40 Years Is Long Enough!

In 1975, Stanley Plotkin and coworkers developed one of the first live attenuated cytomegalovirus (CMV) vaccines, called Towne 125, which was isolated from a congenitally infected infant and attenuated by cell culture passage and plaque purification [1]. Hundreds of subjects, including renal transplant recipients and healthy men and women, received the early investigational vaccine [2, 3]. The studies showed that the Towne CMV vaccine was safe; induced both humoral immunity, including neutralizing antibody, and cellular immunity, including cytotoxic T cells; and provided protection against CMV disease. However, it fell short in preventing CMV infection when compared to immunity from wild-type virus infection and failed at producing long-term measurable immunity, suggesting it was too attenuated to be effective. Several live attenuated vaccines are successfully being used for prevention of diseases, including varicella, caused by varicella zoster virus, a herpesvirus cousin of CMV, as well as measles, mumps, and rubella. In addition, the live oral poliovirus vaccine has helped eradicate polio in almost all parts of the world. Why has a successful live CMV vaccine been so elusive? A nonattenuated, more virulent Toledo strain of CMV was found unsuitable to be a vaccine candidate alone, but, when teamed with Towne as genetically constructed recombinants, 4 Towne/Toledo chimeric live virus next-generation vaccine candidates were produced [4, 5]. In a previous article by Heineman et al, published in a 2006 issue of The Journal of Infectious Diseases, it was shown that these chimeric vaccine candidates were safe in CMV-seropositive subjects, laying the groundwork for the work by Adler et al in this issue, where results of the first phase 1 dose-escalation trial of the 4 chimeras in CMV-seronegative, healthy adult men are reported [5, 6].All 4 chimeras were safe, well tolerated, and not excreted in bodily fluids, and chimera 4 led the pack as the most immunogenic in producing CMV seroconversion. But more work must be done, because the chimera 4 seroconversions were not robust or long lasting in the lower doses studied, leading future investigators to most likely study higher doses in more subjects to establish the optimal dosage of the leading chimera vaccine candidate. If successful, initial target groups for CMV vaccination might include adolescent girls or young women, to prevent CMV infection during childbearing years [7]. Because of the concerns that a live CMV vaccine may not be immunogenic, may be transmitted to other individuals, may be transmitted from the vaccinated mother to her fetus, may reactivate and cause disease at some point in time, or may exhibit an oncogenic potential and potentiate cancer or other illnesses in vaccine recipients, other approaches to CMV vaccine development have been studied. These approaches, with varying degrees of success, include subunit CMV glycoprotein B (gB) adjuvanted with MF59, which induces neutralizing antibodies; CMV phosphoprotein 65 (pp65) peptide–based vaccines, which induce cytotoxic T-cell vaccines for use in therapeutic vaccination of immune compromised hosts; canarypox CMV recombinants ALVAC-CMV (gB) and ALVACCMV (pp65), which appear to induce neutralizing antibody and cytotoxic Tlymphocyte responses; CMV DNA plasmids containing genes for gB and pp65; and dense bodies containing key CMV immunogenic antigens [3, 8]. However, it is not likely that a single-protein or single-component inactivated CMV vaccine will be a successful vaccine candidate. Therefore, strategies that use multiple components that target different or multiple aspects of the exceedingly complex viral replicative cycle of CMV, such as the gH/gL/UL128/UL130/UL131 pentameric complex compromising 5 viral proteins, should be pursued [9]. Since these proteins appear to be missing from many CMV vaccine strains after multiple laboratory passages, it provides a potential explanation for the modest successes for live CMV vaccine candidates so far studied. So why do we continue to pursue the elusive CMV vaccine, live virus or otherwise? First, CMV infection is a major yet thus far neglected public health problem, affecting men, women, and children around the world [10]. Congenital CMV infection is the most common congenital viral infection and a leading cause of deafness and vision loss and developmental and motor disabilities. ACMV vaccine to prevent primary infection or reduce Received and accepted 5 August 2016; published online 11 August 2016. Correspondence: G.J. Demmler Harrison, Department of Pediatrics, Baylor College of Medicine, Attending Physician, Texas Children′s Hospital, 1102 Bates St, Feigin Center Ste 1150, Houston, TX 77030 ([email protected]). The Journal of Infectious Diseases 2016;214:1297–9 © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail [email protected]. DOI: 10.1093/infdis/jiw367