Paramyxoviruses as Vaccine Vectors Against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)

National Institute Of Allergy And Infectious Diseases

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Abstract

We are developing paramyxovirus vectored vaccines for intranasal immunization against SARS-CoV-2. These vectors express immunogenic versions of the SARS-CoV-2 S protein and are designed to be highly attenuated in humans while maintaining a high level of immunogenicity at the primary sites of infection of SARS-CoV-2. The viral vectors are designed to replicate in the superficial layers of the respiratory epithelium, inducing local mucosal and systemic innate immunity, virus-neutralizing serum antibodies, and CD8+ and CD4+ T cells. In 2021, we characterized vaccine candidates in cell culture and in animal models. Pediatric SARS-CoV-2 infections, though generally mild, are associated with substantial morbidity and contribute to transmission dynamics. No SARS-CoV-2 vaccines are available for young children. In 2021, we developed live intranasal vector vaccine candidates for infants and children against coronavirus disease-2019 (COVID-19) based on replication-competent chimeric bovine/human parainfluenza virus type 3 (B/HPIV3) expressing the native (S) or prefusion-stabilized (S-2P) SARS-CoV-2 S spike protein, the major protective and neutralization antigen of SARS-CoV-2. B/HPIV3/S and B/HPIV3/S-2P replicated as efficiently as the empty vector B/HPIV3 control in vitro and stably expressed SARS-CoV-2 S. Prefusion stabilization increased S expression by B/HPIV3 in vitro. In hamsters, a single intranasal dose of B/HPIV3/S-2P induced significantly higher titers compared to B/HPIV3/S of serum SARS-CoV-2-neutralizing antibodies (12-fold higher) and serum IgG and IgA to SARS-CoV-2 S protein (13-fold and 5-fold) and receptor binding domain (10-fold). Antibodies exhibited broad neutralizing activity against SARS-CoV-2 of lineages A, B.1.1.7, and B.1.351. Four weeks after immunization, hamsters were challenged intranasally with SARS-CoV-2. In B/HPIV3 empty vector-immunized hamsters, SARS-CoV-2 replicated to high titers in lungs and nasal tissues and induced moderate weight loss. In B/HPIV3/S-immunized hamsters, SARS-CoV-2 challenge virus was reduced 20-fold in nasal tissues and undetectable in lungs. In B/HPIV3/S-2P-immunized hamsters, infectious challenge virus was undetectable in nasal tissues and lungs; B/HPIV3/S or B/HPIV3/S-2P completely protected against weight loss after SARS-CoV-2 challenge. Characterization of correlates of protection in rhesus macaques is ongoing. Based on our results, B/HPIV3/S-2P is a promising vaccine candidate to protect infants and young children against HPIV3 and SARS-CoV-2. Clinical trial material of this vaccine candidate is being manufactured under cGMP for evaluation of safety and immunogenicity in a Phase 1 study. Single-dose vaccines with the ability to restrict severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication in the respiratory tract are needed for all age groups, aiding efforts towards control of COVID-19. In addition to the B/HPIV3/S-2P candidate described above, we are developing vector vaccine candidates based on vector platforms without pre-existing anti-vector immunity in humans. Preclinical characterizations in vitro and in vivo are ongoing.