FDA Panel Reviews Many Challenges Facing a COVID Vaccine

Coronavirus disease 2019 (COVID-19) is the greatest healthcare challenge our country has faced in over a century. Clifford McDonald, MD, from the US Centers for Disease Control and Prevention (CDC) emphasized at the US Food and Drug Administration’s October 22, 2020 Vaccines and Related Biological Products Advisory Committee meeting that the COVID-19 pandemic is 10 to 15 times more deadly than seasonal influenza. During the FDA’s meeting a number of important areas were discussed:

Vaccine Development: One of the central strategies of the United States’ response to COVID-19 is vaccine development. Past vaccines have taken years, possibly decades, to develop. The SARS-CoV2 vaccine is being developed at “Warp Speed.” Two strategies have greatly reduced the time of vaccine deployment.

The first was preparation. There had been abundant research regarding vaccine development with SARS (SARS-CoV-1) and other coronaviruses. When the genetic code for SARS-CoV-2 was made available, the viruses’ protein code could be modified to increase immunogenicity and a Phase I trial vaccine trial was rapidly started in 65 days, instead of taking years to develop.

The second was the selection of 6 promising vaccine candidates for at-risk vaccine production, where doses are produced before trials are completed and results are known. There were two candidates in each of the 3 different technologies which were chosen for this program. The technologies and candidates are: Viral mRNA (Moderna, Pfizer-BioNTech), adenovirus vectors (AstraZeneca, Janssen) and recombinant protein plus an adjuvant (Novavax, GSK-SANIOFI). Most of these vaccines require two doses. However, they are not interchangeable. A patient must receive the same vaccine for each dose. As a safeguard, the patient will be given a vaccine informational card to be shown to his provider before receiving his second dose.

Kevin Kavanagh, MD

Another problem is that the two RNA vaccines which appear to be the furthest along in the development process, require ultra-cold storage {between -70 to -100 degree Fahrenheit} from manufacturer to patient administration. This will be addressed with special shipping containers and probably require dry ice packing.

Vaccine Trial Design: There is no doubt that initial vaccine design and manufacturing has been greatly accelerated. Guidelines for vaccine approval have been released by the FDA. Of concern is the design and duration of Phase II and most critically Phase III Trials. In the past, Phase II and III trials would take on average 30 months each. The trials have explicit parameters to include individuals who are older than 65 year of age, have comorbidities, and of different races.

The goal appeared to be the awarding of an emergency use authorization (EUA) for vaccine deployment as soon as possible. To meet this goal, preliminary data from Phase III trials can be submitted after an “N” is reached of 3000 subjects and with a minimum of 2 months follow-up.

Vaccine Safety: It was asserted that the vast majority of vaccine adverse events occur within the first 6 weeks after the final dose is administered and that a 2 month follow-up would be sufficient for evaluation of safety. However, there will also be extensive post-market surveillance with patients monitored for a minimum of two years.

Post-market surveillance programs will include VAERS along with active surveillance monitoring using the FDA’s BEST system and partnerships with CMS. VAERS is the CDC’s and FDA’s Vaccine Adverse Event Reporting System which is a well-developed and validated system which receives approximately 50,000 reports per year. The BEST system relies on surveying claims data and electronic medical record systems to detect adverse events. There will also be several innovative new systems such as V-Safe which is an interactive text or email messaging check-in system which monitors patients for the first six weeks after receiving a vaccination.

This was very impressive, but of concern. If millions of individuals are given a vaccine in a very short period of time, there is little one may be able to do to prevent harm if post-market surveillance detects a serious problem.

I found the public comments regarding the COVID-19 vaccination evaluation plan very elucidative, even more so than the formal governmental presentations. Many commenters felt the 2-month EUA follow-up period was too short, since significant complications from vaccines, such as vaccine-associated enhanced disease, as immunity wanes. In addition, 3,000 study participants were by many felt to be too few to detect adverse reactions in racial, pregnant and many high-risk cohorts.
Marcus Schabacker, MD, PhD, CEO of ECRI advised that a minimum trial length should be at least 6 months and consist of data from the full cohort.

Vaccine Effectiveness: Commentators included a BMJ Editor, along with prominent researchers and policymakers from Stanford, ECRI and patient advocacy organizations. A central theme emerged, and many presenters echoed the same points of concern, most surrounded the process of EUA for a COVID-19 vaccine and the implications that EUA would have for patient safety and future vaccine development.

1. Of utmost concern of many of the commentators was that the primary endpoint for vaccine efficacy was the prevention of COVID-19. This sounds like a valid approach, but any case of COVID-19, even those with just a mild cough would be counted as being prevented. There was not a requirement to prevent hospitalizations, disability, or deaths.
2. The second concern was that the minimum acceptable vaccine efficacy was set at 50% with a lower error bar set at 30%.
3. The third concern is that minority populations may be underrepresented. And those who are at high-risk for COVID-19, including children, pregnant women and those immunosuppressed may have exceptionally low or absent representation in the data used for an EUA.
4. The minimal number of subjects in a trial used for EUA application was set to 3000, and the minimum number of severe COVID-19 cases to have occurred in the control group was set to 5. There were concerns regarding the definition of “severe”. A patient with a SpO2 < 93% could be classified as severe. However, many asymptomatic patients can have this finding. And some felt that 5 severe cases were too few to reliably differentiate a true finding from a chance occurrence, especially in high-risk sub-cohorts. There were concerns regarding the definition of “severe.” A patient with a SpO2 < 93% could be classified as severe. However, many asymptomatic patients can have this finding. And some felt that 5 severe cases were too few to reliably differentiate a true finding from a chance occurrence, especially in high-risk sub-cohorts.

As a side note, not discussed at the meeting, was the issue of challenge trials. This has been extensively covered in the lay press with challenge trials being planned in the United Kingdom. In a challenge trial, volunteer subjects would be deliberately given SARS-CoV-2 and monitored for the development of COVID-19. There are significant ethical problems with this approach, since there is no known cure for this disease and many of the promising COVID-19 treatments are performing poorly in randomized controlled trials. But of scientific concern is that by their nature, challenge trials have to be performed in young healthy individuals. SARS-CoV-2 is most lethal in the elderly and those with co-morbidities. Thus, an effective vaccine may be found for the young, but not in the elderly with an aging immune system.

Wider Implications of EUA Approval: Once an EUA is granted for a vaccine, several problems arise. First, current clinical trials of the EUA approved and also of other vaccines may have significant subject dropout, as many subjects in blinded studies may choose to obtain the available vaccine. In addition, the approval process would allow for a vaccine with minimal effectiveness in preventing just minor symptoms of COVID-19 to be approved. If this happens, those who have received a minimally effective vaccine may no longer follow public health guidance.

Vaccine Acceptance: A recent Harris Poll found that 78% of respondents feared the COVID-19 approval process was influenced more by politics than science. This was bipartisan with 72% of Republicans and 82% of Democrats being concerned. And 80% would worry how safe the vaccine was if it was quickly approved. Only 58% of individuals stated they would receive a COVID-19 vaccine as soon as one was available. Even more concerning was that the acceptance was even lower in Black Americans, a high-risk population for COVID-19. Major patient concerns were:

• The speed of the process.
• Distrust of government and government agencies, (such as the CDC who has had changing guidance on masks, testing for asymptomatic carriers and viral aerosolization; and the FDA who has had questionable statements regarding the effectiveness of treatments granted EUAs such as hydroxychloroquine and convalescent serum.)
• Respondents wanted recommendations from a well-established reputable organization without ties to government and industry.
• Concerns about political and economic influences along with trying to get the vaccine out before the election.
• Fear the vaccine will not work. (Similar to the influenza vaccine, different dosages may need to be given to the elderly.)
• That the vaccine is being tested on minorities, similar to the Tuskegee Experiments, at the benefit of the sheltered upper class.

Effectiveness Needed

The overall cost for society is far too high for a flawed and relaxed vaccine approval process. If the vaccine has low effectivity and primarily prevents mild disease, it will offer little protection to society and may cause inconceivable harm. To paraphrase Peter Luri, MD, MPH, from the Center for Science in Public Interest—The benefits of a minimally effective vaccine can be negated if the public relaxes wearing masks and social distancing. But even worse, if the vaccine is ineffective, it will further fuel the antivaccine movement for decades to come.