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. The vaccine vectors express prefusion-stabilized 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 replicate in the superficial layers of the respiratory epithelium, inducing strong local mucosal and systemic immune responses to the SARS-CoV-2 S protein, including virus-neutralizing serum antibodies, and a systemic and mucosal response of multifunctional SARS-CoV-2 S-specific CD8+ and CD4+ T cells. Pediatric SARS-CoV-2 infections, though generally mild, are associated with substantial morbidity and contribute to transmission dynamics. 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 prefusion-stabilized (S-2P) SARS-CoV-2 S spike protein, the major protective and neutralization antigen of SARS-CoV-2. Prefusion stabilization increased S expression by B/HPIV3 in vitro. In hamsters, a single intranasal dose of B/HPIV3/S-2P induced high levels of serum SARS-CoV-2-neutralizing antibodies, and serum IgA and IgG to SARS-CoV-2 S protein. Serum 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 4.5 log10 50% tissue-culture infectious-dose (TCID50) of SARS-CoV-2. In B/HPIV3 empty vector-immunized hamsters, SARS-CoV-2 replicated to mean titers of 6.6 log10 TCID50/g in lungs and 7 log10 TCID50/g in nasal tissues and induced moderate weight loss. In B/HPIV3/S-2P-immunized hamsters, infectious SARS-CoV-2 challenge virus was undetectable in nasal tissues and lungs; immunization with B/HPIV3/S-2P protected against weight loss after SARS-CoV-2 challenge. Based on these results, B/HPIV3 expressing a prefusion-stabilized version of the S protein is a promising vaccine candidate to protect infants and young children against HPIV3 and SARS-CoV-2 (Liu X, Luongo C, Matsuoka Y, Park HS, Santos C, Yang L, Moore IN, Afroz S, Johnson RF, Lafont BAP, Martens C, Best SM, Munster VJ, Holly J, Yewdell JW, Le Nouen C, Munir S, Buchholz UJ. A single intranasal dose of a live-attenuated parainfluenza virus-vectored SARS-CoV-2 vaccine is protective in hamsters. Proceedings of the National Academy of Sciences of the United States of America. 2021;118(50)). Clinical trial material of the lead B/HPIV3-based vaccine candidate was manufactured under cGMP for evaluation of safety and immunogenicity in a Phase 1 study. Single-dose vaccines with the ability to restrict 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, including avian paramyxovirus type 3 (APMV3). In a preclinical study, we found that APMV3 expressing the prefusion-stabilized S-6P version of the S protein (APMV3/S-6P) replicated to high titers in embryonated chicken eggs and was genetically stable. In hamsters, a single intranasal dose of APMV3/S-6P induced strong serum IgG and IgA responses to the S protein and its receptor-binding domain, and strong serum neutralizing antibody responses to the vaccine-matched SARS-CoV-2 isolate WA1/2020 (lineage A). Sera from APMV3/S-6P-immunized hamsters also efficiently neutralized Alpha and Beta variants of concern. Immunized hamsters challenged with WA1/2020 did not exhibit the weight loss and lung inflammation observed in empty vector-immunized controls; SARS-CoV-2 replication in the upper and lower respiratory tract of immunized animals was low or undetectable compared to the substantial replication in controls. Thus, a single intranasal dose of APMV3/S-6P was highly immunogenic and protective against SARS-CoV-2 challenge, suggesting that APMV3/S-6P is suitable for clinical development (Park HS, Matsuoka Y, Luongo C, Yang L, Santos C, Liu X, Ahlers LRH, Moore IN, Afroz S, Johnson RF, Lafont BAP, Dorward DW, Fischer ER, Martens C, Samal SK, Munir S, Buchholz UJ, Le Nouen C. Intranasal immunization with avian paramyxovirus type 3 expressing SARS-CoV-2 spike protein protects hamsters against SARS-CoV-2. NPJ Vaccines. 2022;7(1):72).