Research Article

A stable trimeric influenza hemagglutinin stem as a broadly protective immunogen

Science  18 Sep 2015:
Vol. 349, Issue 6254, pp. 1301-1306
DOI: 10.1126/science.aac7263

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Flu vaccine candidate STEMs the tide

Every year we need a new flu vaccine, because influenza virus constantly mutates the major target of antibodies to flu: the “head” region of the viral hemagglutinin (HA) protein. Avoiding the problem of mutation requires a vaccine that elicits antibodies against the more conserved “stem” region of HA. During infection, antibodies are occasionally produced that recognize the stem and that neutralize a broad range of influenza virus strains. Impagliazzo et al. engineered an HA stem–only vaccine candidate that elicited broadly neutralizing antibodies in mice and nonhuman primates and that protected mice against multiple influenza strains.

Science, this issue p. 1301

Abstract

The identification of human broadly neutralizing antibodies (bnAbs) targeting the hemagglutinin (HA) stem revitalized hopes of developing a universal influenza vaccine. Using a rational design and library approach, we engineered stable HA stem antigens (“mini-HAs”) based on an H1 subtype sequence. Our most advanced candidate exhibits structural and bnAb binding properties comparable to those of full-length HA, completely protects mice in lethal heterologous and heterosubtypic challenge models, and reduces fever after sublethal challenge in cynomolgus monkeys. Antibodies elicited by this mini-HA in mice and nonhuman primates bound a wide range of HAs, competed with human bnAbs for HA stem binding, neutralized H5N1 viruses, and mediated antibody-dependent effector activity. These results represent a proof of concept for the design of HA stem mimics that elicit bnAbs against influenza A group 1 viruses.

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