Variable memory: Immune memory against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) helps to determine protection against reinfection, disease risk, and vaccine efficacy. Using 188 human cases across the range of severity of COVID-19, Dan et al. analyzed cross-sectional data describing the dynamics of SARS-CoV-2 memory B cells, CD8 ⁺ T cells, and CD4 ⁺ T cells for more than 6 months after infection. The authors found a high degree of heterogeneity in the magnitude of adaptive immune responses that persisted into the immune memory phase to the virus. However, immune memory in three immunological compartments remained measurable in greater than 90% of subjects for more than 5 months after infection. Despite the heterogeneity of immune responses, these results show that durable immunity against secondary COVID-19 disease is a possibility for most individuals. Science , this issue p. eabf4063

Limited knowledge is available on the relationship between antigen-specific immune responses and COVID-19 disease severity. We completed a combined examination of all three branches of adaptive immunity at the level of SARS-CoV-2-specific CD4⁺ and CD8⁺ T cell and neutralizing antibody responses in acute and convalescent subjects. SARS-CoV-2-specific CD4⁺ and CD8⁺ T cells were each associated with milder disease. Coordinated SARS-CoV-2-specific adaptive immune responses were associated with milder disease, suggesting roles for both CD4⁺ and CD8⁺ T cells in protective immunity in COVID-19. Notably, coordination of SARS-CoV-2 antigen-specific responses was disrupted in individuals ≥ 65 years old. Scarcity of naive T cells was also associated with aging and poor disease outcomes. A parsimonious explanation is that coordinated CD4⁺ T cell, CD8⁺ T cell, and antibody responses are protective, but uncoordinated responses frequently fail to control disease, with a connection between aging and impaired adaptive immune responses to SARS-CoV-2.

Preexisting immune response to SARS-CoV-2: Robust T cell responses to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus occur in most individuals with coronavirus disease 2019 (COVID-19). Several studies have reported that some people who have not been exposed to SARS-CoV-2 have preexisting reactivity to SARS-CoV-2 sequences. The immunological mechanisms underlying this preexisting reactivity are not clear, but previous exposure to widely circulating common cold coronaviruses might be involved. Mateus et al. found that the preexisting reactivity against SARS-CoV-2 comes from memory T cells and that cross-reactive T cells can specifically recognize a SARS-CoV-2 epitope as well as the homologous epitope from a common cold coronavirus. These findings underline the importance of determining the impacts of preexisting immune memory in COVID-19 disease severity. Science , this issue p. 89

Immune memory after vaccination: Vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has proven highly effective at preventing severe COVID-19. However, the evolution of viral variants, and waning antibody levels over time, raise questions regarding the longevity of vaccine-induced immune protection. Goel et al . examined B and T lymphocyte responses in individuals who received SARS-CoV-2 messenger RNA vaccines. They performed a 6-month longitudinal study of individuals who never had SARS-CoV-2 infection compared with people who had recovered from SARS-CoV-2. Humoral and cellular immune memory was observed in vaccinated individuals, as were functional immune responses against the Alpha (B.1.1.7), Beta (B.1.351), and Delta (B.1.617.2) viral variants. Analysis of T cell activity suggested that robust cellular immune memory may prevent hospitalization by limiting the development of severe disease. —PNK

T-cells have to recognize peptides presented on MHC molecules to be activated and elicit their effector functions. Several studies demonstrate that some peptides are more immunogenic than others and therefore more likely to be T-cell epitopes. We set out to determine which properties cause such differences in immunogenicity. To this end, we collected and analyzed a large set of data describing the immunogenicity of peptides presented on various MHC-I molecules. Two main conclusions could be drawn from this analysis: First, in line with previous observations, we showed that positions P4–6 of a presented peptide are more important for immunogenicity. Second, some amino acids, especially those with large and aromatic side chains, are associated with immunogenicity. This information was combined into a simple model that was used to demonstrate that immunogenicity is, to a certain extent, predictable. This model (made available at http://tools.iedb.org/immunogenicity/) was validated with data from two independent epitope discovery studies. Interestingly, with this model we could show that T-cells are equipped to better recognize viral than human (self) peptides. After the past successful elucidation of different steps in the MHC-I presentation pathway, the identification of variables that influence immunogenicity will be an important next step in the investigation of T-cell epitopes and our understanding of cellular immune responses. T-cells have to recognize peptides presented on MHC molecules to be activated and elicit their effector functions. Some peptide-MHC-I complexes (pMHCs) are better recognized by T-cells; we call such pMHCs more immunogenic. For other pMHCs, no recognizing T-cells seem to exist; we call such pMHCs non-immunogenic. We set out to determine which properties of pMHCs cause such differences in immunogenicity, by carefully collecting a large set of immunogenic and non-immunogenic pMHCs, and analysing the difference between these sets. Two important observations were made: First, in line with previous observations, we showed that positions P4–6 of a presented peptide are more important for immunogenicity. Second, some amino acids, especially those with large and aromatic side chains, seem to be better recognized by T-cells as they associate with immunogenicity. Next, this information was combined into a simple model to predict the immunogenicity of new pMHCs (this model is made available at http://tools.iedb.org/immunogenicity/). Interestingly, with this model we could show that T-cells are equipped to strongly recognize viral peptides. After the past successful elucidation of different steps in the MHC-I presentation pathway, the identification of variables that influence immunogenicity will be an important next step in the investigation of T-cell epitopes and our understanding of cellular immune responses.