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Shingrix Emerges as Alternative to Zostavax

By Mike Bassett

The new shingles vaccine, Shingrix, approved by the FDA in October 2016 and recommended for those aged 50 and older, has demonstrated efficacy above 90%.

Most if not nearly all older Americans harbor within their bodies the varicella zoster virus—acquired with childhood chickenpox—which means they are at risk for shingles and its potentially debilitating complications.

The currently available shingles vaccine, Zostavax, is less than optimal. It prevents only about one-half of shingles cases in individuals over the age of 60 and is even less effective as people age.

For precisely this reason there has been quite a bit of excitement surrounding the development and approval of Shingrix. On October 20, the FDA approved Shingrix, developed by GlaxoSmithKline, for the prevention of shingles in adults aged 50 and older. Five days later the Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices (ACIP) voted not only to recommend the new vaccine but also to recommend it over Zostavax.

Approximately 1 million shingles cases occur in the United States each year, and it is estimated that one of every three people are at risk of developing shingles during their lifetimes.

The risk of developing shingles increases with age. "If we're lucky enough to live to the age of 85, the risk is one out of two, and that's because our immune systems decline as we age," says Leonard Friedland, MD, vice president for scientific affairs and public health for GlaxoSmithKline's North American vaccines unit. "And we can't control it through diet or exercise. It's a biological phenomenon that is just going to happen."

Prevention Is Key
For those individuals who develop shingles, the symptoms can be debilitating. Typically, they include a painful itchy rash, often with pain that has been described as burning, shooting, or stabbing. The rash can last between two and four weeks, but even when it's gone, patients can experience postherpetic neuralgia, a painful complication of shingles that can last months and even years after the rash has gone.

And there's no cure for shingles, which means "the best way to manage shingles is to prevent it," Friedland says.

The two vaccines display striking differences. Whereas Zostavax is a live attenuated vaccine, Shingrix is a recombinant antigen vaccine like the hepatitis B and human papillomavirus vaccines. "The [Shingrix] vaccine is formulated with an adjuvant—AS01B—that helps stimulate and direct the immune response to the antigen and is responsible for providing this very high level of efficacy, independent of age," Friedland says.

Two phase III randomized placebo-controlled trials evaluated Shingrix in adults over the age of 50 (ZOE-50) and adults aged 70 and older (ZOE-70). Shingrix demonstrated efficacy against shingles above 90%, independent of age and sustained its efficacy over the entire follow-up period of four years.

And by preventing shingles, Shingrix also reduced the overall incidence of postherpetic neuralgia, the form of chronic nerve pain commonly associated with shingles.

Another study, Zoster-048, found that Shingrix also induces a strong immune response in older adults who have received the Zostavax vaccine at least five years prior to being vaccinated with Shingrix.

"And that's the major difference between the two vaccines," Friedland says. "The data for Shingrix show we have greater than 90% efficacy independent of age, which is important when the risk of shingles and its complications is much more common and much more serious with age."

Friedland points out other differences between Shingrix and Zostavax. For example, Zostavax requires one dose, while Shingrix requires two doses, with the second dose given anywhere between two and six months after the first. "And the reason for the second dose is that early studies demonstrated than the addition of a second dose gave a much stronger immune response to the vaccine," he says. "And we see that translating to this very high level of efficacy."

Friedland also notes that Zostavax must be stored frozen, which creates issues associated with both shipping and storage. Shingrix, on the other hand, "is a refrigerator-stable vaccine and will reduce those barriers to storage," he says.

New Horizon for Shingles Prevention?
While the 15 ACIP members voted overwhelmingly to recommend Shingrix for immunocompetent adults aged 50 and older, the vote to recommend the vaccine over Zostavax was by only a one-vote margin.

"This [kind of recommendation] is not something that has commonly been done by ACIP," says Edward Belongia, MD, director of the Center for Clinical Epidemiology & Population Health at the Marshfield Clinic Research Founding in Wisconsin, and chair of the ACIP Herpes Zoster Work Group. "There was no disagreement that the vaccine is an excellent vaccine and should be recommended, but it was clear from the discussion that some people felt more comfortable waiting for more postlicensure data to become available before making a preferential recommendation."

One issue that has been associated with Zostavax since it was licensed by the FDA has been its relatively slow uptake. By 2014 only 30% of adults aged 60 and older had received the vaccine.

Last year ACIP suggested that this slow uptake occurred due to a number of factors such as price concerns, vaccine-specific factors including the storage and handling of frozen vaccines such as Zostavax, and systemic factors such as the low prioritization of adult vaccines.

"There are clearly barriers to the implementation of adult vaccines in general," Belongia says. "Zostavax is certainly part of that, and an uptake of 30% or so is not anywhere what we would like to see."

In a release announcing ACIP's recommendations, Patrick Desbiens, senior vice president of US Vaccines at GlaxoSmithKline, suggested implementing efforts to help increase the number of older adults immunized against shingles.

Belongia notes that ACIP based its recommendations on a number of factors, including the cost-effectiveness of the drug as well as its safety profile.

GlaxoSmithKline said the price of Shingrix will be $280 for the required two doses, which compares with $223 for the one dose of Zostavax. "Part of the [ACIP's] discussion concerned what proportion of people will not come back and get the second dose of Shingrix," Belongia says. "And if there are barriers to completing the series, that will have to be addressed, but there are obviously examples of vaccines where multiple doses are needed, so that's not unusual in the vaccine world."

As for the drug's safety profile, the most common side effects of Shingrix are pain, redness, and swelling at the injection site, as well as muscle pain, tiredness, headache, shivering, fever, and upset stomach. "If the vaccine produces any of these short-lived events, they usually last anywhere from one to three days," Friedland says, adding that in studies 95% of patients received a second dose of the vaccine, suggesting that they weren't overly concerned about side effects.

Vaccine Recommendations
ACIP also recommended Shingrix for the prevention of herpes zoster and related complications for immunocompetent adults who have previously received Zostavax.

When should people who have already received Zostavax get the new vaccine? Belongia says that while ACIP felt it was inappropriate to specify a recommended interval, the minimum should be eight weeks and the decision should be left up to physician and their patients.

As for bringing the vaccine to market, Friedland says that after discussions with the Centers for Disease Control and Prevention, GlaxoSmithKline began to look very carefully at projections of demand based on the various recommendation scenarios.

"It's our analysis that we can meet demand based on the recommendations made," he says. "We've been producing vaccine for the last year, and all of our quality assessments have passed without any difficulties."

— Mike Bassett is a freelance writer based in Holliston, Massachusetts.