Department of Pathology, Division of Immunology, Institute of Cell Engineering, Johns Hopkins School of Medicine, Baltimore, MD, USA
Sanjay V. Kottapalli
Department of Pathology, Division of Immunology, Institute of Cell Engineering, Johns Hopkins School of Medicine, Baltimore, MD, USA
Florian P. Breitwieser
Center for Computational Biology, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Danielle E. Anderson
Programme in Emerging Infectious Diseases, Duke-NUS Medical School, 8 College Road, 169857, Singapore
Limin Wijaya
Department of Infectious Diseases, Singapore General Hospital, 20 College Road, 169856, Singapore
Kevin Tan
National Neuroscience Institute, 11 Jalan Tan Tock Seng, 308433, Singapore
Wan Ni Chia
Programme in Emerging Infectious Diseases, Duke-NUS Medical School, 8 College Road, 169857, Singapore
Kai Kammers
Department of Oncology, Division of Biostatistics and Bioinformatics, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
Patrizio Caturegli
Department of Pathology, Division of Immunology, Institute of Cell Engineering, Johns Hopkins School of Medicine, Baltimore, MD, USA
Kathleen Waugh
Barbara Davis Center for Diabetes, University of Colorado Denver, Aurora, CO, USA
Mario Roederer
ImmunoTechnology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
Michelle Petri
Department of Medicine, Division of Rheumatology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
Daniel W. Goldman
Department of Medicine, Division of Rheumatology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
Marian Rewers
Barbara Davis Center for Diabetes, University of Colorado Denver, Aurora, CO, USA
Lin-Fa Wang
Programme in Emerging Infectious Diseases, Duke-NUS Medical School, 8 College Road, 169857, Singapore
H. Benjamin Larman
Department of Pathology, Division of Immunology, Institute of Cell Engineering, Johns Hopkins School of Medicine, Baltimore, MD, USA; Corresponding author.
Summary: Background: Comprehensive characterization of exposures and immune responses to viral infections is critical to a basic understanding of human health and disease. We previously developed the VirScan system, a programmable phage-display technology for profiling antibody binding to a library of peptides designed to span the human virome. Previous VirScan analytical approaches did not carefully account for antibody cross-reactivity among sequences shared by related viruses or for the disproportionate representation of individual viruses in the library. Methods: Here we present the AntiViral Antibody Response Deconvolution Algorithm (AVARDA), a multi-module software package for analyzing VirScan datasets. AVARDA provides a probabilistic assessment of infection with species-level resolution by considering sequence alignment of all library peptides to each other and to all human viruses. We employed AVARDA to analyze VirScan data from a cohort of encephalitis patients with either known viral infections or undiagnosed etiologies. We further assessed AVARDA's utility in associating viral infection with type 1 diabetes and lupus. Findings: By comparing acute and convalescent sera, AVARDA successfully confirmed or detected encephalitis-associated responses to human herpesviruses 1, 3, 4, 5, and 6, improving the rate of diagnosing viral encephalitis in this cohort by 44%. AVARDA analyses of VirScan data from the type 1 diabetes and lupus cohorts implicated enterovirus and herpesvirus infections, respectively. Interpretation: AVARDA, in combination with VirScan and other pan-pathogen serological techniques, is likely to find broad utility in the epidemiology and diagnosis of infectious diseases. Funding: This work was made possible by support from the National Institutes of Health (NIH), the US Army Research Office, the Singapore Infectious Diseases Initiative (SIDI), the Singapore Ministry of Health's National Medical Research Council (NMRC) and the Singapore National Research Foundation (NRF).
