Replicating Single-Cycle Adenovirus Vectors Generate Amplified Influenza Vaccine Responses.
Head-to-head comparisons of conventional influenza vaccines with adenovirus (Ad) gene-based vaccines demonstrated that these viral vectors can mediate more potent protection against influenza virus infection in animal models. In most cases, Ad vaccines are engineered to be replication-defective (RD-Ad) vectors. In contrast, replication-competent Ad (RC-Ad) vaccines are markedly more potent but risk causing adenovirus diseases in vaccine recipients and health care workers. To harness antigen gene replication but avoid production of infectious virions, we developed "single-cycle" adenovirus (SC-Ad) vectors. Previous work demonstrated that SC-Ads amplify transgene expression 100-fold and produce markedly stronger and more persistent immune responses than RD-Ad vectors in Syrian hamsters and rhesus macaques. To test them as potential vaccines, we engineered RD and SC versions of adenovirus serotype 6 (Ad6) to express the hemagglutinin (HA) gene from influenza A/PR/8/34 virus. We show here that it takes approximately 33 times less SC-Ad6 than RD-Ad6 to produce equal amounts of HA antigen in vitro SC-Ad produced markedly higher HA binding and hemagglutination inhibition (HAI) titers than RD-Ad in Syrian hamsters. SC-Ad-vaccinated cotton rats had markedly lower influenza titers than RD-Ad-vaccinated animals after challenge with influenza A/PR/8/34 virus. These data suggest that SC-Ads may be more potent vaccine platforms than conventional RD-Ad vectors and may have utility as "needle-free" mucosal vaccines.


OBJECTIVE
Most adenovirus vaccines that are being tested are replication-defective adenoviruses (RD-Ads). This work describes testing newer single-cycle adenovirus (SC-Ad) vectors that replicate transgenes to amplify protein production and immune responses. We show that SC-Ads generate markedly more influenza virus hemagglutinin protein and require substantially less vector to generate the same immune responses as RD-Ad vectors. SC-Ads therefore hold promise to be more potent vectors and vaccines than current RD-Ad vectors.
Department of Medicine, Division of Infectious Diseases, Mayo Clinic, Rochester, Minnesota, USA.|Virology and Gene Therapy Graduate Program, Mayo Clinic, Rochester, Minnesota, USA.
Catherine M
CM
Crosby
Virology and Gene Therapy Graduate Program, Mayo Clinic, Rochester, Minnesota, USA.
William E
WE
Matchett
Clinical Translational Sciences Graduate Program, Mayo Clinic, Rochester, Minnesota, USA.
Stephanie S
SS
Anguiano-Zarate
Immunology Graduate Program, Mayo Clinic, Rochester, Minnesota, USA.
Christopher A
CA
Parks
Department of Medicine, Division of Infectious Diseases, Mayo Clinic, Rochester, Minnesota, USA.
Eric A
EA
Weaver
Department of Immunology, Mayo Clinic, Rochester, Minnesota, USA.
Larry R
LR
Pease
Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Richard J
RJ
Webby
Department of Medicine, Division of Infectious Diseases, Mayo Clinic, Rochester, Minnesota, USA mab@mayo.edu.|Department of Immunology, Mayo Clinic, Rochester, Minnesota, USA.|Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA.
Michael A
MA
Barry
D000256:Adenoviridae / Q000235:genetics*; D000281:Administration, Intranasal; D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology; D000956:Antigens, Viral / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D006224:Cricetinae; D004261:DNA Replication; D018076:DNA, Complementary / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D005822:Genetic Vectors / Q000235:genetics*; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000235:genetics / Q000276:immunology; D006801:Humans; D007114:Immunization; D009980:Influenza A virus / Q000235:genetics / Q000276:immunology; D007252:Influenza Vaccines / Q000008:administration & dosage / Q000235:genetics* / Q000276:immunology*; D009976:Orthomyxoviridae Infections / Q000276:immunology / Q000517:prevention & control; D051381:Rats; D011993:Recombinant Fusion Proteins; D016205:Sigmodontinae; D014779:Virus Replication
D000914:Antibodies, Viral; D000956:Antigens, Viral; D018076:DNA, Complementary; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D007252:Influenza Vaccines; D011993:Recombinant Fusion Proteins
adenovirus; gene-based vaccine; replication defective; single cycle