The stem of the influenza A virus hemagglutinin (HA) is highly conserved and represents an attractive target for a universal influenza vaccine. The 18 HA subtypes of influenza A are phylogenetically divided into two groups, and while protection with group 1 HA stem vaccines has been demonstrated in animal models, studies on group 2 stem vaccines are limited. Thus, we engineered group 2 HA stem-immunogen (SI) vaccines targeting the epitope for the broadly neutralizing monoclonal antibody CR9114 and evaluated vaccine efficacy in mice and ferrets. Immunization induced antibodies that bound to recombinant HA protein and viral particles, and competed with CR9114 for binding to the HA stem. Mice vaccinated with H3 and H7-SI were protected from lethal homologous challenge with X-79 (H3N2) or A/Anhui/1/2013 (H7N9), and displayed moderate heterologous protection. In ferrets, H7-SI vaccination did not significantly reduce weight loss or nasal wash titers after robust 10 7 TCID 50 H7N9 virus challenge. Epitope mapping revealed ferrets developed lower titers of antibodies that bound a narrow range of HA stem epitopes compared to mice, and this likely explains the lower efficacy in ferrets. Collectively, these findings indicate that while group 2 SI vaccines show promise, their immunogenicity and efficacy are reduced in larger outbred species, and will have to be enhanced for successful translation to a universal vaccine.
Progress has been made towards a universal vaccine targeting the ‘group 2’ subtype of influenza A virus. Today’s flu vaccines target the ‘head’ section of the virus’ hemagglutinin protein; however, this section acquires mutations which require the reformulation of vacccines. In this paper, a vaccine candidate designed to focus an immune response against the more stable protein ‘stem’ is described by a team of scientists led by Kanta Subbarao of the United States’ National Institutes of Health and Raghavan Varadarajan of the Indian Institute of Science. The candidate vaccine offered moderate protection to mice but did not provide significant antiviral effects when tested in ferrets. The authors suggest that, while their approach shows promise, improvement is needed before it could be translated into vaccines against human influenza infection.