A single-dose intranasal live-attenuated codon deoptimized vaccine provides broad protection against SARS-CoV-2 and its variants
Xiang Liu, Wern Hann Ng, Eva Žusinaite, Joseph R. Freitas, Adam Taylor, Venugopal Yerragunta, Shukra M. Aavula, Sambaiah Gorriparthi, P. Santhakumar, Rama Lakshmi Bonda, Priyanka Mani, Sridevi V. Nimmagadda, Sainan Wang, Laura Sandra Lello, Ali Zaid, Ujjwal Dua, Sharon Taft-Benz, Elizabeth J. Anderson, Victoria K. Baxter, Sanjay Sarkar, Zheng Lung Ling, Thomas M. Ashhurst, Samuel M. S. Cheng, Priyabrata Pattnaik, Anand Kumar Kanakasapapathy, Ralph S. Baric, Felicity J. Burt, Malik Peiris, Mark T. Heise, Nicholas J. C. King, Andres Merits, Rajendra Lingala, Suresh Mahalingam
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) continues its significant health and economic impact globally. Despite the success of spike-protein vaccines in preventing severe disease, long-lasting protection against emerging variants and the prevention of breakthrough infections and transmission remain elusive. We generate an intranasal live-attenuated SARS-CoV-2 vaccine, CDO-7N-1, using codon deoptimization. CDO-7N-1 shows highly attenuated replication and minimal or no lung pathology in vivo over multiple passages. It induces robust mucosal and systemic neutralizing antibody and T-cell subset responses, in mice (female K18-hACE2 and male HFH4-hACE2 mice), hamsters, and macaques triggered by a single immunization. Mice and hamsters vaccinated with CDO-7N-1 are protected from challenge with wild-type (WT) SARS-CoV-2 and other variants of concern. Serum from vaccinated animals neutralizes WT SARS-CoV-2, variants of concern (beta and delta), variants of interest (omicron XBB.1.5) and SARS-CoV-1. Antibody responses are sustained and enhanced by repeated immunization or infection with WT SARS-CoV-2. Immunity against all SARS-CoV-2 proteins by CDO-7N-1 should improve efficacy against future SARS-CoV-2 variants. Current SARS-CoV-2 vaccines require several injections for optimal immune protection. Here, the authors report an intranasal live-attenuated vaccine that induces long-term immunity following a single dose and protects from SARS-CoV-2 wildtype and variants in non-human primate and small animal models.