Over the last three years, SARS-CoV-2 has reached every part of the world, killing millions of people and bringing huge financial losses that will take a long time to recover. Continuous circulation of SARS-CoV-2 in humans has led to the emergence of highly transmissible variants of concern (VOC) with immune evasion abilities. While the most recent Omicron variants mainly cause mild upper respiratory disease, high transmission rates and reinfections due to immune evasion can still lead to substantial numbers of hospitalizations and deaths, especially among the elderly. Current available vaccines for SARS-CoV-2 are effective in reducing severe diseases and deaths but less optimal in preventing infection. Therefore, next-generation vaccines which could effectively induce mucosal immunity in the upper respiratory tract to prevent or reduce infections of SARS-CoV-2 variants are urgently needed.
On top of that, it is possible that SARS-CoV-2 continue to evolve and co-circulate with other coronaviruses and influenza viruses in humans, which could led to annual epidemics. A dual functional vaccine that protect against both SARS-CoV-2 and influenza is a better option in the future management of these viruses. That is why we choose influenza as the viral vector to develop our nasal spray vaccines. Our lab has long been interested in developing DelNS1 live attenuated influenza vaccine system for flu and other respiratory pathogens. The identification of adaptative mutations in NS1-deleted (DelNS1) influenza viruses that allow replication in embryonated chicken eggs and MDCK cells provided the opportunity for us to use influenza virus as a potent viral vector to develop various live attenuated vaccines. We have developed many intranasal vaccine candidates based on live attenuated influenza virus (LAIV) with a deleted NS1 gene and insert receptor-binding-domain (RBD) of the SARS-CoV-2 spike protein. The flu surface proteins of our vaccine are changeable to adapt to circulating strain of H1N1 and H3N2.
In December 2022, an early version of our influenza-based DelNS1-RBD LAIV intranasal vaccine for SARS-CoV-2 has been approved for emergency use in humans in China, which marked a significant milestone in the development of our vaccine system. In order to improve the effectiveness of our vaccine system in preventing infection and reducing virus transmission, we further developed a modified version, DelNS1-RBD4N-DAF. In this study, we evaluated it in mouse and hamster models. The current version carries two important features; the addition of a membrane anchoring motif, DAF, that optimizes cell surface RBD expression and introduction of four N-glycosylation sites to shield epitopes outside of the receptor binding motif (RBM) and encourage generation of antibodies specific for ACE2 competing epitopes, and it also increase the expression of RBD in cell lines representing a range of mammalian species.
We showed that DelNS1-RBD4N-DAF LAIVs expressing various RBDs derived from variants of SARS-CoV-2 are immunogenic and able to induce both systemic and mucosal specific immunity against SARS-CoV-2 RBD and effectively protect, and in some instances cross-protect, against infection by SARS-CoV-2 variants in mouse and hamster models. DelNS1-RBD4N-DAF LAIVs induced high levels of neutralizing antibodies against various SARS-CoV-2 variants in mice and hamsters and stimulated robust T cell responses in mice. These influenza-based DelNS1-RBD4N-DAF vaccines distinguish themselves through their ability to induce immunity in respiratory tissues and to provide near-sterilizing immunity against SARS-CoV-2 infection. Our results indicate that immunization with DelNS1-RBD4N-DAF through the intranasal route can induce acute and memory phase T cell responses in lungs and spleens, with much higher levels of acute phase T cells being present in the lungs.
We further tested if DelNS1-RBD4N-DAF LAIVs, which we showed to protect against SARS-CoV-2, can also be used for protection against influenza virus infection. Examination of specific antibodies to hemagglutinin (HA) and influenza nucleoprotein (NP) specific T cells response showed that DelNS1-RBD4N-DAF LAIVs retain the ability to induce immunity to influenza components in immunized mice. Therefore, our results demonstrate that the DelNS1-RBD4N-DAF influenza virus vector vaccine platform has strong potential to be developed into a dual function vaccine for prevention of infection with both influenza and SARS-CoV-2 viruses.
In summary, our team developed a safe and highly effective vaccine that provides protection by inducing high levels of neutralizing antibodies, T-cell responses and mucosal immunity. Compared to currently used vaccines for SARS-CoV-2, our vaccine platform has its unique advantages. Through mucosal immunity, it could block virus replication in the upper respiratory tract before the pathogen gains a foothold. Most importantly, by incorporating HA and NA matching circulating influenza strains, our bi-functional vaccines are able to cope with seasonal influenza and SARS-CoV-2 dual epidemics in the future.
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