College of
Human
Medicine

Dean's Update | October 8, 2021

Friends,

Third vaccinations with Pfizer’s mRNA vaccine are now available for people more than six months past their second shot and are over 65 years of age or at risk for bad COVID-19 due to an underlying health problem or high risk of institutional or occupational exposure. As of now, additional jabs with Moderna and J&J vaccines are under discussion but are not yet available.

This is a complex subject, and to help discuss the data and the reasoning behind the push for third shots, I’ve invited Keith English, MD, chair of the Department of Pediatrics and Human Development to discuss the topic with me. 

Aron:    
Keith, thanks so much for helping me with this update! I know you have been collecting and reading the COVID-19 studies from the beginning of the pandemic. And, if I recall from a Zoom meeting, you are collecting old-school, with paper! Anything you see in the COVID-19 literature that you think we should be following?

Keith:   
More and more evidence continues to accumulate regarding the remarkable efficacy and safety of the available COVID-19 vaccines, especially the two mRNA vaccines (from Pfizer and Moderna). Pediatricians (and parents) are anxiously awaiting FDA review of the Pfizer data regarding immunization of children 5-11 years at the end of the month. As medical professionals, the most important thing we can do to stem this pandemic is to encourage our patients and our family and friends to GET IMMUNIZED!!!

Aron:    
OK. Let’s go to the third shot/booster questions. Why do we use multiple shots and what are additional shots supposed to do for us?

Keith:   
There are THREE reasons why a third dose of vaccine might be needed:

  1. The first reason is that immunocompromised people may not have responded to the first doses (primary vaccine failure) or responded with a weak and transient response (resulting in secondary vaccine failure). Thus, the third dose for immunocompromised may or may not be a “booster” but is highly recommended in this high-risk population. FYI, this is why we give a second dose of MMR to children – because up to 5% may not have responded to the first dose, not because we need a “boost.”
  2. The second reason for giving third doses is that immunocompetent individuals may have had a good response, but immunity may now be waning (potential secondary vaccine failure). In this case a third dose does “boost” the immune response by stimulating a robust memory response. There is strong evidence that third doses of the two mRNA vaccines trigger very strong “booster” responses to this virus (mainly in vitro data measuring antibody production and/or T cell responses) but very little evidence that such a boost is necessary for most healthy people (yes, antibody levels wane over time, and yes, protection against infection wanes over time….from 88% in the first month to 47% after 5 months or more in the large study of the Pfizer vaccine in the Kaiser Permanente study just published in Lancet this week—BUT protection against severe infection and hospitalization remains quite good even 6 months after the second dose). Nonetheless, it is highly likely (though supporting data is currently limited) that a third dose will reduce all infections and help reduce spread to others (especially important for health care workers). This week’s NEJM contains an important article from Bar-On and colleagues in Israel [ed. electronically released September 15]. They found that in patients over 60 years of age, a third dose of the Pfizer vaccine provided significant additional protection against all SARS-CoV-2 infections (lower by a factor of 11.3) and against severe infection (lower by a factor of 19.5).
  3. The third reason to give a third dose would be the emergence of “variants of concern” that are more likely to cause disease in fully immunized people. This is NOT yet the case (and if it does happen might necessitate a third dose with a different vaccine).

Aron:    
I tend to be pretty dedicated to standard evidence-based medicine principles, and for therapy, the standard line for medical students is that we should have randomized clinical trials (RCT) to justify a new or changed therapy. But in the case of the Pfizer booster there are no RCTs. There are some really interesting cohort trials from the US and Israel. Those trials show some decrease in vaccine effectiveness for infection over time, although effectiveness for hospitalization does not seem to change much. The antibody response goes up with a booster, and in another Israeli cohort (the Bar-On piece Keith cites above), it looks like people with the booster were less likely to get infected and less likely to go to the hospital with COVID-19, but again, cohort trial and not randomized.

Randomization helps reduce unknown and confounding data in a study. While sometimes cohort trials are our only option (for example, cohort trials are how scientists proved smoking causes all of its forms of badness), if you really want to know if a therapy works, you need a RCT.  Is that how you see the literature?

Keith:   
Yes, I agree with you that RCTs would be ideal, but studies with a test-negative design can provide strong evidence of vaccine effectiveness in the “real world.” (See Thompson and colleagues from the CDC in this week’s NEJM and an accompanying editorial on “test-negative” design studies by Dean et al. in the same issue.) 

There is also some data indicating that previously infected people have particularly strong responses to even one dose of the mRNA vaccines and may not need a second (or third) dose – but only time will tell there.

Aron:    
So, Keith, did you or will you be boosterized?

Keith:   
Yes, I got my third dose on 10/4/21, along with my annual influenza immunization. And, how about you, Aron?

Aron:    
I start rounding in about 10 days, and I got myself a boost last Saturday.

Regardless if you’re eligible for a booster yet, the most important shot may well be your first shot – the one that gets you some protection rather than no protection. And, you can’t even consider getting additional shots if you have not started with your first one. All of the data about boosters and additional shots build on the fundamental evidence that vaccination works to prevent the spread of COVID-19, illness, hospitalization, and death.

Serving the people with you,

Aron

Aron Sousa, MD
|Interim Dean