Experts torn over changing vaccine doses to speed up lagging rollout

To speed inoculations, the U.S. plans to release all available vaccine doses and open access to anyone over 65. Others suggest straying from recommended doses or intentionally delaying boosters. The best way forward remains uncertain.

AS COVID-19 CASES surge across the U.S., officials are facing increasing pressure to dole out vaccine doses as quickly as possible.

Today, the Department of Health and Human Services (HHS) announced that it will release the rest of its vaccine stockpile to prioritize getting residents their first dose of the vaccine. The policy change comes just days after a spokesperson for the transition team of President-elect Joseph R. Biden, Jr. said the new administration planned to release additional doses of the vaccine.

The HHS also encouraged states to vaccinate people ages 65 and older, as well as those who are immunocompromised and may be at a higher risk of contracting serious cases of COVID-19. Past inoculation efforts prioritized frontline healthcare workers and the elderly in nursing homes.

These changes come amid more extreme proposals that would alter the ways the vaccines are administered to meet the urgent crisis—even if that goes against the proven regimens from vaccine makers and the recommendations of leading experts on infectious disease.

As of today, about 25 million doses of the two vaccines authorized for use in the U.S. have been distributed across the country—but fewer than nine million have been given to patients. Most experts interviewed for this article agreed the U.S. is not facing a vaccine shortage. Instead, the nation is grappling with a combination of a slower-than-anticipated rollout, rising COVID-19 cases, and the arrival of a new, more transmissible variant of the virus.

Last week, Operation Warp Speed Chief Advisor Moncef Slaoui raised the possibility of halving the doses of the vaccine created by biotechnology company Moderna. In response, the National Institutes of Health announced it would work with Moderna to examine the efficacy of administering lower doses of the vaccine, which showed 95-percent efficacy in trials of its full dosage. In theory, this tactic would double the amount of the vaccine available in the country while still allowing people who get vaccinated to receive two shots.

Tinkering with the dosage rather than developing more effective ways to use existing stock is “the right answer to the wrong question,” says Anthony Fauci, the longtime director of the National Institute of Allergy and Infectious Diseases. “The disconnect is not that we want to stretch out the doses, but we want to be more efficient in getting the vaccine into people. If the time comes that we don't have enough vaccine, then you should seriously consider the half-dose approach.”

For now, the U.S. Food and Drug Administration has rejected the idea of halving the doses. In a statement released last week, the agency said that while changing the dosage is worth future clinical exploration, “at this time, suggesting changes to the FDA-authorized dosing or schedules of these vaccines is premature and not rooted solidly in the available evidence.”

The FDA has also rejected another way governments elsewhere are trying to stretch their vaccine supplies: delaying the second doses.

Based on the results so far from clinical trials, most of the vaccines authorized for use in multiple countries require two shots spaced weeks apart for the maximum proven protection. On December 30, the U.K. announced it would lengthen the amount of time between the first and second doses of both its approved vaccines. The move, in theory, allows the country to give more people their initial shots, in the hopes of offering at least some protection to a higher number of at-risk people in a shorter period of time. Denmark similarly will delay second doses of its approved vaccine.

Until now, the U.S. has been holding back some of its vaccine supply to ensure there is enough for people to get their second dose. "We now believe that our manufacturing is predictable enough that we can ensure second doses are available for people from ongoing production," Health and Human Services Secretary Alex told ABC's Good Morning America on Tuesday.

As countries scramble to stop the spread, each will have to weigh the question of “how quickly can we vaccinate our population?” says Ruth Karron, a professor of international health and the director of the Center for Immunization Research and the Johns Hopkins Vaccine Initiative. But with limited data in hand, scientists and healthcare professionals remain divided on whether to deviate from vaccine makers’ recommendations.

Half the dose, double the protection?

In a recent CBS “Face the Nation” interview, Operation Warp Speed’s Slaoui rejected the idea of increasing the time between the first and second doses of the Pfizer-BioNTech and Moderna vaccines, which in clinical trials were given 21 and 28 days apart, respectively.

Slaoui then floated the notion of halving Moderna’s dosage—maintaining its two-shot, 28-day-interval vaccination regimen but reducing the amount given in each shot—as a potential alternative that could allow more people to get inoculated. He referenced Moderna’s phase two clinical trial, which tested both 50 microgram and 100 microgram doses of its vaccine. Experts say the trial found a promising immune response at the lower dosage in adults ages 18 to 55.

Barney Graham, deputy director of the National Institute of Allergy and Infectious Diseases Vaccine Research Center at the NIH, told National Geographic that researchers are exploring many different ways to immunize larger portions of the population more quickly. But for now, he said, “the recommendation is use the vaccine as it was tested” in two 100-microgram doses.

One issue in considering the reduced dosage is that an immune response is not the same thing as proven protection against a disease, warns Paul Offit, director of the Vaccine Education Center at the Children’s Hospital of Philadelphia and a government adviser on vaccine policy. While the presence of antibodies often means that a patient has developed some immune protection, it’s not a given. For example, people can have antibodies against HIV without being protected from the disease. To say that immune response means protection, Offit says, “is to ignore history.”

On the other hand, some experts argue that these drastic times may indeed call for drastic measures. Robert Wachter, chair of the department of medicine at University of California, San Francisco, says that until recently, he would not have supported reducing dosages. But as cases surged, the new variant emerged, and the country fell short on its vaccination schedule, he began thinking differently.

“It felt like it may be time where we have to be a little more creative and accept the possibility that we may need to do something with a little less evidence,” Wachter says.

Delaying booster shots

In the U.K., 1.3 million people—or about two out of every hundred residents—have received the first dose of either the Pfizer-BioNTech or Oxford-AstraZeneca vaccines, which have been approved there for emergency use. Both vaccines require two shots: a prime and then a booster 21 days later. But in the face of the more transmissible variant, which was discovered in the U.K., COVID-19 cases have skyrocketed. To beat back the virus, officials decided to prioritize giving initial injections and stretch the time between the shots to as long as three months.

“What we have in Britain is a crisis,” says Calum Semple, professor of child health and outbreak medicine at the University of Liverpool. On Monday, British hospitals were treating more than 26,000 COVID-19 patients. Many hospitals are postponing elective surgeries, the Associated Press reports; some may delay cancer surgeries or intensive care outside of COVID-19 treatment.

In phase three clinical trials, both vaccines authorized for use in the U.K. have shown high efficacy after the first shot. But none of the trials evaluated how long that efficacy would last, because all participants who received a first vaccine dose got a second shot.

Semple argues that it makes sense, in the context of the crisis, to “give more people the first dose” even if that means delaying a second shot. “Even though we’ve got inadequate data to be entirely sure about what we’re doing here, there is enough data to make a necessarily rapid judgment under the circumstances that will save lives, and will take pressure off our healthcare service,” he says.

But the recommended two doses and timelines between the prime and booster shots were not chosen haphazardly, other scientists warn. Pfizer provided National Geographic with a statement that says, in part, “there are no data to demonstrate that protection after the first dose is sustained after 21 days.” The statement further says that “it is critical health authorities … ensure each recipient is afforded the maximum possible protection, which means immunization with two doses of the vaccine.”

Research over time has shown that two vaccine doses are often the best way to teach the immune system to mount long-lived defenses, says Galit Alter, professor of medicine at Harvard Medical School and a group leader at the Ragon Institute. She likens teaching the immune system to teaching schoolkids: If they read something once, they might retain it, but repetition is what creates real memory recall. The same is basically true for immune defense, and many established vaccines from chickenpox to hepatitis B require boosters.

Trials of COVID-19 vaccines showed not only an impressive immune response after a second dose, but also the presence of T cells, important agents of the immune system that become keyed to specific viruses. Offit says that response “suggests there was immunological memory” after the booster.

The timing between shots can also be crucial. Alter says there’s a sweet spot between prime and booster shots: long enough to create that repetition but also soon enough that people won’t forget it or become complacent. Take the human papillomavirus (HPV) vaccine, which requires at least two shots, given at least six months apart, to be its most effective. Research shows that many people never get their second dose because they forget about it or get confused about scheduling. Researchers have also found that sweet spot is usually about three to four weeks between doses.

In hindsight, it’s easy to look back and ask why vaccine trials didn’t study lower doses or single shots, says Karron. But at the start of the pandemic, vaccine makers were hoping for vaccines that would prove to be at least 50-percent effective—and were surprised and delighted to discover their two-dose regimen showed as much as 95-percent efficacy.

“If they had known how good they would be, they might have done additional studies,” Karron says. “But they wanted to roll out vaccines as quickly as possible,” and additional studies could have bogged things down.

Risk versus reward

The concept of dose sparing, whether by reducing dosages or stretching timelines, carries other risks—including a laboratory phenomenon called escape mutants.

Past research has shown that when less optimal levels of antibodies are delivered against viruses in culture dishes or test tubes, those viruses can create a variant of the virus that escapes the immune system’s defenses, says Erica Ollmann Saphire, professor of molecular immunology at the La Jolla Institute for Immunology. Most such mutants are less potent, she says, but sometimes they can be more potent or more transmissible.

Though it’s theoretically possible that the escape mutant phenomenon gave rise to the U.K. variant of COVID-19, there’s no way to be certain because studies of escape mutants have been limited to lab experiments. Still, Saphire says, the possibility should be considered. “The worry is, if we leave people with inadequate immunity, are we just digging ourselves into a hole by encouraging more mutagenic escape?” she asks.

In addition, though confidence in COVID-19 vaccines appears to be rising, mistrust remains high. A recent Pew Research survey shows as many as 40 percent of Americans say they definitely or probably would not get a vaccine. There’s concern that changing how the vaccines are delivered now, without hard evidence, could heighten hesitancy.

“It gets very confusing for the community that we’re trying to engage and encourage to take this vaccine,” says Graham. “If we start using it in ways that haven’t been tested, I think that message becomes complicated for them.”

Focusing on how the vaccines are administered also ignores another problem: No matter how many doses are available, a strong infrastructure must be in place to give them out. That’s something that Offit says the U.S. doesn’t have, at least not yet.

“You need a mass vaccination strategy, because we’re trying to vaccinate everybody as quickly as possible,” he says. “You’re talking about lining people up at stadiums or synagogues or churches or auditoriums and just massively vaccinating them. And we just haven’t set that up.”

Fauci agrees. Exploring dosing alternatives more aggressively would make sense, he says, “if we had more people that wanted to get vaccinated than we have vaccine. But right now, that's not our problem. We are not vaccinating people as efficiently as we can.”

So while it seems painfully clear that more people need to be inoculated against COVID-19 more quickly, making that happen requires very difficult decisions. “Different scientists, within countries and in different countries, will make different choices depending on what they think is best in a situation where we don't have an obvious, easy, good choice,” says Karron. If the best path was clear, she adds, “everybody would be saying exactly the same thing.”

Editor's note: This story has been updated with news of the Trump plans to release more vaccine doses and to expand access to people 65 and older. It originally published on January 8.

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