Dynamics of immunity over time: decline of anti-SARS-CoV-2 IgG antibodies and T-cell responses after mRNA vaccination in residents and health care workers in nursing homes and homes with assisted living support.

Background: In the present study, we investigated the dynamics of immunity over time by measuring anti SARS-CoV-2 IgG antibodies and SARS-CoV-2 specific T-cell responses (interferon-gamma release assay) after two doses of vaccines in residents and health care workers (HCW). Mostly, 224 (98%) residents and 244 (89%) HCW received two doses of mRNA vaccine (BNT162b2, Pfizer-BioNTech); the rest of the participants received heterologous vaccinations with mRNA and vector vaccines. The study was conducted at the time when the Delta variant of SARS-CoV-2 prevailed. Methods: We analyzed blood samples of 228 residents (median age 83.8 years) and of 273 HCW (median age 49.7 years) from five nursing homes and one home for the elderly with assisted living support at one specific time point. Participants received two vaccinations. The blood samples were analyzed for SARS-CoV-2 specific IgG antibody and T-cell responses. Results: The initial immune responses in the younger participants were about 30% higher than in the older age group. Over time the estimated mean of the parameters (estimated from the study sample for the total population) decreased in all groups within the maximum observation period of 232 days. Comorbidities such as coronary heart disease or diabetes mellitus reduced the initial immune responses regardless of age. With regard to measured IgG antibody levels, absolute values decreased over time, whereas the interferon-gamma response remained at a constant level between day 120 and 180 and seemed to be less dependent on the time elapsed after vaccination. Conclusions: Based on our data, it does not seem possible to determine a reliable threshold of robust immunity, but we suggest that high titres of neutralizing capacity and interferon-gamma response might be an indicator of protection against severe COVID-19 courses.

3D Ex vivo tissue platforms to investigate the early phases of influenza a virus- and SARS-CoV-2-induced respiratory diseases.

Pandemic outbreaks of viruses such as influenza virus or SARS-CoV-2 are associated with high morbidity and mortality and thus pose a massive threat to global health and economics. Physiologically relevant models are needed to study the viral life cycle, describe the pathophysiological consequences of viral infection, and explore possible drug targets and treatment options. While simple cell culture-based models do not reflect the tissue environment and systemic responses, animal models are linked with huge direct and indirect costs and ethical questions. Ex vivo platforms based on tissue explants have been introduced as suitable platforms to bridge the gap between cell culture and animal models. We established a murine lung tissue explant platform for two respiratory viruses, influenza A virus (IAV) and SARS-CoV-2. We observed efficient viral replication, associated with the release of inflammatory cytokines and the induction of an antiviral interferon response, comparable to ex vivo infection in human lung explants. Endolysosomal entry could be confirmed as a potential host target for pharmacological intervention, and the potential repurposing potentials of fluoxetine and interferons for host-directed therapy previously seen in vitro could be recapitulated in the ex vivo model.

Antiviral potential of human IFN-α subtypes against influenza A H3N2 infection in human lung explants reveals subtype-specific activities.

Influenza is an acute respiratory infection causing high morbidity and mortality in annual outbreaks worldwide. Antiviral drugs are limited and pose the risk of resistance development, calling for new treatment options. IFN-α subtypes are immune-stimulatory cytokines with strong antiviral activities against IAV in vitro and in vivo. However, the clinical use of IFN-α2, the only licensed subtype of this multi-gene family, could not prevent or limit IAV infections in humans. However, the other subtypes were not investigated.Therefore, this study evaluated the induction and antiviral potential of all human IFN-α subtypes during H3N2 IAV infection in human lung explants. We found that subtypes with weak antiviral activities were preferentially induced during IAV infection in human lungs. Intriguingly, non-induced subtypes α16, α5 and α4 suppressed viral replication up to 230-fold more efficiently than α2. Furthermore, our results demonstrate that subtypes with stronger antiviral activities induce higher expression of IAV-specific restriction factors and that MxA expression is a determinant of the subtype-specific antiviral activity towards H3N2 IAV. These results corroborate that IFN-α subtypes exhibit differential antiviral activities and emphasize that subtypes α16, α5 and α4 should be further investigated for the prevention and treatment of severe infections with seasonal H3N2 IAV.