Tag: Clinical Trials

Data from Federal Scientists Raise Questions About J.&J. Booster Shots

People who have received the company’s one-shot vaccine may benefit from a booster with another brand. F.D.A. advisers will discuss the data on Friday.

How an Unproven Alzheimer’s Drug Got Approved

Though some of its own senior officials said there was little evidence of benefit for patients, the F.D.A. nonetheless greenlighted Biogen’s Aduhelm, or aducanumab.

Many Alzheimer’s Experts Say Use of Aduhelm Should Be Sharply Limited

Even those who supported the F.D.A.’s approval of the controversial new drug said authorizing it for anyone with Alzheimer’s disease was much too broad.

A new drug for the treatment of Alzheimer’s disease should be given to a much narrower group of patients than the federal approval permits, Alzheimer’s experts — including those who strongly supported approval of the medication — said on Monday.

Since the Food and Drug Administration approved the controversial and expensive drug, Aduhelm, made by Biogen, this month, much discussion has focused on the fact that many scientists, and the F.D.A.’s own independent advisory committee, say the evidence does not convincingly show that the drug works.

But another major issue has received less attention: which patients should receive the drug and what doctors should do to prescribe it responsibly and safely.

The F.D.A. has so far imposed strikingly few limitations on Aduhelm, a monthly intravenous infusion that requires patients to have regular M.R.I. scans because the drug can cause swelling or hemorrhaging in the brain.

While the only patients who received the drug during clinical trials were those with very mild Alzheimer’s or an even milder pre-Alzheimer’s impairment, the F.D.A.’s label for Aduhelm says simply that the drug is “for the treatment of Alzheimer’s disease.” Under “contraindications,” the term for health conditions or other characteristics that should prevent patients from taking a drug, the label says “None.”

The broadness of the label has surprised and concerned even the biggest champions of the drug.

“Oy,” said one enthusiastic supporter of Aduhelm’s approval, Dr. Stephen Salloway, describing his reaction “when I saw from the label that there are no contraindications.”

Dr. Salloway, director of neurology and the Memory and Aging Program at Butler Hospital in Providence, R.I., spoke on Monday in a forum sponsored by the Alzheimer’s Association, a large patient advocacy group that pushed for approval of the drug. He and the five other experts answering questions about the use of the drug emphasized that the use of Aduhelm should be limited to certain patients: those in early stages of the disease whose brains contain high levels of amyloid, a protein that clumps into plaques in people with Alzheimer’s disease.

The panelists, who had varying opinions about whether Aduhelm should have been approved, agreed that the drug’s potential brain side effects must be monitored carefully and that doctors should disclose to interested patients that there are many unknowns about Aduhelm, including whether it can provide any benefit.

Aduhelm was designed to slow the progression of memory and thinking problems in people with mild cognitive symptoms, but its approval has been contentious. A number of scientists objected because only one of two clinical trials showed any hint of benefit, and in that trial the high dose of the medication slowed cognitive decline only slightly — by about four months in an 18-month period.

Dr. Salloway, a site principal investigator for trials of the drug, wasn’t paid for that work but has received research and consulting fees from Biogen. He said doctors should use the drug only for patients whose statuses match those in the clinical trials.

“There’s no evidence that it could be beneficial for any other stage of Alzheimer’s,” he said.

Mary Sano, director of the Mount Sinai Alzheimer’s Disease Research Center in New York City, said the criteria that she and other panelists outlined were “very important” and meant that “it’s going to be very restrictive and the ability to share this drug with a wide range of people will be significantly limited, at least at this time.”

Treating people only with mild symptoms would mean that for dementia clinicians, “most of your people in your current practice are probably not eligible,” Dr. Sano said.

In its decision, the F.D.A. acknowledged that there was not the level of evidence of benefit that the agency usually requires. As a result, it is making Aduhelm available under a program called accelerated approval, citing the drug’s ability to reduce levels of amyloid in the brain. But reducing amyloid is not the same thing as slowing symptoms of dementia. Many amyloid-reducing drugs have failed to slow decline in clinical trials, a history that makes some experts especially wary of placing confidence in Aduhelm based on the evidence produced so far.

Given the agency’s emphasis on amyloid in its approval decision, and the fact that all of the clinical trial participants had to have high amyloid levels, experts have also been surprised that the F.D.A. label does not require patients to be screened for the protein. Doctors at the Alzheimer’s Association forum all said that high levels of amyloid, typically measured by PET scan or spinal tap, should be a condition of treatment.

Several of the panelists said that, at least at the outset, relatively few doctors and clinics would have the ability to adequately diagnose, screen and treat patients.

“This is not a simple medication to use,” said Dr. Paul Aisen, director of the Alzheimer’s Therapeutic Research Institute at the University of Southern California and a co-author of an article that urged the F.D.A. to approve the drug. “I think that establishing the appropriate individuals for treatment, and monitoring treatment, requires knowledge and benefits from experience, and there are very few clinicians who have this experience.”

The panelists devoted considerable discussion to the possibility of brain swelling and hemorrhages, which occurred in about 40 percent of participants who received the high dose in the two large clinical trials. Many cases were mild or asymptomatic, but Dr. Alireza Atri, director of the Banner Sun Health Research Institute in Phoenix and another co-author of the article supporting approval of the drug, said that it was possible that “one out of 200 or 300 individuals can have a serious side effect and need to be in a hospital.”

Dr. Salloway said that it would be “more challenging” for doctors to safely monitor for brain side effects than it was within the strict standards of the clinical trials. He said that people should not be given the drug if they have had a macro-hemorrhage in the brain; more than five micro-hemorrhages; a significant stroke; or “unstable medical conditions that could interfere with treatment.”

Dr. David S. Knopman, a clinical neurologist at the Mayo Clinic and a site principal investigator for one of the trials, who did not support approval, said people who were taking blood thinners should also be excluded.

“We know that this treatment carries considerable risks,” said Suzanne Craft, co-director of the Roena B. Kulynych Center for Memory and Cognition Research at the Wake Forest University School of Medicine. And assessing how and whether it helps patients could be tricky, Dr. Craft and others said.

It will be important to have comprehensive discussions with patients and families about “how to weigh the inconvenience and cost and risk against the possible benefit,” Dr. Aisen said.

“Managing expectations is a huge challenge here,” he said, adding that “our expectation is a modest slowing of the rate of decline. It is impossible to determine on an individual patient level whether someone is benefiting or not.”

Novavax Offers U.S. a Fourth Strong Covid-19 Vaccine

The company’s large U.S. trial found an efficacy rate of about 90 percent. But at this point, the nation is awash in other shots.

Novavax, a small American company buoyed by lavish support from the U.S. government, announced on Monday the results of a clinical trial of its Covid-19 vaccine in the United States and Mexico, finding that its two-shot inoculation provides potent protection against the coronavirus.

In the 29,960-person trial, the vaccine demonstrated an overall efficacy of 90.4 percent, on par with the vaccines made by Pfizer-BioNTech and Moderna, and higher than the one-shot vaccine from Johnson & Johnson. The Novavax vaccine showed an efficacy of 100 percent at preventing moderate or severe disease.

Despite these impressive results, the vaccine’s future in the United States is uncertain and it might be needed more in other countries. Novavax says it may not seek emergency authorization from the Food and Drug Administration until the end of September. And with a plentiful supply of three other authorized vaccines, it’s possible that the agency may tell Novavax to apply instead for a full license — a process that could require several extra months.

The company’s chief executive, Stanley Erck, acknowledged in an interview that Novavax would probably win its first authorization elsewhere. The company is also applying in Britain, the European Union, India and South Korea.

“I think the good news is that the data are so compelling that it gives everybody an incentive to pay attention to our filings,” Mr. Erck said.

By the time Novavax gets the green light from the U.S. government, it may be too late to contribute to the country’s first wave of vaccinations. But many vaccine experts expect that, with waning immunity and emerging variants, the country will need booster shots at some point. And the protein-based technology used in the Novavax vaccine may do a particularly good job at amplifying protection, even if people have previously been vaccinated with a different formulation.

“They may be really the right ones for boosters,” said Dr. Luciana Borio, who was the acting chief scientist at the F.D.A. from 2015 to 2017.

Last year, the Trump administration’s Operation Warp Speed program awarded Novavax a $1.6 billion contract for 100 million future doses. The company won this tremendous support despite never having brought a vaccine to market in over three decades.

The Novavax coronavirus vaccine does not need special refrigeration.
The Novavax coronavirus vaccine does not need special refrigeration.Alastair Grant/Associated Press

In January, Novavax announced that its 15,000-person trial in Britain found that the vaccine had an efficacy of 96 percent against the original coronavirus. Against Alpha, a virus variant first identified in Britain, the efficacy fell slightly to 86 percent. In South Africa, where Novavax ran a smaller trial on 2,900 people and the Beta variant was dominant, the company found an efficacy of just 49 percent.

But the South Africa trial was complicated by the fact that a number of the volunteers had H.I.V., which is known to hamper vaccines. In addition, the study was so small that it was difficult to estimate how much protection the vaccine provided H.I.V.-negative volunteers.

With the support of Operation Warp Speed, Novavax drew up plans for an even larger late-stage trial in the United States and Mexico. But difficulties with manufacturing delayed its launch until December.

By then, the United States had authorized the Pfizer-BioNTech and Moderna vaccines. In February, with the Novavax trial still underway, the government authorized Johnson & Johnson’s.

As it waited for trial results, Novavax partnered with other companies to start making massive quantities of its vaccine. In India, it joined forces with the Serum Institute, and in South Korea, SK Biosciences. Novavax reached an agreement with Gavi, the Vaccine Alliance, to supply 1.1 billion doses to middle- and low-income countries.

But the company’s difficulties with scaling continued, and it needed more time to develop special tests used to confirm the quality of its product.

The new results were based on 77 trial volunteers who came down with Covid-19. The volunteers who received placebo shots were far more likely than the vaccinated ones to get sick, a statistical difference that translated to an efficacy of 90.4 percent.

“It’s a strong result,” said Natalie Dean, a biostatistician at the University of Florida. “It puts them up in that high tier.”

The vaccine showed the same efficacy in a group of high-risk volunteers — people who were over the age of 65, had medical risk factors or had jobs that exposed them to the virus.

Novavax sequenced the genomes of 54 of the 77 viral samples, and found that half were Alpha, the variant that became dominant in the United States this spring.

The vaccine’s side effects were relatively mild. Some volunteers reported fatigue, headaches and other minor symptoms. “This vaccine seems easier on the arms,” said John Moore, a virologist at Weill Cornell Medicine who was a volunteer in the Novavax trial.

A Novavax production facility in Stockton-on-Tees, Britain.Lee Smith/Reuters

Novavax will apply for authorization in the United States after it finishes developing a quality control test, according to its chief executive. “You have to test them every way from Sunday to show that under any conditions you get the same answer,” Mr. Erck said. “And that takes time.”

Mr. Erck said that the company plans on making 100 million doses per month by the end of the third quarter, and 150 million doses per month by the end of the fourth quarter.

With each passing week, the United States is building a bigger supply of authorized vaccines from other companies, raising the question of whether the nation needs to give any more emergency use authorizations, or EUAs.

“The law says that once you have sufficient doses, there’s no need for additional E.U.A.’s,” Dr. Borio said.

One sign that the F.D.A. is changing its approach to Covid-19 vaccines came last week. An American company called Ocugen had been seeking emergency authorization for Covaxin, a Covid-19 vaccine now in use in India. But on Thursday, the company announced that the F.D.A. had recommended they instead take the standard path to a full approval, known as a biologics license application, which takes many additional months.

But because Novavax has been consulting with the F.D.A. since last year about its trials, Mr. Erck said the company might be able to continue with its plans for seeking emergency use authorization.

“So far, they’ve indicated that if you’re in the process for an E.U.A, you can continue for an E.U.A.,” Mr. Erck said. “Anybody could tell you that could change, but I don’t know how to predict that.”

Dr. Paul Offit, a professor at the University of Pennsylvania and a member of the F.D.A.’s vaccine advisory panel, said that Novavax’s highly effective vaccine would be most welcome. “The more the merrier,” he said. “I think there’s room for many more vaccines, because we’re going to be dealing with this virus for years, if not decades.”

Novavax is preparing for that future by investigating how its vaccine could work as a booster. A new version of the vaccine contains the proteins from the Beta variant first identified in South Africa.

Researchers gave Beta boosters to baboons that had been vaccinated with the original version of the Novavax vaccine in experiments a year ago. The researchers found that the baboon’s immunity against Covid-19 shot up after this booster, protecting them against Beta, Alpha and the original version of the coronavirus.

“When you boost, you see a very high recall response,” said Matthew Frieman, a virologist at the University of Maryland School of Medicine and a co-author of the new study. The study has not yet been published in a scientific journal.

Dr. Frieman said the new study offered encouraging evidence that Novavax vaccines might work well as boosters. It also suggested that people getting vaccines for the first time might do well to get a blend of the original and Beta versions to widen their protection against new variants, he said.

“Novavax may be used as a booster in the U.S., but it’s certainly will be the first vaccine a lot of people are going to see around the world,” he said

Alzheimer’s Drug Poses a Dilemma for the F.D.A.

The Food and Drug Administration is on the verge of announcing one of its most contentious decisions in years: the fate of an Alzheimer’s drug that could be the first treatment approved after nearly two decades of failed efforts to find ways to curb the debilitating disease.

On Monday, the agency will rule on the drug, aducanumab, which aims to slow progression of memory and thinking problems early in the disease. If approved, it would be the first new Alzheimer’s medication since 2003 and the first treatment on the market that attacks the disease process rather than just easing symptoms.

It would become a blockbuster drug within several years, analysts predict, costing tens of thousands of dollars annually per patient and bringing a windfall to its manufacturer, Biogen.

Patient groups, desperate for treatments, are pushing for approval. But greenlighting the drug would fly in the face of objections from several prominent Alzheimer’s experts and the F.D.A.’s independent advisory committee.

In November, the committee voted overwhelmingly against recommending approval, saying data failed to demonstrate persuasively that aducanumab slowed cognitive decline. Three advisory committee members later wrote a point-by-point critique of the evidence. Other scientists, and an independent think tank, say aducanumab hadn’t shown convincing benefit to outweigh its safety risks.

“This should not be approved, because substantial evidence of effectiveness hasn’t been shown,” said Dr. Lon Schneider, director of the California Alzheimer’s Disease Center at the University of Southern California and one of many site investigators who helped conduct one of the aducanumab trials. “There’s very little potential that this will address the needs of patients.”

Beyond the status of this particular drug, some experts worry approval could lower standards for future drugs — an especially important question at a time when public trust in science is teetering.

“I simply don’t see a path for approval because of the absence of evidence that’s been shared to date that this product works, and I think it would set a remarkably dangerous precedent — not only for the field of Alzheimer’s research but also for the broader regulation of prescription drugs in our country,” said Dr. G. Caleb Alexander, an F.D.A. advisory committee member and an internist, epidemiologist and drug safety and effectiveness expert at the Johns Hopkins Bloomberg School of Public Health.

About six million people in the United States and roughly 30 million globally have Alzheimer’s, a number expected to double by 2050. Currently, five medications approved in the United States can delay cognitive decline for several months in various Alzheimer’s stages. About two million Americans have mild Alzheimer’s-related impairment, fitting criteria for aducanumab, a monthly intravenous infusion requiring regular imaging to detect potential brain swelling.

Biogen officials declined to comment for this article, but in earnings calls, medical meetings and F.D.A. presentations, they have said the evidence shows cognitive benefit. Several Alzheimer’s experts whose experience includes consulting for Biogen wrote recently that aducanumab “achieves the standard of meaningful efficacy with adequate safety.”

The Biogen headquarters in Cambridge, Mass.
The Biogen headquarters in Cambridge, Mass.Cody O’Loughlin for The New York Times

Debate centers on two never fully completed Phase 3 trials that contradicted each other. One suggested that a high dose could slightly slow cognitive decline; the other showed no benefit. Biogen says that given the need for Alzheimer’s medications, the single positive trial, plus results from a small safety trial and aducanumab’s ability to reduce a key protein, should justify approval.

The F.D.A. typically follows advisory committee recommendations and usually requires two convincing studies for approval, but it has made exceptions, especially for severe diseases that lack treatments.

Two other medications now in trials appear more promising than aducanumab, experts say, but it could be three or four years before data would indicate whether they merit approval. Many families say that’s too long to wait.

“There’s lots of issues with the data,” acknowledged Maria Carrillo, chief science officer for the Alzheimer’s Association, a patient advocacy group campaigning vigorously for approval. But she said her organization must “weigh the crushing reality of what people live with today” and support giving patients something to try instead of waiting several years for more conclusive positive results.

The F.D.A. itself seems divided. In advisory committee presentations, a clinical analyst cited “substantial evidence of effectiveness to support approval.” But an F.D.A. statistician wrote that another trial was needed because “there is no compelling, substantial evidence of treatment effect or disease slowing.”

And some experts, like Dr. Ronald Petersen, director of the Mayo Clinic’s Alzheimer’s Disease Research Center in Rochester, Minn., say they’re “on the fence.” He said he’d like to give patients a new option soon but “the data are iffy.”

Aducanumab, a monoclonal antibody, targets a protein, amyloid, that clumps into plaques in the brains of Alzheimer’s patients. Many amyloid-reducing drugs failed to slow symptoms in trials, a history that, some experts say, makes it especially important that aducanumab’s data be convincing. If effective, it would support a long-held, unproven theory that attacking amyloid can help if done early enough.

Excitement about aducanumab grew after a small early trial to evaluate safety showed amyloid reduction and hinted it might slow cognitive decline. The F.D.A., in a move some experts question, allowed Biogen to skip Phase 2 trials and conduct two Phase 3 trials of about 1,640 patients each.

Both trials were stopped early, in March 2019, when an independent data monitoring committee said aducanumab didn’t appear to be working. Consequently, 37 percent of participants never completed the 78-week trials.

But that October, Biogen announced it found benefit in one trial after evaluating data from 318 participants who finished before the trials were stopped but after the cutoff point for results the monitoring committee assessed.

In that trial, Biogen said, the highest dose slowed cognitive decline by 22 percent, or about four months over 18 months. A lower dose in that trial and high and low doses in the other showed no statistically significant benefit over a placebo.

“One study was positive, and one identically performed study was negative,” said Dr. David Knopman, a clinical neurologist at the Mayo Clinic and a site principal investigator for one trial. “I don’t think it takes a Ph.D. in statistics to see that that’s inconclusive.”

Dewayne Nash, whose mother and brother died of Alzheimer’s, said that for his personal situation, he favored approval because he might decline before other treatments became available. But scientifically, “they really ought to do the studies” first, he said, adding that otherwise, “you’re giving people a drug that may help, but it may not.”Daniel Dreifuss for The New York Times

Dr. Alexander added that Biogen’s interpretation of data using after-the-fact analyses was “like the Texas sharpshooter fallacy — the idea that the sharpshooter shoots up a barn and then goes and draws a bull’s-eye around the cluster of holes that he likes.”

By contrast, Dr. Stephen Salloway, who has received research and consulting fees from Biogen but wasn’t paid for being an aducanumab trial site principal investigator, called himself a “passionate” supporter of approval. He considers the evidence sufficient because Alzheimer’s is so disabling.

“I understand people’s concerns — the data set has issues, of course,” said Dr. Salloway, director of neurology and the Memory and Aging Program at Butler Hospital in Providence, R.I. “F.D.A. is in a tough spot, obviously.”

But he favors giving patients the option. Of his 17 participants in both the safety trial and Phase 3, he said, 10 had remained relatively cognitively stable for several years, while seven had declined at typical rates.

“It didn’t work for everybody,” he said, but “it just seemed like there were more people that were steady for longer than I’m used to.”

One challenge with assessing impact is that many early-stage patients decline slowly anyway, Dr. Schneider said.

Advocates and many patients say delaying deterioration even slightly is meaningful. But some experts say the single trial’s slowing of 0.39 on an 18-point scale rating memory, problem-solving skills and function may be imperceptible to patients’ experience and doesn’t justify approving a drug that floundered in another trial and carries risk of harm.

“This product, even in the best of circumstances, would be not terribly effective at all, with significant safety risks,” Dr. Alexander said.

The potential harm involves brain swelling or bleeding experienced by about 40 percent of Phase 3 trial participants receiving the high dose. Most were either asymptomatic or had headaches, dizziness or nausea. But such effects prompted 6 percent of high-dose recipients to discontinue. No Phase 3 participants died from the effects, but one safety trial participant did.

Henry Magendantz, center, with his wife, Kathy Jellison, who believes his initial years on the drug helped slow his decline enough to allow him to help choose the assisted-living facility where he lives now. “It brought us some time,” she said. Kayana Szymczak for The New York Times

Some trial participants’ views reflect the situation’s complexity.

Dewayne Nash, 71, of Santa Barbara, Calif., learned after the trial that he had received 18 months of a placebo, during which his cognitive scores improved — partly, he believes, because he lowered his cholesterol. Dr. Nash, a retired family physician, then received seven months of aducanumab, scaling up to the high dose, hoping it would slow decline, but “I didn’t notice any difference.”

Dr. Nash, whose mother and brother died of Alzheimer’s, will resume aducanumab soon through Biogen’s study for previous participants. He said that for his situation, he would like it approved because he expects to decline before other therapies become available and is willing to risk “brain bleeding and stuff.”

But scientifically, “I don’t like it when they rush drugs,” he said.

“They really ought to do the studies that need to be done” before approval, he added. Otherwise, “you’re giving people a drug that may help, but it may not.”

Dr. Salloway said one trial patient whose dementia had remained mild considerably longer than he’d expected was Henry Magendantz, a retired obstetrician-gynecologist in Providence, R.I. Dr. Magendantz, 84, started the safety trial after his wife, Kathy Jellison, noticed him having trouble following steps to assemble furniture.

He received a year of placebo, then a year of lower-dose aducanumab, then two years of the high dose before the 2019 halt. During that time, Ms. Jellison said, he was “slipping a bit,” but she believes aducanumab slowed decline enough to allow him to participate in tasks like choosing an assisted-living facility, where he moved in October 2018.

“It brought us some time,” she said.

Debby Rosencrantz, a trial participant, hopes for Alzheimer’s treatments that work well enough to curb her dementia. “It just feels like there’s a blank in places where there shouldn’t be a blank in my brain,” she said.Kayana Szymczak for The New York Times

Another issue with evaluating treatments is that some assessment scales, including in the aducanumab trials, involve reports from relatives or caregivers, who might miss subtle symptom progression.

“It is squishy stuff,” said Susan Woskie, a professor emeritus in public health at the University of Massachusetts Lowell, whose wife, Debby Rosenkrantz, 68, participated in the trial. “This stuff is really difficult, I think, to compile into metrics that have any validity.”

Ms. Rosenkrantz, a former social worker in Cambridge, Mass., said that while receiving roughly eight months of low-dose aducanumab in the trial, “I was really optimistic that there was a drug, and so for me it was like, yes, it’s working.”

Since restarting infusions in Biogen’s study for previous participants last September, though, “I haven’t noticed any change,” she said.

She experiences short-term memory loss and cannot follow recipes. “It just feels like there’s a blank in places where there shouldn’t be a blank in my brain,” she said.

Dr. Woskie said the couple yearns for treatments but that if the F.D.A. told Biogen, “‘No, we don’t fast-track approve you; come back when you have more data,’ that wouldn’t surprise me, and it might make sense.”

Some doctors who consider aducanumab’s evidence weak, including Dr. Knopman, say that if it is approved, they would tell patients their reservations but would feel ethically compelled to offer it.

Still, Dr. Jason Karlawish, a co-director of the University of Pennsylvania’s Penn Memory Center and a site investigator on Biogen-sponsored studies, said, “Physicians like me, who would be prescribers, are saying, ‘I want an effective drug to prescribe to my patients — but this is not the drug.’”

Alzheimer’s Drug Poses a Dilemma for the F.D.A.

The Food and Drug Administration is on the verge of announcing one of its most contentious decisions in years: the fate of an Alzheimer’s drug that could be the first treatment approved after nearly two decades of failed efforts to find ways to curb the debilitating disease.

On Monday, the agency will rule on the drug, aducanumab, which aims to slow progression of memory and thinking problems early in the disease. If approved, it would be the first new Alzheimer’s medication since 2003 and the first treatment on the market that attacks the disease process rather than just easing symptoms.

It would become a blockbuster drug within several years, analysts predict, costing tens of thousands of dollars annually per patient and bringing a windfall to its manufacturer, Biogen.

Patient groups, desperate for treatments, are pushing for approval. But greenlighting the drug would fly in the face of objections from several prominent Alzheimer’s experts and the F.D.A.’s independent advisory committee.

In November, the committee voted overwhelmingly against recommending approval, saying data failed to demonstrate persuasively that aducanumab slowed cognitive decline. Three advisory committee members later wrote a point-by-point critique of the evidence. Other scientists, and an independent think tank, say aducanumab hadn’t shown convincing benefit to outweigh its safety risks.

“This should not be approved, because substantial evidence of effectiveness hasn’t been shown,” said Dr. Lon Schneider, director of the California Alzheimer’s Disease Center at the University of Southern California and one of many site investigators who helped conduct one of the aducanumab trials. “There’s very little potential that this will address the needs of patients.”

Beyond the status of this particular drug, some experts worry approval could lower standards for future drugs — an especially important question at a time when public trust in science is teetering.

“I simply don’t see a path for approval because of the absence of evidence that’s been shared to date that this product works, and I think it would set a remarkably dangerous precedent — not only for the field of Alzheimer’s research but also for the broader regulation of prescription drugs in our country,” said Dr. G. Caleb Alexander, an F.D.A. advisory committee member and an internist, epidemiologist and drug safety and effectiveness expert at the Johns Hopkins Bloomberg School of Public Health.

About six million people in the United States and roughly 30 million globally have Alzheimer’s, a number expected to double by 2050. Currently, five medications approved in the United States can delay cognitive decline for several months in various Alzheimer’s stages. About two million Americans have mild Alzheimer’s-related impairment, fitting criteria for aducanumab, a monthly intravenous infusion requiring regular imaging to detect potential brain swelling.

Biogen officials declined to comment for this article, but in earnings calls, medical meetings and F.D.A. presentations, they have said the evidence shows cognitive benefit. Several Alzheimer’s experts whose experience includes consulting for Biogen wrote recently that aducanumab “achieves the standard of meaningful efficacy with adequate safety.”

The Biogen headquarters in Cambridge, Mass.
The Biogen headquarters in Cambridge, Mass.Cody O’Loughlin for The New York Times

Debate centers on two never fully completed Phase 3 trials that contradicted each other. One suggested that a high dose could slightly slow cognitive decline; the other showed no benefit. Biogen says that given the need for Alzheimer’s medications, the single positive trial, plus results from a small safety trial and aducanumab’s ability to reduce a key protein, should justify approval.

The F.D.A. typically follows advisory committee recommendations and usually requires two convincing studies for approval, but it has made exceptions, especially for severe diseases that lack treatments.

Two other medications now in trials appear more promising than aducanumab, experts say, but it could be three or four years before data would indicate whether they merit approval. Many families say that’s too long to wait.

“There’s lots of issues with the data,” acknowledged Maria Carrillo, chief science officer for the Alzheimer’s Association, a patient advocacy group campaigning vigorously for approval. But she said her organization must “weigh the crushing reality of what people live with today” and support giving patients something to try instead of waiting several years for more conclusive positive results.

The F.D.A. itself seems divided. In advisory committee presentations, a clinical analyst cited “substantial evidence of effectiveness to support approval.” But an F.D.A. statistician wrote that another trial was needed because “there is no compelling, substantial evidence of treatment effect or disease slowing.”

And some experts, like Dr. Ronald Petersen, director of the Mayo Clinic’s Alzheimer’s Disease Research Center in Rochester, Minn., say they’re “on the fence.” He said he’d like to give patients a new option soon but “the data are iffy.”

Aducanumab, a monoclonal antibody, targets a protein, amyloid, that clumps into plaques in the brains of Alzheimer’s patients. Many amyloid-reducing drugs failed to slow symptoms in trials, a history that, some experts say, makes it especially important that aducanumab’s data be convincing. If effective, it would support a long-held, unproven theory that attacking amyloid can help if done early enough.

Excitement about aducanumab grew after a small early trial to evaluate safety showed amyloid reduction and hinted it might slow cognitive decline. The F.D.A., in a move some experts question, allowed Biogen to skip Phase 2 trials and conduct two Phase 3 trials of about 1,640 patients each.

Both trials were stopped early, in March 2019, when an independent data monitoring committee said aducanumab didn’t appear to be working. Consequently, 37 percent of participants never completed the 78-week trials.

But that October, Biogen announced it found benefit in one trial after evaluating data from 318 participants who finished before the trials were stopped but after the cutoff point for results the monitoring committee assessed.

In that trial, Biogen said, the highest dose slowed cognitive decline by 22 percent, or about four months over 18 months. A lower dose in that trial and high and low doses in the other showed no statistically significant benefit over a placebo.

“One study was positive, and one identically performed study was negative,” said Dr. David Knopman, a clinical neurologist at the Mayo Clinic and a site principal investigator for one trial. “I don’t think it takes a Ph.D. in statistics to see that that’s inconclusive.”

Dewayne Nash, whose mother and brother died of Alzheimer’s, said that for his personal situation, he favored approval because he might decline before other treatments became available. But scientifically, “they really ought to do the studies” first, he said, adding that otherwise, “you’re giving people a drug that may help, but it may not.”Daniel Dreifuss for The New York Times

Dr. Alexander added that Biogen’s interpretation of data using after-the-fact analyses was “like the Texas sharpshooter fallacy — the idea that the sharpshooter shoots up a barn and then goes and draws a bull’s-eye around the cluster of holes that he likes.”

By contrast, Dr. Stephen Salloway, who has received research and consulting fees from Biogen but wasn’t paid for being an aducanumab trial site principal investigator, called himself a “passionate” supporter of approval. He considers the evidence sufficient because Alzheimer’s is so disabling.

“I understand people’s concerns — the data set has issues, of course,” said Dr. Salloway, director of neurology and the Memory and Aging Program at Butler Hospital in Providence, R.I. “F.D.A. is in a tough spot, obviously.”

But he favors giving patients the option. Of his 17 participants in both the safety trial and Phase 3, he said, 10 had remained relatively cognitively stable for several years, while seven had declined at typical rates.

“It didn’t work for everybody,” he said, but “it just seemed like there were more people that were steady for longer than I’m used to.”

One challenge with assessing impact is that many early-stage patients decline slowly anyway, Dr. Schneider said.

Advocates and many patients say delaying deterioration even slightly is meaningful. But some experts say the single trial’s slowing of 0.39 on an 18-point scale rating memory, problem-solving skills and function may be imperceptible to patients’ experience and doesn’t justify approving a drug that floundered in another trial and carries risk of harm.

“This product, even in the best of circumstances, would be not terribly effective at all, with significant safety risks,” Dr. Alexander said.

The potential harm involves brain swelling or bleeding experienced by about 40 percent of Phase 3 trial participants receiving the high dose. Most were either asymptomatic or had headaches, dizziness or nausea. But such effects prompted 6 percent of high-dose recipients to discontinue. No Phase 3 participants died from the effects, but one safety trial participant did.

Henry Magendantz, center, with his wife, Kathy Jellison, who believes his initial years on the drug helped slow his decline enough to allow him to help choose the assisted-living facility where he lives now. “It brought us some time,” she said. Kayana Szymczak for The New York Times

Some trial participants’ views reflect the situation’s complexity.

Dewayne Nash, 71, of Santa Barbara, Calif., learned after the trial that he had received 18 months of a placebo, during which his cognitive scores improved — partly, he believes, because he lowered his cholesterol. Dr. Nash, a retired family physician, then received seven months of aducanumab, scaling up to the high dose, hoping it would slow decline, but “I didn’t notice any difference.”

Dr. Nash, whose mother and brother died of Alzheimer’s, will resume aducanumab soon through Biogen’s study for previous participants. He said that for his situation, he would like it approved because he expects to decline before other therapies become available and is willing to risk “brain bleeding and stuff.”

But scientifically, “I don’t like it when they rush drugs,” he said.

“They really ought to do the studies that need to be done” before approval, he added. Otherwise, “you’re giving people a drug that may help, but it may not.”

Dr. Salloway said one trial patient whose dementia had remained mild considerably longer than he’d expected was Henry Magendantz, a retired obstetrician-gynecologist in Providence, R.I. Dr. Magendantz, 84, started the safety trial after his wife, Kathy Jellison, noticed him having trouble following steps to assemble furniture.

He received a year of placebo, then a year of lower-dose aducanumab, then two years of the high dose before the 2019 halt. During that time, Ms. Jellison said, he was “slipping a bit,” but she believes aducanumab slowed decline enough to allow him to participate in tasks like choosing an assisted-living facility, where he moved in October 2018.

“It brought us some time,” she said.

Debby Rosencrantz, a trial participant, hopes for Alzheimer’s treatments that work well enough to curb her dementia. “It just feels like there’s a blank in places where there shouldn’t be a blank in my brain,” she said.Kayana Szymczak for The New York Times

Another issue with evaluating treatments is that some assessment scales, including in the aducanumab trials, involve reports from relatives or caregivers, who might miss subtle symptom progression.

“It is squishy stuff,” said Susan Woskie, a professor emeritus in public health at the University of Massachusetts Lowell, whose wife, Debby Rosenkrantz, 68, participated in the trial. “This stuff is really difficult, I think, to compile into metrics that have any validity.”

Ms. Rosenkrantz, a former social worker in Cambridge, Mass., said that while receiving roughly eight months of low-dose aducanumab in the trial, “I was really optimistic that there was a drug, and so for me it was like, yes, it’s working.”

Since restarting infusions in Biogen’s study for previous participants last September, though, “I haven’t noticed any change,” she said.

She experiences short-term memory loss and cannot follow recipes. “It just feels like there’s a blank in places where there shouldn’t be a blank in my brain,” she said.

Dr. Woskie said the couple yearns for treatments but that if the F.D.A. told Biogen, “‘No, we don’t fast-track approve you; come back when you have more data,’ that wouldn’t surprise me, and it might make sense.”

Some doctors who consider aducanumab’s evidence weak, including Dr. Knopman, say that if it is approved, they would tell patients their reservations but would feel ethically compelled to offer it.

Still, Dr. Jason Karlawish, a co-director of the University of Pennsylvania’s Penn Memory Center and a site investigator on Biogen-sponsored studies, said, “Physicians like me, who would be prescribers, are saying, ‘I want an effective drug to prescribe to my patients — but this is not the drug.’”

Moderna Vaccine Highly Effective in Adolescents, Company Says

The U.S., which has a surplus of vaccines, could soon have two options for teens while many countries face shortages.

Moderna said on Tuesday that its coronavirus vaccine, authorized only for use in adults, was powerfully effective in 12- to 17-year-olds. In a clinical trial of the vaccine in adolescents, there were no cases of symptomatic Covid-19 among fully vaccinated teens, the company reported in a news release.

Moderna plans to apply to the Food and Drug Administration in June for authorization to use the vaccine in adolescents. If approved, its vaccine would become the second Covid-19 vaccine available to U.S. adolescents, after federal regulators authorized the Pfizer-BioNTech vaccine for 12- to 15-year-olds earlier this month.

The Pfizer shot was initially authorized for use in people 16 and older, while Moderna’s has been available for those 18 and up.

The Moderna results are not a surprise and match what Pfizer reported in its trial of young adolescents. But they add to a growing body of evidence that the vaccines are safe and effective in children.

“We were pretty excited to see the data, and we’re excited to see that the numbers look very good,” said Dr. Yvonne Maldonado, a pediatric infectious disease specialist at Stanford Medicine and chair of the American Academy of Pediatrics Committee on Infectious Diseases.

She added, “People are going to be more comfortable being able to go back to school. They’re going to be able to do more activities socially. I do think it’s going to make a big difference in opening our society back up.”

On Monday, Mayor Bill de Blasio said that all public school students in New York City, the largest school system in the United States, would return to in-person learning in the fall. Several other states, including Connecticut, Illinois, Massachusetts and New Jersey, have also indicated that they will restrict online learning.

The widespread availability of safe, effective vaccines for teenagers could allow middle and high schools to operate more safely and restore at least some sense of normalcy.

“Having adolescents vaccinated against the virus is really going to limit spread in school to a great degree,” said Dr. Sean O’Leary, a pediatrics infectious disease expert at the University of Colorado Anschutz Medical Campus. “It potentially could even change mask requirements for school, depending on the level of vaccination uptake. I’m looking forward to a much different school year next year, primarily because of vaccination.”

But Moderna’s announcement comes at a time when there is already a glut of vaccines in the U.S., and amid signs that demand for vaccination may be flagging. And the authorization of vaccines for American adolescents has already raised questions about the ethics of vaccinating children, who are at relatively low risk for serious disease, while many countries do not have enough doses for their health care workers.

“It’s a tough conversation, because we are glad to see vaccine distribution safely expand to children,” said Saskia Popescu, an infectious disease epidemiologist at George Mason University. “But frankly, it’s hard not to see this as privileged when a majority of the world’s essential workers are struggling to get access to vaccines.”

The Moderna results, which the company announced in a statement, are based on a clinical trial that enrolled 3,732 people ages 12 to 17, two-thirds of whom received two vaccine doses. There were no cases of symptomatic Covid-19 in fully vaccinated adolescents, the company reported. That translates to an efficacy of 100 percent, the same figure that Pfizer and BioNTech reported in a trial of their vaccine in 12- to 15-year-olds.

“It’s really great news,” said Akiko Iwasaki, an immunologist at Yale University. “These vaccines are working really well in all the age groups and potentially even better in the younger people.”

Moderna also reported that a single dose of its vaccine had 93 percent efficacy against symptomatic disease.

Doses of the Pfizer-BioNTech vaccine being administered to young people ages 12 to 15 in Minneapolis earlier this month. 
Doses of the Pfizer-BioNTech vaccine being administered to young people ages 12 to 15 in Minneapolis earlier this month. Aaron Nesheim for The New York Times

The side effects were consistent with what has been reported in adults: pain at the site of the injection, headache, fatigue, muscle pain and chills. “No significant safety concerns have been identified to date,” the company said. The adolescents in the study will be monitored for a year after their second dose.

The authorization of a second vaccine for adolescents could help convince more parents, some of whom have expressed reluctance about having their children vaccinated, that the shots are safe, experts said. “Most parents vaccinate their children,” Dr. O’Leary said. “With the Covid vaccines, we’ve seen a little bit more hesitancy, but the further along we get demonstrating safety and effectiveness, the more people we’re seeing wanting the vaccine.”

It would also give parents and teenagers a choice between vaccines, although experts noted that the Pfizer and Moderna vaccines appear to be equally safe and effective.

“This really give parents, I think, a little bit more confidence,” said Rupali Limaye, an expert on vaccine use and hesitancy at Johns Hopkins University. “If they’ve had personal experience, for example, with one of the mRNA products and not the other, they might feel more comfortable then saying, ‘You know, I had a great experience with Moderna, so I really want my child to get Moderna.’”

But because the Pfizer and Moderna vaccines both require two shots, spaced several weeks apart, ensuring that all teens have access to the vaccine may remain a challenge. “I think we’ll still unfortunately not be able to reach more underserved populations that are facing vaccine disparities, because it’s still the two-dose regimen,” Dr. Limaye said. Authorizing a one-dose vaccine, like the Johnson & Johnson shot, for use in adolescents may help close these gaps, she said.

The U.S. already has enough doses to vaccinate adolescents many times over. There are approximately 25 million American children between the ages of 12 and 17, according to estimates from the U.S. Census Bureau. That is roughly the same number of shots that Pfizer and Moderna are distributing, in total, per week in the U.S.

“Right now, we have more than enough supply to vaccinate our teens,” said Dr. Celine Gounder, an infectious disease specialist at Bellevue Hospital Center in New York. “So it’s not so much that the Moderna vaccine is critical for having supply for our population, but rather, having a second vaccine come online for that age group that could be available to the rest of the world — I think that is important.”

Many other countries, however, will not be ready to vaccinate their adolescents for quite some time. Although more than 1.7 billion vaccine doses have been administered globally, there are enormous inequities between countries; 84 percent of doses have gone to people in high- and upper-middle-income countries. Just 0.3 percent have gone to low-income countries.

“A huge proportion of the world’s population actually lives in countries that don’t have access to any doses right now at all,” said Andrea Taylor, assistant director of programs at Duke University’s Global Health Innovation Center. “In one country we are looking at covering children, and in more than 100 other countries we are desperately scrambling to try to inoculate the most vulnerable populations.”

Covax, a global initiative that aims to improve access to vaccines in low- and middle-income countries, has fallen far short of its distribution goal so far. Moderna and Pfizer have pledged to deliver tens of millions of doses to Covax by the end of 2021. Given the vaccine shortages — and dire case numbers — in many other countries, the companies should consider delivering those shots sooner, even if it means postponing the vaccination of adolescents, said Prashant Yadav, an expert in health care supply chains at the Center for Global Development in Washington, D.C.

“If they can upfront that and deliver that now, that will give Covax the option of vaccinating the high-risk individuals in a large number of low-income countries,” he said.

The World Health Organization has called on countries with ample vaccine supply to share their shots with the world. President Biden has pledged to send 80 million vaccine doses — including shots from Pfizer, Moderna, Johnson & Johnson and AstraZeneca — abroad, although many activists and global health experts have called on him to do more.

“It feels like, ‘OK, we are putting this behind us,” Ms. Taylor said. “We’re moving forward and starting to make summer vacation plans. It can be really hard to remember that much of the world actually is still in crisis.”

Noah Weiland contributed reporting.

Why the C.D.C. Changed Its Advice on Masks

Two scientific findings altered the calculus: Vaccinated people don’t transmit the virus, and the shots are effective against variants.

Advice from federal health officials that fully vaccinated people could drop their masks in most settings came as a surprise to Americans, from state officials to scientific experts. Even the White House got less than a day’s notice from the Centers for Disease Control and Prevention, the press secretary, Jen Psaki, said at a news briefing on Friday.

“The C.D.C., the doctors and medical experts there, are the ones who determined what this guidance would be based on their own data, and what the timeline would be,” Ms. Psaki said. “That was not a decision directed by or made by the White House.”

For months, federal officials have vigorously warned that wearing masks and social distancing were necessary to contain the pandemic. So what changed?

Introducing the new recommendations on Thursday, Dr. Rochelle P. Walensky, the C.D.C. director, cited two recent scientific findings as significant factors: Few vaccinated people become infected with the virus, and transmission seems rarer still; and the vaccines appear to be effective against all known variants of the coronavirus.

There is no doubt at this point that the vaccines are powerful. On Friday, the C.D.C. released results from another large study showing that the vaccines made by Pfizer-BioNTech and Moderna are 94 percent effective in preventing symptomatic illness in those who were fully vaccinated, and 82 percent effective even in those only partly vaccinated.

“The science is quite clear on this,” said Zoë McLaren, a health policy expert at the University of Maryland, Baltimore County. Mounting evidence indicates that people who are vaccinated are highly unlikely to catch or transmit the virus, she noted.

The risk “is definitely not zero, but it’s clear that it’s very low,” she said.

One of the lingering concerns among scientists had been that even a vaccinated person might carry the virus — perhaps briefly, without symptoms — and spread it to others. But C.D.C. research, including the new study, has consistently found few infections among those who received the Pfizer-BioNTech and Moderna vaccines.

“This study, added to the many studies that preceded it, was pivotal to C.D.C. changing its recommendations for those who are fully vaccinated against Covid-19,” Dr. Walensky said in a statement on Friday.

Other recent studies confirm that people who are infected after vaccination carry too little virus to infect others, said Florian Krammer, a virologist at the Icahn School of Medicine at Mount Sinai.

“It’s really hard to even sequence the virus sometimes because there’s very little virus, and it’s there for a short period of time,” he said.

Still, most of the data has been gathered on the Pfizer-BioNTech and Moderna vaccines, Dr. Krammer cautioned. Because Johnson & Johnson’s vaccine was authorized later, there are fewer studies assessing its effectiveness.

In clinical trials, the Johnson & Johnson vaccine had 72 percent efficacy — lower than the figure for the Pfizer and Moderna vaccines. And effectiveness was measured in terms of moderate and severe disease, rather than mild disease.

“It’s a very good vaccine, and I’m sure it will save many, many, many lives,” Dr. Krammer said. “But we need more data on how well the J.&J. vaccine prevents infection, and how well it prevents transmission.”

Variants of the virus have been a particular worry for scientists. While Dr. Walensky cited evidence showing that the mRNA vaccines like those from Pfizer and Moderna are effective against the variants circulating in the United States, there is little data about variants and the Johnson & Johnson vaccine. And new variants are emerging constantly.

“I’m not at all saying that this is now a big problem,” Dr. Krammer said. But before lifting the masking requirements, “I might have waited a little bit longer to look at the numbers.”

In a statement on Friday, a C.D.C. spokesman said, “All of the authorized vaccines provide strong protection against serious illness, hospitalization, and death, and we are accumulating data that our authorized vaccines are effective against the variants that are circulating in this country.”

Fully immunized people are unlikely to get seriously ill, even if they are infected with the coronavirus. The risk of infection is greater for the people around them — unvaccinated children and adults, or vaccinated people who remain unprotected because of a medical condition or treatment.

C.D.C. officials said they weighed those factors and were confident in their assessment of the science. And the new advice has other salutary effects, rewarding fully immunized people by giving them permission to end their social isolation — and perhaps incentivizing others to opt for vaccination.

The new advice “signals that we really are on the final stretch here, and I think that’s a very good thing for people,” said Dr. Joshua Sharfstein, the vice dean for public health practice and community engagement at Johns Hopkins University Bloomberg School of Health.

“It’s unlikely that we’re going to have another huge surge in cases,” he added. “But will the final stretch last for weeks or months is still a question.”

The difficulty with the new recommendations, he and other experts said, is not so much the science underpinning them as their implementation.

Leaders at the state, city and county levels still have the authority to require masks even for vaccinated people, as the C.D.C. was quick to acknowledge on Thursday. After the agency’s announcement, some states instantly lifted mask mandates, while others said they would need more time to weigh the evidence.

But in states without mask mandates, the onus of checking vaccination status will fall on shopkeepers, restaurant workers, school officials and workplace managers.

“Without a means to verify vaccination, we will have to rely on an honor system,” said Caitlin Rivers, an epidemiologist at Johns Hopkins University.

The number of cases in the country is the lowest it has been since September, and many experts support lifting mask mandates in much of the country. But doing so will be riskier in places like Michigan, where there are more cases, and for people who are unprotected, including children under 12 and people with a weak immune systems, Dr. Rivers said.

“People who are unvaccinated should continue to wear masks in public indoors and avoid crowds,” she said.

In Nacogdoches, Texas, Dr. Ahammed Hashim fretted that only 36 percent of the population was immunized and the pace seemed to have stalled. And yet only one or two people in 10 in the local shops wore masks.

“I think the C.D.C. might send a wrong message saying that everything’s OK,” said Dr. Hashim, a pulmonologist. “It would feel much better if we had a 60 or 70 percent vaccination.”

The C.D.C.’s guidance is intended for fully vaccinated individuals, and should only be interpreted as such, Dr. Sharfstein cautioned. Nationwide, only 36 percent of the population is fully vaccinated.

“What we’re just seeing is a little bit of the distance between advice that is entirely appropriate for people who are vaccinated, and the reality that there are places that still are seeing viral transmission and a lot of people who aren’t vaccinated,” he said.

Individuals may make choices based on their perception of their own risks, but state and local leaders must decide what’s best for the community based on the rate of infections. “Those are two different things,” Dr. Sharfstein said. “And when they get conflated, that’s when people may make bad judgments about policy.”

The new guidelines should serve as a reminder to health officials to step up their outreach and investment to ensure that everyone has access to vaccines, Dr. McLaren said. Parents of children under 12 should continue to urge them to wear masks indoors.

The C.D.C.’s new policy shifts the onus onto the immunocompromised as well, to protect themselves from unmasked and unvaccinated people.

“When we make policy, we need to balance the needs and desires of everyone,” Dr. McLaren said. “We could keep masking forever, but there are benefits to getting back to a life that looks more normal.”

Health officials should emphasize that the situation may yet change, and official recommendations with it, she added: “We really need to practice being good at responding to changing situations.”

New Drugs Could Help Treat Obesity. Could They End the Stigma, Too?

Obesity has stalked Marleen Greenleaf, 58, all of her life. Like most people with obesity, she tried diet after diet. But the weight always came back.

With that, she has suffered a lifetime of scorn and stigma. Jeering comments from strangers when she walked down the street. Family members who told her, when she trained for a half-marathon, “I don’t think it’s good for you.”

Then, in 2018, Ms. Greenleaf, an administrator at a charter school in Washington, D.C., participated in a clinical trial for semaglutide, which is a new type of obesity drug, known as incretins.

Over the course of the 68-week study, Ms. Greenleaf slowly lost 40 pounds.

Until then, she had always believed that she could control her weight if she really tried.

“I thought I just needed more motivation,” she said. But when she took semaglutide, she said that “immediately, the urge to eat just dissipated.”

Incretins appear to elicit significant weight loss in most patients, enough to make a real medical and aesthetic difference. But experts hope that the drugs also do something else: change how society feels about people with obesity, and how people with obesity feel about themselves.

If these new drugs allow obesity to be treated like a chronic disease — with medications that must be taken for a lifetime — the thought is that doctors, patients and the public might understand that obesity is truly a medical condition.

“We all believe this drug will change the way we see obesity being treated,” said Dr. Caroline Apovian, an obesity specialist at Brigham and Women’s Hospital. (Dr. Apovian, like most leading obesity researchers, consults for several drug companies. She is on the advisory board of Novo Nordisk, the maker of semaglutide, and is paid for attending advisory board meetings.)

Decades of studies have repeatedly showed that there are powerful biological controls over individual body weights. Identical twins reared apart had nearly identical body weights. Adopted children ended up with body mass indexes like those of their biological parents, not those of their adoptive parents. Metabolism slows as people lose weight, forcing them to regain it.

And yet, obesity “is like having a mark on your forehead,” said Dr. Scott Kahan, chair of the clinical committee for The Obesity Society, a scientific membership organization.

People with obesity are more likely to be passed over for jobs, be paid less than others with the same abilities and training, and be treated poorly by doctors, who spend less time with them and offer fewer preventive services.

But people with obesity haven’t had many places to turn for help. The current obesity drugs lead to an average weight loss of only 5 percent to 10 percent. And because some of these drugs are approved only for limited time frames, the lost pounds almost always come back when the intervention ceases.

According to these studies, incretins seem to be different. Unlike other weight-loss drugs, they are naturally occurring hormones that affect systems central to obesity. The drugs slow stomach emptying, regulate insulin and decrease appetite, with mostly mild to moderate short-term gastrointestinal side effects.

The drugs will not banish obesity or make people truly thin. But people who take them can look and feel very different. For some, the medications lead to weight loss approaching that of bariatric surgery.

If incretins pass the approval process, they might help convince the most important constituency of all — doctors — that obesity is a chronic disease and that it can be treated, said Dr. Robert F. Kushner, an obesity researcher and clinician at Northwestern University. One reason many doctors don’t help patients with obesity is that they don’t know how, Dr. Kushner said. Diets and exercise, the usual nostrums, almost always provide short-term weight loss, at best.

Dr. Robert F. Kushner, an obesity researcher and clinician at Northwestern University. “I tell them this is a chronic ongoing medical problem, just like diabetes,” he said.
Dr. Robert F. Kushner, an obesity researcher and clinician at Northwestern University. “I tell them this is a chronic ongoing medical problem, just like diabetes,” he said.Taylor Glascock for The New York Times

The incretin taken by Ms. Greenleaf, semaglutide, made by Novo Nordisk, is before the Food and Drug Administration, with a decision expected in June. On average it elicited a 15 percent weight loss, but a third of those who took it lost 20 percent or more of their body weight in the study, similar to the amount lost with lap-band bariatric surgery.

Eli Lilly has a similar drug, tirzepatide, which combines two incretins. The company is testing it against semaglutide and hopes that it will be even more powerful.

Dr. Louis J. Aronne, an obesity specialist at Cornell Medical School, said that the combination of semaglutide and another experimental Novo Nordisk drug, cagrilintide, could produce as much as a 25 percent weight loss in a year, an amount like that achieved with sleeve gastrectomy, a popular form of bariatric surgery.

Although more than a half-dozen new hormonal drugs are being tested, Dr. Kushner said, only with long-term use can researchers learn if the new drugs control the many medical consequences of obesity, like diabetes and high blood pressure.

There is also the larger riddle of biological destiny: Are the body’s multiple and redundant systems to maintain body weight so powerful that they will exert control in the end, diminishing the effectiveness of the drugs?

Like other obesity specialists, Dr. Rudolph L. Leibel, a researcher at Columbia University who conducted many of the pivotal studies showing obesity is a disease, deplores society’s bias against his patients. But he has his doubts that perceptions will change with new treatments.

“My guess is that bias will persist and might even be exacerbated by the availability of ‘an easy way out,’” he said.

Dr. Kushner is more hopeful and points to the example of statins, which lower cholesterol and became available in the late 1980s. Until then, doctors could only suggest that patients with high cholesterol cut back on eggs and red meat.

Doctors “embraced statins,” Dr. Kushner said, because they could at last treat this condition. More powerful incretins, he added, could have the same effect on the medical profession.

He is unsure, though, whether patients will accept the disease label. They’ve been conditioned, he said, to believe that their weight is their own fault; all they have to do is eat healthier and exercise more.

When talking with patients, he doesn’t spend 20 minutes trying to convince them that they have a disease. In fact, he deliberately avoids using the word “disease” and instead says “condition” or “problem.”

“I tell them this is a chronic ongoing medical problem, just like diabetes,” he said.

Members of the general public pose a different challenge, Dr. Kushner said. With them, he said, “we may need to use a term like ‘disease.’”

He likens the situation to that of alcoholism or drug addiction, which was once thought to be indicative of a weak will or a moral failing. Researchers have successfully changed the conversation; many people now know that those who abuse alcohol or drugs have a disease and need treatment.

As for Ms. Greenleaf, she wants to take semaglutide again. The pounds crept back when the trial ended.

Obesity, she now realizes, “is not your fault.”

FDA Authorizes Pfizer-BioNTech Vaccine for Children 12 to 15

The shots may allow millions of youngsters to get back to school, camps, sleepovers and hangouts with friends.

The Food and Drug Administration on Monday authorized use of the Pfizer-BioNTech Covid-19 vaccine for 12- to 15-year-olds in the United States, a crucial step in the nation’s steady recovery from the pandemic and a boon to millions of American families eager for a return to normalcy.

The authorization caps weeks of anticipation among parents, who have been grappling with how to conduct their lives when only the adults in a household are immunized. It removes an obstacle to school reopenings by reducing the threat of transmission in classrooms, and affords more of the nearly 17 million children in this age group opportunities to attend summer camps, sleepovers and Little League games.

“This is great news,” said Dr. Kristin Oliver, a pediatrician and vaccine expert at Mount Sinai Hospital in New York. “It feels like we’ve been waiting a long time to start protecting children in this age group.” The Pfizer-BioNTech vaccine is already available to anyone over 16.

The F.D.A.’s go-ahead is not the final hurdle. An advisory committee of the Centers for Disease Control and Prevention is expected to meet shortly to review the data and make recommendations for the vaccine’s use in 12- to 15-year-olds.

If the committee endorses the vaccine for that age group, as expected, immunizations in theory can begin immediately. Clinical trials have shown that these children may safely receive the dose already available for adults.

President Biden has said that about 20,000 pharmacies are ready to administer the vaccine to adolescents, and health officials in some states are already drawing up immunization campaigns targeted to youngsters.

In a clinical trial, Pfizer and BioNTech enrolled 2,260 participants ages 12 and 15 and gave them either two doses of the vaccine or a placebo three weeks apart. The researchers recorded 18 cases of symptomatic coronavirus infection in the placebo group, and none among the children who received the vaccine, indicating that it was highly effective at preventing symptomatic illness.

The vaccine also appeared to be safe for these children, with side effects comparable to those seen in trial participants who are 16 to 25 years old. Fevers were slightly more common among inoculated 12- to 15-year-olds; about 20 percent of them had fevers, compared with 17 percent in the older age group.

The trend toward more fevers at younger ages was consistent with observations in an earlier trial, said Dr. Bill Gruber, a senior vice president at Pfizer and a pediatrician.

The trial results were a “trifecta” of good news, Dr. Gruber added: “We have safety, we got the immune response we wanted — it was actually better than what we saw in the 16- to 25-year-old population — and we had outright demonstration of efficacy.”

The company is still gathering information on potential asymptomatic infections by continuing to test the trial participants for the coronavirus every two weeks and checking them for antibodies produced in response to a natural infection, according to Dr. Gruber.

The authorization arrives at a opportune time. Roughly one-third of eighth graders, usually 13 and 14 years old, are still learning fully remotely, and widespread vaccination may help speed a return to classrooms.

Coronavirus outbreaks have been a concern particularly for students participating in team sports, and immunizations should ease the concerns of many parents whose children have been unable to participate in football, basketball and other team sports involving close contact.

In summer, families often catch up the vaccinations required for children to return to schools in the fall, and so pediatricians and family doctors may be best positioned to immunize young teenagers as they come in for annual physical examinations.

The Pfizer-BioNTech vaccine can be stored for only five days in standard refrigerators, but the companies are planning to ship smaller packs for doctors’ offices. It is also developing a formulation that can be refrigerated for up to 10 weeks.

The push to immunize children may run into the same problems with hesitancy that have plagued attempts to inoculate adults. In one recent poll, 30 percent of parents said they would have their children vaccinated right away, while 26 percent said they planned to wait to see how the vaccine was working.

Most of the other parents said they would definitely not have their children vaccinated, or would do so only if schools required it. All 50 states require certain vaccines for children who attend school, but those mandates apply only to vaccines that have been fully approved by the F.D.A. The Pfizer-BioNTech vaccine has been authorized only for emergency use.

The companies have applied to the F.D.A. for full approval, but that process is expected to take several months. Even after approval, students may still opt out by citing medical reasons or religious beliefs.

Still, scientists agreed that the vaccine appeared to meet all expectations regarding safety and efficacy. Dr. Megan Ranney, an emergency room physician and professor at Brown University in Providence, R.I., said she had “zero safety concerns” about the Pfizer-BioNTech vaccine, noting that hundreds of millions of people worldwide had received it.

Her 12-year-old daughter is eager to be vaccinated, and her 9-year-old son will be immunized as soon as he is eligible, she said. Dr. Ranney has not allowed her children to sleep at friends’ houses since the pandemic began. The vaccine should allow them to safely resume social activities, she said.

“The risk of your child catching Covid and getting really sick is low, but it’s not zero,” she said. “And the risk of them getting sick or hospitalized or worse with Covid or with the post-Covid multi-inflammatory syndrome is higher than the risk of something bad from this vaccine.”

Vaccinating children shields others in the community from the virus, she noted, including people who are not protected by the vaccine, such as organ transplant recipients, cancer patients and those with impaired immune responses.

“It also protects all of us from the virus continuing to spread and mutating further,” Dr. Ranney said. “That’s the thing that I’m most scared of right now.”

Vaccinating children is crucial to building up population levels of immunity and curtailing the spread of the coronavirus. Though children spread the virus less efficiently than adults do, they make up about 23 percent of the population.

Experts have said that the country is unlikely to reach the “herd immunity” threshold — the point at which virus transmission essentially stalls — but vaccinating children will be important for getting as close as possible.

Ty Dropic, 14, one of the trial participants, urged others his age to be vaccinated so they could build up widespread immunity and protect themselves. He had no side effects, leading him to suspect that he got the placebo. If that turns out to be the case, he plans to be immunized as soon as possible.

“I know it can be kind of scary, but it’s really not as bad as it seems,” he said. “If you do get Covid, it’ll be a lot worse than getting stuck with a needle for, like, two seconds.”

Ty’s three siblings, ages 8, 10 and 16, are also enrolled in vaccine trials for their age groups. Their mother, Dr. Amanda Dropic, a pediatrician in northern Kentucky, said that in her practice, most parents were eager to have their children vaccinated so they could regain some semblance of normalcy.

“The anxiety and depression that we’re seeing with kids, the social delays, has been tremendous,” she said.

Dr. Dropic said her children understood the risks and were willing to volunteer because they saw it as a civic duty. Every medicine available today came to be because “somebody was willing to go first,” she added.

Pfizer and BioNTech began testing the vaccine in children ages 5 to 11 in March, and last month extended the trial to even younger children, ages 2 to 5. The companies next plan to test children who are 6 months to 2 years old.

Assuming trial results are encouraging, the companies expect to apply to the F.D.A. in September for emergency authorization to administer the vaccine to children ages 2 to 11.

Results from trials of Moderna’s vaccine in 12- to 17-year-olds are expected in the next few weeks. Findings from another trial of the company’s vaccine in children 6 months to 12 years old should be available in the second half of this year.

AstraZeneca is testing its vaccine in children 6 months and older. Johnson & Johnson plans to wait for results from trials in participants older than 12 before testing its vaccine in younger children.

Jan Hoffman contributed reporting.

F.D.A. Authorizes Pfizer-BioNTech Vaccine for Children 12 to 15

The shots may allow millions of youngsters to get back to school, camps, sleepovers and hangouts with friends.

The Food and Drug Administration on Monday authorized use of the Pfizer-BioNTech Covid-19 vaccine for 12- to 15-year-olds in the United States, a crucial step in the nation’s steady recovery from the pandemic and a boon to millions of American families eager for a return to normalcy.

The authorization caps weeks of anticipation among parents, who have been grappling with how to conduct their lives when only the adults in a household are immunized. It removes an obstacle to school reopenings by reducing the threat of transmission in classrooms, and affords the nearly 17 million children in this age group the opportunity to attend summer camps, sleepovers and Little League games.

“This is great news,” said Dr. Kristin Oliver, a pediatrician and vaccine expert at Mount Sinai Hospital in New York. “It feels like we’ve been waiting a long time to start protecting children in this age group.” The Pfizer-BioNTech vaccine is already available to anyone over 16.

The F.D.A.’s go-ahead is not the final hurdle. An advisory committee of the Centers for Disease Control and Prevention is expected to meet shortly to review the data and make recommendations for the vaccine’s use in 12- to 15-year-olds.

If the committee endorses the vaccine for that age group, as expected, immunizations in theory can begin immediately. Clinical trials have shown that these children may safely receive the dose already available for adults.

President Biden has said that about 20,000 pharmacies are ready to administer the vaccine to adolescents, and health officials in some states are already drawing up immunization campaigns targeted to youngsters.

In a clinical trial, Pfizer and BioNTech enrolled 2,260 participants ages 12 and 15 and gave them either two doses of the vaccine or a placebo three weeks apart. The researchers recorded 18 cases of symptomatic coronavirus infection in the placebo group, and none among the children who received the vaccine, indicating that it was highly effective at preventing symptomatic illness.

The vaccine also appeared to be safe for these children, with side effects comparable to those seen in trial participants who are 16 to 25 years old. Fevers were slightly more common among inoculated 12- to 15-year-olds; about 20 percent of them had fevers, compared with 17 percent in the older age group.

The trend toward more fevers at younger ages was consistent with observations in an earlier trial, said Dr. Bill Gruber, a senior vice president at Pfizer and a pediatrician.

The trial results were a “trifecta” of good news, Dr. Gruber added: “We have safety, we got the immune response we wanted — it was actually better than what we saw in the 16- to 25-year-old population — and we had outright demonstration of efficacy.”

The company is still gathering information on potential asymptomatic infections by continuing to test the trial participants for the coronavirus every two weeks and checking them for antibodies produced in response to a natural infection, according to Dr. Gruber.

The authorization arrives at a opportune time. Roughly one-third of eighth graders, usually 13 and 14 years old, are still learning fully remotely, and widespread vaccination may help speed a return to classrooms.

Coronavirus outbreaks have been a concern particularly for students participating in team sports, and immunizations should ease the concerns of many parents whose children have been unable to participate in football, basketball and other team sports involving close contact.

In summer, families often catch up the vaccinations required for children to return to schools in the fall, and so pediatricians and family doctors may be best positioned to immunize young teenagers as they come in for annual physical examinations.

The Pfizer-BioNTech vaccine can be stored for only five days in standard refrigerators, but the companies are planning to ship smaller packs for doctors’ offices. It is also developing a formulation that can be refrigerated for up to 10 weeks.

The push to immunize children may run into the same problems with hesitancy that have plagued attempts to inoculate adults. In one recent poll, 30 percent of parents said they would have their children vaccinated right away, while 26 percent said they planned to wait to see how the vaccine was working.

Most of the other parents said they would definitely not have their children vaccinated, or would do so only if schools required it. All 50 states require certain vaccines for children who attend school, but those mandates apply only to vaccines that have been fully approved by the F.D.A. The Pfizer-BioNTech vaccine has been authorized only for emergency use.

The companies have applied to the F.D.A. for full approval, but that process is expected to take several months. Even after approval, students may still opt out by citing medical reasons or religious beliefs.

Still, scientists agreed that the vaccine appeared to meet all expectations regarding safety and efficacy. Dr. Megan Ranney, an emergency room physician at Rhode Island Hospital in Providence, said she had “zero safety concerns” about the Pfizer-BioNTech vaccine, noting that hundreds of millions of people worldwide had received it.

Her 12-year-old daughter is eager to be vaccinated, and her 9-year-old son will be immunized as soon as he is eligible, she said. Dr. Ranney has not allowed her children to sleep at friends’ houses since the pandemic began. The vaccine should allow them to safely resume social activities, she said.

“The risk of your child catching Covid and getting really sick is low, but it’s not zero,” she said. “And the risk of them getting sick or hospitalized or worse with Covid or with the post-Covid multi-inflammatory syndrome is higher than the risk of something bad from this vaccine.”

Vaccinating children shields others in the community from the virus, she noted, including people who are not protected by the vaccine, such as organ transplant recipients, cancer patients and those with impaired immune responses.

“It also protects all of us from the virus continuing to spread and mutating further,” Dr. Ranney said. “That’s the thing that I’m most scared of right now.”

Vaccinating children is crucial to building up population levels of immunity and curtailing the spread of the coronavirus. Though children spread the virus less efficiently than adults do, they make up about 23 percent of the population.

Experts have said that the country is unlikely to reach the “herd immunity” threshold — the point at which virus transmission essentially stalls — but vaccinating children will be important for getting as close as possible.

Ty Dropic, 14, one of the trial participants, urged others his age to be vaccinated so they could build up widespread immunity and protect themselves. He had no side effects, leading him to suspect that he got the placebo. If that turns out to be the case, he plans to be immunized as soon as possible.

“I know it can be kind of scary, but it’s really not as bad as it seems,” he said. “If you do get Covid, it’ll be a lot worse than getting stuck with a needle for, like, two seconds.”

Ty’s three siblings, ages 8, 10 and 16, are also enrolled in vaccine trials for their age groups. Their mother, Dr. Amanda Dropic, a pediatrician in northern Kentucky, said that in her practice, most parents were eager to have their children vaccinated so they could regain some semblance of normalcy.

“The anxiety and depression that we’re seeing with kids, the social delays, has been tremendous,” she said.

Dr. Dropic said her children understood the risks and were willing to volunteer because they saw it as a civic duty. Every medicine available today is because “somebody was willing to go first,” she added.

Pfizer and BioNTech began testing the vaccine in children ages 5 to 11 in March, and last month extended the trial to even younger children, ages 2 to 5. The companies next plan to test children who are 6 months to 2 years old.

Assuming trial results are encouraging, the companies expect to apply to the F.D.A. in September for emergency authorization to administer the vaccine to children ages 2 to 11.

Results from trials of Moderna’s vaccine in 12- to 17-year-olds are expected in the next few weeks. Findings from another trial of the company’s vaccine in children 6 months to 12 years old should be available in the second half of this year.

AstraZeneca is testing its vaccine in children 6 months and older. Johnson & Johnson plans to wait for results from trials in participants older than 12 before testing its vaccine in younger children.

Jan Hoffman contributed reporting.

This New Covid Vaccine Could Bring Hope to the Unvaccinated World

The German company CureVac hopes its RNA vaccine will rival those made by Moderna and Pfizer-BioNTech. It could be ready next month.

In early 2020, dozens of scientific teams scrambled to make a vaccine for Covid-19. Some chose tried-and-true techniques, such as making vaccines from killed viruses. But a handful of companies bet on a riskier method, one that had never produced a licensed vaccine: deploying a genetic molecule called RNA.

The bet paid off. The first two vaccines to emerge successfully out of clinical trials, made by Pfizer-BioNTech and by Moderna, were both made of RNA. They both turned out to have efficacy rates about as good as a vaccine could get.

In the months that followed, those two RNA vaccines have provided protection to tens of millions of people in some 90 countries. But many parts of the world, including those with climbing death tolls, have had little access to them, in part because they require being kept in a deep freeze.

Now a third RNA vaccine may help meet that global need. A small German company called CureVac is on the cusp of announcing the results of its late-stage clinical trial. As early as next week, the world may learn whether its vaccine is safe and effective.

CureVac’s product belongs to what many scientists refer to as the second wave of Covid-19 vaccines that could collectively ease the world’s demand. Novavax, a company based in Maryland whose vaccine uses coronavirus proteins, is expected to apply for U.S. authorization in the next few weeks. In India, the pharmaceutical company Biological E is testing another protein-based vaccine that was developed by researchers in Texas. In Brazil, Mexico, Thailand and Vietnam, researchers are starting trials for a Covid-19 shot that can be mass-produced in chicken eggs.

Vaccines experts are particularly curious to see CureVac’s results, because its shot has an important advantage over the other RNA vaccines from Moderna and Pfizer-BioNTech. While those two vaccines have to be kept in a deep freezer, CureVac’s vaccine stays stable in a refrigerator — meaning it could more easily deliver the newly discovered power of RNA vaccines to hard-hit parts of the world.

“It’s gone largely under the radar,” said Jacob Kirkegaard, a senior fellow at the Peterson Institute for International Economics in Washington, D.C. But now, he added, “they look pretty well positioned to clean up the global market.”

For CureVac’s co-founder, the biologist Ingmar Hoerr, the company’s Covid-19 vaccine trial is the culmination of a quarter-century’s worth of work with RNA, a molecule that helps turn DNA into the proteins that do the work of our cells. As a graduate student at the University of Tübingen in the 1990s, Dr. Hoerr injected RNA into mice and found that the animals could make the protein encoded by the molecules. He was surprised to find that the mice’s immune systems made antibodies against the new proteins.

Here, Dr. Hoerr thought, might be the basis for a new kind of vaccine. “I was thinking, Wow, if this works like that in humans, then we have a completely new pharmaceutical possibility,” he said.

Ingmar Hoerr, a biologist and one of CureVac’s founders.
Ingmar Hoerr, a biologist and one of CureVac’s founders.Sebastian Gollnow/picture alliance via Getty Images

At the time, only a few scientists in the world considered an RNA vaccine a serious possibility. But proponents thought it might change medicine. You could, in theory, craft an RNA molecule to immunize people against any virus. You might even be able to create an RNA vaccine to cure cancer, if you could make an RNA molecule that encoded a tumor protein.

In 2001, Dr. Hoerr co-founded CureVac to chase the idea, but for the first few years the company struggled to survive. To keep the lights on, it took orders from other labs for custom-built RNA molecules. On the side, CureVac’s scientists tinkered with their own designs for RNA vaccines.

Over time, they found subtle tweaks to RNA vaccine molecules that caused cells to make more proteins. The more potent the RNA, the lower the dose they needed in vaccines.

CureVac’s researchers also figured out how to put the RNA molecules in fatty bubbles to protect them from destruction on their journey to cells. And perhaps most important, they used a form of RNA that could stay stable at relatively warm temperatures. Instead of requiring a deep freezer, CureVac’s vaccine could be refrigerated.

In time, other companies entered the RNA vaccine business as well: BioNTech in Germany in 2008, then Moderna in Boston in 2011. Their experiments began showing that these vaccines could protect animals against an assortment of viruses. In 2013, CureVac injected human volunteers with a rabies RNA vaccine, in the first clinical trial of the technology against an infectious disease.

For years, CureVac and other RNA vaccine companies toiled on perfecting their vaccines. CureVac’s first attempt at a rabies vaccine demonstrated it was safe, but it yielded a weak response from the immune system. The company has since retooled that vaccine, and the updated version has shown promise in early clinical studies. But other efforts ended in failure. In 2017, CureVac announced that its RNA vaccine against prostate cancer offered no benefits to patients.

Despite these setbacks, the company earned a solid reputation. “They ticked the boxes for scientific acumen, speed, scale and access,” said Nicholas Jackson, the head of vaccine research and development at the Coalition for Epidemic Preparedness Innovations, a foundation that supports vaccine research. C.E.P.I. gave $34 million to CureVac in 2019 to support its development of RNA vaccines for future pandemics.

When the coronavirus pandemic hit, CureVac, BioNTech and Moderna all jumped in to make RNA vaccines. But BioNTech and Moderna soon pulled ahead, thanks in part to deep-pocketed allies. BioNTech teamed up with the pharmaceutical giant Pfizer, while Moderna worked with the National Institutes of Health and received a billion dollars from the U.S. government as part of Operation Warp Speed.

CureVac lagged behind. C.E.P.I. provided the company with $15 million, but CureVac would require far more. “If you do this, you need a considerable amount of cash,” Franz-Werner Haas, the chief executive of CureVac, said in an interview. “And the considerable amount of cash was not there.”

In March 2020, German newspapers reported that President Donald J. Trump had offered CureVac $1 billion to move its operations to the United States. CureVac denied the reports, but the chief executive suddenly left, to be replaced by Dr. Haas.

CureVac’s researchers moved ahead with their limited resources, designing an RNA molecule encoding a protein found on the surface of the coronavirus, called spike. Experiments on hamsters showed that it could protect the animals from the virus.

CureVac’s headquarters in Berlin in November.Jeremy Moeller/Getty Images

In June, the German government invested 300 million euros (about $360 million) in CureVac’s Covid-19 research, and other investors soon followed. In December, after promising data from early safety studies, the company started its final, so-called Phase 3 trial, recruiting 40,000 volunteers in Europe and Latin America. The company will get its first look at the data when 56 volunteers develop Covid-19. If most of them are in the placebo group, and few in the vaccinated group, it will be proof that the vaccine works.

Dr. Haas said he expected to have that data by mid-May. There is no way to know in advance how CureVac will fare. But given the performance of other RNA vaccines, along with CureVac’s own early results, some scientists have high expectations.

“I would just be really surprised if it didn’t work well,” said John Moore, a virologist at Weill Cornell Medicine in New York who has collaborated with CureVac on an RNA-based vaccine for H.I.V.

Still, CureVac’s vaccine is facing a challenge that Pfizer and Moderna didn’t have: new variants that may be able to blunt its effectiveness. Experiments in mice have suggested that the vaccine works well against the B.1.351 variant, which first emerged in South Africa.

Last year, CureVac partnered with a number of large companies to scale up production of its Covid vaccine, in case its clinical trials turned out well. The company also negotiated a deal with the European Union for 225 million doses, as well as an option to add another 180 million doses in subsequent months.

But now it is not clear who might receive the CureVac vaccine if it becomes available next month. In January, the European Union gave emergency authorization to a vaccine from AstraZeneca, planning to rely on that company for most of its supply. But AstraZeneca fell drastically short of its supply promises, prompting the bloc to retaliate with a lawsuit.

In April, the European Union finally fixed this shortfall, negotiating with Pfizer and BioNTech to get 1.8 billion doses of their vaccine between now and 2023. That arrangement has left analysts wondering how much demand will be left for CureVac.

“They’re going to miss the boat on the major, advanced-economy markets,” said Dr. Kirkegaard. “The U.S., Europe and Japan are going to be largely vaccinated using these Moderna and Pfizer vaccines.”

Dr. Haas countered that most of the bloc’s doses from Pfizer-BioNTech won’t come until next year. “CureVac sees itself as a major player in ending the Covid-19 pandemic in Europe and elsewhere,” he said.

Ursula von der Leyen, president of the European Commission, said that if the CureVac vaccine worked, it would be in the mix, thanks to two advantages: It is an mRNA vaccine, and it was created in Europe. It is also possible that individual European nations will make side deals with the company.

A worker checked diluent in vials at a plant in central France of the pharmaceutical company Fareva, which produces a component of the CureVac vaccine.Guillaume Souvant/Agence France-Presse — Getty Images

Billions of other people in low- and middle-income countries have yet to receive a vaccine, and experts say that CureVac may meet some of their demand. “We still need a lot of vaccine globally,” said Florian Krammer, a virologist at the Icahn School of Medicine at Mount Sinai in New York. “I think a lot of people can benefit from it.”

The vaccines from Moderna and Pfizer-BioNTech are challenging to distribute in the developing world because of the equipment and power supply required to freeze these vaccines. CureVac’s RNA vaccine can stay stable for at least three months at 41 degrees Fahrenheit, and it can sit for 24 hours at room temperature before it is used.

“The stability is a real advantage,” Dr. Jackson said. C.E.P.I. is “in very active discussions” with CureVac, he said, about distributing the company’s vaccine through Covax, an initiative to distribute vaccines to low- and middle-income countries.

But CureVac is also designing a new generation of vaccines with a goal of eventually moving into markets in the United States and other wealthy nations. Because its potent RNA requires only a small dose, the company could potentially create vaccines for different variants and mix them in a single shot.

But such possibilities are meaningless until CureVac can prove that its vaccine works. Mary Warrell, a vaccine researcher at the University of Oxford, is reluctant to speculate about the fate of the vaccine before that milestone.

“Prediction during this pandemic has rarely been profitable,” she warned.

Matina Stevis-Gridneff contributed reporting.

The Covid-19 Plasma Boom Is Over. What Did We Learn From It?

Scott Cohen was on a ventilator struggling for his life with Covid-19 last April when his brothers pleaded with Plainview Hospital on Long Island to infuse him with the blood plasma of a recovered patient.

The experimental treatment was hard to get but was gaining attention at a time when doctors had little else. After an online petition drew 18,000 signatures, the hospital gave Mr. Cohen, a retired Nassau County medic, an infusion of the pale yellow stuff that some called “liquid gold.”

In those terrifying early months of the pandemic, the idea that antibody-rich plasma could save lives took on a life of its own before there was evidence that it worked. The Trump administration, buoyed by proponents at elite medical institutions, seized on plasma as a good-news story at a time when there weren’t many others. It awarded more than $800 million to entities involved in its collection and administration, and put Dr. Anthony S. Fauci’s face on billboards promoting the treatment.

A coalition of companies and nonprofit groups, including the Mayo Clinic, Red Cross and Microsoft, mobilized to urge donations from people who had recovered from Covid-19, enlisting celebrities like Samuel L. Jackson and Dwayne Johnson, the actor known as the Rock. Volunteers, some dressed in superhero capes, showed up to blood banks in droves.

Mr. Cohen, who later recovered, was one of them. He went on to donate his own plasma 11 times.

But by the end of the year, good evidence for convalescent plasma had not materialized, prompting many prestigious medical centers to quietly abandon it. By February, with cases and hospitalizations dropping, demand dipped below what blood banks had stockpiled. In March, the New York Blood Center called Mr. Cohen to cancel his 12th appointment. It didn’t need any more plasma.

Brandon Connor, right, a phlebotomist, discussed the plasma donation process with Sheila Julich, a long-term-care nurse, at Bloodworks in Seattle in April 2020.
Brandon Connor, right, a phlebotomist, discussed the plasma donation process with Sheila Julich, a long-term-care nurse, at Bloodworks in Seattle in April 2020.Ruth Fremson/The New York Times

A year ago, when Americans were dying of Covid at an alarming rate, the federal government made a big bet on plasma. No one knew if the treatment would work, but it seemed biologically plausible and safe, and there wasn’t much else to try. All told, more than 722,000 units of plasma were distributed to hospitals thanks to the federal program, which ends this month.

The government’s bet did not result in a blockbuster treatment for Covid-19, or even a decent one. But it did give the country a real-time education in the pitfalls of testing a medical treatment in the middle of an emergency. Medical science is messy and slow. And when a treatment fails, which is often, it can be difficult for its strongest proponents to let it go.

Because the government gave plasma to so many patients outside of a controlled clinical trial, it took a long time to measure its effectiveness. Eventually, studies did emerge to suggest that under the right conditions, plasma might help. But enough evidence has now accumulated to show that the country’s broad, costly plasma campaign had little effect, especially in people whose disease was advanced enough to land them in the hospital.

In interviews, three federal health officials — Dr. Stephen M. Hahn, the former commissioner of the Food and Drug Administration; Dr. Peter Marks, a top F.D.A. regulator; and Dr. H. Clifford Lane, a clinical director at the National Institutes of Health — acknowledged that the evidence for plasma was limited.

“The data are just not that strong, and it makes it makes it hard, I think, to be enthusiastic about seeing it continue to be used,” Dr. Lane said. The N.I.H. recently halted an outpatient trial of plasma because of a lack of benefit.

Plasma promotions

Doctors have used the antibodies of recovered patients as treatments for more than a century, for diseases including diphtheria, the 1918 flu and Ebola.

So when patients began falling ill with the new coronavirus last year, doctors around the world turned to the old standby.

In the United States, two hospitals — Mount Sinai in New York City and Houston Methodist in Texas — administered the first plasma units to Covid-19 patients within hours of each other on March 28.

Dr. Nicole M. Bouvier, an infectious-disease doctor who helped set up Mount Sinai’s plasma program, said the hospital had tried the experimental treatment because blood transfusions carry a relatively low risk of harm. With a new virus spreading quickly, and no approved treatments, “nature is a much better manufacturer than we are,” she said.

As Mount Sinai prepared to infuse patients with plasma, Diana Berrent, a photographer, was recovering from Covid-19 at her home in Port Washington, N.Y. Friends began sending her Mount Sinai’s call for donors.

“I had no idea what plasma was — I haven’t taken a science class since high school,” Ms. Berrent recalled. But as she researched its history in previous disease outbreaks, she became fixated on how she could help.

She formed a Facebook group of Covid-19 survivors that grew to more than 160,000 members and eventually became a health advocacy organization, Survivor Corps. She livestreamed her own donation sessions to the Facebook group, which in turn prompted more donations.

“People were flying places to go donate plasma to each other,” she said. “It was really a beautiful thing to see.”

Diana Berrent was recovering from Covid at home on Long Island when she began hearing about the benefits of plasma. She started a Facebook group and encouraged members to donate, forming her group, Survivor Corps.Desiree Rios for The New York Times

Around the same time, Chaim Lebovits, a shoe wholesaler from Monsey, N.Y., in hard-hit Rockland County, was spreading the word about plasma within his Orthodox Jewish community. Mr. Lebovits called several rabbis he knew, and before long, thousands of Orthodox Jewish people were getting tested for coronavirus antibodies and showing up to donate. Coordinating it all was exhausting.

“April,” Mr. Lebovits recalled with a laugh, “was like 20 decades.”

Two developments that month further accelerated plasma’s use. With the help of $66 million in federal funding, the F.D.A. tapped the Mayo Clinic to run an expanded access program for hospitals across the country. And the government agreed to cover the administrative costs of collecting plasma, signing deals with the American Red Cross and America’s Blood Centers.

The news releases announcing those deals got none of the flashy media attention that the billion-dollar contracts for Covid-19 vaccines did when they arrived later in the summer. And the government did not disclose how much it would be investing.

That investment turned out to be significant. According to contract records, the U.S. government has paid $647 million to the American Red Cross and America’s Blood Centers since last April.

“The convalescent plasma program was intended to meet an urgent need for a potential therapy early in the pandemic,” a health department spokeswoman said in a statement. “When these contracts began, treatments weren’t available for hospitalized Covid-19 patients.”

As spring turned to summer, the Trump administration seized on plasma — as it had with the unproven drug hydroxychloroquine — as a promising solution. In July, the administration announced an $8 million advertising campaign “imploring Americans to donate their plasma and help save lives.” The blitz included promotional radio spots and billboards featuring Dr. Fauci and Dr. Hahn, the F.D.A. commissioner.

Dr. Anthony S. Fauci, left, speaking during a roundtable on plasma donation at the American Red Cross headquarters in Washington in July.Doug Mills/The New York Times

A coalition to organize the collection of plasma was beginning to take shape, connecting researchers, federal officials, activists like Ms. Berrent and Mr. Lebovits, and major corporations like Microsoft and Anthem on regular calls that have continued to this day. Nonprofit blood banks and for-profit plasma collection companies also joined the collaboration, named the Fight Is In Us.

The group also included the Mitre Corporation, a little-known nonprofit organization that had received a $37 million government grant to promote plasma donation around the country.

The participants sometimes had conflicting interests. While the blood banks were collecting plasma to be immediately infused in hospitalized patients, the for-profit companies needed plasma donations to develop their own blood-based treatment for Covid-19. Donations at those companies’ own centers had also dropped off after national lockdowns.

“They don’t all exactly get along,” Peter Lee, the corporate vice president of research and incubations at Microsoft, said at a virtual scientific forum in March organized by Scripps Research.

Microsoft was recruited to develop a locator tool, embedded on the group’s website, for potential donors. But the company took on a broader role “as a neutral intermediary,” Dr. Lee said.

The company also provided access to its advertising agency, which created the look and feel for the Fight Is In Us campaign, which included video testimonials from celebrities.

Lack of evidence

In August, the F.D.A. authorized plasma for emergency use under pressure from President Donald J. Trump, who had chastised federal scientists for moving too slowly.

At a news conference, Dr. Hahn, the agency’s commissioner, substantially exaggerated the data, although he later corrected his remarks following criticism from the scientific community.

In a recent interview, he said that Mr. Trump’s involvement in the plasma authorization had made the topic polarizing.

“Any discussion one could have about the science and medicine behind it didn’t happen, because it became a political issue as opposed to a medical and scientific one,” Dr. Hahn said.

The authorization did away with the Mayo Clinic system and opened access to even more hospitals. As Covid-19 cases, hospitalizations and deaths skyrocketed in the fall and winter, use of plasma did, too, according to national usage data provided by the Blood Centers of America. By January of this year, when the United States was averaging more than 130,000 hospitalizations a day, hospitals were administering 25,000 units of plasma per week.

Dr. Stephen Hahn, the former F.D.A. commissioner, during a briefing in April 2020.Anna Moneymaker for The New York Times

Many community hospitals serving lower-income patients, with few other options and plasma readily available, embraced the treatment. At the Integris Health system in Oklahoma, giving patients two units of plasma became standard practice between November and January.

Dr. David Chansolme, the system’s medical director of infection prevention, acknowledged that studies of plasma had showed it was “more miss than hit,” but he said his hospitals last year lacked the resources of bigger institutions, including access to the antiviral drug remdesivir. Doctors with a flood of patients — many of them Hispanic and from rural communities — were desperate to treat them with anything they could that was safe, Dr. Chansolme said.

By the fall, accumulating evidence was showing that plasma was not the miracle that some early boosters had believed it to be. In September, the Infectious Diseases Society of America recommended that plasma not be used in hospitalized patients outside of a clinical trial. (On Wednesday, the society restricted its advice further, saying plasma should not be used at all in hospitalized patients.) In January, a highly anticipated trial in Britain was halted early because there was not strong evidence of a benefit in hospitalized patients.

In February, the F.D.A. narrowed the authorization for plasma so that it applied only to people who were early in the course of their disease or who couldn’t make their own antibodies.

Dr. Marks, the F.D.A. regulator, said that in retrospect, scientists had been too slow to adapt to those recommendations. They had known from previous disease outbreaks that plasma treatment is likely to work best when given early, and when it contained high levels of antibodies, he said.

“Somehow we didn’t really take that as seriously as perhaps we should have,” he said. “If there was a lesson in this, it’s that history actually can teach you something.”

Dr. Nicole Bouvier helped set up Mount Sinai’s plasma program, which ended earlier this year. “That’s what science is — it’s a process of abandoning your old hypotheses in favor of a better hypothesis,” she said.Desiree Rios for The New York Times

Today, several medical centers have largely stopped giving plasma to patients. At Rush University Medical Center in Chicago, researchers found that many hospitalized patients were already producing their own antibodies, so plasma treatments would be superfluous. The Cleveland Clinic no longer routinely administers plasma because of a “lack of convincing evidence of efficacy,” according to Dr. Simon Mucha, a critical care physician.

And earlier this year, Mount Sinai stopped giving plasma to patients outside of a clinical trial. Dr. Bouvier said that she had tracked the scientific literature and that there had been a “sort of piling on” of studies that showed no benefit.

“That’s what science is — it’s a process of abandoning your old hypotheses in favor of a better hypothesis,” she said. Many initially promising drugs fail in clinical trials. “That’s just the way the cookie crumbles.”

Plasma’s future

Some scientists are calling on the F.D.A. to rescind plasma’s emergency authorization. Dr. Luciana Borio, the acting chief scientist at the agency under President Barack Obama, said that disregarding the usual scientific standards in an emergency — what she called “pandemic exceptionalism” — had drained valuable time and attention from discovering other treatments.

“Pandemic exceptionalism is something we learned from prior emergencies that leads to serious unintended consequences,” she said, referring to the ways countries leaned on inadequate studies during the Ebola outbreak. With plasma, she said, “the agency forgot lessons from past emergencies.”

While scant evidence shows that plasma will help curb the pandemic, a dedicated clutch of researchers at prominent medical institutions continue to focus on the narrow circumstances in which it might work.

Dr. Arturo Casadevall, an immunologist at Johns Hopkins University, said many of the trials had not succeeded because they tested plasma on very sick patients. “If they’re treated early, the results of the trials are all consistent,” he said.

Convalescent plasma donations in La Plata, Argentina, last year.Agustin Marcarian/Reuters

A clinical trial in Argentina found that giving plasma early to older people reduced the progression of Covid-19. And an analysis of the Mayo Clinic program found that patients who were given plasma with a high concentration of antibodies fared better than those who did not receive the treatment. Still, in March, the N.I.H. halted a trial of plasma in people who were not yet severely ill with Covid-19 because the agency said it was unlikely to help.

With most of the medical community acknowledging plasma’s limited benefit, even the Fight Is In Us has begun to shift its focus. For months, a “clinical research” page about convalescent plasma was dominated by favorable studies and news releases, omitting major articles concluding that plasma showed little benefit.

Now, the website has been redesigned to more broadly promote not only plasma, but also testing, vaccines and other treatments like monoclonal antibodies, which are synthesized in a lab and thought to be a more potent version of plasma. Its clinical research page also includes more negative studies about plasma.

Nevertheless, the Fight Is In Us is still running Facebook ads, paid for by the federal government, telling Covid-19 survivors that “There’s a hero inside you” and “Keep up the fight.” The ads urge them to donate their plasma, even though most blood banks have stopped collecting it.

Two of plasma’s early boosters, Mr. Lebovits and Ms. Berrent, have also turned their attention to monoclonal antibodies. As he had done with plasma last spring, Mr. Lebovits helped increase acceptance of monoclonals in the Orthodox Jewish community, setting up an informational hotline, running ads in Orthodox newspapers, and creating rapid testing sites that doubled as infusion centers. Coordinating with federal officials, Mr. Lebovits has since shared his strategies with leaders in the Hispanic community in El Paso and San Diego.

And Ms. Berrent has been working with a division of the insurer UnitedHealth to match the right patients — people with underlying health conditions or who are over 65 — to that treatment.

“I’m a believer in plasma for a lot of substantive reasons, but if word came back tomorrow that jelly beans worked better, we’d be promoting jelly beans,” she said. “We are here to save lives.”’