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With the threat of the more transmissible Delta variant and questions around waning immunity following vaccination, healthcare workers are thinking more and more about a third dose of the COVID-19 vaccine.

That's despite the many unknowns on what the true "correlates of protection" are when it comes to immunity, and a lack of hard clinical data that vaccine effectiveness is truly waning.

Still, physicians have been watching as many countries -- , and -- have pulled the trigger on booster doses, especially for more vulnerable populations. Now, they are talking about getting a "booster" for themselves -- even if they're not immunocompromised, and especially if they're 65 and older or if their antibody titers are low.

"I'm not sure I'm willing to wait for the FDA to act on recommending a third dose," , who identified themselves as an MD, PhD in surgery and public health. "I got vaccinated early (in January) and the data from Israel concerns me about my continued immunity. ... I work in a moderately-well vaccinated region (we're not NY, and we're not Louisiana), but not well vaccinated enough for me to feel comfortable."

Robert Schooley, MD, an infectious diseases expert at the University of California San Diego, was more straightforward in a recent interview: "I'm just a guy waiting to get revaccinated."

Other physicians have told 麻豆传媒 that they're concerned about their levels of protection. One California physician who is over 65 said his low antibody titers are a serious concern, and that he's considering a booster. Other doctors he speaks with are considering the same, he said, and they're all using antibody titers as a proxy for making decisions about their protection, even as the CDC still warns against doing so.

They're all eyeing a booster to protect not only themselves, but also their patients and their families -- even though they realize the caveats are many.

The Caveats

that antibody testing shouldn't be used to determine immunity after vaccination, noted Christina Wojewoda, MD, chair of the College of American Pathologists' microbiology committee and director of the clinical microbiology laboratory at the University of Vermont Medical Center in Burlington.

There are many different assays that can measure antibody levels, and some don't even measure antibodies against the spike protein, which is what the vaccine induces. Instead, these tests look for antibodies to the nucleocapsid protein, which would only turn up positive if a person had a prior infection, Wojewoda said.

Schooley also warned that most commercial antibody tests only look for binding antibodies, rather than neutralizing antibodies.

"They don't tell you if the antibodies you're measuring are those that can neutralize, or prevent the virus from infecting cells," Schooley said. While there's a good correlation between binding and neutralizing antibodies, it's not exact, he noted.

Additionally, while people with higher levels of antibodies would be expected to be less likely to be infected, the likelihood of becoming infected also depends on the amount of virus they're exposed to.

Correlates of protection are not yet established, Schooley said, and they're not an easy parameter to establish.

"There's a lot of noise," he said. "If you had 100 people, they'd all have different levels of antibodies. Some would get infected, some wouldn't. Maybe some were exposed for a longer period of time to more virus. It's hard to make a 1-to-1 correlation that would tell you the level of antibody that would trigger revaccination."

What's missing from antibody titer readouts are T-cell and B-cell responses, which are important and likely confer substantial protection, said Alessandro Sette, PhD, of the La Jolla Institute for Immunology in California.

B cells produce antibodies and T cells kill infected cells, Sette said, but these assays aren't really done commercially, save for one FDA-authorized test, T-Detect from Adaptive Biotechnologies (though experts have noted this isn't a true functional assay.)

Emerging data from vaccine and natural infection studies suggest that T and B cells confer good long-term protection against COVID-19, Sette said. He noted that even if the spike protein changes and evades antibodies to some extent, T cells will still recognize infected cells and go after them.

"For a virus to escape a T-cell response, you'd have to mutate so many different parts," Sette told 麻豆传媒. "If you have lower antibody activity but you still have T-cell activity that holds its own ... you may have decreased capacity to prevent infection, but the capacity to prevent severe illness, hospitalizations, and death is still there."

He added that the B-cell response observed thus far has also been impressive, with hints that B cells can continue to increase in numbers months after infection or vaccination, and can continue to evolve to produce additional responses to other variants.

"The data on evolution of B cells are encouraging," Sette noted.

There is a dearth of clinical data on waning immunity. While Pfizer has announced that 6-month data show protection against infection , the study hasn't been peer reviewed.

Sette said that this preliminary 84% overall efficacy rate is still "remarkably good." At this point, he added, there's "no convincing evidence that a booster is needed" -- but scientists "should continue to monitor the situation and address whether there are decreases in the immune response induced by vaccines."

Boosters Inevitable

Schooley agreed that close monitoring for increasing breakthrough infections is needed -- especially for vulnerable populations -- and that regulators shouldn't be so cautious that they don't act fast enough to prevent hospitalizations and deaths, especially as additional doses look like an inevitability.

"We should be careful about waiting too long to begin to revaccinate populations that are getting into trouble," Schooley said. "If we do that, we will be doing people a disservice. Studies are ongoing now, and I'm happy they are, but I don't want us to be so cautious that suddenly on September 1 we realize we have nursing homes seeing big breakthroughs of severe disease."

Nursing home residents were among the first to be vaccinated in January and February, and they were already at a disadvantage in that their immune response to the vaccines may not have been as vigorous, he said. They've also had a longer time for their immunity to decay.

"That's probably the group where we'll see more and more breakthrough infections associated with disease," he noted.

Younger populations who were vaccinated later, and who may have had a better immune response to begin with, are more likely to have residual immunity, though they may have breakthrough infections with viral shedding and minimal symptoms.

"We need to watch those populations that started out at a disadvantage and were vaccinated earlier. We need to be ready to get them revaccinated," Schooley said. "We also need to know who we should study immune responses in to get a better idea of what general levels of immunity should raise red flags in other populations as we go forward."

Stanley Weiss, MD, an infectious disease specialist and epidemiologist at Rutgers New Jersey Medical School, agreed that "it's getting to be obvious that we need a booster. It's already clear for certain groups that we need a booster. And the time is now."

In the absence of availability of booster doses, Weiss reminds doctors that being vaccinated means they're "pretty safe," but advises masking up indoors with a mask that fits well. Improved ventilation systems in their offices could also be helpful, he said, and clinicians should keep an eye out for policy changes.

"I'm hoping federal officials act sooner rather than later and implement something similar to what Israel is doing," offering boosters to those age 60 and up, Weiss said.

Give the Facts, Not the 'Message'

Being upfront about what's likely -- even if it's not conclusive at this time, but strongly suggested -- is important, according to Schooley.

"We've had this flat 'there's no evidence boosters are indicated' message," he said. "The messaging should be, 'yes, we're going to need boosters.' We're studying carefully which populations need them and when they're going to need them. And it's probably going to happen some time in the next several months."

Schooley equated the messaging around boosters to that of mask-wearing, in that people will question advice if it seems to be an about-face from previous policy.

"The message lost through this whole pandemic is that we may give different advice as conditions change," he said. "It's not because the underlying science has changed, it's because the conditions have changed."

Cheryl Clark contributed to this report.

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