Protection against multiple subtypes of influenza viruses by virus-like particle vaccines based on a hemagglutinin conserved epitope.

Shaoheng Chen,Fang Fang,Xueying Liu,Ze Chen,Dan Zheng,Wenjie Zhang,Changgui Li,Wenting Xu

doi:10.1155/2015/901817

Abstract

We selected the conserved sequence in the stalk region of influenza virus hemagglutinin (HA) trimmer, the long alpha helix (LAH), as the vaccine candidate sequence, and inserted it into the major immunodominant region (MIR) of hepatitis B virus core protein (HBc), and, by using the E. coli expression system, we prepared a recombinant protein vaccine LAH-HBc in the form of virus-like particles (VLP). Intranasal immunization of mice with this LAH-HBc VLP plus cholera toxin B subunit with 0.2% of cholera toxin (CTB*) adjuvant could effectively elicit humoral and cellular immune responses and protect mice against a lethal challenge of homologous influenza viruses (A/Puerto Rico/8/1934 (PR8) (H1N1)). In addition, passage of the immune sera containing specific antibodies to naïve mice rendered them resistant against a lethal homologous challenge. Immunization with LAH-HBc VLP vaccine plus CTB* adjuvant could also fully protect mice against a lethal challenge of the 2009 pandemic H1N1 influenza virus or the avian H9N2 virus and could partially protect mice against a lethal challenge of the avian H5N1 influenza virus. This study demonstrated that the LAH-HBc VLP vaccine based on a conserved sequence of the HA trimmer stalk region is a promising candidate vaccine for developing a universal influenza vaccine against multiple influenza viruses infections.

Highlights

Influenza viruses cause acute infections in the respiratory tract
The gene fragments coding for HA2 76–130aa and hepatitis B virus core protein (HBc) 1–149aa were, respectively, amplified from A/PR/8/34 (PR8) HA gene and the genome of hepatitis B virus strain 56, and the former fragment was inserted into the tip of the spike of the major immunodominant region of HBc, producing the long alpha helix (LAH)-HBc fusion gene
Electron microscope examination of the purified recombinant proteins revealed that the LAH-HBc proteins were presented in particle form with a diameter of about 30 nm (Figure 1(c)), indicating that the LAH-HBc recombinant protein, expressed by the E. coli expression system, could successfully self-assemble into virus-like particles (VLP)

Summary

Introduction

Influenza viruses cause acute infections in the respiratory tract. Each year, seasonal influenza results in influenzarelated human diseases and deaths around the world. Current influenza vaccines are designed for particular influenza strains, which could hardly respond to variations and transmission of influenza viruses. There is an urgent need for universal influenza vaccines (UIV) against multiple influenza virus strains, which could quickly and effectively prevent infections and lower transmissions of influenza viruses among human populations at early time. UIV research has been focused on basic sequences of conserved virus proteins, such as matrix protein 2 (M2) [2] and nucleoprotein (NP) [3]. These experimental vaccines have demonstrated good protection in animal studies, and some have undergone clinical trials. Our team has used these conserved proteins as vaccine candidate antigens before, such as M2 [4] and NP [5], and explored protection of these sequences in animal models by using multiple vaccine forms such as DNA vaccine [6] and recombinant protein

Methods

Results

Discussion

Conclusion