Welcome to our first installment of our “League of Science Superfriends Covid Mailbag” as our team answers questions about Covid-related topics from the general public. Have a burning question for our team to answer-send us an email at sciencesuperfriends@gmail.com

All submissions are anonymized upon posting to our webpage. As a disclaimer, our mailbag is meant to provide guidance on the latest scientific developments and not to supersede the recommendations of your medical professional.

For our first mailbag, Dr. Peter Morawski addressed the following question:

Dear LSS,

I am immunocompromised and saw my doctor virtually this week regarding a booster shot as I am close to 6 months since my 3rd vaccine dose. I’ve had 3 full Moderna, and he recommended I get Pfizer this time based on the research of mixing. I’m participating in an antibody study, and in November I still had a high number of antibodies from the vaccine though no one can tell me what that means.

Do you know any immunocompromised who received their 4th shot in a mix/match approach and how they did post-injection? Any sense of how to interpret my current high antibody titer in relation to protection against Covid and the Omicron variant? Thank you so much for your help!

-J. Mayberry Jr. , Texas

Hi J. Mayberry Jr.,

Thanks for your questions. Please allow me to respond thoroughly.

The CDC is now recommending a 4th dose for individuals more than 5 months past their initial 3 doses if they are moderately to severely immunocompromised. Guidelines and additional information are on the CDC website. In vaccinology, realistically, anything after dose 1 is a booster. However, the CDC here refers to the 3rd dose (administered any time 28 days after the initial two-dose series [Pfizer/Moderna]) as an “additional primary dose” and calls subsequent vaccines beginning 5 months after the 3rd primary dose as a “booster.” These guidelines were also recently updated to shorten the time to booster for all individuals from 6 months to 5 months after the primary dose series. This is likely based on data reporting waning antibody levels. Based on reports of early studies in immunocompromised individuals (performed in Israel as well as the USA), including work I personally contributed to, these recommendations seem reasonable, particularly in people who struggle to mount a strong antibody response (see: correlates of protection below!). What’s clear is that there is no negative effect observed in those receiving these additional vaccine doses, and immunogenicity - the strength of reaction to the vaccine/how sick you get - does not appear any more severe.

Regarding mixing and matching, there are 3 efficacy studies I’ve seen with data to support this (3, 4, 5). Unfortunately, all studies were conducted outside of the USA, mixing one vaccine we do have access to (i.e., Pfizer) with one we don’t have access to (i.e., Chadox). To this end, the NIH is in the process of doing large powered studies, but none of the results are posted yet on clinicaltrials.gov. However, early safety trials here do indicate that mixing the 3 approved US vaccines in any combination is safe and induces a robust immune response. So, whether you choose to boost with Moderna or Pfizer probably makes no clinically significant difference. They are both really good vaccines, the only difference being the doses: Moderna uses a primary/booster dosing of 100ug/50ug while Pfizer uses 30ug for every dose. It’s unclear whether this dose difference matters, especially when considering a 4th dose. As with all things, it may depend on a number of factors.

You also asked what high antibody levels mean. The fact that you still have high antibody numbers is a great sign. This is not the case for all immunocompromised folks, even after 3 doses. Following vaccination, it is typical for scientists to look for “immune correlates of protection.” This means they evaluate the types of immune responses generated [by vaccination] and then measure which of these responses can predict long-term efficacy of the treatment for a population.

Two large studies I have read on correlates of protection are from Oxford in the UK and from the NIH/Moderna. Both of these groups continued to study the immune responses in their clinical trial participants to evaluate correlates of protection. Both studies concluded that antibody levels following the full vaccine-regimen are a strong immune correlate of protection.

The NIH/Moderna study is most relevant to the USA because it is a follow-up to the US Moderna vaccine trial, which was a really powerful and well-conducted study. Although I haven’t seen a similar study for the Pfizer/BioNTech vaccine (BTNb162b), I anticipate that their results would be consistent with the Moderna data owing to the similarity of these vaccines. For now we know that the higher the antibody response, the better the correlation to long-term protection.

My speculation, based on my own research on another arm of the immune system, T cells, is that long-term protection against severe disease is associated with a good T cell response even when antibody levels wane. Although it appears that boosting the immune response with additional vaccine doses serves to prevent initial infection by elevating B cells and antibody levels in the short term, the T cells can act to limit disease severity in the long term. It’s pretty cool!

Thanks for the great questions and glad to provide you with the latest in Immunology!

Peter Morawski, PhD Peter Morawski, PhD