Engineered Dengue Virus Domain III Proteins Elicit Cross-Neutralizing Antibody Responses in Mice.

Autor: Frei JC; Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York, USA., Wirchnianski AS; Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York, USA., Govero J; Department of Medicine, Washington University in St. Louis School of Medicine, St. Louis, Missouri, USA., Vergnolle O; Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York, USA., Dowd KA; Viral Pathogenesis Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA., Pierson TC; Viral Pathogenesis Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA., Kielian M; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York, USA., Girvin ME; Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York, USA., Diamond MS; Department of Medicine, Washington University in St. Louis School of Medicine, St. Louis, Missouri, USA.; Department of Molecular Microbiology, Washington University in St. Louis School of Medicine, St. Louis, Missouri, USA.; Department of Pathology and Immunology, Washington University in St. Louis School of Medicine, St. Louis, Missouri, USA., Lai JR; Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York, USA jon.lai@einstein.yu.edu.
Jazyk: angličtina
Zdroj: Journal of virology [J Virol] 2018 Aug 29; Vol. 92 (18). Date of Electronic Publication: 2018 Aug 29 (Print Publication: 2018).
DOI: 10.1128/JVI.01023-18
Abstrakt: Dengue virus is the most globally prevalent mosquito-transmitted virus. Primary infection with one of four cocirculating serotypes (DENV-1 to -4) causes a febrile illness, but secondary infection with a heterologous serotype can result in severe disease, due in part to antibody-dependent enhancement of infection (ADE). In ADE, cross-reactive but nonneutralizing antibodies, or subprotective levels of neutralizing antibodies, promote uptake of antibody-opsonized virus in Fc-γ receptor-positive cells. Thus, elicitation of broadly neutralizing antibodies (bNAbs), but not nonneutralizing antibodies, is desirable for dengue vaccine development. Domain III of the envelope glycoprotein (EDIII) is targeted by bNAbs and thus is an attractive immunogen. However, immunization with EDIII results in sera with limited neutralization breadth. We developed "resurfaced" EDIII immunogens (rsDIIIs) in which the A/G strand epitope that is targeted by bNAb 4E11 is maintained but less desirable epitopes are masked. RsDIIIs bound 4E11, but not serotype-specific or nonneutralizing antibodies. One rsDIII and, unexpectedly, wild-type (WT) DENV-2 EDIII elicited cross-neutralizing antibody responses against DENV-1 to -3 in mice. While these sera were cross-neutralizing, they were not sufficiently potent to protect AG129 immunocompromised mice at a dose of 200 μl (50% focus reduction neutralization titer [FRNT 50 ], ∼1:60 to 1:130) against mouse-adapted DENV-2. Our results provide insight into immunogen design strategies based on EDIII. IMPORTANCE Dengue virus causes approximately 390 million infections per year. Primary infection by one serotype causes a self-limiting febrile illness, but secondary infection by a heterologous serotype can result in severe dengue syndrome, which is characterized by hemorrhagic fever and shock syndrome. This severe disease is thought to arise because of cross-reactive, non- or poorly neutralizing antibodies from the primary infection that are present in serum at the time of secondary infection. These cross-reactive antibodies enhance the infection rather than controlling it. Therefore, induction of a broadly and potently neutralizing antibody response is desirable for dengue vaccine development. Here, we explore a novel strategy for developing immunogens based on domain III of the E glycoprotein, where undesirable epitopes (nonneutralizing or nonconserved) are masked by mutation. This work provides fundamental insight into the immune response to domain III that can be leveraged for future immunogen design.
(Copyright © 2018 American Society for Microbiology.)
Databáze: MEDLINE
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