As Zika-related brain abnormalities resulting from congenital infection continue to claim center stage, there has been less fanfare drawn to other viral infections competing for resources in pharmaceutical development. Cytomegalovirus (CMV) infections continue to pass under the radar, despite accounting for congenital birth defects at a far greater rate. As of September 2016, in only 16 U.S. cases of birth defects in liveborn infants has there been laboratory evidence of Zika.  By contrast, despite remaining unknown to the majority of pregnant women and largely unscreened for by obstetricians,  some 40,000 children are born with CMV infection annually, resulting in an estimated 400 deaths each year and permanent disabilities in 8,000 children. 
Primary CMV infection is typically asymptomatic, which belies a U.S. seroprevalence estimated to range from 60 to 80%  and a disease that is the most common cause of congenital infection worldwide. Additionally, CMV takes a further toll in immunosuppressed patients such as transplant recipients and HIV-positive patients at risk for CMV infections.
Vaccine development against CMV has been hampered by several factors such as a lack of collaboration among sponsors holdings the assets necessary for a vaccine  as well as the unavailability of animal models for predicting immune response, with there being no non-human primates known to have cross-placental transfer of the virus until recently.  There is no marketed CMV vaccine and treatment is primarily relegated to DNA polymerase inhibitors ganciclovir and valganciclovir. With the heightened attention to congenital defects and promising recent data for antivirals such as maribavir as a therapeutic option,  it is timely to look at the historical and current landscape of CMV vaccine development.
Prior vaccine development has been pockmarked by high-profile failures such as the live-attenuated Towne strain. This volatility has led to several sponsors, Sanofi and GSK among them, to exit from the development space. However, overall tempo remains high, with the number of trials currently ongoing rivalling the number completed over the last four years. Of note is that the total set of trials remains small relative to the potential revenue, as CMV accounts for direct economic costs exceeding two billion USD annually,  indicating that the sponsor first to market could enjoy considerable revenue streams that are unlikely to be challenged in the near term. There is also a marked disparity between the two potential indications of a candidate, with prophylactic vaccine development lagging in phase both historically and at present.
Leading the pack as the only candidate in Phase III is Vical’s therapeutic ASP0113, for which a readout last month signalled that the vaccine failed to meet primary endpoints in a Phase II kidney transplant patients trial.  Although pursuit of solid organ transplant recipients as an indication was accordingly terminated and doubt has now been cast on the expected Q1 2018 topline results of the Phase III study for the same DNA plasmid vaccine, Vical remains committed to the allogeneic HCT recipients program.   As well, two Phase II candidates identified by City of Hope are waiting in the wings. Triplex, the recombinant modified vaccinia Ankara viral vector vaccine, has had Phase I results published last month with promising safety and immunogenicity data for the entire cohort. 
On the prophylactic front development is attempting to make up for several stalled programs (most notably Sanofi’s CMV gB vaccine which had disappointing efficacy results in a Phase II trial last year), with all candidates remaining in Phase I for the moment. VBI Vaccine’s study is prominent - recruitment has completed in Q3 2016 and a readout is expected next year. Merck and Hookipa round out the stable with a Phase I trial apiece. There are also promising preclinical prophylactic candidates, despite the Phase I trial of CyMVectin being terminated prior to initiation earlier this year, as both Pfizer and City of Hope are expected to announce trials in the coming months.
It has now been nearly two decades since the National Institute of Medicine reviewed 26 conditions with the potential for vaccine prevention based on cost impact and quality of life, ranking a congenital CMV vaccine as the highest priority.  With most of the ongoing trials expecting topline results in 2017, hopefully the emergence of an approved vaccine won’t have to wait much longer.
4. Staras, S.A.; Dollard, S.C.; Radford, K.W.; Flanders, W.D.; Pass, R.F.; Cannon, M.J. Seroprevalence of cytomegalovirus infection in the United States, 1988–1994. Clin. Infect. Dis. 2006, 43, 1143–1151
8. Stratton KR et al, Committee to Study Priorities for Vaccine Development, Inst. of Med.; Washington, DC
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