A Vaccine Reality Check
So much hope is riding on a breakthrough, but a vaccine is only the beginning of the end.
By Sarah Zhang
Nearly five months into the pandemic, all hopes of extinguishing COVID-19 are riding on a still-hypothetical vaccine. And so a refrain has caught on: We might have to stay home — until we have a vaccine. Close schools — until we have a vaccine. Wear masks — but only until we have a vaccine. During these months of misery, this mantra has offered a small glimmer of hope. Normal life is on the other side, and we just have to wait — until we have a vaccine.
Feeding these hopes are the Trump administration’s exceedingly rosy projections of a vaccine as early as October, as well as the media’s blow-by-blow coverage of vaccine trials. Each week brings news of “early success,” “promising initial results,” and stocks rising because of “vaccine optimism.” But a COVID-19 vaccine is unlikely to meet all of these high expectations. The vaccine probably won’t make the disease disappear. It certainly will not immediately return life to normal.
Biologically, a vaccine against the COVID-19 virus is unlikely to offer complete protection. Logistically, manufacturers will have to make hundreds of millions of doses while relying, perhaps, on technology never before used in vaccines and competing for basic supplies such as glass vials. Then the federal government will have to allocate doses, perhaps through a patchwork of state and local health departments with no existing infrastructure for vaccinating adults at scale. The Centers for Disease Control and Prevention, which has led vaccine distribution efforts in the past, has been strikingly absent in discussions so far — a worrying sign that the leadership failures that have characterized the American pandemic could also hamper this process. To complicate it all, 20 percent of Americans already say they will refuse to get a COVID-19 vaccine, and with another 31 percent unsure, reaching herd immunity could be that much more difficult.
The good news, because it is worth saying, is that experts think there will be a COVID-19 vaccine. The virus that causes COVID-19 does not seem to be an outlier like HIV. Scientists have gone from discovery of the virus to more than 165 candidate vaccines in record time, with 27 vaccines already in human trials. Human trials consist of at least three phases: Phase 1 for safety, Phase 2 for efficacy and dosing, and Phase 3 for efficacy in a huge group of tens of thousands of people. At least six COVID-19 vaccines are in or about to enter Phase 3 trials, which will take several more months.
We are almost five months into the pandemic and probably another five from a safe and effective vaccine — assuming the clinical trials work out perfectly. “Even when a vaccine is introduced,” says Jesse Goodman, the former chief scientist at the Food and Drug Administration, “I think we will have several months of significant infection or at least risk of infection to look forward to.”
All of this means that we may have to endure more months under the threat of the coronavirus than we have already survived. Without the measures that have beat back the virus in much of Europe and Asia, there will continue to be more outbreaks, more school closings, more loneliness, more deaths ahead. A vaccine, when it is available, will only mark the beginning of a long, slow ramp down. And how long that ramp down takes will depend on the efficacy of a vaccine, the success in delivering hundreds of millions of doses, and the willingness of people to get it at all. It is awful to contemplate the suffering still ahead. It is easier to think about the promise of a vaccine.
“There’s a lot of hope riding on these vaccines,” says Kanta Subbarao, the director of the World Health Organization’s flu collaborating center in Melbourne, who has also worked on other coronavirus vaccines. “Nobody wants to hear it’s not just right around the corner.”
Vaccines are, in essence, a way to activate the immune system without disease. They can be made with weakened viruses, inactivated viruses, the proteins from a virus, a viral protein grafted onto an innocuous virus, or even just the mRNA that encodes a viral protein. Getting exposed to a vaccine is a bit like having survived the disease once, without the drawbacks. A lot remains unknown about the long-term immune response to COVID-19, but, as my colleague Derek Thompson has explained, there are good reasons to believe getting COVID-19 will protect against future infections in some way.
Vaccine-induced immunity, though, tends to be weaker than immunity that arises after an infection. Vaccines are typically given as a shot straight into a muscle. Once your body recognizes the foreign invader, it mounts an immune response by, for example, producing long-lasting antibodies that circulate in the blood.
But respiratory viruses don’t normally fling themselves into muscle. They infect respiratory systems, after all, and they usually sneak in through the mucous membranes of the nose and throat. Although vaccine shots induce antibodies in the blood, they don’t induce many in the mucous membranes, meaning they’re unlikely to prevent the virus from entering the body. But they could still protect tissues deeper in the body such as the lungs, thus keeping an infection from getting worse. “The primary benefit of vaccination will be to prevent severe disease,” says Subbarao. A COVID-19 vaccine is unlikely to achieve what scientists call “sterilizing immunity,” which prevents disease altogether.
One way to boost the effectiveness of a respiratory-virus vaccine is to mimic a natural infection, by spraying live but weakened virus into the nose. FluMist, for example, contains weakened flu viruses, and a handful of research groups are looking into the strategy for COVID-19. But live virus vaccines are riskier because, well, the virus is live. “We don’t want to be spraying coronavirus up people’s noses until [we] are absolutely sure that it’s actually a virus that can’t spread from person to person and that it can’t make somebody sick,” says Kathleen Neuzil, the director of the University of Maryland’s Center for Vaccine Development and Global Health. “It will just take time.”
With this first generation of vaccines, though, speed is of the essence. An initial vaccine might limit COVID-19’s severity without entirely stopping its spread. Think flu shot, rather than polio vaccine. The FDA’s guidelines for a COVID-19 vaccine recognize it may be far from 100 percent effective; to win approval, the agency says, a vaccine should prevent or reduce severe disease in at least 50 percent of people who get it. “That’s obviously not ideal,” says Walter Orenstein, a vaccine researcher at Emory University who previously worked as the director of the National Immunization Program. “But it’s better than zero percent.”
Inrecent weeks, multiple vaccine groups have released promising data that show their candidates can induce antibodies that neutralize the coronavirus in lab tests. Their next challenges are about scale: testing the vaccine in a Phase 3 trial with tens of thousands of people to prove it prevents infection in the real world, and then, if it works, manufacturing hundreds of millions, even billions, of doses. This is why even a vaccine that has already been tested in small numbers of people is still many months away.
Phase 3 trials are the largest and longest of the three phases — normally, they would take years, but they’re being compressed into months because of the pandemic. Still, vaccine makers need to enroll tens of thousands of people to confirm efficacy and to look for rare and long-term side effects. It will take time to recruit participants, time to wait for them to be naturally exposed to COVID-19, time for any long-term side effects to show up, and time to simply analyze all of the data.
Perversely, the high and rising rates of COVID-19 in the United States do make it easier to test vaccine candidates here. Any given participant is more likely to get exposed to the virus at some point. “It’s not good news for our country in any way, shape, or form, but … it makes it possible to accumulate cases,” says Ruth Karron, the director of the Center for Immunization Research at Johns Hopkins University, who also served on the Data and Safety Monitoring Board for Moderna’s Phase 2 vaccine trial. Moderna, an American company, is conducting its Phase 3 trial in the U.S. A group based at the University of Oxford, which is collaborating with the British-Swiss biotech company AstraZeneca, is running trials in the U.K., Brazil, and South Africa — the latter two countries chosen specifically because of their high numbers of COVID-19 cases.
In the U.S., the Trump administration’s Operation Warp Speed is helping several vaccine makers invest in manufacturing facilities while these trials are ongoing. This could reduce the lag time between the approval and the availability of a vaccine, since companies might otherwise wait for FDA approval before scaling up manufacturing. But making hundreds of millions of doses is still a considerable challenge, especially for a novel vaccine.
The leading COVID-19 vaccine candidates rely on technology that’s never been used before in approved vaccines. Moderna’s vaccine, for example, is a piece of RNA that encodes a coronavirus protein. Oxford and AstraZeneca’s vaccine attaches a coronavirus protein to a chimpanzee adenovirus. Neither has been manufactured before on the necessary scale.
Consider what happened in 2009, the most recent time the world mobilized to produce vaccines to stop a pandemic. The disease was H1N1, more commonly known as the “swine flu,” and vaccine makers had the much simpler task of subbing the H1N1 strain into the seasonal flu vaccine they make every year. Despite many, many years of experience in making flu vaccines, the manufacturers hit an unexpected snag. Most flu vaccines are made from viruses grown in chicken eggs, and for some reason, the H1N1 strain did not grow very well in the eggs at first. “The amounts produced from a given amount of eggs were much lower than normal,” says Goodman, who led the FDA’s pandemic response in 2009. “So that really delayed things.” Then, once millions of doses were in the works, Goodman says, there weren’t enough facilities that could package the bulk vaccine into individual vials.
The Department of Health and Human Services created a network of fill-and-finish facilities to address this problem in the future. Right now, Operation Warp Speed is also awarding contracts to make the millions of syringes and glass vials needed to package a COVID-19 vaccine. Without careful planning on these fronts, the U.S. could run into a demoralizing scenario where vaccines are available, but there is no way to physically get them to people.
Even if all of this goes well — the earliest candidates are effective, the trials conclude quickly, the technology works — another huge task lies ahead: When vaccines are approved, 300 million doses will not be available all at once, and a system is needed to distribute limited supplies to the public. This is exactly the sort of challenge that the U.S. government has proved unprepared for in this pandemic.
In the H1N1 pandemic, the U.S. government purchased the vaccines and allocated doses to state and local health departments, which in turn vaccinated people through mass clinics as well as employers, schools, hospitals, pharmacies, and doctor’s offices. Nationwide, the program eventually vaccinated about a quarter of all Americans — demand fell because the pandemic itself peaked not long after the vaccine became available.
The 2009 vaccination program was built on the infrastructure of the Vaccines for Children Program, in which the CDC buys and distributes vaccines to states for children who usually are uninsured or on Medicaid. Immunization managers who work in these programs are well versed in the intricacies of vaccine storage and distribution, such as maintaining a cold chain for vaccines that could become ineffective at room temperature. But because they work with children’s vaccines, they deal mostly with pediatrician’s offices. “We didn’t have relationships with hospitals and internists and people who vaccinated adults,” says Kelly Moore, who was the director of the Tennessee Immunization Program in 2009. In August that year, two months before they got their first shipment of the vaccine, Moore’s team created a sign-up on the state immunization registry and sent out a newsletter every Friday with updates and training modules for handling vaccines.
“Unfortunately,” says Moore, “that network has not been maintained because we haven’t had other vaccines to send them in 11 years.” Contact information is out of date. Rebuilding this network for adults will be even more important with COVID-19. Although the H1N1 vaccine was recommended for all ages, the focus was on kids, for whom the flu was particularly dangerous. The opposite is true of COVID-19, which is more of a threat to older adults.
Some of the leading COVID-19 vaccine candidates could also pose new logistical challenges, if they require storage at temperatures as low as –80 degrees Celsius or multiple doses to be effective. In fact, a COVID-19 vaccine is quite likely to require two doses; the first primes the immune system, allowing the second to induce a stronger immune response. Officials would have to balance giving one dose to as many people as possible with giving a second dose to those who already had one. “That was a complication we didn’t face in 2009, and we were so grateful,” says Moore.
Although the CDC took the lead in distributing H1N1 vaccines in 2009, Claire Hannan, the executive director of the Association of Immunization Managers, says the agency has been oddly silent about plans for a COVID-19 vaccine since April. “Initially, we were having planning calls with CDC right away,” she says. “And then nothing.” She has unsuccessfully tried to get in touch with Operation Warp Speed, which has suggested the Department of Defense may also get involved in vaccine distribution. “We continue to ask CDC these many, many questions. And they don’t know,” she says.
The CDC’s Advisory Committee on Immunization Practices is also normally responsible for recommendations on how to prioritize vaccines. The committee, which is composed of outside experts, last met in late June, when they discussed prioritizing vaccines for health-care workers, the elderly, and those with underlying conditions. They also considered prioritizing vaccination by race, given the racial disparities in COVID-19 cases. But now the National Academy of Medicine is convening a panel on the same topic, which is again causing confusion about who is responsible for making these decisions.
In 2009, Moore’s job was to put the CDC advisory committee’s recommendations into practice. Two or three times a week, she would get an email from the CDC’s vaccine distributor letting her know the number of doses available for her entire state. In practice, though, an initial shipment of vaccines might not be enough to cover everyone in even the highest priority group, such as health-care workers. It was up to people like Moore to decide which hospital got how many doses, with the promise of more on the way next week. Then individual hospitals administered the actual vaccines to their employees based on priority status.
This system is meant to be flexible and responsive to local conditions, but it also means the availability of a vaccine might seem to vary from place to place. For example, Emily Brunson, an anthropologist at Texas State University who studies vaccines, says that in 2009 there were cases in which one district interpreted recommendations strictly, giving the vaccine only to high-priority groups, and a neighboring district offered it to anyone who wanted it. The decision to distribute the vaccine through employee health centers in New York, which happened to include several Wall Street firms, also caused a big backlash. “There are many ways that things can be misinterpreted,” Brunson says. And during an initial shortage, these decisions can feel unfair — especially given tensions seeded earlier in the pandemic when the rich and the famous were getting COVID-19 tests while ordinary people were being turned away at clinics.
If the pandemic so far is any indication, a vaccination program is likely to take place against a backdrop of partisanship and misinformation. Already, conspiracy theories are spreading about a COVID-19 vaccine, some of them downright outlandish. But the emphasis on speed — as in “Operation Warp Speed” — has also created real worries about vaccines being rushed to market. At a congressional hearing with five vaccine makers on Tuesday, company officials had to repeatedly push back against the idea that the industry might cut corners for a COVID-19 vaccine.
“We’re going to be in a situation where some people will be desperate to get the vaccine and some people will be afraid to get the vaccine. And there’ll be probably a lot of people in between who are a little bit of both or not sure,” says Michael Stoto, a public-health researcher at Georgetown University. A vaccine, especially a novel one that doesn’t offer complete protection against COVID-19, will require careful communication about risk. “The fact that we can’t get ourselves straight about wearing masks will make that harder,” he adds. Given the number of Americans who are currently unsure of or opposed to getting a COVID-19 vaccine, Anthony Fauci, the director of the National Institute of Allergy and Infectious Diseases, has warned that even a vaccine might not get the country to herd immunity if too many people refuse it.
For the Americans pinning their hopes on a vaccine, a botched rollout could feel like yet another example of failure in the time of COVID-19. That could have disastrous consequences that last well beyond the pandemic itself. Brunson worries that such a scenario could undermine trust in public-health expertise and in all vaccines. “Both of those would be disasters,” she says, “in addition to the COVID itself being a disaster.” It could mean, for example, further resurgences of vaccine-preventable diseases such as measles and an even bigger challenge when battling future pandemics.
For all the uncertainties that remain ahead for a COVID-19 vaccine, several experts were willing to make one prediction. “I think the question that is easy to answer is, ‘Is this virus going to go away?’ And the answer to that is, ‘No,’” says Karron, the vaccine expert at Johns Hopkins. The virus is already too widespread. A vaccine could still mitigate severe cases; it could make COVID-19 easier to live with. The virus is likely here to stay, but eventually, the pandemic will end.