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.

The Adjuvanted Recombinant Zoster Vaccine Confers Long-Term Protection Against Herpes Zoster: Interim Results of an Extension Study of the Pivotal Phase 3 Clinical Trials ZOE-50 and ZOE-70.

BACKGROUND: This ongoing follow-up study evaluated the persistence of efficacy and immune responses for 6 additional years in adults vaccinated with the glycoprotein E (gE)-based adjuvanted recombinant zoster vaccine (RZV) at age ≥50 years in 2 pivotal efficacy trials (ZOE-50 and ZOE-70). The present interim analysis was performed after ≥2 additional years of follow-up (between 5.1 and 7.1 years [mean] post-vaccination) and includes partial data for year (Y) 8 post-vaccination. METHODS: Annual assessments were performed for efficacy against herpes zoster (HZ) from Y6 post-vaccination and for anti-gE antibody concentrations and gE-specific CD4[2+] T-cell (expressing ≥2 of 4 assessed activation markers) frequencies from Y5 post-vaccination. RESULTS: Of 7413 participants enrolled for the long-term efficacy assessment, 7277 (mean age at vaccination, 67.2 years), 813, and 108 were included in the cohorts evaluating efficacy, humoral immune responses, and cell-mediated immune responses, respectively. Efficacy of RZV against HZ through this interim analysis was 84.0% (95% confidence interval [CI], 75.9-89.8) from the start of this follow-up study and 90.9% (95% CI, 88.2-93.2) from vaccination in ZOE-50/70. Annual vaccine efficacy estimates were >84% for each year since vaccination and remained stable through this interim analysis. Anti-gE antibody geometric mean concentrations and median frequencies of gE-specific CD4[2+] T cells reached a plateau at approximately 6-fold above pre-vaccination levels. CONCLUSIONS: Efficacy against HZ and immune responses to RZV remained high, suggesting that the clinical benefit of RZV in older adults is sustained for at least 7 years post-vaccination. Clinical Trials Registration. NCT02723773.

The Adjuvanted Recombinant Zoster Vaccine in Adults Aged ≥65 Years Previously Vaccinated With a Live-Attenuated Herpes Zoster Vaccine.

BACKGROUND: Efficacy of the live-attenuated herpes zoster (HZ) vaccine (ZVL) wanes substantially over time. We evaluated immunogenicity and safety of the adjuvanted recombinant zoster vaccine (RZV) in previous ZVL recipients. METHODS: Adults aged ≥65 years who were previously vaccinated with ZVL ≥5 years earlier (n = 215) were group-matched with ZVL-naive individuals (n = 215) and vaccinated with RZV. Glycoprotein E (gE)-specific humoral and cell-mediated immune responses and the correlation between them, polyfunctional gE-specific CD4 T-cell responses, safety, and confirmed HZ cases were assessed. RESULTS: Through 12 months after dose 2, anti-gE antibody concentrations, gE-specific CD4 T-cell frequencies, and activation marker profiles were similar between groups. Safety outcomes were also similar. No HZ episodes were confirmed. CONCLUSIONS: RZV induced strong humoral and polyfunctional cell-mediated immune responses that persisted above prevaccination levels through 1 year after dose 2 in adults aged ≥65 years irrespective of previous ZVL vaccination. The RZV safety profile was not affected. CLINICAL TRIALS REGISTRATION: NCT02581410.

Immunogenicity of the Adjuvanted Recombinant Zoster Vaccine: Persistence and Anamnestic Response to Additional Doses Administered 10 Years After Primary Vaccination.

BACKGROUND: The adjuvanted recombinant zoster vaccine (RZV) is highly immunogenic and efficacious in adults ≥50 years of age. We evaluated (1) long-term immunogenicity of an initial 2-dose RZV schedule, by following up adults vaccinated at ≥60 years of age and by modeling, and (2) immunogenicity of 2 additional doses administered 10 years after initial vaccination. METHODS: Persistence of humoral and cell-mediated immune (CMI) responses to 2 initial RZV doses was assessed through 10 years after initial vaccination, and modeled through 20 years using a Piecewise, Power law and Fraser model. The immunogenicity and safety of 2 additional RZV doses were also evaluated. RESULTS: Seventy adults were enrolled. Ten years after initial vaccination, humoral and CMI responses were approximately 6-fold and 3.5-fold, respectively, above those before the initial vaccination levels. Predicted immune persistence through 20 years after initial vaccination was similar across the 3 models. Sixty-two participants (mean age [standard deviation], 82.6 [4.4] years) received ≥1 additional RZV dose. Strong anamnestic humoral and CMI responses were elicited by 1 additional dose, without further increases after a second additional dose. CONCLUSIONS: Immune responses to an initial 2-dose RZV course persisted for many years in older adults. Strong anamnestic immune responses can be induced by additional dosing 10 years after the initial 2-dose course. CLINICAL TRIALS REGISTRATION: NCT02735915.

Efficacy and serious adverse events profile of the adjuvanted recombinant zoster vaccine in adults with pre-existing potential immune-mediated diseases: a pooled post hoc analysis on two parallel randomized trials.

ABSTRACT OBJECTIVE: In the ZOE-50 (NCT01165177) and ZOE-70 (NCT01165229) phase 3 clinical trials, the adjuvanted recombinant zoster vaccine (RZV) demonstrated ≥90% efficacy in preventing herpes zoster (HZ) in all age groups ≥50 years. Given the increased HZ risk associated with certain underlying autoimmune diseases or their treatment regimes, we conducted a post hoc analysis of RZV's efficacy against HZ and safety profile [specifically, the occurrence of serious adverse events (SAEs)] in ZOE-50/70 participants who reported pre-existing potential immune-mediated diseases (pIMDs) at enrolment and were not on immunosuppressive therapies. METHODS: Adults aged ≥50 (ZOE-50) and ≥70 (ZOE-70) years were randomized to receive two doses of RZV or placebo 2 months apart. In this subgroup analysis of participants with at least one pIMD at enrolment, the efficacy was calculated for two-dose recipients who did not develop confirmed HZ before 30 days post-dose 2. SAE occurrence was evaluated for all participants who received at least one dose. RESULTS: Of the 14 645 RZV and 14 660 placebo recipients from the ZOE-50/70 studies, 983 and 960, respectively, reported at least one pre-existing pIMD at enrolment and were included in these analyses. The most frequent pre-existing conditions were psoriasis, spondyloarthropathy and RA. Efficacy against HZ was 90.5% (95% CI: 73.5, 97.5%) overall with the lowest being 84.4% (95% CI: 30.8, 98.3%) in the 70-79-year-old age group. SAEs and fatal SAEs were similar between RZV and placebo recipients. CONCLUSION: In ZOE-50/70 participants with pre-existing pIMDs, RZV was highly efficacious against HZ and SAE incidence was similar between RZV and placebo recipients. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT01165177 (ZOE-50), NCT01165229 (ZOE-70).

Immunogenicity and Safety of an AS03-Adjuvanted H7N9 Pandemic Influenza Vaccine in a Randomized Trial in Healthy Adults.

BACKGROUND: Almost 700 cases of human infection with avian influenza A/H7N9 have been reported since 2013. Pandemic preparedness strategies include H7N9 vaccine development. METHODS: We evaluated an inactivated H7N9 vaccine in an observer-blind study in healthy adults aged 18-64 years. Participants (420) were randomized to receive 1 of 4 AS03-adjuvanted vaccines (low or medium dose of hemagglutinin with AS03A or AS03B), one nonadjuvanted vaccine, or placebo. The coprimary immunogenicity objective determined whether adjuvanted vaccines elicited an immune response against the vaccine-homologous virus, 21 days after the second vaccine dose per US and European licensure criteria in the per-protocol cohort (n = 389). RESULTS: All adjuvanted vaccines met regulatory acceptance criteria. In groups receiving adjuvanted formulations, seroconversion rates were ≥85.7%, seroprotection rates ≥91.1%, and geometric mean titers ≥92.9% versus 23.2%, 28.6%, and 17.2 for the nonadjuvanted vaccine. The AS03 adjuvant enhanced immune response at antigen-sparing doses. Injection site pain occurred more frequently with adjuvanted vaccines (in ≤98.3% of vaccinees) than with the nonadjuvanted vaccine (40.7%) or placebo (20.0%). None of the 20 serious adverse events reported were related to vaccination. CONCLUSIONS: Two doses of AS03-adjuvanted H7N9 vaccine were well tolerated and induced a robust antibody response at antigen-sparing doses in healthy adults. CLINICAL TRIALS REGISTRATION: NCT01999842.

Immunogenicity and Safety of an EB66 Cell-Culture-Derived Influenza A/Indonesia/5/2005(H5N1) AS03-Adjuvanted Vaccine: A Phase 1 Randomized Trial.

BACKGROUND: Cell-culture-derived (CC) influenza vaccine production methods could provide benefits over classical embryonated-egg technology, including a higher production capacity and the faster creation of a supply that meets demand. METHODS: A CC-inactivated split-virus influenza A/Indonesia/5/2005(H5N1) vaccine derived from the EB66 cell line (hereafter, "CC-H5N1") was investigated in a phase 1 randomized, blinded study. Healthy adults (n = 521) received 2 vaccine doses (days 0 and 21) of either investigational CC-H5N1 vaccine (1.9 µg or 3.75 µg of hemagglutinin antigen [HA] with the AS03 adjuvant system or 15 µg of plain HA), embryonated-egg-derived vaccines (3.75 µg of HA with AS03 or 15 µg of plain HA), or placebo. Assessment of the adjuvant effect and immunogenicity was performed using Center for Biologics Evaluation and Research acceptability criteria 21 days after dose 2. Safety was assessed until month 12. RESULTS: AS03-adjuvanted CC-H5N1 elicited a homologous hemagglutination inhibition antibody response that satisfied immunogenicity criteria 21 days after dose 2 and persisted at month 12. Adjuvant effect and immune response against a drift-variant strain were demonstrated. No vaccine-related serious adverse events were reported. The immunogenicity and safety of the CC-H5N1 formulation containing 3.75 µg of HA and AS03 appeared to be similar to those for the licensed egg-derived AS03-adjuvanted control vaccine. CONCLUSIONS: The feasibility of the EB66 cell line to produce an immunogenic influenza vaccine with acceptable safety profile was demonstrated. Antigen sparing was achieved through combination with AS03 adjuvant. This CC-H5N1 might contribute to the rapid access of vaccine in the event of an influenza A(H5N1) pandemic. CLINICAL TRIALS REGISTRATION: NCT01236040.

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).

Adjuvanted recombinant zoster vaccine decreases herpes zoster-associated pain and the use of pain medication across 3 randomized, placebo-controlled trials.

ABSTRACT: Herpes zoster (HZ) and HZ-associated pain greatly affect patients' quality of life, particularly in older and immunocompromised adults, for whom comorbidities and polypharmacy are often reported. Three phase III, randomized, placebo-controlled clinical trials have reported the adjuvanted recombinant zoster vaccine (RZV) as highly efficacious in preventing HZ and reducing pain severity in healthy adults ≥50 years old (Zoster Efficacy Study [ZOE]-50 study, NCT01165177) and ≥70 years old (ZOE-70; NCT01165229) and in immunocompromised adults ≥18 years old undergoing autologous hematopoietic stem cell transplantation (ZOE-HSCT; NCT01610414). Here, we investigated efficacy of RZV in reducing (i) the duration of clinically significant pain (Zoster Brief Pain Inventory pain score ≥3) and (ii) HZ-associated pain medication use and duration of use in participants with confirmed HZ ("breakthrough cases") from the 3 studies. Recombinant zoster vaccine effectively reduced the duration of clinically significant HZ-associated pain during HZ episodes by 38.5% ( P -value: 0.010) in the ZOE-HSCT study. Although a similar trend was observed in the ZOE-50 and ZOE-70 studies, the results were not statistically significant because of the high vaccine efficacy (VE) against HZ resulting in rare breakthrough cases. VE in reducing pain medication use (39.6%; P -value: 0.008) and duration of medication use (49.3%, P -value: 0.040) was reported in the ZOE-70 study; corresponding positive VE estimates were observed in the ZOE-50 and ZOE-HSCT studies but were not statistically significant. Data reported here demonstrate efficacy of RZV in reducing HZ-associated pain duration and pain medication use in breakthrough cases, thereby improving quality of life of those with HZ.

Impact, cost-effectiveness, and budget implications of HPV vaccination in Kenya: A modelling study.

BACKGROUND: Sub-Saharan Africa has the highest rate of cervical cancer cases and deaths worldwide. Kenya introduced a quadrivalent HPV vaccine (GARDASIL, hereafter referred to as GARDASIL-4) for ten-year-old girls in late 2019 with donor support from Gavi, the Vaccine Alliance. As Kenya may soon graduate from Gavi support, it is important to evaluate the potential cost-effectiveness and budget impact of the current HPV vaccine, and potential alternatives. METHODS: We used a proportionate outcomes static cohort model to evaluate the annual budget impact and lifetime cost-effectiveness of vaccinating ten-year-old girls over the period 2020-2029. We included a catch-up campaign for girls aged 11-14 years in 2020. We estimated cervical cancer cases, deaths, disability adjusted life years (DALYs), and healthcare costs (government and societal perspective) expected to occur with and without vaccination over the lifetimes of each cohort of vaccinated girls. For each of the four products available globally (CECOLIN©, CERVARIX©, GARDASIL-4©, and GARDASIL-9 ©), we estimated the cost (2021 US$) per DALY averted compared to no vaccine and to each other. Model inputs were obtained from published sources, as well as local stakeholders. RESULTS: We estimated 320,000 cases and 225,000 deaths attributed to cervical cancer over the lifetimes of the 14 evaluated birth cohorts. HPV vaccination could reduce this burden by 42-60 %. Without cross-protection, CECOLIN had the lowest net cost and most attractive cost-effectiveness. With cross-protection, CERVARIX was the most cost-effective. Under either scenario the most cost-effective vaccine had a 100 % probability of being cost-effective at a willingness-to-pay threshold of US$ 100 (5 % of Kenya's national gross domestic product per capita) compared to no vaccination. Should Kenya reach its target of 90 % coverage and graduate from Gavi support, the undiscounted annual vaccine program cost could exceed US$ 10 million per year. For all three vaccines currently supported by Gavi, a single-dose strategy would be cost-saving compared to no vaccination. CONCLUSION: HPV vaccination for girls is highly cost-effective in Kenya. Compared to GARDASIL-4, alternative products could provide similar or greater health benefits at lower net costs. Substantial government funding will be required to reach and sustain coverage targets as Kenya graduates from Gavi support. A single dose strategy is likely to have similar benefits for less cost.

Impact and Cost-Effectiveness of Alternative Human Papillomavirus Vaccines for Preadolescent Girls in Mozambique: A Modelling Study.

Mozambique has one of the highest rates of cervical cancer in the world. Human papillomavirus (HPV) vaccination was introduced in 2021. This study evaluated the health and economic impact of the current HPV vaccine (GARDASIL® hereafter referred to as GARDASIL-4) and two other vaccines (CECOLIN® and CERVARIX®) that could be used in the future. A static cohort model was used to estimate the costs and benefits of vaccinating girls in Mozambique over the period 2022-2031. The primary outcome measure was the incremental cost per disability-adjusted life-year averted from a government perspective. We conducted deterministic and probabilistic sensitivity analyses. Without cross-protection, all three vaccines averted approximately 54% cervical cancer cases and deaths. With cross-protection, CERVARIX averted 70% of cases and deaths. Without Gavi support, the discounted vaccine program costs ranged from 60 million to 81 million USD. Vaccine program costs were approximately 37 million USD for all vaccines with Gavi support. Without cross-protection, CECOLIN was dominant, being cost-effective with or without Gavi support. With cross-protection and Gavi support, CERVARIX was dominant and cost-saving. With cross-protection and no Gavi support, CECOLIN had the most favorable cost-effectiveness ratio. Conclusions: At a willingness-to-pay (WTP) threshold set at 35% of Gross Domestic Product (GDP) per capita, HPV vaccination is cost-effective in Mozambique. The optimal vaccine choice depends on cross-protection assumptions.

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.

Association Between Hemagglutination Inhibition Antibody Titers and Protection Against Reverse-Transcription Polymerase Chain Reaction-Confirmed Influenza Illness in Children 6-35 Months of Age: Statistical Evaluation of a Correlate of Protection.

BACKGROUND: Data from a randomized controlled efficacy trial of an inactivated quadrivalent influenza vaccine in children 6-35 months of age were used to determine whether hemagglutination inhibition (HI) antibody titer against A/H1N1 and A/H3N2 is a statistical correlate of protection (CoP) for the risk of reverse-transcription polymerase chain reaction (RT-PCR)-confirmed influenza associated with the corresponding strain. METHODS: The Prentice criteria were used to statistically validate strain-specific HI antibody titer as a CoP. The probability of protection was identified using the Dunning model corresponding to a prespecified probability of protection at an individual level. The group-level protective threshold was identified using the Siber approach, leading to unbiased predicted vaccine efficacy (VE). A case-cohort subsample was used for this exploratory analysis. RESULTS: Prentice criteria confirmed that HI titer is a statistical CoP for RT-PCR-confirmed influenza. The Dunning model predicted a probability of protection of 49.7% against A/H1N1 influenza and 54.7% against A/H3N2 influenza at an HI antibody titer of 1:40 for the corresponding strain. Higher titers of 1:320 were associated with >80% probability of protection. The Siber method predicted VE of 61.0% at a threshold of 1:80 for A/H1N1 and 46.6% at 1:113 for A/H3N2. CONCLUSIONS: The study validated HI antibody titer as a statistical CoP, by demonstrating that HI titer is correlated with clinical protection against RT-PCR-confirmed influenza associated with the corresponding influenza strain and is predictive of VE in children 6-35 months of age. CLINICAL TRIALS REGISTRATION: NCT01439360.

Prevalence of human papillomavirus infection and associated risk factors in young women in Brazil, Canada, and the United States: a multicenter cross-sectional study.

To determine the prevalence of cervical human papillomavirus (HPV) infection and risk factors in young women from Brazil, Canada, and the USA. Cross-sectional study in 3204 healthy women, aged 15 to 25 years. Cervical samples were collected for cytology and for HPV DNA detection (SPF 10-LiPA 25 system). Serum samples were collected for the measurement of HPV-16 and HPV-18 antibodies by enzyme-linked immunosorbent assay. Risk factors were obtained through a questionnaire. Overall, 26.6% of women had DNA detected for at least 1 HPV type. The prevalence for oncogenic HPV types was 21.7% (25% in Brazil, 16.9% in Canada, and 19.1% in the USA). HPV-16 was the most prevalent oncogenic type (5.2%). The next most common oncogenic HPV types were 51 (3.3%), 52 (3.3%), 31 (2.9%), 66 (2.3%), and 39 (2.0%). Multiple oncogenic types were detected in one-third of the infections. The prevalence of HPV-16 and/or HPV-18 infections detected by DNA and/or enzyme-linked immunosorbent assay was 24.8%. The majority of women (85%) had a normal cervical cytology. Sexual behavior was the main determinant for HPV-16/18 infections and squamous intraepithelial lesions. The prevalence of HPV oncogenic infections was high and linked to sexual behavior. Strategies to reduce the burden of oncogenic HPV infection, such as prophylactic vaccination programs, are likely to impact the burden of disease due to cervical precancer and cancer.

Immunogenicity and safety of the HPV-16/18 AS04-adjuvanted vaccine administered as a 2-dose schedule compared with the licensed 3-dose schedule: results from a randomized study.

The immunogenicity of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine (Cervarix®, GlaxoSmithKline Biologicals) administered according to its licensed vaccination schedule (3-dose, 3D) and formulation (20 µg of each HPV antigen; 20/20F) has previously been demonstrated. This partially-blind, controlled, randomized trial (NCT00541970) evaluated 2-dose (2D) schedules using the licensed 20/20F or an alternative formulation containing 40 µg of each antigen (40/40F), compared with the licensed 3D schedule. Healthy females stratified by age (9-14, 15-19, 20-25 y) were randomized to receive 2 doses of 20/20F at Months (M) 0,6 (n=240), 40/40F at M0,6 (n=241) or 40/40F at M0,2 (n=240), or 3 doses of 20/20F at M0,1,6 (licensed schedule/formulation, n=239). One month after the last dose, the 3D schedule was not immunologically superior to 2D schedules except in the 40/40F M0,2 group for HPV-16 (lower limit of 95% CI geometric mean antibody titer (GMT) ratio [2D/3D] < 0.5). For both HPV-16 and HPV-18, the 2D schedules in girls 9-14 y were immunologically non-inferior to the 3D schedule in women 15-25 y (the age group in which efficacy has been demonstrated) (upper limit of 95% CI for GMT ratio [3D/2D] < 2) one month after the last dose. At Month 24, non-inferiority was maintained for the 2D M0,6 schedules in girls 9-14 y versus the 3D schedule in women 15-25 y. All formulations had acceptable reactogenicity and safety profiles. These results indicate that the HPV-16/18 vaccine on a 2D M0,6 schedule is immunogenic and generally well tolerated in girls 9-14 y and that the 2D schedule is likely adequate for younger females.

Comparison of the immunogenicity of the human papillomavirus (HPV)-16/18 vaccine and the HPV-6/11/16/18 vaccine for oncogenic non-vaccine types HPV-31 and HPV-45 in healthy women aged 18-45 years.

Protection against oncogenic non-vaccine types (cross-protection) offered by human papillomavirus (HPV) vaccines may provide a significant medical benefit. Available clinical efficacy data suggest the two licensed vaccines (HPV-16/18 vaccine, GlaxoSmithKline Biologicals (GSK), and HPV-6/11/16/18 vaccine, Merck & Co., Inc.) differ in terms of protection against oncogenic non-vaccine HPV types -31/45. The immune responses induced by the two vaccines against these two non-vaccine HPV types (cross-reactivity) was compared in an observer-blind study up to Month 24 (18 mo post-vaccination), in women HPV DNA-negative and seronegative prior to vaccination for the HPV type analyzed (HPV-010 [NCT00423046]). Geometric mean antibody titers (GMTs) measured by pseudovirion-based neutralization assay (PBNA) and enzyme-linked immunosorbent assay (ELISA) were similar between vaccines for HPV-31/45. Seropositivity rates for HPV-31 were also similar between vaccines; however, there was a trend for higher seropositivity with the HPV-16/18 vaccine (13.0-16.7%) versus the HPV-6/11/16/18 vaccine (0.0-5.0%) for HPV-45 with PBNA, but not ELISA. HPV-31/45 cross-reactive memory B-cell responses were comparable between vaccines. Circulating antigen-specific CD4+ T-cell frequencies were higher for the HPV-16/18 vaccine than the HPV-6/11/16/18 vaccine (HPV-31 [geometric mean ratio [GMR] =2.0; p=0.0002] and HPV-45 [GMR=2.6; p=0.0092]), as were the proportion of T-cell responders (HPV-31, p=0.0009; HPV-45, p=0.0793). In conclusion, immune response to oncogenic non-vaccine HPV types -31/45 was generally similar for both vaccines with the exception of T-cell response which was higher with the HPV-16/18 vaccine. Considering the differences in cross-protective efficacy between the two vaccines, the results might provide insights into the underlying mechanism(s) of protection.

Safety of the adjuvanted recombinant zoster vaccine in adults aged 50 years or older. A phase IIIB, non-randomized, multinational, open-label study in previous ZOE-50 and ZOE-70 placebo recipients.

BACKGROUND: Efficacy of the adjuvanted recombinant zoster vaccine (RZV) against herpes zoster (HZ) was demonstrated in pivotal trials ZOE-50 (NCT01165177) and ZOE-70 (NCT01165229). This study was designed to offer RZV to placebo recipients of these parent studies. METHODS: Vaccine safety and suspected HZ episode occurrence were assessed for 12 months following vaccination. RESULTS: Of the 14,550 eligible participants, 8687 received RZV and 97.8% completed the 2-dose schedule. During the 30-day post-vaccination period, 5175 (59.6%) participants experienced ≥ 1 unsolicited adverse event (AE), 4422 (50.9%) were vaccination-related. The most common AEs were injection-site reactions, pyrexia, and headache. During the study, 734 (8.4%) participants reported ≥ 1 serious AE (SAE) and 62 (0.7%) reported ≥ 1 potential immune-mediated disease (pIMD); 2 of each were assessed as vaccination-related. Suspected HZ episodes were reported by 30 participants (0.3%). CONCLUSIONS: Nature and incidence of AEs, SAEs, and pIMDs were as expected and in line with the parent studies.

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.

Non-neutralizing antibody responses following A(H1N1)pdm09 influenza vaccination with or without AS03 adjuvant system.

BACKGROUND: Non-neutralizing antibodies inducing complement-dependent lysis (CDL) and antibody-dependent cell-mediated cytotoxicity (ADCC) activity may contribute to protection against influenza infection. We investigated CDL and ADCC responses in healthy adults randomized to receive either non-adjuvanted or AS03-adjuvanted monovalent A(H1N1)pdm09 vaccine (containing 15 µg/3.75 µg of hemagglutinin, respectively) on a 2-dose schedule 21 days apart. METHODS: We conducted an exploratory analysis of a subset of 106 subjects having no prior history of A(H1N1)pdm09 infection or seasonal influenza vaccination enrolled in a previously reported study (NCT00985673). Antibody responses against the homologous A/California/7/2009 (H1N1) vaccine strain and a related A/Brisbane/59/2007 (H1N1) seasonal influenza strain were analyzed up to Day 42. RESULTS: Baseline seropositivity determined with hemagglutination inhibition (HI), CDL and ADCC antibody titers against viral strains was high; A/California/7/2009 (HI [40.4-48.1%]; CDL [34.6-36.0%]; ADCC [92.1-92.3%]); A/Brisbane/59/2007 (HI [73.1-88.9%]; CDL [38.0-42.0%]; ADCC [86.8-97.0%]). CDL seropositivity increased following vaccination with both adjuvanted and non-adjuvanted formulations (A/California/7/2009 [95.9-100%]; A/Brisbane/59/2007 [75.5-79.6%]). At Day 21, increases in CDL and ADCC antibody geometric mean titers against both strains were observed for both formulations. After 2 doses of AS03-adjuvanted vaccine, vaccine responses of 95.8% (≥9-fold increase from baseline in CDL titers) and 34.3% (≥16-fold increase from baseline in ADCC titers) were seen against A/California/7/2009; and 22.4% and 42.9%, respectively, against A/Brisbane/59/2007. Vaccine responses after 2 doses of the non-adjuvanted vaccine were broadly similar. CONCLUSIONS: Broadly comparable non-neutralizing immune responses were observed following vaccination with non-adjuvanted and AS03-adjuvanted A(H1N1)pdm09 formulations; including activity against a related vaccine strain.

Safety Profile of the Adjuvanted Recombinant Zoster Vaccine in Immunocompromised Populations: An Overview of Six Trials.

INTRODUCTION: The adjuvanted recombinant zoster vaccine (RZV) has demonstrated high efficacy against herpes zoster in older adults and immunocompromised populations. We present comprehensive safety data from six clinical trials in immunocompromised populations (autologous hematopoietic stem cell transplant and renal transplant recipients, patients with hematologic malignancies, patients with solid tumors, and human immunodeficiency virus-infected adults) who are at an increased risk of herpes zoster. METHODS: In all trials, immunocompromised adults ≥ 18 years of age were administered RZV or placebo. Safety was evaluated in the total vaccinated cohort. Solicited adverse events (AEs) were collected for 7 days and unsolicited AEs for 30 days after each dose. Serious AEs, fatal serious AEs, and potential immune-mediated diseases were collected from dose 1 until 12 months post-last dose or study end. Data were pooled for solicited AEs; unsolicited AEs, (fatal) serious AEs, and potential immune-mediated diseases were analyzed for each individual trial. All AEs were analyzed for sub-strata of adults 18-49 years of age and ≥ 50 years of age. RESULTS: In total, 1587 (RZV) and 1529 (placebo) adults were included in the pooled total vaccinated cohort. Solicited AEs were more common after RZV than placebo, were generally more common in the younger age stratum, and were mostly mild to moderate and resolved within 3 days (median duration). Unsolicited AEs and serious AEs were in line with underlying diseases and therapies. Across studies, the percentage of adults reporting one or more unsolicited AE was comparable between RZV and placebo, irrespective of age stratum. The percentage of adults reporting one or more serious AE, fatal serious AE, or potential immune-mediated diseases was generally similar for RZV and placebo, irrespective of age stratum. Overall, no safety concerns were identified. CONCLUSIONS: Recombinant zoster vaccine has a clinically acceptable safety profile. With the previously published vaccine efficacy and immunogenicity results, these data support a favorable benefit-risk profile of RZV vaccination in immunocompromised populations who are at an increased risk of herpes zoster.

Varicella zoster virus leads to chickenpox after primary infection and herpes zoster upon reactivation of the latent virus. Older adults and immunocompromised people, whose immune system is impaired because of the age-related decline in immunity and their underlying disease and/or treatment, respectively, are at an increased risk of herpes zoster and its complications. Recombinant zoster vaccine has been approved to prevent herpes zoster and its complications in adults aged ≥ 50 years in over 30 countries. In Europe, the vaccine has recently received approval to expand its use in adults aged 18 years or older who are at an increased risk of herpes zoster. We present an overview of the safety data from six clinical trials in immunocompromised patients vaccinated with recombinant zoster vaccine. We found that solicited adverse events were more common after the vaccine than placebo but that these were mild to moderate in intensity. Furthermore, the frequency of unsolicited adverse events was similar between the vaccine and placebo, and most of the reported adverse events and severe adverse events (e.g., infections or tumors) could be attributed to the pre-existent diseases and/or therapies. As such, no safety concern was identified following the review of the available clinical data. This overview, together with the published efficacy data in the prevention of herpes zoster and the vaccine immunogenicity, provides useful medical information and supports the use of the recombinant zoster vaccine in an immunocompromised population at an increased risk of herpes zoster.