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Q&A on Coronavirus Vaccines

In the more than eight months since the novel coronavirus emerged and then spread around the world, scientists across the globe have made rapid progress on developing a COVID-19 vaccine.

As of Sept. 3, at least 176 vaccines are in the works, with nearly three dozen already in clinical trials, according to the World Health Organization. But until a vaccine is tested in large numbers of people and weighed against a placebo, scientists won’t know if one or more vaccines are safe or effective.

Here, we give an overview of the vaccine development efforts underway and answer some questions about the testing process, the likelihood and timing of a vaccine in the U.S., and what to expect from a COVID-19 vaccine.

How likely is it that there will be a COVID-19 vaccine?

Very likely. Every expert we contacted was confident that there would be a COVID-19 vaccine, although details beyond that are uncertain.

“We should get something that can induce immunity to the virus,” said Dr. Stanley Perlman, a coronavirus researcher at the University of Iowa, in a phone interview. “The challenge, though, is knowing whether the immunity is long-lasting. And how protective it’ll be.”

“I’m fairly confident we will have several COVID-19 vaccines because the technical hurdles for making a COVID-19 vaccine are not that steep,” Dr. Peter Hotez, the dean of Baylor College of Medicine’s National School of Tropical Medicine, told us, adding that researchers know to target the so-called “spike” protein on the outside of the virus.

“This is sort of an old school problem in virology, and we have several vaccines where we’ve done this in the past,” he said, “so I’m pretty confident we will have not just one but probably several COVID-19 vaccines.”

Dr. Paul Offit, a vaccine expert and pediatrician at Children’s Hospital of Philadelphia, told us he was “very confident” there would be a vaccine, and likewise said he thought there would be more than one.

As he has before, Dr. Anthony Fauci, a coronavirus task force member and director of the National Institute of Allergy and Infectious Diseases, cautioned in July 31 congressional testimony that “there’s never a guarantee that you’re going to get a safe and effective vaccine.” 

But, he added, the signs so far are promising. “From everything we’ve seen now — in the animal data as well as the early human data — we feel cautiously optimistic that we will have a vaccine by the end of this year and as we go into 2021.”

How do coronavirus vaccines work, and what are the various vaccine designs?

As with other vaccines, the basic idea behind a coronavirus vaccine is to train the body’s immune system to recognize the virus, or SARS-CoV-2, so that if a person encounters it, they will either not become infected or will develop a less severe case of the disease.

Exposure to either a tiny amount of the virus — either weakened or killed — or a viral protein prompts the development of immune T and B cells that specifically recognize the virus and spurs the creation of antibodies by B cells, including so-called neutralizing antibodies that can glom onto the virus and prevent the pathogen from entering cells. 

The COVID-19 vaccines in development around the world run the gamut from traditional approaches using killed, or inactivated, virus to never-before-approved genetic vaccines, which are made of pieces of DNA or messenger RNA that correspond to a viral protein. Once injected into the body, the DNA or mRNA is made into the protein, to which the immune system can then react.

For the coronavirus, most vaccine designs that don’t use inactivated or weakened virus target the spike protein, since it coats the outside of the virus and it’s what SARS-CoV-2 uses to enter cells.

Protein subunit vaccines for COVID-19, for example, are made of the purified viral spike protein, while viral vector vaccines are made of harmless viruses that are modified to contain a gene that codes for the spike protein.

Of the leading candidates being supported by the U.S. government, Moderna’s and Pfizer/BioNTech’s vaccines are both mRNA-based and are now in phase 3 trials. AstraZeneca’s adenovirus viral vector vaccine, which was developed at Oxford University, became the third vaccine to enter trials in the U.S. on Aug. 31. All three use technology that has never been used in any previously licensed vaccine.

Other candidates include Novavax’s protein subunit vaccine, Johnson & Johnson’s adenoviral vaccine — both in phase 1 testing — as well as Sanofi’s protein subunit vaccine, which is in combined phase 1/2 testing. Merck’s viral vector-based entry, which borrows technology from its Ebola vaccine, is still in preclinical testing.

No American vaccine uses inactivated or weakened virus, and most vaccines being designed require two doses.

What do the data say so far about the U.S. vaccine candidates?

Much of the information that has emerged thus far is promising. Experiments in monkeys have shown that after giving animals one of several experimental COVID-19 vaccines, the animals produce strong immune responses and are either protected from infection or prevented from becoming sick after purposely being infected with SARS-CoV-2.

In the case of Moderna’s mRNA vaccine, some monkeys could still become infected after receiving the vaccine, but the animals quickly cleared the virus from their bodies.

Results from Oxford’s AstraZenca vaccine showed that rhesus macaques getting the vaccine had less virus in their bodies than control animals, and none developed pneumonia.

One of J&J’s vaccine designs performed especially well, with one dose being sufficient to trigger high levels of neutralizing antibodies and protecting five of six monkeys from becoming infected upon challenge.

Early trial results in humans, many of which were initiated before the animal data came in, also look encouraging. Phase 1 trials are typically conducted in fewer than 100 volunteers to assess initial safety and to find the correct dose; phase 2 trials continue monitoring for any safety concerns and look for efficacy in a pool of several hundred participants.

A phase 1 trial of Moderna’s vaccine, which was tested at three dosages in a total of 45 participants, found that after two doses subjects generally produced more neutralizing antibodies than patients who had recovered from COVID-19, with no serious side effects.

Pfizer/BioNTech’s mRNA vaccine showed similar results in an unpublished combined phase 1/2 trial, also in 45 people.

Oxford’s AstraZeneca vaccine sparked a T cell and neutralizing antibody response in participants after one dose, although it elicited more side effects than those experienced by patients who were given a meningitis vaccine as a control.

All 106 participants who received Novavax’s protein subunit vaccine produced neutralizing antibodies, on average about four times the level of those recovering from COVID-19.

The results bode well for an eventual vaccine, but as Offit explained, nothing is certain until there’s data from a phase 3 trial, when the shot goes into the arms of tens of thousands of volunteers and is compared in a randomized controlled trial to placebo.

“Even though we have excellent immune responses” in the early phase studies, he said, “it doesn’t necessarily mean these are protective immune responses. The only way that can be known is in a phase 3 trial.”

And he noted that the existing results are in an extremely small number of people — just 15 people for the dose Moderna selected, for example. Ideally, he said, the number of people that you see having a consistent, brisk immune response “should be more than the number of people you can invite to a small outdoor BBQ.”

A consistent finding across these early trials is that a COVID-19 vaccine may be somewhat more annoying for people than other vaccines. While no serious effects have been observed, most of the vaccines are what scientists call reactogenic, producing tenderness and swelling at the injection site, among other short-term symptoms. 

Especially given the fact that two doses will likely be needed, public health experts say it’s important for people to know going in that the shot isn’t dangerous but may be unusually painful, so they’re not concerned or surprised.

What is Operation Warp Speed?

As we’ve written, Operation Warp Speed is the government’s nearly $10 billion effort to fast-track vaccine development as well as therapeutics and diagnostics. The program’s stated mission is to “produce and deliver 300 million doses of safe and effective vaccines with the initial doses available by January 2021.” 

A key component of OWS’ approach is to offer funding to promising vaccine candidates so that companies can begin manufacturing vaccines even before scientists know that they work, or what’s called manufacturing at risk. 

If trial results are good, the Food and Drug Administration can either license the vaccine or authorize a vaccine for use via an emergency use authorization, which Offit believes is more likely. But if testing reveals a vaccine to be unsafe or ineffective, those doses would be thrown out.

“Rather than eliminating steps from traditional development timelines, steps will proceed simultaneously, such as starting manufacturing of the vaccine at industrial scale well before the demonstration of vaccine efficacy and safety as happens normally,” an OWS fact sheet explains. “This increases the financial risk, but not the product risk.”

The FDA said in a June guidance document that it expects any vaccine it authorizes to be at least 50% effective at preventing disease or decreasing COVID-19 severity, which is on par or slightly better than the seasonal influenza vaccine.

As of Sept. 4, the Biomedical Advanced Research and Development Authority, or BARDA, has backed seven different vaccines with either funding for research and development or for manufacturing. 

It’s worth noting that OWS is not unique. Other countries and organizations around the world are taking the same approach, said Dr. Nicole Lurie, a former assistant secretary for preparedness and response under President Barack Obama. Lurie now advises the Coalition for Epidemic Preparedness Innovations, a nongovernmental organization dedicated to developing vaccines to stop epidemics, including COVID-19.

“All the major vaccine development efforts around the world are trying to do the same thing right now, and the major concept is doing the manufacturing before you do the trials,” she said in a phone interview.

And while the scale this time is different — both in the U.S. and around the world — Lurie said, making vaccines at risk was done during the 2009 H1N1 influenza pandemic, “so it’s not a new concept.”

The U.S. has declined to participate in the COVAX initiative, which is part of the WHO’s vaccine accelerator program, and is also led by CEPI and the Gavi, the Vaccine Alliance. As with OWS, the idea is to bank on multiple candidates to increase the chance of a successful vaccine, but the idea is more ambitious and guards against so-called vaccine nationalism, or countries competing against one another and those of means hoarding vaccines at the expense of poorer nations. 

Under the program, wealthy countries collectively bankroll a much broader portfolio of vaccines than they could support on their own, gaining access to more potentially successful candidates while also ensuring that lower-income nations have access to doses.

When will the U.S. have a safe and effective vaccine?

An exact time frame is impossible to know, despite the president’s insistence that the U.S. “will produce a vaccine before the end of the year, or maybe even sooner,” as President Donald Trump said in his speech at the Republican National Convention.

The CEO of Pfizer said on Sept. 3 that the company had enrolled 23,000 of its minimum 30,000 trial participants. He said Pfizer expected to know by the end of October whether its vaccine works, and would submit the appropriate regulatory paperwork right away.

According to its website, Moderna had enrolled nearly 17,500 participants as of Aug. 28.

The Centers for Disease Control and Prevention began asking states at the end of August to prepare for distribution of a limited number of doses as early as late October or early November, raising the possibility of a vaccine before Election Day.

The agency, however, cautioned that the vaccine distribution scenarios were “hypothetical” and might “evolve as more information is available” given uncertainties in the vaccine landscape.

Officials have also explained that having a vaccine so soon is improbable. In a Sept. 3 interview with NPR, Moncef Slaoui, the chief adviser of Operation Warp Speed, said that there is “a very, very low chance that the trials that are running as we speak could read before the end of October,” adding that while he thought it was “extremely unlikely,” it wasn’t impossible, and so preparation was appropriate.

The head of the National Institutes of Health, Dr. Francis Collins, similarly told CNN on Sept. 2 that the CDC guidance was meant to get states to prepare, even if the likelihood of such an early arrival “is pretty low.”

Slaoui said that he was confident that a vaccine could be ready by the end of the year, with around 25 million doses to start, and enough shots for the entire U.S. population to be immunized by the middle of 2021.

Fauci said in a CNN interview on Sept. 3 that he thought it was unlikely that a vaccine would be ready in October. “I think most of the people feel it’s going to be November, December,” he said. “It is conceivable that you can have it by October, though I don’t think that that’s likely.”

Other experts, however, are skeptical of even those time frames. Offit thinks the beginning of 2021 is more likely, given the logistics of the trials.

“There is no predicting success in science,” he said. “They haven’t finished recruiting totally for dose one and you have to wait a month for dose two, and we’re already in September. Then you have to wait two weeks after dose two to really have the maximum immunological effect from those two doses. Then you have to hope that there’s probably 150 people in your placebo group who get sick with COVID-19.”

An independent group known as a Data and Safety Monitoring Board, Offit said, can peek at the data and see whether a trial can show, statistically, that a vaccine works. That information could be used to end the trial early if the signals are good. But Offit cautioned that such an approach, if not done properly, could jeopardize valuable information about how well the vaccine works in subsets of the population, including people 65 and older and minorities. A vaccine shouldn’t be given to certain groups, he said, until it is shown to be safe and effective for them.

With fewer people tested in a trial, slightly less will also be known about safety, which Offit said is always about reducing — rather than eliminating — uncertainty, since the final word about the potential for rare side effects only comes after vaccine approval with surveillance.

“It all depends on the levels of transmission, where the trials are going on, and it depends on how good the vaccine is,” CEPI’s Lurie said of vaccine timing. “So if we test in areas with lots of transmission and the vaccine is good, we might know sooner. Or if the first dose provides some protection, we might know sooner than if we have to wait for two doses. We just don’t know.”

In an interview in late July, Lurie said she thought people were being “overly optimistic” and was concerned that it was setting up “unrealistic expectations” and raising concerns about whether any vaccine authorization is premature.

On the manufacturing side, she noted, even if vaccine doses are made, it can still take six weeks to get the product into vials or syringes, plus additional time to do sterility testing.

Who will get a vaccine first?

Even with Operation Warp Speed’s efforts to manufacture vaccine doses before knowing whether a vaccine works, health officials acknowledge there won’t be enough doses for everyone to be immunized right away.

Thus, a critical question is who should receive a vaccine first. To answer this question, the CDC’s Advisory Committee on Immunization Practices has formed a COVID-19 vaccine work group to, among other functions, “ensure equity in vaccine allocation and distribution.” 

At the request of the CDC and the National Institutes of Health, the National Academies of Sciences, Engineering and Medicine is also thinking through how to maximize the benefit of a vaccine and the ethics of prioritization when supplies are limited.

According to the National Academies’ Sept. 1 draft report, scientists propose starting with high-risk health care workers and first responders, followed by adults with underlying conditions that put them at a “significantly” higher risk, along with older individuals who live in places such as nursing homes. 

In a second phase, vaccines would be distributed to essential workers at higher risk of exposure, teachers and school staff, and older people without other risk factors, among other groups. Young people, children and lower-risk essential workers would get a vaccine in a third phase.

The report notes that while people of color have been disproportionately impacted by COVID-19, those differences do not seem to stem from biological differences, but rather from systemic racism that leads to “comorbidities that increase the severity of COVID-19 infection and the socioeconomic factors that increase likelihood of acquiring the infection.”

As a result, the strategy does not explicitly recommend prioritizing certain racial or ethnic groups, but within the identified phases calls for giving priority to certain geographic regions based on metrics of social vulnerability.

In documents sent to states in late August, the CDC said the “likely” groups for initial prioritization include members of the “critical workforce,” such as health care workers, and staff and residents of long-term care facilities.

While groups are starting the planning now, the exact details of prioritization could change depending on the specific vaccine or vaccines that first become available, and in what quantities.

“There’s no simple answer” to prioritization, Harvard epidemiologist Marc Lipsitch, who has done modeling to help determine which strategies would be most beneficial, said in a press call with reporters in mid-August. “It depends on what your goal is and on the characteristics of the vaccine.” 

If the vaccine can prevent transmission and there is enough of it to inoculate several tens of a percent of the population, then the best way to reduce the number of cases is to vaccinate the groups responsible for transmission, he said. That might include targeting young adults rather than those at highest risk.

But if there are only a limited number of doses and the goal is to reduce deaths, Lipsitch said, then it makes sense to give the vaccine to the elderly, even if the vaccine works less well for them. Of course, if the vaccine is significantly worse at preventing disease in older folks, then that strategy won’t be most effective.

Even obvious-seeming prioritizations might fall by the wayside depending on the particular vaccine in question.

As Lipsitch noted in a presentation before the National Academies on Aug. 7, giving priority to nursing home staff, for example, could actually backfire in certain instances.

“Vaccinating staff works if it stops infection,” he said. But it’s “potentially even counterproductive if it purely suppresses symptoms and makes people less easy to identify as carriers.”

A few reports suggest some people infected with the coronavirus don’t produce antibodies against the virus for very long and that some people can become reinfected. Does that mean a vaccine won’t work?


Several studies have found that antibodies against SARS-CoV-2 wane shortly after recovery, especially if coronavirus patients had no or only mild symptoms.

While it’s true that people might need to receive booster shots of a COVID-19 vaccine if immunity to the coronavirus does turn out to be less durable, it’s important to recognize that a lack of antibodies doesn’t necessarily mean someone has zero immunity — and not all studies have replicated those findings.

“What really matters is not that you have antibody in your blood, but that the cells that make antibody are still there, so they can charge up immediately if they see the infection,” said the University of Iowa’s Perlman. 

If those cells are still there, along with other immune cells that recognize the virus, then a person could be infected again if they lack neutralizing antibodies, but they would be far less likely to become seriously ill. 

That’s probably what happened in several reported cases of reinfection, including what’s thought to be the first confirmed case of reinfection in a man from Hong Kong, who had his viruses sequenced to show that he likely was infected on two separate occasions.

The man had a cough, sore throat, fever and headache the first time around, but had no symptoms upon infection a second time nearly five months later. 

“This is no cause for alarm – this is a textbook example of how immunity should work,” Yale immunologist Akiko Iwasaki said on Twitter. “While immunity was not enough to block reinfection, it protected the person from disease.”

Slightly more troublesome is another report, as yet unpublished in a peer-reviewed journal, about an instance of reinfection in a Nevada man whose second COVID-19 infection was worse than his first.

But given that this is only one case, it’s unclear how much to make of it. As one of the scientists reporting the Nevada finding said, “[T]his is a singular finding. It does not provide any information to us with regard to the generalizability of this phenomenon.”

Other experts also recommended against overinterpreting the reinfection case reports. 

E. John Wherry, an immunologist at the University of Pennsylvania, said in a tweet that although there’s evidence that reinfection can occur, “it is likely unusual, if not rare,” and protective immunity “remains the more likely outcome of infection (and effective vaccination).” 

Jesse Bloom, a researcher studying viral evolution at the Fred Hutchinson Cancer Research Center, also pointed out that reinfection has been documented for influenza and measles — two viral diseases for which there are vaccines.

“[W]e should pay attention to SARS-CoV-2 re-infections, and assess how frequent they are and why they occur,” he said in a Twitter thread. “But recall that #SARSCoV2 is the most intensely surveilled virus in history … and humans are highly heterogeneous, so until we know the statistical frequency of these re-infections, they should not alarm us any more than the occasional influenza or measles re-infections do.”

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