Herpes zoster vaccine: the definitive field trial

July 2005

An enormous amount of thought and effort went into the planning, designing and execution of the herpes zoster vaccine field trial recently published in The New England Journal of Medicine (2005:352;2271-2284), and it has paid off; this will likely become recognized as a “model” multi-institutional field trial!

The group responsible for this is known as the Shingles Prevention Study Group, with members selected from 22 study sites, all within the United States, for their expertise and interest. Funding for this study was provided by Merck and the Veterans Administration as well as by some of lead researcher Dr. Michael N. Oxman’s private grant support.

The study design met all contemporary standards: it was randomized, placebo-controlled and double-blinded and eligible subjects were adults ages 60 years or older, who had resided in the United States for at least 30 years, or who had a history of varicella. The study vaccine was made by Merck, and contained between 18,700 and 60,000 plaque-forming units per dose of live-attenuated Oka/Merck VZV vaccine. This is the same vaccine strain used in Merck’s varicella vaccine, Varivax. The shingles vaccine, however, contains at least 14 times more infectious virus than the pediatric preparation.

Active follow-up was carried out by an automated and interactive telephone response system, which patients agreed to call monthly. Any responses that suggested a possible case of herpes zoster resulted in a request to contact the local study site immediately; the local site was concurrently notified. Cases were confirmed – or not – as herpes zoster using an algorithm that incorporated results of a PCR assay done in a central study laboratory, a virus culture done in the local site’s virus laboratory and ultimately a five-physician clinical evaluation committee. The primary endpoint was a measure of the burden of illness caused by herpes zoster, as measured by duration and severity of pain and discomfort. A Zoster Brief Pain Inventory was used for a 182-day following the onset of rash to derive a severity-of-illness score.

Study results

Just over 38,500 participants were enrolled between November 1998 and September 2001; follow-up was completed in April 2004. The mean duration of herpes zoster follow-up surveillance was slightly more than three years. The results, in a nutshell, were as follows: 642 confirmed cases of herpes zoster occurred in the placebo group (n=19,276) and 315 cases occurred in the vaccinated group (n=19,270). There were 80 cases of postherpetic neuralgia in placebo recipients, and 27 among vaccine recipients. The burden of illness was reduced by 61% among vaccinees, and the incidence of postherpetic neuralgia was reduced by 66.5%. The incidence of herpes zoster was reduced by 51%.

When the results were stratified by age (60 to 69 and >70) and sex, the effect of vaccine on the incidence of herpes zoster was somewhat reduced among older subjects; the effect on the severity of illness was actually increased. In that way, the effect on the overall burden of illness was the same in both age groups. There was no significant sex difference.

Local site reactions were more frequent among vaccinees, but were generally mild; there were no long-term sequelae.

The accompanying editorials to the study were written by Ann Arvin, pediatrics, microbiology and immunology investigator from Stanford University, and Don Gilden, herpes neurovirologist from the University of Colorado. The first focuses on immunity to the varicella virus and the aging process, and the second on the impact of shingles in the aging population. Dr. Gilden was himself a patient with herpes zoster several years ago.

Several things strike me as of unusual interest as this vaccine moves forward. First, follow-up was terminated in April 2004; 14 months later the entire study is published in The New England Journal of Medicine! This must surely be some kind of record for large multicenter studies of this nature (at least for studies that do not involve antiretroviral drugs or statins).

Second, as pointed out by Dr. Gilden, if the FDA requires additional field trials prior to licensure, it will be at least a decade before this vaccine reaches the marketplace. This trial was so well done that, at least in my judgment, it would be difficult to justify the need for additional studies.

Third, the implications of these studies for Merck are obviously huge! Merck has had, and continues to go through, a tough time. This product, assuming approval and licensure, would likely go a long way toward restoring Merck’s image.

Pricing issues

Pricing will be a thorny issue, however. The pediatric vaccine, Varivax, is available on the open market for $50 to $100 per dose. The much larger dose of virus in the VZV (shingles) vaccine was determined on the basis of previous dose-response studies, and seems to assure that the shingles vaccine will likely cost substantially more than Varivax. How much will aging adults pay for a shingles vaccine with the efficacy parameters outlined above? $200? $500? It will be interesting to watch that debate as it unfolds, particularly when CMS weighs in on what, if anything, Medicare will reimburse for this product. Will the Veterans Administration, which helped to support this field trial, provide it to its beneficiaries?

I’m getting way ahead of where we are today. For now, and in the months ahead, we must continue to treat herpes zoster with antiviral drugs after it occurs and attempt to deal with postherpetic neuralgia as best we can. Meanwhile, we shall eventually see whether Merck and the FDA can move with anywhere near the same kind of efficiency and dispatch that characterized the investigators (and the NEJM) in analyzing, writing and publishing their data!