ABSTRACT
Background: ZOSTAVAX (ZVL; Zoster Virus Live), is a single dose, live, attenuated vaccine licensed for the prevention of herpes zoster (HZ) and post herpetic neuralgia (PHN) in adults ≥50 years of age. Injection site adverse events (AEs) of erythema, swelling and pain were solicited within 5 days post vaccination in the 2 pivotal studies of ZVL; ZEST (ZOSTAVAX Efficacy and Safety Trial) and SPS (Shingles Prevention Study). Protocol specified criteria were used to report the frequency and intensity of injection site AEs in ZEST and SPS studies. Subsequently, the FDA Toxicity Grading Scale provided guidance for uniform assessment of AEs across all adult vaccine clinical trials. The objective of this post-hoc analysis was to categorize the previously reported injection site AEs in two pivotal trials of ZVL according to the current FDA Toxicity Grading Scale.
Methods: The current FDA Toxicity Grading Scale provides a measure for classifying injection site AEs by four grades [Grade 1 (mild); Grade 2 (moderate); Grade 3 (severe) and Grade 4 (life threatening)]. Injection site erythema, swelling, and pain intensity gradings were assigned to the respective FDA Toxicity Grade based on this appropriation. A descriptive analysis of the proportion and risk difference (within 95% confidence intervals) of injection site AEs per the FDA Toxicity Grading Scale is provided.
Results: The frequency of injection site AEs (erythema, swelling, pain) after subcutaneous vaccination with ZVL were higher in recipients of ZVL compared with placebo. Majority of the injection site AEs observed were Grade 1 (mild) or Grade 2 (moderate) in intensity. Additionally, Grade 3 (severe) injection site AEs were observed infrequently.
Conclusions: Application of the FDA Toxicity Grading Scale provides a uniform AE assessment tool across different adult vaccines. This post hoc summary of injection site AEs using FDA Toxicity Grading Scale provides further evidence of low frequency of severe injection site AEs post ZVL vaccination.
Introduction
Zoster vaccine live (ZVL: ZOSTAVAX™; Merck & Co., Inc., Kenilworth, NJ USA), a single dose, live, attenuated vaccine, is licensed for the prevention of herpes zoster (HZ) in adults ≥50 years of age Citation1–Citation4. The clinical efficacy, immunogenicity, safety and tolerability of ZVL has been demonstrated in two large phase III clinical trials, the ZOSTAVAXTM Efficacy and Safety Trial (ZEST) in subjects 50–59 years old and the Shingles Prevention Study (SPS) in subjects ≥60 years of age. Overall, the efficacy of ZVL for preventing HZ was shown to be 69.8% (N = 22,210) in subjects 50–59 years old, 63.9% (N = 20,726) in subjects 60–69 years old and 37.6% (N = 17,775) in subjects over 70 years old Citation5,Citation6. In the SPS trial, ZVL was shown to reduce the burden of illness due to HZ by 61% and the incidence of PHN by 67% in subjects 60 years and olderCitation7. In both trials, ZVL was generally well toleratedCitation5-Citation8.
A thorough understanding of the safety and tolerability of vaccines using a standardized and uniform assessment tool across all vaccine products is an important goal for health care providers, vaccine manufacturers and patients. In 2007, the US FDA issued guidance for the industry to help standardize the Toxicity Grading Scale for healthy adult volunteers in preventative vaccine clinical trialsCitation9. This guidance provides recommendations on assessing the severity of clinical and laboratory abnormalities in healthy adult and adolescent volunteers enrolled in clinical trials. The toxicity grading is provided across four categories of clinical abnormalities (local reaction to injectable product; vital signs; systemic (general); and systemic illness) and three categories of laboratory abnormalities (serum; hematology; and urine)Citation9. Each category of abnormality includes four grading scales; Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), and Grade 4 (potentially life threatening).
The objective of this post-hoc analysis was to report the injection site adverse events (AEs) following administration of ZVL in SPS and ZEST studies (phase 3, randomized, placebo controlled, multicenter clinical trials of ZVL) according to the current FDA Toxicity Grading Scale as this standardized scale was not available when ZVL phase 3 program was initiated. Summary of solicited injection site AEs observed within 5 days post vaccination is provided utilizing the current FDA Toxicity Grading Scale.
Results
Overall, using the FDA Toxicity Grading Scale across all grades (Grade 1 or mild, Grade 2 or moderate and Grade 3 or severe) of injection site AEs, injection site erythema, swelling and pain, post-vaccination with ZVL, were infrequent and decreased by increasing age category (50–59, 60–69, and 70+ years old) (, ). Most injection site AEs were categorized as Grade1 (mild) or Grade 2 (moderate). Grade 3 (severe) injection site erythema, swelling and pain were reported at low frequency. As shown in , in the ZEST study, 15.6%, 15.3% and 1.2% of vaccinated subjects reported a Grade 1 (mild), Grade 2 (moderate) and Grade 3 (severe) erythema, respectively. The risk difference between subjects in ZVL versus placebo groups was 15.2% for grade 1 (mild) and grade 2 (moderate) AEs and 1.2% for Grade 3 (severe) erythema. Similarly, amongst vaccinated subjects who reported swelling, 11.9% had Grade 1 (mild), 11.4% had a Grade 2 (moderate) AE and 0.8% subjects reported a Grade 3 (severe) swelling. The risk difference between ZVL and Placebo groups was 11.5% in grade 1 (mild), 11.1% in grade 2 (moderate) and 0.7% in grade 3 (severe) AEs. Most subjects (46.1% and 7.8% respectively) reported Grade 1 (mild) & Grade 2 (moderate) injection site pain. Grade 3 (severe) injection site pain occurred in 0.5% of recipients of ZVL (). The risk difference between ZVL and placebo groups was 37.7%, 7.3%, 0.5% in grade 1 (mild), grade 2 (moderate) and grade 3 (severe) events, respectively. No Grade 4 (life threatening) injection site erythema, swelling and pain were observed in ZEST.
Table 1. Comparison of AE grading intensity using protocol specified criteria (ZEST and SPS) and the FDA toxicity grading scale.
Table 2. Injection site AEs reported 1–5 days post-vaccination in the ZEST study using the FDA toxicity grading scale.
Table 3. Injection site AEs reported 1–5 days post-vaccination in the SPS study using the FDA toxicity grading scale.
As shown in in the SPS AE Monitoring sub-study, amongst 60–69 years olds, 15.2%, 7.1% and 0.3% of ZVL vaccinated subjects reported a Grade 1 (mild), Grade 2 (moderate) or Grade 3 (severe) erythema, respectively. In the older age group, i.e. subjects 70+ years old, 9.4%, 4% and 0.1% of ZVL vaccinated subjects reported a Grade 1 (mild), Grade 2 (moderate) or Grade 3 (severe) erythema, respectively. Similarly amongst ZVL vaccinated subjects (60–69 years old), who reported swelling, 10.9% had Grade 1 (mild), 4.8% had a Grade 2 (moderate) and 0.1% reported a Grade 3 (severe) swelling. In the older age group (70+ years old), amongst the ZVL vaccinated subjects, 5.1% reported Grade 1 (mild), 3.1% reported Grade 2 (moderate) and 0.1% reported Grade 3 (severe) erythema. Injection site pain was mostly Grade 1 (mild) and reported more frequently in subjects 60–69 years old than those70 years old or older. Grade 3 or severe injection site pain occurred in 0.2% of adults 60–69 years old and in 0.1% of adults > 70 years old. No Grade 4 (life threatening) injection site erythema, swelling and pain were observed in SPS.
Discussion
In conclusion, these results indicate that the overall trend in the frequency of injection site AEs observed using the FDA Toxicity Grading Scale is similar to that observed using the protocol specified criteria of ZEST and SPSCitation5,Citation6,Citation8 whereby low frequencies of injection site AEs are observed upon post hoc analysis using the FDA Toxicity Grading Scale. In the pivotal phase 3 trials (ZEST and SPS) used to support the licensure of ZVLCitation5–Citation8, the current FDA Toxicity Grading Scale was not available to assess injection site AEs. Therefore, the use of this uniform FDA guided assessment tool to elucidate the frequencies of injection site AEs in the two pivotal trials of ZVL (SPS and ZEST) provides additional confidence in the safety and tolerability of vaccination with ZVL. These results indicate that overall frequencies of injection site AEs utilizing the FDA Toxicity Grading Scale are similar to the results from per protocol specified criteria of ZEST and SPSCitation5,Citation6,Citation8. Notably, low frequencies of Grade 3 (severe) AEs were noted when the FDA Toxicity Grading Scale was applied (, ).
The most commonly reported injection site AEs after ZV vaccination, using the protocol specified criteria in ZEST and SPS were erythema, swelling, pain; Grade 1 (mild) to Grade 2 (moderate) in intensity, as previously reportedCitation5,Citation7,Citation8. These symptoms are commonly associated with most vaccinesCitation10–Citation12. Additionally, using the FDA scale, the previously reported inverse trend in age related findings of AEs upon ZVL vaccination was observed again whereby higher frequency of severe injection site reactions with ZVL were observed in subjects 50–59 years old when compared to the subjects 60–69 and 70+ years old using protocol specified criteria in ZEST and SPS studiesCitation6,Citation8. While this observation provides additional confidence to the consistency and comparability of SPS and ZEST protocol specified criteria to the FDA issued guidance, this finding is not restricted to vaccination with ZVL. The administration of influenza virus vaccine and placebo has also shown similar results where locally higher reactogenicity in younger subjects was observedCitation13,Citation14.
Since licensure in 2006, several large real-world studies have examined the safety of ZVL and have demonstrated that ZVL is well tolerated when administered in real world practice Citation15–Citation18. No reports of an unfavorable safety profile from any of these surveillance projects have been reported to date. These findings are consistent with post-licensure safety surveillanceCitation19.
There were some limitations to this post-hoc analysis. In the ZEST trial, unlike SPS, the mean duration of severe injection site reactions (erythema, swelling, or pain) could not be reported since duration of the AE intensity category was not recorded in the database. Unlike the FDA scale that uses metric units (i.e. cm) to define the intensity of erythema and swelling, the ZEST and SPS trials used non-metric units (i.e. inches). Therefore, for this post-hoc analysis the criteria of >4 inches was used instead of 10 cm (3.94 inches) as defined by the FDA toxicity grading scale.
The prophylactic nature of vaccines and their administration in a healthy population necessitate maintaining unbiased and universal safety classification parameters. While the application of the FDA Toxicity Grading Scale across different vaccine development programs provides a common tool to enable comparison between different products from different vaccine manufacturers; other validated scales in use such as the Brighton ScaleCitation20 and Merck AE grading scaleCitation21,Citation22 are also viable, commonly used options. The low frequency of Grade 3 (severe) AEs observed in this post-hoc analysis, upon implementation of the FDA toxicity grading scale, further supports the evidence regarding the safety profile of ZVL.
Methods
In both ZEST and SPS studies, a single dose of ZVL or placebo was administered subcutaneously. All subjects in ZEST study (N = 22,210) received a Vaccination Report Card (VRC) at the time of the vaccination to evaluate the adverse events (AEs) temporally associated with the vaccination. In SPS, a subset of subjects who participated in the SPS- Adverse Event (SPS-AE) monitoring sub-study (N = 6,575), received a VRC for evaluation of AEsCitation5–Citation8. Injection site AEs were recorded on the VRC from Day 1 to Day 42 post-vaccination. In both studies, injection site AEs were solicited for the first 5 days post-vaccination whereby subjects were prompted via VRC to report injection site AEs, if applicable; however, unsolicited injection site AEs continued to be reported on the VRC through 42 days post-vaccination to ensure adequate surveillance of AEs. Vaccine-related AEs were determined by the investigator to be possibly, probably, or definitely vaccine related. All participants who received a single dose of study vaccination (ZVL or placebo) and had follow-up data for solicited injection site AEs (day 1-day 5) are included in this analysis.
In both ZEST and SPS, injection site AEs (swelling and erythema) were reported by size (inches; quantitative measurements). In addition to quantitative assessment, in the SPS study subjects also reported injection site AEs via intensity categories, as participants in the SPS study were asked to rate the AE symptom as mild (awareness of sign or symptom but easily tolerated), moderate (discomfort enough to cause interference with usual activities), or severe (incapacitating with inability to work or do usual activity). The definitions of injection site pain were consistent across ZEST and SPS trials. Injection site AEs results utilizing the protocol specified criteria of ZEST and SPS studies have been previously reportedCitation5–Citation8.
For ZEST and SPS data, the size of injection site erythema and swelling was collected in imperial scale. In order to classify injection site erythema and swelling according to the FDA Toxicity Grading Scale, the imperial scale was approximated into metric scale (cm). provides an overall summary of injection site AE (erythema and swelling) category grading criteria of the FDA Toxicity Grading Scale (Grade 1, 2 or 3) based on this approximation. For example, Grade 2 erythema and swelling in the FDA Toxicity Grading Scale are categorized by size as 5.1 cm to 10 cm. When converted to inches 10 cms = 3.94 inches. Thus, the data analysis for Grade 2 (moderate) events on the FDA Toxicity Grading Scale used the criterion of injection site swelling or erythema >2 to ≤4 inches. Analysis for Grade 3 (severe) events on the FDA Toxicity Grading Scale used injection site erythema or swelling criteria of >4 inches. For comparison, the protocol specified criteria for injection site AE classifications in ZEST and SPS and its comparison to the FDA Toxicity Grading Scale are included in . The definitions of injection site pain were mostly consistent across ZEST and SPS trials and aligned with the FDA Toxicity Grading Scale (). Risk difference between ZVL and placebo groups were calculated using the Miettinen &Nurminen (M&N) method.
Disclosure of potential conflicts of interest
No potential conflict of interest was reported by the authors.
Acknowledgments
We are grateful to all subjects and their caregivers who participated in the clinical trials. We would also like to thank Ms. Jennifer Pawlowski and Ms. Karyn Davis of Merck & Co., Inc., Kenilworth, NJ, USA for editorial support.
Additional information
Funding
References
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