We are developing parainfluenza virus- and pneumovirus-vectored vaccines for intranasal immunization against SARS-CoV-2. These viral vectors are designed to be highly attenuated in humans. They replicate to low levels in the superficial layers of the respiratory epithelium, and are optimized to induce strong local mucosal and systemic immune responses to the SARS-CoV-2 spike protein S, the major protective antigen of SARS-CoV-2. Pediatric SARS-CoV-2 infections, though generally mild, are associated with substantial morbidity and contribute to transmission dynamics. A pediatric COVID vaccine for intranasal immunization would have the potential to reduce the burden of COVID illness while also restricting SARS-CoV-2 transmission. We developed bivalent vaccine candidates to protect infants and children against coronavirus disease-2019 (COVID-19) and parainfluenza virus type 3, another major cause of pediatric respiratory illness. These candidates are based on replication-competent chimeric bovine/human parainfluenza virus type 3 (B/HPIV3) expressing the prefusion-stabilized SARS-CoV-2 spike protein (S). Previously, we showed that prefusion stabilization increased S expression by B/HPIV3 in vitro. In hamsters, a single intranasal dose of B/HPIV3/S-2P or B/HPIV3/S-6P (expressing the 2P or 6P-stabilized version of the S protein) induced high levels of serum SARS-CoV-2-neutralizing antibodies, as well as S-specific IgA and IgG. In 2024, we advanced B/HPIV3/S-6P to clinical evaluation. In a first study, the safety of B/HPIV3/S-6P following intranasal immunization was evaluated in adults (NCT06026514). The clinical evaluation has been completed, and sample and data analysis are ongoing. A manuscript will be prepared. We also continued the preclinical development of these B/HPIV3 vectors. To further improve the breadth of the S-specific immune response, we generated versions of B/HPIV3/S-6P that express spike proteins of recently-circulating variants, and we evaluated their immunogenicity and antigenic breadth in hamsters. In addition, we developed a live vaccine based on murine pneumonia virus (MPV) as a next-generation SARS-CoV-2 vaccine for intranasal delivery. Murine pneumonia virus (MPV), a murine homolog of respiratory syncytial virus, is attenuated by host-range restriction in nonhuman primates and has a tropism for the respiratory tract. We generated MPV vectors expressing the wild-type SARS-CoV-2 spike protein (MPV/S) or its prefusion-stabilized form (MPV/S-2P). Both vectors replicated similarly in cell culture and stably expressed S. However, only S-2P was associated with MPV particles. After intranasal/intratracheal immunization of rhesus macaques, MPV/S and MPV/S-2P replicated to low levels in the airways. Despite its low-level replication, MPV/S-2P induced high levels of mucosal and serum IgG and IgA to SARS-CoV-2 S or its receptor-binding domain. Serum antibodies from MPV/S-2P-immunized animals efficiently inhibited ACE2 receptor binding to S proteins of variants of concern. Based on its attenuation and immunogenicity in macaques, MPV/S-2P will be further evaluated as a live-attenuated vaccine for intranasal immunization against SARS-CoV-2 (Kaiser et al., iScience, 2023; PMCID: PMC10746510). In 2024, we further evaluated the immunogenicity and protective efficacy of one or two doses of MPV/S-2P, delivered intranasally/intratracheally to rhesus macaques. A single dose of MPV/S-2P was highly immunogenic, and a second dose increased the magnitude and breadth of the mucosal and systemic anti-S antibody responses and increased levels of dimeric anti-S IgA in the airways. MPV/S-2P also induced S-specific CD4+ and CD8+ T-cells in the airways that differentiated into large populations of tissue-resident memory cells within a month after the boost. One dose induced substantial protection against SARS-CoV-2 challenge, and two doses of MPV/S-2P were fully protective against SARS-CoV-2 challenge virus replication in the airways. A prime/boost immunization with a mucosally-administered live-attenuated MPV vector could thus be highly effective in preventing SARS-CoV-2 infection and replication (Kaiser et al., Nat Commun. 2024; PMCID: PMC11053155). Based on these results, clinical trial material has been generated, and we advanced this vaccine candidate to a Phase 1 study in collaboration with DMID's NextGen COVID vaccine study network (NCT06441968; PI: Hana Sahly, Houston, TX).