This evidence synthesis has been compiled by members of the CITF Secretariat and does not necessarily represent the views of all CITF members.

By Varun Anipindi

Immune mechanisms following SARS-CoV-2 infection remain largely unknown. For instance, while it is evident that COVID-19 manifests itself in a wide range of outcomes, it is unclear if differences in disease severity are associated with specific immunological determinants. As such, it is difficult to determine where patients will fall along the spectrum as the disease progresses. Likewise, although it is well established that both humoral and cell-mediated immunity are induced in response to SARS-CoV-2 infection, the longevity of the memory responses are not well understood.

A recent study published in Immunity on February 9, 2021, by Bonifacius A. et al. aims to address these critical questions. In this study, samples were collected from 82 healthy donors, 204 patients who recovered from mild COVID-19 and 92 patients hospitalized with active COVID-19 to examine immune responses at a variety of time points. They sought to understand the progression of immune responses against SARS-CoV-2 during infection and subsequent recovery. Specifically, they focused on understanding the correlations between humoral and cellular immunity during infection. They also examined whether pre- existing immunity to other seasonal coronaviruses could impact the outcome of SARS-CoV-2 infection.

When examining humoral immunity, they found that IgG antibodies against either N or S1 proteins of the virus developed during active infection and peaked at day 50 post-symptom onset, after which levels declined over time in recovered patients. Interestingly, higher IgG antibody levels were associated with more severe disease outcomes. As such, they also looked at T cell immunity and found that both patients with active COVID-19 and those who had recovered had SARS-CoV-2-specific T cells, however, there was a significant difference in the functionality of these cells between the two groups. Specifically, those with active COVID-19 had an overall reduced T cell repertoire than those who had recovered while also demonstrating impaired T cell function, which was linked to the presence of inhibitory molecules. They also exhibited characteristic immunological cellular profiles associated with  the development of lymphopenia (reduction of white blood cell counts) as well as strong pro-inflammatory responses during active infection. Conversely, those who had recovered demonstrated restored T cell repertoires, characterized by polyfunctional, mainly interferon-γ-secreting CD4+ T cells, which remained stable for up  to 102 days after symptom onset. Interestingly, individuals in both the active and recovered groups that had existing T cell immunity against other human coronavirus strains, exhibited higher  SARS-CoV-2- specific T cells as well, suggesting that pre-existing cellular immunity against endemic coronaviruses might be beneficial for the development of SARS-CoV-2 cellular immunity.

Overall, this study suggests that while antibody-mediated immunity plays an important role during initial SARS-CoV-2 infection, T cell immunity is critical for lasting protection. Active COVID-19 patients were associated with impaired T cell responses compared to the robust T cell immunity seen in those who had recovered from COVID-19. There was also evidence demonstrating that higher frequencies of SARS-CoV-2- specific T cells were associated with higher SARS-CoV-2 IgG antibodies, indicating a relationship between humoral and cellular immunity in moderate cases of COVID-19. Ultimately, this study helps us understand some of the important biomarkers that can help with COVID-19 diagnosis and prognosis and opens new avenues for the development of vaccines and therapies.

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