Low gH/gL (sub)species-specific antibody levels indicate elephants at risk of fatal elephant endotheliotropic herpesvirus hemorrhagic disease

Abstract Elephant endotheliotropic herpesviruses (EEHVs), of which seven species and multiple subspecies are currently distinguished, naturally infect either Asian ( Elephas maximus ) or African elephants ( Loxodonta species). While all adult elephants are latently infected with at least one EEHV (sub)species, EEHV infections in young elephants may lead to acute, fatal hemorrhagic disease (EEHV-HD). The disease is primarily observed in calves with low to non-detectable EEHV-specific antibodies, suggesting it is the result of an uncontrolled primary infection. Yet, young elephants showing high antibody levels in serological assays based on EEHV(1A) gB, which detect antibodies against multiple EEHV (sub)species, are not necessarily protected against EEHV-HD. To better determine which animals are at risk of EEHV-HD, we developed gB and gH/gL ELISAs for all Asian elephant EEHV (sub)species and assessed their specificity using 396 sera from 164 Asian elephants kept in Europeans zoos. Antibody levels measured against gB of different EEHV (sub)species correlated strongly with one another, indicating gB-specific antibodies are highly cross-reactive. In contrast, antibody responses towards gH/gL of different EEHV (sub)species were far less correlated and could be used to distinguish between infections with different (sub)species. Subsequently, antibody responses in sera of 23 EEHV-HD fatalities were analyzed. Whereas high antibody levels against gB could be detected in sera of multiple EEHV-HD fatalities, all fatalities had low antibody levels against gH/gL of the EEHV (sub)species they succumbed to. Overall, our data indicate that (sub)species-specific gH/gL ELISAs may be used to identify animals at risk of developing EEHV-HD upon infection with a particular EEHV (sub)species.