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 ...
We previously reported that long-term rhesus cytomegalovirus (RhCMV) excretion in infected macaques was related to UL/b′ coding content. Acute biopsy specimens of the inoculation sites from the previous study have now been analyzed to determine whether there were acute phenotypic predictors of long-term RhCMV infection. Only in animals displaying acute endothelial tropism and neutrophilic inflammation was RhCMV excretion detected. The results imply that vaccinating against these early viral determinants would significantly impede long-term RhCMV infection.
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