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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.

Supplemental Digital Content is available in the text., Background: This phase 2 observer-blind, randomized, multicenter, dose-ranging study evaluated immunogenicity and safety of different formulations of an AS03-adjuvanted H5N1 influenza vaccine in children 6–35 months of age. Methods: One hundred eighty-five children randomized into 5 groups [1.9 µg hemagglutinin (HA)/AS03B, 0.9 µg HA/AS03C, 1.9 µg HA/AS03C, 3.75 µg HA/AS03C or 3.75 µg HA/AS03D] were to receive 2 doses administered 21 days apart (primary vaccination). AS03 was classified by amount of DL-α-tocopherol, with AS03B the highest amount. One year later, all subjects were to receive unadjuvanted 3.75 µg HA as antigen challenge. Immunogenicity was assessed 21 days after primary vaccination (day 42) and 7 days after antigen challenge (day 392). Immunogenicity-fever index, based on hemagglutination inhibition and microneutralization antibody titers at day 42 and fever 7 days after each vaccination, was used to guide the selection of an acceptable formulation. Results: After primary vaccination, formulations elicited strong homologous immune responses with all subjects’ hemagglutination inhibition titers ≥1:40 post-vaccination. Immunogenicity-fever index based on hemagglutination inhibition and microneutralization assays showed that 1.9 µg HA/AS03B ranked the highest. Antibody levels persisted >4 times above baseline 12 months after primary vaccination with all formulations (day 385). Antibodies increased >4-fold after antigen challenge (day 392/day 385) with 1.9 µg HA/AS03B, 0.9 µg HA/AS03C and 1.9 µg HA/AS03C formulations. Overall per subject, the incidence of fever ranged from 28.6% (3.75 µg HA/AS03D) to 60.5% (1.9 µg HA/AS03B). Conclusions: All formulations were highly immunogenic and demonstrated acceptable safety profiles, with the 1.9 µg HA/AS03B providing the most favorable balance of immunogenicity versus reactogenicity for use in children 6–35 months of age.

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.

In two large clinical trials (ZOE-50 [NCT01165177] and ZOE-70 [NCT01165229]), two doses of the adjuvanted recombinant zoster vaccine (RZV) demonstrated >90% efficacy (VE) against herpes zoster (HZ) in adults ≥50 years of age (YOA). This post-hoc analysis assessed the VE against HZ and postherpetic neuralgia (PHN), in participants from Asian study sites enrolled in ZOE-50/70. Reactogenicity and safety were also assessed. Participants ≥50 YOA were randomized 1:1 to receive 2 doses of either RZV or placebo, 2 months apart. VE was evaluated for a median follow-up of 4 years post-vaccination overall and by age in the ZOE-50 Asian population ≥50 YOA and in the pooled ZOE-50/70 Asian population ≥70 YOA. Of the 2,729 participants included in the ZOE-50 Asian population ≥50 YOA, 3 RZV and 66 placebo recipients reported a confirmed HZ episode. Overall VE was 95.6% (95% confidence interval [CI]: 86.4–99.1) against HZ and 100% (95% CI: 35.44–100) against PHN. In the pooled ZOE-50/70 Asian population ≥70 YOA, 4 RZV and 75 placebo recipients out of the 2,723 participants reported a confirmed HZ episode. Overall VE was 94.7% (95% CI: 85.9–98.6) against HZ and 89.8% (95% CI: 28.39–99.77) against PHN. Pain and myalgia were the most frequent solicited local and general adverse events, respectively, in both populations. No safety concern was identified during the study periods. RZV is highly efficacious against HZ and PHN and has an acceptable safety profile in Asian populations ≥50 YOA, similar to what was observed in the general ZOE-50/70 populations. Trademark statement: Shingrix is a trademark owned by or licensed to the GSK group of companies.

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.

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)., Graphical Abstract

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.

In children 39°C, acute otitis media, lower respiratory tract infection (LRTI), or extra-pulmonary complications; otherwise, they were classified as mild. We used multivariable log-binomial models to assess whether M-S influenza disease was associated with increased healthcare utilization. Nearly half of the 1,105 influenza positive children were classified as M-S. Children 6–35 months had the highest proportion of M-S disease (35.1%), mostly due to LRTI (63.2%) and fever (44.6%). Children ≥6 months who had M-S disease were associated with a 1.6 to 2.8 times increased likelihood of having had an emergency department or any follow-up outpatient visits. Those who had M-S disease were associated with an increased likelihood of receiving antibiotics, with the highest likelihood in children 6–35 months (RR 9.0, 95% CI 4.1, 19.8). While more studies are needed, an influenza classification system may distinguish children with more clinically significant disease.

Background A moderate to severe (M/S) influenza clinical endpoint has been proposed in children, defined as fever >39°C, otitis media, lower respiratory tract infection, or serious extrapulmonary manifestations. The objective of the study was to evaluate the M/S measure against clinically relevant outcomes including hospitalization, emergency room visits, antimicrobial use, and child/parental absenteeism. Methods We conducted a prospective observational study of children aged 6 months–8 years at the Children’s Hospital Colorado emergency department (ED) and urgent care site during 2016–2017 and 2017–2018. Children with influenza-like illness (ILI) underwent influenza testing by polymerase chain reaction (PCR); children who tested positive and a subset of matched test-negative controls underwent follow-up at 2 weeks. The primary outcome was the proportion of children who were hospitalized. Secondary outcomes included recurrent ED visits, antimicrobial use, hospital charges, and child/parental absenteeism within 14 days. Results Among 1478 children enrolled with ILI, 411 (28%) tested positive for influenza by PCR. Of children with influenza illness, 313 (76%) met the M/S definition. Children with M/S influenza were younger (3.8 years vs 4.8 years), infected with influenza A (59% vs 44%), and more frequently hospitalized (unadjusted risk difference [RD], 6.3%; 95% confidence interval [CI], 2.1–10.4; P = .03) and treated with antibiotics (unadjusted RD, 13.3%; 95% CI, 4.3–22.4; P < .01) compared to those with mild disease. Conclusions Children with M/S influenza have a higher risk of hospitalization and antibiotic use compared with mild disease. This proposed definition may be a useful clinical endpoint to study the public health and clinical impact of influenza interventions in children. Clinical Trials Registration NCT02979626.

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.

HPV is extremely common worldwide and mainly transmitted through sexual contact; most people are infected with HPV shortly after onset of sexual activity. There are >200 types of HPV, of which at least 12 are cancer-causing (oncogenic or high-risk types). HPV is a causal factor for several anogenital and a subset of oropharyngeal cancers with 2 HPV types (16 and 18) causing 72% of all HPV-associated cancers. Cervical cancer is the fourth most common cancer among women globally with nearly 90% of the deaths occurring in low- and middle-income countries. Comprehensive cervical cancer control includes primary prevention (vaccination against HPV), secondary prevention (screening and treatment of pre-cancerous lesions) as well as treatment of invasive cervical cancer. The currently licensed vaccines are L1 VLP-based and prophylactic; they have been shown to be safe and highly effective in preventing HPV infections and HPV-associated lesions, precancer and cancer. Neutralizing antibodies are the mechanism of protection for prophylactic HPV VLP-based vaccines. Therapeutic HPV vaccines targeting the oncoproteins E6 and E7 are in clinical development.

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., Strain-specific hemagglutination inhibition antibody titer is a statistical correlate of protection against RT-PCR–confirmed influenza associated with the corresponding influenza strain in children 6–35 months of age. The Dunning model predicted probability of protection against illness of 43.2%–60.2% at a titer of 1:40.

PLAIN LANGUAGE SUMMARY What is the context? After haematopoletic stem cell transplantation, patlents 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 immuonocompromised patients. A non-live, adjuvanted recombinant zoster vaccine (RZV, Shingrix, GSK), has been approved for use in adults 250 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 haematopoleticstem cell transplant. What is new? In autologous haematopoietic stem cell transplant recipients in whom Shingrix has demonstrated efficacy, two doseselicited 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 studies, as well as the characteristics of the elicited cell-mediated immune responses. What is the impact? These results indicate that Shingrix, given shortly after haematopoletic 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. 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., GlaxoSmithKline Biologicals SA, This work was sponsored by GlaxoSmithKline Biologicals SA in all stages of the study conduct and analysis. GlaxoSmithKline Biologicals SA also took responsibility for all costs associated with the development and publishing of the present manuscript.

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.

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. Supplementary Information The online version contains supplementary material available at 10.1007/s40264-021-01076-w., Plain Language Summary 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. Supplementary Information The online version contains supplementary material available at 10.1007/s40264-021-01076-w.

Background: In an exploratory analysis of an inactivated quadrivalent influenza vaccine (IIV4) trial in children 6-35 months without risk factors for influenza, we evaluated clinical presentation of influenza illness and vaccine impact on health outcomes. Methods: This phase III trial was conducted in 13 geographically diverse countries across 5 influenza seasons (2011-2014). Children were randomized 1:1 to IIV4 or control. Active surveillance was performed for influenza-like episodes (ILE); influenza was confirmed by reverse transcription polymerase chain reaction (RT-PCR). The total vaccinated cohort was evaluated (N = 12,018). Results: 5702 children experienced >= 1 ILE; 356 (IIV4 group) and 693 (control group) children had RT-PCR-confirmed influenza. Prevalence of ILE was similar in RT-PCR-positive and RT-PCR-negative cases regardless of vaccination. Breakthrough influenza illness was attenuated in children vaccinated with IIV4; moderate-to-severe illness was 41% less likely to be reported in the IIV4 group than the control group [crude odds ratio: 0.59 (95% confidence intervals: 0.44-0.77)]. Furthermore, fever >39 degrees C was 46% less frequent following vaccination with IIV4 than with control [crude odds ratio: 0.54 (95% confidence intervals: 0.39-0.75)] in children with breakthrough illness. Health outcome analysis showed that, each year, IIV4 would prevent 54 influenza cases per 1000 children and 19 children would need to be vaccinated to prevent 1 new influenza case. Conclusions: In addition to preventing influenza in 50% of participants, IIV4 attenuated illness severity and disease burden in children who had a breakthrough influenza episode despite vaccination.

Clinical and post-licensure data have demonstrated that AS03-adjuvanted inactivated split virion vaccines, many with reduced antigen content, are effective against influenza infection. The objective of this review is to provide a comprehensive assessment of the safety of trivalent seasonal, monovalent pre-pandemic and pandemic AS03-adjuvanted influenza vaccines, based on non-clinical, clinical and post-licensure data in various populations. Non-clinical studies on local tolerance, toxicology and safety pharmacology did not raise any safety concerns with AS03 administered alone or combined with various influenza antigens. Data from clinical trials with over 55,000 vaccinated subjects showed that AS03-adjuvanted influenza vaccines were generally well tolerated and displayed an acceptable safety profile, although the power to detect rare events was limited. Approximately 90 million doses of A/H1N1pdm09 pandemic influenza vaccines (Pandemrix and Arepanrix H1N1) were administered worldwide, which contributed post-licensure data to the collective safety data for AS03-adjuvanted influenza vaccines. An association between Pandemrix and narcolepsy was observed during the A/H1N1pdm09 pandemic, for which a role of a CD4 T cell mimicry sequence in the haemagglutinin protein of A/H1N1pdm09 cannot be excluded. Provided that future AS03-adjuvanted influenza vaccines do not contain this putative mimicry sequence, this extensive safety experience supports the further development and use of AS03-adjuvanted inactivated split virion candidate vaccines against seasonal and pandemic influenza infections.

In compliance with the European Medicine Agency guidance to detect any potential safety concerns associated with influenza vaccination, an enhanced safety surveillance study was conducted in England during the 2017/18 influenza season. The primary objective was to estimate the incidence rates of adverse events occurring within seven days of vaccination with Fluarix Tetra. In nine General Practices, seasonal influenza vaccine was administered to patients according to local guidelines. Events following immunization were collected using customized cards (enhanced component) combined with electronic health records [EHRs] (EHR component) to estimate incidence rates of adverse events experienced post vaccination. The study ran from 01-Sep-2017 to 30-Nov-2017. A total of 23,939 subjects were vaccinated of whom 16,433 received Fluarix Tetra. The cumulative incidence rates of adverse events of interest for Fluarix Tetra were 7.25% [95% CI, 5.95–8.73] for events reported by card alone, and 9.21% [95% CI, 7.37–11.34] when combined with EHR data. The type and frequency of events reported were consistent with the Fluarix Tetra Summary of Product Characteristics. The study supports and confirms the safety profile of Fluarix Tetra. ClinicalTrials.gov number: NCT03278067

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.

In two large clinical trials (ZOE-50 [NCT01165177] and ZOE-70 [NCT01165229]), two doses of the adjuvanted recombinant zoster vaccine (RZV) demonstrated >90% efficacy against herpes zoster in adults ≥50 years of age. Solicited adverse events (AEs) were collected for 7 days post-each dose in a study sub-cohort. The incidence of reported solicited AEs was higher for RZV compared to placebo recipients. Since reactogenicity may contribute to a person’s willingness to be vaccinated, knowing about expected reactogenicity might help keep high compliance with the second dose. This post hoc analysis assessed the intensity of solicited AEs post-dose 2 reported to the same event’s intensity post-dose 1. Intensity was graded from 0 to 3, grade 3 indicating the highest severity. Of the vaccinees who did not experience a specific AE post-dose 1, 72.6–91.7% did not experience the same event after dose 2. Although the frequency of grade 3 AEs post-dose 2 was the highest in participants reporting the same AEs at grade 3 post-dose 1, 65.8–89.3% of vaccinees with grade 3 specific AEs post-dose 1 reported the same AEs at lower intensity post-dose 2. These data can help inform health-care professionals about the frequency and intensity of AEs post-dose 2 with respect to post-dose 1.

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., Long-term immunogenicity data and mathematical models suggest that immune responses to a 2-dose recombinant zoster vaccine course persist for many years in older adults. Strong anamnestic immune responses can be induced by additional dosing 10 years after the initial course.

Supplemental Digital Content is available in the text., Background: We evaluated an inactivated quadrivalent influenza vaccine (IIV4) in children 6–35 months of age in a phase III, observer-blind trial. Methods: The aim of this analysis was to estimate vaccine efficacy (VE) in preventing laboratory-confirmed influenza in each of 5 independent seasonal cohorts (2011−2014), as well as vaccine impact on healthcare utilization in 3 study regions (Europe/Mediterranean, Asia-Pacific and Central America). Healthy children were randomized 1:1 to IIV4 or control vaccines. VE was estimated against influenza confirmed by reverse transcription polymerase chain reaction on nasal swabs. Cultured isolates were characterized as antigenically matched/mismatched to vaccine strains. Results: The total vaccinated cohort included 12,018 children (N = 1777, 2526, 1564, 1501 and 4650 in cohorts 1−5, respectively). For reverse transcription polymerase chain reaction confirmed influenza of any severity (all strains combined), VE in cohorts 1−5 was 57.8%, 52.9%, 73.4%, 30.3% and 41.4%, respectively, with the lower limit of the 95% confidence interval >0 for all estimates. The proportion of vaccine match for all strains combined in each cohort was 0.9%, 79.3%, 72.5%, 24.1% and 28.6%, respectively. Antibiotic use associated with influenza illness was reduced with IIV4 by 71% in Europe, 36% in Asia Pacific and 59% in Central America. Conclusions: IIV4 prevented influenza in children 6−35 months of age in each of 5 separate influenza seasons in diverse geographical regions. A possible interaction between VE, degree of vaccine match and socioeconomic status was observed. The IIV4 attenuated the severity of breakthrough influenza illness and reduced healthcare utilization, particularly antibiotic use.

INTRODUCTION: The European Medicines Agency (EMA) requires vaccine manufacturers to conduct enhanced safety surveillance (ESS) of seasonal influenza vaccines including a near real-time evaluation of collected data. The objective was to identify whether the use of passive surveillance or active surveillance provides different results of reported adverse events of interest (AEIs) by specified age strata and AEI type. We report the weekly incidence rates of AEIs within 7 days following seasonal influenza vaccination using passive and active surveillance. METHODS: AEIs were collected within 7 days of vaccination from ten general practices predominantly administering inactivated quadrivalent influenza vaccine (IIV4, Fluarix Tetra, GSK). Vaccinees completed an adverse drug reaction (ADR) card. ADR card and medically attended AEIs data were recorded in practice electronic health records. We report the outcome of the first 5 weeks of safety surveillance (September 12, 2016-October 16, 2016); in an exploratory analysis, rates of AEI for IIV4 are compared to those passively reported through a sentinel network. RESULTS: Practices vaccinated 13.1% (12,864/98,091) of their registered population; 5.6% (95% CI 5.20-6.00) of them reported AEIs, none serious. The most frequent were respiratory 2.60% (95% CI 2.33-2.88), musculoskeletal 1.82% (95% CI 1.59-2.05) and neurological 1.05% (95% CI 0.88-1.23). AEIs were more frequently reported for adults than for children; 5.91% (95% CI 5.49-6.34) compared to 1.49% (95% CI 0.69-2.29); 47.18% of the adults reported AEI using the ADR card, none were returned for subjects CONCLUSION: The ESS did not reveal any safety signal and we demonstrated the feasibility of conducting ESS following EMA recommendations. The use of a customised ADR card led to a doubling of AEIs reports over passive surveillance in adults. FUNDING: GlaxoSmithKline Biologicals SA, Wavre, Belgium.

Background Herpes zoster can negatively impact older adults’ health and quality of life. An adjuvanted recombinant zoster vaccine (RZV) has excellent vaccine efficacy (VE), including in older adults. Given that frailty is strongly associated with vulnerability to illness and adverse health outcomes, we studied how frailty impacts RZV VE, immunogenicity, reactogenicity, and safety. Methods In the ZOE-50 and ZOE-70 pivotal Phase 3 efficacy studies of RZV, 29,305 participants aged 50–96 received 2 doses of RZV vs. placebo in 1:1 randomization. In this secondary analysis (NCT03563183), a baseline frailty index (FI) was created retrospectively following previously validated methods using pre-existing comorbidities and patient reported outcomes. Participants were categorized as non-frail (FI≤ 0.08), pre-frail (FI=0.08–0.25) or frail (FI≥ 0.25) for stratified analyses. Results FI was calculated for 99.8% of participants included in this secondary analysis (n=26,976), and was balanced between RZV and placebo groups. 45.6% were pre-frail and 11.3% were frail. Mean age was 68.8 years; 58.1% were women. RZV VE against HZ was consistently above 90% for all frailty categories [non-frail: 95.8% (95%CI: 91.6–98.2), pre-frail: 90.4% (84.4–94.4), frail: 90.2% (75.4–97.0)]. The RZV group demonstrated robust antibody responses post-dose 2 across frailty categories. In the RZV group, the percentage of participants reporting solicited adverse events decreased with increasing frailty. Unsolicited medically attended visits and serious adverse events increased with frailty and were balanced between placebo and RZV groups. Conclusion The ZOE studies included older adults who were frail and pre-frail, and VE was high across frailty categories. Reactogenicity decreased with increasing frailty, and no safety concerns were identified in any frailty group. Disclosures Melissa K. Andrew, MD, PhD, MSc(Ph), GSK (Grant/Research Support, Research Grant or Support) Joon Hyung Kim, MD, GSK (Employee, Shareholder) Sean Matthews, MSc, GSK (Consultant) Christophe Dessart, MSc, GSK (Employee) myron J. levin, MD, Curevo (Advisor or Review Panel member)GlaxoSmithKline (Grant/Research Support, Advisor or Review Panel member)GlaxoSmithKline (Grant/Research Support, Advisor or Review Panel member)Merck Research Laboratories (Advisor or Review Panel member, GlaxoSmithKline)Merck Research Laboratories (Advisor or Review Panel member)Merck ResearchLaboratories (Advisor or Review Panel member) Lidia Oostvogels, MD, GSK (Shareholder) Megan Riley, PhD, GSK (Employee) Shelly McNeil, FRCPC, MD, GSK (Grant/Research Support, Scientific Research Study Investigator, Research Grant or Support, Other Financial or Material Support, honoraria for talks) Anne Schuind, MD, GSK (Employee, Other Financial or Material Support, own GSK stock options or restricted shares as part of renumeration) Desmond Curran, PhD, GSK (Employee, Shareholder)

Background Older and immunocompromised adults are at increased risk for herpes zoster (HZ) and often experience persistent, severe HZ-related pain, impacting their quality of life and activities of daily living. High vaccine efficacy (VE) of the adjuvanted recombinant zoster vaccine (RZV) in preventing HZ and reducing severe and clinically significant HZ-related pain has been shown in adults ≥ 50 years of age (YOA; ZOE-50 study; NCT01165177), ≥ 70 YOA (ZOE-70; NCT01165229) and ≥ 18 YOA undergoing autologous hematopoietic stem cell transplantation (ZOE-HSCT; NCT01610414). Methods In patients with confirmed HZ from the above phase III, randomized, placebo-controlled studies, we analyzed VE of RZV in reducing the duration of clinically significant HZ-related pain and in reducing the use and duration of HZ-related pain medication. Pain was assessed by the Zoster Brief Pain Inventory (ZBPI). Use of all HZ-related medication was recorded. Results VE in reducing the duration of clinically significant HZ-related pain (ZBPI pain score ≥3) during HZ episodes was 38.5% (p-value: 0.0099) in RZV-vaccinated patients from the ZOE-HSCT study compared to placebo. A similar trend (not statistically significant) was observed in the ZOE-50 (VE: 26.9%; p-value: 0.4318) and ZOE-70 (VE: 28.4%; p-value: 0.1877) studies. VE in reducing the use (Table 1) and duration (Table 2) of HZ-related pain medication was 39.6% (p-value: 0.0083) and 49.3%(p-value: 0.0404), respectively, in the ZOE-70 study; corresponding positive VE estimates were also seen in the ZOE-50 and ZOE-HSCT studies. Non-opioids were used by 61.2%, 44.3% and 22.1% of patients in the ZOE-50, ZOE-70 and ZOE-HSCT studies, respectively; weak opioids by 18.6%, 13.0% and 10.8% of patients, and strong opioids by 8.0%, 2.0% and 5.3% of patients (Table 3). Table 1. Reduction in the use of HZ-related pain medication in patients with confirmed HZ Table 2. Reduction in the duration of HZ-related pain medication use in patients with confirmed HZ Table 3. HZ-related medication types in patients with confirmed HZ Conclusion In addition to a high VE in preventing HZ in these studies, we also observed an attenuation of HZ-related pain, and thus lower use and duration of pain medication in breakthrough cases after RZV vaccination, thereby potentially improving patient quality of life. Funding: GlaxoSmithKline Biologicals SA Acknowledgment: Kristel Vercauteren/Sander Hulsmans (Modis c/o GSK) provided medical writing/editorial support Disclosures Joon Hyung Kim, MD, GSK (Employee, Shareholder) Robert Johnson, MD, FRCA, GSK (Other Financial or Material Support, I accept no fees but have had expense reimbursement in the past.) Martina Kovac, MD, GSK (Other Financial or Material Support, I was an employee of GSK at the time of the study) Anthony L. Cunningham, MBBS, MD, FRACP, FRCPA, GSK (Consultant) Srikanth Emmadi, MSc, GSK (Employee) Keith Sullivan, MD, FASTCT, GSK (Consultant) Alemnew F. Dagnew, MD, GSK group of companies (Employee, Shareholder) Desmond Curran, PhD, GSK (Employee, Shareholder) Anne Schuind, MD, GSK (Employee, Other Financial or Material Support, own GSK stock options or restricted shares as part of renumeration)

Background Avian influenza A H9N2 strains have pandemic potential. Methods In this randomized, observer-blind study (ClinicalTrials.gov: NCT01659086), 420 healthy adults, 18–64 years of age, received 1 of 10 H9N2 inactivated split-virus vaccination regimens (30 participants per group), or saline placebo (120 participants). H9N2 groups received 2 doses (days 0, 21) of 15 µg hemagglutinin (HA) without adjuvant, or 1.9 µg HA + AS03A, 1.9 µg HA + AS03B, 3.75 µg HA + AS03A, or 3.75 µg HA + AS03B; followed by the same H9N2 formulation or placebo (day 182). AS03 is an adjuvant system containing α-tocopherol (AS03A: 11.86 mg; AS03B: 5.93 mg) and squalene in an oil-in-water emulsion. Immunogenicity (hemagglutination inhibition [HI] and microneutralization assays) and safety were assessed up to day 546. Results All adjuvanted formulations exceeded regulatory immunogenicity criteria at days 21 and 42 (HI assay), with seroprotection and seroconversion rates of ≥94.9% and ≥89.8% at day 21, and 100% and ≥98.1% at day 42. Immunogenicity criteria were also met for unadjuvanted vaccine, with lower geometric mean titers. In groups administered a third vaccine dose (day 182), an anamnestic immune response was elicited with robust increases in HI and microneutralization titers. Injection site pain was reported more frequently with adjuvanted vaccines. No vaccine-related serious adverse events were observed. Conclusions All H9N2 vaccine formulations were immunogenic with a clinically acceptable safety profile; adjuvanted formulations were 4–8 times dose-sparing (3.75–1.9 vs 15 µg HA). Trial registration Registered on ClinicalTrials.gov: NCT01659086.

Background Human cases of highly pathogenic avian-origin influenza A/H5N1 infection continue to be reported to the World Health Organization, and recent outbreaks of human cases of other zoonotic influenza strains highlight the continued need for strategies to mitigate influenza pandemic potential. Methods A Phase II–III randomized, placebo-controlled, observer-blind trial was conducted to assess the immunogenicity, reactogenicity, and safety of two 1.9 μg hemagglutinin doses of AS03B-adjuvanted H5N1 (AS03B-H5N1; A/Indonesia) vaccine in children (6 months to B-H5N1 vaccine. Here we report the safety analysis in Year 2. Results A total of 155 children were vaccinated in Year 2. The most frequent solicited adverse event (AE) during 7 days post vaccination was injection site pain. Irritability or fussiness was reported in about one-third of younger children (aged B-H5N1 vaccine had a clinically acceptable safety profile up to 385 days post vaccination. Conclusions Safety in the crossover phase was acceptable and consistent with that observed in vaccine recipients in the randomized, blinded phase of the study. Clinical trial registration ClinicalTrials.gov: NCT01310413.

Background H7 influenza strains have pandemic potential. AS03-adjuvanted H7N1 A/mallard/Netherlands/12/2000 split-virion vaccine formulations were evaluated as model H7-subtype vaccine and tested after H7N9 emerged in China, and caused severe human disease with high mortality. Methods In this phase I/II, observer-blind, randomized trial in US and Canada, 420 healthy adults (21–64 years) were randomized to receive 1 of 4 H7N1 vaccine formulations (3.75 or 7.5 μg hemagglutinin adjuvanted with either AS03 A or AS03 B ), 15 μg unadjuvanted H7N1 hemagglutinin, or saline placebo, given as 2-dose series. Immunogenicity was assessed using hemagglutination-inhibition (HI) and microneutralization (MN) assays, at day 42 (21 days post-dose 2), month 6, and month 12 (HI only) for the per-protocol cohorts (398, 379 and 368 participants, respectively). Safety is reported up to month 12. Results Beneficial AS03 adjuvant effect was demonstrated. Committee for Medical Products for Human Use, and Center for Biologics Evaluation and Research (CBER) criteria were met for all adjuvanted formulations at day 42 (H7N1 HI assay); seroprotection (SPR) and seroconversion rates (SCR) were 88.5–94.8%, mean geometric increase (MGI) 19.2–34.9, and geometric mean titers (GMT) 98.3–180.7. Unadjuvanted H7N1 vaccine did not meet CBER criteria. In adjuvanted groups, antibody titers decreased over time; month 12 SPRs and GMTs were low (2.0–18.8% and 8.1–12.2). MN antibodies showed similar kinetics, with titers persisting at higher range than HI at month 6. All adjuvanted groups showed cross-reactivity against H7N9, with HI responses similar to H7N1. The most frequent solicited symptom in adjuvanted groups was injection site pain (71.2–86.7%); grade 3 solicited symptoms were infrequent. Nine participants reported 17 serious adverse events; none were considered causally related to vaccination. Conclusions Adjuvanted H7N1 vaccine formulations had an acceptable safety profile and induced an antibody response after 2 doses with cross-reactivity to H7N9. ClinicalTrials.gov: NCT01934127

Background In the pivotal clinical trials, ZOE-50 (NCT01165177) and ZOE-70 (NCT01165229), the adjuvanted recombinant zoster vaccine (RZV) showed high efficacy against herpes zoster and postherpetic neuralgia. The incidence of reported solicited events was higher in RZV compared with placebo recipients. Methods In these phase III, observer-blind, placebo-controlled trials conducted in 18 countries, adults ≥50 years of age (YOA, ZOE-50) and ≥70 YOA (ZOE-70), randomized 1:1, received 2 doses of RZV or placebo 2 months apart. Injection-site and general events were solicited for 7 days after each dose via diary cards in a participant subset. For this post-hoc analysis, ZOE-50 and ZOE-70 data from participants having completed the diary cards for both RZV doses were pooled. The intensity of each solicited event after dose 2 was stratified by the intensity of the same event after dose 1. Results Solicited injection-site and general events were recorded for both RZV doses by 4,676 and 4,668 vaccinees, respectively (Figure 1). Of 1,235 vaccinees with no injection-site event at dose 1, 881 (71.3%) reported no injection-site event and 20 (1.6%) reported a grade 3 event after dose 2. A total of 433 (9.3%) vaccinees reported a grade 3 injection-site event, either after dose 1 or dose 2. Of 244 vaccinees with grade 3 injection-site events at dose 1, 79 (32.4%) also reported a grade 3 event after dose 2. Of 2,312 vaccinees with no general event at dose 1, 1,617 (69.9%) reported no general event and 67 (2.9%) reported a grade 3 event after dose 2. A total of 499 (10.7%) vaccinees reported a grade 3 general event, either after dose 1 or dose 2. Of 222 vaccinees with grade 3 general events at dose 1, 81 (36.5%) also reported a grade 3 general event after dose 2. In general, vaccinees who did not experience a certain event after dose 1, did not experience this event after dose 2 either. Most vaccinees reporting a specific event at high intensity after dose 1, reported the same event at a lower intensity (or not at all) after dose 2 (Figures 2 and 3). Conclusion While not powered to predict event intensity of the second RZV dose, our data provides an overview of event intensity after RZV dose 2 according to the intensity of the same event experienced after dose 1. Funding: GlaxoSmithKline Biologicals SA. Disclosures All authors: No reported disclosures.

Background The adjuvanted recombinant zoster vaccine (RZV, GSK), administered to adults ≥ 50 years of age (YOA) demonstrated ≥ 90% efficacy against herpes zoster across all age cohorts. Vaccine-specific immune responses elicited by two RZV doses in adults ≥ 60 YOA have been shown to persist above pre-vaccination levels at least up to 9 years after initial vaccination. Here we present persistence of the humoral and cellular immunity and safety up to 10 years after initial vaccination as well as data from mathematical modeling, performed to predict immune persistence up to 15 years. Methods This phase IIIB, open-label extension trial (NCT02735915) included 70 participants who had received two RZV doses in the initial trial (NCT00434577) and builds on a previous extension trial (NCT01295320). Cellular and humoral immune responses up to year 10 after an initial 2-dose vaccination schedule are presented here. Additionally, prediction of immunological persistence at year 15 was assessed by mathematical modeling (Piecewise, Power-law, Fraser), using the individual subject values for available data up to year 10. Results The median frequency of varicella-zoster virus glycoprotein E (gE)-specific CD4+ T-cells expressing ≥ 2 activation markers plateaued at 3.3-fold above pre-vaccination levels starting around year 4 up to year 10 post-initial vaccination. Anti-gE antibody concentrations plateaued starting around year 3 up to year 10 post-initial vaccination.Ten years after initial vaccination, humoral responses remained 5.9-fold higher as compared with pre-initial vaccination levels (Figure 1). No relevant safety events were identified during the study (year 9–10 post-initial vaccination). In line with previous modeling data, the year 10 analysis predicts that both cellular and humoral immune responses will remain above pre-vaccination levels for at least 15 years after initial vaccination (Figures 2 and 3). Conclusion In adults vaccinated when ≥ 60 YOA, humoral and cellular immune responses induced by two RZV doses persist above pre-vaccination levels for at least 10 years post-initial vaccination. Mathematical modeling predicts a maintained vaccine-related immune response for at least 15 years after initial vaccination. Funding. GlaxoSmithKline Biologicals SA. Disclosures All Authors: No reported Disclosures.

Background The adjuvanted recombinant zoster vaccine (RZV) is efficacious in preventing herpes zoster in adults ≥ 50 years. The current study investigates whether the vaccinees’ quality of life (QoL) and physical functioning (PF) are impacted by local and systemic reactions due to RZV. In a previous report of this phase III, open-label, multicenter study (NCT02979639), overall PF and QoL were not significantly affected by a first RZV dose. [1] Here we report the results from the same study after a second RZV dose and safety results from dose 1 up to study end. Methods Adults aged ≥ 50 years were to receive 2 doses of RZV 2 months apart. Changes in mean Short Form health survey (SF-36) PF score between pre- and post-each RZV dose for 7 days, QoL, reactogenicity and safety were assessed. Results 401 adults received dose 1 and 391 received dose 2 of RZV. Post-second RZV dose, the reported solicited local symptoms were pain (75.1%), erythema (22.4%) and swelling (13.9%), and the most frequent solicited systemic symptoms were fatigue (46.3%), headache (37.5%) and myalgia (32.9%). Grade 3 solicited symptoms were reported by 7.2% (local) and 11.1% (general) of participants, and 5 (1.2%) participants reported reactogenicity triggering medical attention post-second RZV dose. From first dose up to study end, 14 (3.5%) participants reported 21 serious adverse events, none related to RZV. In days 1–2, post-second RZV dose, a transient, clinically-important decrease in SF-36 PF score (table) was seen in those reporting grade 3 solicited symptoms, which impacted activities such as walking and climbing stairs. Overall, during the 7 days post-second RZV dose, a mean change of −0.4 points was observed from the mean baseline score, indicating the PF was not clinically meaningfully impacted. No overall quality-adjusted-life-year loss was recorded. Conclusion Overall, the QoL and PF of adults ≥ 50 years were not affected post-second RZV dose; a transient impact was observed in adults with grade 3 reactogenicity. These results and the observed reactogenicity and safety profile are consistent with first RZV dose results, as well as that of previous studies with the RZV vaccine in adults of similar age. Funding: GlaxoSmithKline Biologicals SA. 1. Schmader et al., Abstract 2488, IDWeek 2018 Disclosures All authors: No reported disclosures.

Background Herpes zoster (HZ) risk appears to vary by sex and geographic ancestry/ethnicity. Methods In 2 randomized clinical trials, participants received 2 doses of adjuvanted recombinant zoster vaccine (RZV) or placebo intramuscularly, 2 months apart. In this post-hoc analysis, we investigate efficacy of RZV against HZ and postherpetic neuralgia (PHN) by sex, geographic region, and geographic ancestry/ethnicity in ≥50-year-olds (ZOE-50: NCT01165177) and ≥70-year-olds (pooled data from ZOE-50 and ZOE-70: NCT01165229). Results Vaccine efficacy against HZ or PHN was similar in women and men. Across geographic regions, efficacy against HZ ranged between 95.7 and 97.2% in ≥50-year-olds, and between 87.3% and 95.1% in ≥70-year-olds; efficacy against PHN ranged between 86.8 and 100% in ≥70-year-olds. Across ancestral/ethnic groups, efficacy ranged between 88.1 and 100% against HZ and between 65.9 and 100% against PHN in ≥70-year-olds. Conclusions While the ZOE-50/70 studies were not powered or pre-designed for these post-hoc analyses, RZV appears efficacious against HZ and PHN irrespective of sex, region, or geographic ancestry/ethnicity.

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.

BACKGROUND: The adjuvanted recombinant zoster vaccine (Shingrix) can prevent herpes zoster in older adults and autologous haemopoietic stem cell transplant recipients. We evaluated the safety and immunogenicity of this vaccine in adults with haematological malignancies receiving immunosuppressive cancer treatments. METHODS: In this phase 3, randomised, observer-blind, placebo-controlled study, done at 77 centres worldwide, we randomly assigned (1:1) patients with haematological malignancies aged 18 years and older to receive two doses of the adjuvanted recombinant zoster vaccine or placebo 1-2 months apart during or after immunosuppressive cancer treatments, and stratified participants according to their underlying diseases. The co-primary objectives of the study were the evaluation of safety and reactogenicity of the adjuvanted recombinant zoster vaccine compared with placebo from the first vaccination up to 30 days after last vaccination in all participants; evaluation of the proportion of participants with a vaccine response in terms of anti-glycoprotein E humoral immune response to the adjuvanted recombinant zoster vaccine at month 2 in all participants, excluding those with non-Hodgkin B-cell lymphoma and chronic lymphocytic leukaemia; and evaluation of the anti-glycoprotein E humoral immune responses to the vaccine compared with placebo at month 2 in all participants, excluding those with non-Hodgkin B-cell lymphoma and chronic lymphocytic leukaemia. We assessed immunogenicity in the per-protocol cohort for immunogenicity and safety in the total vaccinated cohort. The study is registered with ClinicalTrials.gov, number NCT01767467, and with the EU Clinical Trials Register, number 2012-003438-18. FINDINGS: Between March 1, 2013, and Sept 10, 2015, we randomly assigned 286 participants to adjuvanted recombinant zoster vaccine and 283 to placebo. 283 in the vaccine group and 279 in the placebo group were vaccinated. At month 2, 119 (80·4%, 95% CI 73·1-86·5) of 148 participants had a humoral vaccine response to adjuvanted recombinant zoster vaccine, compared with one (0·8%, 0·0-4·2) of 130 participants in the placebo group, and the adjusted geometric mean anti-glycoprotein E antibody concentration was 23 132·9 mIU/mL (95% CI 16 642·8-32 153·9) in the vaccine group and 777·6 mIU/mL (702·8-860·3) in the placebo group (adjusted geometric mean ratio 29·75, 21·09-41·96; p

Supplemental Digital Content is available in the text., Background: It has not yet been demonstrated whether 2 doses of inactivated quadrivalent influenza vaccine (IIV4) prime a booster response in infants. We evaluated the anamnestic immune response to an IIV4 in children 17−48 months of age. Methods: Children were randomized to 2 doses of IIV4 or control in the primary phase III study (NCT01439360). One year later, in an open-label revaccination extension study (NCT01702454), a subset of children who received IIV4 in the primary study (primed group) received 1 IIV4 dose and children who received control in the primary study (unprimed) received 2 IIV4 doses 28 days apart. The primary objective was to evaluate hemagglutination inhibition (HI) antibody titers 7 days after first IIV4 vaccination in the per-protocol cohort (N = 224 primed; N = 209 unprimed). Neutralizing and antineuraminidase antibodies were also measured. Safety was analyzed in the total vaccinated cohort (N = 241 primed; N = 229 unprimed). Results: An anamnestic response was observed in primed children relative to unprimed controls, measured by age-adjusted geometric mean HI titer ratios against strains homologous (A/H1N1: 9.0; B/Victoria: 3.9) and heterologous (A/H3N2: 2.7; B/Yamagata: 6.7) to those in the primary vaccination series. The anamnestic response in primed children included increases in neutralizing antibodies (mean geometric increase: 5.0–10.6) and antineuraminidase antibodies (4.9–8.8). No serious adverse events related to vaccination were reported. Conclusions: In this study, 2-dose priming with IIV4 induced immune memory that was recalled with 1-dose IIV4 the following year to boost HI, antineuraminidase and neutralizing antibodies, even though the IIV4 strain composition partially changed.

Background Immunocompromised (IC) populations are at increased risk of developing herpes zoster (HZ) due to disease- and/or therapy-induced immunosuppression. The adjuvanted recombinant zoster vaccine (RZV) has demonstrated 68.2% efficacy in preventing HZ in autologous hematopoietic stem cell transplant (HSCT) recipients and 87.2% efficacy in a post-hoc analysis in hematologic malignancy (HM) patients ≥ 18 years of age (YOA). Here we present the immunogenicity of RZV in representative IC populations. Methods Our analysis includes five phase I/II/III clinical trials conducted worldwide between 2010–2017 (Table 1) in IC populations (autologous HSCT, human immunodeficiency virus [HIV]-infected, HM, solid tumor [ST] on chemotherapy and renal transplant [RT] patients) ≥ 18 YOA. Anti-glycoprotein E (gE) antibody geometric mean concentrations (GMCs) and gE-specific CD4 T cell frequencies were descriptively evaluated by age group (18–49 YOA and ≥ 50 YOA) and overall at 1 month (M) and 12M post-last RZV dose. Table 1. Clinical studies with immunocompromised populations included in our analysis Results The according-to-protocol cohorts for immunogenicity from the included trials are presented in Table 1. At 1M post-last RZV dose, anti-gE GMCs and median CD4 T-cell frequencies increased in all IC populations compared to pre-vaccination and persisted above baseline up to 12M post-last RZV dose (Figures 1 and 2). No meaningful differences were seen between age groups in terms of humoral (except a slight trend for stronger responses in the 18–49 YOA RT and HM patients compared to their corresponding ≥ 50 YOA group) and gE-specific CD4 T-cell responses in any of the IC populations. Figure 1. Humoral immune responses to RZV in immunocompromised populations (adapted ATP cohort for humoral immunogenicity) Figure 2. Cell-mediated immune responses to RZV in immunocompromised populations (adapted ATP cohort for cell-mediated immunogenicity) Conclusion RZV induced robust and persistent humoral and cell-mediated immune (CMI) responses that lasted up to at least 12M post-last vaccination in all evaluated IC populations. Humoral responses in the IC populations were robust although not as strong as in the non-IC adults ≥ 50 YOA. CMI responses were mostly similar across IC populations and adults ≥ 50 YOA, with a potent response occurring even in ST patients undergoing chemotherapy. This data shows that RZV is immunogenic even in severely IC adults. Funding: GlaxoSmithKline Biologicals SA Acknowledgment: M Maior/S Hulsmans (Modis c/o GSK) provided writing/editorial support Disclosures Alemnew F. Dagnew, MD, MSc, GSK group of companies (Employee, Shareholder) Peter Vink, MD, GSK group of companies (Employee, Shareholder) Mamadou Drame, MSc, GSK group of companies (Employee) David Willer, PhD, GSK group of companies (Employee, Shareholder) Bruno Salaun, PhD, GSK group of companies (Employee) Anne Schuind, MD, GSK (Employee, Other Financial or Material Support, own GSK stock options or restricted shares as part of renumeration)

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.

Background The risk of herpes zoster (HZ) has been reported to vary by sex and ethnicity. In 2 large-scale clinical trials, ZOE-50 (NCT01165177) and ZOE-70 (NCT01165229), the adjuvanted recombinant zoster vaccine (RZV) demonstrated high vaccine efficacy (VE) against HZ and post-herpetic neuralgia (PHN). We present a post-hoc analysis of RZV efficacy against HZ and PHN in the ZOE-50/70 population stratified by sex, geographic region and geographic ancestry/ethnicity. Methods The ZOE-50 and ZOE-70 studies were phase III, observer-blind, placebo-controlled trials conducted across 5 geographic regions. Adults ≥ 50 years of age (YOA; ZOE-50) and ≥ 70 YOA (ZOE-70), randomized 1:1, received 2 doses of RZV or placebo 2 months apart. Here, VE against HZ by sub-population was estimated from the ZOE-50 population (≥ 50 YOA) and the pooled ZOE-50/70 population (pooled ≥ 70 YOA), and VE against PHN by sub-population was evaluated in the pooled ≥ 70 YOA. Results VE was evaluated in 7,340 RZV and 7,413 placebo recipients ≥ 50 YOA (mean age: 62.3 [RZV], 62.2 [placebo] YOA) and 8,250 RZV and 8,346 placebo recipients in pooled ≥ 70 YOA (mean age: 75.5 [RZV, placebo] YOA). VE against HZ and PHN was similar for women and men in the ≥ 50 YOA and pooled ≥ 70 YOA (Tables 1 and 2). Point estimates for VE against HZ by geographic region ranged from 95.7% to 97.2% in ≥ 50 YOA and from 87.3% to 95.1% in pooled ≥ 70 YOA (Table 1). Point estimates for VE against PHN by geographic region ranged from 86.8% to 100% in pooled ≥ 70 YOA. VE was similar across geographic ancestry groups in pooled ≥ 70 YOA: VE point estimates against HZ ranged from 89.6% to 100% and VE against PHN ranged from 87.5% to 100% (Tables 1 and 2). VE against HZ was 88.1% and against PHN was 65.9% in Hispanic participants in pooled ≥ 70 YOA (Tables 1 and 2). Conclusion Acknowledging the limitations including the post-hoc character of these analyses and the small number of participants and cases available, our data suggest that RZV is efficacious against HZ and PHN irrespective of sex, geographic region, geographic ancestry, and ethnicity. Funding: GlaxoSmithKline Biologicals SA. Disclosures All authors: No reported disclosures.

Ongoing assessment of influenza vaccine effectiveness (VE) is critical to inform public health policy. This study aimed to determine the VE of trivalent influenza vaccine (TIV) for preventing influenza-related hospitalizations and other serious outcomes over three consecutive influenza seasons.The Serious Outcomes Surveillance (SOS) Network of the Canadian Immunization Research Network (CIRN) conducted active surveillance for influenza in adults ≥16 years (y) of age during the 2011/2012, 2012/2013 and 2013/2014 seasons in hospitals across Canada. A test-negative design was employed: cases were polymerase chain reaction (PCR)-positive for influenza; controls were PCR-negative for influenza and were matched to cases by date, admission site, and age (≥65 y or65 y). All cases and controls had demographic and clinical characteristics (including influenza immunization status) obtained from the medical record. VE was estimated as 1-OR (odds ratio) in vaccinated vs. unvaccinated patients × 100%. The primary outcome was VE of TIV for preventing laboratory-confirmed influenza-related hospitalization; secondary outcomes included VE of TIV for preventing influenza-related intensive care unit (ICU) admission/mechanical ventilation, and influenza-related death.Overall, 3394 cases and 4560 controls were enrolled; 2078 (61.2%) cases and 2939 (64.5%) controls were ≥65 y. Overall matched, adjusted VE was 41.7% (95% Confidence Interval (CI): 34.4-48.3%); corresponding VE in adults ≥65 y was 39.3% (95% CI: 29.4-47.8%) and 48.0% (95% CI: 37.5-56.7%) in adults65 y, respectively. VE for preventing influenza-related ICU admission/mechanical ventilation in all ages was 54.1% (95% CI: 39.8-65.0%); in adults ≥65 y, VE for preventing influenza-related death was 74.5% (95% CI: 44.0-88.4%).While effectiveness of TIV to prevent serious outcomes varies year to year, we demonstrate a statistically significant and clinically important TIV VE for preventing hospitalization and other serious outcomes over three seasons. Public health messaging should highlight the overall benefit of influenza vaccines over time while acknowledging year to year variability. ClinicalTrials.gov Identifier: NCT01517191.

BackgroundDespite the importance of vaccinating children younger than 5 years, few studies evaluating vaccine prevention of influenza have been reported in this age group. We evaluated efficacy of an inactivated quadrivalent influenza vaccine (IIV4) in children aged 6–35 months.MethodsIn this phase 3, observer-blinded, multinational trial, healthy children from 13 countries in Europe, Central America, and Asia were recruited in five independent cohorts, each in a different influenza season. Participants were randomly assigned (1:1) to either IIV4 (15 μg haemagglutinin antigen per strain per 0·5 mL dose; a single dose on day 0 for vaccine-primed children, and two doses, on days 0 and 28, for vaccine-unprimed children) or to one or two doses of a non-influenza control vaccine. Primary endpoints were moderate-to-severe influenza or all influenza (irrespective of disease severity) confirmed by RT-PCR on nasal swabs. Cultured isolates were further characterised as antigenically matched or mismatched to vaccine strains. Efficacy was assessed in the per-protocol cohort and total vaccinated cohort (time-to-event analysis), and safety was assessed in the total vaccinated cohort.FindingsBetween Oct 1, 2011, and Dec 31, 2014, 12 018 children were recruited into the total vaccinated cohort (6006 children in the IIV4 group and 6012 children in the control group). 356 (6%) children in the IIV4 group and 693 (12%) children in the control group had at least one case of RT-PCR-confirmed influenza. Of these 1049 influenza strains, 138 (13%) were A/H1N1, 529 (50%) were A/H3N2, 69 (7%) were B/Victoria, and 316 (30%) were B/Yamagata. Overall, 539 (64%) of 848 antigenically characterised isolates were vaccine-mismatched (16 [15%] of 105 for A/H1N1; 368 [97%] of 378 for A/H3N2; 54 [86%] of 63 for B/Victoria; 101 [33%] of 302 for B/Yamagata). Vaccine efficacy was 63% (97·5% CI 52–72) against moderate-to-severe influenza and 50% (42–57) against all influenza in the per-protocol cohort, and 64% (53–73) against moderate-to-severe influenza and 50% (42–57) against all influenza in the total vaccinated cohort. There were no clinically meaningful safety differences between IIV4 and control.InterpretationIIV4 prevented influenza A and B in children aged 6–35 months despite high levels of vaccine mismatch. Vaccine efficacy was highest against moderate-to-severe disease, which is the most clinically important endpoint associated with greatest burden.FundingGlaxoSmithKline Biologicals SA.

Background A clinical endpoint of moderate-to-severe (M/S) influenza has been proposed in children, defined as fever >39°C, otitis media, lower respiratory tract infection, or serious extrapulmonary manifestations. This definition has not been evaluated against clinically relevant outcomes like hospitalization, emergency room care, antimicrobial use, and child/parental absenteeism. Methods We conducted a prospective observational study of children aged 6 months–8 years with influenza at the Children’s Hospital Colorado Emergency Department (ED) and its affiliates during two influenza seasons (2016–2017 and 2017–2018). Children with influenza-like-illness (ILI) were enrolled and tested for influenza by polymerase chain reaction (PCR). Parents of influenza cases and matched influenza-negative controls were contacted 2 weeks later for follow-up. The primary outcome was hospitalization for M/S influenza vs. mild influenza. Secondary outcomes included recurrent ED visits, antimicrobial use, child/parental absenteeism. Interim analyses were conducted using SAS v9.4. Results Among the 1,480 enrolled children with ILI, 410 (28%) tested positive for influenza by PCR. The median age of influenza cases was 4.0 years (IQR 2.2–6.1), and 20% were considered high-risk for influenza complications. Of influenza cases, 284 (69%) met the definition for M/S influenza. Among M/S influenza subjects, 8.4% were hospitalized, compared with 1.6% with mild influenza (risk difference (RD) 6.9%; 95% CI: 3.0–10.8, P < 0.01). Subjects with M/S influenza were more likely to receive antibiotics (RD 12.0%, 95% CI: 3.4–20.6, P < 0.01) with a trend to higher antiviral use (RD 6.9%, 95% CI: −0.7–14.5, P = 0.09). There was no significant difference for recurrent ED visits nor child/parental absenteeism. After adjusting for comorbidities, age, and influenza strain, the relative risk (RR) of hospitalization or recurrent ED visits was higher among those with M/S influenza vs. mild influenza (RR 2.18, 95% CI: 1.02–4.64, P = 0.04). Conclusion Children with M/S influenza have a higher risk of hospitalization compared with mild disease. This proposed definition is a useful clinical endpoint to study the public health and clinical impact of influenza interventions in children. Disclosures S. Rao, GSK: Investigator, Research grant. E. Yanni, GSK: Employee, Salary. R. Bekkat-Berkani, GSK: Employee, Salary. A. Schuind, GSK: Employee, Salary. B. Innis, GSK: Employee, Salary. R. Mistry, GSK: Investigator, Research support. E. J. Asturias, GSK: Investigator, Research grant and Research support.

Background Patients with hematologic malignancies treated with anticancer immunosuppressive therapies (ITs) are at increased risk of herpes zoster (HZ). In a previous report of this phase 3, observer-blind, multicenter trial (NCT01767467), the adjuvanted recombinant zoster vaccine (RZV) was shown to be immunogenic and well-tolerated in ≥18 years of age patients with hematologic malignancies who completed or were undergoing anticancer IT.1 Here we report end-of-study results from the same trial. Methods Participants were randomized 1:1 to receive 2 doses of RZV or placebo (PL) 1–2 months apart, either ≥10 days before or after a cancer therapy cycle, or 10 days to 6 months after cancer therapy ended. Humoral and cell-mediated immune (CMI) responses were evaluated at 1 month and 12 months post-dose 2 (month 2 and month 13, respectively). Confirmatory objectives were to evaluate humoral response rate to RZV and to compare humoral immune responses to RZV and PL at month 2 excluding either subjects with chronic lymphocytic leukemia and non-Hodgkin B-cell lymphoma (NHBCL), or only those with NHBCL. Efficacy against HZ was explored in a post-hoc analysis of confirmed HZ cases. Solicited and unsolicited adverse events (AEs) were recorded for 7 and 30 days after each dose, respectively. Serious AEs (SAEs) and potential immune-mediated diseases (pIMDs) were recorded throughout the study. Results Of the 562 (RZV: 283, PL: 279) treated participants, 415 (RZV: 217, PL: 198)/310 (RZV: 168, PL: 142) were included in the according-to-protocol (ATP) cohort for humoral immunogenicity/immune persistence. The ATP sub-cohort for CMI included 132 (RZV: 69, PL: 63) participants at month 2 and 100 (RZV: 54, PL: 46) at month 13. All confirmatory immunogenicity objectives were met (Table 1). RZV efficacy against HZ, assessed post-hoc, was 87.2% (Table 2). RZV was more reactogenic than PL. The occurrence of unsolicited AEs, SAEs, and pIMDs was similar between the study groups (Table 3). Conclusion RZV induced robust humoral and cellular immune responses and showed an effect in the reduction of HZ incidence in patients with hematologic malignancies who completed or were undergoing anticancer IT. No safety concerns were identified. Reference 1. Oostvogels et al. IDWeek2017, abs 1344. Funding. GlaxoSmithKline Biologicals SA. Disclosures A. F. Dagnew, GSK: Employee and Shareholder, Salary. J. Murphy, GSK: Investigator, Research support. S. A. McNeil, GSK group of companies: Grant Investigator, Research grant and Research support. B. Salaun, GSK group of companies: Employee and Shareholder, Salary. E. Di Paolo, GSK group of companies: Employee, Salary. L. Campora, GSK group of companies: Employee and Shareholder, Salary. M. López-Fauqued, GSK group of companies: Employee, Salary. M. El Idrissi, GSK group of companies: Employee, Salary. A. Schuind, GSK: Employee, Salary. T. C. Heineman, GSK group of companies: Consultant, Employee and Shareholder, Consulting fee and Salary. P. Van Den Steen, GSK: Employee and Shareholder, Restricted shares and Salary. L. Oostvogels, GSK: Employee, Salary and Stock and stock options.

Introduction We compared co-administration versus separate administration of an inactivated quadrivalent influenza vaccine (IIV4) with a 23-valent pneumococcal polysaccharide vaccine (PPV23) in adults at high risk of complications of influenza and pneumococcal infection. Methods This phase III, placebo-controlled, observer-blind trial (NCT02218697) was conducted in France and Belgium during the 2014-2015 influenza season. Adults≥50years of age meeting their country's vaccination recommendations were randomized 1:1 to co-administration or separate administration. Immunogenicity was assessed by hemagglutination inhibition (HI) titers for IIV4 and 22F-inhibition ELISA for PPV23. Co-primary objectives were to demonstrate non-inferiority of co-administration versus separate administration in terms of geometric mean titer (GMT) ratio for each influenza strain in the IIV4 and geometric mean concentration (GMC) ratio for six pneumococcal serotypes (1, 3, 4, 7F, 14, 19A) in the PPV23 in the per-protocol cohort (N=334). Results The study met its co-primary objectives, with the upper limit of the 95% confidence interval of the GMT and GMC ratios (separate administration over co-administration) being ≤2.0 for all four antigens of the IIV4 and the six pre-selected serotypes of the PPV23, respectively. Immunogenicity of the IIV4 and PPV23 was similar regardless of administration schedule. In a post hoc analysis pooling participants ≥60years of age from the co-administration and separate administration groups, IIV4 immunogenicity was similar in higher risk adults with comorbidities (diabetes; respiratory, heart, kidney, liver, or neurological diseases; morbid obesity) versus those without. Both vaccines had an acceptable safety and reactogenicity profile; pain was the most common symptom, occurring more often with co-administration than separate administration. Conclusion The IIV4 and PPV23 can be co-administered without reducing antibody responses reflecting protection against influenza or pneumococcal disease. Co-administration of PPV23 at the annual influenza vaccination visit may improve uptake. Comorbidities had no impact on IIV4 immunogenicity, supporting its value in older adults with chronic medical conditions. Clinical Trial Registry Number: NCT02218697.