CMV Trials In Seronegative Patients Would Need More Preclinical Data

Human cytomegalovirus vaccine trials in seronegative patients require more preclinical data, FDA's Vaccines & Related Biological Products Advisory Committee concluded Nov. 4.

"It does not seem like there has been a serious attempt to look at non-human primates and whether or not we can do studies there before we proceed to human studies," committee member Barbara Fisher, National Vaccine Information Center, said.

The committee convened to discuss the safety and utility of a Phase I trial Aviron has proposed in collaboration with the National Institute for Allergy and Infectious Diseases, which will investigate four candidate vaccine strains in patients who are seropositive for HCMV.

The four different strains contain varying proportions of the attenuated Towne strain and the non-attenuated Toledo strain that "develop a chimeric CMV strain that is more immunogenic than Towne but is also more attenuated than a low passage clinical isolate."

FDA questioned the levels of attenuation. "Neither biochemical nor molecular characterization of recombinant strains provides reliable information regarding the expected level of attenuation, if any, in vivo," FDA's materials to the committee state. In addition, infectivity of the strains is not known in seronegative patients. Additionally, there is a potential to reactivate previous infection in seropositive patients.

"Current animal models of human CMV infection are inadequate to assess the virulence of viral strains, and hence, attenuation of recombinant strains," FDA added.

Committee member David Stephens, MD, Emory University, recommended developing models before conducting a trial: "It sounds like there is some potential...animal model that might shed some light [regarding] attenuation in these vaccine candidates."

Aviron has proposed using data from the seropositive trials to initiate a Phase I trial in seronegative subjects for HCMV. However, the committee was unable to assess how the data from Aviron's trial in seropositive subjects would pertain to future seronegative trials needed to prove vaccine efficacy.

"Even if this trial goes forward...what we all want is a CMV vaccine and for that we need some sense of direction beyond this particular trial," committee consultant Stanley Riddell, MD, Rhode Island Hospital, remarked.

The committee generally agreed with Riddell. FDA Office of Vaccine Research & Review medical officer Cynthia Kleppinger, MD, said the agency acknowledges "that the administration of a live recombinant CMV vaccine to seropositive subjects, as is being currently proposed, may prove safe in initial Phase I studies. However, safety data from seropositive subjects may not accurately predict that safety profile of such a vaccine in seronegative subjects."

One committee member, Alice Hwang, PhD, California Institute of Technology, was less circumspect about the trial. "If we are going to move towards a vaccine that has any usefulness, we are sort of at a position in which that movement cannot go ahead due to inability to test in animals. Therefore, the test in seropositive subjects is one that can certainly go ahead," she said.

The Aviron trial is a single-site randomized trial that would enroll 25 seropositive (but not with active infection) males and surgically sterile females into five arms, for the four chimeras and placebo. After vaccination, patients would be followed weekly for eight weeks and then infrequently out to a year, to monitor safety and immunogenicity.

The committee also recommended safety changes for the seropositive trial, including monitoring of a wider range of "close contacts" of patients, who are at increased risk for infection.

HCMV is one of eight known herpes viruses and is the most common congenital viral infection in humans. Over 40,000 fetuses are infected in the U.S. annually and almost 8,000 newborns suffer from CMV disease each year, FDA said.

Chronic infection (which is 90% asymptomatic) may lead to atherosclerosis and vascular disease. The Institute of Medicine has labeled the need for a vaccine as "Priority Level 1" and estimates an annual savings of $1 bil.-$4 bil.