Journal Article

The respiratory syncytial virus fusion protein-specific B cell receptor repertoire reshaped by post-fusion subunit vaccination

Schneikart, Gerald, Buricchi, Francesca, Finco, Oretta, Sammicheli, Chiara, Guidotti, Silvia, Andreano, Emanuele, Tavarini, Simona, D'Oro, Ugo, Bardelli, Monia, Torricelli, Giulia

2020

Overview

[Display omitted] •B cell receptor repertoire analysis in RSV post-fusion subunit vaccinees.•Post-fusion subunit vaccine expands pre-/post-fusion cross-reactive memory B cells.•VH4-encoded B cell receptors preferentially selected for memory B cell expansion.•Clonotype analysis applied for detection of RSV-neutralizing antibodies. Respiratory syncytial virus (RSV) is the major cause of acute lower respiratory illness in children of less than 5 years of age which usually results in hospitalization or even in death. Vaccine development is hampered in consequence of a failed vaccine trial with fatalities in the 1960s. Even though research has been more focused on the RSV fusion protein in its pre-fusion conformation, maternal vaccination with post-fusion protein (post F) was considered as a promising vaccine strategy for passive immunization of babies, because post F preserves very potent neutralizing epitopes. We extensively analyzed post F-binding B cell receptor (BCR) repertoires of three vaccinees who received a post F-subunit vaccine in the context of a first-in-human, Phase 1, randomized, observer-blind, placebo-controlled clinical trial (ClinicalTrials.gov Identifier: NCT02298179). In order to compare the vaccine-induced BCR repertoires with BCR repertoires induced by natural infection, we also analyzed pre F- and post F-binding BCRs isolated from a healthy blood donor with relatively high F-binding memory B cell (MBC) frequencies. Analysis of the vaccine-induced repertoires revealed that preferentially VH4-encoded BCRs were expanded in response to vaccination. Estimation of antigen-driven selection further demonstrated that expanded BCRs accumulated positively selected replacement mutations which substantiated the hypothesis that post F-vaccination induces diversification of VH4-encoded BCRs in germinal centers. Comparison of the vaccine-induced BCR repertoires with clonally related pre and post F-binding BCRs of the healthy blood donor suggested that the vaccine expanded pre/post F cross-reactive MBCs. Interestingly, several vaccine-induced BCRs shared stereotypic VDJ gene junctions with known neutralizing Abs. Once expressed for functional characterization, the selected monoclonal Abs demonstrated the predicted neutralization activities in plaque reduction neutralization assays indicating that the post F-vaccine induced expansion of neutralizing BCRs.

• Publisher: Elsevier Ltd,Elsevier Limited
• Subject: Allergy and Immunology / Antibodies, Neutralizing / Antibodies, Viral / Antigens / B cell receptor repertoire / B-cell receptor / B-lymphocytes / Babies / Binding / Blood / blood donors / Cell fusion / Child / Clinical medicine / Clinical trials / Clonal relatedness / death / Deoxyribonucleic acid / DNA / DNA polymerase / Epitopes / Fusion protein / genes / Germinal centers / Humans / Illnesses / Immunization / Immunization (passive) / Immunological memory / Infections / Monoclonal antibodies / Mutation / Neutralization / Neutralizing / Neutralizing antibody / Post-fusion subunit vaccine / Protein structure / Proteins / Randomized Controlled Trials as Topic / Receptors / Receptors, Antigen, B-Cell - genetics / Respiratory syncytial virus / Respiratory Syncytial Virus Infections - prevention & control / Respiratory Syncytial Virus Vaccines / Respiratory Syncytial Virus, Human / respiratory tract diseases / Single cell-sorting / Vaccination / Vaccine development / Vaccines / Vaccines, Subunit / Viral Fusion Proteins - genetics / Viruses