Immunological memory is the basis for durable protective immunity after infections or vaccinations. Duration of immunological memory after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and COVID-19 is unclear. Immunological memory can consist of memory B cells, antibodies, memory CD4⁺ T cells, and/or memory CD8⁺ T cells. Knowledge of the kinetics and interrelationships among those four types of memory in humans is limited. Understanding immune memory to SARS-CoV-2 has implications for understanding protective immunity against COVID-19 and assessing the likely future course of the COVID-19 pandemic.

Assessing virus-specific immune memory over at least a 6-month period is likely necessary to ascertain the durability of immune memory to SARS-CoV-2. Given the evidence that antibodies, CD4⁺ T cells, and CD8⁺ T cells can all participate in protective immunity to SARS-CoV-2, we measured antigen-specific antibodies, memory B cells, CD4⁺ T cells, and CD8⁺ T cells in the blood from subjects who recovered from COVID-19, up to 8 months after infection.

The study involved 254 samples from 188 COVID-19 cases, including 43 samples at 6 to 8 months after infection. Fifty-one subjects in the study provided longitudinal blood samples, allowing for both cross-sectional and longitudinal analyses of SARS-CoV-2–specific immune memory. Antibodies against SARS-CoV-2 spike and receptor binding domain (RBD) declined moderately over 8 months, comparable to several other reports. Memory B cells against SARS-CoV-2 spike actually increased between 1 month and 8 months after infection. Memory CD8⁺ T cells and memory CD4⁺ T cells declined with an initial half-life of 3 to 5 months. This is the largest antigen-specific study to date of the four major types of immune memory for any viral infection.

Among the antibody responses, spike immunoglobulin G (IgG), RBD IgG, and neutralizing antibody titers exhibited similar kinetics. Spike IgA was still present in the large majority of subjects at 6 to 8 months after infection. Among the memory B cell responses, IgG was the dominant isotype, with a minor population of IgA memory B cells. IgM memory B cells appeared to be short-lived. CD8⁺ T cell and CD4⁺ T cell memory was measured for all SARS-CoV-2 proteins. Although ~70% of individuals possessed detectable CD8⁺ T cell memory at 1 month after infection, that proportion declined to ~50% by 6 to 8 months after infection. For CD4⁺ T cell memory, 93% of subjects had detectable SARS-CoV-2 memory at 1 month after infection, and the proportion of subjects positive for CD4⁺ T cells (92%) remained high at 6 to 8 months after infection. SARS-CoV-2 spike-specific memory CD4⁺ T cells with the specialized capacity to help B cells [T follicular helper (T_FH) cells] were also maintained.

The different types of immune memory each had distinct kinetics, resulting in complex interrelationships between the abundance of T cell, B cell, and antibody immune memory over time. Additionally, substantially heterogeneity in memory to SARS-CoV-2 was observed.

Substantial immune memory is generated after COVID-19, involving all four major types of immune memory. About 95% of subjects retained immune memory at ~6 months after infection. Circulating antibody titers were not predictive of T cell memory. Thus, simple serological tests for SARS-CoV-2 antibodies do not reflect the richness and durability of immune memory to SARS-CoV-2. This work expands our understanding of immune memory in humans. These results have implications for protective immunity …