A Bivalent Heterologous DNA Virus-Like-Particle Prime-Boost Vaccine Elicits Broad Protection against both Group 1 and 2 Influenza A Viruses.
Current seasonal influenza vaccines are efficacious when vaccine strains are matched with circulating strains. However, they do not protect antigenic variants and newly emerging pandemic and outbreak strains. Thus, there is a critical need for developing so-called "universal" vaccines that protect against all influenza viruses. In the present study, we developed a bivalent heterologous DNA virus-like particle prime-boost vaccine strategy. We show that mice immunized with this vaccine were broadly protected against lethal challenge from group 1 (H1, H5, and H9) and group 2 (H3 and H7) viruses, with 94% aggregate survival. To determine the immune correlates of protection, we performed passive immunizations andin vitroassays. We show that this vaccine elicited antibody responses that bound HA from group 1 (H1, H2, H5, H6, H8, H9, H11, and H12) and group 2 (H3, H4, H7, H10, H14, and H15) and neutralized homologous and intrasubtypic H5 and H7 and heterosubtypic H1 viruses and hemagglutinin-specific CD4 and CD8 T cell responses. As a result, passive immunization with immune sera fully protected mice against H5, H7, and H1 challenge, whereas with both immune sera and T cells the mice survived heterosubtypic H3 and H9 challenge. Thus, it appears that (i) neutralizing antibodies alone fully protect against homologous and intrasubtypic H5 and H7 and (ii) neutralizing and binding antibodies are sufficient to protect against heterosubtypic H1, (iii) but against heterosubtypic H3 and H9, binding antibodies and T cells are required for complete survival. We believe that this vaccine regimen could potentially be a candidate for a "universal" influenza vaccine.IMPORTANCEInfluenza virus infection is global health problem. Current seasonal influenza vaccines are efficacious only when vaccine strains are matched with circulating strains. However, these vaccines do not protect antigenic variants and newly emerging pandemic and outbreak strains. Because of this, there is an urgent need to develop so-called "universal" influenza vaccines that can protect against both current and future influenza strains. In the present study, we developed a bivalent heterologous prime-boost vaccine strategy. We show that a bivalent vaccine regimen elicited broad binding and neutralizing antibody and T cell responses that conferred broad protection against diverse challenge viruses in mice, suggesting that this bivalent prime-boost strategy could practically be a candidate for a "universal" influenza vaccine.
Unit of Antiviral Immunity and Genetic Therapy, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.
Wenbo
W
Jiang
Unit of Antiviral Immunity and Genetic Therapy, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.|Shanghai Tech University, Shanghai, China.
Shuangshuang
S
Wang
The University of Hong Kong, Hong Kong Special Administrative Region, China.
Honglin
H
Chen
Unit of Antiviral Immunity and Genetic Therapy, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.
Huanhuan
H
Ren
Unit of Antiviral Immunity and Genetic Therapy, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.
Xun
X
Huang
Unit of Antiviral Immunity and Genetic Therapy, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.
Guiqin
G
Wang
Shanghai Institute of Biological Products, Shanghai, China.
Ze
http://orcid.org/0000-0003-4717-0747
Z
Chen
State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
Ling
L
Chen
The University of Hong Kong, Hong Kong Special Administrative Region, China.
Zhiwei
Z
Chen
Unit of Antiviral Immunity and Genetic Therapy, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China blzhou@sibs.ac.cn.|Shanghai Tech University, Shanghai, China.
Paul
http://orcid.org/0000-0002-9192-9231
P
Zhou
D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D002460:Cell Line; D056738:Cross Protection / Q000276:immunology*; D004285:Dogs; D005260:Female; D057809:HEK293 Cells; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000276:immunology*; D006801:Humans; D007106:Immune Sera / Q000276:immunology; D007116:Immunization, Passive; D009980:Influenza A virus / Q000276:immunology*; D007252:Influenza Vaccines / Q000276:immunology*; D007251:Influenza, Human / Q000276:immunology / Q000517:prevention & control; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D009976:Orthomyxoviridae Infections / Q000276:immunology* / Q000517:prevention & control; D010957:Plasmids / Q000235:genetics / Q000276:immunology; D014611:Vaccination; D019444:Vaccines, DNA / Q000276:immunology*; D058425:Vaccines, Virus-Like Particle / Q000276:immunology*
D057134:Antibodies, Neutralizing; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D007106:Immune Sera; D007252:Influenza Vaccines; D019444:Vaccines, DNA; D058425:Vaccines, Virus-Like Particle
influenza vaccine