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.