The zoster vaccine

The lead article in yesterday’s NEJM, A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults, presents the results of a VA Cooperative Study looking at the efficacy of a high potency, live attenuated VZV vaccine developed by Merck from the Oka/Merck strain. The results are encouraging, with a reduction in the incidence of herpes zoster of 51.3% during 3 years of follow-up.

The authors state that the incidence of post-herpetic neuralgia was reduced by 66.5%. They are referring to the incidence in the overall study population: there were 27 cases of PHN among the 19,254 subjects who received the vaccine, vs. 80 cases among the 19,247 subjects who did not receive the vaccine. If you look at the number of cases of PHN among patients with zoster, the numbers are 27/315, vs. 80/642, a reduction of about 31%. Both of these numbers are important to judge the vaccine.

In other words, the vaccine reduced the incidence of zoster by about a half, the overall incidence of PHN by about 2/3 and the incidence of PHN among patients with zoster by about a third.

What about the choice of vaccine? The study used a live attenuated vaccine that was of higher potency than the standard vaccine given to children. Why not study the vaccine that is already available in the United States? Two reasons, one medical, one economic:

  • Medical: a higher potency vaccine may be necessary to boost the immune response in older patients sufficiently to prevent zoster.
  • Economic: a new vaccine formulation for this specific purpose can be priced much higher than the already available childhood vaccine.

Turning to the economic consideration first, in the accompanying editorial, Gilden states:

“To nonindigent recipients of the currently used childhood VZV vaccine (Varivax), the price of vaccination is between $50 and $100 (the sum of the cost of vaccine plus the visit or facility fee). An adult vaccine might cost more, given its greater potency. Nevertheless, the zoster vaccine appears to have been highly cost-effective in the Shingles Prevention Study (i.e., in the range of $2,000 per quality-adjusted life-year gained, even assuming a vaccine cost of $500).”

Clearly, Merck stands to make a lot of money if the vaccine used is a new one, costing several hundred dollars, rather than the existing vaccine which costs under $100 per dose.

What about the possibility of using the currently available vaccine, possibly with a booster dose, rather than a new, higher potency one? The vaccine used in this study contained between 18,700 and 60,000 plaque-forming units of virus, versus about 1,350 pfu’s in the Oka/Merck vaccine that is commercially available and is administered to children. In the concluding paragraph of the current study, the authors state:

“The minimum potency of the zoster vaccine administered to subjects in the study was at least 14 times greater than the minimum potency of Varivax (Merck), the vaccine currently licensed to prevent varicella. A preliminary study indicated that potencies of this magnitude are required to elicit a significant increase in the cell-mediated immunity to VZV among older adults hence, the need to formulate a high-potency vaccine for this study. We know of no data to suggest that the licensed varicella vaccine would be efficacious in protecting older adults from herpes zoster or postherpetic neuralgia. Thus, we do not recommend the use of the current varicella vaccine in an attempt to protect against herpes zoster and postherpetic neuralgia. “

The authors provide no references to back up the results of their “preliminary study” indicating that such high potencies are necessary. In fact, a 1992 article published by some of the same authors of the current study, Immune response of elderly individuals to a live attenuated varicella vaccine, seems to indicate that such high doses may not be necessary. From the abstract of that article:

“The Oka strain live attenuated varicella-zoster virus (VZV) vaccine was administered subcutaneously to 202 VZV-immune individuals who were 55 to greater than 87 years old. The dose administered varied from 1100 to 12,000 pfu… Most significantly, VZV-specific proliferating T cells in PBMC of vaccinees were increased in frequency from 1 in 68,000 to 1 in 40,000… Dose and age of the vaccinees did not significantly influence the magnitude of the mean cell-mediated immune response…”

I understand that pharmaceutical companies may reformulate a drug before launching a large, expensive trial for a new indication, in order to maximize their profit. That’s how the health care market works. And it may well be that a higher potency vaccine is necessary to achieve adequate protection.

Still, it would have been nice if the authors of this trial had justified their use of a new vaccine with a published reference.

3 thoughts on “The zoster vaccine

  1. Niels Olson

    “It would have been nice”?! From Merck’s perspective justifying the NDA application is the whole point of the study. They can’t submit that study to the FDA and have the words “the current vaccine is also effective” in there. I mean, they can, but it certainly doesn’t improve their odds of approval. Supporting the old, off-patent vaccine doesn’t add to Merck’s bottom line. Supporting a new, on-patent vaccine does add to Merck’s bottom line, and, from Merck’s perspective, getting a new vaccine past the FDA is a statistical issue so it pays to suppress any information that doesn’t actively support the new preparation.

  2. paul kerr

    Thanks for the review – I’ve drawn on it for my journal club next week! What do you think of Gilden’s comment that a drug cost of $500 would give a cost of $2000 per quality life year saved? Is my maths wrong – doesn’t that mean that for every four patient vaccinated one will gain a full QALY? My own calculation shows the number needed to treat to prevent one case of Zoster is about 60 (642 – 315 = 327 less cases for 19,000 vaccinations – 19000/315 = 60) but to prevent one case of post herpetic neuralgia is about 360 vaccinations(80 – 27 = 53 less cases from 19000 vaccinations) – so preventing one case of post herpetic neuralgia would cost about $180000 – but this includes pain scores above 3, ie includes very mild cases, most of which were over within one to two months. Also the majority of the benefit was seen in the older age group. IE to prevent one case of moderate to severe post herpetic neuralgia in a patient in their sixties may take up to a 1000 vaccinations and may cost half a million dollars, and may cause one death from toxicity.

    Best wishes,

    Paul

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