Safety and tolerability of a high-potency zoster vaccine in adults ≥50 years of age

Vaccine 25 (2007) 1877–1883

Safety and tolerability of a high-potency zoster vaccine in adults ≥50 years of age Stephen K. Tyring a , Francisco Diaz-Mitoma b , Larry G. Padget c , Margarita Nunez d , Gregory Poland e , William M. Cassidy f , Nickoya D. Bundick g , Jianjun Li g , Ivan S.F. Chan g , Jon E. Stek g , Paula W. Annunziato g,∗ , The Protocol 009 Study Group a

f

University of Texas Health Science Center, Houston, TX, United States b Children’s Hospital of E. Ontario, Ottawa, Canada c Georgetown Medical Center, Georgetown, TX, United States d CNS Clinical Trials, St. Petersburg, FL, United States e Mayo Clinic, Rochester, MN, United States Louisiana State University Health Science Center, Baton Rouge, LA, United States g Merck & Co., Inc., West Point, PA, United States

Received 5 June 2006; received in revised form 5 October 2006; accepted 10 October 2006 Available online 30 October 2006

Abstract Background: Herpes zoster (HZ) incidence rises with age, especially after 50 years of age, probably due to waning varicella-zoster virus (VZV)-specific immunity. The Shingles Prevention Study [Oxman MN, Levin MJ, Johnson GR, Schmader KE, Straus SE, Gelb LD, et al. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults, N Engl J Med 2005;352:2271–84], enrolled people ≥60 years of age and showed that zoster vaccine prevents HZ and postherpetic neuralgia (PHN), presumably through boosting VZV-specific immunity. This study of people ≥50 years of age compared the safety and tolerability of two zoster vaccine potencies. Methods: Adults ≥50 years old enrolled in a randomized, double-blind, multicenter study to compare the safety and tolerability of one dose of two zoster vaccine potencies, ∼58,000 and ∼207,000 plaque-forming units/dose. Adverse experiences (AEs) were recorded on a standardized Vaccination Report Card for 42 days postvaccination. For assessment of injection-site AEs, clinically acceptable tolerability was predefined based on experience with PNEUMOVAXTM 23, a licensed vaccine recommended for use in older people. Results: Six hundred and ninety-eight subjects (age 50–90 years, median 64 years) were enrolled. No serious vaccine-related AEs were reported. Similar AE rates were observed in the higher and lower potency groups (overall systemic AEs: 37.5 and 39.3%, vaccine-related systemic AEs: 10.9 and 13.2%, injection-site AEs: 63.0 and 59.8%). Rates for a combined endpoint of moderate or severe injection-site pain/tenderness/soreness and swelling were 17.2% (95% CI 13.9, 21.0) and 9.0% (95% CI 5.6, 13.4), respectively. Most combined endpoint events were reported as moderate in intensity. Conclusions: Both vaccine potencies were generally well tolerated in this study of people ≥50 years of age. Although rates of some moderate or severe injection-site AEs were greater in the higher potency group, all rates met the prespecified criteria for clinically acceptable tolerability. © 2006 Elsevier Ltd. All rights reserved. Keywords: Safety; Tolerability; Zoster vaccine

1. Introduction ∗ Corresponding author at: Merck Research Laboratories, P.O. Box 4, UNC-151, West Point, PA 19486, United States. Tel.: +1 484 344 2141; fax: +1 484 344 3292. E-mail address: paula [email protected] (P.W. Annunziato).

0264-410X/$ – see front matter © 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.vaccine.2006.10.027

Herpes zoster (HZ), known also as shingles, is a manifestation of reactivation of varicella-zoster virus (VZV), which, as a primary infection, produces chickenpox (varicella).

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Following initial infection, the virus remains latent in the dorsal root of spinal nerves or cranial sensory ganglia until it reactivates and replicates, producing HZ [1,2]. In the United States, Canada, and Europe, the overall annual incidence of HZ is consistently estimated to be 3–4/1000 population [1,3–8]. The incidence and severity of HZ increase with age [2,8–12] with the annual risk of developing HZ increasing markedly around 50 years of age and rising sharply afterwards, up to 1% per year among those over 75 years of age. The lifetime risk of HZ is estimated to range from 10 to 30% in the general population, with estimates closer to 30% in the more recent studies [13], and is as high as 50% in individuals reaching 85 years of age [2,9,14,15]. Based on current census data, an estimated one million cases of HZ are diagnosed in the United States every year. Chronic, long-lasting HZ-associated pain, know as postherpetic neuralgia (PHN), constitutes the most common severe complication and cause of morbidity in the HZ patient. PHN is characterized by pain persisting in the area of the HZ rash, beyond the time of cutaneous healing. The frequency and severity of PHN increase with age and may occur in as many as 25–50% of patients over the age of 50 years [2,15–19]. If initiated within 72 h of rash onset, treatment with an antiviral agent like acyclovir has been shown to reduce the severity and duration of the acute phase of HZ, as well as the duration of PHN, but has no impact on the risk of developing PHN [20–24]. Once PHN is established, it is difficult to treat and patients may be left with potentially debilitating pain for several months or years [15,25–27]. The U.S. Food and Drug Administration approved ZOSTAVAXTM [zoster vaccine live (Oka/Merck)] for prevention of HZ (shingles) in individuals ≥60 years of age. As demonstrated in the Shingles Prevention Study, ZOSTAVAXTM has been shown to reduce the incidence of HZ and PHN in adults ≥60 years of age, and lessen acute and chronic pain associated with HZ, presumably through boosting VZV-specific immune responses [28]. The present study was designed to compare the safety and tolerability of 2 zoster vaccine potencies administered to adults ≥50 years of age to provide data on an expanded age group. Given the excellent safety experience of zoster vaccine, occurrences of unusual adverse experiences (AEs) were not anticipated. Past experience with PNEUMOVAXTM 23 (pneumococcal vaccine, polyvalent), a licensed vaccine indicated for routine use in older adults, provided an example of clinically acceptable rates of injection-site AEs.

2. Methods 2.1. Study design This international, randomized clinical trial (blinded to subject, investigator, and sponsor) was conducted at 18 sites in the United States, Canada, United Kingdom, Germany, and

Belgium between October 2003 and June 2004. The protocol was approved by the Ethical Review Committee of each site. Healthy, varicella history-positive (or resident for >30 years in a country with endemic VZV infection), HZ historynegative, men and women ≥50 years of age (females had to be postmenopausal or have a negative urine pregnancy test) were eligible for the study. Subjects were to have: no history of hypersensitivity reaction to any component of the vaccine; no prior receipt of any varicella or zoster vaccine; no recent receipt of immune globulin and/or blood products; no live or inactivated vaccine during the study period; no known immune dysfunction; no concomitant use of antiviral therapy with activity against herpesviruses; and no participation in an investigational drug or vaccine study within 30 days prior to vaccination. Subjects provided written informed consent before they were enrolled. This study compared the safety and tolerability profile of a higher potency zoster vaccine (∼207,000 plaque forming units [PFU]/0.65-mL dose) with that of a lower potency (∼58,000 PFU/0.65-mL dose). The lower potency vaccine used in this study was similar to vaccine potencies studied in the Shingles Prevention Study [28]. The lyophilized vaccines were supplied to the study centers in 0.7-mL singledose vials and stored at −15 ◦ C or colder. The vaccines were reconstituted with sterile diluent immediately prior to administration. The two potency formulations were indistinguishable in appearance. All subjects received a single 0.65-mL subcutaneous injection of either the higher potency zoster vaccine or the lower potency zoster vaccine. This study did not include a placebo group. Subjects were randomized in a 2:1 ratio to receive one injection of either the higher potency or lower potency zoster vaccine. Randomization was stratified by age group (1:2 ratio; 50–59 years and ≥60 years of age, respectively). Subjects were followed for local and systemic clinical AEs, varicella or varicella-like rash, and HZ or HZ-like rash for 42 days postvaccination using a standard patient Vaccination Report Card. The primary hypothesis of this study was that among adults ≥50 years of age, the higher potency vaccine would be generally well tolerated as compared with the zoster vaccine at a lower potency. 2.2. Safety surveillance The population for the primary safety analysis consisted of all vaccinated subjects who had safety follow-up data. Of primary interest were the incidences of vaccine-related serious clinical AEs reported day 1 through day 42 postvaccination and a composite endpoint of moderate or severe injectionsite pain/tenderness/soreness or swelling (>2 in. at the largest diameter) reported day 1 through day 5 postvaccination. Vaccine-relatedness was determined by the investigator. The secondary safety endpoints were varicella or varicella-like rashes (noninjection-site, nondermatomal in distribution) with >100 lesions reported day 1 through day 42 postvaccination, HZ or HZ-like rashes (noninjection-site) reported

S.K. Tyring et al. / Vaccine 25 (2007) 1877–1883

day 1 through day 42 postvaccination, and fevers (maximum reported temperature ≥101.0 ◦ F [≥38.3 ◦ C] oral) reported day 1 through day 21 postvaccination. 2.3. Rash analysis All subjects with varicella, varicella-like, HZ or HZ-like rashes were to be seen by the investigator. Collection of lesion swabs or vesicular fluid for analysis by polymerase chain reaction (PCR) was to be obtained for each investigatordiagnosed rash for virus strain identification. The VZV PCR assay used to detect VZV and herpes simplex virus DNA was performed as described previously [28]. 2.4. Statistical analysis For vaccine-related serious clinical AEs occurring day 1 through day 42 postvaccination, a test of risk difference between the higher potency and lower potency vaccine groups was performed at the two-sided 0.05 level. If no serious clinical AEs were observed in both groups, this study provided 97.5% confidence that the true rate was <0.92% with 400 subjects in the higher potency vaccine group, or <1.8% with 200 subjects in lower potency vaccine group. The study had ∼85% power to detect a 7.4-percentage-point increase in incidence rates of AEs in the higher potency vaccine group from a hypothetical incidence rate in the lower potency vaccine group of 5.0%. The incidence of moderate or severe injection-site pain/tenderness/soreness or swelling occurring day 1 through day 5 postvaccination in the higher potency vaccine group, was assessed as a composite endpoint rela-

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tive to a predefined clinical significance. Clinical significance for this endpoint was defined by the upper bound of the 95% confidence interval (CI) for the observed incidence rate exceeding 21.5%, which was pre-established based on past clinical trial experience with pneumococcal vaccine [29].

3. Results 3.1. Study population Of the 698 subjects enrolled in the study, 459 subjects in the higher potency group and 233 subjects in the lower potency group were vaccinated and completed 42 days of postvaccination follow-up (Fig. 1). With regard to gender, age, and race, the frequencies observed were comparable between vaccine potency groups (Table 1), even though a slightly larger proportion of females was enrolled in the higher potency group (61.2% female) than in the lower potency group (57.3% female). 3.2. Vaccine safety and tolerability Clinical follow-up for AEs was obtained on all but two vaccinated subjects enrolled in the study (Table 2). Five serious clinical AEs were reported, but none was determined by the investigator to be vaccine related (Table 2). The two vaccination groups were comparable with regard to systemic clinical AEs, vaccine-related systemic clinical AEs and injection-site AEs, other than pain/tenderness/soreness and swelling. More episodes of moderate or severe injection-site

Table 1 Study demographics Zoster vaccine higher potency (N = 461)

Zoster vaccine lower potency (N = 234)

n

(%)

n

(%)

Gender Male Female

179 282

(38.8) (61.2)

100 134

(42.7) (57.3)

Age (years) 50–59 ≥60 Mean S.D. Median

123 338 65.2 9.2 64.0

(26.7) (73.3)

62 172 65.6 9.7 65.0

(26.5) (73.5)

Range Male Female Race Asian Black Hispanic Multi-racial Native American Caucasian

50–90 50–88 50–90

10 6 10 1 2 432

50–90 50–88 50–90

(2.2) (1.3) (2.2) (0.2) (0.4) (93.7)

6 4 8 2 0 214

N: number of vaccinated subjects per vaccination group, n: number of subjects in each category, S.D.: standard deviation.

(2.3) (1.7) (3.4) (0.9) (0.0) (91.5)

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Fig. 1. Subject accounting. * One subject withdrew prior to completion of follow-up period, but was included in the safety analyses.

pain/tenderness/soreness or swelling were detected among recipients of the higher potency zoster vaccine than among recipients of the lower potency zoster vaccine (Fig. 2), but the incidence rate in the higher potency vaccine group was below the pre-established clinically meaningful limit. The mean duration until complete resolution of moderate or severe

injection-site pain/tenderness/soreness (higher potency: 5.3 days; lower potency: 4.6 days) and swelling (higher potency: 6.0 days; lower potency: 5.8 days) appeared similar in both groups. Only 10 rashes were reported within 42 days postvaccination (Table 3); seven diagnosed as HZ or HZ-like rashes (four

Table 2 Summary of adverse experiences (AEs) Higher potency

Lower potency

50–59 years

≥60 years

n

n

%

Total %

n

%

n

n

%

%

%

102 102 83 84 73 25

82.9 82.9 67.5 68.3 59.3 20.3

198 187 142 132 115 32

58.9 55.7 42.3 39.3 34.2 9.5

300 289 225 216 188 57

65.4 63.0 49.0 47.1 41.0 12.4

46 43 35 32 27 4

74.2 69.4 56.5 51.6 43.5 6.5

99 97 76 59 50 15

57.6 56.4 44.2 34.3 29.1 8.7

145 140 111 91 77 19

62.0 59.8 47.3 38.9 32.9 8.1

17

13.8

33

9.8

50

10.9

13

21.0

18

10.5

31

13.2

Serious AEsa Depression Angina pectoris Enteritis Coronary artery disease Small cell lung cancer

2 1 0 1 0 0

1.3 0.8 0.0 0.8 0.0 0.0

2 0 1 0 1 0

0.6 0.0 0.3 0.0 0.3 0.0

4 1 1 1 1 0

0.9 0.2 0.2 0.2 0.2 0.0

1 0 0 0 0 1

1.6 0.0 0.0 0.0 0.0 1.6

0 0 0 0 0 0

0.0 0.0 0.0 0.0 0.0 0.0

1 0 0 0 0 1

0.4 0.0 0.0 0.0 0.0 0.4

Vaccine-related serious AEsa Deaths

0 0

0.0 0.0

0 0

0.0 0.0

0 0

0.0 0.0

0 0

0.0 0.0

0 0

0.0 0.0

0 0

0.0 0.0

Vaccine-relatedness determined by the investigator. All injection-site AEs were assumed to be vaccine-related.

172

n

Vaccine-related AEsa Injection-siteb Erythema Pain Swelling Pruritus

a

62

Total

123

b

459

≥60 years

Subjects with follow-up

Systemic

336

50–59 years

234

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Table 3 Listing of PCR results for subjects with herpes zoster, herpes zoster-like, varicella, or varicella-like rash by vaccination group Rash diagnosis

Intensity

Onset (days post-vaccination)

Duration (days)

Maximum number of lesions

PCR result

Higher potency zoster vaccine groupa Herpes zosterb F 54 Herpes zosterc F 88 Herpes zosterd M 61 Herpes zostere M 74 Varicella-like F 73 Varicella-like F 73

Mild Moderate Mild Severe Mild Mild

17 20 4 10 5 42

Unknown 4 40 14 31 16

11 80 Unknown 146 50 32

Insufficient sample Positive wild type VZV No sample Positive wild type VZV Negativef Negativef

Lower potency zoster vaccine groupa Herpes zoster-like M 71 Herpes zoster-like M 73

Mild Mild

18 3

13 16

21 48

Moderate Moderate

10 15

7 34

124 41

Negativef Positive herpes simplex virus Insufficient sample Negativef

Herpes zoster-like Varicella-like a b c d e f

Gender

F M

Age (years)

73 62

No varicella or varicella-like rashes with >100 lesions were reported in either group. Dermatome: L3 left side. Dermatome: T5 right side. Dermatome: T5 right side. Dermatome: C5 left side. Negative: negative for wild type VZV, Oka attenuated VZV, and herpes simplex virus DNA.

higher potency group; three lower potency group). Of these 10 rash diagnoses, only seven had sufficient lesion samples collected. Two subjects in the higher potency vaccine group developed HZ, confirmed by detection of wild type VZV in their skin lesions. One case, occurring in an 88-year-old female 20 days after vaccination, was reported as moderate, whereas the other case, occurring in a 74-year-old male 10 days after vaccination, was reported as severe in intensity. No varicella or varicella-like rashes with >100 lesions were reported in either group. Nearly 40% of subjects in each vaccine potency group reported a systemic clinical AE, whereas only about 10% reported one or more vaccine-related systemic clinical AEs in either group. Approximately 60% of subjects reported one or more injection-site AEs in either group. Less than 1% of subjects reported an elevated oral temperature (≥101.0 ◦ F [≥38.3 ◦ C]) in either group from day 1 to day 21 postvaccination. The percentage of subjects 50–59 years of age reporting AEs was numerically greater than the percentage of subjects

Fig. 2. Proportion of subjects with moderate to severe injection-site pain/tenderness/soreness or swelling (>2 in. at largest diameter). Compared to the historical reference*. * Indicates the incidence rate of moderate or severe injection-site pain/tenderness/soreness or swelling observed in a previous trial of PNEUMOVAXTM 23.

≥60 years of age (Fig. 3). No enrolled subjects died during the study period and no subjects discontinued due to a clinical AE.

4. Discussion Overall, one dose of the higher potency zoster vaccine (∼207,000 PFU/0.65-mL dose) was generally well tolerated when compared with the zoster vaccine at a lower potency (∼58,000 PFU/0.65-mL dose) when either was administered to subjects ≥50 years of age. No vaccine-related serious clinical AEs were reported. The serious clinical AEs that were reported by subjects reflected illnesses typical of this age group and did not predominantly involve a specific disease state or body system. The most frequently reported AEs were at the injection site. Most of these were of mild or moderate intensity and short duration. The rate of moderate and severe injection-site AEs was greater in the higher potency vaccine group compared with the lower potency vaccine group, but the rate did not exceed that seen in an earlier trial of PNEUMOVAXTM 23 that served as a historical reference for acceptable tolerability. In this earlier clinical trial that administered pneumococcal vaccine to 621 subjects 50 years of age and older, approximately 70% of the recipients of pneumococcal vaccine reported injection-site AEs [29]. The vast majority of these were mild; approximately 18.2% (95% confidence interval [CI], [15.2, 21.5%]) of recipients reported moderate or severe injection-site AEs [29]. The percentage of subjects 50–59 years of age reporting AEs was numerically greater than the percentage of subjects ≥60 years of age reporting AEs. Among those 50–59 years of age, the most frequently reported AEs were at the injection-

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Fig. 3. Proportion of subjects with adverse experiences (AEs) according to vaccine potency and age. *All injection-site AEs are considered to be vaccine related. **The % of subjects is calculated based upon the total number of subjects in each category.

site. The rate of injection site AEs in the younger age cohort was greater in the higher potency group compared with the lower potency group, but most of these AEs were of mild or moderate intensity and short duration. Among those 50–59 years of age, the rates of systemic AEs were comparable in the two vaccination groups. Therefore, the overall clinical impact of the increased rate of injection-site reactions in subjects 50–59 years of age appears to be relatively small. Two subjects developed HZ, confirmed by PCR detection of natural VZV in skin lesion specimens. The events that result in reactivation of latent VZV in sensory ganglia are not known, nor are the timing between initiation of virus replication and appearance of skin lesions. In the Shingles Prevention Study, HZ occurred in fewer subjects in the vaccine group than in the placebo group during the first 30 days following vaccination [28], indicating that vaccine efficacy against HZ may occur soon after vaccination. In summary, this study demonstrated that among vaccinated subjects ≥50 years of age, the higher potency zoster vaccine was generally well tolerated, as compared with a lower potency zoster vaccine. Importantly, this study supports the acceptable safety and tolerability profile of zoster vaccine at the potencies higher than those studied in the Shingles Prevention Study [28], and these data provide important information on the safety and tolerability of a higher potency live attenuated zoster vaccine in a population ≥50 years of age.

Acknowledgements The authors would like to thank the subjects for their participation in this study and the other members of the Pro-

tocol 009 Study Group.i We are particularly grateful to Carol Cheney for coordinating sample collection/submission, to Paul Keller for overseeing the laboratory assays, and to Laura Connor for ensuring adequate study vaccine and placebo supplies.

References [1] Hope-Simpson RE. Postherpetic neuralgia. J R Coll Gen Pract 1975;25:571–5. [2] Gnann Jr JW, Whitley RJ. Herpes zoster. N Engl J Med 2002;347:340–6. [3] Brisson M, Edmunds WJ. Epidemiology of Varicella-Zoster Virus in England and Wales. J Med Virol 2003;70:S9–14.

i

Other Study Group Principal Investigators (a ), Sub-Investigators (b ), and Study Coordinators—Edinger Medical Group, Fountain Valley, CA: Malcolm J. Sperlinga ; Cindy Carr-Bootman. Central Texas Clinical Research, Austin, TX: Gregg Lucksingera ; Robin Ward. CNS Clinical Trials, St. Petersburg, FL: Judy Shea. Georgetown Medical Center, Georgetown, TX: Jody Ping. Kuakini Medical Center, Honolulu, HI: Patricia Blanchettea ; Dennis Shewell. Louisiana State University Health Science Center, Baton Rouge, LA: Pam Saloom. Mayo Clinic, Rochester, MN: Paul Targonskib ; Joe Hockert. Mission Geriatric Medical Associates, Laguna Woods, CA: Robert Feldmana ; Mary Burt. Northfield Health Centre, Northfield, Birmingham, United Kingdom: Douglas Fleminga ; Philip Saundersb ; Jo Walker. Private Practice, Anaheim, CA: Robin Dorea ; Alfonso Soriano. Private Practice, Limburg, Belgium: Paul Reyndersa ; Jos Weckxb . St¨adtische Krankenh¨auser Krefeld, Krefeld, Germany: Sawko W. Wassilewa . TASC-CMX Research Services, Surrey, British Columbia: Roland Guaspirinia . Texas Medical Research, San Antonio, TX: Patrick Petersa ; Kimberly Japhet. The Portland Clinic, Portland, OR: Burton Lazara ; Nancy Chess. University of Texas Health Science Center, Houston, TX: Evangeline Yu. Wenatchee Valley Medical Center, Wenatchee, WA: James Cooka ; Kendra Sanders.

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