Fundamental aspects of immunity to SARS-CoV-2 remain elusive. Here is an examination of some potential clues to protection.
The current coronavirus 2019 (COVID-19) pandemic, caused by the SARS-CoV-2 virus, has been an unprecedented exercise in real-time data gathering and analysis. Since the first patients presented for treatment in China, scientists and physicians have scrambled to keep up in terms of understanding this virus’ many nuances. We have searched every scrap of data as they have been collected for meaning, trying to explain how this novel virus managed to profoundly disrupt our lives in every way and trying to understand the biological basis by which we can return to some semblance of normalcy.
For this reason, extraordinary attention has been paid to the growing body of data about immunity, since the most successful way of vanquishing major viral pathogens throughout history has been to choke them out of existence by depriving them of susceptible hosts. The concept of “herd immunity” rests on the principle that viruses, which are obligate parasites and require a host to reproduce themselves, cannot continue to spread in a population in which the majority of individuals are immune to them. While this can be achieved by immunity acquired by natural infection, as may be the case with Zika virus,1 the cost in lives is often too high and natural infections may not induce lifelong immunity.
Therefore, the development of vaccines and mass vaccination programs are the gold standard for inducing herd immunity in the global population. Developing safe and effective vaccines, however, depends on an understanding of functional immune protection, which has led scientists to the most important questions of this pandemic: How does immunity to SARS-CoV-2 work? And how can we use that information to end the current public health crisis?
At first, immunity seems like a deceptively simple concept: In response to infection, the immune system springs into action to clear the infection. What’s more, the immune system stays on alert, protecting against future exposures. In reality, it’s much more complex than that, which is why fundamental aspects of immunity to SARS-CoV-2 remain elusive. Immune function cannot be measured simply by quantifying immunoglobulin G (IgG) titers or gauging the presence of antigen-specific T cells, and immune responses gone awry contribute significantly to disease severity. Understanding the immune responses to SARS-CoV-2 infection is essential to understanding how they contribute to protection or pathogenicity.
However, a consistent theme of the public discussions about immunity to SARS-CoV-2 has been whether the virus is somehow different than other viruses. Reports of reinfection and recrudescence, as well as observations about antibody responses, have fueled speculation about whether immunity works in the same way for SARS-CoV-2 as for other respiratory viruses and influenza. Fortunately, although the data are still limited, the emerging picture so far is that SARS-CoV-2 is consistent with what we know about immunity to other viruses that infect the human respiratory tract: It does induce immunity in most people, as measured by antibody and T cell responses.
Antibodies are often the first immune parameter measured in response to a novel emerging virus, as serum antibodies are easy to detect with a conventional blood draw. Therefore, numerous serology studies have been conducted in convalescent COVID-19 patients. The results of multiple studies have demonstrated that convalescent patients do mount antibody responses, including responses showing robust neutralizing IgG titers that occur very rapidly following diagnosis.2-12 Although study results have shown that overall neutralizing titers may be low, most patients produced some IgG targeting the SARS-CoV-2 spike protein receptor-binding domain with potent neutralizing capacity.13 Results of numerous studies also show that antibody titers correlate with disease severity14 and with sex (with men at greater risk of severe COVID-19 and death than women).15,16
While there is no direct evidence that antibody titers correlate with protection from infection in human COVID-19 patients, some evidence from rhesus macaque challenge studies suggests that antibodies do protect against reinfection upon a second challenge in convalescent animals.17,18 Similarly, a number of vaccine candidates that also induced high neutralizing antibody titers protected against severe disease and infection in macaque challenge studies.19-22 An outbreak on a fishing vessel served as a natural experiment, in which high titers of neutralizing antibodies were found in crew members who did not become infected.23 This suggests that neutralizing antibodies play an important role in both protecting against reinfection and attenuating disease severity in those who become infected.
There is some evidence that these responses wane over time in terms of the titer of detectable neutralizing antibodies in the blood,24-27 although the implications of this are not clear. Normally, after an initial spike in IgG during and immediately after the initial infection, antibody titers decrease to a baseline level unless there are subsequent exposures. The observed decreases in antibody titer after several months are consistent with this paradigm, and they do not indicate a corresponding loss of immune memory or functional immunity.
Whether or not functional immune protection decreases over a longer period of time is unknown, although studies with SARS-CoV suggest that it might.28,29 The Virome of Manhattan study results demonstrated that humans can become reinfected with other common cold coronaviruses within months,30 although those coronaviruses cause milder disease and are not directly comparable with more pathogenic coronaviruses such as SARS-CoV, MERS-CoV, and SARS-CoV-2. However, as SARS-CoV has not reemerged, it is impossible to determine whether the reduction in detectable antibody titers resulted in a complete loss of immune protection; it is possible that other branches of the adaptive immune system also may offer protection.
Antibody titers have been shown to correlate with T-cell function, and SARS-CoV-2–specific T cells have been observed in numerous studies,31-44 In particular, follicular CD4 T cells, which coordinate adaptive immune responses, are particularly important for both CD8 T-cell function and B-cell responses. Thus, T-cell responses to SARS-CoV-2 are likely critical for mounting protective immune responses against SARS-CoV-2 and for maintaining immunological memory responses after the primary infection has been cleared. Additionally, SARS-CoV-2–specific T cells have been identified in subjects with no history of SARS-CoV-2 infection36,37,45 suggesting the presence of cross-reactive T cells primed by prior exposure to common cold coronaviruses, although their functional significance in protective immunity is not clear. They may attenuate disease or enhance B-cell responses to an initial exposure to SARS-CoV-2, or they may not play a significant role at all in immune protection.
The results of at least 1 vaccine study have suggested that antibody neutralization is the single most significant correlate of protection, so the importance of preexisting cross-reactive T-cell immunity in pathogenesis remains unknown. T-cell polarization is likely important for the balance between protection and pathogenesis, although this is not well studied in SARS-CoV-2 natural infection. T helper cell type 1 (Th1) responses are usually associated with antiviral responses, such as CD8-mediated cytolytic responses and neutralizing antibody production, and Th1 responses have been observed in vaccine challenge studies demonstrating protective efficacy against COVID-19. On the other hand, Th2 responses are associated with acute respiratory distress syndrome and airway hyperreactivity46 and could contribute to increased COVID-19 severity, although the relationship between Th2 polarization and COVID-19 severity is unknown.
Although we have begun to characterize fundamental components of the immune response to SARS-CoV-2 infection, there are still several major gaps in our knowledge. A more comprehensive understanding of the determinants of functional immunity is essential to develop effective immunotherapies for SARS-CoV-2, such as monoclonal antibodies. While it is a relief to know that this virus operates within the existing paradigm of immunity and does not appear to evade the immune system in unique ways, there is still much to be learned about how we can generate lasting protective immunity across the population and categorize SARS-CoV-2 as a preventable disease without the ability to circulate in the human population.
Rasmussen is an associate research scientist, Center for Infection and Immunity, at the Mailman School of Public Health at Columbia University.
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