A cytomegalovirus vaccine for transplantation: are we closer?

Cytomegalovirus (CMV), a betaherpesvirus, causes significant human morbidity and mortality. It is present in at least 60% of the US population [1], with a prevalence of 90% in high-risk groups, including men who have sex with men [2, 3]. In immunocompetent hosts, CMV infection is usually asymptomatic, but it persists throughout an individual’s lifetime and has the potential to reactivate and cause disease. CMV also causes significant disease in newborns, which can result in sensorineural hearing loss, other central nervous system abnormalities, and death. In immunocompromised individuals, CMV is the most common viral cause of severe disease, including gastrointestinal manifestations and pneumonia in the transplant population and, in addition, retinitis in HIV-positive individuals [4, 5]. Current management of CMV disease uses antivirals that may have significant hematopoietic and renal toxicities along with sometimes-adverse drug-drug interactions. Thus, an effective CMV vaccine would be beneficial in decreasing the need for anti-CMV drugs. In 2001, the Institute of Medicine reported that the development of a CMV vaccine is of the highest priority in the 21st century [6]. Vaccine strategies have targeted CMV structural proteins, including the major surface glycoprotein B (gB) and tegument phosphoprotein 65 (pp65), because they have been shown to induce the dominant antibody and cellular immune responses, respectively [7–9]. CMV nonstructural proteins that elicit a strong humoral response, such as immediate-early 1 (IE1), have also been used. Several CMV vaccines have been studied, with mixed results [10]. Initial animal studies have been performed using an alphavirus-like replicon particle that expresses various combinations of pp65, IE1, and gB, with promising results [11]. Studies with live attenuated human Towne strain CMV vaccine have been disappointing in that the vaccine has not prevented CMV infection in seronegative individuals [12–15]. A phase 1 study of live recombinant human CMV Towne/ Toledo chimeric vaccines in CMVseropositive subjects produced no significant cellular or humoral immune response to the vaccine [16]. A recombinant gB protein with MF59 adjuvant (gB/MF59) vaccine induced high levels of IgG antibodies to gB in healthy adults who were given 2 priming doses followed by a booster dose at 6 months [17]. A canarypox-CMV recombinant gB vaccine, ALVAC-CMV(gB), could not elicit a significant neutralizing antibody response [18], nor did it show benefit in a prime-boost strategy or in a simultaneousvaccine strategy with the gB/MF59 vaccine [19]. Since immunocompromised individuals such as transplant recipients are a target population for CMV vaccination, it would be of benefit to use a virus-free vaccine [20]. DNA vaccines have been shown to induce significant T cell (both CD4 and CD8 ) and antibody responses [21] and, theoretically, for prolonged periods [22]. Alone, they are poorly immunogenic, but they can be combined with an adjuvant or modified to increase their immunogenic potential. They usually require large quantities of antigen to obtain a sufficient response, but they are relatively easy to produce. In this issue of the Journal, Wloch et al. [23] present the results of a phase 1 clinical trial of a bivalent DNA CMV vaccine, VCL-CB01 [24], containing plasmids encoding for gB and pp65 along with poloxamer CRL1005 and benzalkonium chloride to increase immunogenicity. The trial was an open-label, dose-escalating study of 44 adults who were either seronegative or seropositive for CMV. Wloch et al. evaluated 2 doses, 1 and 5 mg, in a Received 11 February 2008; accepted 11 February 2008; electronically published 29 April 2008. Potential conflicts of interest: R.B.P. has received grant support from Boehringer-Ingelheim Pharmaceuticals, Hoffman LaRoche, Kronis Pharmaceuticals, Merck, Pfizer, Schering Plough, and Tibotec; is a consultant for Abbott Laboratories, Genetic Immunity, Tobira, Tibotec, and VirxSys; and is on the speakers’ bureau for Bristol-Myers Squibb, Gilead, and Pfizer. V.G. reports no potential conflicts. Reprints or correspondence: Dr. Richard B. Pollard, Div. of Infectious Diseases, Dept. of Internal Medicine, University of California, Davis, Health System, 4150 V St., PSSB Suite G500, Sacramento, CA 95817 ([email protected]). The Journal of Infectious Diseases 2008; 197:1631–3 © 2008 by the Infectious Diseases Society of America. All rights reserved. 0022-1899/2008/19712-0001$15.00 DOI: 10.1086/588386 E D I T O R I A L C O M M E N T A R Y