The authors' full names, academic degrees, and affiliations are listed in the Appendix. Prof. Orkin can be contacted at c . m .

In animal models, resident memory CD8+ T (Trm) cells assist in respiratory virus elimination but their importance in man has not been determined. Here, using experimental human respiratory syncytial virus (RSV) infection, we investigate systemic and local virus-specific CD8+ T-cell responses in adult volunteers. Having defined the immunodominance hierarchy, we analyse phenotype and function longitudinally in blood and by serial bronchoscopy. Despite rapid clinical recovery, we note surprisingly extensive lower airway inflammation with persistent viral antigen and cellular infiltrates. Pulmonary virus-specific CD8+ T cells display a CD69+CD103+ Trm phenotype and accumulate to strikingly high frequencies into convalescence without continued proliferation. While these have a more highly differentiated phenotype, they express fewer cytotoxicity markers than in blood. Nevertheless, their abundance before infection correlates with reduced symptoms and viral load, implying that CD8+ Trm cells in the human lung can confer protection against severe respiratory viral disease when humoral immunity is overcome.

Rationale: Despite relative antigenic stability, respiratory syncytial virus (RSV) reinfects throughout life. After more than 40 years of research, no effective human vaccine exists and correlates of protection remain poorly defined. Most current vaccine candidates seek to induce high levels of RSV-specific serum neutralizing antibodies, which are associated with reduced RSV-related hospitalization rates in observational studies but may not actually prevent infection.Objectives: To characterize correlates of protection from infection and the generation of RSV-specific humoral memory to promote effective vaccine development.Methods: We inoculated 61 healthy adults with live RSV and studied protection from infection by serum and mucosal antibody. We analyzed RSV-specific peripheral blood plasmablast and memory B-cell frequencies and antibody longevity.Measurements and Main Results: Despite moderately high levels of preexisting serum antibody, 34 (56%) became infected, of whom 23 (68%) developed symptomatic colds. Prior RSV-specific nasal IgA correlated significantly more strongly with protection from polymerase chain reaction-confirmed infection than serum neutralizing antibody. Increases in virus-specific antibody titers were variable and transient in infected subjects but correlated with plasmablasts that peaked around Day 10. During convalescence, only IgG (and no IgA) RSV-specific memory B cells were detectable in peripheral blood. This contrasted with natural influenza infection, in which virus-specific IgA memory B cells were readily recovered.Conclusions: This observed specific defect in IgA memory may partly explain the ability of RSV to cause recurrent symptomatic infections. If so, vaccines able to induce durable RSV-specific IgA responses may be more protective than those generating systemic antibody alone.

The variable outcome of viral exposure is only partially explained by known factors. We administered respiratory syncytial virus (RSV) to 58 volunteers, of whom 57% became infected. Mucosal neutrophil activation before exposure was highly predictive of symptomatic RSV disease. This was associated with a rapid, presymptomatic decline in mucosal interleukin-17A (IL-17A) and other mediators. Conversely, those who resisted infection showed presymptomatic activation of IL-17– and tumor necrosis factor–related pathways. Vulnerability to infection was not associated with baseline microbiome but was reproduced in mice by preinfection chemokine-driven airway recruitment of neutrophils, which caused enhanced disease mediated by pulmonary CD8+ T cell infiltration. Thus, mucosal neutrophilic inflammation at the time of RSV exposure enhances susceptibility, revealing dynamic, time-dependent local immune responses before symptom onset and explaining the as-yet unpredictable outcomes of pathogen exposure.

Background Healthcare worker (HCW)-associated coronavirus disease 2019 (COVID-19) is of global concern due to the potential for nosocomial spread and depletion of staff numbers. However, the literature on transmission routes and risk factors for COVID-19 in HCWs is limited. Aim To examine the characteristics and transmission dynamics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in HCWs in a university teaching hospital in London, UK. Methods Staff records and virology testing results were combined to identify staff sickness and COVID-19 rates from March to April 2020. Comparisons were made with staff professional groups, department of work, and ethnicity. Findings COVID-19 rates in our HCWs largely rose and declined in parallel with the number of community cases. White and non-White ethnic groups among our HCWs had similar rates of infection. Clinical staff had a higher rate of laboratory-confirmed COVID-19 than non-clinical staff, but total sickness rates were similar. Doctors had the highest rate of infection, but took the fewest sickness days. Critical care had lower rates than the emergency department (ED), but rates in the ED declined when all staff were advised to use personal protective equipment (PPE). Conclusion Sustained transmission of SARS-CoV-2 among our hospital staff did not occur, beyond the community outbreak, even in the absence of strict infection control measures in non-clinical areas. Current PPE appears to be effective when used appropriately. Our findings emphasize the importance of testing both clinical and non-clinical staff groups during a pandemic.