Could Sars-CoV-2 vaccines make the immune response less effective against new variants?

Question

Some viral diseases (e.g. influenza and dengue fever) are thought to exhibit original antigenic sin. The immune system remembers viruses that it has been previously exposed to, allowing the body to mount an effective defense if the same virus is seen again. However, in some cases, this immunological memory can be overly specific. When the body is exposed to a new variant of a familiar virus, it produces antibodies against the old variant rather than the new variant. If these antibodies are less effective against the new variant, the infection can be more severe than it would have been in a person with a naive immune system.

Is there reason to believe that the same phenomenon could occur for Sars-CoV-2 and its variants? In particular, could people who were infected by or vaccinated against the original strain be more vulnerable to Omicron or other future variants?

Answer 1

The wikipedia article for Original Antigenic Sin (OAS) oversells it a bit, in my subjective analysis. While the effect is experimentally verified - e.g. patients with a Dengue type 4 infection will produce antibodies that bind type 1 much more strongly than 4 if they were first infected with type 1 (source) - there is no evidence I'm aware of that proves the resulting immune response is less effective than a naive immune system of the same age would mount. From Original Antigenic Sin: How First Exposure Shapes Lifelong Anti–Influenza Virus Immune Responses:

Although OAS has often historically been depicted as a problematic response, recent data have demonstrated that, in certain contexts, eliciting OAS may also be beneficial.

It's not obvious that the poor match of OAS antibodies to the second infection is enough to make up for the much more rapid response compared to that of a naive immune system. Mismatched antibodies generally still neutralize other strains, it's just that a higher concentration is required.

A big confounding factor here is another mechanism, Antibody-Dependent Enhancement. ADE is most infamous in Dengue, which causes mild disease the first time but can be deadly after that if later infections come from a different strain than the first virus. ADE arises in this case because Dengue virus can infect the white blood cells that envelop and attempt to destroy antibody-bound particles. This results in accelerated virus production and a dysfunctional immune response. Despite the fact that immune cells do not display the ACE2 receptor that their spike protein needs to bind before it can fuse with the cell membrane, both SARS and SARS2 have been found to also infect macrophages when spike-binding antibodies are bound. Unlike Dengue, though:

Macrophages infected with SARS-CoV, however, did not support productive replication of the virus.

and

SARS-CoV-2 infection thus produces antibodies that elicit ADE of infection, but these antibodies do not contribute to excess cytokine production by macrophages.

Which, together with the protective effect observed for SARS2 vaccination and prior infection, we can conclude ADE isn't an issue for COVID severity, even if variations arise that can escape antibody neutralization.

Finally, there is some important context here that is not obvious to the casual investigator. The new omicron variant of SARS2 has been described as "highly mutated" because it has more than 30 mutations in the spike protein, out of 1250 amino acids in the full sequence. In other words, the other ~97.6% AA are identical. For comparison, I looked up and ran a BLASTp analysis of hemaglutinin (analogous receptor binding protein in influenza virus) from H1N1 and H3Nx strains of influenza. (uniprot accession nos. P03452 and F1KLX3, respectively) These two antigens have only 42% identical amino acids. So they are far more dissimilar than different variants of SARS2. COVID is not likely to reach similar levels of differentiation anytime soon, and we can expect any potential OAS effects to be mild for a long time as well.

Answer 2

No.

Let's approach this issue from the beginning. At first, we have what is called innate, nonspecific or natural immunity... many synonyms to say that it is

" the body's first line of defense against germs entering the body " quote

Now, one important feature that this mechanism has is that it will be the first to contact with the target antigen and thenceforward do another specialty of them that is Antigen Presentation (dendritic cells are the most famous for that)

APCs may interact with two classes of lymphocytes: the B or bone marrow-derived lymphocytes, but especially with the T or thymus-derived lymphocytes. quote

From here adaptive immunity appears which includes everything you have refereed.

In that sense, all that will matter here and related to the subject is that if Ig's will have affinity for the antigen.

1. Let's assume they have cellular immunity, which is

a protective immune process that involves the activation of phagocytes, antigen-sensitized cytotoxic T cells and the release of cytokines and chemokines in response to antigen. Cellular immunity is most effective against cells infected with viruses, intracellular bacteria, fungi and protozoans, and cancerous cells. It also mediates transplant rejection nature

2. Let's assume they don't have affinity to the antigen

In that case (that could be due to a mutation of virus surface...) your immune system will not recognize that epitope (fancy word to say antigenic determinant, it's the fragment that the immune system will recognize).

As a result of that a new Antigen Presentation must be done. In parallel HIV is a good example of that, the virus that infects a person at first is continuously suffering mutation after mutation (due to the inefficient reverse transcriptase enzyme), and thus when the body has Ig's to attack the infection, there's already another virus to attack, and so on, and so on..