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Genomic and Bioinformatics Analyses of HAdV-4vac and HAdV-7vac, Two Human Adenovirus (HAdV) Strains That Constituted Original Prophylaxis against HAdV-Related Acute Respiratory Disease, a Reemerging Epidemic Disease

Anjan Purkayastha,^1,2,3 Jing Su,^1,2,3 John McGraw,^3,4 Susan E. Ditty,^3,4, Ted L. Hadfield,^3,4, Jason Seto,¹ Kevin L. Russell,^3,5 Clark Tibbetts,^2,3 and Donald Seto^1,2,3*

Bioinformatics and Computational Biology Program, School of Computational Sciences, George Mason University, 10900 University Boulevard, MSN 5B3, Manassas, Virginia 20110,¹ HQ USAF Surgeon General Office, Directorate of Modernization (SGR),² Epidemic Outbreak Surveillance (EOS) Consortium, 5201 Leesburg Pike, Suite 1401, Falls Church, Virginia 22041,³ Division of Microbiology, Department of Infectious and Parasitic Diseases Pathology, Armed Forces Institute of Pathology, 5300 Georgia Avenue, N.W., Washington D.C. 20306,⁴ Department of Defense Center for Deployment Health Research, Naval Health Research Center, San Diego, California 92186⁵

Received 25 December 2004/ Returned for modification 21 March 2005/ Accepted 6 April 2005

Vaccine strains of human adenovirus serotypes 4 and 7 (HAdV-4vac and HAdV-7vac) have been used successfully to prevent adenovirus-related acute respiratory disease outbreaks. The genomes of these two vaccine strains have been sequenced, annotated, and compared with their prototype equivalents with the goals of understanding their genomes for molecular diagnostics applications, vaccine redevelopment, and HAdV pathoepidemiology. These reference genomes are archived in GenBank as HAdV-4vac (35,994 bp; AY594254) and HAdV-7vac (35,240 bp; AY594256). Bioinformatics and comparative whole-genome analyses with their recently reported and archived prototype genomes reveal six mismatches and four insertions-deletions (indels) between the HAdV-4 prototype and vaccine strains, in contrast to the 611 mismatches and 130 indels between the HAdV-7 prototype and vaccine strains. Annotation reveals that the HAdV-4vac and HAdV-7vac genomes contain 51 and 50 coding units, respectively. Neither vaccine strain appears to be attenuated for virulence based on bioinformatics analyses. There is evidence of genome recombination, as the inverted terminal repeat of HAdV-4vac is initially identical to that of species C whereas the prototype is identical to species B1. These vaccine reference sequences yield unique genome signatures for molecular diagnostics. As a molecular forensics application, these references identify the circulating and problematic 1950s era field strains as the original HAdV-4 prototype and the Greider prototype, from which the vaccines are derived. Thus, they are useful for genomic comparisons to current epidemic and reemerging field strains, as well as leading to an understanding of pathoepidemiology among the human adenoviruses.

Present address: Midwest Research Institute, 1470 Treeland Blvd., S.E., Palm Bay, FL 32909.

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