Protective Efficacy of a Human Endogenous Retrovirus Envelope-Coated, Nonreplicable, Baculovirus-Based Hemagglutin Vaccine against Pandemic Influenza H1N1 2009

Abstract

Despite the advantages of DNA vaccines, overcoming their lower efficacy relative to that of conventional vaccines remains a challenge. Here, we constructed a human endogenous retrovirus (HERV) envelope-coated, nonreplicable, baculovirus-based HA vaccine against swine influenza A/California/04/2009(H1N1) hemagglutin (HA) (AcHERV-sH1N1-HA) as an alternative to conventional vaccines and evaluated its efficacy in two strains of mice, BALB/c and C57BL/6. A commercially available, killed virus vaccine was used as a positive control. Mice were intramuscularly administered AcHERV-sH1N1-HA or the commercial vaccine and subsequently given two booster injections. Compared with the commercial vaccine, AcHERV-sH1N1-HA induced significantly higher levels of cellular immune responses in both BALB/c and C57BL/6 mice. Unlike cellular immune responses, humoral immune responses depended on the strain of mice. Following immunization with AcHERV-sH1N1-HA, C57BL/6 mice showed HA-specific IgG titers 10- to 100-fold lower than those of BALB/c mice. In line with the different levels of humoral immune responses, the survival of immunized mice after intranasal challenge with sH1N1 virus (A/California/04/2009) depended on the strain. After challenge with 10-times the median lethal dose (MLD50) of sH1N1 virus, 100% of BALB/c mice immunized with the commercial vaccine or AcHERV-sH1N1-HA survived. In contrast, C57BL/6 mice immunized with AcHERV-sH1N1-HA or the commercial vaccine showed 60% and 70% survival respectively, after challenge with sH1N1 virus. In all mice, virus titers and results of histological analyses of lung tissues were consistent with the survival data. Our results indicate the importance of humoral immune response as a major defense system against influenza viral infection. Moreover, the complete survival of BALB/c mice immunized with AcHERV-sH1N1-HA after challenge with sH1N1 virus suggests the potential of baculoviral vector-based vaccines to achieve an efficacy comparable to that of killed virus vaccines.

Long-Term Immunogenicity of an Inactivated Split-Virion 2009 Pandemic Influenza A H1N1 Virus Vaccine with or without Aluminum Adjuvant in Mice

“…Although aluminum-adjuvanted inactivated split-virion 2009 pandemic influenza A H1N1 vaccine provides long-term protection against lethal influenza virus challenge in mice after a single immunization, as shown in this study, various other forms of influenza vaccine have also been developed and reported (20)(21)(22). Giles et al reported that mice were immunized with influenza virus-like particles (VLPs) expressing the hemagglutinin (HA) and genes from the 1918 influenza virus, and the results showed that 3 g of purified 1918 VLPs protected mice from 2009 pandemic H1N1 virus challenge 16 months after double vaccination via intramuscular injection at 0 and 3 weeks (20).…”

Effect of AcHERV-GmCSF as an Influenza Virus Vaccine Adjuvant

“…Although 2 μg of killed vaccine has been reported to elicit a sufficient immune response and afford protection [ 21 ], an adjuvant is expected reduce the quantity of antigen needed for effective immunization. Thus, in preliminary experiments to evaluate the efficacy of AcHERV-GmCSF, we determined the minimum necessary dose of killed vaccine for use in conjunction with AcHERV-GmCSF.…”

“…A recombinant baculoviral vector expressing HERV env (pFastBac1-HERV) was previously constructed by inserting a synthetic, codon-optimized envelope gene of HERV type W (GenBank accession number NM014590; GenScript, Piscataway, NJ, USA) into pFastBac1 (Invitrogen) [ 21 ].…”

Immunogenicity of Virus Like Particle Forming Baculoviral DNA Vaccine against Pandemic Influenza H1N1

“…These attributes have fueled interest in exploring baculoviruses as vectors for recombinant protein expression systems and gene therapy [ 18 – 20 ]. In spite of the advantages of baculovirus, overcoming their lower efficacy relative to that of conventional vaccines remains a challenge [ 21 ]. We previously reported that a non-replicable baculovirus vector containing antigen-encoding DNA could serve as a nano-delivery system, and improve exogenous gene delivery into human cells by incorporating the envelope glycoprotein of human endogenous retrovirus (HERV-W) on recombinant baculovirus [ 21 – 23 ].…”

“…However, the AcHERV-HA vaccine only elicited an immune response to HA proteins. Such monovalency may limit the degree of protection against heterologous influenza viruses [ 21 ]. Here, we constructed a baculovirus carrying pH1N1 HA, NA, and M1 genes that is able to assemble VLPs in mammalian cells.…”