Musings on the 4th dose (second booster) mRNA COVID-19 vaccine

What follows is not medical advice; you should contact your doctor for that. It also does not represent an opinion from Michigan Medicine. But, since many people are confused about the “second booster” or 4th overall mRNA vaccine shot, this is my take.

I have been reluctant to weigh in on the need for a second booster of the COVID-19 mRNA vaccines. Everyone has been hedging their bets on this, particularly both the FDA and the CDC that suggested people could get a second booster, but didn’t necessarily have to get a second booster.

Unfortunately, many sources of health information have added to the confusion by providing conflicting advice on the who and the when of a 4th shot/second booster. Even the Atlantic, usually a good source of medical guidance, published two articles that seemed to take opposing views!

From my perspective, the important booster to have is the first one! Taking a third mRNA shot six months or more after your second vaccination makes a huge difference in terms of protection from severe disease, hospitalization, and death from COVID-19. Since only 67% of individuals above the age of 65 in the United States have gotten a first booster, we should press everyone to receive a third shot of COVID mRNA vaccine.

In terms of a 4th dose/2nd booster, the first question is what is the benefit? That is hard to ascertain, and information mainly comes from a few preliminary articles from Israel.  A study of a few hundred health care workers in the New England Journal of Medicine did not show a great deal of improvement in protection from serious illness. It concluded, “a fourth vaccination of healthy young health care workers may have only marginal benefits.” The authors did add, “Older and vulnerable populations were not assessed.”

Older individuals were evaluated in a more recent, but as yet unreviewed, study from Israel. It suggests that one week after the 4th dose, “the rate of severe illness in newly vaccinated was lower by a factor of 4.0 (95% CI, 2.2 to 7.5).” That sounds like a lot, but it is important to remember that the prior three shots of the mRNA vaccines have already markedly reduced COVID-19 illness. The difference in the rate of severe illness was 3.5 (95% CI, 2.1 to 5.1) cases per 100,000 person-days even at 12 days after vaccination. Basically, this means taking a 4th dose prevented fewer than 4 significant COVID illnesses per 100,000 elderly people per day. This is a tiny difference that likely will decrease over time as immunity wanes. 

Risk ratio for any COVID-19 infection in individuals over 65 years of age with 4 vs. 3 doses of COVID-19 vaccine. The rate plateaus at 2 fold difference (higher in 3 dose individuals) 18-23 days after the 4th shot. Despite this, the actual number of significant infections prevented was minimal.

While both studies suggested the 4th vaccine dose (2nd booster) was safe, the real need for this shot remains unclear. It’s easier to define who doesn’t need it: anyone under the age of 50 in good health with the third shot does not currently need a fourth shot. In addition, anyone over the age of 50 who is less than six months out from their third shot is good right now. So, who does that leave?

I would suggest an immediate, 4th vaccine dose only to individuals over the age of 65 who are at extreme risk from infection, either because of communal living, significant immune dysfunction, or severe lung disease. Remember, the vaccine is much less effective in individuals with immune problems, like lymphoma or an organ transplant, so the benefit in people is limited, and these folks should continue preventive meds like Evusheld despite a 4th dose. 

Unless the current level of COVID-19 infections radically increases, everyone else, even those over 65 who are healthy, should probably wait until the early fall to get a 4th dose. At that time, the vaccine may be different and cover more variants, or we will simply be closer to an expected winter outbreak. Any benefit from another vaccine dose would therefore more closely match the risk from new infections.

If you have been infected and vaccinated, look at the infection like an additional booster shot. In particular, do not get another booster unless you are four months beyond either an infection or a vaccination.

Those who received the Johnson and Johnson vaccine should know that studies now show that you need to eventually get two doses of an mRNA vaccine. The timing related to prior vaccine doses should be similar to what I have suggested above.

Finally, I think the need for COVID vaccine boosters will be better defined by the fall. Either we will need something yearly, like the Flu vaccine, or potentially require an additional shot less often dependent on the amount of endemic disease. The good news is that whatever the requirement we now have the vaccines we will need.

Published by jbakerjrblog

Immunologist, former Army MD, former head of allergy and clinical immunology at University of Michigan, vaccine developer and opinionated guy.

4 thoughts on “Musings on the 4th dose (second booster) mRNA COVID-19 vaccine

  1. I am 67 & work with diverse healthcare populations, I hesitated getting a 2nd booster or 4th dose. My asthma has been well controlled but … as it has been over 7 months since my last in the Moderna trial, I decided to get my dose today at Rite Aid.


  2. Nicely summarized.

    I think far too often, research focuses on percentage changes rather than rates per population.

    Hope all is well with you and the fam.

    Liked by 1 person

  3. How about household members of high risk elderly? Is there any evidence 4th dose reduces overall infection rates (so we don’t get infected and expose our high risk family member)? Thank you!


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