Influenza Hemagglutinin Stem-fragment Immunogen Elicits Broadly Neutralizing Antibodies and Confers Heterologous Protection

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2014 Jun 14

PMID 24927560

Citations 121

Authors

Vamsee V A Mallajosyula

Michael Citron

Francesca Ferrara

Xianghan Lu

Cheryl Callahan

Gwendolyn J Heidecker

Siddhartha P Sarma

Jessica A Flynn

Nigel J Temperton

Xiaoping Liang

Raghavan Varadarajan

Affiliations

Soon will be listed here.

Abstract

Influenza hemagglutinin (HA) is the primary target of the humoral response during infection/vaccination. Current influenza vaccines typically fail to elicit/boost broadly neutralizing antibodies (bnAbs), thereby limiting their efficacy. Although several bnAbs bind to the conserved stem domain of HA, focusing the immune response to this conserved stem in the presence of the immunodominant, variable head domain of HA is challenging. We report the design of a thermotolerant, disulfide-free, and trimeric HA stem-fragment immunogen which mimics the native, prefusion conformation of HA and binds conformation specific bnAbs with high affinity. The immunogen elicited bnAbs that neutralized highly divergent group 1 (H1 and H5 subtypes) and 2 (H3 subtype) influenza virus strains in vitro. Stem immunogens designed from unmatched, highly drifted influenza strains conferred robust protection against a lethal heterologous A/Puerto Rico/8/34 virus challenge in vivo. Soluble, bacterial expression of such designed immunogens allows for rapid scale-up during pandemic outbreaks.

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