Polyclonal epitope mapping reveals temporal dynamics and diversity of human antibody responses to H5N1 vaccination

Julianna Han,Aaron J Schmitz,Sara T Richey,Ya-Nan Dai,Hannah L Turner,Bassem M Mohammed,Daved H Fremont,Ali H Ellebedy,Andrew B Ward

doi:10.1016/j.celrep.2020.108682

Julianna Han, Aaron J Schmitz + Show 7 more

Open Access

https://doi.org/10.1016/j.celrep.2020.108682

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Abstract

SUMMARYNovel influenza A virus (IAV) strains elicit recall immune responses to conserved epitopes, making them favorable antigenic choices for universal influenza virus vaccines. Evaluating these immunogens requires a thorough understanding of the antigenic sites targeted by the polyclonal antibody (pAb) response, which single-particle electron microscopy (EM) can sensitively detect. In this study, we employ EM polyclonal epitope mapping (EMPEM) to extensively characterize the pAb response to hemagglutinin (HA) after H5N1 immunization in humans. Cross-reactive pAbs originating from memory B cells immediately bound the stem of HA and persisted for more than a year after vaccination. In contrast, de novo pAb responses to multiple sites on the head of HA, targeting previously determined key neutralizing sites on H5 HA, expanded after the second immunization and waned quickly. Thus, EMPEM provides a robust tool for comprehensively tracking the specificity and durability of immune responses elicited by novel universal influenza vaccine candidates.

Highlights

Despite decades of endeavors to produce a lasting therapeutic and effective vaccine, seasonal influenza virus still causes a tremendous burden to public health each year, and pandemic influenza virus is a constantly looming threat
Robust serum response to H5N1 vaccination To assess the humoral response to vaccination with a novel strain of influenza, we obtained serum from human subjects who participated in a pandemic H5N1 vaccination trial (ClinicalTrials.gov: NCT01910519, A/Indonesia/5/2005 H5N1) (Ellebedy et al, 2020)
To investigate the heterosubtypic breadth of polyclonal antibodies elicited by H5N1 vaccination, we examined the ability of polyclonal antibody (pAb) from donor 43 at day 21 to bind H1 HA using EM polyclonal epitope mapping (EMPEM) (Figures 7B and S7)

Summary

Introduction

Despite decades of endeavors to produce a lasting therapeutic and effective vaccine, seasonal influenza virus still causes a tremendous burden to public health each year, and pandemic influenza virus is a constantly looming threat. Current vaccines are strain-specific, eliciting antibody responses primarily to the variable head region of hemagglutinin (HA). This creates a challenge for generating vaccines to potentially pandemic strains, since it is almost impossible to predict which strain can cause a pandemic. Due to frequent exposure to seasonal influenza virus HAs, humans harbor memory B cells that are directed against epitopes shared between such HAs and H5 HA These epitopes predominantly reside within the conserved stem region of HA and are the targets of broadly reactive antibodies (Throsby et al, 2008; Ekiert et al, 2009). To inform rational vaccine design, there must first be a comprehensive structural description of these conserved epitopes in complex with antibodies, as well as an understanding of the dynamics of the polyclonal antibody (pAb) response to these epitopes

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