As America awaits vaccination against COVID-19, ACP members and Annals of Internal Medicine subscribers got an inside look at the ongoing work to get us there. Five experts spoke during “ACP and Annals of Internal Medicine COVID-19 Vaccine Forum: What Physicians Need to Know,” held virtually on Oct. 16, and highlighted both the progress and the challenges. (The full forum recording is available for replay online at www.annals.org/covid-forum-cme and is described in an accompanying article in Annals of Internal Medicine.)
“Implementation is going to be very complex,” said Beth P. Bell, MD, MPH, in what she described as the understatement of her presentation. “And there are a number of pitfalls. And there are some complexities that we can anticipate and others that we cannot.” Dr. Bell, a member of the Advisory Committee on Immunization Practices (ACIP), described how the committee has been preparing to offer guidance on use of a vaccine as soon as one is available.
That should be fairly soon, according to Anthony S. Fauci, MD, MACP, director of the Institute of Allergy and Infectious Diseases (NIAID), who spoke via a pretaped presentation. “The way things are going now with the trials, we project that by November and December, we will know whether we have safe and effective vaccines, and I think there'll be more than one,” he said.
Dr. Fauci reviewed the multiple avenues to this goal researchers are currently pursuing in the U.S. “There are three separate platforms: the nucleic acid, which is utilization of new technologies, such as mRNA; viral vectors, such as adenovirus and [vesicular stomatitis virus]; and the standard typical protein subunits.”
Some of those platforms likely sound more familiar than others, an issue that H. Clifford Lane, MD, MACP, the NIAID deputy director for clinical research and special projects, addressed when he took questions from attendees after Dr. Fauci's talk.
The vaccine that moved most swiftly to phase 3 research was RNA based, because it was faster to develop despite its relative novelty, he noted. “Nucleic acid-based vaccines, they're easy to mass produce, that's a very rapid, adaptive platform,” Dr. Lane said. “The rub is we don't have any licensed vaccines with those platforms, so we don't really know how good they are.”
Similar vaccines were in the works for other novel viruses but never got to large trials. “The irony, which was in a way fortunate, was by the time we got things ready for SARS or MERS or Zika, those pretty much disappeared. So we really haven't had a good test case,” he said.
Dr. Lane was also asked to compare the current vaccine research to that for another deadly virus. A questioner noted that after decades of effort, there's still no HIV vaccine. “HIV is pretty amazing in terms of how it gets into the cell, how it rapidly mutates,” Dr. Lane said. “One thing that has been quite comforting in a way is that [SARS-CoV-2's] rate of mutation appears to be extraordinarily slow.”
There's another important difference between the viruses, he noted. “People don't clear their HIV. They do clear this virus. … We just need to be clever enough to do that without infection.”
So far, Dr. Lane added, the evidence on this front is promising. “The neutralizing antibody responses that one has seen with the candidate vaccines that are in the phase 3 trials are as high, if not a little bit higher, than what is seen with natural infection. So there's some hope, in fact, that the vaccines may give us a bit more protection even than what is seen with natural infection.”
He also had a positive answer on whether the vaccine would be effective in older patients. “There's a little bit of data that has come out on this, and it actually appears that the people who are older are making as good, if not a slightly better, immune response than some of the younger adults, suggesting that there may be recall going on with the immune response to the SARS-CoV-2,” Dr. Lane said.
Forum speaker David A. Kessler, MD, addressed what specific proof of safety and effectiveness will be required for FDA authorization of a vaccine.
Dr. Kessler, a former FDA commissioner, noted that the FDA has given emergency use authorization (EUA) to several treatments for COVID-19. EUAs carry less stringent standards for effectiveness than normal drug approvals—only requiring that there is reason to believe that the product may be effective—but recent FDA guidance has indicated that the vaccine candidates will likely be held to a higher standard than a typical EUA, he said.
“The most important thing in that guidance is the recognition that giving a vaccine to healthy people is probably among the weightiest decisions that FDA can ever make,” Dr. Kessler said. “FDA has said, and I would agree with this, that before you give a vaccine to healthy people, that vaccine needs to be found to be safe and effective.”
The FDA will require SARS-CoV-2 vaccines to be tested in large, randomized, placebo-controlled trials that provide evidence of protection against infection. “Not a surrogate,” Dr. Kessler noted. To prove this, researchers are tracking how many infections occur in their entire trial populations and then comparing case rates in the vaccinated and control arms to see if the vaccine has met the required 50% effectiveness.
The FDA also mandated that researchers report at least eight weeks of safety data, based on the assumption that most adverse events will occur in that time frame, he said. But whether that's enough is one of many current uncertainties, he said. Others include how to make sure that vaccines are targeted to those who will most benefit from them and that vaccine research continues after an EUA.
Keeping an eye on the safety of vaccines after authorization is one way internists can help, according to Dr. Kessler. “I certainly know the members of the American College of Physicians take seriously the role … if and when a vaccine is cleared for the market or approved, that we as doctors make sure that we're monitoring for adverse events and reporting those adverse events,” he said.
ACP members have already contributed to vaccine efforts by involvement in ACIP, Dr. Bell said. The medical experts who comprise ACIP, particularly those in the COVID-19 workgroup, are currently working on issues related to vaccine recommendations.
One major challenge will be deciding who gets the vaccine first. “It's pretty clear that administration of COVID-19 vaccines is going to require a phased approach,” she said. The workgroup has agreed on ethical principles to guide the selection of groups for phased vaccination, before proceeding to more specific decision making.
“There is a general consensus in the ACIP that health care personnel, very broadly defined, probably should be the group in what we were calling phase 1a,” Dr. Bell said. Other priority groups will include other types of essential workers, people with high-risk medical conditions, and adults ages 65 years and older.
“We estimate that probably this represents about 200 million people,” she said. Given the size of that population, experts will likely have to prioritize within it. Factors to consider will be the effectiveness of the vaccine in various populations—a reason that recommendations for each vaccine will be considered separately, Dr. Bell noted—and the morbidity and mortality different groups face from COVID-19.
There will also be practical considerations regarding distribution. “There are some vaccines that need to be shipped and held at minus 70 [degrees Celsius]. That obviously changes the various scenarios we might consider,” said Dr. Bell. “The next steps for the ACIP are to continue to build a scientific understanding of the epidemiology of the outbreak and of risk groups—modeling the impact of various vaccination strategies, which we've been doing quite a bit of, and interpreting clinical trials safety data, and continuing to strengthen our plans for postmarketing safety monitoring.”
She reiterated the importance of practicing physicians in that monitoring and charged her listeners with some additional tasks. “Public confidence is key to success of any vaccination program … and you can talk to your patients, answer their questions, validate their concerns, and inspire trust and confidence,” Dr. Bell said. She also encouraged clinicians to be prepared to collaborate closely with state and local public health departments on vaccination efforts.
A representative of one such department was the closing speaker of the forum. Rachel Levine, MD, secretary of the Pennsylvania Department of Health, addressed the politics of COVID-19 vaccination.
“This extreme political environment poses a challenge to the effective development, and then the effective distribution and administration, of a vaccine,” she said. “One thing that we all have agreed upon—local public health officials, state public health officials, and federal public health officials—is that there should not be the politicization of COVID-19 response and should not be politicization of the vaccine. And that's what we're going to work for.”
In addition to the problem of longstanding hesitancy or opposition regarding vaccines generally, health officials will have to combat public concerns about the speed with which these vaccines are being developed by providing transparent, apolitical information, she noted. There will also be the opposite challenges that more people will want vaccination than can get it immediately and that many will expect to be able to discontinue all other mitigation measures as soon as a vaccine is available, Dr. Levine said.
Like ACIP, the state has experts working on plans for prioritization, as well as distribution, and they will be engaging practicing clinicians. “We're going to be working with the whole spectrum of our health care environment in Pennsylvania. We'll be working with hospitals and health systems. We're going to be working with private physicians,” said Dr. Levine. “That collaboration on the ground will be so important.”