2. SARS-CoV-2 Infection-Induced Immunity That Mediates Protection against Disease

Natural SARS-CoV-2 infection results in both humoral and cellular immune responses. Humoral immunity induced by viral infection appears to play important roles in mediating protection against COVID-19 disease. SARS-CoV-2 surface glycoproteins, mainly the spike protein, as well as the internal nucleocapsid protein, are the main targets of humoral immune responses. Most PCR-confirmed SARS-CoV-2–infected persons seroconverted by 2 weeks after disease onset [12]. Virus-specific IgG, IgA, and IgM responses were detected in acute and convalescent COVID-19 patients ^[13][14][13,14]. Zohar et al. explored the early evolution of the humoral response in COVID-19 patients and found complicated associations between disease severity and trajectories of antibody subtypes [15]. While a rapid and potent IgG class switching is correlated with survival, a delay but ultimate maturation of IgG subclasses is associated with milder disease [15]. Interestingly, such a trend was not found for IgA and IgM subtypes, which evolve rapidly regardless of disease severity [15].

The protective potential of humoral immunity was confirmed by some early studies on transfusion of plasma from convalescent patients or animal studies using potent purified monoclonal antibody cocktails ^{[16][17][18][19][20]}[16,17,18,19,20]. However, a recent clinical trial did not verify the clinical benefits in patients with severe COVID-19 pneumonia who received convalescent plasma [21]. A short window of time for successful administration of the plasma/antibody cocktails might be the key to explain this discrepancy, as suggested also for administration of monoclonal antibodies.

Similar to humoral immune responses, circulating SARS-CoV-2-specific CD4⁺ T-cell and CD8⁺ T-cell responses were detectable in most of SARS-CoV-2-infected patients within 1–2 weeks of symptom onset or at the convalescent stage ^[22][23][22,23]. Most virus specific CD4⁺T cell responses target spike and nucleocapsid glycoproteins as immunodominant. The responses were robust and mainly skewed towards Th1 cells, with the production of one or more of the Th1 cytokines, TNFα, IL-2, and IFNγ ^[22][23][24][22,23,24]. Though evidence of direct involvement of SARS-CoV-2-specific CD4⁺ T cells in mediating protection is lacking, for effective induction and long-term maintenance of antibody responses against COVID-19, a high-quality helper T cell response might be the key [25]. Several studies found that virus-specific CD4⁺ T cell responses were correlated with the magnitude of the anti-SARS-CoV-2 IgG and IgA against spike protein and nucleocapsid protein, live virus neutralizing antibody titers, and SARS-CoV-2 pseudovirus neutralization titers in COVID-19 patients ^{[13][22][23][26]}[13,22,23,26].

Data on other coronavirus infections in animals and humans suggested that the humoral immune responses waned within a short period of time, whereas cellular immunity might persist longer. For SARS-CoV-2, while the duration of protective immunity is not yet known, a recent study suggests that IgG spike protein was relatively stable over at least 6 months, CD4⁺ and CD8⁺ T cell responses declined with a half-life of 3–5 months [27]. Previous exposure to other coronaviruses might elicit responses cross-reactive with SARS-CoV-2. In light of this, studies on pre-existing immunity against SARS-CoV-2 showed that cross-reactive T cells and antibodies are present ^[28][29][30][28,29,30]. While pre-existing T cell responses targeting a variety of viral proteins have been reported, the pre-existing antibody responses were predominantly of the IgG class and targeted the S2 subunit ^[28][29][30][28,29,30]. Whether the pre-existing immunity affects COVID-19 disease severity, or the dynamics of the current pandemic remains to be determined. Furthermore, SARS-CoV-2 -specific T cell responses were more sensitive to antigen exposure than antibody responses, as virus-specific T-cell responses were induced in antibody-seronegative individuals who had been exposed to SARS-CoV-2 ^[31][32][31,32].

SARS-CoV-2-specific CD8⁺ T cell responses were detectable in up to 70% of convalescent COVID-19 patients ^{[13][22][23][28][31]}[13,22,23,28,31]. Virus-specific T cells displayed different phenotypes at different phases: highly activated cytotoxic phenotype at the acute stage, and polyfunctional and stem-like phenotype at the convalescent-stage [31]. Though there is some evidence suggesting that higher CD8⁺ T-cell responses were associated with mild disease, more studies are needed to elucidate whether virus-specific CD8⁺ T cells are pathogenic or protective in SARS-CoV-2 infections ^[23][31][33][23,31,33].

To identify the immune correlates of protection, though information from SARS-CoV-2 infections and vaccines are both valuable, extra caution is needed. Interpretation of the immune correlates from SARS-CoV-2–infected persons can be complicated and sometimes misleading. Like other viral infectious diseases, viral loads are a major driver of induced immune responses. Usually, patients with severe disease have high viral loads, which lead to high innate, and humoral/cellular immune responses, while the asymptomatic patients with lower viral loads induce lower immune responses. This is also true for SARS-Cov-2 infected patients. For example, vast numbers of studies have been carried out to characterize the humoral immune responses in COVID-19 acute or convalescent patients and most found that higher titers of neutralizing antibodies were induced in COVID-19 patients with severe disease than in those with mild disease [26]. The antibody responses also lasted longer in the patients with severe disease. Consistent with this, asymptomatic individuals manifested much weaker immune responses to SARS-CoV-2 infections than symptomatic ones [34]. Furthermore, in the early convalescent phase, IgG and neutralizing antibody levels in asymptomatic individuals declined much more quickly than those in the symptomatic patients [34]. However, these inverse correlations between disease severity and the magnitude of immune responses most likely indicate that severe disease, with high viral burden, leads to more robust immune responses, rather than the other way around.