Calls to administer as many first doses of two-dose COVID-19 vaccines as soon as possible are growing and the White House faces questions about why it’s not redirecting vaccines to hot spots as some U.S. regions see surges of the disease and problems have halted the delivery of millions of doses.

Manufacturing mistakes and reports of an extremely rare but serious blood clot have put on hold millions of Johnson & Johnson vaccines, stretching supply.

President Joe Biden’s pandemic response strategy, released on his second day in office, said the federal government would explore strategies to conserve COVID-19 vaccine doses. But in the three months since, administration officials haven’t budged on declining to space out doses or follow other recommendations from some public health experts.

The Biden administration is counting on vaccines to stamp out surges driven by the more infectious and more deadly B.1.1.7 variant that originated in the United Kingdom. The question among some former Biden advisers is why the United States wouldn’t flood the country with as many first doses as possible to ensure that happens.

“You can protect two people at 80 percent effectiveness or you can protect one person with 90 percent effectiveness,” said University of Minnesota epidemiologist Michael Osterholm, a former Biden adviser. “It’s simple math.”

“Drug manufacturers selected the three- or four-week interval currently used between doses to rapidly prove efficacy in clinical trials,” Zeke Emanuel, a top Obama administration health official and another former Biden adviser, wrote in an April 8 op-ed. “They did not choose such short intervals based on the optimal way of using the vaccines to quell a pandemic.”

Another former Biden adviser who was formerly skeptical of delaying second doses, Atul Gawande, recently suggested he is warming to the idea.

Others, including Céline Gounder, remain opposed. Gounder cites evidence that one dose does not generate enough long-term protection against variants, including the dominant B.1.1.7 strain, and worries the strategy could fuel their spread.

“We may be observing the benefits of delaying 2nd doses and spreading out first doses now, in the short term. We won’t observe the harms of delaying 2nd doses until later,” she tweeted.

Centers for Disease Control and Prevention guidance currently allows for up to a six-week delay. Osterholm called for doubling that to a 12-week delay, noting the recommended three- to four-week interval is mostly arbitrary, picked so the pharmaceutical companies could finish the clinical trials quickly. Some booster shots for other common diseases are given months after the first dose.

Michigan Gov. Gretchen Whitmer, a Democrat, has repeatedly appealed to the administration to give the state more doses so it can get the outbreak there under control, but doses continue to be distributed on a per capita basis, just as under the Trump administration.

“Now is not the time to change course on allocation,” Jeff Zients, the coronavirus response coordinator, said Friday.

White House chief medical adviser Anthony Fauci acknowledged extending the dose interval has merit but said he prefers a cautious approach because the length of immunity from a first dose is uncertain, especially against variants.

Fauci also cited the rapid pace of vaccinations, at a seven-day average of more than 2.8 million doses per day, though it’s unclear how many are first doses.

“Given the number of vaccines we’re able to give every day… although we always continue to keep an open mind, we consider the route that we’re on now is the best route,” Fauci said last week.

By May, vaccine supply is expected to surpass the number of people requesting doses.

But bioethicists caution against complacency. Before May, thousands more people are projected to die from COVID-19.

Osterholm predicted in February that delaying second doses could spare 40,000 lives, though the pace of vaccinations in older adults was much speedier than he projected.

“If everyone in a big college football stadium, 40,000 to 60,000 people died, you would call that an American tragedy. That’s still a tragedy even against the backdrop of 600,000 deaths,” said Govind Persad, a bioethicist with the University of Denver.

CDC group’s rejection of the idea

The January Biden COVID-19 strategy said the administration would explore “dose sparing.”

“Dose sparing refers to any policy that is not maximizing individual protection, but instead maximizing protection for the group and minimizing lives lost,” explained Sarah Cobey, an epidemiologist and evolutionary biologist at the University of Chicago.

The idea of stretching the interval between doses apparently stalled after a March 1 CDC advisers’ meeting. A working group told the CDC’s Advisory Committee on Immunization Practices that there is “insufficient data to suggest changes to guidance.”

“There is important uncertainty regarding protection from variants following one dose of mRNA COVID-19 vaccines,” reads a summary of the meeting.

The working group acknowledged that the second dose was likely to be effective at a longer interval. But the group was concerned that one dose could leave people susceptible to variants, increase transmission of variants, and contradict the Food and Drug Administration’s emergency use authorization.

The working group also considered giving only first doses to people who were previously infected, given that people previously exposed to the virus seem to develop a strong immune response.

“Two studies evaluated a single dose for people with confirmed prior infection and both showed higher titers following 1 dose for seropositive persons compared to seronegative persons,” meeting minutes say.

Still, the working group decided against the strategy because the data is limited and testing people for antibodies before vaccination would be difficult, and it would contradict FDA recommendations.

Since then, more supportive data has emerged.

The CDC released a study showing one dose of the vaccine is 80 percent effective after two weeks.

The United Kingdom, which gives doses of the Pfizer and AstraZeneca vaccines 12 weeks apart, has seen average daily deaths plummet over the last month, and a single shot of the Pfizer vaccine appeared to reduce hospitalizations and generate a durable T-cell response, according to preliminary research.

Canada, where doses are more scarce, has moved to stretch the dosing interval to four months.

A March modeling study shows that dose-sparing strategies are beneficial in the short term when doses are scarce.

Any updates to CDC guidance on the timing of doses would need to be made after a public discussion and in partnership with the FDA, experts say.

But one member of the FDA’s advisory committee opposed the idea.

Paul Offit, a University of Pennsylvania vaccinologist and member of the Vaccines and Related Biological Products Advisory Committee, said delaying second shots could be confusing.

“What worries me is that people will get one dose and say: ‘80 percent is close enough. I don’t want to deal with more side effects from a second dose. I’m good,’” Offit said. “The messaging has to be clear that these are two-dose vaccines.”

Offit also said he worries that more durable T-cell immunity wouldn’t be generated by a single shot, citing FDA documents describing the clinical trials.

Those briefing documents show that T-cell response after one dose was not studied.

“There are no data to demonstrate that protection after the first dose is sustained after 21 days,” Pfizer spokesperson Keanna Ghazvini said in an email. “While decisions on alternative dosing regimens reside with health authorities, Pfizer believes it is critical health authorities conduct surveillance efforts on any alternative schedules implemented and to ensure each recipient is afforded the maximum possible protection, which means immunization with two doses of the vaccine.”

Offit said he did not think there would be an uptick in deaths due to the UK variant because of the speed of the vaccination push, pre-existing immunity, and because the virus is seasonal — an idea experts are divided on.

One concern is also that a lower level of immunity, or short-term immunity, could create evolutionary pressure that would give rise to variants.

But Cobey, the evolutionary biologist, wrote in Nature that the opposite is true: as long as one dose reduces transmission, the chances of breakthrough variants decrease with that one dose.

While she acknowledges there is some uncertainty, she said when it comes to the most urgent reasons for vaccinating like reducing hospitalizations and deaths, the possibility of an increase in variants is not enough of a concern to hold off.

“From a moral perspective, you need a really good excuse not to do it,” Cobey said.