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To EBV or not to EBV: Rational vaccine design for a common infection

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Science Immunology  04 May 2018:
Vol. 3, Issue 23, eaat9661
DOI: 10.1126/sciimmunol.aat9661

Abstract

A human antibody that prevents EBV infection is identified by studying memory B cells that recognize core EBV fusion proteins.

Epstein-Barr virus (EBV) is a common saliva-transmitted viral infection that causes a range of acute phenotypes, including infectious mononucleosis (or “mono”). Patients eventually enter a latent phase, and infection carries the additional risk of certain types of malignancy (e.g., lymphoma and nasopharyngeal carcinoma) as well as B cell lymphoproliferation in the setting of immune dysfunction. However, there is no vaccine or specific treatment. To infect the host, this herpesvirus targets B cells and epithelial cells using a set of glycoproteins (e.g., gH/gL, gB, gp42, and gp350) in various ways to fuse the host and viral membranes. Thus far, identified neutralizing antibodies have been from mice and only able to block infection of either B cells or epithelial cells, which is not sufficiently protective clinically.

Snijders and colleagues used a reverse vaccinology strategy to identify antibodies that can neutralize EBV infection of both B cells and epithelial cells. They isolated and cultured rare human memory B cells that bound the core EBV glycoproteins (e.g., gH/gL and gB) from EBV-infected donors. Antibody variable heavy and light chain (VH-VL) genes were cloned into expression vectors for further testing. A single gH/gL-specific memory B cell was found and produced the antibody “AMMO1”; four gB-specific memory B cells were identified, and their antibodies were named “AMMO2” to “AMMO5.” Only AMMO1 prevented infection of both B cells and epithelial cells. Using structural studies (i.e., cryoEM and x-ray crystallography) they determined that AMMO1 binds to parts of both gH and gL simultaneously. Mechanistically, AMMO1 binding can block membrane fusion.

The authors described a pipeline for rational vaccine design focused on learning from our immune response to viral infection to yield novel insight into the nature of the pathogen and practical insight into host protection. With regards to EBV specifically, they identified an effective human antibody directed toward membrane fusion machinery. AMMO1 requires more clinical testing for possible therapeutic use, and its epitope is a promising start for rational EBV vaccine design. More broadly, this strategy can be used to target related herpesviruses, including CMV, each of which has its own substantial impact.

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