The ZOE Trials - Herpes Zoster Recombinant Subunit Vaccine - Time to Upgrade!

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Lal H, Cunningham AL, Godeaux O, et al. Efficacy of an adjuvanted herpes zoster subunit vaccine in older adults. N Enlg J Med. 2015;372(22):2087-96. and Cunningham AL, Lal H, Kovac M, et al. Efficacy of the herpes zoster subunit vaccine in adults 70 years of age or older. N Enlg J Med. 2016;375(11):1019-32.

We now have two vaccinations to protect against herpes zoster — a live-attenuated vaccine (Zostavax) and the new recombinant subunit vaccine (Shingrix). While the live-attenuated vaccine has been available for more than a decade and a CDC-recommended vaccine in older adults, only one in three eligible patients have received it.1 While several logistical barriers to vaccination exist,2 two main concerns have limited the use of the live-attenuated vaccine: 1) declining efficacy with age, and 2) a limited duration of benefit. Based on the results of two recently published studies, the new recombinant subunit vaccine appears to provide substantially improved efficacy and duration.

 

Herpes zoster (HZ) or shingles results from the reactivation of the varicella-zoster virus, which after its primary infection remains dormant in the dorsal-root ganglia. HZ causes a localized vesicular rash and pain in most individuals. In the United States there are estimated to be one million cases annually, affecting about one in three individuals in a lifetime.3 The incidence of HZ increases from 5 per 1000 in the fifth decade of life to 11 per 1000 in those 80 years and older.4 While antiviral medications can reduce the severity and duration of the acute symptoms, they do not significantly impact the development of postherpetic neuralgia (PHN),5 a problematic and potentially debilitating complication. In older adults who develop shingles, about 10-15% will develop PHN but, like the infection itself, PHN is more common with increasing age. Treatments available for PHN aren’t terribly effective and have significant side effects.  For these reasons, vaccination stands as the only intervention that really works but requires foresight and planning.6

 

To understand the potential advantages of the new subunit vaccine requires us to review the history of the older, live-attenuated vaccine (Zostavax). This single-dose vaccine was approved by the FDA in 2006 for use in patients 60 years of age and older.  The Advisory Committee on Immunization Practices (ACIP) endorsed its widespread use in adults age 60 and older in 2008.3 These recommendations were based on the Shingles Prevention Study (SPS) trial7 that showed, when compared to placebo, the vaccine reduced the incidence of both the development of HZ (by 51.3%) and post-herpetic neuralgia (by 66.5%). These data are for the study population as a whole.  However, when analyzed by age, the efficacy of the vaccine had declining efficacy with increasing age and appeared to offer very limited protection from developing HZ in those 80 years and older. Despite waning efficacy against the development of HZ, vaccinated patients still experienced a lower incidence of PHN. See Table 1.

 

When the FDA expanded the labeling to vaccinate individuals starting at age 50 in 2011, the ACIP declined to update their recommendations;8 citing concerns about vaccine supply and the lack of long-term efficacy.9  The duration of protection appears to be age dependent and protection wanes to zero after 4-12 years.4 This could leave people unprotected and a second dose of the live-attenuated vaccine as a booster is not currently recommended.

 

The recombinant subunit vaccine was approved by the FDA and endorsed by the ACIP in October 2017.4 These recommendations include:

  • the recombinant subunit vaccine is preferred over the liveattenuated vaccine for use in immunocompetent individuals 50 years and older
  • the recombinant subunit vaccine is recommended even in those who have been previous vaccinated with the liveattenuated product.

These recommendations are based on two phase 3, concurrent and identical, randomized, double-blind, placebo-controlled trials. One enrolled participants 50 years and older (ZOE-50)10 and the other enrolled patients 70 years and older (ZOE-70).11 Participants were immunocompetent, shingles vaccine-naïve, and had no history of HZ.  The HZ subunit vaccine or placebo were administered intramuscularly at 0 and 2 months. The primary objective was overall vaccine efficacy against HZ with secondary objectives related to vaccine safety, reactogenicity, and efficacy against PHN. Since these two trials were identical in design, the investigators pre-planned a pooled analysis. Each study enrolled over 10,000 participants from sites in 18 countries. While groups were well matched, over half of participants were European, over 70% were white, and a slight majority were female in both trials. Participants were followed for more than 3 years. Both trials were funded by the vaccine manufacturer.

 

Vaccine efficacy in the ZOE-50 trial was 97.2% among participants 50 years and older. Very similar findings were observed in ZOE-70. See pooled results in Table 1. Unlike the previous live-attenuated product, the HZ subunit vaccine was effective in all age groups and was not attenuated by age. Protection was maintained for the trial duration, even in the older age group.6 As expected, the vaccinated groups in both trials experienced more injection site reactions including pain, myalgia and fatigue. However, all reactions were transient, lasting no more than 3 days, and did not impact patients’ willingness to take the second dose in the series. The rate of serious adverse effects was similar in the vaccinated and placebo groups.

 

Table 1 – Overview of SPS and ZOE-Trial Results

 

SPS Trials

(live-attenuated vaccine)

ZOE-Trials

(recombinant subunit vaccine)

Measure

n

%

95% CI

n

%

95% CI

Vaccine efficacy against HZ

 

 

All subjects

 

19,254

 

51

 

44–58

ZOE50

14,759

ZOE70

13,163

 

97

 

90

 

94–99

 

84–94

50-59 years

22,354§

72

57-83

7,017

97

90–99

60-69 years

10,370

64

56–71

4,307

97

90–100

70-79 years

7,621

41

28–52

13,022*

91

86–95

> 80 years

1,263

18

-29–48

3,574*

91

80–97

Vaccine efficacy against PHN

 

All subjects

19,254

67

48–79

27,916*

91

76–98

50-59 years

 

 

 

7,014

100

41–100

60-69 years

10,370

66

20–87

4,306

100

-443–100

70-79 years

 

 

 

13,022*

93

72–99

>70 years

8,884

67

43–81

16,596*

89

69–97

> 80 years

 

 

 

3,574*

71

-51–97

 

§ Reference 12

† ZOE-50 Data; ‡ ZOE-70 Data;
* Pooled from ZOE-50 and ZOE-70

 

While the live-attenuated and recombinant subunit vaccines were not compared head to head, these data support the preferential use of the recombinant HZ subunit vaccine.  Previous vaccination with the live-attenuated vaccine > 5 years prior to receipt of the new agent has not been shown to impact efficacy of the recombinant HZ subunit vaccine.4 While shorter intervals between vaccinations have not been studied, there is no theoretical reason to believe the efficacy would be impacted. Expert opinion recommends that providers should wait at least 2-months between vaccination with the live-attenuated and recombinant subunit vaccines.

 

Table 2

Live-attenuated vaccine (Zostavax)

Shared Characteristics

Recombinant subunit vaccine

(Shingrix)

Indicated > 60 years of age

 

Indicated > 50 years of age

Pros

Cons

Pros

Cons

Pros

Cons

Single dose

Efficacy against PHN beyond preventing HZ

Efficacy dependent on age at administration

Waning efficacy over time

Freezer storage

Vaccination only available intervention to prevent PHN

Use limited to immunocompetent individuals

For Medicare recipients, covered by Part D

Efficacy independent on age at administration

Currently, no concerns for waning efficacy but longer follow-up needed

Refrigerator storage

Two-dose series

 

 

Vaccinating adults starting at age 50 may shift the culture and increase vaccination rates against shingles by increasing the window of opportunity. With the older vaccine, the targeted age group was largely Medicare eligible. Given that the live-attenuated vaccine was covered by the Part D benefit, community pharmacies were a common location where patients received the vaccination. On the other hand, many clinics and health systems consider the HZ vaccine a burden and often do not have efficient systems for billing. Under Medicare Part D coverage, patients are required to pay a larger portion of the cost when compared to Part B eligible vaccines. The recombinant subunit vaccine is also covered by Medicare Part D, but may be covered by other insurers prior to Medicare eligibility. This is a great opportunity for pharmacists in clinic-based practices and community pharmacies. There is currently no concern about concomitant administration of the HZ subunit vaccine with other vaccines like influenza.13 Therefore, the new recombinant HZ subunit vaccine could easily be part of any patient encounter focusing on disease prevention and health promotion.

 

Tell us what you think.  Do you routinely offer and administer the HZ vaccine in your practice?  What are some best-practices for increasing HZ vaccination rates?