Designed, highly expressing, thermostable dengue virus 2 envelope protein dimers elicit quaternary epitope antibodies.

Autor:	Kudlacek ST; Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27514, USA., Metz S; Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27514, USA., Thiono D; Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27514, USA., Payne AM; Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27514, USA., Phan TTN; Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27514, USA., Tian S; Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27514, USA., Forsberg LJ; Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27514, USA., Maguire J; Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27514, USA., Seim I; Curriculum in Bioinformatics and Computational Biology, University of North Carolina, Chapel Hill, NC 27514, USA.; Department of Biology, University of North Carolina, Chapel Hill, NC 27514, USA.; Department of Applied Physical Sciences, University of North Carolina, Chapel Hill, NC 27514, USA., Zhang S; Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27514, USA., Tripathy A; Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27514, USA., Harrison J; Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27514, USA., Nicely NI; Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27514, USA., Soman S; Viral Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA., McCracken MK; Viral Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA., Gromowski GD; Viral Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA., Jarman RG; Viral Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA., Premkumar L; Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27514, USA., de Silva AM; Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27514, USA., Kuhlman B; Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27514, USA.; Department of Biology, University of North Carolina, Chapel Hill, NC 27514, USA.
Jazyk:	angličtina
Zdroj:	Science advances [Sci Adv] 2021 Oct 15; Vol. 7 (42), pp. eabg4084. Date of Electronic Publication: 2021 Oct 15.
DOI:	10.1126/sciadv.abg4084
Abstrakt:	Dengue virus (DENV) is a worldwide health burden, and a safe vaccine is needed. Neutralizing antibodies bind to quaternary epitopes on DENV envelope (E) protein homodimers. However, recombinantly expressed soluble E proteins are monomers under vaccination conditions and do not present these quaternary epitopes, partly explaining their limited success as vaccine antigens. Using molecular modeling, we found DENV2 E protein mutations that induce dimerization at low concentrations (<100 pM) and enhance production yield by more than 50-fold. Cross-dimer epitope antibodies bind to the stabilized dimers, and a crystal structure resembles the wild-type (WT) E protein bound to a dimer epitope antibody. Mice immunized with the stabilized dimers developed antibodies that bind to E dimers and not monomers and elicited higher levels of DENV2-neutralizing antibodies compared to mice immunized with WT E antigen. Our findings demonstrate the feasibility of using structure-based design to produce subunit vaccines for dengue and other flaviviruses.
Databáze:	MEDLINE
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