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In Phase 3 Trial, Adjuvanted Herpes Zoster Subunit Vaccine Shows 97 Percent Efficacy in Older Adults

ARTICLE IN BRIEF

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THE NEW VACCINE could be highly effective at preventing shingles and its complications, such as post-herpetic neuralgia, in older adults, the study suggests.

An adjuvanted herpes zoster subunit vaccine was 97.2 percent effective at reducing the risk of herpes zoster in adults aged 50 and older, and remained between 96.6 and 97.9 percent effective among adults 70 years or older.

An adjuvanted herpes zoster subunit vaccine was 97.2 percent effective at reducing the risk of herpes zoster in adults aged 50 years and older, researchers reported in the April 28 online edition of the New England Journal of Medicine. What's more, the vaccine remained between 96.6 and 97.9 percent effective among adults aged 70 years or older.

The results suggest that the new vaccine could be highly effective at preventing shingles and its complications, such as post-herpetic neuralgia, in older adults. In particular, people over age 70, who are at increased risk for shingles and in whom the vaccine has demonstrated high efficacy, stand to benefit, study author Thomas C. Heineman, MD, PhD, director of global clinical development of vaccines at GlaxoSmithKline, the vaccine's manufacturer, told Neurology Today.

“This is very encouraging from the point of view of older people,” he said, “because the incidence of shingles increases as you age, and so do the incidence and severity of its complications. Therefore, a vaccine that remains highly effective even as people age into their 60s, 70s, and beyond is certainly a benefit for the public.”

Experts who spoke with Neurology Today agreed that the vaccine shows great promise as a preventive measure against herpes zoster and its complications, but said it will be important to see the results of other clinical trials of the vaccine already underway. These include a trial to test the vaccine's safety and efficacy in an immunocompromised population, and a head-to-head comparison of the adjuvanted subunit vaccine and the licensed vaccine.

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DR. THOMAS HEINEMAN: “This is very encouraging from the point of view of older people because the incidence of shingles increases as you age, and so do the incidence and severity of its complications. Therefore, a vaccine that remains highly effective even as people age into their 60s, 70s, and beyond is certainly a benefit for the public.”

STUDY METHODOLOGY, RESULTS

Zostavax, the live attenuated herpes zoster vaccine, is approximately 51.3 percent effective against herpes zoster and 66.5 percent effective against post-herpetic neuralgia in adults aged 60 or older, according to figures cited in the study. But its efficacy against the virus decreases with age, and it is only 37.5 percent effective in those aged 70 or older.

The new vaccine, which contains varicella-zoster virus glycoprotein E and the currently unlicensed AS01B adjuvant system (called HZ/su), was shown to have an acceptable safety profile and to elicit a robust immune response that persisted for at least three years in phase 1 and 2 clinical trials, Dr. Heineman and his colleagues reported. For the randomized, placebo-controlled phase 3 trial, they assigned 15,411 participants to receive either the vaccine (7,698 participants) or placebo (7,713). Participants received two intramuscular doses of the vaccine or placebo two months apart.

During a mean follow-up of 3.2 years, herpes zoster was confirmed in six patients in the vaccine group and 210 participants in the placebo group (incidence rate, 0.3 vs. 9.1 per 1,000 person-years). The vaccine was 97.2 percent effective in the entire cohort (95% confidence interval [CI], 93.7 to 99.0; p<0.001), and efficacy remained between 96.6 and 97.9 percent when the researchers stratified the results by age, separating out participants in their 50s, 60s, and 70s.

There were significantly more reports of injection-site and systemic reactions — including pain, redness, and swelling at the injection site, as well as fatigue, fever, gastrointestinal symptoms, headache, myalgia, and shivering — within seven days after inoculation in the vaccine group compared with the placebo group. Grade 3 symptoms — those that prevented normal everyday activities — were reported in 17 percent of those receiving the vaccine and 3.2 percent of those receiving placebo. The majority of these were injection-site reactions, and median durations ranged from one to three days. The proportion of participants who had serious adverse events, potential immune-mediated diseases, or who died during follow-up were similar in both groups (103 in the vaccine group vs. 128 in the placebo group).

“There have been hypothetical concerns that adjuvanted vaccines may be associated with an increased risk of autoimmune diseases. But there was no imbalance between the vaccine and placebo groups with regard to serious adverse events, autoimmune diseases, or deaths,” said Dr. Heineman.

Given these results, the vaccine “has the potential, once it's approved, to dramatically reduce the number of shingles cases, especially in the elderly,” he said. “It also has the potential to prevent most of the misery caused by the various complications of shingles, including post-herpetic neuralgia, which can be quite common.

“It is a very interesting and, I think, unexpected finding that even in the oldest population we studied, people over 70, there was no indication of a decline in efficacy,” he added. “With most vaccines, the effectiveness declines with age, presumably because as people get older, their immune responses to vaccinations become less robust. We did not see that effect here. That's a very important result, because it potentially provides the basis for better addressing other vaccine-preventable diseases in the elderly, for which the necessary immune responses have been harder to attain.”

And because the adjuvanted subunit vaccine does not contain live virus, it may potentially be used in immunocompromised patients, for instance those who have had an autologous stem cell transplant. For these patients, the risk for herpes zoster is higher but the live attenuated vaccine is contraindicated, Dr. Heineman noted. “Over the next year or so we'll have more data on the vaccine's safety, immunogenicity, and efficacy in immunocompromised people, who may someday substantially benefit from it,” he said.

EXPERTS COMMENT

Experts who reviewed the study were impressed by the vaccine's efficacy, especially in patients over age 70, and were intrigued by its potential to protect against herpes zoster in an immunocompromised population.

“Since it is not a live attenuated vaccine and it's not infectious, this new vaccine can potentially be used in immunocompromised patients, such as HIV patients or those on immunomodulatory therapies,” said Maria Nagel, MD, an associate professor of neurology at the University of Colorado, who specializes in neurovirology and studies varicella zoster virus (VZV) and stroke. If effective in clinical trials, the new vaccine “could reach a population that the current live vaccine does not reach.”

It could also potentially protect against cardiovascular events such as stroke and heart attack that have been linked to herpes zoster in past research, she said.

But certain important questions remain. For instance, Dr. Nagel noted that “immunity was only studied through 3.2 years, so it is still unclear how long the protective effect against zoster lasts.” Other questions include whether a booster will be necessary, and whether the vaccine will reduce the incidence of post-herpetic neuralgia in the small number of immunized patients who still contract herpes zoster, she said.

Hung-Fu Tseng, PhD, MPH, a research scientist who focuses on infectious diseases and vaccine safety and efficacy research at Kaiser Permanente in Southern California, agreed. “Post-marketing surveillance will be important,” he said. “We should closely monitor the performance of the vaccine and its safety when it is being used in the general population.”

From a practice standpoint, Dr. Tseng said, there may also be challenges in getting patients to return to the clinic or pharmacy for the second dose of the vaccine. Dr. Nagel agreed, noting that even the single-dose live attenuated vaccine, which is widely publicized and readily available at pharmacies, has a very low adoption rate — around 24 percent.

In addition, the vaccine's high rate of side effects might discourage patients from getting a second dose, said Laura Hurley, MD, MPH, an assistant professor of medicine at the University of Colorado Denver School of Medicine, who studies adult immunization. “A study setting is sort of a utopia of vaccine implementation,” she said. “In the real world, if you're trying to get people to come back for a second vaccine after having a significant reaction, even if it is a local reaction, there are going to be problems.”

That issue aside, it will be interesting to see whether the adjuvanted vaccine system can be harnessed to make other vaccines more effective in older adults, she said. “It makes you wonder. If this mechanism could be invoked for other vaccines, for example the pneumococcal vaccine, to improve the immune response, could those vaccines have better effects? These results are very interesting, and potentially very promising.”

EXPERTS: ON A NEW VACCINE FOR HERPES ZOSTER

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DR. MARIA NAGEL: “Since it is not a live attenuated vaccine and its not infectious, this new vaccine can potentially be used in immunocompromised patients, such as HIV patients or those on immunomodulatory therapies.”

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DR. HUNG-FU TSENG: “Post-marketing surveillance will be important. We should closely monitor the performance of the vaccine and its safety when it is being used in the general population.”

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DR. LAURA HURLEY: “A study setting is sort of a utopia of vaccine implementation. In the real world, if youre trying to get people to come back for a second vaccine after having a significant reaction, even if it is a local reaction, there are going to be problems.”

LINK UP FOR MORE INFORMATION:

•. Lal H, Cunningham AL, Godeaux O, et al. Efficacy of an adjuvanted herpes zoster subunit vaccine in older adults http://www.nejm.org/doi/full/10.1056/NEJMoa1501184. N Engl J Med 2015. Epub 2015 Apr 28.
    •. Cohen JI. A new vaccine to prevent herpes zoster http://www.nejm.org/doi/full/10.1056/NEJMe1505050. N Engl J Med 2015. Epub 2015 Apr 28.
      •. ClinicalTrials.gov: Study to evaluate efficacy, safety and immunogenicity of GlaxoSmithKline (GSK) biologicals' herpes zoster (HZ) vaccine GSK1437173A in adults aged 70 years and older: http://bit.ly/ZOE-70
        •. ClinicalTrials.gov: Comparison of a live herpes zoster vaccine and a recombinant vaccine in 50-59 and 70-85 Year Olds: http://bit.ly/vaccine-comparison
          •. Neurology Today archive on herpes zoster: http://bit.ly/NT-HSV