Although there is broad concern about the rapid pace and oversight of COVID-19 vaccine development, infection preventionists (IPs) are ready to trust the time-honored protocols and process for safety and efficacy, says Connie Steed, MSN, RN, CIC, FAPIC, president of the Association for Professionals in Infection Control and Epidemiology (APIC).

“We need to trust that the medical system will follow the prescribed steps to ensure the safety and efficacy of the vaccine,” says Steed, director of infection prevention and control at Prisma Health in Greenville, SC. “I really can’t imagine our agencies the Food and Drug Administration (FDA) and others releasing a vaccine that isn’t safe.”

Peter Marks, MD, PhD, is director of the FDA’s Center for Biologics Evaluation and Research (CBER), which is responsible for ensuring the safety and effectiveness of vaccines and biological products. In a recent live-streamed interview, he expressed a personal stake in the safety issue.

“We will do what we need to do to get the appropriate safety data to make sure the deployment of any vaccine is safe,” Marks said. “Safety is what keeps me up at night.”

The review process for the COVID-19 vaccines in various trials will undergo the scrutiny of hundreds of FDA career officials working in areas such as biologics quality, biostatistics, and epidemiology, undertaking a meticulous line-by-line review of submitted data, he said.

“We have the ability to do our own analysis and compare it to the company,” he says. “Perhaps there is a certain type of patient that the company included in the analysis that we don’t think should be included. We can leave those out and see if the end result is similar or different between the company’s and our own.”

The tone of Marks’ comments and FDA guidelines suggest an emergency use authorization rather than full licensure will be the first step for a vaccine. “We will look at the safety datasets that come in, and we have made it clear that we want a medium of two months of follow-up for any vaccine that [is submitted],” he said. “While it would be nice to have [longer], we have to balance the safety we get up front with the need to try to save lives with the vaccine. We have a virus that is killing some 1,000 people a day in the [United States], so there is a balance there.”

The White House initially balked at this two-month follow-up period, continuing a pattern of political pressure to fast-track a vaccine that targets healthcare workers as priority one. However, the FDA held fast and the requirement remains in place in a recently issued vaccine guideline.

“Data from Phase III studies should include a median follow-up duration of at least two months after completion of the full vaccination regimen to help provide adequate information to assess a vaccine’s benefit-risk profile, including: adverse events; cases of severe COVID-19 disease among study subjects; and cases of COVID-19 occurring during the timeframe when adaptive (rather than innate) and memory immune responses to the vaccine would be responsible for a protective effect,” the FDA draft states.1

‘Vaccinations Require Trust’

However, distrust still shrouds the vaccine process, driven in part by ancillary incidents like the White House’s tight-lipped response to the president’s illness and a large COVID-19 outbreak at 1600 Pennsylvania Avenue. Rochelle Walensky, MD, MPH, FIDSA, recently put these events in context at a press conference by the Infectious Diseases Society of America (IDSA).

“Public trust is going to be key,” said Walensky, chief of infectious diseases at Massachusetts General Hospital in Boston. “There is a level of public trust associated with what is happening in the White House, but even over the last several months there has been real challenges in public trust of what is going on at the FDA and the CDC (Centers for Disease Control and Prevention). Those potentially could do more damage because we really very much need the science to lead the way. There is a famous line that says vaccines don’t save people, but vaccinations do. Vaccinations require trust.”

The CDC recently reissued previously pulled guidance on airborne transmission of the coronavirus. The CDC now says airborne transmission SARS-CoV-2 appears to have occurred under the following circumstances:

  • Enclosed spaces within which an infectious person either exposed susceptible people at the same time or to which susceptible people were exposed shortly after the infectious person had left the space.
  • Prolonged exposure to respiratory particles, often generated with expiratory exertion (e.g., shouting, singing, exercising) that increased the concentration of suspended respiratory droplets in the air space.
  • Inadequate ventilation or air handling that allowed a build-up of suspended small respiratory droplets and particles.2

The cumulative effect of these backtracks and revisions may create doubt that will be seized on by the nation’s well-established anti-vaccine movement.

“What I am particularly concerned about is that if there’s any rush to judgment about a COVID vaccination if they end trials early, if there is an inadequate safety database that will really energize the anti-vaccination [movement],” says William Schaffner, MD, professor of preventive medicine at Vanderbilt University. “They will come out and say an awful lot about conspiracies between the government and industry, big pharma and wanting to make profits we will hear this very strongly. If it has the taint of political influence, that could really harm us across the spectrum of vaccination.”

A liaison member on the CDC’s Advisory Committee on Immunization Practices (ACIP), Schaffner says there is vaccine skepticism even in the medical community. “I don’t just mean doctors I mean nurses and other staff about the process whereby vaccines will be evaluated both for effectiveness and safety,” he says. “I’ve had exchanges with people through email and phone, and virtually everyone around the country is saying, ‘We are seeing medical colleagues express both annoyance and real skepticism about the vaccine evaluation process.’ Even among healthcare workers, we are going to have to do an awful lot of education, provide data and reassurance, in order for them to take the vaccine.”

However, a thorough review by FDA scientists could bridge the gap between skepticism and trust, particularly if the eventual vaccine is recommended by the agency’s highly regarded Vaccines and Related Biological Products Advisory Committee, he says.

“If that committee speaks to the American public and says we have reviewed this and think it is appropriate to go forward for emergency use authorization, I think practicing doctors, nurses, and others will take much comfort and reassurance in that,” he says.

Any vaccine release will include a pharmacological vigilance plan that will follow those immunized through claim databases linked to medical records, Marks said. “We see if there are issues arising in real time as these vaccines are deployed,” he said. “The FDA will do that in collaboration with the CDC.”

The CDC will conduct text-message monitoring of healthcare workers and other vaccine recipients through a program called the Vaccine Safety Assessment for Essential Workers (V-SAFE). The existing Vaccine Adverse Event Reporting System (VAERS) also will include a COVID-19 vaccine component. That includes a requirement that COVID-19 vaccine-related deaths must be reported in one day, serious incidents in three days, and non-serious reports within five days.

Editor’s note: There is a precedent for a disastrous rollout of a pandemic vaccine. In 1976, the H1N1 “swine flu” vaccine was linked to paralysis and fatalities in a pandemic that never materialized after an initial cluster of infections.3 One adverse effect of that vaccine was an increase in Guillain-Barré syndrome (GBS), a rare autoimmune disease in which the body turns on its own nerve cells. In 1976, public health officials immunized more than 40 million people with a newly developed vaccine. There were several hundred cases of GBS that included about 30 deaths, prompting the enduring observation that the vaccine killed more people than the disease did. The adverse reactions were not fully recognized until a large rollout of the vaccine program, which then was halted.

Healthcare Workers on Point

Healthcare workers have been designated as the highest priority group to receive the first safe and effective SARS-CoV-2 vaccine that is cleared for use in the United States, according to ACIP.

The committee used an ethical framework to make what one member described as a series of Solomonic decisions at a Sept. 22, 2020, meeting. “When and if a safe and effective COVID-19 vaccine is approved by the [FDA], healthcare workers would be tier one recipients,” ACIP recommended. “This group includes some 20 million people who work in hospitals, long-term care facilities, assisted living facilities, skilled nursing facilities, outpatient settings, home healthcare, pharmacies, [emergency medical services], public health, and other groups.”

After healthcare workers, the subsequent 1B priority groups for COVID-19 vaccination were open to further refinement, but the order described at the meeting placed non-healthcare essential service workers next, followed by people with high-risk medical conditions, and those over age 65 years.

Some ethical models for pandemic vaccine uptake have broken out frontline medical workers, but ACIP argued for a broader immunization strategy throughout healthcare. The ACIP healthcare category includes those not directly involved in patient care but potentially exposed to infectious agents while working in a healthcare setting.

There was some discussion of voting on the matter at a previous meeting, but ACIP Chair José Romero, MD, FAAP, chief medical officer at the Arkansas Department of Health in Little Rock, said the committee would await weigh-in from the FDA before formally voting.

“Once the data is available from Phase III clinical trials, the ACIP Vaccine COVID-19 Workgroup will conduct an independent review of safety and efficacy data and present policy options to the full committee,” Romero said. “If and when the FDA authorizes or approves a vaccine, then ACIP will have an emergency meeting and vote on vaccine recommendations and populations for use.”

Ethical Principles

An ACIP workgroup reviewed ethical principles by several medical groups on allocating a potential vaccine, concluding that all ranked vaccine administration to healthcare workers as critical to the pandemic response. The ethical standards consulted by ACIP include those by the World Health Organization (WHO) Strategic Advisory Group of Experts (SAGE), the Johns Hopkins Bloomberg School of Public Health, and the National Academies of Sciences, Engineering, and Medicine.

“These are the right principles they take the best components of the SAGE, Hopkins, and [National Academy of Medicine] models,” said ACIP member Peter Szilagyi, MD, MPH, a pediatrics and research professor at the University of California in Los Angeles. “I think one of the challenges we are all facing and this feels very much like a Solomon’s choice we have to remember that over [time], the vaccine supply will go up. What we are really talking about is making the decisions for shorter time periods. One of the challenges we feel is that there is a wide diversity of risk even in all of these groups. Even in the healthcare group, essential workers, and those with chronic conditions, there is a wide diversity of risk.”

Given the unknowns, the emphasis on safety and trust must be underscored throughout the process, said ACIP member Grace M. Lee, MD, MPH, of Stanford University.

“I agree that it is challenging to communicate around vaccines and vaccine confidence without actually having the clinical trial data in hand,” she said. “But I still think that perhaps what we can do is continue to emphasize the process for decision making and how much emphasis we are all placing on transparency.”

With transparency placed as the key structural underlying principle, ACIP ethical reasons for selecting healthcare workers as priority one recipients of COVID-19 vaccine included multiple factors, such as maximizing immunization benefits essential to the pandemic response as well as equity, since healthcare has a high degree of representation of minorities and low-income workers. (See “Ethical Framework for Prioritizing Healthcare Workers for Vaccine.”)

In that regard, healthcare workers have paid a high price for holding the line against the pandemic. In what is likely a substantial undercount, the CDC reports that between Feb. 12 and July 16, 2020, there were 100,570 COVID-19 cases in healthcare workers and 641 deaths reported in the United States.4 General trends in COVID-19 in healthcare mortality include the deaths occurred in those who were older, male, Asian, Black, and with an underlying medical condition, the CDC reported. The agency cobbled together data from various reporting systems and methods, and some data reflect only the subset provided by forms and limited public health jurisdictions.

“Compared with nonfatal COVID-19 [healthcare personnel] cases, a higher percentage of fatal cases occurred in males (38% vs. 22%), persons age 65 years (44% vs. 4%), non-Hispanic Asians (20% vs. 9%), non-Hispanic Blacks (32% vs. 25%), and persons with any of the 10 underlying medical conditions specified on the case report form (92% vs. 41%),” the CDC reported.

“In terms of feasibility, large health systems have occupational health departments to facilitate vaccine clinics,” said Kathleen Dooling, MD, MPH, a member of the ACIP workgroup and a medical officer in the CDC’s division of viral diseases.

Healthcare facilities also may have freezers, if needed, for cold storage of vaccines. Another plus is that healthcare workers have fairly high rates of influenza vaccine acceptance.

“However, it will be more challenging to reach rural healthcare facilities, long-term care, small independent clinics, and home healthcare workers,” Dooling said.

Medical workers also have high scientific literacy, a factor ACIP weighed in favor of beginning with healthcare overall.

Social Vulnerability

Although healthcare workers may be more open to vaccine receipt than members of the public, particularly vulnerable minority populations, the theme of distrust in the process and the ultimate vaccine that emerges was a common thread throughout ACIP discussions. ACIP Chair Romero warned vaccine hesitancy and distrust was going to be an ongoing issue.

“I can only speak from my experience within the advisory groups from our department of health for underrepresented minorities,” he said. “There is an extreme disconfidence in this vaccine disconfidence. I have been trying to reach out to the Latino population primarily by having specific, targeted talks with the leaders of that group. I think we need to begin these now if there is to be any sense of confidence in the vaccine among the minority populations.”

Given this backdrop, one ACIP member said the federal government’s name for its vaccine development push is unfortunate.

“The title ‘Operation Warp Speed’ scares a lot of people,” said Lynn Bahta, RN, MPH, CPH, an immunization consultant in the Minnesota Department of Health in Saint Paul. “It would be helpful if our national leaders at the FDA and CDC could talk about what that means in plain language. [That] might help people with some of the anxiety that we have been hearing about vaccinations for COVID-19.”

The challenge of gaining trust was underscored by a presentation showing how maps of COVID-19 cases and hospitalization virtually mirror maps of ethnic minority and poverty indicators.

In that regard, Megan Wallace, DrPH, MPH, described the Social Vulnerability Index (SVI), which was developed by the CDC to identify communities that need support before, during, and after public health emergencies. The index uses a measure of social determinants of health using census data and ranks each county and census tract on 15 social vulnerability factors. Counties with the highest social vulnerability had greater risk of being a COVID-19 hotspot compared to counties with the lowest social vulnerability. Racial and ethnic minority groups represent 40% of the total U.S. population, but nearly 60% of COVID-19 cases, Wallace said.

“We need to be very proactive in our educational pieces to reach out to our racial and ethnic minorities, our essential workers and people with low economic means,” said Sandra Fryhofer, MD, an ACIP liaison member representing the American Medical Association.

Historical context is important. Researchers even some ostensibly representing the government have enacted egregious experiments on minority and vulnerable populations. To cite one of the most infamous, the Tuskegee, AL, syphilis experiment studied the progression of the disease in elderly black men from 1942 to 1972, continuing decades after safe and effective treatment was available in the 1940s.

The National Medical Association (NMA), a group of Black physicians with broad representation in public health, has established a taskforce to weigh in on the safety and efficacy of a COVID-19 vaccine and provide recommendations to their respective communities.5

“We do have a crisis in vaccine confidence now,” the FDA’s Marx said. “There are a lot of factors that have led to that, but our job at FDA is to do whatever we can through transparency and make it clear for one purpose only to make sure we get a quality, safe, and effective vaccine and people can see transparently that is what is happening here.”

A vaccine with 70% to 80% efficacy given to 70% to 80% of the population would give the country “a chance of having herd immunity,” he said. “But it is only going to happen if people have confidence enough to get vaccinated.”

REFERENCES

  1. Food and Drug Administration. Emergency Use Authorization for vaccines to prevent COVID-19. Oct. 9, 2020. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/emergency-use-authorization-vaccines-prevent-covid-19
  2. Centers for Disease Control and Prevention. Scientific Brief: SARS-CoV-2 and potential airborne transmission. Updated Oct. 5, 2020. https://www.cdc.gov/coronavirus/2019-ncov/more/scientific-brief-sars-cov-2.html
  3. Fineberg HV. Swine flu of 1976: Lessons from the past. Bull World Health Organ 2009;87:414-415.
  4. Hughes MM, Groenewold MR, Lessem SE, et al. Update: Characteristics of health care personnel with COVID-19 — United States, February 12-July 16, 2020. MMWR Morb Mortal Wkly Rep 2020;69:1364-1368.
  5. National Medical Association. NMA forms COVID-19 Task Force Take the Politics Out of Vaccine Development. Sept. 21, 2020. https://www.nmanet.org/news/527978/NMA-Forms-COVID-19-Task-Force-Take-the-Politics-Out-of-Vaccine-Development.htm