Abstract
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Understanding immune memory to SARS-CoV-2 is critical for improving diagnostics and vaccines, and for assessing the likely future course of the COVID-19 pandemic. We analyzed multiple compartments of circulating immune memory to SARS-CoV-2 in 254 samples from 188 COVID-19 cases, including 43 samples at ≥ 6 months post-infection. IgG to the Spike protein was relatively stable over 6+ months. Spike-specific memory B cells were more abundant at 6 months than at 1 month post symptom onset. SARS-CoV-2-specific CD4+ T cells and CD8+ T cells declined with a half-life of 3-5 months. By studying antibody, memory B cell, CD4+ T cell, and CD8+ T cell memory to SARS-CoV-2 in an integrated manner, we observed that each component of SARS-CoV-2 immune memory exhibited distinct kinetics.
Coronavirus disease 2019 (COVID-19), caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a serious disease that has resulted in widespread global morbidity and mortality. Humans make SARS-CoV-2-specific antibodies, CD4+ T cells, and CD8+ T cells in response to SARS-CoV-2 infection (1–4). Studies of acute and convalescent COVID-19 patients have observed that T cell responses are associated with reduced disease (5–7), suggesting that SARS-CoV-2-specific CD4+ T cell and CD8+ T cell responses may be important for control and resolution of primary SARS-CoV-2 infection. Ineffective innate immunity has been strongly associated with a lack of control of primary SARS-CoV-2 infection and a high risk of fatal COVID-19 (8–12), accompanied by innate cell immunopathology (13–18). Neutralizing antibodies have generally not correlated with lessened COVID-19 disease severity (5, 19, 20), which was also observed for Middle Eastern respiratory syndrome (MERS), caused by MERS-CoV (21). Instead, neutralizing antibodies are associated with protective immunity against secondary infection with SARS-CoV-2 or SARS-CoV in non-human primates (3, 22–25). Passive transfer of neutralizing antibodies in advance of infection (mimicking pre-existing conditions upon secondary exposure) effectively limits upper respiratory tract (URT) infection, lower respiratory tract (lung) infection, and symptomatic disease in animal models (26–28). Passive transfer of neutralizing antibodies provided after initiation of infection in humans have had more limited effects on COVID-19 (29, 30), consistent with a substantial role for T cells in control and clearance of an ongoing SARS-CoV-2 infection. Thus, studying antibody, memory B cell, CD4+ T cell, and CD8+ T cell memory to SARS-CoV-2 in an integrated manner is likely important for understanding the durability of protective immunity against COVID-19 generated by primary SARS-CoV-2 infection (1, 19, 31).
While sterilizing immunity against viruses can only be accomplished by high-titer neutralizing antibodies, successful protection against clinical disease or death can be accomplished by several other immune memory scenarios. Possible mechanisms of immunological protection can vary based on the relative kinetics of the immune memory responses and infection. For example, clinical hepatitis after hepatitis B virus (HBV) infection is prevented by vaccine-elicited immune memory even in the absence of circulating antibodies, because of the relatively slow course of HBV disease (32, 33). The relatively slow course of severe COVID-19 in humans (median 19 days post-symptom onset (PSO) for fatal cases (34)) suggests that protective immunity against symptomatic or severe secondary COVID-19 may involve memory compartments such as circulating memory T cells and memory B cells (which can take several days to reactivate and generate recall T cell responses and/or anamnestic antibody responses) (19, 21, 31).
Immune memory, from either primary infection or immunization, is the source of protective immunity from a subsequent infection (35–37). Thus, COVID-19 vaccine development relies on immunological memory (1, 3). Despite intensive study, the kinetics, duration, and evolution of immune memory in humans to infection or immunization are not in general predictable based on the initial effector phase, and immune responses at short time points after resolution of infection are not very predictive of long-term memory (38–40). Thus, assessing responses over an interval of six months or more is usually required to ascertain the durability of immune memory.
A thorough understanding of immune memory to SARS-CoV-2 requires evaluation of its various components, including B cells, CD8+ T cells, and CD4+ T cells, as these different cell types may have immune memory kinetics relatively independent of each other. Understanding the complexities of immune memory to SARS-CoV-2 is key to gain insights into the likelihood of durability of protective immunity against re-infection with SARS-CoV-2 and secondary COVID-19 disease. In the current study, we assessed immune memory of all three branches of adaptive immunity (CD4+ T cell, CD8+ T cell, and humoral immunity) in a predominantly cross-sectional study of 188 recovered COVID-19 cases, extending up to eight months post-infection. The findings have implications for immunity against secondary COVID-19, and thus the potential future course of the pandemic (41, 42).
COVID-19 cohort
188 individuals with COVID-19 were recruited for this study. Subjects (80 male, 108 female) represented a range of asymptomatic, mild, moderate, and severe COVID-19 cases (Table 1), and were recruited from multiple sites throughout the United States. The majority of subjects were from California or New York. Most subjects had a “mild” case of COVID-19, not requiring hospitalization. 93% of subjects were never hospitalized for COVID-19; 7% of subjects were hospitalized, some of whom required intensive care unit (ICU) care (Table 1). This case severity distribution was consistent with the general distribution of symptomatic disease severity among COVID-19 cases in the USA. The study primarily consisted of symptomatic disease cases (97%, Table 1), due to the nature of the study recruitment design. Subject ages ranged from 19 to 81 years old (Table 1). Most subjects provided a blood sample at a single time point, between 6 days post-symptom onset (PSO) and 240 days PSO (Table 1), with 43 samples at ≥ 6 months PSO (178 days or longer). Additionally, 51 subjects in the study provided longitudinal blood samples over a duration of several months (2-4 time points; Table 1), allowing for longitudinal assessment of immune memory in a subset of the cohort.
Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection
Abstract - Understanding immune memory to SARS-CoV-2 is critical for improving diagnostics and vaccines, and for assessing the likely future course of the COVID-19 pandemic. We analyzed multiple compartments of circulating immune memory to SARS-CoV-2 in 254 samples from 188 COVID-19 cases, including 43 samples at ≥ 6 months post-infection. IgG to the Spike protein was relatively stable over 6+ months. Spike-specific memory B cells were more abundant at 6 months than at 1 month post symptom onset. SARS-CoV-2-specific CD4+ T cells and CD8+ T cells declined with a half-life of 3-5 months. By studying antibody, memory B cell, CD4+ T cell, and CD8+ T cell memory to SARS-CoV-2 in an integrated manner, we observed that each component of SARS-CoV-2 immune memory exhibited distinct kinetics.
Coronavirus disease 2019 (COVID-19), caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a serious disease that has resulted in widespread global morbidity and mortality. Humans make SARS-CoV-2-specific antibodies, CD4+ T cells, and CD8+ T cells in response to SARS-CoV-2 infection (1–4). Studies of acute and convalescent COVID-19 patients have observed that T cell responses are associated with reduced disease (5–7), suggesting that SARS-CoV-2-specific CD4+ T cell and CD8+ T cell responses may be important for control and resolution of primary SARS-CoV-2 infection. Ineffective innate immunity has been strongly associated with a lack of control of primary SARS-CoV-2 infection and a high risk of fatal COVID-19 (8–12), accompanied by innate cell immunopathology (13–18). Neutralizing antibodies have generally not correlated with lessened COVID-19 disease severity (5, 19, 20), which was also observed for Middle Eastern respiratory syndrome (MERS), caused by MERS-CoV (21). Instead, neutralizing antibodies are associated with protective immunity against secondary infection with SARS-CoV-2 or SARS-CoV in non-human primates (3, 22–25). Passive transfer of neutralizing antibodies in advance of infection (mimicking pre-existing conditions upon secondary exposure) effectively limits upper respiratory tract (URT) infection, lower respiratory tract (lung) infection, and symptomatic disease in animal models (26–28). Passive transfer of neutralizing antibodies provided after initiation of infection in humans have had more limited effects on COVID-19 (29, 30), consistent with a substantial role for T cells in control and clearance of an ongoing SARS-CoV-2 infection. Thus, studying antibody, memory B cell, CD4+ T cell, and CD8+ T cell memory to SARS-CoV-2 in an integrated manner is likely important for understanding the durability of protective immunity against COVID-19 generated by primary SARS-CoV-2 infection (1, 19, 31).
While sterilizing immunity against viruses can only be accomplished by high-titer neutralizing antibodies, successful protection against clinical disease or death can be accomplished by several other immune memory scenarios. Possible mechanisms of immunological protection can vary based on the relative kinetics of the immune memory responses and infection. For example, clinical hepatitis after hepatitis B virus (HBV) infection is prevented by vaccine-elicited immune memory even in the absence of circulating antibodies, because of the relatively slow course of HBV disease (32, 33). The relatively slow course of severe COVID-19 in humans (median 19 days post-symptom onset (PSO) for fatal cases (34)) suggests that protective immunity against symptomatic or severe secondary COVID-19 may involve memory compartments such as circulating memory T cells and memory B cells (which can take several days to reactivate and generate recall T cell responses and/or anamnestic antibody responses) (19, 21, 31).
Immune memory, from either primary infection or immunization, is the source of protective immunity from a subsequent infection (35–37). Thus, COVID-19 vaccine development relies on immunological memory (1, 3). Despite intensive study, the kinetics, duration, and evolution of immune memory in humans to infection or immunization are not in general predictable based on the initial effector phase, and immune responses at short time points after resolution of infection are not very predictive of long-term memory (38–40). Thus, assessing responses over an interval of six months or more is usually required to ascertain the durability of immune memory.
A thorough understanding of immune memory to SARS-CoV-2 requires evaluation of its various components, including B cells, CD8+ T cells, and CD4+ T cells, as these different cell types may have immune memory kinetics relatively independent of each other. Understanding the complexities of immune memory to SARS-CoV-2 is key to gain insights into the likelihood of durability of protective immunity against re-infection with SARS-CoV-2 and secondary COVID-19 disease. In the current study, we assessed immune memory of all three branches of adaptive immunity (CD4+ T cell, CD8+ T cell, and humoral immunity) in a predominantly cross-sectional study of 188 recovered COVID-19 cases, extending up to eight months post-infection. The findings have implications for immunity against secondary COVID-19, and thus the potential future course of the pandemic (41, 42).
COVID-19 cohort
188 individuals with COVID-19 were recruited for this study. Subjects (80 male, 108 female) represented a range of asymptomatic, mild, moderate, and severe COVID-19 cases (Table 1), and were recruited from multiple sites throughout the United States. The majority of subjects were from California or New York. Most subjects had a “mild” case of COVID-19, not requiring hospitalization. 93% of subjects were never hospitalized for COVID-19; 7% of subjects were hospitalized, some of whom required intensive care unit (ICU) care (Table 1). This case severity distribution was consistent with the general distribution of symptomatic disease severity among COVID-19 cases in the USA. The study primarily consisted of symptomatic disease cases (97%, Table 1), due to the nature of the study recruitment design. Subject ages ranged from 19 to 81 years old (Table 1). Most subjects provided a blood sample at a single time point, between 6 days post-symptom onset (PSO) and 240 days PSO (Table 1), with 43 samples at ≥ 6 months PSO (178 days or longer). Additionally, 51 subjects in the study provided longitudinal blood samples over a duration of several months (2-4 time points; Table 1), allowing for longitudinal assessment of immune memory in a subset of the cohort.