Abstract
Human cytomegalovirus (HCMV) is an ubiquitous herpesvirus that can cause serious morbidity and mortality in immunocompromised or immune-immature individuals. A vaccine that induces immunity to CMV in these target populations is therefore highly needed. Previous attempts to generate efficacious CMV vaccines primarily focused on the induction of humoral immunity by eliciting neutralizing antibodies. Current insights encourage that a protective immune response to HCMV might benefit from the induction of virus-specific T cells. Whether addition of antiviral T cell responses enhances the protection by antibody-eliciting vaccines is however unclear. Here, we assessed this query in mouse CMV (MCMV) infection models by developing synthetic vaccines with humoral immunity potential, and deliberately adding antiviral CD8+ T cells. To induce antibodies against MCMV, we developed a DNA vaccine encoding either full-length, membrane bound glycoprotein B (gB) or a secreted variant lacking the transmembrane and intracellular domain (secreted (s)gB). Intradermal immunization with an increasing dose schedule of sgB and booster immunization provided robust viral-specific IgG responses and viral control. Combined vaccination of the sgB DNA vaccine with synthetic long peptides (SLP)-vaccines encoding MHC class I-restricted CMV epitopes, which elicit exclusively CD8+ T cell responses, significantly enhanced antiviral immunity. Thus, the combination of antibody and CD8+ T cell-eliciting vaccines provides a collaborative improvement of humoral and cellular immunity enabling enhanced protection against CMV.
Highlights
Human cytomegalovirus (HCMV), a member of the b-herpesvirus family, is estimated to infect 6080% of the world population
We show in experimental CMV models that the effectivity of antibody-eliciting DNA vaccines against CMV infection via the intranasal and intraperitoneal route can be improved by the addition of CD8+ T cell responses induced by synthetic long peptide (SLP) vaccines
The sgB antibody-eliciting DNA vaccine outperformed the glycoprotein B (gB) DNA vaccine, which is in line with Lauterbach et al, who showed >10 fold higher IgG titers after DNA vaccines encoding soluble antigen compared to membrane bound antigen [54]
Summary
Human cytomegalovirus (HCMV), a member of the b-herpesvirus family, is estimated to infect 6080% of the world population. CMV establishes low-level viral persistence with little or no clinical symptoms with the exception of sporadically causing a mononucleosis-like illness [1]. In immunocompromised individuals, including both solid organ and bone. Congenital HCMV infection in the immunological immature unborn and newborn babies can cause severe morbidity, lifelong invalidity and even mortality [2]. Treatment options such as antiviral drugs and cellular therapy are available against HCMV-associated disease, preventive strategies such as vaccines are highly desired. Antiviral drugs require prolonged treatment, are accompanied by significant toxicity, and viral resistance to the drug is not uncommon [3]. No licensed effective prophylactic or therapeutic HCMV vaccines are available yet
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