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It appears science may have found the Covid-19 pandemic’s off-ramp.

Two vaccines developed with stunning speed — and showing remarkable initial efficacy — are poised to be approved for emergency use in the United States in December. A number of other vaccines are expected to follow.

Vaccines that prevent symptomatic Covid infection in roughly 95% of people vaccinated — as the data from clinical trials of the Pfizer-BioNTech and Moderna vaccines suggest — should, over time, help the country and the world return to a life where we can travel without quarantining; where sporting events can be played before live audiences, not cardboard cutouts; and where snowstorms are the only reasons school gets canceled.

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But if we’re not careful, we could fail to take full advantage of the opportunity scientists and governments, pharmaceutical companies and philanthropic foundations have created for us.

And there’s a possibility that the pandemic off-ramp doesn’t merge with a straight road back to Normalville, but instead becomes a meandering country lane with the occasional detour. We may need to choose the right turns and avoid the potholes as we make our way to our destination. It will require patience.

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Missteps will come with real consequences, in a pandemic that has already cost 270,000 lives in the United States alone.

STAT spoke with more than two dozen public health experts, epidemiologists, state officials, bioethicists, and others about how to make the most of this opportunity — the biggest vaccination effort in the country’s history — and also about the challenges we face in the days, weeks, and months ahead.

Here’s what they had to say.

Vaccine - Operation Warp Speed
Operation Warp Speed leaders Army Gen. Gustave Perna (right) and Moncef Slaoui at an event in the Rose Garden of the White House in November. Evan Vucci/AP

Launching a 24- to 48-hour rollout

Operation Warp Speed, the U.S. project to fast-track development of Covid-19 vaccines, therapeutics, and diagnostics, has a singular vision as the time for vaccine deployment nears: move with military-like precision.

A tightly choreographed series of actions is planned, beginning with a meeting of an expert advisory committee to the Food and Drug Administration that will make recommendations about whether and for whom emergency use should be allowed. The FDA is then expected to issue emergency use authorizations. State officials, based on the guidance of a separate panel advising the Centers for Disease Control and Prevention, will determine who gets the first doses.

If all goes as planned, sites will start vaccinating health care workers within 24 to 48 hours of FDA decisions, using vaccine shipments that have been pre-positioned.

It’s more than a goal, however; it’s a diktat, with federal officials leaving no doubt about their expectations of state officials. States have also been told by the military-led Operation Warp Speed that, over time, their vaccination efforts will be graded and color-coded based on their level of efficiency.

Some experts worry the artificial deadline could lead to a botched rollout.

“There are things that the armed forces do amazingly well, and logistics is one of them. And logistics is a big challenge for this vaccination program,” said Tom Frieden, former CDC director and now president of the nonprofit Resolve to Save Lives. “But logistics is just one of many challenges for the program. And the impression I have is of a program being run as a logistics challenge, rather than a vaccination program with a logistic challenge within it.”

“There’s tremendous pressure to get the vaccine out and then administered in 24 hours, and I think that it’s not going to work that way,” said Claire Hannan, executive director of the Association of Immunization Managers. “I think it remains to be seen if states will actually hit the ‘go’ button.”

Make no mistake: People in public health are eager to administer Covid-19 vaccines as quickly and efficiently as possible. But some, at least, are daunted by what such a compressed timeline will require: an incredible amount of organization that people outside health care would likely never consider — and that now has to be carried out at a time when hospitals across the country are slammed and public health workers are exhausted.

“Organizing a clinic and clearing space and having throughput and scheduling appointments and really educating your employees on the need to get vaccinated and the value — difficult to do that when you’re putting out fires and trying to find bed space and dealing with a surge in patients,” Hannan said.

Kristen Ehresmann, director of infectious disease epidemiology, prevention, and control for the Minnesota Department of Health, said she, too, is worried that prioritizing speed over all else could compromise the success of the effort.

“We desperately want a vaccine. But no one wants a rushed job,” Ehresmann said. “We need to be able to convince the public that this is a safe vaccine. And if they feel that this is all about hurry up and get it out there, that is not going to build confidence.”

There’s also the fact that states are struggling to get ready for the vaccine deployment. Public health departments have been pedal-to-the-metal responding to Covid all year and are “running on fumes,” said Jeffrey Duchin, an infectious diseases professor at the University of Washington who also works for the Seattle and King County public health department.

The Association of Immunization Managers and ASTHO — the Association of State and Territorial Health Officers — have been pleading with Congress for money to do the work on the ground to get people vaccinated. They argue states need $8.4 billion to recruit and train extra workers, to run local advertising, to beef up software programs that are not currently up to the task. So far, they’ve received $340 million.

Vaccine - Public/community distrust
Local residents fill out paperwork at a mobile Covid-19 testing station in Compton, Calif. ROBYN BECK/AFP via Getty Images

Overcoming distrust

Poll after poll has suggested that in a sizable portion of the public, there is a deep reticence to take Covid vaccines.

Distrust is particularly high among Black and Latino communities, which is worrying given that people of color are being infected and dying at a disproportionately high rate in the pandemic. A Pew Research Center poll released in mid-September indicated only 32% of Black adults said they were definitely or probably going to be vaccinated. That hesitation has been attributed in part to the historic mistreatment of communities of color both in medicine and in clinical research.

Concern about the vaccines, however, cuts across ethnic and socioeconomic groups. President Trump’s overt efforts to pressure the FDA to issue EUAs before the Nov. 3 election — before the vaccine trials were finished — has deepened the sense of unease. The CDC’s early pandemic testing fiasco, coupled with its sidelining by the Trump administration, has eroded its standing as a trusted source of information.

Alison Buttenheim, an associate professor of nursing and health policy at the University of Pennsylvania, refers to the current situation as a perfect storm of “justified distrust.”

“People who don’t think twice about vaccinating their kids totally on time, who get their flu shot every year, are in the sort of, ‘Hmmm. Might wait six months on this one,’” Buttenheim, who works on vaccine acceptance, told STAT. “I’ve heard people say, ‘I’ll get the European one,’” she said, adding other people have said they would get vaccinated after Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, gets vaccinated.

And it’s not just the general public. A recent survey of 2,000 doctors and nurses in New Jersey found that 60% of doctors planned to take a Covid vaccine, but only 40% of nurses intended to, Health Commissioner Judith Persichilli said in a recent “60 Minutes” segment about Operation Warp Speed.

That jibes with the experience during the 2009 H1N1 flu pandemic, when many health workers eschewed the new flu vaccine when it became available.

“We shouldn’t be assuming just because they’re health care professionals that they’re going to be lining up,” said Heidi Larson, director of the Vaccine Confidence Project and a professor at the London School of Hygiene and Tropical Medicine.

Larson believes more needs to be done to encourage people to want to be vaccinated when their time comes to get in line.

“I feel we should be doing a lot more in terms of engaging relevant communities, getting more information about these different types of vaccines, what they mean. Listening. Just listening. Trying to understand the concerns,” she said. “We need to use every minute we have. Because you can’t start waiting to answer people’s questions when you’re standing there with a syringe in your hand.”

Chelsea Clinton, who works on vaccine acceptance issues at the Clinton Foundation, agreed with Larson, saying during the recent STAT Summit that it is long past time the work to generate demand for the vaccines begins.

“While what our scientists have done is extraordinary, we need to have a commensurate effort … to build public demand for an eventual and hopefully very soon-to-be Covid vaccine or vaccines. And none of that work has happened,” she said.

Trusted public figures, leaders in communities of color, and notable scientists need to be enlisted to the task, Clinton said. She added one name to the roster that might seem unexpected from her: Trump, saying the president and his family could play a key role in persuading his supporters to get vaccinated.

Herd immunity protects those with vulnerable immune systems. Here’s how. Alex Hogan/STAT

Getting enough vaccines in (the right) arms

In an ideal world, everyone would want to be vaccinated against Covid and there’d be enough vaccine to do that job. We don’t live in that world.

In the United States, it is conceivable that all the people who want to be vaccinated will be able to do so in 2021, and potentially by the summer. But other parts of the world will take much longer to vaccinate their populations. As World Health Organization officials keep saying, the pandemic isn’t over anywhere till it’s over everywhere.

Modelling studies have suggested in the U.S. we might need 60% to 70% of people to be vaccinated to reach “herd immunity” — the point at which a pathogen stops spreading because there are so many people protected it cannot make its way to the people who are still susceptible.

For reference, only close to half of U.S. adults get vaccinated every year against influenza. The hope is that it will be possible to reach 60% to 70% of Americans with Covid vaccines, in part because they are expected to protect at much higher levels than flu shots and thus may be more attractive to people who would otherwise be hesitant.

Still, Kate O’Brien, director of the WHO’s immunization, vaccines, and biologics program, cautions against putting too much weight on the above estimates for herd immunity. We need to know more about how well and for how long vaccines work before being able to calculate that estimate, she said.

It’s also possible that reaching that goal depends not just on vaccinating enough people but vaccinating the right people. If we want to use vaccines to try to stop SARS-2 from spreading, vaccination programs may need to be “surgical,” said Mike Ryan, head of the WHO’s health emergencies program. That means targeting people who are most likely to transmit the virus and those who are most likely to be involved in superspreading events — if they can be identified.

“I don’t think anyone can promise eradication of this virus until we understand much more about the vaccine and about how the vaccines work in the real world and until we understand much more about the details of transmission of this virus,” Ryan said during a recent WHO briefing.

Even if it’s too early to talk about eradicating SARS-2 — that is, getting rid of it forever — can we expect life to become easier, less restricted, if a sizeable portion of Americans get vaccinated?

Natalie Dean, an assistant professor of biostatistics at the University of Florida, said gains will be gradual as the pool of vaccinated people grows. But there are other factors at play, including whether the country persists with control measures like mask-wearing and social distancing and whether the vaccines can protect against severe Covid disease, as the Pfizer and Moderna studies suggest they can.

Marc Lipsitch, an infectious diseases epidemiologist at Harvard’s T.H. Chan School of Public Health, agreed, saying vaccines that at least prevent infections in the elderly from turning into life-threatening illnesses would make a major difference.

“I’m of the opinion that if we vaccinate the very old and the people with significant comorbidities” — medical conditions — “that would be the quickest way to get back towards a more normal life,” Lipsitch said, suggesting that might require as little as a third or a half of the population — “if we vaccinate the right third or a half.”

Lipsitch said he’d add teachers to his vaccine priority list, because of how much stress closing schools places on families and society as a whole.

Currently, the Advisory Committee on Immunization Practices, which advises the CDC, is signaling it plans to recommend vaccinating essential workers — including teachers — before adults over 65 and people with health conditions that have been linked to severe Covid disease.

Vaccine - pregnancy
A man wearing a protective mask holds the hand of his pregnant wife during the Covid-19 pandemic in Paris. MARTIN BUREAU/AFP via Getty Images

Vaccinating people who are pregnant

Already there are some very clear potholes on the road toward making the best use of vaccine. And, unfortunately, one of them involves pregnant people.

Companies developing vaccines of any kind are reluctant to test them in pregnant people, because they don’t want to put them or their fetuses at risk. When the vaccines are approved for use, pregnant people are either denied access to them or asked if they want to be vaccinated with a product that hasn’t been studied in pregnancy.

Vaccine makers, regulatory agencies, vaccine researchers — everyone knows this happens. Researchers have written reports pleading for a new approach. In February, three researchers who have pressed for progress on this issue wrote in STAT that history should not repeat itself with the development of Covid vaccines.

And yet …

“Here we are again,” said the WHO’s O’Brien.

“Our failure to address this with intention and attention has resulted in pregnant women … being fully left out of the potential benefits of vaccines and other [medical] products,” O’Brien said.

In the case of Covid-19, it is impossible to kick the can down the road. While health care workers are going to be at the front of the line for vaccines in the United States, three-quarters of them are women, and most them are of childbearing age. A significant number of them — roughly 330,000 — are either pregnant or are breastfeeding a baby, the CDC estimates.

Are Covid vaccines, and especially these first two vaccines, safe for this subset of health workers? There are no data upon which to answer that question. There aren’t even data that could be extrapolated from previous experience. The Pfizer and Moderna products will be the first mRNA vaccines to be authorized for use.

For now, the American College of Obstetricians and Gynecologists believes the best option is to offer pregnant people the choice to take vaccine.

“We feel that women who are pregnant and are lactating should not be excluded from what are high priority populations for a Covid-19 vaccine allocation strategy,” Linda O’Neal Eckert, the liaison for the American College of Obstetricians and Gynecologists, told ACIP in late October.

The work group did not reach a decision on the issue, but the majority of its members seemed to agree. They may not recommend the vaccine for pregnant people, but may say being pregnant does not preclude its use.

Some manufacturers have said they will test their vaccine in pregnant people after their Phase 3 studies are finished.

Geeta Swamy, associate vice president for research at Duke University, has been urging them to act sooner, noting that time is of the essence. About half of pregnant people are either health care workers or have medical conditions that put them at risk of developing severe Covid if they contract the virus — meaning that, all else being equal, they could be close to the front of the line for vaccine.

Swamy’s idea: Conduct Phase 2 “companion trials” to generate safety data in pregnant people.

Time has run out to do this work before the vaccine rollout begins. But researchers will need to come up with answers soon.

Vaccine - kids
Students in La Puente, Calif., where pre-kindergarten to second grade students in need of special services returned to the classroom in November for in-person instruction. FREDERIC J. BROWN/AFP via Getty Images

Vaccinating children

Another pothole: kids.

As with pregnant people, studies needed to show whether the vaccines are safe and effective in kids haven’t yet been done; the reason is based on the belief that vaccines must first be proven safe and effective in adults. The good news is that children are mostly — mostly — spared the worst of Covid’s wrath. It’s why there’s been no debate about plans to put them at or near the back of the vaccination priority line.

But the risk to children isn’t zero, and at some point, there will be a need to vaccinate them.

“Children are not little adults. We must include children in the trials as soon as it is safe to do so,” Yvonne Maldonado, chair of the American Academy of Pediatrics’ infectious diseases committee, said in recent statement. “This research takes time. If this does not begin soon, it will be less likely a vaccine will be available for children before the next school year.”

This fall Pfizer expanded its trial to enroll volunteers as young as 12. But there may not be enough data on 12- to 18-year-olds to make a recommendation for vaccine use when the FDA considers issuing an emergency use authorization. And no studies have been conducted in preteens to date.

Some vaccine experts are anxious about that prospect of vaccinating children against Covid-19.

Cody Meissner, director of pediatric infectious diseases at Tufts University School of Medicine, advocates a go-slow approach. Meissner is concerned that vaccine could trigger a condition known as multisystem inflammatory syndrome in children, or MIS-C, which has been diagnosed in children who have had recent Covid infections. Children who develop the syndrome become quite ill.

Though incidence is rare and though most children who develop MIS-C survive, there have been a few deaths reported, even among previously healthy children.

Meissner and some others worry that if the spike protein on the surface of the SARS-CoV-2 virus is what sets off the over-exuberant immune response, vaccines that train the immune system to identify the spike protein may do so as well.

“We need a vaccine for children. There’s no question. But we don’t have the urgency in children that we have in the elderly,” said Meissner, who is a member of the FDA’s advisory committee.

MIS-C seems to happen in about two in 100,000 children infected with Covid, Meissner said. But if MIS-C occurs at a higher rate among vaccinated children, “that is going to be devastating for the whole vaccine program,” he added.

Moncef Slaoui, the scientific leader of Operation Warp Speed, believes the scenario Meissner fears is unlikely, saying a child infected with SARS-2 encounters far greater amounts of spike protein than Covid vaccines induce. “The level of systemic inflammation taking place in an [infected] child versus through immunization are dramatically different,” he said.

Regardless, researchers agree not vaccinating children is not an option. The problem is that the frontrunner vaccines may not be the best options, warned Florian Krammer, a professor of vaccinology at the Icahn School of Medicine at Mount Sinai Hospital in New York.

Those vaccines — from Pfizer, Moderna, AstraZeneca, and Johnson & Johnson — are, in the language of vaccinology, quite reactogenic. They carry a kick, sometimes inducing fevers, aches, and malaise.

“If they’re very reactogenic in adults, they [will be] super reactive in children,” Krammer said. “I think at some point, we’ll think about vaccinating children. And I think that might not be possible with those vaccines.”

He wasn’t suggesting the vaccines would be dangerous for children. But when kids feel miserable after vaccination, it fuels parental concerns — which could give rise to vaccine hesitancy.

Vaccine - freezer
A refrigerator suitable for the storage and the transport of the Pfizer vaccine at a -80 degrees Celsius. TIZIANA FABI/AFP via Getty Images

Getting more vaccines out the door

The more safe, effective vaccines the world can throw at this pandemic, the better. Not only could they provide more supply, they could come with advantages over the first two vaccines. Johnson & Johnson, for example, is the only manufacturer among the major players currently testing a one-dose vaccine. It and others that are behind Pfizer and Moderna don’t require ultracold storage, so they could be easily given in doctors’ offices.

But once Pfizer’s and Moderna’s vaccines are cleared by the FDA — assuming they are — the ground under the remaining vaccine candidates starts to shift, both for those already in Phase 3 trials and for those not quite there yet.

Let’s start with the potential problems for Phase 3 trials that are already underway.

While supplies of the Pfizer and Moderna vaccines are tight and only people at the very front of the priority line — health workers and long-term care residents — are being offered vaccine, the vast majority of people in clinical trials for other vaccines have little incentive to drop out to try to get one of the approved vaccines.

But when supply becomes greater, in February and beyond, older adults and people with health conditions that put them at risk of severe Covid disease may become eligible to get a Moderna or Pfizer vaccine. Those in clinical trials have a right to quit at any time, and many might think: Why take the chance of being assigned to the placebo arm of a trial instead of simply getting a vaccine known to be highly effective?

If large numbers of participants elect to drop out of ongoing trials, researchers won’t have all the data they need to determine a vaccine’s efficacy.

There’s a possibility that won’t be a problem for some trials. Larry Corey, co-leader of the National Institutes of Health’s Covid-19 Prevention Network and a virologist at the Fred Hutchinson Cancer Research Center, said the hope is that Phase 3 trials of the Johnson & Johnson vaccine, for instance, could be completed before the Pfizer’s and Moderna’s become widely available — in other words, before availability of vaccine for the broader public erodes the willingness of people to remain in Johnson & Johnson’s trial.

But what of some of the other vaccines? AstraZeneca is now expected to conduct an additional Phase 3 trial to investigate a finding that suggests a half dose of vaccine followed by a full dose four weeks later was more protective than two full doses. Sanofi and Novavax, which are both making protein subunit vaccines that can be stored at refrigerator temperature, are looking at late December or early January for their trial starts at this point. How will they find enough people willing to take the risk of being randomized to a placebo arm?

And can they, from an ethical standpoint, run a placebo-controlled Phase 3 when a vaccine that’s been shown to be efficacious has been cleared for use by the FDA? If they cannot — and ethicists would likely argue they can’t — would they have to conduct what’s known as a non-inferiority trial, comparing their vaccine to one of the two cleared for use?

There are no easy answers, acknowledged Christine Grady, chief of the department of bioethics at the National Institutes of Health Clinical Center. “That’s why it keeps me up at night,” she said.

Showing a vaccine works better than salt water is much easier than showing it works as well as vaccines that have been shown to work — especially ones that appears to be 95% effective. The trials needed to do this would have to enroll many more than the 30,000-subject trial Moderna conducted, potentially three to five times as many, if they wanted to get an answer within months rather than years.

Corey said there is discussion underway to try to figure out a solution. “We are digging our heels in to get this up the hill,” he said.

One approach might involve trials that recruit some of their subjects in countries where vaccine is not yet available. Novavax, for instance, is already planning to conduct part of its U.S. Phase 3 trial in Mexico. Corey said companies could potentially generate data on seniors and high-risk people abroad, while still enrolling healthy adults in the U.S., if they can get their trials going before the vaccine rollout here goes wide.

Jesse Goodman, a former chief scientist at the FDA, believes there will be viable ways to use this approach.

“The global supply is not going to be settled and adequate, even by the end of 2021,” said Goodman, a professor of medicine at Georgetown University and chair of the science committee at GSK. “I think it will still be ethical to do trials where there are not available approved vaccines.”

Grady is not so sure. She noted that asking people in another country to agree to be part of a placebo-controlled trial — when the world knows an effective vaccine exists — would typically be seen as exploitation.

Vaccine - Mask poster
A pedestrian walks past posters showing a health care worker wearing a mask in Los Angeles. ROBYN BECK/AFP via Getty Images

Getting answers on transmission

One of the biggest questions about these vaccines is: Will they stop people from being infected? Or will they just prevent infected people from becoming sick by jump-starting an immune response? It’s no small distinction.

If people who are vaccinated are not showing signs of illness but are still infected and emitting virus, they’re contributing to the spread of Covid to others who have not been vaccinated. In infectious diseases parlance, the emission of infectious virus is called shedding.

The clinical trials being conducted to test the various vaccines right now can’t tell us whether they prevent infection — only whether they prevent symptomatic infection.

“If you still have shedding, of course that brings up the question of how soon can we all go back to normal-normal. And that’s going to be a while,” said Anna Durbin, a vaccines researcher at the Johns Hopkins Bloomberg School of Public Health.

Michael Mina, an epidemiologist at Harvard’s T.H. Chan School of Public Health, agreed answering this question is critical.

“We absolutely need to know if these vaccines are going to stop transmission, but no data that we’re going to get is going to give us that at this point,” he said. “And that leaves me very concerned because so much of our plans for vaccines center around herd immunity.”

Evidence from animal studies raises at least some concern. Vincent Munster, a virologist at the National Institute of Allergy and Infectious Diseases’ Rocky Mountain Laboratories in Hamilton, Mont., tested the AstraZeneca vaccine in primates. Vaccinated animals that were deliberately exposed of SARS-2 were protected against disease in the lungs — the dangerous kind with Covid-19 — but the animals did shed infectious virus.

The work Munster and his team conducted doesn’t perfectly mirror what is seen in the real world. The primates had high doses of the virus puffed up their noses, which may not replicate the way people are infected. He suggested that vaccinated people, if they do become infected, may shed less virus, for a shorter period of time, than unvaccinated people.

Krammer, the Mount Sinai medical school vaccinologist, agrees that will likely be the case, as does Slaoui.

“I expect the vaccines, even if they are not totally sterilizing in terms of immunity, like 100% prevention, I think they will decrease transmission,” Slaoui said.

Slaoui and others raise the possibility that, even if infected people shed virus, there could be a benefit, at least for those who have been vaccinated already. Being reexposed to the virus after vaccination should provoke the immune system to kick into gear, acting almost like a booster shot. It’s called “anamnestic boosting.”

Krammer believes that, in the near term, if the vaccines don’t fully block infection and prevent viral shedding, that wouldn’t be a huge problem.

“I think we should get people who are really at risk vaccinated as quickly as possible. We should try to vaccinate everybody else, and it will bring the virus load in the population down,” he said. “We need to get this under control.”

Krammer wasn’t dismissing the importance of getting answers on this issue, for any number of reasons. For example, if Covid-19 vaccines don’t work well in people whose immune systems are compromised, they become vulnerable to shedding by others, such as their caregivers. “In the long run, these things might matter,” he said.

Scientists can now design genetic material called mRNA to help us build immunity to certain viruses, including SARS-CoV-2, the coronavirus that causes Covid-19. Find out how mRNA vaccines work in this video. Hyacinth Empinado/STAT

Answering other known unknowns

There are many other things we won’t be able to know about Covid-19 vaccines until they have been in use for years. But getting those answers is critical to protecting society in the long term.

For starters: How well do these vaccines actually work? Real-world vaccine effectiveness is generally lower than clinical trial estimates, experts caution. Trials typically enroll mostly young, healthy people; even the older adults in these studies are likely to be healthier than the frail elderly people we are hoping the vaccines can protect.

And there are even questions about the clinical trial estimates themselves. The mRNA vaccines Pfizer and Moderna are developing showed roughly 95% efficacy in their Phase 3 trials. But Soumya Swaminathan, the WHO’s chief scientist, cautions that those findings may actually be misleading. These types of vaccines are very good at triggering an innate immune response — an overall boosting of the immune system that is not specific to the SARS-2 virus. It wanes after a period of time.

The current efficacy estimates are based on two months of follow-up after vaccination; a more accurate picture, based on the immunity the vaccine triggers that is specific to SARS-2 may emerge over time, Swaminathan said. “So, while we hope that these vaccines do have over 90% efficacy, it would be wise to wait a little bit to look at the follow-up results from people in these trials,” she said.

Side effects in clinical trials so far have been minimal and short-lived. But that does not guarantee vaccines won’t have rare and serious side effects. Rare side effects are simply unlikely to show up in a trial involving 30,000 people, only half of whom got vaccine. It’s only when vaccines are given to millions of people that we’ll have a better sense of the possibility.

Likewise, it will take time to see how long vaccine protection lasts. Nearly a year into the Covid pandemic, we still don’t even know how long people who were infected are protected. It’s known that immunity to human coronaviruses, relatives of SARS-2, can be pretty short-lived; some people, at least, can be reinfected within a year. Is that true for Covid? So far reports of reinfection are still rare. Will reinfections carry the same risk of severe illness, or will our immune systems respond quicker and turn future infections into colds, not killers? Too soon to say.

Will all the vaccines have the same durability, or will protection triggered by some be more fleeting? We’ll see.

If vaccinated people need to have their immunity boosted down the road with another shot, will they be able to get the same product they got the first time, or would they get better protection by moving to a different type of vaccine? That will have to be studied.

The situation that is about to unfold is absolutely unprecedented. There has never been a time when multiple brand-new vaccines, made with different approaches, some never used before, have hit markets around the globe in a relatively short period of time.

Budding epidemiologists take note: A whole new field of study is opening up.

“There’s just so many aspects and so many difficulties and so much to sort through,” said Beth Bell, a retired director of the CDC’s National Center for Emerging and Zoonotic Infectious Diseases who now sits on ACIP and chairs its Covid vaccine work group.

The cleanest and clearest way to study something is to conduct randomized controlled trials, where groups of similar people are randomly assigned to get an intervention — in this case a vaccine — or a placebo. These studies are prospective; they follow people forward in time. They are considered the gold standard of trials.

But once a product has been approved for use and placebo-controlled trials are out of the question, researchers turn to different tools to try to answer questions. For example, they can do retrospective analyses, comparing people who got one vaccine to people who got another after the fact. Studies like these produce answers that are generally not as clear-cut as prospective, randomized trials, often requiring multiple groups to take a stab at the same question.

Still, it is inevitable that the world will have to rely on these studies to find answers to the above questions and others, including which vaccines work best for seniors.

“Coronavirus vaccines and coronavirus itself will be the career of thousands of scientists. Absolutely,” said WHO’s O’Brien.

Vaccine - Sinovac
A container carrying doses of the CoronaVac vaccine is unloaded last month from a cargo plane that arrived from China at Guarulhos International Airport in Brazil. NELSON ALMEIDA/AFP via Getty Images

A coda

Governments, nongovernmental agencies, and major medical philanthropies like the Gates Foundation and the Wellcome Trust have been working for years to try to find ways to fast-track development of vaccines to respond to pandemics and other dangerous new disease threats.

That work, plus the efforts of academic and pharmaceutical industry scientists, have paid off in spades in 2020.

Clearly there remains work to be done. A few rich countries will be vaccinating most of their populations before low-income countries get vaccine for their health workers, let alone a sizable portion of their populations. Global vaccine production has been ramped up dramatically, but it will be several years before wide swathes of the globe can be vaccinated.

Still, the vaccine development accomplishments racked up this year have been extraordinary. China and Russia have already begun vaccinating people — albeit with vaccines approved for use without Phase 3 efficacy trials. The United States and the United Kingdom, which are requiring Phase 3 trials, will soon follow suit. Only a few years ago the notion that the world could start vaccinating against a pathogen within a year of its emergence from nature would have been seen as an aspirational goal unlikely to become reality.

Pfizer and Moderna, the two frontrunners in the United States, used a part of the virus’s genetic code to start their vaccine efforts; these vaccines will be the first to be licensed using a technology known as messenger RNA, or mRNA. Moderna, working with scientists at the National Institutes of Allergy and Infectious Diseases, was able to produce a candidate vaccine ready to be tested in people in record time, just 42 days after the virus’ genetic sequence was shared by China.

Vaccine makers compressed clinical trials, running Phase 1/2s or Phase 2/3s in place of the normal sequence of three phases with pauses in between to analyze data. With the help of a number of partners — the U.S. government’s Operation Warp Speed and the Biomedical Advanced Research and Development Authority, the Coalition for Epidemic Preparedness Innovations, and the Gates Foundation — batches of vaccines were made and stockpiled before they were yet proven to work, shaving months off the time to vaccine deployment.

“My approach was if there is a 1% chance that it could happen, this is so dramatic, we have to take that 1% chance,” Slaoui said. “Turns out it can happen.”

Pandemic vaccine production has been forever changed.

— An earlier version of this story incorrectly stated the CDC center where Beth Bell served as director.

  • Vaccinate at haste repent at leisure. Here in the U K our head of Vaccine taskforce believes these vaccines are for the old and vulnerable To give these Vaccines to the young and healthy risks Freak Health.Also dismayed at this rush to jab everyone, when perhaps 40,% of the population haved immunity through previous infection Why no research into this, does it just not make enough money?I’m not anti Vax but I’m not prepared to be sy lab rat either We all remember Pandemrix don’t we

  • If a person gets their first Covid vaccine by Pfizer must their second vaccine also be Pfizer? Can the various vaccines be cross-given?

  • This article seems very misleading, because it all but ignores the acquired immunity of the many millions who are now Covid-recovered persons. There is abundant evidence that Covid-recovered persons typically have persistent and robust immunity, certainly at least as strong and at much higher rates than the 90-95% being reported for the vaccines. A reasonable estimate of the percentage of Covid-recovered persons in the US, based on a rather high estimated Infection Fatality Rate (IFR) of 0.3%, and current reported fatalities of around 275,000, would be around 30% (around 100 million Covid-recovered persons). So the number of people who are not Covid-recovered who need to be vaccinated to reach 70% of the US population with immunity is perhaps half the number the “experts” quoted here are mentioning. Every article about vaccination and “herd immunity” needs to address the acquired immunity of Covid-recovered persons. It is silly to keep saying we “don’t know” anything about how persistent and robust this acquired immunity is proving to be, given the abundant evidence, including the extremely low rates, virtually zero, of re-infection in Covid-recovered persons.

    • I wonder too why there is (apparently) no requirement or recommendation to do an antibody test for immunity before giving the vaccine at this stage when vaccine supplies are so limited. Especially since the first-target community is relatively easy to contact for a third time, as health care workers working with Covid or elderly residents of group homes.

      What I do think we don’t know is whether the immunity from an infection lasts as long as that from a vaccine. I know there is at least some ongoing study of this, but given that the post-infection immunity of many coronaviruses is either untested (SARS went away) or not very long-lasting (the coronaviruses that cause colds), I wouldn’t mind seeing the vaccine given to those who have existing antibodies from infection once we have enough vaccine to use for that.

  • The recent vaccines prevent disease, and not infection, according to the manufacturers themselves.

    The very first assumption in this article is wrong:

    “Vaccines that prevent symptomatic Covid infection in roughly 95% of people vaccinated — as the data from clinical trials of the Pfizer-BioNTech and Moderna vaccines”

  • We do not know whether vaccines using messenger RNA could cause autoimmune diseases or neoplasms in the future. Because of the urgency, I understand the need to use these vaccines. However, old-fashioned vaccines should also be studied. Perhaps children can benefit from this product! Regarding bioethics, we have a problem with placebo use! Certainly different vaccines would be well evaluated if compared to each other!

  • We are in a place where the importance of vaccines are always highly always needed (like having fresh air)in Africa .we have not yet heard about how can the new vaccines be valuable to the people and if this three different kind of vaccines are available which phase could be needed in Africa?
    It is very much important to read about what is on hand for the up coming very soon.
    Thank you.

    • You might want to seek information about the Astra Zenica vaccine, which is much easier to distribute because it does not need the super-cold refrigeration that the Pfizer and Moderna ones do. Some of the articles I have read about it specifically mention distribution in Africa and India for this reason.

  • How does distancing and masking effect the vaccine efficacy? I assume once people get these slowly masking and distancing will lapse. Will that make a 95% effective vaccine much less effective? Viral dose is suspected to play a big factor, hence not having masking might be dramatic to efficacy.

  • HERES A WAYTO SOLVE THE NEED FOR DATA VS THE ETHICAL DILEMMA OF GIVING PLACEBOS WHEN THERE ARE EFFECTIVE VACCINES: MAKE GOOD USE OF THE POPULACE WHO DON’T BELEIVE covid IS REAL, OR BELEIVE IT’S “JUST THE FLU”. THESE PEOPLE HAVE ALREADY SELF SELECTED TO THINK THERE’S NO RISK, AND THEY COULD BE SCREENED BY THEIR STATED BELEIFS, TO BE USED FOR THE PLACEBO SIDE OF THE TRIALS, DESIGNATED BY SOME CODE KNOWN ONLY TO THE FINAL DATA ANALYSTS. in this strange circumstance, all of those deniers would be helpful to include, in finding out if the vaccine was effective compared to placebo receivers. the administers wont know whether they are giving vaccine or placebo, preserving double blind purity. the data set is preserved, generating numbers needed to analyze results. and those who state they don’t beleive COVID is real, or it’s “just the flu” legally absolve the ethics of administering placebo, by their willingness to “proceed at your own risk”. if they signed waivers to attend Trump rallies en masse, thye have already demonstrated their agreement to do such a thing. make them part of the solution. even they can play a valuable part in the science.

  • Thank you Helen, for another great overall picture.

    I’d like to know why, if shedding can be detected in primates, the first studies didn’t test for that. Yes, I see that the shedding test would require additional appointments. But if even 10% or 20% of the participants were tested for shedding, we could get an answer to the yes/no question. If those results are not statistically significant we’d have a stronger argument for focusing on that.

    In the meantime, I always figure that when I get my flu shot I won’t be protected for a few weeks, and I’ll figure the same with this one and stay restricted for however long it looks like I should until the protection kicks in. (Maybe by the time I get the vaccine we’ll have data on that.) That’ll protect everyone outside my household. OTOH, if I know there is shedding, my husband and I will have to isolate from each other for the indicated time. So it’s complicated, but beats the heck out of dying.

    Regarding the trials of the later vaccines, thanks for describing the issues, but it seems to me an easy path would be a trial in a group that has limited access to the Pfizer and Moderna, whether that is a part of the U.S. population that hasn’t been prioritized yet or some other country, then trial the Moderna or Pfizer against the candidate. You want to vaccinate as many as you can anyway… That would mean diverting some Pfizer or Moderna vaccine to an prioritized population, but the priorities are still being debated anyway.

    • Responding to your question about how long it will take to get immunity – I do not know but the Pfizer Phase 3 test protocols were to give both shots and wait at least a week before taking antibody tests – So if you get the first shot by say April 1, you are not thought to have maximum antibody until about the middle of May. My guess is, the epidemic will be vastly reduced by about that time, and then we will find out what happens when people do not get the second shot, as many will be lax about it.

  • I want the vaccine and want it now, and feel just a little bit of nervousness taking it, so this is not meant to offend, but any delay related to messaging that it is safe seems like a waste of time. I am not sure what the doctors who raised the issue meant, but right now we have 10 times more eager would be recipients than doses.
    I would point out also, vaccine trust may be a hard sell. The entire history of the FDA has been one, according to many, of refusing to approve anything until years of consideration and truly mountains of documentation, leading, we are told, to a cost of $100M for new drug approval. To their critics they always said it was all absolutely necessary. Now we have a new ( to humans ) vaccine technology to be given to everyone in the country after 8 months? This will not sound right to a lot of people.

    • If people refuse the vaccine, they can go the herd immunity route and try their luck with the virus and long haul effects…

    • Adding to my own comment- it seems very desirable to get “everyone” vaccinated, to keep this virus from persisting in the human population, where it can adaptively mutate to humans even more. Anyway that is a fear being expressed by some experts- but in the short term, even at only 50% acceptance, we will need about 330M shots, and have somewhere around 50M – not really a need to talk the holdouts into it right away.
      I am a layman who is in the Pfizer study and I do not know if i got the vaccine or not, so I have no education in this, but seems to me if the worries expressed about immunity waning fast turn out to be true, there will be need for mandatory vaccination laws with this disease. If immunity never wanes, then if I have my vaccination, what other people do is their business, sort of , but if immunity wanes, at some unknown rate, unless you test everybody, regularly, forever, they are always a danger = instead, get everyone vaccinated every year or so and if there are large numbers who do not remain immune, then herd immunity protects them, ”

      Big political battle coming I guess but for now, just worry about those who want it.

    • SW is right on the money. Every night we are pummeled with television advertisement from attorneys about class action lawsuits against drug companies for items that were tested over a much longer period of time and approved. Years later we discover that things are not so rosy, people have been harmed, and the 20-20 hindsight attorneys are raking in the dollars.

      These frontrunners are a vaccine type never used in humans before and created in record time (Albeit part of that record time is due to the new method). There is NO knowledge of if or how people may be affected long term. So to Steve below…Yes I will take my chances and pass on the vaccine and most people that I know are also going to pass on it as well. If you look at the huge brand name pharmaceutics that have been pulled from the market our concerns, based upon recent and long term history, would appear to be well founded.

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