Headless hemagglutinin-containing influenza viral particles direct immune responses toward more conserved epitopes.

Autor:	Hamele CE; Department of Molecular Genetics and Microbiology, Duke University School of Medicine Durham, Durham, North Carolina, USA., Luo Z; Department of Molecular Genetics and Microbiology, Duke University School of Medicine Durham, Durham, North Carolina, USA., Leonard RA; Department of Molecular Genetics and Microbiology, Duke University School of Medicine Durham, Durham, North Carolina, USA., Spurrier MA; Department of Molecular Genetics and Microbiology, Duke University School of Medicine Durham, Durham, North Carolina, USA., Burke KN; Department of Molecular Genetics and Microbiology, Duke University School of Medicine Durham, Durham, North Carolina, USA., Webb SR; Department of Molecular Genetics and Microbiology, Duke University School of Medicine Durham, Durham, North Carolina, USA., Rountree W; Duke Human Vaccine Institute, Duke University School of Medicine Durham, Durham, North Carolina, USA., Li Z; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.; Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts, USA., Heaton BE; Department of Molecular Genetics and Microbiology, Duke University School of Medicine Durham, Durham, North Carolina, USA., Heaton NS; Department of Molecular Genetics and Microbiology, Duke University School of Medicine Durham, Durham, North Carolina, USA.; Duke Human Vaccine Institute, Duke University School of Medicine Durham, Durham, North Carolina, USA.
Jazyk:	angličtina
Zdroj:	Journal of virology [J Virol] 2024 Oct 22; Vol. 98 (10), pp. e0116624. Date of Electronic Publication: 2024 Sep 26.
DOI:	10.1128/jvi.01166-24
Abstrakt:	Seasonal influenza vaccines provide mostly strain-specific protection due to the elicitation of antibody responses focused on evolutionarily plastic antigenic sites in the hemagglutinin head domain. To direct the humoral response toward more conserved epitopes, we generated an influenza virus particle where the full-length hemagglutinin protein was replaced with a membrane-anchored, "headless" variant while retaining the normal complement of other viral structural proteins such as the neuraminidase as well as viral RNAs. We found that a single administration of a headless virus particle-based vaccine elicited high titers of antibodies that recognized more conserved epitopes on the major viral glycoproteins. Furthermore, the vaccine could elicit these responses even in the presence of pre-existing, hemagglutinin (HA) head-focused influenza immunity. Importantly, these antibody responses mediated protective, but non-neutralizing functions such as neuraminidase inhibition and antibody-dependent cellular cytotoxicity. Additionally, we show the vaccine can provide protection from homologous and heterologous challenges in mouse models of severe influenza without any measurable HA head-directed antibody responses. Thus, headless hemagglutinin containing viral particles may represent a tool to drive the types of antibody responses predicted to increase influenza vaccine breadth and durability.IMPORTANCECurrent seasonal influenza vaccines provide incomplete protection from disease. This is partially the result of the antibody response being directed toward parts of the virus that are tolerant of mutations. Redirecting the immune response to more conserved regions of the virus has been a central strategy of next-generation vaccine designs and approaches. Here, we develop and test a vaccine based on a modified influenza virus particle that expresses a partially deleted hemagglutinin protein along with the other viral structural proteins. We demonstrate this vaccine elicits antibodies that recognize the more conserved viral epitopes of the hemagglutinin stalk and neuraminidase protein to facilitate protection against influenza viruses despite a lack of classical viral neutralization activity. Competing Interests: Duke University has filed for intellectual property protection of the vaccine production approaches and antigen designs described in this work.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu