Bovine Adenovirus Vectored Vaccine for Avian Influenza
Authors: Dan H Barouch
Journal: Molecular Therapy (2008)

Reports of avian influenza in humans over the past several years have raised concerns about a potential H5N1 influenza pandemic. The development of a vaccine against H5N1 influenza is therefore an important research priority. In this issue of Molecular Therapy, Singh and colleagues1Singh N Pandey A Jayashankar L Mittal SK Bovine adenoviral vector–based H5N1 influenza vaccine overcomes exceptionally high levels of pre-existing immunity against human adenovirus.Mol Ther. 2008; 16: 965-971Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar report the construction of a bovine adenovirus serotype 3 (BAd3)–based vector expressing the hemagglutinin (HA) protein from the H5N1 influenza virus.A vaccine against influenza would need to be deployed immediately in the event of sustained person-to-person spread of H5N1 influenza. It would therefore be important for an avian influenza vaccine to have the capacity to protect against heterologous virus strains, because the vaccine sequence, at least initially, would probably not match the circulating virus sequence. Because most of the current influenza vaccines based on inactivated viruses are strain-specific, there is a need to develop novel vaccine approaches for avian influenza.Recombinant, replication-incompetent adenovirus (Ad) vector-based vaccines are being developed for a variety of pathogens. Ad vectors offer the advantage of efficiently generating both humoral and cellular immune responses, which theoretically may afford a degree of protection against heterologous virus strains if there are sufficient cross-reactive antibody or T-lymphocyte epitopes. The majority of studies involving Ad vectors have used human Ad serotype 5 (Ad5). A potential major limitation of Ad5 vectors, however, is the high degree of preexisting immunity to Ad5 in human populations. Approximately 30% to 40% of individuals in the developed world have preexisting immunity to Ad5, whereas 80% to 90% of individuals in the developing world have been reported to be Ad5-seropositive.2Vogels R Zuijdgeest D van Rijnsoever R Hartkoorn E Damen I de Bethune MP et al.Replication-deficient human adenovirus type 35 vectors for gene transfer and vaccination: efficient human cell infection and bypass of preexisting adenovirus immunity.J Virol. 2003; 77: 8263-8271Crossref PubMed Scopus (399) Google ScholarPreclinical3Barouch DH Pau MG Custers JH Koudstaal W Kostense S Havenga MJ et al.Immunogenicity of recombinant adenovirus serotype 35 vaccine in the presence of pre-existing anti-Ad5 immunity.J Immunol. 2004; 172: 6290-6297Crossref PubMed Scopus (330) Google Scholar and clinical4Catanzaro AT Koup RA Roederer M Bailer RT Enama ME Moodie Z et al.Phase 1 safety and immunogenicity evaluation of a multiclade HIV-1 candidate vaccine delivered by a replication-defective recombinant adenovirus vector.J Infect Dis. 2006; 194: 1638-1649Crossref PubMed Scopus (266) Google Scholar studies have shown that individuals with pre-existing immunity to Ad5 generate substantially lower transgene-specific immune responses to Ad5 vector–based vaccines as compared with subjects without pre-existing immunity to Ad5, although the degree of this suppressive effect has been debated. Moreover, a recent phase 2b efficacy study evaluating an Ad5 vector-based vaccine for HIV-1 showed that individuals with preexisting immunity to Ad5 may have had increased rates of HIV-1 acquisition, suggesting that there may also be safety considerations associated with using Ad5 vaccine vectors in individuals with pre-existing immunity to the vector.5Fauci AS The release of new data from the HVTN 502 (STEP) HIV vaccine study.NIH News. 2007; (7 November 2007)Google Scholar These data suggest the need for the development of novel Ad vectors that are not suppressed by such pre-existing immunity. Current strategies being explored include the development of Ad vectors from human serotypes that are rare in human populations, such as Ad35 (ref. 2Vogels R Zuijdgeest D van Rijnsoever R Hartkoorn E Damen I de Bethune MP et al.Replication-deficient human adenovirus type 35 vectors for gene transfer and vaccination: efficient human cell infection and bypass of preexisting adenovirus immunity.J Virol. 2003; 77: 8263-8271Crossref PubMed Scopus (399) Google Scholar) and Ad26 (ref. 6Abbink P Lemckert AA Ewald BA Lynch DM Denholtz M Smits S et al.Comparative seroprevalence and immunogenicity of six rare serotype recombinant adenovirus vaccine vectors from subgroups B and D.J Virol. 2007; 81: 4654-4663Crossref PubMed Scopus (375) Google Scholar), chimeric Ad vectors in which dominant hexon neutralizing epitopes have been removed,7Roberts DM Nanda A Havenga MJ Abbink P Lynch DM Ewald BA et al.Hexon-chimaeric adenovirus serotype 5 vectors circumvent pre-existing anti-vector immunity.Nature. 2006; 441: 239-243Crossref PubMed Scopus (399) Google Scholar and Ad vectors from species other than humans such as chimpanzees.8Farina SF Gao GP Xiang ZQ Rux JJ Burnett RM Alvira MR et al.Replication-defective vector based on a chimpanzee adenovirus.J Virol. 2001; 75: 11603-11613Crossref PubMed Scopus (225) Google ScholarSingh and colleagues1Singh N Pandey A Jayashankar L Mittal SK Bovine adenoviral vector–based H5N1 influenza vaccine overcomes exceptionally high levels of pre-existing immunity against human adenovirus.Mol Ther. 2008; 16: 965-971Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar constructed an E1/E3-deleted, replication-incompetent BAd3 vector expressing the HA protein from the H5N1 influenza virus A/Hong Kong/156/97. The authors demonstrate that the BAd3-H5HA vector elicited potent HA-specific humoral and cellular immune responses in mice and afforded robust protection against challenge with an antigenically similar H5N1 influenza virus A/Hong Kong/483/97. The immunogenicity and protective efficacy of the vaccine were comparable in mice both with and without pre-existing immunity to Ad5, indicating that the BAd3 vector was not suppressed by high levels of pre-existing Ad5 immunity. Unfortunately, mice that received only human Ad5 vaccine vectors were not included in the challenge studies, although it would be predicted that Ad5 vectors would fail to afford protection in the presence of immunity to Ad5. These data, therefore, add to the existing literature showing that novel Ad vectors can effectively circumvent immunity to Ad5.A particularly interesting aspect of this study is the demonstration that a heterologous prime-boost regimen using both bovine and human Ad vectors elicited higher HA inhibition titers than did homologous regimens of either vector alone. Moreover, the heterologous regimen also protected against influenza virus challenge in the presence of immunity to Ad5, suggesting the potential utility of such combination vaccine regimens. Based on these observations, it is possible that an optimal regimen may consist of two Ad vectors that are serologically distinct from each other and that both evade immunity to Ad5.Future studies must evaluate the degree to which the BAd3-H5HA vaccine will protect against genetically more divergent strains of H5N1 influenza virus. Moreover, the BAd3 vector system will need to be assessed in greater detail for stability, manufacturability, and scale-up feasibility. Additional biologic aspects of the BAd3 vector will also need to be clarified, such as its cellular receptors, its tropism in vivo, and the phenotype of vaccine-elicited immune responses. The seroprevalence of this vector and the degree of cross-reactive T-lymphocyte responses with common human Ad vectors in large-scale human populations would also be important to investigate.The robust protection afforded by the BAd3-H5HA vaccine against a lethal avian influenza virus challenge raises the possibility that BAd3 vectors will prove useful not only for influenza but also for other pathogens. This study therefore adds BAd3 to the growing armamentarium of novel Ad vectors that effectively evade immunity to Ad5 and that could potentially be developed for both vaccination and gene therapy applications. Reports of avian influenza in humans over the past several years have raised concerns about a potential H5N1 influenza pandemic. The development of a vaccine against H5N1 influenza is therefore an important research priority. In this issue of Molecular Therapy, Singh and colleagues1Singh N Pandey A Jayashankar L Mittal SK Bovine adenoviral vector–based H5N1 influenza vaccine overcomes exceptionally high levels of pre-existing immunity against human adenovirus.Mol Ther. 2008; 16: 965-971Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar report the construction of a bovine adenovirus serotype 3 (BAd3)–based vector expressing the hemagglutinin (HA) protein from the H5N1 influenza virus. A vaccine against influenza would need to be deployed immediately in the event of sustained person-to-person spread of H5N1 influenza. It would therefore be important for an avian influenza vaccine to have the capacity to protect against heterologous virus strains, because the vaccine sequence, at least initially, would probably not match the circulating virus sequence. Because most of the current influenza vaccines based on inactivated viruses are strain-specific, there is a need to develop novel vaccine approaches for avian influenza. Recombinant, replication-incompetent adenovirus (Ad) vector-based vaccines are being developed for a variety of pathogens. Ad vectors offer the advantage of efficiently generating both humoral and cellular immune responses, which theoretically may afford a degree of protection against heterologous virus strains if there are sufficient cross-reactive antibody or T-lymphocyte epitopes. The majority of studies involving Ad vectors have used human Ad serotype 5 (Ad5). A potential major limitation of Ad5 vectors, however, is the high degree of preexisting immunity to Ad5 in human populations. Approximately 30% to 40% of individuals in the developed world have preexisting immunity to Ad5, whereas 80% to 90% of individuals in the developing world have been reported to be Ad5-seropositive.2Vogels R Zuijdgeest D van Rijnsoever R Hartkoorn E Damen I de Bethune MP et al.Replication-deficient human adenovirus type 35 vectors for gene transfer and vaccination: efficient human cell infection and bypass of preexisting adenovirus immunity.J Virol. 2003; 77: 8263-8271Crossref PubMed Scopus (399) Google Scholar Preclinical3Barouch DH Pau MG Custers JH Koudstaal W Kostense S Havenga MJ et al.Immunogenicity of recombinant adenovirus serotype 35 vaccine in the presence of pre-existing anti-Ad5 immunity.J Immunol. 2004; 172: 6290-6297Crossref PubMed Scopus (330) Google Scholar and clinical4Catanzaro AT Koup RA Roederer M Bailer RT Enama ME Moodie Z et al.Phase 1 safety and immunogenicity evaluation of a multiclade HIV-1 candidate vaccine delivered by a replication-defective recombinant adenovirus vector.J Infect Dis. 2006; 194: 1638-1649Crossref PubMed Scopus (266) Google Scholar studies have shown that individuals with pre-existing immunity to Ad5 generate substantially lower transgene-specific immune responses to Ad5 vector–based vaccines as compared with subjects without pre-existing immunity to Ad5, although the degree of this suppressive effect has been debated. Moreover, a recent phase 2b efficacy study evaluating an Ad5 vector-based vaccine for HIV-1 showed that individuals with preexisting immunity to Ad5 may have had increased rates of HIV-1 acquisition, suggesting that there may also be safety considerations associated with using Ad5 vaccine vectors in individuals with pre-existing immunity to the vector.5Fauci AS The release of new data from the HVTN 502 (STEP) HIV vaccine study.NIH News. 2007; (7 November 2007)Google Scholar These data suggest the need for the development of novel Ad vectors that are not suppressed by such pre-existing immunity. Current strategies being explored include the development of Ad vectors from human serotypes that are rare in human populations, such as Ad35 (ref. 2Vogels R Zuijdgeest D van Rijnsoever R Hartkoorn E Damen I de Bethune MP et al.Replication-deficient human adenovirus type 35 vectors for gene transfer and vaccination: efficient human cell infection and bypass of preexisting adenovirus immunity.J Virol. 2003; 77: 8263-8271Crossref PubMed Scopus (399) Google Scholar) and Ad26 (ref. 6Abbink P Lemckert AA Ewald BA Lynch DM Denholtz M Smits S et al.Comparative seroprevalence and immunogenicity of six rare serotype recombinant adenovirus vaccine vectors from subgroups B and D.J Virol. 2007; 81: 4654-4663Crossref PubMed Scopus (375) Google Scholar), chimeric Ad vectors in which dominant hexon neutralizing epitopes have been removed,7Roberts DM Nanda A Havenga MJ Abbink P Lynch DM Ewald BA et al.Hexon-chimaeric adenovirus serotype 5 vectors circumvent pre-existing anti-vector immunity.Nature. 2006; 441: 239-243Crossref PubMed Scopus (399) Google Scholar and Ad vectors from species other than humans such as chimpanzees.8Farina SF Gao GP Xiang ZQ Rux JJ Burnett RM Alvira MR et al.Replication-defective vector based on a chimpanzee adenovirus.J Virol. 2001; 75: 11603-11613Crossref PubMed Scopus (225) Google Scholar Singh and colleagues1Singh N Pandey A Jayashankar L Mittal SK Bovine adenoviral vector–based H5N1 influenza vaccine overcomes exceptionally high levels of pre-existing immunity against human adenovirus.Mol Ther. 2008; 16: 965-971Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar constructed an E1/E3-deleted, replication-incompetent BAd3 vector expressing the HA protein from the H5N1 influenza virus A/Hong Kong/156/97. The authors demonstrate that the BAd3-H5HA vector elicited potent HA-specific humoral and cellular immune responses in mice and afforded robust protection against challenge with an antigenically similar H5N1 influenza virus A/Hong Kong/483/97. The immunogenicity and protective efficacy of the vaccine were comparable in mice both with and without pre-existing immunity to Ad5, indicating that the BAd3 vector was not suppressed by high levels of pre-existing Ad5 immunity. Unfortunately, mice that received only human Ad5 vaccine vectors were not included in the challenge studies, although it would be predicted that Ad5 vectors would fail to afford protection in the presence of immunity to Ad5. These data, therefore, add to the existing literature showing that novel Ad vectors can effectively circumvent immunity to Ad5. A particularly interesting aspect of this study is the demonstration that a heterologous prime-boost regimen using both bovine and human Ad vectors elicited higher HA inhibition titers than did homologous regimens of either vector alone. Moreover, the heterologous regimen also protected against influenza virus challenge in the presence of immunity to Ad5, suggesting the potential utility of such combination vaccine regimens. Based on these observations, it is possible that an optimal regimen may consist of two Ad vectors that are serologically distinct from each other and that both evade immunity to Ad5. Future studies must evaluate the degree to which the BAd3-H5HA vaccine will protect against genetically more divergent strains of H5N1 influenza virus. Moreover, the BAd3 vector system will need to be assessed in greater detail for stability, manufacturability, and scale-up feasibility. Additional biologic aspects of the BAd3 vector will also need to be clarified, such as its cellular receptors, its tropism in vivo, and the phenotype of vaccine-elicited immune responses. The seroprevalence of this vector and the degree of cross-reactive T-lymphocyte responses with common human Ad vectors in large-scale human populations would also be important to investigate. The robust protection afforded by the BAd3-H5HA vaccine against a lethal avian influenza virus challenge raises the possibility that BAd3 vectors will prove useful not only for influenza but also for other pathogens. This study therefore adds BAd3 to the growing armamentarium of novel Ad vectors that effectively evade immunity to Ad5 and that could potentially be developed for both vaccination and gene therapy applications.