Fresh details from the world’s first major study on fourth-dose COVID vaccines bode ill — but not as ill as it may seem.
Antibody levels rise significantly after a fourth shot of the Pfizer vaccine, researchers at Sheba Medical Center announced on Monday.
“What we see is that after two weeks, the Pfizer vaccine gives an enhancement or increase in the number of antibodies, including neutralizing antibodies,” said Prof. Gili Regev-Yochay, a lead researcher in the experiment, in a press briefing.
There is a “a pretty nice increase, even higher than what we had after the third dose,” she said, noting that it had risen a little since she reported last week that the booster gave a fivefold increase, but declining throughout her briefing to give more numbers.
But the rise that she documented “is probably not enough for Omicron,” she lamented, meaning that it won’t deliver highly effective protection against infection by the fast-spreading variant.
As elderly and at-risk Israelis who were the world’s first population to take fourth shots en masse desperately try to understand whether it’s made them safer, it was an answer of sorts — but one that left important questions hanging.
The study is small, with around 150 participants — Sheba employees who received fourth Pfizer shots last month. There were 120 others who received a Moderna shot, after earlier getting three Pfizer shots, and they are building antibodies at a similar rate but are at an earlier stage of the experiment.
Regev-Yochay said there have been some infections among the fourth shot recipients, but her main variable for the study is antibody counts. And what makes her research an important one is that it includes context for what the measurements may mean in Omicron vulnerability.
This is because Sheba has been tracking antibody levels of a 6,000-strong control group for months — and in recent weeks cross-referencing them with rates of Omicron infection. When Regev-Yochay said antibodies of fourth-shot recipients probably aren’t enough to prevent Omicron infection, she meant they’re commonly within ranges at which many in her control group are getting infected.
Experts say the results don’t come as a surprise. “In a sense they were expected,” Bar Ilan University immunologist Prof. Cyrille Cohen, who wasn’t involved in the Sheba study, told The Times of Israel. “They reflect the fact that the Omicron spike protein is extremely different from the spike protein included in the vaccine.”
But the truly important question was not addressed in the study, Cohen observed, noting, “What we should be measuring is how many of them end up in severe condition — this is what we need to know, and not how many are vulnerable to infection and just testing positive.”
Cohen was a co-author of a seminal study, published in The Lancet, that found that the third shot was 92% effective in preventing serious illness — mostly against the Delta variant — compared to those who received only two doses.
“It’s difficult to predict what the equivalent figure will be for effectiveness of fourth shots in reducing serious illness against Omicron, but I do expect, or at least hope, that it will help — yet any contribution is expected to be smaller than it was against Delta.”
Cohen emphasized that while antibody levels can be a reasonable indicator of infection risk, assessing vulnerability to serious disease is far more complex.
“You can’t only predict this based on antibodies alone,” he said. “Protection from severe disease involves other immune components such as T-cells, and since the reactivity of the latter is not measured, it is difficult to say how this will pan out for different people.”
The Sheba research is important but is unlikely to deliver this data with the precision needed, Cohen believes. This is because the overall sample size of fourth-shot recipients is small, and among these the number that get seriously ill is likely to be too small to draw reliable conclusions.
What’s more, he said, the study is focused on the wrong demographic to deliver the conclusions that are needed. It’s conducted on hospital workers, who received a fourth shot on the basis of increased exposure to the coronavirus — a very different reason from the rationale behind boosting most fourth-shot recipients, namely disproportionately high chances of serious illness if infected.
“While this research makes an important contribution to medical knowledge, I’m not sure to what extent this research will be able to show effectiveness in the vulnerable group, since it’s a trial with a small sample and given it’s a hospital staff in which there is a lot of young people whose response to infection could be markedly different to the older patients who are our real Omicron concern,” Cohen said.
Though the report is pessimistic about the ability of the fourth shot to prevent infection, it is agnostic on its ability to lessen the chances of demise, Cohen noted, saying: “More data on the fourth dose impact is crucially needed and it may very well be that we shall see at least a modest benefit in giving it to the most vulnerable people.
“I trust that with the current high infection rate and the fact that over half a million of Israelis received the fourth dose, it is likely that within two to three weeks, we will get a ‘real-life’ estimation of the effectiveness of this second booster shot in preventing serious illness, and an estimation of its value.”
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