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Pfizer and Moderna say fourth doses of COVID-19 vaccines may be necessary, but many Canadians still haven’t gotten a third shot.

COVID booster uptake stalling as experts debate fourth shots

As Canadian provinces are lifting mask mandates and proof of vaccination policies, experts are worried that only 56% of adults, and far fewer children, have received three doses of a SARS-COV-2 vaccine. Meanwhile, vaccine manufacturers are warning that fourth doses may be necessary to maintain immunity.

Canada has enough vaccine supply to offer third doses to everyone who is eligible, but uptake has slowed dramatically in recent weeks. As of mid-March, Newfoundland and Labrador had the highest booster coverage at about 66%, while Saskatchewan had the lowest at 45%.

Why is booster uptake slowing?

“We’re basically in a situation where people either don’t have the appetite for third doses anymore,” or they’ve been infected and have to wait three months before getting a booster, said Peter Jüni, formerly of Ontario’s COVID-19 science advisory table. Based on wastewater analysis, some 3.5 to 4.5 million people in Ontario alone may have been infected with SARS-CoV-2 since December 1.

Jeff Kwong of the Institute for Clinical Evaluative Sciences in Toronto attributes slowing booster uptake to a combination of “complacency, hesitancy, and access” issues.

“A lot of people think, ‘I’ve already had my two doses. This Omicron is not that bad. I don’t need another dose.’ or maybe they’ve already had an infection, so they feel they don’t need it,” Kwong says.

Meanwhile, it’s possible that the booster campaign hasn’t benefited from “the same push” as the first two doses, he says.

Calling a third dose a booster may also be a “double-edged sword,” and mislead people to think it’s not necessary, according to Catherine Hankins of the COVID-19 Immunity Task Force.

With immunity waning over time and more infectious variants circulating, “we do need to have that third dose,” Hankins says. Effectively, “it is a three-dose series.”

A third dose restores immunity – but for how long?

While two mRNA vaccine doses still appear to protect against severe COVID-19 and death, “we don’t understand fully how well all arms of the immune system are working,” Hankins says.

“The longer you go out from that second dose,” the more antibody levels decline, and the less protection SARS-CoV-2 vaccines offer against infection, she says. However, cellular immunity and the protection it provides against hospitalizations and deaths is “probably equally important,” although harder to measure.

A preprint study from Ontario showed that two doses of available SARS-CoV-2 vaccines were 80% effective against infection with the Delta variant after eight months but offered no protection against infection with Omicron after six. A third vaccine dose brought efficacy to 97% for Delta and 61% for Omicron.

For both variants, efficacy against hospitalization and death after a booster was greater than 95%.

“That’s why having three doses of the vaccine, even if you have had an infection, is still a good idea,” says Kwong, who coauthored the study.

However, it’s unclear how long good protection from a third shot will last.

Studies from Qatar and the United Kingdom show that protection against symptomatic infection dropped below 50% within a few months of a third dose.

More recent data from the UK show that booster vaccination remains more than 70% protective against hospitalization and death in people with breakthrough Omicron infections.

Likewise, the United States Centers for disease control and prevention reported that vaccine effectiveness against hospitalizations dropped within four months of receiving a booster from 91% to 78%.

Yet, even at the peak of the Omicron wave in early January, three vaccine doses were 94% effective at preventing the very worst outcomes of COVID-19 – mechanical ventilation and death.

Will a fourth dose be necessary?

According to the head of Pfizer, fourth doses are necessary “right now,” even though the protection offered by three doses remains “quite good for hospitalizations and deaths.”

Canada’s National Advisory Committee on Immunization currently recommends fourth doses for people who are immunocompromised, but most provinces are also offering fourth shots to seniors. Both groups may face increased risks of severe illness and greater declines in vaccine efficacy than the general population.

Otherwise, experts remain divided on the value of repeat boosters.

Some argue the goal of vaccination should be to prevent severe disease and deaths, not infections, so three shots may be sufficient for most people so long as efficacy against hospitalizations holds steady.

Others argue it makes more sense to focus on distributing vaccines globally and developing new variant-specific vaccines rather than repeatedly using the same shots in a few wealthy countries, with diminishing returns.

Financial considerations may also factor into the rollout of additional boosters. The White House recently announced it has exhausted funding to buy fourth doses for all Americans.

Meanwhile, the evidence to support four doses is limited.

Interim data from Israel, one of the first countries to offer additional boosters, found that a fourth vaccine dose restored antibody levels to third-dose peaks, but did not surpass them – suggesting we’ve hit the upper limit of immunity conferred by more of the same shots.

One pre-print observational study found that rates of confirmed infections and severe disease were 2 and 4.3 times lower, respectively, among people who received two Pfizer boosters versus one.

Immunity beyond antibodies

Waning immunity is normal and expected, says Steven Kerfoot, an associate professor of microbiology and immunology at Western University in Ontario.

“When you’re either infected or vaccinated, your immune system has to learn the specific thing it needs to attack, and mounts a very large response,” Kerfoot explains. “But this is an emergency status for the immune system and that’s unsustainable in the long term because eventually, you’ll need to fight off something else.”

While antibody levels are a good measure of immunity, “there’s a lot more to the immune system,” he says.

Cellular immunity is much longer-lasting but much harder to measure, says Maria Tokuyama, a viral immunologist and assistant professor at the University of British Columbia.

Even if antibody levels decline, memory B cells can generate more if the body reencounters a virus, while T cells will seek and destroy infected cells.

A recent paper in The Lancet Microbe found that while the body’s neutralizing antibody response to SARS-CoV-2 seems to drop over time, and varies depending on the strain of the virus, T-cell responses were still detectable one year after infection, even in people who had no neutralizing antibody response.

Other research has shown that levels of SARS-CoV-2 specific memory B cells increase for at least six months after infection, even as antibody levels decline. According to the authors, “these vaccine-induced memory B cells were also capable of rapidly generating new antibody responses,” which may explain why vaccine efficacy against hospitalizations and deaths remains high, even if protection against infection declines.

Photo credit: iStock.com/Wachiwit

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