Safety and immunogenicity of Innovax bivalent human papillomavirus vaccine in girls 9-14 years of age: Interim analysis from a phase 3 clinical trial.

BACKGROUND: World Health Organization human papillomavirus (HPV) vaccination recommendations include a single- or two-dose schedule in individuals 9-20 years old and advice for generating data on single-dose efficacy or immunobridging. The ongoing Phase 3 trial of Innovax's bivalent (types 16 and 18) HPV vaccine (Cecolin®) assesses in low- and middle-income countries alternative dosing schedules and generates data following one dose in girls 9-14 years old. Interim data for the 6-month dosing groups are presented. METHODS: In Bangladesh and Ghana, 1,025 girls were randomized to receive either two doses of Cecolin at 6-, 12-, or 24-month intervals; one dose of Gardasil® followed by one dose of Cecolin at month 24; or two doses of Gardasil 6 months apart (referent). Serology was measured by enzyme-linked immunosorbent assay (ELISA) and, in a subset, by neutralization assays. Primary objectives include immunological non-inferiority of the Cecolin schedules to referent one month after the second dose. Safety endpoints include reactogenicity and unsolicited adverse events for 7 and 30 days post-vaccination, respectively, as well as serious adverse events throughout the study. RESULTS: Interim analyses included data from the two groups on a 0, 6-month schedule with 205 participants per group. One month after Dose 2, 100% of participants were seropositive by ELISA and had seroconverted for both antigens. Non-inferiority of Cecolin to Gardasil was demonstrated. Six months following one dose, over 96% of participants were seropositive by ELISA for both HPV antigens, with a trend for higher geometric mean concentration following Cecolin administration. Reactogenicity and safety were comparable between both vaccines. CONCLUSIONS: Cecolin in a 0, 6-month schedule elicits robust immunogenicity. Non-inferiority to Gardasil was demonstrated one month after a 0, 6-month schedule. Immunogenicity following one dose was comparable to Gardasil up to six months. Both vaccines were safe and well tolerated (ClinicalTrials.gov No. 04508309).

Cost-effectiveness of human papillomavirus (HPV) vaccination in Burkina Faso: a modelling study.

BACKGROUND: Africa has some of the highest cervical cancer incidence and mortality rates globally. Burkina Faso launched a human papillomavirus (HPV) vaccination programme for 9-year-old girls in 2022 with support from Gavi, the Vaccine Alliance (Gavi). An economic evaluation of HPV vaccination is required to help sustain investment and inform decisions about optimal HPV vaccine choices. METHODS: We used a proportionate outcomes static cohort model to evaluate the potential impact and cost-effectiveness of HPV vaccination for 9-year-old girls over a ten-year period (2022-2031) in Burkina Faso. The primary outcome measure was the cost (2022 US$) per disability-adjusted life year (DALY) averted from a limited societal perspective (including all vaccine costs borne by the government and Gavi, radiation therapy costs borne by the government, and all other direct medical costs borne by patients and their families). We evaluated four vaccines (CERVARIX®, CECOLIN®, GARDASIL-4®, GARDASIL-9®), comparing each to no vaccination (and no change in existing cervical cancer screening and treatment strategies) and to each other. We combined local estimates of HPV type distribution, healthcare costs, vaccine coverage and costs with GLOBOCAN 2020 disease burden data and clinical trial efficacy data. We ran deterministic and probabilistic uncertainty analyses. RESULTS: HPV vaccination could prevent 37-72% of cervical cancer cases and deaths. CECOLIN® had the most favourable cost-effectiveness (cost per DALY averted < 0.27 times the national gross domestic product [GDP] per capita). When cross-protection was included, CECOLIN® remained the most cost-effective (cost per DALY averted < 0.20 times the national GDP per capita), but CERVARIX® provided greater health benefits (66% vs. 48% reduction in cervical cancer cases and deaths) with similar cost-effectiveness (cost per DALY averted < 0.28 times the national GDP per capita, with CECOLIN® as the comparator). We estimated the annual cost of the vaccination programme at US$ 2.9, 4.1, 4.4 and 19.8 million for CECOLIN®, GARDASIL-4®, CERVARIX® and GARDASIL-9®, respectively. A single dose strategy reduced costs and improved cost-effectiveness by more than half. CONCLUSION: HPV vaccination is cost-effective in Burkina Faso from a limited societal perspective. A single dose strategy and/or alternative Gavi-supported HPV vaccines could further improve cost-effectiveness.

State-of-the-Science of human papillomavirus vaccination in women with human immunodeficiency Virus: Summary of a scientific workshop.

The burden of cervical cancer is disproportionately distributed globally, with the vast majority of cases occurring in low- and middle-income countries. Women with human immunodeficiency virus (HIV) (WWH) are at increased risk of human papillomavirus (HPV) infection and cervical cancer as compared to HIV-negative individuals. HPV vaccination remains a priority in regions with a high burden of cervical cancer and high HIV prevalence. With HPV vaccines becoming more accessible, optimal use beyond the initial World Health Organization-recommended target population of 9 to 14-year-old girls is an important question. In March 2022, a group of experts in epidemiology, immunology, and vaccinology convened to discuss the state-of-the-science of HPV vaccination in WWH. This report summarizes the proceedings: review of HIV epidemiology and its intersection with cervical cancer burden, immunology, HPV vaccination including reduced-dose schedules and experience with other vaccines in people with HIV (PWH), HPV vaccination strategies and knowledge gaps, and outstanding research questions. Studies of HPV vaccine effectiveness among WWH, including duration of protection, are limited. Until data from ongoing research is available, the current recommendation for WWH remains for a multi-dose HPV vaccination regimen. A focus of the discussion included the potential impact of HIV acquisition following HPV vaccination. With no data currently existing for HPV vaccines and limited information from non-HPV vaccines, this question requires further research. Implementation research on optimal HPV vaccine delivery approaches for WWH and other priority populations is also urgently needed.

Adjuvanted recombinant zoster vaccine in adult autologous stem cell transplant recipients: polyfunctional immune responses and lessons for clinical practice.

Immunocompromised individuals, particularly autologous hematopoietic stem cell transplant (auHSCT) recipients, are at high risk for herpes zoster (HZ). We provide an in-depth description of humoral and cell-mediated immune (CMI) responses by age (protocol-defined) or underlying disease (post-hoc) as well as efficacy by underlying disease (post-hoc) of the adjuvanted recombinant zoster vaccine (RZV) in a randomized observer-blind phase III trial (ZOE-HSCT, NCT01610414). 1846 adult auHSCT recipients were randomized to receive a first dose of either RZV or placebo 50-70 days post-auHSCT, followed by the second dose at 1-2 months (M) later. In cohorts of 114-1721 participants, at 1 M post-second vaccine dose: Anti-gE antibody geometric mean concentrations (GMCs) and median gE-specific CD4[2+] T-cell frequencies (CD4 T cells expressing ≥2 of four assessed activation markers) were similar between 18-49 and ≥50-year-olds. Despite lower anti-gE antibody GMCs in non-Hodgkin B-cell lymphoma (NHBCL) patients, CD4[2+] T-cell frequencies were similar between NHBCL and other underlying diseases. The proportion of polyfunctional CD4 T cells increased over time, accounting for 79.6% of gE-specific CD4 T cells at 24 M post-dose two. Vaccine efficacy against HZ ranged between 42.5% and 82.5% across underlying diseases and was statistically significant in NHBCL and multiple myeloma patients. In conclusion, two RZV doses administered early post-auHSCT induced robust, persistent, and polyfunctional gE-specific immune responses. Efficacy against HZ was also high in NHBCL patients despite the lower humoral response.

PLAIN LANGUAGE SUMMARYWhat is the context?After haematopoietic stem cell transplantation, patients have impaired immunity from conditioning chemotherapy regimens, often exacerbated by underlying diseases, putting them at high risk of developing herpes zoster. In this population, antiviral prophylaxis is the current standard of care to reduce herpes zoster risk. Vaccination provides an additional means to prevent herpes zoster. Live-attenuated vaccines are generally contraindicated in immunocompromised patients. A non-live, adjuvanted recombinant zoster vaccine (RZV, Shingrix, GSK), has been approved for use in adults ≥50 years of age in the European Union, United States, Canada, Australia, Japan, and China. This vaccine is highly efficacious at preventing herpes zoster in adults over 50 years of age, as demonstrated in large, placebo-controlled randomised trials. Importantly, Shingrix use is not contraindicated in immunocompromised conditions, and was found to be highly efficacious in adults who had recently undergone autologous haematopoietic stem cell transplant.What is new?In autologous haematopoietic stem cell transplant recipients in whom Shingrix has demonstrated efficacy, two doses elicited high and persistent immune responses. Date presented here further support our understanding of the impact of specific factors such as age or underlying diseases on the vaccine's effect in the population studied, as well as the characteristics of the elicited cell-mediated immune responses.What is the impact?These results indicate that Shingrix, given shortly after haematopoietic stem cell transplant, can induce robust immune responses and reduce the risk of herpes zoster, even in individuals with immunosuppression due to underlying disease and/or use of immunosuppressive therapies, regardless of age or underlying disease.

Immune responses to the adjuvanted recombinant zoster vaccine in immunocompromised adults: a comprehensive overview.

Immunocompromised (IC) persons are at increased risk for herpes zoster (HZ) and its complications, mainly due to impairment of cell-mediated immunity (CMI). The adjuvanted recombinant zoster vaccine (RZV) demonstrated efficacy against HZ in autologous hematopoietic stem cell transplant (auto-HSCT) recipients and hematologic malignancy (HM) patients. We review immune responses to RZV in 5 adult IC populations, 4 of which were receiving multiple, concomitant immunosuppressive medications: auto-HSCT and renal transplant recipients, HM and solid tumor patients, and human immunodeficiency virus-infected adults. Although administered in most cases when immunosuppression was near its maximum, including concomitantly with chemotherapy cycles, RZV induced robust and persistent humoral and, more importantly, CMI responses in all 5 IC populations. Based on the overall clinical data generated in older adults and IC individuals, RZV is expected to provide benefit in a broad adult population at risk for HZ.

Impact of Reactogenicity After Two Doses of Recombinant Zoster Vaccine Upon Physical Functioning and Quality of Life: An Open Phase III Trial in Older Adults.

BACKGROUND: Herpes zoster may significantly impact quality of life (QoL) in older adults. The recombinant zoster vaccine (RZV) is efficacious in adults aged ≥50 and older and is associated with increased reactogenicity compared to placebo. We report here on the impact of reactogenicity of the second RZV dose on the QoL and physical functioning (PF) of vaccine recipients, and summarize findings following both doses. METHOD: In this single-arm study, 401 adults aged ≥50 and older were enrolled to receive two RZV doses 2 months apart. Change in mean Short Form Survey-36 (SF-36) PF and EuroQol-5 Dimension (EQ-5D) scores, reactogenicity, safety, productivity loss, and healthcare resource utilization were evaluated. RESULTS: In total, 391 (97.5%) participants received dose 2. Post-dose 2, the most common solicited local symptoms were injection site pain (75.1%), erythema (22.4%), and swelling (13.9%), and the most common systemic symptoms were fatigue (46.3%), headache (37.5%), and myalgia (32.9%). Grade 3 solicited (local and systemic) adverse events were reported by 61 (15.6%) participants and were associated with a transient clinically significant decrease in SF-36 PF score on Days 1-2 post-dose 2 that recovered by Day 3. Overall, no clinically important reduction in mean SF-36 PF scores was observed from baseline to post-dose 2 (mean change -0.4), and no quality-adjusted-life-year loss was recorded. CONCLUSIONS: Overall, QoL and PF of RZV vaccinees were not affected by vaccine-related reactogenicity. A transient reduction was observed in the first 2 days after RZV vaccination in individuals with Grade 3 adverse events. No safety concerns were identified.

Recombinant Zoster Vaccine Is Efficacious and Safe in Frail Individuals.

BACKGROUND/OBJECTIVES: Frail participants are often under-represented in randomized trials, raising questions about outcomes of interventions in real-world settings. Frailty is strongly associated with vulnerability to illness and adverse health outcomes. We studied the impact of frailty on recombinant zoster vaccine (RZV) clinical outcomes. DESIGN/SETTING: Data from two previously conducted phase III randomized trials of RZV were pooled. These two parent trials were conducted concurrently at the same study sites using the same methods. PARTICIPANTS/INTERVENTION: In the two parent studies, participants aged ≥50 years (ZOE-50 study) and ≥70 years (ZOE-70 study), respectively, were randomized 1:1 to receive two doses of RZV or placebo. MEASUREMENTS: In the current ZOE-Frailty study (NCT03563183), a frailty index was created using previously validated methods. Clinical outcomes assessed by frailty status included vaccine efficacy, immunogenicity, reactogenicity, and safety. RESULTS: Of 29,305 participants from the pooled ZOE-50 and ZOE-70 total vaccinated cohort, 92% were included in this study. Mean age was 68.8 years; 58.1% were women; 45.6% were pre-frail and 11.3% frail. The percentage of frail participants increased with age from 5.7% aged 50-59 years to 22.7% aged ≥80 years. RZV vaccine efficacy against herpes zoster was >90% for all frailty subgroups (non-frail: 95.8% (95% confidence interval = 91.6-98.2), pre-frail: 90.4% (84.4-94.4), frail: 90.2% (75.4-97.0)). The RZV group demonstrated robust anti-gE antibody and gE-specific CD42+ responses, with mean concentrations remaining above pre-vaccination levels at least 3 years post-dose two, in all frailty subgroups. In the RZV group, the percentage of participants reporting solicited adverse events tended to decrease with increasing frailty. CONCLUSION: The relatively nonrestrictive inclusion/exclusion criteria in the parent ZOE studies resulted in a range of participants that included frail and pre-frail older adults. RZV significantly reduced the risk of herpes zoster across all frailty subgroups.

The adjuvanted recombinant zoster vaccine co-administered with a tetanus, diphtheria and pertussis vaccine in adults aged ≥50 years: A randomized trial.

BACKGROUND: This study evaluated immunogenicity and safety of the adjuvanted recombinant zoster vaccine (RZV) and the reduced-antigen-content diphtheria-tetanus-acellular pertussis vaccine (Tdap) when co-administered in adults aged ≥50 years. METHODS: In this open label, multi-center study (NCT02052596), participants were randomized 1:1 to the Co-Administration group (RZV dose 1 and Tdap at Day 0 [D0], RZV dose 2 at Month 2 [M2]) or Control group (Tdap at D0, RZV dose 1 at M2, RZV dose 2 at M4). Co-primary objectives were evaluation of the vaccine response rate (VRR) to RZV in the Co-Administration group, and demonstration of non-inferiority of the humoral responses to RZV and Tdap in the Co-Administration compared to Control group. Reactogenicity and safety of RZV and Tdap were also assessed. RESULTS: VRR to RZV was 97.8% in the Co-Administration group. The non-inferiority criterion was met for the humoral response to RZV and for 4 Tdap antigens, but was not met for the Tdap antigen pertactin. Occurrences of solicited, unsolicited and serious adverse events, and potential immune-mediated diseases were similar between groups. CONCLUSIONS: Co-administration of RZV and Tdap did not interfere with the humoral immune response to RZV or 4 of the 5 Tdap antigens. No safety concerns were identified.