There are currently over 140 SARS-cov2 vaccine candidates (here’s the full list). Many of those will likely fail at some point due to lack of funding, poor efficacy, or unacceptable side effects but it is hoped that sufficient number will complete phase III trials and be acceptable to the regulatory authorities. It’s understandable to hope that a vaccine might do more than protect us from COVID-19 pneumonia. Most of us hope a vaccine could give us back life as we once knew it. Pay close attention, because the devil, as always, is in the details. Let’s begin by looking at how vaccine trials are conducted.

 

Vaccine Trials: How they Work

Vaccine trials are in many ways similar to therapeutic drug trials. They need to have satisfactory results from three phases following acceptable exploratory and pre-clinical stages:

  • Phase I: A relatively small group of healthy people are exposed to the vaccine (various dosage regimens) and monitored for adverse events.
  • In Phase II: The vaccine is given to people who have characteristics similar to those for whom the new vaccine is intended (e.g. age and physical health) and both safety and efficacy are tracked. (Efficacy means a sufficiently robust immune response that following exposure to the pathogen, the effects of the pathogen are minimized.)
  • Phase III: These trials involve several thousand subjects and nearly always are randomized controlled trials, sometimes involving a placebo, depending on whether the vaccine is the first of its kind to be used in the context of a pathogen-induced disease. Both safety and efficacy are followed.

 

It goes without saying that each phase must be successful before proceeding to the next phase.

 

In the US, The FDA’s Center for Biologics Evaluation and Research (CBER) is responsible for regulating vaccines and the sponsor (that’s the organization manufacturing the vaccine) must follow a multi-step approval process. Typically, it includes:

  • An investigational new drug (IND) application
  • Pre-licensure vaccine clinical trials (as outlined above)
  • A biologics license application (BLA)
  • Inspection of the manufacturing facility
  • Presentation of findings to FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC)
  • Usability testing of product labeling

 

Once a vaccine is approved, the FDA continues to oversee not only its manufacture but adverse events generated by its use through the Vaccine Adverse Event Reporting System (VAERS), a national vaccine safety surveillance program cosponsored by the CDC and FDA, with manufacturers, as well as physicians, nurses, and individuals able to provide data via a secure system.

 

Normally, it takes 10-15 years from the time the vaccine is first conceived to administration in patients, although the Ebola vaccine, known as rVSV-ZEBOV, was approved in 2019 after 5 years of research, which was considered a breakneck pace. Obviously if it takes 5 years to develop a COVID-19 vaccine, it will not be available in time to provide any serious help (because given how infectious it is, after 5 years nearly everyone will have already been infected). To develop a vaccine in less than 5 years, it is necessary to use a lot of shortcuts.

 

Efficiency of Vaccines: Fast and Loose?

While the time frame for development and testing can reasonably shortened be under emergency conditions (and obviously the current situation qualifies as an emergency), let’s be clear: there are huge risks to approving a vaccine within a year or less. These risks must be weighed against the potential pay-offs of curtailing the pandemic so we can return to some kind of normalcy. The FDA has recently outlined its guidance to industry, as well as its Emergency Use Authorization (EUA) and accelerated approval in regard to vaccines. In the words of the FDA Commissioner, Dr. Stephen Hahn: ““We have not lost sight of our responsibility to the American people to maintain our regulatory independence and ensure our decisions related to all medical products, including COVID-19 vaccines, are based on science and the available data. This is a commitment that the American public can have confidence in and one that I will continue to uphold.” There’s no doubt that in the months to come he will be under tremendous pressure to grant accelerated approval for at least one vaccine. That pressure includes approving vaccines that may be marginal with regard to efficacy and safety. There have already been missteps with regard to COVID related EUAs. The FDA already made one big U-turn on hydroxychloroquine, two-and-a-half months after granting an EUA for it. Also, in retrospect, the EUA for several COVID-19 testing kits might have been poor decisions given the fact there were several withdrawals of products after initial approval.

 

Traditionally, phase III outcome data (vaccine efficacy) are expressed as a proportionate reduction in disease attack rate (AR) between the unvaccinated (ARU) and vaccinated (ARV) study cohorts. It is calculated from the relative risk (RR) of disease among the vaccinated group with use of the following formulas: Efficacy = ((ARU – ARV)/ARU) x 100) or Efficacy = (1-RR) x 100.

 

Normally the “bar” for efficacy, at least in terms of FDA approval depends on what type of infectious disease the vaccine is aimed at preventing. In this instance the FDA has made it very clear to sponsors that it expects any vaccine to be at least 50% effective in a placebo-controlled trial, with an adjusted lower bound of >30%. That’s on a par with many flu vaccines, but there are many arguments as to whether the bar is too low or in fact too high. We won’t really get a sense of whether the bar has been set correctly until several vaccines have finished their phase III trials. I suspect the efficacy bar should be higher than 50% if vaccines are going to make a serious impact on the pandemic, but I’m also sure that we’re all going to learn from this process regardless of how it turns out.

 

Real world vaccine effectiveness (meaning, not how it performs mathematically but ACTUALLY in the population), is proportional to vaccine efficacy but affected by how well target groups in the population are immunized. In other words, there are issues that can reduce how well the vaccine actually works that are NOT due to whether it CAN work.  For example, there may be difficulties in maintaining the proper cold storage conditions of the vaccine, problems with access to the vaccine, barriers related to vaccine cost, and many other nonvaccine-related factors. Together these influence the real-world outcome of the vaccination, measured in terms of number of people hospitalized, outpatient doctor visits and the cost of COVID related illnesses. We won’t know the real-world vaccine effectiveness based on the above parameters until it’s been in the field for many months. As I’ve discussed in a previous blog, a lot of people in the USA are vaccine-averse. If a person people does not support the use of a vaccine with a high rate of efficacy and an incredibly low rate of adverse events that has been proven to prevent deaths in children, they will not support a COVID-19 vaccine. If COVID-19 vaccination rates are low, it is sure to have a negative effect on outcome because, absent vaccination, it will take a much longer period of time for COVID infection caseloads to come down to manageable levels..

 

Vaccine Safety: Perceptions Versus Reality

We also need to understand the safety profile of a vaccine, which is a complicated story. Let’s begin with the results from a phase III trial. While many parameters are collected to evaluate adverse events (AEs), two key items are the severity and relatedness (causality) to the treatment. A common severity scheme used is CTCAE v4

Table 1: AE Severity Grading Scale

Severity Grade

Description

Mild (1)

Awareness of sign, symptom, or event, but easily tolerated; does not interfere with usual daily activities or tasks.

Moderate (2)

Discomfort enough to cause interference with usual daily activity.  It may warrant therapeutic intervention.

Severe (3)

Incapacitating; inability to perform usual activities and daily tasks; significantly affects clinical status; requires therapeutic intervention.

Life-threatening (4)

Emergency treatment required, life-threatening, death.

 

As an example, since I am over 65 years of age, I was vaccinated against pneumonia. I got the PC13 shot first and then the PPSV23. Following the first shot I got just a little localized aching which probably wouldn’t have qualified as a mild AE. The second vaccination was a different story: I felt like I had nasty flu for about 3 days which would have qualified as a 2 on the above scale.

 

In terms of relatedness, here are the definitions (I’ve truncated them quite a bit for space reasons but you get the picture).

 

Table 2: AE Relatedness Scale

 

Severity Grade

Description

Not Related

No relationship exists between the AE and the clinical investigation procedure or medical treatment. The event is attributed to a pre-existing medical condition or an inter-current event unrelated to the clinical investigation procedure or medical treatments. Another cause of the AE is more plausible

Possibly Related

Follows the clinical investigation procedure or medical treatment, but may have developed as a result of an underlying clinical condition or treatments / interventions unrelated to the clinical investigation.

Probably Related

Follows the clinical investigation procedure or medical treatment, but is unlikely to have developed as a result of the subject’s underlying clinical condition or other treatment or other interventions.

Definitely Related 

Follows the clinical investigation procedure or medical treatment and physical evidence shows a convincing relationship to the study procedure or medical treatment and/or the event cannot be reasonably explained by another cause.

 

Judging the relatedness requires much judgment and expertise, but going back to my own injections, because the symptoms started later in the day after the injection, one could easily say that the AE was definitely related to the vaccine (the chances that I got the flu at exactly the same time as the vaccine are low). However, sorting out an AE that happens several months after a vaccine injection is not nearly so simple.

 

Finally, we have serious adverse events defined very briefly as any AE that:

  • Results in death
  • Leads to a serious deterioration in the health of the subject
  • Leads to fetal distress, fetal death, or a congenital abnormality or birth defect.

 

There are several safety issues that that could be problems for any potential COVID-19 vaccine. First, immediate side effects. If there are a substantial percentage of AEs (rated as 2 or 3 in terms of severity) this may affect the perception of young adults that the vaccine isn’t worth it. Currently, many of them do not care about the consequences of the virus because for most of them, it causes little or no symptoms, so why would they take something they know might well make them very sick for a while?

 

Second, there is the phenomenon of ADE (antibody-dependent enhancement), which we have talked about before. We can consider it the result of a priming effect in which the immune response to the virus is incomplete and allows the virus a much better entry into the human body the second time around, rather like giving the codes of your home security system to a burglar. If they do occur, ADE issues are most likely to take place after vaccination because of challenges to different coronavirus strains months or years down the line. While vaccine makers are fully aware of the issue we won’t know whether this phenomenon will turn out to be a nothing burger or a major disaster until millions have been vaccinated and we have a year’s post-market safety data to sift through.

Next there are the SUSARs: suspected serious unexpected adverse reactions. Typically, these are quite rare, and develop months, sometimes years after the administration of the vaccine. Proving that a type of SUSAR was not linked to vaccination is an arduous exercise, and these days resolution of such events has become even more clouded in the public’s perception due to previous controversies, such as autism and thimerosal, a mercury-based preservative that was used in many vaccines.

Finally, there is the issue of contaminants. Although most vaccines have a good track record in this regard, that’s not always been the case.

In part 2, we’ll look at some leading COVID-19 vaccine contenders, take a deeper dive into their mechanisms of action, examine the timeline of vaccinations, and sum up the most likely outcomes.

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