Immune suppression of challenged vaccinates as a rigorous assessment of sterile protection by lentiviral vaccines

Abstract

We previously reported that an experimental live-attenuated equine infectious anemia virus (EIAV) vaccine, containing a mutated S2 accessory gene, provided protection from disease and detectable infection after virulent virus (EIAV PV ) challenge [1,2]. To determine if attenuated EIAV vaccines actually prevent persistent infection by challenge virus, we employed a 14-day dexamethasone treatment of vaccinated horses post-challenge to suppress host immunity and amplify replication levels of any infecting EIAV. At two months post-challenge the horses were all protected from virulent-virus challenge, evidenced by a lack of EIA signs and detectable challenge plasma viral RNA. Upon immune suppression, 6/12 horses displayed clinical EIA. Post-immune suppression characterizations demonstrated that the attenuated vaccine evidently prevented detectable challenge virus infection in 50% of horses. These data highlight the utility of post-challenge immune suppression for evaluating persistent viral vaccine protective efficacy.

Envelope variation as a primary determinant of lentiviral vaccine efficacy

“…Twenty-four ponies of mixed age and gender (SI Table 3) were inoculated intramuscularly with two 10 3 TCID 50 doses, at a 4-week interval, of EIAV D9 . The inoculated ponies were monitored daily for clinical signs of EIA, and blood samples were taken at regular intervals for standard measurements of disease, virus replication, and host immune responses, as described (23)(24)(25)35). Six months after the second vaccination, the immunized ponies were randomly divided into three challenge groups, each consisting of eight animals (SI Table 3).…”

“…Differential diagnostics that consisted of sensitive RT-PCR and sequencing techniques of infecting viral strains were preformed at day of challenge and after challenge (during febrile episode or 3 weeks after challenge if nonfebrile) on each animal from all three groups as previously described (23). The results of these diagnostic assays revealed distinct differences among the three challenge groups; challenge virus was detected in two EV0, five EV6, and all eight EV13 ponies.…”

“…We have previously reported serial studies evaluating the efficacy of an attenuated EIAV proviral vaccine containing a mutation in the viral S2 accessory gene (EIAV D9 ) (23)(24)(25). The results of these studies indicate that horses inoculated with the EIAV D9 viral vaccine were 100% protected from disease by virulent EIAV challenge.…”

“…Initial vaccine studies indicated that the experimentally immunized horses achieved an apparent ''sterilizing immunity,'' based on the lack of detectable challenge virus infection by using sensitive diagnostic serological and genetic assays. However, further rigorous assays of plasma RNA from vaccinated and challenged animals subjected to chemical immune suppression demonstrated that Ϸ50% of the animals harbored challenge virus, despite the fact that 100% remained asymptomatic for EIA (23). Although the attenuated EIAV proviral vaccine may not achieve sterilizing immunity, the attenuated EIAV vaccine consistently provides complete protection from disease.…”

Restriction of Equine Infectious Anemia Virus by Equine APOBEC3 Cytidine Deaminases

“…EIAV infections are used as a model for natural immunologic control of lentivirus replication and virus persistence and as a test system to improve vaccines against lentiviruses (10,40,41,82). In vivo EIAV replicates predominantly in macrophages (77).…”