Abstract
Vaccination is the best way to prevent influenza virus infections, but the diversity of antigenically distinct isolates is a persistent challenge for vaccine development. In order to conquer the antigenic variability and improve influenza virus vaccine efficacy, our research group has developed computationally optimized broadly reactive antigens (COBRAs) in the form of recombinant hemagglutinins (rHAs) to elicit broader immune responses. However, previous COBRA H1N1 vaccines do not elicit immune responses that neutralize H1N1 virus strains in circulation during the recent years. In order to update our COBRA vaccine, two new candidate COBRA HA vaccines, Y2 and Y4, were generated using a new seasonal-based COBRA methodology derived from H1N1 isolates that circulated during 2013–2019. In this study, the effectiveness of COBRA Y2 and Y4 vaccines were evaluated in mice, and the elicited immune responses were compared to those generated by historical H1 COBRA HA and wild-type H1N1 HA vaccines. Mice vaccinated with the next generation COBRA HA vaccines effectively protected against morbidity and mortality after infection with H1N1 influenza viruses. The antibodies elicited by the COBRA HA vaccines were highly cross-reactive with influenza A (H1N1) pdm09-like viruses isolated from 2009 to 2021, especially with the most recent circulating viruses from 2019 to 2021. Furthermore, viral loads in lungs of mice vaccinated with Y2 and Y4 were dramatically reduced to low or undetectable levels, resulting in minimal lung injury compared to wild-type HA vaccines following H1N1 influenza virus infection.
Highlights
Influenza is an acute respiratory infection caused by a virus, belonging to the Orthomyxoviridae family, which circulates in all parts of the world
Viral loads in lungs of mice vaccinated with Y2 and Y4 were dramatically reduced to low or undetectable levels, resulting in minimal lung injury compared to wild-type HA vaccines following H1N1 influenza virus infection
In order to determine the protective efficacy of the generation H1N1 computationally optimized broadly reactive antigens (COBRAs) HA vaccines, BALB/c mice (n = 11/group) were intramuscularly inoculated with purified virus-like particles (VLPs) expressing either COBRA or wild-type HA antigens (1 μg/HA content) formulated with AddaVax three times at 4-week intervals
Summary
Influenza is an acute respiratory infection caused by a virus, belonging to the Orthomyxoviridae family, which circulates in all parts of the world. Seasonal influenza viruses represent a year-round disease burden, causing illnesses that range in severity, leading to hospitalization and numerous deaths worldwide [1,2]. An average of 389,000 deaths were estimated to be associated with influenza virus infections each year during the period of 2002–2011 [3]. In the United States, 9–45 million people have been infected with seasonal influenza viruses annually since 2010, resulting in 140,000 to 810,000 hospitalizations and 12,000 to 61,000 deaths (https://www.cdc.gov/flu/anout/burden/, accessed on 12 April 2021). Vaccination is still the most effective intervention to prevent and control influenza virus infection
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