Category Archives: infectious diseases

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.

Stretching the flu vaccine?

In this flu-vaccine shortage year, any means of extending the vaccine supply is worth examining. There is evidence that giving vaccines intradermally rather than intramuscularly is more effective. In last week’s NEJM are two articles examining the effect of administering a lower dose of the flu vaccine intradermally. There is also a letter to the editor looking at the effect of simply giving a lower dose of the vaccine by the traditional i.m. route.

In the first study, sponsored by Glaxo SmithKline, 238 subjects were randomized to either a standard 0.5 ml i.m. dose of flu vaccine or a 0.1 ml intradermal dose of a candidate vaccine that was double concentrated (yielding an intradermal vaccine with 40% the concentration of antigen of the standard vaccine). 130 subjects were aged 18-60 years, 108 were over 60 years of age (average age: 69). In the younger group, the antibody responses were almost the same and were adequately protective in the intradermal group. In the group of subjects over 60 years old, the intradermal route yielded antibody titers that were generally lower, significantly lower for one strain and probably only incompletely protective.

In the second study, suppored by NIH grants, 100 subjects 18-40 years of age were randomized to receive either a standard 0.5 ml i.m. dose of a standard flu vaccine, or 0.1 ml of the same vaccine given intradermally. The intradermal route yielded, overall, a similar (for some strains better) antibody response as the i.m. route.

In the letter to the editor, a group from Canada gave healthy volunteers aged 18-40 years old either a full dose or a 1/10 dose of an influenza vaccine by the intramuscular route. Those given the 1/10 dose achieved protective antibody levels (although lower titers for most strains).

These studies indicate that the intradermal route produces better immunogenicity than the i.m. route. This could be used to enhance the immune response in populations that mount a less effective response (such as the elderly). It could also be used to stretch the vaccine supply in case of future shortages, particularly in the younger population. The practical effectiveness of these approaches will depend, at least in part, on FDA approval of different dosages and routes. It seems unlikely that a manufacturer of a conventional influenza vaccine will apply for approval of one-fifth of the dose of that same vaccine, administered intradermally. The Glaxo SmithKline approach of manufacturing a different product is more likely to be financially attractive.
 

Another case-control study ?

This week’s JAMA has a cohort study from the Netherlands looking at the risk of community-acquired pneumonia and use of gastric acid–suppressive drugs. The authors used a large, private practice clinical database to investigate a hypothesized linkage between the prescription of proton pump inhibitors or H2 receptor blockers and community acquired pneumonia. In order to adjust for the fact that many patients on these drugs are sicker, or more likely to have certain diseases, the authors performed a nested case-control examination that looked at recent acid-suppression therapy compared with previously discontinued therapy, adjusting for a large number of factors and diseases (such as age, sex, indication for the therapy, presence of diabetes, copd and stomach cancer).

The unadjusted relative risk of pneumonia for patients who had been prescribed acid-suppressant therapy vs. those who had not was quite high (4.5). In the matched, adjusted case-control cohort of recent therapy vs. past therapy, the adjusted odds ratio was 1.63, much lower, but still significant.

I believe it is impossible to properly adjust for all the reasons why pneumonia patients might have been prescribed acid-suppressant therapy shortly before getting pneumonia. Some of the factors that the authors controlled for are surely valid, but there are likely to be others. Even an individual practitioner’s style and personality could be linked with both the likelihood of prescribing these drugs and that particular patient population’s risk for pneumonia. Adequate adjustment is just not possible.

After multiple case-control and cohort studies showed significant cardiovascular benefit from estrogen replacement therapy, properly randomized trials demonstrated that this was not the case, forcing an incredible about-face. One would think that the estrogen replacement scandal would have put a major brake on performing and publishing these sorts of studies, yet they seem be flourishing. Has nothing been learned?