Safety and efficacy of inactivated varicella zoster virus vaccine in immunocompromised patients with malignancies: a two-arm, randomised, double-blind, phase 3 trial

doi:10.1016/S1473-3099(19)30310-X

The Lancet Infectious Diseases

Volume 19, Issue 9, September 2019, Pages 1001-1012

https://doi.org/10.1016/S1473-3099(19)30310-X Get rights and content

Summary

Background

Patients who are immunocompromised because of malignancy have an increased risk of herpes zoster and herpes zoster-related complications. We aimed to investigate the efficacy and safety of an inactivated varicella zoster virus (VZV) vaccine for herpes zoster prevention in patients with solid tumour or haematological malignancies.

Methods

This phase 3, two-arm, randomised, double-blind, placebo-controlled, multicentre trial with an adaptive design was done in 329 centres across 40 countries. The trial included adult patients with solid tumour malignancies receiving chemotherapy and those with haematological malignancies, either receiving or not receiving chemotherapy. Patients were randomly assigned (1:1) to receive four doses of VZV vaccine inactivated by γ irradiation or placebo approximately 30 days apart. The patients, investigators, trial site staff, clinical adjudication committee, and sponsor's clinical and laboratory personnel were masked to the group assignment. The primary efficacy endpoint was herpes zoster incidence in patients with solid tumour malignancies receiving chemotherapy, which was assessed in the modified intention-to-treat population (defined as all randomly assigned patients who received at least one dose of inactivated VZV vaccine or placebo). The primary safety endpoint was serious adverse events up to 28 days after the fourth dose in patients with solid tumour malignancies receiving chemotherapy. Safety endpoints were assessed in all patients who received at least one dose of inactivated VZV vaccine or placebo and had follow-up data. This trial is registered (NCT01254630 and EudraCT 2010-023156-89).

Findings

Between June 27, 2011, and April 11, 2017, 5286 patients were randomly assigned to receive VZV vaccine inactivated by γ irradiation (n=2637) or placebo (n=2649). The haematological malignancy arm was terminated early because of evidence of futility at a planned interim analysis; therefore, all prespecified haematological malignancy endpoints were deemed exploratory. In patients with solid tumour malignancies in the modified intention-to-treat population, confirmed herpes zoster occurred in 22 of 1328 (6·7 per 1000 person-years) VZV vaccine recipients and in 61 of 1350 (18·5 per 1000 person-years) placebo recipients. Estimated vaccine efficacy against herpes zoster in patients with solid tumour malignancies was 63·6% (97·5% CI 36·4 to 79·1), meeting the prespecified success criterion. In patients with solid tumour malignancies, serious adverse events were similar in frequency across treatment groups, occurring in 298 (22·5%) of 1322 patients who received the vaccine and in 283 (21·0%) of 1346 patients who received placebo (risk difference 1·5%, 95% CI −1·7 to 4·6). Vaccine-related serious adverse events were less than 1% in each treatment group. Vaccine-related injection-site reactions were more common in the vaccine group than in the placebo group. In the haematological malignancy group, VZV vaccine was well tolerated and estimated vaccine efficacy against herpes zoster was 16·8% (95% CI −17·8 to 41·3).

Interpretation

The inactivated VZV vaccine was well tolerated and efficacious for herpes zoster prevention in patients with solid tumour malignancies receiving chemotherapy, but was not efficacious for herpes zoster prevention in patients with haematological malignancies.

Funding

Merck & Co, Inc.

Introduction

Advanced malignancy and associated immunosuppressive therapies are risk factors for herpes zoster.1, 2, 3, 4 The incidence of herpes zoster is approximately 15 cases per 1000 person-years in patients with solid tumour malignancies receiving chemotherapy³ and 31 cases per 1000 person-years in patients with haematological malignancies,1, 4 compared with nine cases per 1000 person-years in the general adult population aged 50 years and older (five cases per 1000 person-years across all ages).² Patients who are immunocompromised are at increased risk of developing severe and life-threatening complications of herpes zoster, including disabling post-herpetic neuralgia, visceral organ involvement, and bacterial superinfection.5, 6 The clinical presentation of herpes zoster can be atypical in these patients, including disseminated varicella-like skin lesions and no obvious primary dermatome involvement or severe abdominal pain preceding the appearance of rash.

Research in context

Evidence before this study

We searched PubMed for published articles in English with no date restrictions with the terms “varicella zoster virus vaccine”, “herpes zoster”, in conjunction with the terms “cancer”, “tumour”, or “malignancy”, and found that patients immunocompromised either because of malignancy or receipt of immunosuppressive cancer therapy have a higher incidence of herpes zoster than the general immunocompetent adult population. A live, attenuated varicella zoster virus (VZV) vaccine, licensed for use in healthy adults aged 50 years and older for herpes zoster prevention, is contraindicated in patients who are immunocompromised, including patients with solid tumour malignancies receiving chemotherapy and those with haematological malignancies. A phase 1 trial showed immunogenicity and safety of a heat-inactivated VZV vaccine in patients with solid tumour malignancies receiving chemotherapy and with haematological malignancies. Another phase 1 trial showed safety and immunogenicity of VZV vaccine inactivated by γ irradiation in patients with haematological malignancies receiving anti-CD20 monoclonal antibodies. A phase 3 trial was done to assess the efficacy and safety of this vaccine for prevention of herpes zoster and herpes zoster-related complications in patients with solid tumour malignancies receiving chemotherapy or haematological malignancies. Phase 2 immunogenicity and safety trials of an adjuvant recombinant subunit VZV vaccine in patients who are immunocompromised were ongoing when the phase 3 study was planned.

Added value of this study

To our knowledge, this is the first randomised, double-blind, placebo-controlled, international, phase 3 trial evaluating the efficacy and safety of the investigational VZV vaccine inactivated by γ irradiation for the prevention of herpes zoster and herpes zoster-related complications in patients with solid tumour malignancies receiving chemotherapy and those with haematological malignancies.

Implications of all the available evidence

The results of this trial show that the vaccine is well tolerated in both patient populations and that inactivated VZV vaccine is effective for herpes zoster prevention in patients with solid tumour malignancies receiving chemotherapy but not in patients with haematological malignancies.

Treatment of herpes zoster in patients who are immuno-compromised typically includes intravenous aciclovir,7, 8 and in cases of aciclovir-resistant herpes zoster, foscarnet or cidofovir.6, 9 Two licensed vaccines for herpes zoster prevention in healthy adults aged 50 years and older are available: a live attenuated varicella zoster virus (VZV) vaccine (Zostavax; Merck & Co, Inc, Kenilworth, NJ, USA),10, 11, 12 which is contraindicated in patients who are immunocompromised, and an adjuvanted recombinant subunit VZV vaccine (Shingrix; GlaxoSmithKline, King of Prussia, PA, USA), for which efficacy in patients with malignancies has not yet been established.13, 14, 15, 16, 17 Thus, prevention of herpes zoster disease in patients with solid tumour or haematological malignancies represents an area of substantial unmet medical need.

In proof-of-concept studies and a small phase 1 trial, heat-inactivated VZV vaccine reduced herpes zoster morbidity and decreased herpes zoster incidence in haematopoietic stem-cell transplant recipients,18, 19 and showed immunogenicity and safety in patients with solid tumour malignancies receiving chemotherapy and in patients with haematological malignancies.²⁰ Phase 1 and 2 trials showed safety and immunogenicity of a VZV vaccine inactivated by γ irradiation (Merck & Co, Inc) in patients with haematological malignancies receiving anti-CD20 monoclonal antibodies and in patients with autoimmune disease receiving immunosuppressive therapy.21, 22 Subsequently, the efficacy, immunogenicity, and safety of this vaccine was established in a large phase 3 trial in recipients of autologous haematopoietic stem-cell transplants.²³ In this study, we aimed to assess the efficacy and safety of the VZV vaccine inactivated by γ irradiation for prevention of herpes zoster and herpes zoster-related complications in patients with solid tumours receiving chemotherapy or patients with haematological malignancies.

Section snippets

Study design and participants

This adaptively designed, two-arm, phase 3, randomised, double-blind, placebo-controlled, multicentre trial was done in 329 centres across 40 countries. Eligible patients were aged 18 years or older, had been diagnosed with a solid tumour malignancy (for which they were receiving a cytotoxic or immunosuppressive chemotherapy regimen) or haematological malignancy, and were not likely to undergo haematopoietic stem-cell transplantation. Patients had to have a history of varicella infection

Results

Between June 27, 2011, and April 11, 2017, 5507 patients were assessed for eligibility, of whom 5286 were enrolled and randomly assigned to receive VZV vaccine inactivated by γ irradiation (n=2637) or placebo (n=2649; figure 1). Baseline characteristics of both groups were similar across treatment groups and patient populations, with a median age of 60 years (IQR 52–69) and a slight predominance of female participants (2810 [53·2%] of 5285; table 1). 1619 (62·9%) of 2573 patients with

Discussion

The results of our phase 3 trial of a VZV vaccine inactivated by γ irradiation add to those from earlier trials of inactivated VZV vaccines in patients who were immunocompromised,18, 19, 20, 21, 22 and provide evidence of inactivated VZV vaccine efficacy for prevention of herpes zoster in patients with solid tumour malignancies receiving chemotherapy. Patients with solid tumour malignancies who received inactivated VZV vaccine had a significantly lower herpes zoster incidence than did patients

Data sharing

The data sharing policy of Merck & Co, Inc, including restrictions, is available at http://engagezone.merck.com/ds_documentation.php. Requests for access to the clinical study data can be submitted through the EngageZone site or via email to [email protected].

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ArticlesSafety and efficacy of inactivated varicella zoster virus vaccine in immunocompromised patients with malignancies: a two-arm, randomised, double-blind, phase 3 trial

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Study design and participants

Results

Discussion

Data sharing

Vaccine

Lancet

J Virol Methods

The epidemiology of herpes zoster in patients with newly diagnosed cancer

Cancer Epidemiol Biomarkers Prev

Annual incidence rates of herpes zoster among an immunocompetent population in the United States

BMC Infect Dis

Healthcare utilization and costs among patients with herpes zoster and solid tumor malignancy on chemotherapy: a retrospective cohort study

Medicine

The epidemiology of herpes zoster and its complications in Medicare cancer patients

BMC Infect Dis

Real-world effectiveness and safety of a live-attenuated herpes zoster vaccine: a comprehensive review

Adv Ther

Recommendations for the management of herpes zoster

Clin Infect Dis

Varicella-zoster virus: atypical presentations and unusual complications

J Infect Dis

Atypical disseminated herpes zoster: management guidelines in immunocompromised patients

Cutis

Herpes zoster

N Engl J Med

Package insert

Articles
Safety and efficacy of inactivated varicella zoster virus vaccine in immunocompromised patients with malignancies: a two-arm, randomised, double-blind, phase 3 trial