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
Immune memory relationships
Immune memory to SARS-CoV-2 were considered, including relationships between the compartments of immune memory. Males had higher Spike IgG (ANCOVA p=0.00018, Fig. 5A) and RBD and Nucleocapsid IgG (ANCOVA p=0.00077 and p=0.018, fig. S6, A and B), consistent with other studies (46, 47). Higher Spike IgG was also observed in males when only non-hospitalized cases were considered (ANCOVA p=0.00025, fig. S6C). In contrast, no differences were observed in IgA or PSV neutralization titers (fig. S6, D to F), and no differences were detected in SARS-CoV-2 memory B cell, memory CD8+ T cell, or memory CD4+ T cell frequencies between males and females (fig. S6, G to K).
Immune memory was examined for associations between magnitude of memory and COVID-19 disease severity. The number of previously hospitalized COVID-19 cases (n=13) limited analysis options. However, the cases were well distributed between males and females (Table 1), data from large numbers of non-hospitalized cases were available for comparison, and the analyses in Figs. 1 to 4 demonstrated that immune memory was relatively stable over the time window analyzed. Therefore, we could simplify the disease severity analysis by grouping all samples from 120+ days PSO [also limiting data to a single sample per subject (figs. S7to S9); most of the previously hospitalized subjects were sampled at two timepoints. fig. S7A] and then comparing non-hospitalized and hospitalized subjects. Spike and RBD IgG titers in hospitalized cases were higher than non-hospitalized cases, consistent with other studies. Spike and RBD-specific memory B cell frequencies were also higher in hospitalized cases (~1.7-fold and ~2.5-fold, respectively. Fig. 5C and fig. S8). In contrast, memory CD8+ T cell frequencies were not higher in hospitalized cases compared to non-hospitalized cases (Fig. 5D and fig. S9) and memory CD4+ T cell frequencies trended lower in hospitalized cases compared to non-hospitalized cases (Fig. 5E and fig. S9). Therefore, while conclusions are limited by the number of hospitalized subjects, increased Spike IgG titers was consistent across three independent studies, and increased memory B cells among hospitalized cases were observed here (not measured in other studies), indicating that both compartments of long-term humoral immunity to SARS-CoV-2 are higher in individuals who experienced a more severe COVID-19 disease course. T cell memory did not follow the same pattern, consistent with indications that hospitalized cases of COVID-19 can be associated with poorer T cell responses in the acute phase (5, 59). Additionally, these data show that, while gender and COVID-19 disease severity contribute to differences in immune memory to SARS-CoV-2, neither factor could account for the majority of the heterogeneity in immune memory to this virus.
Very few published data sets compare antigen-specific antibody, B cell, CD8+ T cell, and CD4+ T cell memory to an acute viral infection in the same individuals. We therefore made use of this combined data set to examine interrelationships between compartments of immune memory. We focused on RBD IgG, RBD memory B cells, Spike IgA, total SARS-CoV-2-specific CD8+ T cells, and total SARS-CoV-2-specific CD4+ T cells, due to their putative potential roles in protective immunity. The majority (64%) of COVID-19 cases were positive for all five of these immune memory compartments at 1 to 2 months PSO (Fig. 5, F and G), with the incomplete responses largely reflecting individuals with no detectable CD8+ T cell memory and/or poor IgA responses (Fig. 5G). At 5 to 8 months after COVID-19, the proportion of individuals positive for all five of these immune memory compartments had dropped to 43%; nevertheless, 95% of individuals were still positive for at least three out of five SARS-CoV-2 immune memory responses. Immune memory at 5 to 8 months PSO represented contributions from different immune memory compartments in different individuals (Fig. 5G). Similar results were obtained if RBD IgG was replaced by neutralizing antibodies (fig. S10A). Overall, these findings again highlight heterogeneity of immune memory, with different patterns of immune memory in different individuals.
Interrelationships between the components of memory were next examined by assessing ratios between immune memory compartments over time. The ratio of SARS-CoV-2 CD4+ T cell memory to SARS-CoV-2 CD8+ T cell memory was largely stable over time (Fig. 5H and fig. S10B). Given that serological measurements are the simplest measurements of immune memory at a population scale, we examined how well such serological measurements may serve as surrogate markers of other components of SARS-CoV-2 immune memory over time. The relationship between circulating RBD IgG and RBD-specific memory B cells changed ~20-fold over the time range studied (R=0.60, Fig. 5H and fig. S10C). The changing relationship between circulating Spike IgA and RBD-specific memory B cells was even larger (R=0.55, Fig. 5H and fig. S10D). The relationship between RBD IgG and SARS-CoV-2 CD4+ T cell memory was relatively flat over the time range studied; however, variation spanned a ~1000-fold range (fig. S10E). Thus, predictive power of circulating RBD IgG for assessing T cell memory was poor because of the heterogeneity between individuals (R=0.046). In sum, while heterogeneity of immune responses is a defining feature of COVID-19, immune memory to SARS-CoV-2 develops in almost all subjects, with complex relationships between the individual immune memory compartments.
Concluding remarks In this study, we aimed to fill gaps in our basic understanding of immune memory after COVID-19. This required simultaneous measurement of circulating antibodies, memory B cells, CD8+ T cells, and CD4+ T cells specific for SARS-CoV-2, in a group of subjects with a full range of disease, and distributed from short time points after infection out to 8 months later. By studying these multiple compartments of adaptive immunity in an integrated manner, we observed that each component of SARS-CoV-2 immune memory exhibited distinct kinetics.
The Spike IgG titers were durable, with modest declines in titers at 6 to 8 months PSO at the population level. RBD IgG and SARS-CoV-2 PSV neutralizing antibody titers were potentially similarly stable, consistent with the RBD domain of Spike being the dominant neutralizing antibody target. We collected data at two time points for most longitudinal individuals herein. It is well recognized that the magnitude of the antibody response against SARS-CoV-2 is highly heterogeneous between individuals. We observed that heterogeneous initial antibody responses did not collapse into a homogeneous circulating antibody memory; rather, heterogeneity is also a central feature of immune memory to this virus. For antibodies, the responses spanned a ~200-fold range. Additionally, this heterogeneity means that long-term longitudinal studies will be required to precisely define antibody kinetics to SARS-CoV-2. We are reporting the simplest statistical models that explain the data. These curve fits do not disprove more complex kinetics such as overlapping kinetics, but those models would require much denser longitudinal sampling in future studies. Biologically, IgG antibodies having a half-life of ~21 days, and the magnitude of the antibody response over time reflects antibodies produced first by short-lived plasma cells and then long-lived plasma cells, with affinity maturation also impacting the apparent magnitude in conventional binding assays and neutralization assays. Overall, at 5 to 8 months PSO, almost all individuals were positive for SARS-CoV-2 Spike and RBD IgG.
Notably, memory B cells specific for the Spike protein or RBD were detected in almost all COVID-19 cases, with no apparent half-life at 5 to 8 months post-infection. Other studies of RBD memory B cells are reporting similar findings. B cell memory to some other infections has been observed to be long-lived, including 60+ years after smallpox vaccination, or 90+ years after infection with influenza. The memory T cell half-lives observed over 6+ months PSO in this cohort (~125-225 days for CD8+ and ~94-153 days for CD4+ T cells) were comparable to the 123 days t1/2 observed for memory CD8+ T cells after yellow fever immunization. SARS-CoV-2 T cell memory at 6 months has also now been reported in another study. Notably, the durability of a fraction of the yellow fever virus-specific memory CD8+ T cells possessed an estimated t1/2 of 485 days by deuterium labeling. Using different approaches, the long-term durability of memory CD4+ T cells to smallpox, over a period of many years, was an estimated t1/2 of ~10 years, which is also consistent with recent detection of SARS-CoV-T cells 17 years after the initial infection. These data suggest that T cell memory might reach a more stable plateau, or slower decay phase, beyond the first 8 months post-infection.
While immune memory is the source of long-term protective immunity, direct conclusions about protective immunity cannot be made on the basis of quantifying SARS-CoV-2 circulating antibodies, memory B cells, CD8+ T cells, and CD4+ T cells, because mechanisms of protective immunity against SARS-CoV-2 or COVID-19 are not defined in humans. Nevertheless, some reasonable interpretations can be made. Antibodies are the only component of immune memory that can provide truly sterilizing immunity. Immunization studies in non-human primates have indicated that circulating neutralization titers of ~200 may provide sterilizing immunity against a relatively high dose URT challenge (66), and neutralizing titers of ~3,400 may provide sterilizing immunity against a very high dose URT challenge (67), although direct comparisons are not possible because the neutralizing antibody assays have not been standardized (3). Conclusions are also constrained by the limited overall amount of data on protective immunity to SARS-CoV-2.
Beyond sterilizing immunity, immune responses that confine SARS-CoV-2 to the URT and oral cavity would minimize COVID-19 disease severity to that of a ‘common cold’ or asymptomatic disease. This outcome is the primary goal of current COVID-19 vaccine clinical trials. Such an outcome could potentially be mediated by a mixture of memory CD4+ T cells, memory CD8+ T cells, and memory B cells specific for RBD producing anamnestic neutralizing antibodies, based on mechanisms of action in mouse models of other viral infections. In human COVID-19 infections, SARS-CoV-2-specific CD4+ T cells and CD8+ T cells are associated with less COVID-19 disease severity during an ongoing SARS-CoV-2 infection. Rapid seroconversion was associated with significantly reduced viral loads in acute disease over 14 days. Both of those associations are consistent with the hypothesis that SARS-CoV-2 memory T cells and B cells would be capable of substantially limiting SARS-CoV-2 dissemination and/or cumulative viral load, resulting in reduced COVID-19 disease severity. The likelihood of such outcomes is also closely tied to the kinetics of the infection, as memory B and T cell responses can take 3-5 days to successfully respond to an infection. As noted above, given the relatively slow course of severe COVID-19 in humans, resting immune memory compartments can potentially contribute in meaningful ways to protective immunity against pneumonia or severe secondary COVID-19. The presence of sub-sterilizing neutralizing antibody titers at the time of SARS-CoV-2 exposure would blunt the size of the initial infection, and may provide an added contribution to limiting COVID-19 severity, based on observations of protective immunity for other human respiratory viral infections and observations of SARS-CoV-2 vaccines in non-human primates.
The current study has some limitations. Longitudinal data for each subject, with at least three time points per subject, would be required for more precise understanding of the kinetics of durability of SARS-CoV-2 antibodies. Nevertheless, the current cross-sectional data describe well the dynamics of SARS-CoV-2 memory B cells, CD8+ T cell, and CD4+ T cell over 8 months PSO. This study was not sufficiently powered to control for many variables simultaneously. Additionally, circulating memory was assessed here; it is possible that local URT immune memory is a minimal, moderate, or large component of immune memory after a primary infection with SARS-CoV-2. This remains to be determined.
Individual case reports show that reinfections with SARS-CoV-2 are occurring. However, a 2,800 person study found no symptomatic re-infections over a ~118 day window, and a 1,246 person study observed no symptomatic re-infections over 6 months. We observed heterogeneity in the magnitude of adaptive immune responses to SARS-CoV-2 persisting into the immune memory phase. It is therefore possible that a fraction of the SARS-CoV-2-infected population with low immune memory would become susceptible to re-infection relatively soon. While gender and disease severity both contribute some to the heterogeneity of immune memory reported here, the source of much of the heterogeneity in immune memory to SARS-CoV-2 is unknown and worth further examination. Perhaps heterogeneity derives from low cumulative viral load or a small initial inoculum in some individuals. Nevertheless, our data show immune memory in at least three immunological compartments was measurable in ~95% of subjects 5 to 8 months PSO, indicating that durable immunity against secondary COVID-19 disease is a possibility in most individuals.
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