Phase 3, open-label, Russian, multicenter, single-arm trial to evaluate the immunogenicity of varicella vaccine (VARIVAX™) in healthy adults

ABSTRACT

Varicella (chickenpox) is a common, highly contagious disease caused by primary infection with varicella zoster virus (VZV). Adults typically experience more severe symptoms than children and have a higher risk of developing complications. Stage 1 of this Phase 3 open-label study enrolled healthy adults in Russia aged 18–75 years without a clinical history of varicella infection. Eligible participants (n = 50) were administered 2 doses of VARIVAX™ (Varicella Virus Vaccine Live [Oka/Merck]) 0.5 mL 6 weeks apart. For participants seronegative at baseline (VZV antibody titer <1.25 glycoprotein enzyme-linked immuno-sorbent assay [gpELISA] units/mL), immunogenicity was assessed by seroconversion (VZV antibody titer ≥5 gpELISA units/mL) and assessment of geometric mean titers of VZV antibody as measured by gpELISA 6 weeks after Dose 2. For VZV seropositive participants at baseline (VZV antibody titer ≥1.25 gpELISA units/mL), immunogenicity was assessed by geometric mean fold rise in antibody titer and percentage of participants with a ≥ 4-fold rise in antibody titer 6 weeks after Dose 2. A Vaccine Report Card was used to record solicited and unsolicited adverse events through 42 days post-vaccination. All participants who were seronegative (n = 26) at baseline demonstrated seroconversion 6 weeks after Dose 2. Among participants who were seropositive at baseline (n = 23), 60.9% had a ≥4-fold rise in antibody titer 6 weeks after Dose 2. Vaccination was generally well tolerated, with no new safety signals identified. Administration of 2 doses of VARIVAX in adults in Russia results in acceptable immune responses with safety data consistent with the licensed product (Clinicaltrials.gov identifier: NCT03843632).

KEYWORDS:

• Varicella vaccine
• VARIVAX™
• chickenpox
• adults
• Phase 3
• immunogenicity
• safety
• Russia

Introduction

Varicella (chickenpox) is a highly contagious childhood infectious disease caused by primary infection with varicella zoster virus (VZV), a double-stranded DNA α-herpes virus that can be spread via airborne transmission or contact with skin lesions.^1,2 By mid-adulthood, the majority of individuals in countries without a varicella vaccination program will be infected by VZV.³

Primary varicella infection typically presents as a generalized vesicular, pruritic rash that appears in crops concentrated on the head and trunk and then spreads to the extremities, which is preceded by a prodrome of malaise, loss of appetite, fever, and headache.^1,2 Prodromal symptoms and rash tend to be mild in children; however, these symptoms are often more severe and take longer to resolve in adolescents and adults.² Furthermore, mortality rates are 25 times higher in adults over the age of 20 years than in children or adolescents.¹ It has been hypothesized that this may be due to a less robust cell-mediated response to VZV in adults.⁴ While severely immunocompromised individuals are at greater risk,^1,2,5 most patients suffering severe complications (particularly pneumonia and central nervous system complications) are previously healthy adults.^1,2,6 Primary VZV infection during pregnancy can rarely cause devastating fetal complications, including congenital varicella syndrome and miscarriage.^1,2,7

During primary infection, VZV establishes latency in the dorsal root ganglia of the spinal nerve; reactivation of VZV may result in the development of herpes zoster (HZ), which can occur years after the initial infection.^1,2 Herpes zoster may also occur following VZV vaccination; however, the incidence of herpes zoster is lower after vaccination than after infection with wild-type VZV, even in immunocompromised vaccinees.^1,2,8

In the absence of universal immunization, the annual burden of varicella across Europe in 2015 was estimated at 5.5 million cases, 3.0–3.9 million primary care consultations, 18,200–23,500 hospitalizations, and 80 varicella-related deaths.⁹ Herpes zoster surveillance was implemented in Russia in 2019, with an estimated annual incidence of 559.1 per 100,000 inhabitants, resulting in 820,000 registered cases and 5 deaths (4 of which were in children).¹⁰ A similar rate of VZV was observed in neighboring countries (e.g., Estonia, Lithuania, and Poland), with annual VZV incidence rates exceeding 450 per 100,000 inhabitants.¹¹ Notably, the prevalence of varicella is 75% lower than the national average in regions of Russia where VZV vaccination has been incorporated into the regional vaccination schedule.¹²

VZV vaccination reduces the incidence of VZV infection and associated complications such as hospitalization and death. A single vaccine dose reduces the risk of moderate or severe varicella by >80%; a second vaccine dose further reduces the risk of moderate or severe varicella by at least 98% compared with unvaccinated individuals.^3,13,14 Accordingly, the World Health Organization recommends 1 VZV vaccine dose to reduce severe varicella-related morbidity and mortality, and 2 doses to reduce the number of varicella cases and outbreaks.³ Universal VZV vaccination programs have led to substantial reductions in the economic burden associated with VZV infection, as evidenced by the implementation of a universal 2-dose VZV vaccination program in the United States, which saved the healthcare system an estimated $900 million USD in 2008.¹⁵

Monovalent varicella vaccines are licensed and available throughout the world for the prevention of infection in healthy children, adolescents, and adults.¹⁶ VARIVAX™ (Varicella Virus Vaccine Live [Oka/Merck], Merck & Co., Inc., Kenilworth, NJ, USA) was first approved in the United States in 1995 and is licensed in more than 78 countries worldwide.²

This Phase 3, open-label study was conducted at 4 centers in Russia to evaluate immunogenicity and safety of VARIVAX™ in adults for the purpose of obtaining licensure in the Russian Federation. The study was conducted in 2 stages; results of Stage 1 were reviewed by the Russian Ministry of Health before Stage 2 (enrolling participants aged 12 months or older) commenced.

Methods

Study design

Participants were administered 2 subcutaneous doses of varicella virus vaccine (VARIVAX™; Varicella Virus Vaccine Live [Oka/Merck]) 0.5 mL, 6 weeks apart. The study protocol (V210-058), information provided to participants, and recruitment materials were reviewed and approved by relevant regulatory bodies and independent ethics committees at each center prior to initiating the study. The study was prospectively registered in the European Union Drug Regulating Authorities Clinical Trials Database (EudraCT; study identifier: 2019–003903-36) and Clinicaltrials.gov (Clinicaltrials.gov identifier: NCT03843632) registries prior to enrolling the first participant. All aspects of the study were conducted in conformance with the ethical principles originating from the Declaration of Helsinki (October 2013), Good Clinical Practice, and relevant local statutes and regulations. All participants provided written informed consent prior to enrollment.

Participants

Eligible participants were healthy adults 18–75 years of age who had a negative clinical history of varicella and herpes zoster infection. Female participants of reproductive potential must have had a negative pregnancy test on the day of vaccination and agreed to remain abstinent or use 2 acceptable methods of birth control for the duration of the study period.

Individuals were excluded from participating in the study if they had a history of allergy or anaphylactic reaction to any component of the study vaccine, received any varicella or herpes zoster vaccine at any time before the study, been exposed to varicella or herpes zoster in the 4 weeks before the study, been vaccinated with a non-live or live vaccine ≤30 days prior, or were expected to be vaccinated during the 42-day safety follow-up period following study vaccination. Any individuals with a febrile illness associated with a temperature of ≥38.9°C within 72 hours of study vaccination were also excluded from the study. Any individuals who lived with a person who had, or themselves had, immune deficiency, neoplastic disease, or depressed immunity, including immunosuppressive therapy, were ineligible to participate in the study. Participants must also not have been pregnant or breastfeeding.

Immunogenicity

Serum samples were collected prior to vaccination at Visit 1 and at Day 43 post-vaccination. Antibodies to VZV were detected using a glycoprotein enzyme-linked immunosorbent assay (gpELISA).¹⁷

For participants who were seronegative at baseline (VZV antibody titer <1.25 gpELISA units/mL), immunogenicity was assessed using 3 co-primary endpoints: seroconversion rate defined as a VZV antibody titer ≥1.25 gpELISA units/mL; antibody response, defined as a VZV antibody titer ≥5 gpELISA units/mL; and geometric mean titers (GMTs) of VZV antibody as measured by gpELISA at 6 weeks after Dose 2. For participants who were VZV seropositive at baseline, the co-primary endpoints were GMTs, geometric mean fold rise in antibody titers (GMFRs), and percentage of participants with a ≥ 4-fold rise in antibody titer 6 weeks after Dose 2.

Safety

Each participant was provided a Vaccine Report Card to record safety data, including solicited local reactions (redness, swelling, pain/tenderness) through Day 5 following vaccination and unsolicited injection-site reactions through Day 42 post-vaccination, temperature through Day 28 post-vaccination, varicella-like or herpes zoster-like rash through 42 days post-vaccination, and all other systemic adverse events (AEs) through 42 days post-vaccination. Urine and additional blood samples were obtained 3 days following each vaccination.

Statistical analysis

Primary immunogenicity analyses were based on the per-protocol population, while a supportive analysis of the full analysis set population was also performed. Results are presented as descriptive statistics with 2-sided 95% confidence intervals (CIs) for antibody response rate and VZV sero-conversion. CIs were computed using the exact method for a single binomial proportion. GMTs were calculated at each time point by averaging the log of titers across all participants’ values, then back-transforming to the original scale. The 95% CI for each GMT was calculated based on a t-distribution.

Summary statistics were provided for all pre-specified safety events, including the number and proportion of participants with AEs. AEs were reported using Medical Dictionary for Regulatory Activities (MedDRA) version 22.0.

Results

Participants

In total, 50 participants were enrolled at 4 centers across Russia. Overall, 36 (72%) participants were female, all were white, and the median age was 22.0 years (range 18–44 years) (Table 1). Nearly half of all enrolled participants (n = 24, 48%) had a VZV antibody titer ≥1.25 gpELISA units/mL at baseline.

Table 1. Baseline characteristics

Characteristic	N = 50
Sex, n (%) Male Female	14 (28) 36 (72)
Age, years, median (range)	22 (18–44)
Race, n (%) White	50 (100)
Varicella zoster virus serostatus, n (%) ≥1.25 gpELISA units/mL	24 (48)

gpELISA, glycoprotein enzyme-linked immunosorbent assay.

All participants received at least 1 dose of study vaccine, and nearly all participants (49/50 [98%]) completed the protocol-specified 2-dose vaccination regimen. One participant withdrew from the study prior to receiving Dose 2 and was not included in the per-protocol immunogenicity analyses.

Immunogenicity

Among participants who were seronegative at baseline, the antibody response rate at 6 weeks post-Dose 2 was 100% (26/26; per-protocol population), with a corresponding GMT of 71% (95% CI, 47.9–104.2) gpELISA units/mL (Figure 1); the GMFR from baseline was 173 (95% CI, 120.9–246.2).

Figure 1. Changes in geometric mean titer from baseline among adults in Russia administered 2 doses of varicella vaccine 6 weeks apart. A titer of ≥5 gpELISA units/mL 6 weeks after vaccination is considered an approximate correlate of protection for individual vaccinees.

CI, confidence interval; gpELISA, glycoprotein enzyme-linked immunosorbent assay.

Among participants who were seropositive at baseline, 61% (14/23; per-protocol population) had a ≥ 4-fold rise in antibody titer 6 weeks after Dose 2, with a corresponding GMT of 217 (95% CI, 132.8–353.6) gpELISA units/mL (Figure 1); the GMFR from baseline was 3 (95% CI, 2.0–4.8).

Safety

AEs were reported by 41 (82.0%) participants over the course of the study (n = 50; all-participants-as-treated population). A comparable proportion of participants reported AEs after Dose 1 and Dose 2.

Thirty-six (72%) participants experienced injection-site AEs after Dose 1 or Dose 2, which were all considered to be vaccine-related (Table 2). Approximately half of the participants (48%) reported solicited injection-site AEs between Days 1 and 5 post-Dose 1, with a slightly higher frequency post-Dose 2 (57%). The most common solicited injection-site AE was injection-site pain (post-Dose 1, 40.0%; post-Dose 2, 49%), followed by injection-site erythema (post-Dose 1, 16%; post-Dose 2, 18%), and injection-site swelling (post-Dose 1, 10%; post-Dose 2, 8%; Table 2). All injection-site AEs occurring 1–5 days after vaccination were mild in intensity, except for 1 instance of injection-site pain of moderate intensity after Dose 2. All instances of injection-site erythema and injection-site swelling were ≤5.0 cm in size, except for 1 event of injection-site erythema measuring between 5.0 and 7.4 cm on Day 2 after Dose 2.

Table 2. Injection-site adverse events

n (%)	Participants, n (%)
	Days 1–42post-Dose 1(n = 50)	Days 1–42post-Dose 2(n = 49)	Days 1–42post-Dose 1 or 2(N = 50)
≥1 injection-site AE	24 (48)	28 (57)	36 (72)
Solicited injection-site AEs^a Pain Erythema  0–≤2.4 cm  >2.4–≤5.0 cm  >5.0–≤7.4 cm Swelling  0–≤2.4 cm  >2.4–≤5.0 cm	20 (40) 8 (16) 6 (12) 2 (4) 0 (0) 5 (10) 3 (6) 2 (4)	24 (49) 9 (18) 7 (14) 1 (2) 1 (2) 4 (8) 3 (6) 1 (2)	–
Unsolicited injection-site AEs Pruritus	1 (2)	–	–

^aDetermined by the investigator to be related to the study vaccine; AE, adverse event.

Systemic AEs after vaccination were reported by 38% of participants post-Dose 1 and 29% of participants post-Dose 2, but all systemic AEs were mild or moderate in intensity (Table 3). The most frequently reported systemic AEs were headache (post-Dose 1, 14%; post-Dose 2, 10%) and body temperature increased (i.e., a change in body temperature that did not meet the criteria for fever; post-Dose 1, 10%; post-Dose 2, 6%).

Table 3. Systemic adverse events

n (%)	Participants, n (%)
	Days 1–42 post- Dose 1 (n = 50)	Days 1–42 post- Dose 2 (n = 49)
≥1 systemic AE^a GI disorder Infections and infestations Investigations  Body temperature increased Nervous system disorders  Headache Skin and subcutaneous tissue disorders  Rash vesicular Reproductive system and breast disorders  Dysmenorrhea	19 (38) 4 (8) 5 (10) 5 (10) 8 (16) 7 (14) 4 (8) 3 (6) – –	14 (29) – 3 (6) 3 (6) 5 (10) 5 (10) – – 3 (6) 3 (6)
≥1 vaccine-related systemic AE Pyrexia^b Increased body temperature Facial spasm Headache Rash vesicular	0 (0) 4 (8) 1 (2) 2 (4) 3 (6)	1 (2)^b 3 (6) 0 (0) 0 (0) 1 (2)
Serious AEs	0 (0)	0 (0)
Discontinued due to an AE	0 (0)	0 (0)

^aIncidence ≥5%.

^bPyrexia was reported by a participant with a 38.7°C oral equivalent temperature, which did not fit the protocol-defined definition of fever (i.e. ≥39.0°C oral or oral equivalent); AE, adverse event; GI, gastrointestinal.

An elevated temperature of ≥39.0°C (meeting the protocol-specified definition of fever) was reported in 1 participant after Dose 1 and assessed to be unrelated to the study vaccine. No elevated temperatures meeting criteria for fever were reported after Dose 2.

Four instances of varicella-like rash were reported by 3 participants (6%) after Dose 1. One of these participants (2%) also reported a varicella-like rash after Dose 2. All varicella-like rashes were mild or moderate in severity. No herpes zoster-like rashes were observed.

Laboratory abnormalities meeting predetermined criteria were rated as Grade 1 or Grade 2, except for 1 participant (2%) with a Grade 3 hemoglobin value after Dose 2 and 1 participant (2%) with a Grade 4 potassium value after Dose 2. None of the laboratory abnormalities were reported as vaccine-related AEs.

No participants discontinued the study vaccine due to AEs. No deaths or other serious AEs were reported during the study.

Discussion

The varicella vaccine (VARIVAX™) induced an acceptable immune response and was generally well tolerated in adults in Russia receiving 2 doses 6 weeks apart. Although previous clinical studies suggested this vaccine may be less immunogenic in adolescents and adults than in children ≤12 years of age, results presented herein suggest 2 doses are highly immunogenic.^4,18 The increased GMTs in adults in this study may be the result of an anamnestic effect, where prior exposure to VZV may have occurred despite a negative clinical history, and which may not have been evident in baseline antibody titers due to titers declining with time.¹⁹ However, T- and B-cell memory may remain, so exposure to the VZV vaccine in apparently seronegative adults may have resulted in a more robust antibody response than expected. Interestingly, the GMTs observed in this study were higher than those previously reported for children, who are more likely to be naive to VZV.¹⁹ The seroconversion rates in adults reported here are comparable to those reported in younger individuals.²⁰

While the proportion of seropositive participants at baseline was lower than expected, the majority had a ≥ 4-fold increase in antibody titer. Because both seronegative and seropositive adults were observed to have robust immune responses, this observation supports the broad use of a varicella vaccine in adults regardless of prior exposure provided by clinical history, which may be subject to recall bias or limited records.²¹ No apparent sex- or age-differences were observed for immunogenicity, but due to the relatively small sample size and preponderance of women in the study, significance of sex- and age-based differences could not be determined.

There is ample real-world evidence on the effectiveness and safety of varicella vaccine since its licensure in 1995^22,23 and no unexpected safety or tolerability concerns were observed in this study. Data presented herein are consistent with the vaccine’s >25-year licensure,²⁴ including clinical trial data as well as real-world experience globally where VARIVAX™ has proven to be highly efficacious in protecting against varicella, highly immunogenic, and generally well tolerated.²⁴

The impact of varicella vaccination on a population basis has also been well established, with epidemiologic data confirming that widespread utilization of varicella vaccines reduces the incidence of varicella in both vaccinated and unvaccinated individuals (herd immunity). Earlier studies have indicated that the reduced risk of infection for both vaccinated and unvaccinated individuals is maintained at a population level for at least 15 years.^3,13,14,25 Additionally, severe VZV infection is rare in adults vaccinated against VZV.²⁶ While the effect of varicella vaccination on overall zoster epidemiology continues to be evaluated, it is unlikely that varicella vaccination contributes to an increase in zoster incidence in vaccinated adults,⁵ as evidenced by the lower rates of HZ reported among healthy adults administered a varicella vaccine than in unvaccinated populations.^5,8 Use of the HZ vaccine still remains crucial, especially in older individuals who are at higher risk of developing shingles.² It is important to stress that the varicella vaccine does not obviate the need for the HZ vaccine in indicated populations.²⁷

A systematic literature review examining varicella burden in Central and Eastern European countries suggested that varicella vaccination has the potential to directly and indirectly reduce the clinical and economic burden of varicella in this region,¹¹ with similar benefits expected in the Russian Federation. Potential cost reductions due to universal varicella vaccination can be linked to reduced healthcare utilization.¹ Cost-effectiveness studies providing economic evaluations of selective vaccination programs among adults, military recruits, and healthcare workers have been published from many countries.¹⁶ Importantly, most studies did not include dynamic models that account for herd immunity and are likely to have underestimated the impact of varicella vaccination programs. As VZV vaccination coverage increases over time, leading to decreases in disease reactivation, models predict that the net health savings from varicella vaccination will increase substantially.¹⁶

This study was limited by its sample size, high proportion of participants who were seropositive at baseline, and the adult population enrolled, which differs from the real-world population targeted for VZV vaccination, namely seronegative children and adults without evidence of immunity. However, this study was designed to verify the immunogenicity and safety of this varicella vaccine prior to its clinical investigation in infants, children, and adolescents for the purpose of obtaining licensure in the Russian Federation.

In conclusion, varicella vaccine (VARIVAX™: Varicella Virus Vaccine Live [Oka/Merck], Merck & Co., Inc., Kenilworth, NJ, USA) has demonstrated immunogenicity and safety in seronegative and seropositive adults administered 2 doses 6 weeks apart, supporting the rationale for further evaluation of this vaccine in infants, children, and adolescents for the purpose of licensure in the Russian Federation.

Disclosure of potential conflicts of interest

EP, XC, HLP and NB are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (MSD). OT and AF are employees of MSD, Russia.

Acknowledgments

The authors thank the participants and clinical research staff who participated in this trial. Medical writing and editorial assistance, under the direction of the authors, were provided by Toinette Labuschagne of Apothecom in accordance with Good Publication Practice (GPP3) guidelines.

Additional information

Funding

Funding for this research was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.