Vaccine-Induced Control of Viral Shedding following Rhesus Cytomegalovirus Challenge in Rhesus Macaques

Abstract

The use of animal models of human cytomegalovirus (HCMV) infection is critical to refine HCMV vaccine candidates. Previous reports have demonstrated that immunization of rhesus monkeys against rhesus cytomegalovirus (RhCMV) can reduce both local and systemic replication of RhCMV following experimental RhCMV challenge. These studies used prime/boost combinations of DNA expression plasmids alone or DNA priming and boosting with either inactivated virion particles or modified vaccinia virus Ankara (MVA) expressing the same antigens. Viral outcomes included reduced RhCMV replication at the site of subcutaneous inoculation and RhCMV viremia following intravenous inoculation. Since shedding of cytomegalovirus from mucosal surfaces is critical for horizontal transmission of the virus, DNA priming/MVA boosting was evaluated for the ability to reduce oral shedding of RhCMV following subcutaneous challenge. Of six rhesus monkeys vaccinated exclusively against RhCMV glycoprotein B (gB), phosphoprotein 65 (pp65), and immediate-early 1 (IE1), half showed viral loads in saliva that were lower than those of control monkeys by 1 to 3 orders of magnitude. Further, there was a strong association of memory pp65 T cell responses postchallenge in animals exhibiting the greatest reduction in oral shedding. These results highlight the fact that a DNA/MVA vaccination regimen can achieve a notable reduction in a critical parameter of viral replication postchallenge. The recently completed clinical trial of a gB subunit vaccine in which the rate of HCMV infection was reduced by 50% in the individuals receiving the vaccine is consistent with the results of this study suggesting that additional immunogens are likely essential for maximum protection in an outbred human population.The nearly 40-year quest for a vaccine that confers protective efficacy against congenital infection with human cytomegalovirus (HCMV) remains unmet, although considerable progress has been made. Complexities in HCMV's natural history, incompletely defined correlates of immune protection, and financial and logistical factors in designing sufficiently powered clinical trials all contribute to the absence of a licensed HCMV vaccine(s). Animal model studies with rhesus monkey, mouse, and guinea pig systems have demonstrated that multiple vaccine strategies, including approaches based on those proposed for HCMV, are effective at limiting the extent of challenge virus replication. Immunization of HCMV-negative women with recombinant gB has been clinically evaluated (50,51). A recently completed phase II trial assessed the efficacy of the vaccine to decrease cases of maternal HCMV infection (34). The endpoint of this study was the time to HCMV infection (50, 51), and the trial ended earlier than planned because vaccine efficacy exceeded goals. The results offer strong encouragement that vaccination regimes directed at prominent neutralizing epitopes can significantly decrease the rate of primary infection in HCMV-negative women. The impressive, but less than 100%, level ...

Cytomegalovirus pp65 limits dissemination but is dispensable for persistence

“…In the RM model, it was previously demonstrated that vaccination with subunit vaccines consisting of pp65b (with or without IE1) as T cell-inducing components and gB as neutralizing antibody-inducing component reduced RhCMV viremia and shedding (44)(45)(46). However, our data also suggest that T cell responses to antigens other than pp65 play an important role in the protective effect of RhCMV infection against ΔUS2-11 challenge.…”

“…In this previous work, it was shown that this vaccination regimen, while unable to protect against superinfection with RhCMV, reduced local and systemic viremia as well as viral shedding. Moreover, reduction in shedding correlated with the magnitude of pp65-specific T cell responses (44). In our hands, the heterologous prime-boost vaccination induced a robust CD4 + and CD8 + T cell response to pp65b that in the blood was similar in magnitude to pp65-specific T cell responses elicited by RhCMV infection.…”

“…Conceivably, pp65 vaccination could affect the viral loads of ΔUS2-11gag, as has been reported for pp65/gB-vaccinated animals challenged with RhCMV (44). Since primary infection with RhCMV 68-1 (the parental strain of ΔUS2-11gag) does not result in robust viremia (see below), direct measurements of viral loads were unlikely to be informative.…”

“…We used a DNA-prime/ MVA-boost protocol employed previously to vaccinate animals with a combination of pp65, IE1, and gB (44). In this previous work, it was shown that this vaccination regimen, while unable to protect against superinfection with RhCMV, reduced local and systemic viremia as well as viral shedding.…”

Identification of a Neutralizing Epitope within Antigenic Domain 5 of Glycoprotein B of Human Cytomegalovirus

“…Another phase II study, using solid organ transplant recipients, showed 50% efficacy in controlling viremia in high-risk patients (35). In addition, vaccination studies with gB in rhesus macaques and subsequent rhesus CMV (RhCMV) challenge showed significantly reduced RhCMV DNA in plasma (36,37). Finally, a number of studies using the guinea pig model demonstrated that congenital infection and mortality in pups were reduced following gB DNA or recombinant protein subunit vaccination strategies (38).…”