Why would you only be protected against Omicron after a vaccine booster?

A report from Pfizer yesterday suggested that three doses of their vaccine (the initial two doses plus a booster shot) were protective against the Omicron variant of COVID-19 virus. This came a day after it was announced that two doses of the vaccine, the standard initial course of therapy, had little efficacy in preventing infection with Omicron. 

These two statements seem contradictory. But can they both be true?

To appreciate the basis of these comments one needs to understand the testing process that was used to measure vaccine defense against Omicron.

Antibodies against a small part of the COVID spike protein on the synthetic virus can prevent it infecting target cells.

The testing that led to these conclusions does not directly measure protection against Omicron. Instead, it involves mixing a “pseudo-virus,” a synthetic virus displaying the COVID virus spike protein, with the blood fluid from someone who has been immunized with the Pfizer vaccine. If the vaccine produced antibodies (in the blood) that bind to the Omicron spike pseudo-virus and prevent it from infecting cells, then a presumption is made that the person who was immunized (and donated the blood) is protected from infection.

This measures only antibodies to a very small part of the COVID virus spike protein called the “RBD” (short for receptor binding domain). This is the part of the protein that directly binds to human cells. The assays that are now being reported therefore measure only a small percentage of antibodies generated to the virus spike protein.

Antibodies to the RBD (in red) prevent infection in these assays, but the RBD is only a small part of the spike protein. Antibodies to other parts of the protein which could provide immunity are not detected.

The reason people are concerned that the vaccine would not protect against Omicron is that most of the changes (mutations) in the spike protein are in the RBD in the new variant. If the vaccine induces antibodies to the original spike protein that cannot bind to Omicron, one can understand why it might not protect against Omicron.

Spike proteins from delta and omicron virus variants compared. Most of the changes in omicron are in the RBD (yellow colored areas). An antibody against the COVID-19 delta RBD (left panel) might not recognize the same area in omicron (right panel) because of the many mutations (red dots). But antibodies against other parts of the protein with many fewer mutations still bind to omicron.

But why would the same vaccine protect against Omicron after three shots, but not two, especially if the vaccine includes the same (not Omicron) spike protein. If you are simply making antibodies against the same virus spike protein, how can that protect against a different virus variant?

The key here is that the booster immunization not only induces antibodies against the original protein, but results in what is called “epitope spreading.” This means that new antibody binding sites (called epitopes) in the spike protein are identified after subsequent booster immunization, and these binding sites include areas in the Omicron RBD that are not mutated. These new antibodies take advantage of the similarities between the original and the Omicron viruses and prevent COVID-19 infection with the new variant.

While this is VERY reassuring and suggests that you can be protected from Omicron with a booster of the current Pfizer and Moderna vaccines, the bad news is that none of these measures truly reflects protection in people from the real virus! That will require studies with the actual Omicron virus and subsequent real-world monitoring of Omicron infections in vaccinated/boosted individuals. Those studies should be forthcoming in the next few weeks and months.

The good news is that beyond what is currently being studied there is a much broader range of immunity provided by vaccines, in particular cellular immunity. Cellular immunity is a totally different, additional kind of immunity that protects agains viruses.

Cellular immunity recognizes many smaller pieces of viral protein and is less prone to be defeated by mutation. This means some cellular immunity is likely to be shared between all the COVID-19 viral variants. Cellular immunity could protect against Omicron regardless of what antibody immunity provides and could prevent severe infections and death in immunized people. We have seen this with the Delta variant.

Importantly, the evidence of any immunity to Omicron from our current COVID-19 vaccines suggests this variant has not totally outwitted our defenses. This should provide a significant advantage to vaccinated individuals fighting Omicron.

Published by jbakerjrblog

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

6 thoughts on “Why would you only be protected against Omicron after a vaccine booster?

  1. Why does immunity broaden to include cellular immunity after repeating the same mRNA vaccine (with the same limited spike protein sequence) three times.


    1. Because it is due to actual mutations in antibody genes engendered by repeated exposure to antigens (affinity maturation and epitope spreading). Need to be able to enhance a preexisting immune response and requires a time of rest before the exposure. 3 weeks between the first and second doses not enough.


  2. The last three paragraphs of the post suggest that immunity provided by natural infection may be the best as it would be to more aspects of the virus than just the spike protein. The vaccine has been wonderful at attenuating, not preventing, disease and presumably natural infection is even better.

    Liked by 1 person

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s

%d bloggers like this: