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Vaccine Emergency Use Authorized!

The recommendation vote was not unanimous, but it was a clear message and the FDA moved quickly. Overall, the vaccine profile looks good, but some unknowns deserved more attention.


The FDA process (covered in our last post) delivered on its promise to provide enough information to better understand what we know, what we don’t know, and how to make the right call about getting immunized. At the moment, the only people who need to be personally concerned about making the right call are those who will be offered vaccination in phase 1a of the rollout (and that includes one of us here at Public Health Rising!). This phase accounts for more than 20 million health care workers and residents of long term care facilities, and by the time we are ready to move on to subsequent phases we will have the volume of data that will allow us to reach pretty solid conclusions about real-life vaccine efficacy and safety. In the meantime, FDA has determined that benefits outweigh risks. And this is how we talk about “safety” -- it’s always relative (benefit vs. risk) and there is no definitive level at which something is perfectly “safe.”


Benefits are pretty clear: the vaccine almost certainly offers excellent protection against COVID disease (we’re not as sure to what extent it prevents infection with few or no symptoms). Efficacy findings have been consistent across age, sex, race, ethnicity, underlying comorbidities, and even across different manufacturers (Pfizer and Moderna), which is really reassuring. Your potential benefit from immunization is magnified as your potential for COVID infection and severe disease increase. Returning to how we talk about safety: for an individual, higher potential benefit may mean that immunization makes sense, even if the vaccine has a higher risk profile. That same vaccine wouldn’t make sense for someone who may not get much benefit (e.g. younger, healthy, not exposed to COVID through work). We agree with an emergency use authorization (EUA) that makes this vaccine available for those who will potentially have significant benefit from immunization in phase 1a.


The other side of the equation -- risk -- is where we have most of our doubts. Why were there “no” votes from the FDA committee, recommending against an EUA? Some were likely driven by age cutoffs. One piece of the picture that became clear was how little we know about immunizing people under age 18, while the vote before the committee covered ages 16 and older. Additional “no” votes may have been related to concerns about hypersensitivity. This is a known and manageable issue for immunization programs, but preliminary reports emerging from the UK have raised concerns about vaccine-associated allergic / hypersensitivity reactions, and little definitive information has emerged so far.


Two other concerns were raised but are not likely considerable safety threats and did not seem to drive the “no” votes. First, antibody-dependent enhancement. This phenomenon can make future illness (with COVID or a related virus) paradoxically worse in those who were vaccinated. If this were occurring, we likely would have seen evidence emerge based on the number and duration of the trials so far. But there is no guarantee this will not emerge in the future. Considering the current and present danger of COVID, it seems fair that this hypothetical concern did not dissuade committee members from supporting rollout of the vaccine. Second, this vaccine is very reactogenic, which refers to the tendency of a vaccine to trigger fever, headache, etc. (but, importantly, these are not allergic / hypersensitivity responses). COVID vaccine recipients reported injection site reactions (84.1%), fatigue (62.9%), headache (55.1%), muscle pain (38.3%), chills (31.9%), joint pain (23.6%), and fever (14.2%). These are very high figures, much higher than you would see, for example, with a flu vaccine. Again, not a clear safety threat but an important element to understand about this vaccine.


Finally, some the “no” votes may have been driven by greater unknowns, specifically related to the mRNA vaccine technology. It’s the first time this type of vaccine will be administered to so many people. No RNA vaccine has ever before received an EUA, let alone a full license. We’ll cover vaccine technology in a future post, especially as different vaccines start coming before the FDA for additional EUA’s. But for now, the main thing to know is that COVID RNA vaccines are an elegant solution: they put the code (messenger RNA, or mRNA) for a tiny part of the COVID virus into a lipid drop which allows the mRNA to get into our cells, and the cells then translate that code into one of the key COVID proteins that immune cells recognize (that’s the spike protein, and those immune cells generate antibodies against it). So, if mRNA vaccines are so great, why haven’t they been used before? There is nothing too scary in the answer: decades of research, technical breakthroughs, and experimentation were required to even get us to this point. This background work gave Pfizer (and Moderna) a good starting point to figure out how to make an effective mRNA COVID vaccine. And COVID is not the only disease being tackled with mRNA vaccines: Moderna alone has at least a handful of human trials underway. The mRNA vaccine technology is new as an authorized vaccine, but not exactly new in the broader sense.


But all of this adds up to a limited body of knowledge when it comes to knowing what will happen when we start vaccination at the population level. Dr. Paul Offit, a vaccine expert and member of the FDA committee who voted “yes” to recommend the EUA, likes this quote from Maurice Hilleman: “I never breathe a sigh of relief until the first 3 million doses are out there.”

Beyond needing more information on age cutoffs and hypersensitivity, as mentioned above, there was only brief discussion of Bell’s palsy, which is temporary weakness or paralysis of the muscles in the face. FDA noted four cases in the vaccine group, compared to zero cases in the placebo group, and concluded that “there is no clear basis upon which to conclude a causal relationship at this time, but FDA will recommend surveillance for cases of Bell’s palsy with deployment of the vaccine into larger populations.” Side note: it appears FDA alone identified this issue, which they labeled as a non-serious adverse event. We could not locate any meaningful reference to Bell’s palsy in Pfizer’s report or presentation to the FDA committee. This is good work by FDA, and aligned with the transparency and honesty that is necessary for vaccine confidence.


Bell’s palsy is not a show stopper -- it’s not fatal and usually resolves in 2-6 months, although patients can be pretty miserable during this time and there are potential complications. Bell’s palsy has not been a consistent finding in the many mRNA vaccine trials underway, as noted above. But those trials are small; and, remarkably, an earlier trial of an mRNA vaccine against rabies reported, “One unexpected, possibly related, serious adverse reaction” occurred. What was that adverse reaction? Bell’s palsy.


Why did the rabies vaccine researchers believe that the case of Bell’s palsy was related to the vaccine, while the COVID vaccine researchers do not? And why did one team label this adverse as “serious” while the other did not? We’re not sure. This is where the humility we discussed in our prior post comes into play: Bell’s palsy is not well understood. It’s also called idiopathic facial paralysis (idiopathic means unknown cause). If we do see more cases of Bell’s palsy emerge as the COVID vaccine rolls out, it would be reminiscent of what happened when the first vaccine against rotavirus was licensed, in 1998. That vaccine was ultimately found to be associated with a complication called intussusception. At the FDA committee hearing leading up to licensure of the rotavirus vaccine, 5 cases of intussusception were noted in the vaccine group, and none in the placebo group (later, one case was identified in the placebo group). This observation was not attributed to the vaccine, and the conclusion was that the observation was consistent with the general population frequency of intussusception (or background rate). Fast forward to today: regarding Bell’s palsy in the COVID vaccine trial, FDA believes “the four cases in the vaccine group do not represent a frequency above that expected in the general population.” A key difference today is that FDA and Pfizer have committed to careful tracking of Bell’s palsy during COVID vaccine rollout. And to be clear: COVID can be deadly, and rare occurrences of Bell’s palsy would likely not change the benefit vs. risk balance for phase 1a. We’ll see Moderna’s data next week, and will be looking for any related safety concerns.


Putting the pieces together, the benefits of this COVID vaccine outweigh risks for phase 1a rollout, and we’ll have more information that will allow us to recalculate before other phases get underway. The vote to issue an EUA is a great step forward in our pandemic response, and we look forward to seeing immunizations get underway. One of us is in phase 1a, and if the vaccine becomes available tomorrow, our sleeve will be rolled up to take that shot!


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