Channel Catfish Virus Disease (CCVD) is the principal viral disease of US farm-raised catfish. The causative agent is Ictalurid herpesvirus 1 (IcHV-1). It primarily infects juvenile catfish (< 1 yr old; <15 cm) during the summer months, typically in the first few months post-stocking. Environmental stressors strongly influence disease outbreaks and transmission can occur both vertically and horizontally. Mortality rates may approach 100% in catastrophic outbreaks. Previous research has identified three distinct genetic group variants based on RFLP analysis, namely IcHV-1A, IcHV-1B and the recently described Blue catfish alloherpesvirus (BcAHV). Herein, the differential susceptibility of channel, hybrid and blue catfish against three genetic variants of IcHV-1 was investigated. Channel and hybrid catfish were exposed to three, discrete representative isolates of IcHV-1A and IcHV-1B at dosages equating the median lethal dose of the ATCC type strain (IcHV-1 Auburn). Differences in mortality between channel and hybrid catfish or between RFLP group were insignificant (p>0.05). Mortality for channel and hybrid catfish exposed to IcHV-1A was 30.6% (±7.3%) and 32.8% (±9.4%), respectively. Comparably, exposure of channel and hybrid catfish to IcHV-1B yielded mortality of 36.7% (±7.0%) and 46.1% (10.35%). After 28 days, survivors were re-exposed to IcHV-1A and IcHV-1B representative isolates. Previous exposure to IcHV-1 resulted in significantly improved survival compared to naïve controls (p<0.05). Relative percent survival (RPS) ranged from 53.8-100% for channels and 82.8-100% for hybrids, suggesting a cross-protective immune response develops in IcHV-1 survivors. Similarly, channel, hybrid and blue catfish were exposed to BcAHV, resulting in 51.6% mortality in blue catfish. No mortality was observed in either channel or hybrid catfish. Twenty-eight days post challenge, channel and hybrids surviving BcAHV exposure were exposed to IcHV-1A, resulting in 100% RPS for both groups. In addition to these infectivity trials, catfish fry were collected from commercial catfish hatcheries in Mississippi to estimate prevalence of IcHV-1 RFLP groups in US farm-raised catfish. Validation of qPCR assays to differentiate between IcHV-1 RFLP groups is ongoing and will be used to assess IcHV-1 prevalence in hatchery samples. Further, in collaboration with researchers at the University of Florida and the USDA-ARS, the genomes of representative IcHV-1 field isolates were sequenced to probe inter- and intra-species genomic diversity. Comparative genome analysis between BcAHV and other alloherpes virus revealed BcAHV possesses distinct genome characteristics indicating a unique viral “species.” Lastly, a command line based, customizable genome data analysis pipeline was developed with Snakemake and Python workflows to analyze IcHV-1 genome data. Infectivity trials, hatchery surveys and IcHV-1 comparative genomics will lead to better understanding of the molecular drivers of IcHV-1 transmission dynamics, immunogenicity, pathogenicity and latency. Furthermore, data indicates BcAHV has potential as a vaccine candidate against IcHV-1 in channel and hybrid catfish.