Phase 1 Study of Safety, Reactogenicity, and Immunogenicity of a Novel MVA-SARS-2-ST Vaccine Candidate Administered as Inhalation Boost in SARS-CoV-2 Immunized Adults

Background: Existing parenteral SARS-CoV-2 vaccines protect against severe disease but do not reliably prevent infection or reinfection. Inhaled vaccines may elicit localized immunity in the respiratory tract, a principal entry site for SARS-CoV-2. Methods: In this investigator-initiated, single-center, open-label phase 1 trial (NCT05226390, ClinicalTrials.gov), 23 healthy adults previously immunized with EU-approved SARS-CoV-2 vaccines received a single inhaled dose of Modified Vaccinia virus Ankara-(MVA)-SARS-2-ST (1x107 IU), engineered to express a prefusion-stabilized SARS-CoV-2 spike. Participants were followed for 140 days. Primary endpoints included solicited local and systemic reactogenicity through day 7, unsolicited adverse events through day 28, serious adverse events throughout, and changes in spirometry and laboratory parameters. Secondary endpoints were changes in SARS-CoV-2 S1-specific IgG in serum and bronchoalveolar lavage; exploratory endpoints included changes in S1-specific IgA in serum and bronchoalveolar lavage, and methacholine responsiveness. Results: No serious adverse events were observed. Over 28 days, mild or moderate adverse events occurred in 87% of participants, predominantly cough, headache, and fatigue, all resolved. Pulmonary function and methacholine responsiveness were stable, except for one transient 20% decrease in FEV1 on Day 14 that normalized subsequently. Serum IgG responses remained minimal, whereas a subset displayed increased bronchoalveolar IgA. Conclusion: A single inhaled booster dose of MVA-SARS-2-ST was safe and generally well tolerated. While systemic antibody levels did not rise substantially, the observed mucosal IgA response in some participants points to a localized mucosal effect. Further studies are warranted to clarify underlying mechanisms and the significance of this response in diverse populations.