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

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

Double whammy: Dengue and Zika virus epidemics have been lapping each other around the globe. These are closely related mosquito-borne viruses with about 40% homology within the envelope protein. We know that subsequent dengue infections bring a risk of antibody-dependent disease enhancement. Whereas emphasis has been placed on how prior dengue immunity affects Zika infection, little is known about how prior Zika immunity may affect dengue disease. Katzelnick et al. have been following a well-characterized and established pediatric cohort in Nicaragua who were serially exposed to both flaviviruses in recent years (see the Perspective by Clapham). This study shows not only that a previous history of just one round of dengue is a problem but also that prior Zika immunity creates an increased risk for severe dengue virus sereotype 2 infection. By contrast, multiple infections raise antibodies to protective levels. Science , this issue p. 1123 ; see also p. 1055

A stabilized dimer of the surface protein from dengue virus has been engineered to elicit antibodies that neutralize the virus.

Zika virus (ZIKV) is an emerging flavivirus that can cause birth defects and neurologic complications. Molecular tests are effective for diagnosing acute ZIKV infection, although the majority of infections produce no symptoms at all or present after the narrow window in which molecular diagnostics are dependable. Serology is a reliable method for detecting infections after the viremic period; however, most serological assays have limited specificity due to cross-reactive antibodies elicited by flavivirus infections. Since ZIKV and dengue virus (DENV) widely cocirculate, distinguishing ZIKV infection from DENV infection is particularly important for diagnosing individual cases or for surveillance to coordinate public health responses. Flaviviruses also elicit type-specific antibodies directed to non-cross-reactive epitopes of the infecting virus; such epitopes are attractive targets for the design of antigens for development of serological tests with greater specificity. Guided by comparative epitope modeling of the ZIKV envelope protein, we designed two recombinant antigens displaying unique antigenic regions on domain I (Z-EDI) and domain III (Z-EDIII) of the ZIKV envelope protein. Both the Z-EDI and Z-EDIII antigens consistently detected ZIKV-specific IgG in ZIKV-immune sera but not cross-reactive IgG in DENV-immune sera in late convalescence (>12 weeks postinfection). In contrast, during early convalescence (2 to 12 weeks postinfection), secondary DENV-immune sera and some primary DENV-immune sera cross-reacted with the Z-EDI and Z-EDIII antigens. Analysis of sequential samples from DENV-immune individuals demonstrated that Z-EDIII cross-reactivity peaked in early convalescence and declined steeply over time. The Z-EDIII antigen has much potential as a diagnostic antigen for population-level surveillance and for detecting past infections in patients.

Understanding vaccine-mediated protection against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is critical to overcoming the global coronavirus disease 2019 (COVID-19) pandemic. We investigate mRNA-vaccine-induced antibody responses against the reference strain, seven variants, and seasonal coronaviruses in 168 healthy individuals at three time points: before vaccination, after the first dose, and after the second dose. Following complete vaccination, both naive and previously infected individuals developed comparably robust SARS-CoV-2 spike antibodies and variable levels of cross-reactive antibodies to seasonal coronaviruses. However, the strength and frequency of SARS-CoV-2 neutralizing antibodies in naive individuals were lower than in previously infected individuals. After the first vaccine dose, one-third of previously infected individuals lacked neutralizing antibodies; this was improved to one-fifth after the second dose. In all individuals, neutralizing antibody responses against the Alpha and Delta variants were weaker than against the reference strain. Our findings support future tailored vaccination strategies against emerging SARS-CoV-2 variants as mRNA-vaccine-induced neutralizing antibodies are highly variable among individuals.