Response to Mishra et al . re “Postinfectious Immunity After COVID-19 and Vaccination Against SARS-CoV-2”

To the Editor:

We thank Mishra et al. (4) for taking an interest in our publication (3). Their findings demonstrate that naturally acquired immunity through SARS-CoV-2 infection (COVID-19) dramatically reduces reinfection with symptomatic disease. They report significant protection in seropositive individuals, who experienced 97.7% fewer cases than seronegative individuals, of what we assume to be symptomatic COVID-19 based on the reported description.

Mishra et al. highlight the importance of the humoral immune system in preventing reinfection. B cells initially expressing IgM with low affinity for SARS-CoV-2 epitopes at the time of initial infection or vaccination will be selected to undergo isotype switching and affinity maturation. IgG antibodies (the majority of antibodies generated by vaccination) may be neutralizing, according to their ability to inhibit infection of infected cells, or non-neutralizing, for example, in the form of antibody-mediated clearance by phagocytosis. IgA antibodies (a component of natural immunity but not a significant feature of current vaccine-derived protection) can prevent colonization of mucosal surfaces (8). Repeat infection or immunization leads to increased antibody affinity owing to somatic hypermutation and “hybrid immunity” when natural immunity and vaccination synergize (2). Beyond that, multiple approaches targeting the development of broadly neutralizing antibodies against SARS-CoV-2 across multiple variants and even across the clades of SARS-related coronaviruses are currently in consideration (6,10).

To supplement the focus on antibodies alone, studies have highlighted the value of memory T cells in a more durable recognition of SARS-CoV-2 variants (9). Although vaccine-derived antibodies lose neutralizing activity against variants (1), T cell recognition of the same variants is largely unaffected (7). In addition to supporting B cell activation and maturation, CD4⁺ T cells activate CD8⁺ cytotoxic T cells and promote cellular memory in both B cell and T cell compartments. Recently, Painter et al. demonstrated that previously infected individuals generated a more robust CD4⁺ and CD8⁺ T cell response in response to single-dose vaccination compared with naive individuals, with little augmentation following a second vaccine dose (5). The narrower vaccine-derived COVID-19 immunity features a larger quantity of S-protein targeting antibodies along with S-protein-focused T-cell response. In comparison to that, the breadth of epitopes recognized by the components of natural immunity and its robust T-cell component are critical for protection against a broader range of variants, despite somewhat reduced capacity to provide sterilizing immunity against a narrower selection of variants with specific characteristics of the S-protein.

The current clinical paradigm to assess immunity against SARS-CoV-2 is based on measurement of IgG or total antibodies in serum. Serological studies do not comprehensively assess the adaptive immune response, which remains difficult to overcome in the clinical setting. Nonetheless these immunological mechanisms are at play and underlie immune protection in previously infected as well as vaccinated individuals. Identification of correlates for humoral and cellular immunity would be invaluable to understand risk for development of symptomatic infection, hospitalization, and transmission in general.