To boost, or not to boost, that is the complicated question

Lisa Jarvis

The Food and Drug Administration has authorised a fourth dose of COVID-19 vaccines — a second booster — for people 50 and older (in the United States). But is a fourth dose really necessary, or beneficial?

This is a question that health officials worldwide are scrambling to answer.
European regulators have said there’s no need yet for fourth shots, but European countries are setting their own schedules for extra doses. Sweden is giving the additional shot to people over the age of 80, while Germany set the bar at 70.

Israel initially picked 60, and the United Kingdom is offering a second booster only to the immunocompromised.

The lower cut-off of 50 in the US is perplexing. It’s below the age threshold for people typically considered at high risk, and sits between the ages that the two mRNA vaccine makers requested. Moderna wanted approval for anyone older than 18, while Pfizer limited its ask to people over 65.

Unfortunately, none of these recommendations is based on the kind of robust data on vaccine effectiveness that guided the use of the original doses. And the FDA authorised the second boosters without input from its panel of vaccine experts, which meets next week.

All this creates a conundrum for anyone considering whether and when to get that fourth jab. Here are four questions to weigh in making the decision.

What is the FDA trying to achieve by rolling out second boosters?
The agency seems to be trying to get ahead of a potential new wave of infections with the BA.2 omicron subvariant. BA.2 is already causing an uptick in cases in Europe, even in places where vaccination rates exceed those in the US. And the CDC’s wastewater data suggest that in some parts of the US infections are rising.

Nevertheless, health officials can’t be sure that the US is on the cusp of another wave. And even if one comes, vaccinations and widespread exposure to omicron and earlier variants could make it less severe than previous outbreaks. On the other hand, indoor masking rules and vaccine requirements have been lifted virtually everywhere, so the virus will have a relatively easy time spreading among the vulnerable.

For that reason, and because of what’s known about waning antibody levels in people who have had the first booster, some vaccine experts say a fourth shot isn’t a bad idea for those in higher risk categories. The immunocompromised already had been cleared for an extra boost, and now the FDA says that middle-aged and older people could enhance their personal safety by getting another shot.

These second boosters aren’t meant to build herd immunity — that ship sailed long ago. But if the most vulnerable people get the shot, that might at least hold hospitalisations from new COVID-19 variants to a minimum.

What is the evidence to support a fourth shot?
Plenty of data suggest that levels of neutralising antibodies created by vaccination wane over time. It’s also known that the immune response that older people mount following vaccination is less strong than that in younger people, and the older folks experience a more precipitous drop in virus-fighting antibodies. The key unknown is whether a fourth shot can boost antibody levels in a way that offers meaningful protection.

The real-world evidence on fourth shots comes from Israel, which in early 2022 began giving them to healthcare workers and people over 60. That evidence has been mixed. In February, a small study (not yet peer-reviewed) suggested that, in Israeli healthcare workers, a fourth shot of the Pfizer/BioNTech vaccine propped up antibody levels, but that did little to prevent mild or asymptomatic infections.

Another disappointing finding in that report: The extra booster didn’t seem to enhance the T-cell response. If antibodies are the bouncers that keep virus out of cells, T-cells handle any rogue virus that slips past the door and starts to replicate. While they can’t prevent infections, T-cells are the more durable side of the immune response — the part that can recognise subtle changes in the virus and keep any breakthrough infections mild.

Israeli researchers also noticed that fourth doses failed to push antibody levels any higher than they were after a third shot. This suggests there may be a ceiling on the value of boosting. “It stands to reason that eventually you get to a point where there are diminishing returns,” says Alessadro Sette, an immunologist at the La Jolla Institute for Immunology.
There’s a lot more to learn.

Should people get the second booster simply because they’re eligible?
Here, there’s no one-size fits-all answer. Doctors largely agree that for people over 65, who stand an increased risk of severe infections, the rationale for a boost is stronger. Ted Ross, director of the Center for Vaccine and Immunology at the University of Georgia, says he told his mother, who is nearly 80, “If you’re offered, take it.”

For those under 65, the equation isn’t so simple. The third dose is still keeping younger people out of the hospital, says immunologist E John Wherry of the University of Pennsylvania.

It’s also worth factoring in lifestyle. For anyone who’s still sticking close to home, the fourth shot might not have much value yet. But for those who’ve gone back to traveling and eating out, it may make sense.
Weighing the disruption of mild COVID-19 on everyday life is also important — though data are sparse on how well a fourth dose might lower the risk of mild infections.

Will another booster be needed in the fall? Every year?
Maybe. People will probably need some sort of regular immune-system nudging to keep COVID-19 in check. Ideally, future boosters will be better than the ones used now.

The existing shots train the immune system to recognise the virus’s spike protein, but that is the part that changes most with each new variant.
Vaccine makers are already developing new variant-specific vaccines, but a better strategy might be to design boosters that include parts of the virus that tend to stay the same, even as other pieces mutate. Cultivating an immune response to those components might not improve the chance of preventing infections, but it could provide more lasting protection.

Lisa Jarvis, the former executive editor of Chemical & Engineering News, writes about biotech, drug discovery and the pharmaceutical industry for Bloomberg Opinion. Views are personal, and do not represent the stand of this publication.