A Replicating Modified Vaccinia Tiantan Strain Expressing an Avian-Derived Influenza H5N1 Hemagglutinin Induce Broadly Neutralizing Antibodies and Cross-Clade Protective Immunity in Mice

Abstract

To combat the possibility of a zoonotic H5N1 pandemic in a timely fashion, it is necessary to develop a vaccine that would confer protection against homologous and heterologous human H5N1 influenza viruses. Using a replicating modified vaccinia virus Tian Tan strain (MVTT) as a vaccine vector, we constructed MVTTHA-QH and MVTTHA-AH, which expresses the H5 gene of a goose-derived Qinghai strain A/Bar-headed Goose/Qinghai/1/2005 or human-derived Anhui Strain A/Anhui/1/2005. The immunogenicity profiles of both vaccine candidates were evaluated. Vaccination with MVTTHA-QH induced a significant level of neutralizing antibodies (Nabs) against a homologous strain and a wide range of H5N1 pseudoviruses (clades 1, 2.1, 2.2, 2.3.2, and 2.3.4). Neutralization tests (NT) and Haemagglutination inhibition (HI) antibodies inhibit the live autologous virus as well as a homologous A/Xingjiang/1/2006 and a heterologous A/Vietnam/1194/2004, representing two human isolates from clade 2.2 and clade 1, respectively. Importantly, mice vaccinated with intranasal MVTTHA-QH were completely protected from challenge with lethal dosages of A/Bar-headed Goose/Qinghai/1/2005 and the A/Viet Nam/1194/2004, respectively, but not control mice that received a mock MVTTS vaccine. However, MVTTHA-AH induced much lower levels of NT against its autologous strain. Our results suggest that it is feasible to use the H5 gene from A/Bar-headed Goose/Qinghai/1/2005 to construct an effective vaccine, when using MVTT as a vector, to prevent infections against homologous and genetically divergent human H5N1 influenza viruses.

Avian Influenza A Virus Pandemic Preparedness and Vaccine Development

“…Recombinant MVA vaccines expressing the HA genes from various A/H5N1 influenza viruses have been constructed and tested for protective efficacy against challenge viruses belonging to different antigenic clades in animal models [ 95 ]. It has been shown that a rMVA expressing HA from the clade 1 A/H5N1 virus A/Vietnam/1194/04 can offer protection from homologous challenge, in addition to protection from several antigenically distinct A/H5N1 viruses in mice and macaques [ 96 , 97 , 98 , 99 , 100 ]. In mice, the rMVA-H5 vaccine induced high levels of HA-specific CD4 and CD8 T-cells targeting epitopes that are conserved among different HA clades [ 98 ].…”

Global transcriptome analysis of H5N1 influenza virus-infected human cells

“…H5N1 A/QH virus was used to infect A549 and 293 T cells. The virus is characterized to spread rapidly via migratory birds and is likely the major agents for several human infections throughout Europe and China in the past few years [20, 21]. Interestingly, virus propagation was higher in A549 cells than in 293 T cells.…”

“…It has been estimated that more than 50 million people globally have died from influenza [2]. The highly pathogenic avian influenza (HPAI) H5N1 has infected thousands of people and spread globally in transported poultry or via indirect contact [3, 4]. Currently, it is impossible to eliminate the virus during its infection [5].…”

Unique safety issues associated with virus-vectored vaccines: Potential for and theoretical consequences of recombination with wild type virus strains

“…Two examples are provided. Attenuated vaccinia Tiantan [65,66] used in China for smallpox eradication is being assessed as a replication-competent vector for both HIV-1 [67] and H5N1 [68] vaccines and in its replication-defective form for hepatitis C vaccine [69]. Similarly, replication-competent adenovirus serotype 4 (Ad4) has been tested in humans as a vector for H5N1 [70] HIV and anthrax.…”