TY - JOUR
T1 - Protective efficacy of influenza group 2 hemagglutinin stem-fragment immunogen vaccines
AU - Sutton, Troy C.
AU - Chakraborty, Saborni
AU - Mallajosyula, Vamsee V.A.
AU - Lamirande, Elaine W.
AU - Ganti, Ketaki
AU - Bock, Kevin W.
AU - Moore, Ian N.
AU - Varadarajan, Raghavan
AU - Subbarao, Kanta
N1 - Funding Information:
CR9114 and X-79 (H3N2) (A/Philippines/2/1982 (H3N2): A/Puerto Rico/8/1934 (H1N1)) virus were kindly provided by Dr. Jessica Flynn at Merck Research Laboratories and Dr. Suzanne Epstein, Food and Drug Administration, respectively. This research was supported in part by the Intramural Research Program of the NIH, National Institutes of Allergy and Infectious Diseases (NIAID). The RV lab acknowledges funding for infrastructural support from the following programs of the Government of India: DST-FIST, UGC Centre for Advanced Study, Ministry of Human Resource development (MHRD), JC Bose Fellowship and the DBT-IISc Partnership Program.
Publisher Copyright:
© 2017 The Author(s).
PY - 2017/12/1
Y1 - 2017/12/1
N2 - 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 107 TCID50 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.
AB - 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 107 TCID50 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.
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U2 - 10.1038/s41541-017-0036-2
DO - 10.1038/s41541-017-0036-2
M3 - Article
C2 - 29263889
AN - SCOPUS:85042233316
SN - 2059-0105
VL - 2
JO - npj Vaccines
JF - npj Vaccines
IS - 1
M1 - 36
ER -