To Boost or not to Boost — That is the Question

InpharmD™ Clinical Literature Summaries — S3E9

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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.

To Boost or not to Boost — That is the Question.

As we continue to see high case numbers of COVID-19, there’s been lots of talk about boosters. If you’ve had two shots, is there value to the third? Well, we decided to take a closer look at this question based on some data from Israel.

As many of you know, Israel has continually been a couple months ahead of the US in vaccination strategies, and we sometimes follow their lead based on the data they produce.

In this retrospective study, over eight hundred thousand participants aged 50 or older who had received two doses of the Pfizer vaccine over 5 months ago were followed during the Delta surge from early August to late September of 2021 to assess mortality due to COVID-19.

The group was split into those who got the booster and those who didn’t. The vast majority of participants in the study opted to receive the booster, so the non-boosted group numbered about eighty-five thousand.

As you might expect, since this was not a randomized trial, the baseline characteristics of those who chose to boost were quite different than those who didn’t. The boosted group had significantly more participants over the age of 65 and on average was about 4 years older than the non-boosted group. To deal with differences between the two groups, the researchers adjusted for sociodemographic factors and co-existing conditions in a Cox proportional hazards model.

They found that after adjustment, those in the boosted group had 90% lower mortality from COVID-19. In a key secondary outcome, the boosted group had 83% fewer infections from COVID-19. Both results were of course statistically significant.

One caveat of all this we have to remember is that this study was done during a period of Delta predominance in Israel. Now that we have Omicron raging, we have to ask, how relevant are these results? We’ve got some interesting preliminary data showing neutralization efficiency of individuals who had received 2 or 3 doses of the Pfizer vaccine. In those who only had two doses over 5 months ago, there was low but still measurable neutralization against Delta, but essentially no neutralization against Omicron. But once that third dose was given, neutralization titers went up 100-fold against Omicron! Despite the increase, neutralization titers after the third dose were still 4-fold lower for Omicron compared to Delta.

A lot of people might be wondering, why does giving a third dose of the exact same vaccine based on the original COVID-19 virus cause our body to produce antibodies that all of a sudden are able to neutralize Omicron? Its likely due to a complex process called affinity maturation, which occurs in the germinal centers of our lymph nodes. Basically, our B cells have devised a way to make better and better antibodies the more they are exposed to an antigen. Our B cells mutate the gene encoding the antibody they express and as they do this, they divide rapidly. This results in a diverse population of B cells expressing many different antibodies against the same antigen, in this case the spike protein of COVID-19. The key here is, the germinal center is set up with bits of antigen that the B cells need to bind to and hold on to… to survive. So only B cells expressing antibodies with very high affinity to the antigen can survive.

Now that you’ve had your immunology lesson for the day, how can we apply this to the Omicron neutralization data? We might expect those boosted with a third dose to do much better than those with 2 doses due to affinity matured antibodies, but maybe not quite to the extent that is seen with Delta. Its hard to predict though, because this is only taking into account our antibody response and completely ignores our T cells, which are also crucial for fighting off viruses.

While the data is more robust for Delta in those over 50 based on the study we’ve reviewed, it appears clear that the third dose of COVID-19 vaccine provides value against Omicron too based on neutralizing antibody titers.

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