A 4th Dose of the COVID-19 Vaccine

InpharmD™ Clinical Literature Summaries — S3E14

4 min readApr 29, 2022

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On behalf of all of us here at InpharmD, whether you’re listening to this from your home or on the front lines, we hope you’re well and we thank you for the important work you’re doing.

With this podcast, we recap innovative, practice changing studies in ten minutes or less. And remember, nothing here is medical advice; we just present the evidence and our (sometimes hot) takes.

What’s the Evidence for a 4th Dose of COVID-19 Vaccine?

We know we know, haven’t we already talked about a 2nd shot and then a 3rd shot of the COVID-19 vaccine?… Well now with new variants continuing to emerge, some countries have started a 4th round of vaccinations. We’ll look to Israel today to examine the evidence for this approach.

When Omicron came along, it changed the dynamic of the fight against COVID-19. Suddenly the vaccines that seemed so strong were no longer bulletproof. People who had been boosted with a 3rd shot were getting infected. So Israel decided to try a 4th shot in those 60 years of age and older to see if this could benefit such a vulnerable population while Omicron was raging. This approach isn’t without controversy. Some might argue every 4th shot we give to someone could’ve been the first dose in the series for another person in a less developed country. We’ll just examine the evidence for the 4th dose and let you all form your own opinions on the right approach!

The study we’ll look at today is a retrospective trial from Israel of more than a million adults over the age of 60 who had received a 3 dose series of the Pfizer COVID-19 vaccine at least 4 months earlier. The researchers looked at over six hundred thousand patients who received a 4th dose of Pfizer vaccine vs another six hundred thousand who did not receive the 4th dose.

They did some complex statistical maneuvering, but essentially the goal was to look at the rates of confirmed infection and severe infection between the two groups over a 2 month period. They also compared their results to an internal control group, which was the same people who received the 4th dose, but looking only at the time period of 3–7 days post vaccine. They did this because this group should not yet see efficacy from the vaccine, but would serve as an internal control since they should have the exact same age, comorbidities and other risk factors as the vaccine group.

Here’s what they found: Severe infections occurred two to three and a half times less frequently in the 4th dose group compared to the internal control group and the no vaccine group. This efficacy did not appear to wane over the 6 week study period. When looking just at confirmed infections the protection from a 4th dose lowered risk by a factor of two relative to both control groups, but importantly this efficacy waned over the 6 week study period.

Other smaller studies have shown a 4th dose of mRNA vaccine restores antibody titers against omicron to the same levels as after the third dose, but doesn’t really go any higher. Taken together, it seems a 4th dose may provide some temporary benefit against infection, but the real value may be in preventing severe disease. The problem is, we just don’t know how long a 4th dose will protect against severe disease. Clearly this effect lasts longer than protection against infection, but we do know that even protection against severe disease

waned after a 3rd dose, especially when Omicron came along. So who’s to say how long this protection will last after a 4th dose.

So the next question we have to ask is if the 4th dose is really worth it? This is not an easy one to answer and probably depends on how high risk the individual is. As suggested by a small study in Israeli healthcare workers, there may only be a marginal benefit against infection ranging from 11–30% vaccine efficacy depending on which mRNA vaccine was given. The value of the 4th dose might lie in protecting more vulnerable populations or those who did not have a strong antibody response to 3 previous doses. This aligns with the new emergency authorization by the FDA allowing for a 4th dose to be given to those over 50 or the immunocompromised.

At the end of the day, everyone has to make their own decision, we just provide the evidence! And who knows, as variants continue to emerge, things may change. But don’t worry, we’ll still be here to break down all the new data as it comes out.

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