already been invaded by the incoming threat and stimulate production of B cells, which produce antibodies.

T cells are harder to measure than antibodies, hence the heavy reliance on antibody-based metrics. But there have been recent advancements in procedures to measure T cells that improve the precision of the work and make it more scalable, the authors of the letter argued. The letter also suggested the FDA encourage industry to develop better and easier to use T cell assays.

“If we had a better sort of overall understanding of T cell responses and their durability, we might be able to A) make some more rational decisions about when to boost based on what we expect the boost to do – that is, protect from all disease or protect from hospitalization and severe disease? – and B) create public messaging that creates the right expectations, ”Wherry said.

Neuzil, who in her pre-Covid career focused a lot on influenza, can see the rationale for boosting this fall. And maybe every fall – or at least at regular intervals.

The worst waves of the pandemic have occurred during the past two winters. If the thinking is that pattern may repeat itself this winter, it would make sense to boost before that happens, she said.

“You unfortunately have to make the decision to vaccinate before you know how bad the season is,” Neuzil pointed out. Covid is “still the overwhelming respiratory virus that’s causing severe disease and death right now. And to me, it does justify serious consideration of a fall booster to mitigate against what would be a third straight winter surge, were it to occur. ”

But continually boosting will make it impossible to determine when boosters are actually needed, Wherry and others argued.

“What we need to understand is where do we really settle in for durability of protection after three doses or if we decide it’s four doses, after four doses? What is the steady state level of vaccine efficacy that we have and how durable is that over time? ” he said. “And if we keep boosting people, we’re never going to get the answer to that question. I worry about that. ”

Even though Neuzil can envision a situation arising where we need regular boosters, she can see Wherry’s point.

“We’re making decisions based on very short-term data,” she said. “The more that we do that, the more that we get in a cycle of doing that because the more we can not learn. … Those decisions make it tough to wait and see if there are better options. ”

These decisions have implications. Public health experts are worried that the message being sent to a Covid-weary public by the addition of a fourth and potentially a fifth shot in the fall is that the vaccines aren’t all they were originally cracked up to be.

And there’s evidence some Americans – people who got vaccinated – are tuning out. Nearly half of the people who are eligible to get a first booster shot have not yet done so. The expectation is that uptake of the second booster will be poorer still.

“I’m very concerned about booster fatigue. And I’m also very concerned about people losing confidence in the vaccination program, ”Beth Bell, a member of the ACIP, said during last week’s meeting.

Borio said a more deliberative decision-making process is needed to determine whether we need annual Covid boosters.

“We may need it. It’s just that it’s just not clear at this moment, ”she said. “Whether we need it or not is also predicated into how the virus evolves and how population immunity holds up over time.”

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