The FDA recently approved a new vaccine against herpes zoster, which brings with it considerations for internists about efficacy, insurance, and patient communication.
The herpes zoster subunit vaccine, which is manufactured by GlaxoSmithKline and marketed under the brand name Shingrix, is approved for use in immunocompetent adults ages 50 years and older. Based on recent recommendations from the CDC's Advisory Committee on Immunization Practices (ACIP), the new vaccine should be considered the preferred option for prevention of shingles in adults and should be given in place of the existing shingles vaccine, Zostavax, which is manufactured by Merck.
“These two vaccines are fundamentally very different,” said John O’Neill Jr., DO, MACP, an internist in Middletown, Del., and chair of ACP's Immunization Technical Advisory Committee. “The new subunit vaccine is not a live virus but is an inactivated subunit, a glycoprotein antigen combined with an adjuvant that stimulates the immune system.”
The effectiveness of the subunit vaccine, more than 90%, tipped the scales with regard to the ACIP recommendations, according to Dr. O’Neill. With Shingrix expected to become widely available sometime early in 2018, internists must begin now to learn about its efficacy, side effects, storage, administration, and reimbursement.
Among a group of more than 15,000 participants ages 50 years and older who received the two-dose subunit vaccine, the overall vaccine efficacy against herpes zoster was 97.2%, according to the results of a phase III trial (ZOE-50) published in The New England Journal of Medicine in 2015. A second trial published in 2016, of almost 14,000 adults ages 70 years and older (ZOE-70), showed an overall vaccine efficacy against herpes zoster of 89.8%. Pooled results from patients ages 70 years and older from ZOE-50 and ZOE-70 showed a vaccine efficacy of 91.3% in patients older than age 70 years. The vaccine also had high efficacy (88.8%) in preventing post-herpetic neuralgia in the pooled analysis.
“When Zostavax is initially given it is about 51.3% effective, but then the efficacy of the vaccine declines over time,” said Sandra Adamson Fryhofer, MD, MACP, an internist in Atlanta who served as liaison representative to the 2017 ACIP Herpes Zoster Work Group for both ACP and the American Medical Association. “Although we only have four years of data, the new vaccine seems to maintain its efficacy.”
The CDC currently recommends vaccination with Zostavax in patients ages 60 years and older. Based on the results from the ZOE trials, the ACIP voted to recommend the subunit vaccine 1) for the prevention of herpes zoster and related complications for immunocompetent adults ages 50 years and older, 2) for the prevention of herpes zoster and related complications for immunocompetent adults who previously received the live-attenuated vaccine, and 3) as the preferred vaccine for the prevention of herpes zoster and related complications.
According to Dr. Fryhofer, the third recommendation on preferred use passed by only one vote.
“Some people had concerns that since the vaccine was only studied in clinical trials, introducing it into the real world might have some unforeseen complications,” she said. “Use of this vaccine will be closely watched.”
There are some practical considerations about the subunit vaccine for internists planning to administer it to patients, experts said.
First, unlike the live-attenuated vaccine, which is stored in a freezer, the subunit vaccine can be stored in a standard vaccine refrigerator that most physicians already have in their offices, Dr. O’Neill said. (In addition, the manufacturer of Shingrix, GlaxoSmithKline, noted in a Feb. 6 e-mail to ACP that the vaccine is to be administered intramuscularly only, not subcutaneously, and must be reconstituted with the adjuvant liquid suspension provided.)*
Second, unlike the one-dose live-attenuated vaccine, the subunit vaccine is a two-dose vaccine with the second dose administered at least eight weeks after the first.
“Education on this point will be key, especially given the increased rate of adverse effects associated with Shingrix compared with the old vaccine,” said Richard R. Watkins, MD, MS, FACP, an infectious disease specialist in Akron, Ohio, and an associate professor of internal medicine at the Northeast Ohio Medical University.
Results of ZOE-50 indicated that about 80% of patients who received the subunit vaccine reported injection-site and systemic reactions within seven days of injection compared with only 30% of people assigned to placebo.
“Doctors have to alert patients to this before the needle goes in so that patients are not surprised, angry, hurt, disappointed, or unhappy about this,” said William Schaffner, MD, MACP, professor of preventive medicine and infectious diseases at Vanderbilt University School of Medicine in Nashville, Tenn. “Patients have to be prepared for this again when they come in for their second dose, but what do they get in exchange? They get an incredibly fabulous protection.”
Zostavax is substantially less reactogenic than Shingrix, according to Dr. Schaffner. He noted that multiple studies have found similar rates of serious adverse events with Zostavax and with placebo, with local injection-site reactions occurring in fewer than one-half of patients receiving Zostavax versus 17% of placebo recipients.
Whether patients who have already received the previous vaccine will object to additional vaccination with the new vaccine remains to be seen, according to Dr. O’Neill, especially considering the latter's two injections, higher incidence of mild local and systemic adverse reactions, and uncertainties about insurance coverage.
“The best approach for physicians initially will be to educate patients about the new vaccine to assist them in their decision-making process,” Dr. O’Neill said.
According to Dr. Fryhofer, another reason some members of ACIP voted for the preferred vaccine recommendation was to increase the likelihood that insurance companies would cover the cost of the new vaccine. The New York Times has reported that GlaxoSmithKline estimates a total cost of $280 for the new two-dose vaccine, compared with $223 for the previous vaccine.
“Some were afraid that insurance companies would say that they would only cover the one-dose vaccine but not the two-dose vaccine, which might be a little more expensive,” Dr. Fryhofer explained.
Given the ACIP recommendation, Dr. Fryhofer expects that the subunit vaccine will be covered but said that she cannot be sure. Right now immunizations are covered without cost-sharing for non-Medicare patients under the Patient Protection and Affordable Care Act (ACA). Insurance companies have a year after recommendations are published in Morbidity and Mortality Weekly Report (MMWR) to begin to cover vaccines, although some may decide to do so earlier, Dr. Fryhofer noted. The MMWR published the ACIP recommendations on use of herpes zoster vaccines on Jan. 26.
“The clock for coverage does not start until the recommendation is published in MMWR,” Dr. Fryhofer said. “There is also a lot of concern about what is happening with coverage of essential health benefits under the ACA.”
Coverage under essential health benefits will make administration and reimbursement for the subunit vaccine for people ages 50 to 64 years easier. However, coverage issues may remain for patients on Medicare, since the new vaccine, like the previous one, is likely to be included under Medicare Part D, which not all Medicare recipients opt for, according to Dr. Schaffner.
“Even when they had Part D, some patients had co-pays or deductibles, some had to pay upfront and submit for reimbursement from the insurance company [for Zostavax],” Dr. Schaffner said. “These were real barriers, and doctors found it difficult to administer vaccines under Part D.”
In addition, the Part D prescription drug benefit was designed to be managed at pharmacies, while shingles vaccines are most often administered at physician offices.
“We anticipate that once again Shingrix will also be put into Part D, the prescription drug benefit, and the Medicare population will have the same problem that it had with Zostavax,” Dr. Schaffner said.
A positive change
Despite the possibility of some associated challenges related to administration of two doses, adverse effects, and Medicare coverage, Dr. Schaffner said that internists should really be insistent that their patients get this vaccine.
“If you only say that a patient should consider getting the vaccine, that opens the door for patients to say, ‘No.’” Dr. Schaffner said. “That is not what we say when a patient has hypertension. We tell them it needs to be treated and give them the medicine.”
However, physicians must still decide if administering the subunit vaccine in-office is the right decision for their practice. The recently approved vaccine is just beginning to become commercially available, and reimbursement is still unknown. Even after it is available, clinicians and patients are going to have to be patient and check with each insurance provider about coverage, according to Dr. O’Neill.
In addition, Dr. O’Neill recommended that all physicians do a financial analysis before ordering the subunit vaccine to help them decide whether they are going to offer it.
“You could be left with a big loss on this vaccine if you do not plan ahead, because a lot of times the margin on vaccines in general is very close to zero,” Dr. O’Neill said. “Any smart doctor running a practice will look at how much it's going to cost upfront, where they will buy it, how they will store it, and look into reimbursement from insurers.”