Longitudinal Tracking of Immune Responses in COVID-19 Convalescents Reveals Absence of Neutralization Activity Against Omicron and Staggered Impairment to Other SARS-CoV-2 Variants of Concern.

Evaluating long-term protection against SARS-CoV-2 variants of concern in convalescing individuals is of high clinical relevance. In this prospective study of a cohort of 46 SARS-CoV-2 patients infected with the Wuhan strain of SARS-CoV-2 we longitudinally analyzed changes in humoral and cellular immunity upon early and late convalescence. Antibody neutralization capacity was measured by surrogate virus neutralization test and cellular responses were investigated with 31-colour spectral flow cytometry. Spike-specific, isotype-switched B cells developed already during the disease phase, showed a memory phenotype and did not decrease in numbers even during late convalescence. Otherwise, no long-lasting perturbations of the immune compartment following COVID-19 clearance were observed. During convalescence anti-Spike (S1) IgG antibodies strongly decreased in all patients. We detected neutralizing antibodies against the Wuhan strain as well as the Alpha and Delta but not against the Beta, Gamma or Omicron variants for up to 7 months post COVID-19. Furthermore, correlation analysis revealed a strong association between sera anti-S1 IgG titers and their neutralization capacity against the Wuhan strain as well as Alpha and Delta. Overall, our data suggest that even 7 month after the clearance of COVID-19 many patients possess a protective layer of immunity, indicated by the persistence of Spike-specific memory B cells and by the presence of neutralizing antibodies against the Alpha and Delta variants. However, lack of neutralizing antibodies against the Beta, Gamma and Omicron variants even during the peak response is of major concern as this indicates viral evasion of the humoral immune response.

Intranasal Delivery of MVA Vector Vaccine Induces Effective Pulmonary Immunity Against SARS-CoV-2 in Rodents.

Antigen-specific tissue-resident memory T cells (Trms) and neutralizing IgA antibodies provide the most effective protection of the lungs from viral infections. To induce those essential components of lung immunity against SARS-CoV-2, we tested various immunization protocols involving intranasal delivery of a novel Modified Vaccinia virus Ankara (MVA)-SARS-2-spike vaccine candidate. We show that a single intranasal MVA-SARS-CoV-2-S application in mice strongly induced pulmonary spike-specific CD8+ T cells, albeit restricted production of neutralizing antibodies. In prime-boost protocols, intranasal booster vaccine delivery proved to be crucial for a massive expansion of systemic and lung tissue-resident spike-specific CD8+ T cells and the development of Th1 - but not Th2 - CD4+ T cells. Likewise, very high titers of IgG and IgA anti-spike antibodies were present in serum and broncho-alveolar lavages that possessed high virus neutralization capacities to all current SARS-CoV-2 variants of concern. Importantly, the MVA-SARS-2-spike vaccine applied in intramuscular priming and intranasal boosting treatment regimen completely protected hamsters from developing SARS-CoV-2 lung infection and pathology. Together, these results identify intramuscular priming followed by respiratory tract boosting with MVA-SARS-2-S as a promising approach for the induction of local, respiratory as well as systemic immune responses suited to protect from SARS-CoV-2 infections.