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.

Changing with the times: Pandemic spread of a virus in naïe populations can select for mutations that alter pathogenesis, virulence, and/or transmissibility. The ancestral form of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that emerged from China has now been largely replaced by strains containing the mutation D614G (Asp ⁶¹⁴ -to-Gly) in the viral spike protein. Hou et al. compared the characteristics of the new variant against the ancestral form in a series of experiments in human cells and animal models. The variant is better at infecting upper-airway epithelial cells and replicates in greater numbers than the ancestral virus. Evidence indicates modest, if any, significant changes to virulence in animal models. Therefore, the virus appears to have evolved for greater transmissibility in humans rather than for greater pathogenicity. The mutation renders the new virus variant more susceptible to neutralizing antisera without altering the efficacy of vaccine candidates currently under development. Science , this issue p. 1464

The serum level of RBD-binding antibodies correlates with SARS-CoV-2 neutralization and can be used for population-level surveillance.

Seeking broad protection: As scientists develop therapeutic antibodies and vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the risk of emergent coronaviruses makes it important to also identify broadly protective antibodies. Wec et al. isolated and characterized hundreds of antibodies against the viral spike protein of SARS-CoV-2 from the memory B cells of a survivor of the 2003 outbreak caused by the related coronavirus, SARS-CoV. In both of these viruses, the spike protein facilitated viral entry by binding to the angiotensin-converting enzyme 2 (ACE2) receptor on human cells. The antibodies targeted multiple sites on the spike protein, but of nine antibodies that showed strong cross-neutralization, eight targeted the domain that binds to ACE2. These eight antibodies also neutralized a bat SARS-related virus. Illuminating the epitopes on the viral spike protein that bind cross-neutralizing antibodies could guide the design of broadly protective vaccines. Science , this issue p. 731

Targeting sarbecoviruses: As we continue to battle the COVID-19 pandemic, we must confront the possibility of new pathogenic coronaviruses emerging in humans in the future. With this in mind, Rappazzo et al. isolated antibodies from a survivor of the 2003 severe acute respiratory syndrome coronavirus (SARS-CoV), used yeast display libraries to introduce diversity into these antibodies, and then screened for binding to SARS-CoV-2. One of the affinity-matured progeny strongly neutralized SARS-CoV-2, SARS-CoV, and two SARS-related viruses from bats. In addition, this antibody bound to the receptor-binding domains from a panel of sarbecoviruses, suggesting broader activity, and provided protection against SARS-CoV and SARS-CoV-2 in mouse models. Science , this issue p. 823