Optimal designs of an HA-based DNA vaccine against H7 subtype influenza viruses

Zhang, Lu; Jia, Na; Li, Jun; Yan, Han; Cao, Wu‐Chun; Wang, Shixia; Huang, Zhibin; Lu, Shan

doi:10.4161/hv.28795

Cited by 8 publications

(4 citation statements)

References 38 publications

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“…HA is the major protective antigen in clinically licensed inactivated and live-attenuated influenza vaccines. DNA vaccines expressing HA have been shown to be immunogenic in eliciting HA-specific antibodies in both animal and human studies (2,(30)(31)(32)(33)(34). The expression of HA antigen by pH1HA used in the current study was confirmed by Western blot and its immunogenicity to elicit HA-specific antibody response was verified in a pilot mouse study (data not shown).…”

Section: Dna Vaccine Plasmid Induces Expression Of Aim2 Caspase-1 Anmentioning

confidence: 57%

Identification of Aim2 as a Sensor for DNA Vaccines

Suschak

Wang

Fitzgerald

et al. 2015

The Journal of Immunology

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Recent human study data has re-established the value of DNA vaccines, especially in priming high-level antigen-specific antibody responses, but also raised questions about the mechanisms responsible for such effects. Whereas previous reports have shown involvement of downstream signaling molecules in the innate immune system, the current study investigated the role of Aim2 as a sensor for DNA vaccines. The Aim2 inflammasome directs maturation of the pro-inflammatory cytokines IL-1β and IL-18 and an inflammatory form of cell death called pyroptosis. Both the humoral and cellular antigen-specific adaptive responses were significantly reduced in Aim2−/− mice in an IL-1β/IL-18 independent manner after DNA vaccination. Surprisingly, Aim2−/− mice also exhibited significantly lower levels of IFN-α/β at the site of injection. These results indicate a previously unreported link between DNA vaccine induced pyroptotic cell death and vaccine immunogenicity that is instrumental in shaping the antigen specific immune response to DNA vaccines.

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Section: Dna Vaccine Plasmid Induces Expression Of Aim2 Caspase-1 Anmentioning

confidence: 57%

Identification of Aim2 as a Sensor for DNA Vaccines

Suschak

Wang

Fitzgerald

et al. 2015

The Journal of Immunology

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“…For seasonal viruses, it has long been known that antibody titers of 40 or higher, as measured by HI assays, correlate with protection against infection ( 19 – 21 ). More recently, MN titers of 80 or more have been suggested to provide similar protection ( 24 , 25 ).…”

Section: Discussionmentioning

confidence: 99%

“…Especially since the A(H7N9) outbreak that began in 2013, efforts to develop prepandemic H7 vaccines have increased, including attempts to induce higher HI and MN responses using different manufacturing platforms ( 24 – 28 ), higher doses ( 15 ), and adjuvants ( 29 , 30 ). Additionally, efforts have been made to explore components of H7 immunity other than neutralizing antibodies ( 31 ).…”

Section: Introductionmentioning

confidence: 99%

Inactivated H7 Influenza Virus Vaccines Protect Mice despite Inducing Only Low Levels of Neutralizing Antibodies

Kamal

Blanchfield

Belser

et al. 2017

J Virol

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Avian influenza viruses of the H7 hemagglutinin (HA) subtype present a significant public health threat, as evidenced by the ongoing outbreak of human A(H7N9) infections in China. When evaluated by hemagglutination inhibition (HI) and microneutralization (MN) assays, H7 viruses and vaccines are found to induce lower level of neutralizing antibodies (nAb) than do their seasonal counterparts, making it difficult to develop and evaluate prepandemic vaccines. We have previously shown that purified recombinant H7 HA appear to be poorly immunogenic in that they induce low levels of HI and MN antibodies. In this study, we immunized mice with whole inactivated reverse genetics reassortant (RG) viruses expressing HA and neuraminidase (NA) from 3 different H7 viruses [A/Shanghai/2/2013(H7N9), A/Netherlands/219/2003(H7N7), and A/New York/107/2003(H7N2)] or with human A(H1N1)pdm09 (A/California/07/2009-like) or A(H3N2) (A/Perth16/2009) viruses. Mice produced equivalent titers of antibodies to all viruses as measured by enzyme-linked immunosorbent assay (ELISA). However, the antibody titers induced by H7 viruses were significantly lower when measured by HI and MN assays. Despite inducing very low levels of nAb, H7 vaccines conferred complete protection against homologous virus challenge in mice, and the serum antibodies directed against the HA head region were capable of mediating protection. The apparently low immunogenicity associated with H7 viruses and vaccines may be at least partly related to measuring antibody titers with the traditional HI and MN assays, which may not provide a true measure of protective immunity associated with H7 immunization. This study underscores the need for development of additional correlates of protection for prepandemic vaccines.IMPORTANCE H7 avian influenza viruses present a serious risk to human health. Preparedness efforts include development of prepandemic vaccines. For seasonal influenza viruses, protection is correlated with antibody titers measured by hemagglutination inhibition (HI) and virus microneutralization (MN) assays. Since H7 vaccines typically induce low titers in HI and MN assays, they have been considered to be poorly immunogenic. We show that in mice H7 whole inactivated virus vaccines (WIVs) were as immunogenic as seasonal WIVs, as they induced similar levels of overall serum antibodies. However, a larger fraction of the antibodies induced by H7 WIV was nonneutralizing in vitro. Nevertheless, the H7 WIV completely protected mice against homologous viral challenge, and antibodies directed against the HA head were the major contributor toward immune protection. Vaccines against H7 avian influenza viruses may be more effective than HI and virus neutralization assays suggest, and such vaccines may need other methods for evaluation.

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“…These issues underscore the need for new production platforms with the capacity to produce large quantities of efficacious vaccines in a short period [13]. So far, various H7 vaccine candidates have been evaluated for their immunogenicity and protective capacity, with variable success [14][15][16][17][18][19][20][21][22]. Recombinant DNA technology may facilitate the production of purified recombinant viral proteins, DNA vaccines, but also viral vectors, such as modified vaccinia virus Ankara (MVA) [18][19][20][21]23].…”

mentioning

confidence: 99%

A Single Immunization With Modified Vaccinia Virus Ankara-Based Influenza Virus H7 Vaccine Affords Protection in the Influenza A(H7N9) Pneumonia Ferret Model

Kreijtz¹,

Wiersma²,

Gruyter³

et al. 2014

Journal of Infectious Diseases

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Since the first reports in early 2013, >440 human cases of infection with avian influenza A(H7N9) have been reported including 122 fatalities. After the isolation of the first A(H7N9) viruses, the nucleotide sequences became publically available. Based on the coding sequence of the influenza virus A/Shanghai/2/2013 hemagglutinin gene, a codon-optimized gene was synthesized and cloned into a recombinant modified vaccinia virus Ankara (MVA). This MVA-H7-Sh2 viral vector was used to immunize ferrets and proved to be immunogenic, even after a single immunization. Subsequently, ferrets were challenged with influenza virus A/Anhui/1/2013 via the intratracheal route. Unprotected animals that were mock vaccinated or received empty vector developed interstitial pneumonia characterized by a marked alveolitis, accompanied by loss of appetite, weight loss, and heavy breathing. In contrast, animals vaccinated with MVA-H7-Sh2 were protected from severe disease.

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Optimal designs of an HA-based DNA vaccine against H7 subtype influenza viruses

Cited by 8 publications

References 38 publications

Identification of Aim2 as a Sensor for DNA Vaccines

Identification of Aim2 as a Sensor for DNA Vaccines

Inactivated H7 Influenza Virus Vaccines Protect Mice despite Inducing Only Low Levels of Neutralizing Antibodies

A Single Immunization With Modified Vaccinia Virus Ankara-Based Influenza Virus H7 Vaccine Affords Protection in the Influenza A(H7N9) Pneumonia Ferret Model

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