Abstract
Based on the life-time cost to the health care system, the Institute of Medicine has assigned the highest priority for a vaccine to control human cytomegalovirus (HCMV) disease in transplant patients and new born babies. In spite of numerous attempts successful licensure of a HCMV vaccine formulation remains elusive. Here we have developed a novel chimeric vaccine strategy based on a replication-deficient adenovirus which encodes the extracellular domain of gB protein and multiple HLA class I & II-restricted CTL epitopes from HCMV as a contiguous polypeptide. Immunisation with this chimeric vaccine consistently generated strong HCMV-specific CD8+ and CD4+ T-cells which co-expressed IFN-γ and TNF-α, while the humoral response induced by this vaccine showed strong virus neutralizing capacity. More importantly, immunization with adenoviral chimeric vaccine also afforded protection against challenge with recombinant vaccinia virus encoding HCMV antigens and this protection was associated with the induction of a pluripotent antigen-specific cellular and antibody response. Furthermore, in vitro stimulation with this adenoviral chimeric vaccine rapidly expanded multiple antigen-specific human CD8+ and CD4+ T-cells from healthy virus carriers. These studies demonstrate that the adenovirus chimeric HCMV vaccine provides an excellent platform for reconstituting protective immunity to prevent HCMV diseases in different clinical settings.
Highlights
Human cytomegalovirus (HCMV) is a classic example of a group of herpes viruses, which is found universally throughout all geographic locations and socioeconomic groups, and infects 50% of adults in developed countries [1]
The data presented in this study provides a highly efficient strategy for the prevention of human cytomegalovirus (HCMV) disease in different clinical settings ranging from congenital infection to primary or reactivation of the virus in immunosuppressed adults
Immunocompromised individuals such as transplant recipients and HIV-infected individuals with CD4 counts below 50/ml are impacted by HCMV infection and this virus is regarded as the most important viral pathogen affecting transplantation, including both solid organ transplant and allogeneic hematopoietic stem cell transplant recipients [1,32,33]
Summary
Human cytomegalovirus (HCMV) is a classic example of a group of herpes viruses, which is found universally throughout all geographic locations and socioeconomic groups, and infects 50% of adults in developed countries [1]. During the last 30 years, various strategies, including whole virus, subunit vaccines based on recombinant gB protein, vector vaccines expressing immunodominant antigens (gB protein, pp and/or IE-1 protein), DNA vaccine and dense bodies have been developed, and some of these formulations have shown encouraging results in preclinical studies and can even induce HCMV-specific immune responses in some clinical studies [8,9,10,11]. None of these vaccines have shown convincing clinical efficacy in the control of HCMV infection or disease, and a clinically licensed HCMV vaccine is still not available
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