Vaccination against a Virus-Encoded Cytokine Significantly Restricts Viral Challenge

Abstract

T here is ample precedent from studies of licensed viral and microbial vaccines that vaccine-mediated stimulation of pathogen-specific B cell immunity is critical for protection from infection and/or disease (1). Many new vaccine designs are predicated on the induction of antibodies that neutralize viral attachment to susceptible cells. As phase 2 clinical trials on human cytomegalovirus (HCMV) vaccination have shown, however, this approach only partially protects against challenge virus infection. In one study, seronegative women who had given birth within the previous year were vaccinated against HCMV glycoprotein B (gB) (2), the predominant virion target for antibodies that neutralize infection of fibroblasts. While significant protection against primary HCMV infection was observed in the vaccine group, the effect was limited in magnitude (50%) and duration. In the second placebocontrolled, randomized study, liver and kidney transplant candidates were similarly immunized with gB and prospectively evaluated for parameters of HCMV infection posttransplantation (3). Vaccine-mediated increases in gB-specific antibody titers were inversely correlated with the duration of HCMV viremia posttransplantation. Similar to the trial involving seronegative women, however, vaccination against gB alone in transplant recipients did not completely protect those at risk for HCMV infection.

Exploitation of Interleukin-10 (IL-10) Signaling Pathways: Alternate Roles of Viral and Cellular IL-10 in Rhesus Cytomegalovirus Infection

“…Put another way, distal sites, from which RhCMV is persistently shed following primary infection, are seeded with progeny virions during the period of time when there appears to be an immunosuppressive milieu for innate and adaptive effector cells. Moreover, the decline in basal cIL-10 production in unstimulated cells is just prior to the appearance of de novo antibodies that neutralize rhcmvIL-10 function (17), suggesting that early expression of rhcmvIL-10 may drive the peripheral production of cIL-10.…”

“…It is well established that rhcmvIL-10 M1/M2 vaccination is capable of stimulating robust humoral immune responses in both naive and RhCMV-infected animals and that preexposure vaccination alters the course of the RhCMV challenge infection, significantly lowering shedding titers and frequency (17,19). The fundamental goal of this study was to determine if postinfection vaccination was able to modify one phenotype of persistent infection, namely, chronic detection of RhCMV DNA in the saliva of long-term-infected animals.…”

“…The results suggested that primary RhCMV infection is associated with a nonspecific systemic increase in cIL-10 from mononuclear cells in the peripheral circulation. It is important to note that the period during which cIL-10 expression is increased from unstimulated cells (4 to 8 weeks) is contemporaneous with the first detection of RhCMV DNA in saliva and urine and also the first detection of antibodies that neutralize rhcmvIL-10 function (17). Put another way, distal sites, from which RhCMV is persistently shed following primary infection, are seeded with progeny virions during the period of time when there appears to be an immunosuppressive milieu for innate and adaptive effector cells.…”

“…Since the results of previous studies implied that rhcmvIL-10 is important for establishing a persistent infection (17), our study sought to determine whether long-term rhcmvIL-10 expression may be involved in maintaining persistence in immunocompetent animals.…”

“…Unlike MCMV, both HCMV and RhCMV encode a cIL-10 ortholog (cmvIL-10 and rhcmvIL-10, respectively) that binds to IL-10R1, and each viral ortholog exhibits comparable functionality to that of cIL-10 (3,8,15,16). A recent RhCMV study that employed vaccinemediated disruption of rhcmvIL-10-mediated signaling revealed that vaccine-mediated neutralization of rhcmvIL-10 function significantly restricted long-term parameters of primary RhCMV infection, particularly the frequency and magnitude of RhCMV detection in the saliva and urine of vaccinated/challenged rhesus macaques (17). Similarly, Chang et al reported that animals infected with a rhcmvIL-10 knockout variant of RhCMV (68-1) had quantitatively enhanced innate immune responses and developed more robust antiviral adaptive immune responses than animals expressing the parental virus, rhcmvIL-10 (18).…”