Natural immunity to SARS-CoV-2

September 03 2021

Background

SARS-CoV-2 causes Covid-19. This pathogen is dangerous to the very elderly and to a subset of those vulnerable usually due to co-morbidities. However many people don’t get seriously ill or may not notice they have been infected. Part of the reason for this existing immunity to a relatively new virus is likely due to cross reactive immunity from exposure to the similar common coronaviruses that are already circulating. Briefly, it means we have made T cells from a previous infection that are are specific to the similar parts of the new virus. This has been shown in numerous studies 1 that measure T cell reactivity to virus specific antigens in unexposed controls. So SARS-Cov-2 is technically novel if defined as a newly emergent strain, but not brand new. This partial population immunity is the same means by which many are not susceptible to circulating influenzas or colds at a given time. There are other mechanisms that exists alongside this that may also be responsible such as the innate immune system, which seems to play a role in children.

Children

Children are much less susceptible to severe COVID-19 than adults. Early on, this was ascribed to a possibly stronger innate immune response. A recent study 2 in Nature further supports this hypothesis. The authors studied the variety of cell types in the upper respiratory tract of sets of SARS-CoV-2-negative and positive children and adults. Along with confirming the presence of viral RNA by PCR, the samples were analysed with single cell RNA sequencing. This allows the genes being expressed in individual cells to be profiled and thus identify the kinds of cell present. There was a clear difference in the cell composition between adults and children. Adult samples rarely contained immune cells but samples from children contained high levels of almost every immune cell subset. Neutrophils made a significant portion of this, these are immune cells that act early in the innate immune response. Child samples also contained a subpopulation of cytotoxic T cells that was absent in adults. These T cells produced high levels of interferon gamma, which inhibits viral replication. See this article for more details of the study.

Reinfection is rare

There have been numerous confusing and conflicting media reports on this subject in relation to Covid-19, such as this one from the Irish Times and then another in the Guardian that contradicts it. Despite previous inaccurate reports, frequent reinfection has not been shown in any study. A recent national surveillance of possible COVID-19 reinfection has been published by Public Health England (PHE). This found 15,893 possible reinfections (up to 30 May 2021) in England out of nearly 4 million people with confirmed infections. This is 0.4%. I would take these figures as rough estimates given the difficulty in defining a reinfection. In this case reinfections were defined as consecutive positive test results in the same person are at least 90 days apart. This assumes the test is not detecting the the same virus twice. 478 reinfections were considered ‘probable’ - a strain detected the second time that was not present during the time of first infection. Only 53 reinfections were actually confirmed by sequencing of two distinct strains at both time points. This result also clearly depends on the threshold used for the PCR test to consider a test positive for viral RNA. This is notoriously inconsistent or opaque with community testing regimes. The result is probably a reasonably good estimate though.

Natural infection provides robust immunity

Given the fact that reinfection (within say 8-12 months) is quite rare, how long should existing immunity last? Infection against a viral infection sometimes provides lifelong immunity. This is the case for measles. But it’s not true for influenza, colds and coronaviruses. One reason is that they can mutate into functional strains that are different enough to evade the memory immune response. It’s also possible that we may not have needed to mount a sufficiently strong immune response to even activate the memory part of the immune system.

Natural immunity to SARS-CoV-2 has been the subject of multiple studies. A recent article in Nature points out that those infected will probably make antibodies against the virus for most of their lives. This is due to the ability of our body to retain memory B cells that can produce the required antibodies when needed. The study quoted found these cells present 8 months after infection. This is complementary to the T cell immunity mentioned above. Another notable result came from a retrospective cohort study of the 52,238 employees of the Cleveland Clinic 3. It is described here by Sebastian Rushworth in more detail. The outcome showed that prior infection is highly effective at protecting against Covid. Another study, now published in the journal Science, is outlined on the Gavi website. This was done by the group of Alessandro Sette 4 and measured the presence of antibody, memory B and T cells post infection. 92% of subjects (most with mild symptoms) had high levels of CD4+ T cells at 6 to 8 months after infection. The studies are not conclusive but are a very good indication of long term partial or complete immunity.

Variants

Of course, as the virus is probably endemic, new strains will constantly emerge. Eventually, even if previously infected, we may encounter one new enough to produce symptoms. But it is still likely a previous infection will provide some protection. It is quite unlikely that a variant will arise that will completely escape this natural cell mediated immunity in the population. This was indicated in a study in Science from May 2021 5 that showed changes in the spike protein of SARS-CoV-2 variants of concern do not impact T cell reactivity. So a variant may appear that escapes humoral immunity (antibodies) but is less likely to affect T cell immunity. Though antibody cross reactivity also exists 6. A brief and sensible discussion of escape variants is given here. The constant media discussion about variants should be understood in this context.

Glossary

  • Antigen - The piece of the pathogen that is detected by the immune system, e.g. a protein, sugar or lipid.
  • Innate immunity - The innate immune responses are the first line of defense against invading pathogens. They are a generic set of defenses. They are also required to initiate specific adaptive immune responses.
  • B cell - B cells produce receptors that bind to antigen. If infected, they present antigen on the surface and can be activated to turn into plasma cells that pump out antibodies specific to the pathogen. Some of these can live a long time.
  • T cell - T cells play a central role in the adaptive immune response. They can attack infected cells or help other types of cells (like B cells) to activate during an immune response. Memory T cells can live a long time and be reactivated later.

References

  1. Gustavo Echeverría et al. Pre-existing T-cell immunity to SARS-CoV-2 in unexposed healthy controls in Ecuador, as detected with a COVID-19 Interferon-Gamma Release Assay, International Journal of Infectious Diseases, 2021, https://doi.org/10.1016/j.ijid.2021.02.034.
  2. Loske, J., Röhmel, J., Lukassen, S. et al. Pre-activated antiviral innate immunity in the upper airways controls early SARS-CoV-2 infection in children. Nat Biotechnol (2021). https://doi.org/10.1038/s41587-021-01037-9
  3. Necessity of COVID-19 vaccination in previously infected individuals. Nabin K. Shrestha et al. medRxiv 2021.06.01.21258176; doi: https://doi.org/10.1101/2021.06.01.21258176
  4. Jennifer M. Dan et al. Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection Science 05 Feb 2021. DOI: 10.1126/science.abf4063
  5. Geers at al. SARS-CoV-2 variants of concern partially escape humoral but not T cell responses in COVID-19 convalescent donors and vaccine recipients. Science Immunology. 25 May 2021. DOI: 10.1126/sciimmunol.abj1750
  6. Majdoubi, Abdelilah et al. “A majority of uninfected adults show preexisting antibody reactivity against SARS-CoV-2.” JCI insight vol. 6,8 e146316. 22 Apr. 2021, doi:10.1172/jci.insight.146316