With the first vaccine for SARS-CoV-2 on the horizon and targeted for healthcare workers, there are safety concerns and trust issues that threaten to undermine immunization. However, all new vaccines are followed closely for adverse effects, and the oversight of COVID-19 immunization will include multiple systems of passive and active surveillance.

Addressing the widespread public mistrust in the vaccine development at “warp speed,” an immunization expert and Food and Drug Administration (FDA) advisor said pressures, political and otherwise, to rush the process will not undermine stringent review for safety and efficacy.

“There has been so much attention on that fear that I just don’t think it’s going to happen,” Paul Offit, MD, said recently at the IDWeek 2020 infectious disease conference. “I am optimistic that there are things in place now between the data safety monitoring boards and the FDA Vaccine Advisory committee that is not going to happen.”

Offit is director of the Vaccine Education Center and an infectious disease physician at Children’s Hospital of Philadelphia. 

“I am a member of the FDA’s Vaccine Advisory Committee as well as the data safety monitoring board,” he said. “Both [boards] are composed of people who are academicians, clinicians, and researchers. These people are not associated with the government or the pharmaceutical industry. I think they will give a clear, unvarnished, honest opinion of what they think about these vaccines. So, I really don’t think that a vaccine that is inadequately tested for safety and efficacy will be given to the American public.”

Even if the vaccine is found safe, there will be people who refuse immunization. Historically, there are essentially two groups — vaccine skeptics and antivaccine activists, Offit said.

“Vaccine skeptics are people who are reasonably concerned that the speed with which we are developing this vaccine is unprecedented,” he said. “We just had this virus in hand really in January and now within roughly a year we are going to have a vaccine. That’s the fastest vaccine that has ever been made.”

In addition, the messaging of doing something potentially dangerous at “warp speed,” along with media descriptions of a “race to a vaccine,” have “made people nervous,” Offit said. “I do think we are going to have to explain these vaccines to people.”

Antivaccine activists have adopted belief systems beyond science and reason, and therefore can’t be reached using them, he added.

“These people aren’t skeptics — I think they are cynics,” he said. “They just believe the pharmaceutical companies control everything and they are not going to believe anything you have to say.”

Science Denial, Neural Connections

In general, low public scientific literacy and accompanying conspiracy theories have undermined the COVID-19 response in the United States, the author of new paper noted. Although this effect tends to diminish with level of education, “low science literacy cause[s] otherwise rational and competent people to misunderstand the threat of COVID-19 and allow[s] them to feel more comfortable with false data,” wrote Bruce L. Miller, MD, director of the Memory and Aging Center at the University of California, San Francisco.1

“Beliefs grounded in false information, just like those grounded in truth, have neural origins and reflect connections in dedicated brain circuits,” Miller stated. “Individuals are organized to hold beliefs and to evaluate their merit based on facts and experiences. Studies of neurodegenerative disorders that target selective brain networks shed light on the neural mechanisms that underlie the creation and sustenance of beliefs that are not based in reality.”

To prevent such “science denial,” the medical community should strongly emphasize science education beginning in childhood, he said. For now, scientists, clinicians, and public health experts should engage in dialogue on issues of public health, such as masks, vaccines, and medications.

“A systematic analysis of ‘what went wrong’ with COVID-19 policies during and after this pandemic is the responsibility of the scientific community,” Miller emphasized.

Touching on this theme at IDWeek, Michael Ryan, MD, MPH, director of the health emergencies program at the World Health Organization, said an “infodemic” is occurring in conjunction with the pandemic. Part of the reason there is “this information and disinformation is [people] have had to face the endemic with the sense of being on their own,” he said. “In fact, there is a sense of fatigue and in some cases hopelessness for the future in terms of what can be done to stop this virus.”

Going forward, public health officials need to acknowledge publicly the information gaps and challenges, he said.

“We have to get much better at filling those channels with good information,” Ryan said. “We need to work on our side to make it the place where people come to get information. The world has changed, and disinformation is part of that. We need to be aware and track that. We don’t need to be turning this into another combat between us and the bad people who put out the misinformation. A lot of that misinformation is genuinely held belief and therefore can’t be countered by scolding and censoring.”

Social and behavioral sciences can help understand these attitudes and beliefs.

“It’s not about who wins the information,” Ryan said. “It’s who wins the trust war, the behavioral war.”

Although he did not criticize the Centers for Disease Control and Prevention (CDC) specifically, Tom Frieden, MD, MPH, former director of the agency under the Obama administration, described critical aspects of public health messaging that have been conspicuously lacking under current CDC leadership.

“Communication is crucial and at CDC, your principles are be first, be right, be credible,” he said at IDWeek 2020. “It is so important to epidemic response. Tell people what you know and tell them how you know it. Tell them what you don’t know and what you will do to figure it out. Consistent, sincere, transparent. Give people concrete, practical things to do to protect themselves, their families, and their communities.”

The CDC has issued, revised, and recalled recommendations under political pressure, some believe.

“I think we have to recognize that there are some things we can control and some we can’t control,” Frieden said. “We need clear communication. We need to be speaking regularly to the public day in and day out in plain language, transparently, telling them what we know and don’t know.”

Close Follow-up on Vaccinations

That includes multiple systems of follow-up and surveillance after the first approved vaccines are administered. Healthcare workers have been designated by the CDC’s Advisory Committee on Immunization Practices (ACIP) as the first group to receive a safe and effective SARS-CoV-2 (COVID-19) vaccine cleared for use in the United States. About 10% of healthcare workers with COVID-19 develop serious infections, with outcomes including hospitalizations, intensive care, and death. Beyond the clinical consequences, healthcare workers report for duty knowing that they may be endangering their own lives and those of their families, colleagues, and patients.

“Our healthcare workforce is exhausted,” said ACIP member Grace Lee, MD, MPH, a frontline pediatrician and professor at Stanford University. “The constant worry about COVID is just hanging over us as we are caring for patients and [interacting with] their family members. It’s going to be one really important strategy and it will give us a sense of enhanced protection. It won’t take away the need for us to continue to use personal protective equipment (PPE), but I feel like it will give me an extra layer of confidence that if I don’t do everything perfectly all of the time then I am putting myself and my family at risk. I think that is what gets exhausting.”

Although the post-election nation still is divided on the issue, there has been prior suggestions that a Biden administration would attempt a mask mandate for the public. A recently published paper by Anthony Fauci, MD, said wearing masks will be critical if the vaccine efficacy is suboptimal or the uptake is low.

The director of the National Institute of Allergy and Infectious Diseases, Fauci recently coauthored a paper that said “multiple lines of evidence support the effectiveness of masks for the prevention of SARS-CoV-2 transmission.2 Mandates for the wearing of masks in public have been associated with a decline in the daily growth rate of COVID-19 cases in the U.S. The implementation of such mandates averted more than 200,000 cases of COVID-19 by May 22, 2020, according to modeling estimates.”

Other “low-tech” measures to prevent SARS-CoV-2 include physical distancing, hand hygiene, and limiting crowds and gatherings. “If a vaccine has only moderate efficacy, or if vaccine uptake is low, these … modalities will be even more critical,” Fauci and colleagues noted. “Wearing face coverings — masks — in the community setting to prevent the spread of SARS-CoV-2 is a key component of this combination approach.”

The sheer size of the COVID-19 vaccine clinical trials will enhance prelicensure safety and efficacy evaluation, and a number of post-market evaluations are being put in place to bolster existing surveillance for adverse events.

“The FDA typically advises a minimum population size of approximately 3,000 individuals for prelicensure assessments of vaccine safety,” Lee and colleagues said in a new paper.3 “In contrast, Phase III clinical trials for COVID-19 vaccines are enrolling or plan to enroll between 30,000 to 50,000 individuals each, providing the largest databases on prelicensure vaccine safety to date and an opportunity to better understand safety profiles within and across vaccine candidates prior to approval.”

“These are some of the biggest trials we have seen,” she says. “The reason for the size of these trials is really for the speed [of vaccine development], because they need to detect an efficacy signal of at least 50% with a lower boundary of 30%. Because of the need for the high numbers, it actually is a great opportunity for vaccine safety.”

Typical Phase III trials with a much smaller number of participants may take many years to parse this data out, she notes.

“One way to gain [statistical] power is by following people for a long period of time,” she says. “And the other way is to really focus on high numbers and make sure you are in areas where they are at a high risk of infection, so they can challenge efficacy. It is an advantage for safety because, typically, we don’t see trials of this size that capture safety data.”

In the United States, eight vaccine candidates have received federal support under Operation Warp Speed, and four have entered Phase III trials.

“Vaccines will be critical for the prevention and control of COVID-19 in the U.S. and worldwide, yet these efforts cannot succeed without public confidence in a vaccination program,” Lee and coauthors emphasized. “Demonstrating vaccine efficacy and safety during clinical trials and implementing a robust post-licensure vaccine safety monitoring system as the vaccine is deployed in larger, more diverse populations is central to public confidence and enabling timely and accurate policy decisions for population-level use.”

FDA Follow-up Ratio Questioned

Lee questioned if the FDA fell short in requiring submitted vaccine data to include a median of two months follow-up for at least 50% of the population.

“I wish it were all of the population,” she says. “[The FDA] means if you have 30,000 trial participants, 15,000 of them would have two months follow-up at a minimum.”

One surveillance system that will be used is the CDC’s National Healthcare Safety Network (NHSN), which primarily conducts surveillance for healthcare-associated infections in hospitals and long-term care facilities.

“NHSN routinely collects annual aggregate data on healthcare personnel influenza vaccination rates and is currently exploring the additional capture of COVID-19 vaccination rates,” the authors noted. “Capabilities for enhanced monitoring of early COVID-19 vaccine recipients (e.g., essential workers) through smartphone or web-based surveys are also being developed to capture potential adverse events following vaccination.”

Although the larger vaccine trials will capture a lot of prelicensure safety data for short-term adverse events, “they won’t speak to anything long-term,” Lee says. “As each of these trials go on, they will potentially be submitted to the FDA at different time points, so all of that data wouldn’t be available immediately, but cumulatively over time we would start to see from the various vaccines that might come in.”

Adverse events of special interest related to vaccines include allergic reactions, Guillain-Barré syndrome, transverse myelitis, myocarditis/pericarditis, vaccine-associated enhanced respiratory disease, and multisystem inflammatory syndrome in children. Vaccine safety systems include the longstanding Vaccine Adverse Event Reporting System (VAERS), which is passive surveillance in that it relies on clinicians, manufacturers, and public reports. “VAERS is comanaged by the FDA and CDC and serves as an early warning system for potential safety signals that may be temporally related to vaccines,” the authors noted. “The rapid identification of an intussusception signal after widespread use of rotavirus vaccines in infants exemplifies the essential role of passive surveillance in the U.S.”

Active systems include the Vaccine Safety Datalink, a three-decade partnership between the CDC and nine healthcare systems. The system collects healthcare encounter data and electronic medical records to capture vaccine outcomes in more than 11 million patients. Datalink has “near real-time capabilities for signal detection, signal refinement, and signal evaluation … These well-established active safety surveillance systems form the foundation of monitoring COVID-19 vaccine safety,” Lee and coauthors concluded.

Regardless, some level of risk is part of any medical intervention, and much of life for that matter, Lee says.

“There is the question of benefits and risks to a population, and there is the question of the benefits and risks to an individual,” she says. “You have to weigh the benefits and the risks to make sure, and you try to mitigate those risks as much as possible. We also see, for example, that there are vaccines that have local reactions and systemic reactions. For example, zoster vaccine can be quite reactogenic. A lot of people get pretty significant local side effects, like tender and swollen arms at the site of the injection, or some people get low-grade [temperatures] and myalgias.”

REFERENCES

  1. Miller BL. Science denial and COVID conspiracy theories: Potential neurological mechanisms and possible responses. JAMA 2020; Nov. 2. doi:10.1001/jama.2020.21332. [Online ahead of print].
  2. Lerner AM, Folkers GK, Fauci AS. Preventing the spread of SARS-CoV-2 with masks and other “low-tech” interventions. JAMA 2020; Oct. 26. doi:10.1001/jama.2020.21946. [Online ahead of print].
  3. Lee GM, Romero JR, Bell BP. Postapproval vaccine safety surveillance for COVID-19 vaccines in the US. JAMA 2020; Oct. 16. doi:10.1001/jama.2020.19692. [Online ahead of print].