Expert Insight: Immune responses to SARS-CoV-2: All your questions answered

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Prof. Akiko Iwasaki, Waldemar Von Zedtwitz Professor of Immunobiology and of Molecular, Cellular, and Developmental Biology, Yale School of Medicine 

The clinical presentation of COVID-19 involves a broad range of symptoms and disease trajectories. Understanding the nature of the immune response that leads to recovery from severe disease is key to developing effective treatments for COVID-19.

In this SelectScience webinar, now available on demand, Prof. Akiko Iwasaki, Yale School of Medicine, discusses immune responses in COVID-19 patients with moderate and severe disease. Highlights of Professor Iwasaki’s presentation revealed:

• Mutations in the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein in variants of concern alter the affinity (KD) for the host-entry receptor, ACE2
• The neutralization ability of post-infection antibodies found in convalescent serum may be driven by increases in ACE2 affinity or changes in epitope

Think you’d benefit, but missed the live event? Register now to watch the webinar at a time that suits you or read on for highlights from the Q&A session.

Q: Is there a difference in immune response in immunocompromised patients?

AI: Yes, absolutely. Immunocompromised patients develop impaired immune responses against the virus, both with respect to natural infection as well as vaccines. We are following up on a couple of interesting cases within our own cohort. Depending on the kinds of immunosuppression and immunocompromised status they have, they either develop very low levels of antibodies or very low levels of T cell response, or both in some cases.

This has an important implication for the vaccination-mediated control of disease, and it's possible that immunocompromised people need more than two doses to get their antibody levels to the point that they can protect themselves against the virus. This is an ongoing area of study.

Q: What do you think about the role of IgA in the response to the infection?

AI: We actually have a separate study where we are studying IgA from two different sources. One is the nasopharyngeal swabs, and the other is the saliva, and we're correlating the level of IgA to viral titers within these respective tissues.

It's very interesting because IgA, unlike IgG, can be secreted actively through the polymeric Ig receptor to transverse the epithelia into the mucosal lumen. We know how important IgA is against other respiratory infections, and so we are in the midst of analyzing these data.

Unlike the natural infection, though, the vaccine-induced IgA may not be the mucosal type. It may just be the exudate from the sera, which is the monomeric IgA. They may or may not contribute in the same way, and we're also testing that as well.

Q: Most mutations of concern reported are in spike proteins and increase infectivity. Should we be concerned about mutations elsewhere, in particular those that may increase virulence without increasing the infectivity?

AI: Yes absolutely. I've only focused on the spike mutations for the neutralizing antibodies, but we are also studying other mutations that are seen in different viral genes, particularly those that inhibit MHC Class I that could impair T cell recognition of infected cells, and many other mutations that might increase the viral replication rates and immune evasion.

I think we really need to look at this comprehensively across the genome to understand why some of the variants are so successful in transmission.

Q: Is there any evidence of antibody-dependent disease enhancement in the patients studied in your analysis?

AI: I've written pieces on antibody-dependent enhancement (ADE) concerns for SARS-CoV-2, and there are some reports showing that an antibody against the end terminal domain of the spike protein may change the conformation of the spike to be able to become more infectious, an interesting new way of antibody-dependent enhancement of infection and potentially disease.

There are also other numerous reports, including our own, showing that the antibody titers are actually elevated according to the severity of disease, so the more severe the symptom, the more elevated the antibody is. There's also the afucosylated antibody that can bind to different types of Fc receptors and engage inflammatory responses.

I think there's emerging evidence of a few different examples in which antibodies can enhance infection and disease in a setting of COVID-19 disease. However, fortunately, I haven't seen any ADE associated with any vaccines. I think we can be comforted in that knowledge and really promote this message for vaccine-hesitant people.

Q: Could antibodies that are not directed to RBD but in proximity be modified to sterically inhibit binding? 

AI: Yes, absolutely. I think there are all kinds of antibodies that we can consider, not just the anti-RBD antibody, but any anti-spike antibody that may inhibit interaction with the target cells. These non-neutralizing antibodies are also important because they engage the Fc receptor of other leukocytes to clear the virus. There are other types of antibodies that we can also pursue that may be even more resistant to other variations that we see with the variants of concern.

However, it's interesting to note that not everyone makes different sets of antibodies, and not everyone makes the right kind of antibodies. In the case of vaccines, I think because it induces such robust antibody levels, any sort of anti-spike antibody is showing some helpful effects.

But with natural infection, we're seeing patients who really develop poor antibody response or the wrong kind of antibodies. Therefore, to correct all that imperfection in the natural immunity, vaccination of previously infected people is going to be important.

Q: Are there any differences between the expected protection immunity produced by getting the infection and the one induced by vaccines? 

AI: There are many differences in the immune response to natural infections versus vaccines. One obvious one is the antigen. The virus includes numerous proteins, so if you're naturally infected with the virus, you're going to generate antibody and T cell immunity to all these other viral antigens, while most vaccines are targeting the spike protein.

The other difference is the magnitude of antibody response generated by vaccine. At least for the two doses of mRNA vaccines that we studied, it's orders of magnitude better than some of the natural-induced immunity.

Thirdly, people who are previously infected, even though they may have developed certain levels of immunity, are seeing enormous benefits from vaccination. It's all good to vaccinate people who have had COVID-19 before just to normalize and equalize the type of immune responses that are needed to combat new variants.

I can go into many other differences, but the message is that, yes, natural immunity can confer some level of protection, but vaccine-induced immunity really boosts that level.

Watch the full webinar here>>

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