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PURPOSE: To assess the risk of three autoimmune diseases - autoimmune thyroiditis (AIT), Guillain-Barré syndrome (GBS), and inflammatory bowel disease (IBD) - in females following AS04-HPV-16/18 vaccination. METHODS: This meta-analysis included data from 18 randomized controlled trials, one cluster-randomized trial, two large observational retrospective cohort studies, and one case-control study. Following vaccination, a risk window of 2 years was defined for AIT and IBD and 42 days for GBS. Odds ratios (ORs) were estimated using three methods: meta-analysis inverse-variance with continuity correction (primary analysis), pooled estimate, and beta-binomial regression. RESULTS: In all studies apart from the case-control study, 154 398 exposed and 1 504 322 non-exposed subjects were included, among whom there were 141 and 1972 cases of (autoimmune) thyroiditis; 2 and 2 cases of GBS; and 43 and 401 cases of IBD, respectively. In the case-control study, there were 97 cases of AIT and 13 of GBS; matched with 802 and 130 controls, respectively. The primary analysis OR estimates were 1.46 (95% confidence interval [CI] 1.22-1.76), 11.14 (2.00-61.92), and 1.11 (0.75-1.66) for (autoimmune) thyroiditis, GBS, and IBD, respectively. CONCLUSIONS: This meta-analysis did not show an increased risk of IBD following vaccination with AS04-HPV-16/18. The 1.5-fold increased risk of (autoimmune) thyroiditis does not allow us to conclude about a causal association. For GBS, the very low number of cases and wide 95% CIs negate any firm conclusion.
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Síndrome de Guillain-Barré/epidemiología , Enfermedades Inflamatorias del Intestino/epidemiología , Infecciones por Papillomavirus/prevención & control , Vacunas contra Papillomavirus/efectos adversos , Tiroiditis Autoinmune/epidemiología , Adyuvantes Inmunológicos/efectos adversos , Estudios de Casos y Controles , Causalidad , Síndrome de Guillain-Barré/inmunología , Humanos , Incidencia , Enfermedades Inflamatorias del Intestino/inmunología , Estudios Observacionales como Asunto , Infecciones por Papillomavirus/virología , Ensayos Clínicos Controlados Aleatorios como Asunto , Factores de Riesgo , Tiroiditis Autoinmune/inmunologíaRESUMEN
PURPOSE: To evaluate the safety of HPV-16/18 AS04-adjuvanted vaccine when administered as per the PI in Korea. METHODS: A total of 3084 women aged 10-25 years were enrolled in this post-marketing surveillance from 2008 to 2014. Subjects were invited to receive three doses of the vaccine (0, 1 and 6 months), and participants who received at least one dose were included in the analysis. Adverse events (AEs), adverse drug reactions (ADRs) and serious AEs (SAEs) were recorded after each dose. All AEs, ADRs and SAEs were presented with exact 95% confidence intervals (CI) (NCT01101542). RESULTS: Injection-site pain was the most frequent AE and ADR reported by 322 subjects (10.4% [95%CI: 9.4-11.6]); the local pain was transient and lasted 4-7 days in most cases. Dysmenorrhoea and vaginitis were the most common unexpected AEs reported by 30 (1.0% [95%CI: 0.7-1.4]) and 16 subjects (0.7% [95%CI: 0.3-0.8]), respectively. Pain (toe pain, leg pain and body pain [one case each]; foot pain [two cases]) was the most common unexpected ADR reported by five subjects (0.2% [95%CI: 0.1-0.4]). Four subjects reported a single SAE (one case each of exostosis, gastroenteritis, abortion and tonsillitis); none were fatal. All SAEs were assessed as unlikely to be related to vaccination; gastroenteritis, exostosis and tonsillitis resolved during the study period. CONCLUSIONS: This is the first post-marketing surveillance study in Korea that provides 6-year safety data for HPV-16/18 AS04-adjuvanted vaccine. The vaccine showed an acceptable safety profile and favourable benefit/risk ratio when given to women aged 10-25 years in Korea. © 2017 The Authors. Pharmacoepidemiology & Drug Safety Published by John Wiley & Sons Ltd.
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Infecciones por Papillomavirus/prevención & control , Vacunas contra Papillomavirus/efectos adversos , Vacunas contra Papillomavirus/inmunología , Vigilancia de Productos Comercializados , Adolescente , Adulto , Niño , Femenino , Papillomavirus Humano 16/inmunología , Papillomavirus Humano 18/inmunología , Humanos , Infecciones por Papillomavirus/epidemiología , República de Corea/epidemiología , Adulto JovenRESUMEN
Immunogenicity and safety of different adjuvants combined with a model antigen (HBsAg) were compared. Healthy HBV-naïve adults were randomized to receive HBs adjuvanted with alum or Adjuvant Systems AS01B, AS01E, AS03A or AS04 at Days 0 and 30. Different frequencies of HBs-specific CD4+ T cells 14days post dose 2 but similar polyfunctionality profiles were induced by the different adjuvants with frequencies significantly higher in the AS01B and AS01E groups than in the other groups. Antibody concentrations 30days post-dose 2 were significantly higher in AS01B, AS01E and AS03A than in other groups. Limited correlations were observed between HBs-specific CD4+ T cell and antibody responses. Injection site pain was the most common solicited local symptom and was more frequent in AS groups than in alum group. Different adjuvants formulated with the same antigen induced different adaptive immune responses and reactogenicity patterns in healthy naïve adults. The results summary for this study (GSK study number 112115 - NCT# NCT00805389) is available on the GSK Clinical Study Register and can be accessed at www.gsk-clinicalstudyregister.com.
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Formación de Anticuerpos/inmunología , Linfocitos B/inmunología , Linfocitos T CD4-Positivos/inmunología , Antígenos de Superficie de la Hepatitis B/inmunología , Vacunas/inmunología , Adyuvantes Inmunológicos/administración & dosificación , Adulto , Método Doble Ciego , Femenino , Anticuerpos contra la Hepatitis B/sangre , Anticuerpos contra la Hepatitis B/inmunología , Humanos , Inmunoensayo/métodos , Mediciones Luminiscentes , Masculino , Vacunación/métodos , Vacunas/administración & dosificaciónRESUMEN
PURPOSE: A proof-of-concept study has previously highlighted the added value of a method using time-to-onset (TTO) for quantitative and non-parametric signal detection on spontaneous report data. The aim of this study was to assess the added value of this new TTO signal detection method adapted to observational studies. METHODS: For each adverse event collected during the conduct of an observational study of H1N1 pandemic influenza vaccine, the TTO distribution was tested against the 'follow-up distribution' from vaccination to 'lost to follow-up' by a Kolmogorov-Smirnov test. Events rejecting the null hypothesis of similar distribution were flagged as signals, and a safety physician evaluated their relevance for further medical assessment. We simulated ongoing surveillance by performing retrospective weekly signal detection based on TTO. RESULTS: The TTO method detected 21, 15 and 4 signals within a 30-day period post-dose 1 with confidence levels set at 90%, 95% and 99%, respectively. Of these signals, 14 (67%), 10 (67%) and 2 (50%) were considered as relevant. Among the 14, six had not been identified by previous signal detection activities. When performed weekly, the Kolmogorov-Smirnov test detected 26 events as signals (alpha = 0.05). Three weeks after first participant first dose, one of the six new signals could theoretically have been detected. CONCLUSIONS: This study provided evidence that the Kolmogorov-Smirnov method can screen all TTO distributions and objectively flag the unexpected, leading to earlier detection of signals, and thus potential safety issues.
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Sistemas de Registro de Reacción Adversa a Medicamentos/estadística & datos numéricos , Vacunas contra la Influenza/efectos adversos , Estudios Observacionales como Asunto/métodos , Vacunación/efectos adversos , Humanos , Subtipo H1N1 del Virus de la Influenza A , Vacunas contra la Influenza/administración & dosificación , Gripe Humana/prevención & control , Perdida de Seguimiento , Estudios Retrospectivos , Estadísticas no Paramétricas , Factores de TiempoRESUMEN
PURPOSE: To summarise post-licensure safety surveillance over more than 4 years of routine use of the human papillomavirus-16/18-AS04-adjuvanted vaccine (HPV-16/18 vaccine: Cervarix®, GlaxoSmithKline, Belgium). METHODS: We describe global post-licensure passive surveillance data based on routine pharmacovigilance from 18 May 2007 until 17 November 2011 and enhanced surveillance implemented during the 2-year national immunisation programme in the UK (school years 2008-2010). RESULTS: Spontaneous reports from countries worldwide showed a similar pattern for the most frequently reported adverse events after HPV-16/18 vaccination. No patterns or trends were observed for potential immune-mediated diseases after vaccination. Observed incidences of Bell's palsy and confirmed Guillain-Barré syndrome were within the expected range in the general population. Outcomes of pregnancy in women who were inadvertently exposed to HPV-16/18 vaccine during pregnancy, were in line with published reports for similar populations. Enhanced surveillance of adverse events in the UK triggered a review of cases of anaphylaxis, angioedema and syncope reports, leading to an update to the prescribing information. CONCLUSION: Collaborative partnerships between industry and national regulatory agencies facilitated rapid notification and transfer of safety information, allowing for rapid responses in the event of a safety signal of adverse event of concern. More than 4 years of post-licensure experience may provide confidence to providers and the public about the safety profile of HPV-16/18 vaccine in routine use. The safety profile appears to be consistent with pre-licensure data reporting that HPV-16/18 vaccine has an acceptable benefit-risk profile in adolescent girls and women.
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Adyuvantes Inmunológicos/administración & dosificación , Infecciones por Papillomavirus/prevención & control , Vacunas contra Papillomavirus/efectos adversos , Adolescente , Adulto , Sistemas de Registro de Reacción Adversa a Medicamentos , Femenino , Humanos , Programas de Inmunización , Vacunas contra Papillomavirus/administración & dosificación , Embarazo , Vigilancia de Productos Comercializados , Vacunación/efectos adversosRESUMEN
A European legislation was put in place for the reporting of medication errors, and guidelines were drafted to help stakeholders in the reporting, evaluation, and, ultimately, minimization of these errors. As part of pharmacovigilance reporting, a proper classification of medication errors is needed. However, this process can be tedious, time-consuming, and resource-intensive. To fulfill this obligation regarding medication errors, we developed an algorithm that classifies the reported errors in an automated way into four categories: potential medication errors, intercepted medication errors, medication errors without harm (i.e., not associated with adverse reaction(s)), and medication errors with harm (i.e., associated with adverse reaction(s)). A fifth category ("conflicting category") was created for reported cases that could not be unambiguously classified as either potential or intercepted medication errors. Our algorithm defines medication error categories based on internationally accepted terminology using the Medical Dictionary for Regulatory Activities (MedDRA®) preferred terms. We present the algorithm and the strengths of this automated way of reporting medication errors. We also give examples of visualizations using spontaneously reported vaccination error data associated with the adjuvanted recombinant zoster vaccine. For this purpose, we used a customized web-based platform that uses visualizations to support safety signal detection. The use of the algorithm facilitates and ensures a consistent way of categorizing medication errors with MedDRA® terms, thereby saving time and resources and avoiding the risk of potential mistakes versus manual classification. This allows further assessment and potential prevention of medication errors. In addition, the algorithm is easy to implement and can be used to categorize medication errors from different databases.
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Compared with the general population, older adults with immune senescence and individuals who are immunocompromised (IC) due to disease or immunosuppressive therapy are at increased risk for herpes zoster (HZ) and its associated complications, which can be debilitating and life-threatening. Vaccination can be an effective strategy against HZ and studies have shown that HZ vaccination in IC individuals can elicit immune responses and provide protection from infection. Recently, the first approvals have been granted in the United States and the European Union for the recombinant HZ vaccine (RZV) in adults ≥ 18 years of age at risk of HZ due to immunodeficiency or immunosuppression. Existing systematic reviews have highlighted the risks for HZ in limited immunocompromising conditions and have only examined clinical data for RZV. This review details the risks and burden of HZ in a broad range of clinically relevant IC populations and summarizes key efficacy and safety data for RZV and live HZ vaccine in these individuals. Research has shown IC individuals can benefit from HZ vaccination; however, these insights have yet to be fully incorporated into vaccination guidelines and clinical care. Clinicians should consider HZ vaccination in eligible at-risk populations to protect against HZ and its associated complications and thereby, reduce the burden that HZ poses on the healthcare system. Electronic health records and linked personal health records could be used to identify and contact patients eligible for HZ vaccination and provide clinical decision support-generated alerts for missing or delayed vaccinations. This review will help clinicians identify eligible IC individuals who may benefit from HZ vaccination. A video abstract linked to this article is available on Figshare https://doi.org/10.6084/m9.figshare.21517605.
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Vacuna contra el Herpes Zóster , Herpes Zóster , Humanos , Estados Unidos , Anciano , Herpes Zóster/epidemiología , Herpesvirus Humano 3 , Huésped Inmunocomprometido , Vacunación/efectos adversos , Enfermedad CrónicaRESUMEN
INTRODUCTION: During the clinical development of a vaccine, study participants are monitored for the occurrence of adverse events (AEs) over a defined period post-vaccination to assess the safety of prophylactic vaccines. Among the safety data collected, a standard practice in prophylactic vaccine clinical trials involves collecting reactogenicity data through daily AE solicitation of pre-defined sets of symptoms (i.e. solicited AEs). AREAS COVERED: This paper aims to propose recommendations to improve and harmonize the collection of active AE solicitation in prophylactic vaccine clinical trials. EXPERT OPINION: We recommend using limited lists of solicited AEs adapted to the vaccine technology and target population. While the US Food and Drug Administration toxicity grading scale is commonly used in adolescents/adults, harmonizing grading criteria in infants/children would facilitate the comparison of vaccines' safety profiles. Solicited systemic AEs should not systematically be considered causally related to vaccination. Collection of solicited AEs should occur in cohorts of a maximum of 1,000 vaccinated participants, as larger cohort sizes do not improve substantially the precision of AE incidence. The incidence of daily solicited AEs should be compared with a control group for improved interpretations of their clinical relevance. These suggestions would improve the characterization of safety profiles of vaccines.
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Vacunas , Niño , Lactante , Adulto , Adolescente , Estados Unidos , Humanos , Vacunación/efectos adversos , United States Food and Drug Administration , IncidenciaRESUMEN
Background: In a parallel-group, international, phase 3 study (ClinicalTrials.govNCT04762680), we evaluated prototype (D614) and Beta (B.1.351) variant recombinant spike protein booster vaccines with AS03-adjuvant (CoV2 preS dTM-AS03). Methods: Adults, previously primed with mRNA (BNT162b2, mRNA-1273), adenovirus-vectored (Ad26.CoV2.S, ChAdOx1nCoV-19) or protein (CoV2 preS dTM-AS03 [monovalent D614; MV(D614)]) vaccines were enrolled between 29 July 2021 and 22 February 2022. Participants were stratified by age (18-55 and ≥ 56 years) and received one of the following CoV2 preS dTM-AS03 booster formulations: MV(D614) (n = 1285), MV(B.1.351) (n = 707) or bivalent D614 + B.1.351 (BiV; n = 625). Unvaccinated adults who tested negative on a SARS-CoV-2 rapid diagnostic test (control group, n = 479) received two primary doses, 21 days apart, of MV(D614). Anti-D614G and anti-B.1.351 antibodies were evaluated using validated pseudovirus (lentivirus) neutralization (PsVN) assay 14 days post-booster (day [D]15) in 18-55-year-old BNT162b2-primed participants and compared with those pre-booster (D1) and on D36 in 18-55-year-old controls (primary immunogenicity endpoints). PsVN titers to Omicron BA.1, BA.2 and BA.4/5 subvariants were also evaluated. Safety was evaluated over a 12-month follow-up period. Planned interim analyses are presented up to 14 days post-last vaccination for immunogenicity and over a median duration of 5 months for safety. Findings: All three boosters elicited robust anti-D614G or -B.1.351 PsVN responses for mRNA, adenovirus-vectored and protein vaccine-primed groups. Among BNT162b2-primed adults (18-55 years), geometric means of the individual post-booster versus pre-booster titer ratio (95% confidence interval [CI]) were: for MV (D614), 23.37 (18.58-29.38) (anti-D614G); for MV(B.1.351), 35.41 (26.71-46.95) (anti-B.1.351); and for BiV, 14.39 (11.39-18.28) (anti-D614G) and 34.18 (25.84-45.22 (anti-B.1.351). GMT ratios (98.3% CI) versus post-primary vaccination GMTs in controls, were: for MV(D614) booster, 2.16 (1.69; 2.75) [anti-D614G]; for MV(B.1.351), 1.96 (1.54; 2.50) [anti-B.1.351]; and for BiV, 2.34 (1.84; 2.96) [anti-D614G] and 1.39 (1.09; 1.77) [anti-B.1.351]. All booster formulations elicited cross-neutralizing antibodies against Omicron BA.2 (across priming vaccine subgroups), Omicron BA.1 (BNT162b2-primed participants) and Omicron BA.4/5 (BNT162b2-primed participants and MV D614-primed participants). Similar patterns in antibody responses were observed for participants aged ≥56 years. Reactogenicity tended to be transient and mild-to-moderate severity in all booster groups. No safety concerns were identified. Interpretation: CoV2 preS dTM-AS03 boosters demonstrated acceptable safety and elicited robust neutralizing antibodies against multiple variants, regardless of priming vaccine. Funding: Sanofi and Biomedical Advanced Research and Development Authority (BARDA).
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BACKGROUND: We evaluated our SARS-CoV-2 prefusion spike recombinant protein vaccine (CoV2 preS dTM) with different adjuvants, unadjuvanted, and in a one-injection and two-injection dosing schedule in a previous phase 1-2 study. Based on interim results from that study, we selected a two-injection schedule and the AS03 adjuvant for further clinical development. However, lower than expected antibody responses, particularly in older adults, and higher than expected reactogenicity after the second vaccination were observed. In the current study, we evaluated the safety and immunogenicity of an optimised formulation of CoV2 preS dTM adjuvanted with AS03 to inform progression to phase 3 clinical trial. METHODS: This phase 2, randomised, parallel-group, dose-ranging study was done in adults (≥18 years old), including those with pre-existing medical conditions, those who were immunocompromised (except those with recent organ transplant or chemotherapy) and those with a potentially increased risk for severe COVID-19, at 20 clinical research centres in the USA and Honduras. Women who were pregnant or lactating or, for those of childbearing potential, not using an effective method of contraception or abstinence, and those who had received a COVID-19 vaccine, were excluded. Participants were randomly assigned (1:1:1) using an interactive response technology system, with stratification by age (18-59 years and ≥60 years), rapid serodiagnostic test result (positive or negative), and high-risk medical conditions (yes or no), to receive two injections (day 1 and day 22) of 5 7mu;g (low dose), 10 7mu;g (medium dose), or 15 7mu;g (high dose) CoV2 preS dTM antigen with fixed AS03 content. All participants and outcome assessors were masked to group assignment; unmasked study staff involved in vaccine preparation were not involved in safety outcome assessments. All laboratory staff performing the assays were masked to treatment. The primary safety objective was to describe the safety profile in all participants, for each candidate vaccine formulation. Safety endpoints were evaluated for all randomised participants who received at least one dose of the study vaccine (safety analysis set), and are presented here for the interim study period (up to day 43). The primary immunogenicity objective was to describe the neutralising antibody titres to the D614G variant 14 days after the second vaccination (day 36) in participants who were SARS-CoV-2 naive who received both injections, provided samples at day 1 and day 36, did not have protocol deviations, and did not receive an authorised COVID-19 vaccine before day 36. Neutralising antibodies were measured using a pseudovirus neutralisation assay and are presented here up to 14 days after the second dose. As a secondary immunogenicity objective, we assessed neutralising antibodies in non-naive participants. This trial is registered with ClinicalTrials.gov (NCT04762680) and is closed to new participants for the cohort reported here. FINDINGS: Of 722 participants enrolled and randomly assigned between Feb 24, 2021, and March 8, 2021, 721 received at least one injection (low dose=240, medium dose=239, and high dose=242). The proportion of participants reporting at least one solicited adverse reaction (injection site or systemic) in the first 7 days after any vaccination was similar between treatment groups (217 [91%] of 238 in the low-dose group, 213 [90%] of 237 in the medium-dose group, and 218 [91%] of 239 in the high-dose group); these adverse reactions were transient, were mostly mild to moderate in intensity, and occurred at a higher frequency and intensity after the second vaccination. Four participants reported immediate unsolicited adverse events; two (one each in the low-dose group and medium-dose group) were considered by the investigators to be vaccine related and two (one each in the low-dose and high-dose groups) were considered unrelated. Five participants reported seven vaccine-related medically attended adverse events (two in the low-dose group, one in the medium-dose group, and four in the high-dose group). No vaccine-related serious adverse events and no adverse events of special interest were reported. Among participants naive to SARS-CoV-2 at day 36, 158 (98%) of 162 in the low-dose group, 166 (99%) of 168 in the medium-dose group, and 163 (98%) of 166 in the high-dose group had at least a two-fold increase in neutralising antibody titres to the D614G variant from baseline. Neutralising antibody geometric mean titres (GMTs) at day 36 for participants who were naive were 2189 (95% CI 1744-2746) for the low-dose group, 2269 (1792-2873) for the medium-dose group, and 2895 (2294-3654) for the high-dose group. GMT ratios (day 36: day 1) were 107 (95% CI 85-135) in the low-dose group, 110 (87-140) in the medium-dose group, and 141 (111-179) in the high-dose group. Neutralising antibody titres in non-naive adults 21 days after one injection tended to be higher than titres after two injections in adults who were naive, with GMTs 21 days after one injection for participants who were non-naive being 3143 (95% CI 836-11â815) in the low-dose group, 2338 (593-9226) in the medium-dose group, and 7069 (1361-36â725) in the high-dose group. INTERPRETATION: Two injections of CoV2 preS dTM-AS03 showed acceptable safety and reactogenicity, and robust immunogenicity in adults who were SARS-CoV-2 naive and non-naive. These results supported progression to phase 3 evaluation of the 10 7mu;g antigen dose for primary vaccination and a 5 7mu;g antigen dose for booster vaccination. FUNDING: Sanofi Pasteur and Biomedical Advanced Research and Development Authority.
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Vacunas contra la COVID-19 , COVID-19 , Adyuvantes Inmunológicos , Adolescente , Adulto , Anciano , Anticuerpos Neutralizantes , Anticuerpos Antivirales , COVID-19/prevención & control , Vacunas contra la COVID-19/efectos adversos , Método Doble Ciego , Femenino , Humanos , Inmunogenicidad Vacunal , Lactancia , Persona de Mediana Edad , Proteínas Recombinantes , SARS-CoV-2 , Vacunas Sintéticas , Adulto JovenRESUMEN
INTRODUCTION: With the approval of the adjuvanted recombinant zoster vaccine (RZV; Shingrix, GSK) in October 2017, GSK established enhanced safety surveillance measures to allow prompt identification of potential safety signals not observed during clinical development. In Germany, cases of vesicular and bullous cutaneous eruptions following RZV vaccination were reported. OBJECTIVE: Our objective was to search and analyse 2.5 years of worldwide spontaneously reported post-marketing data for vesicular and bullous cutaneous eruptions, represented by adverse events suggestive of (1) herpes zoster (HZ) and (2) non-HZ vesicular and bullous cutaneous eruptions, that occurred following RZV vaccination. METHODS: We conducted a descriptive analysis of all identified reports of HZ and non-HZ vesicular and bullous cutaneous eruptions following RZV vaccination and an observed versus expected (O/E) analysis of reports of HZ that met criteria of varicella zoster virus (VZV) reactivations following RZV vaccination (i.e., time to onset [TTO] of the event < 30 days or missing after any dose). RESULTS: Until the data lock point, 32,597,779 RZV doses had been distributed globally. There were 2423 reports of HZ (including complications) identified, of which 645 met the criteria of possible vaccination failure (i.e., TTO of the event ≥ 30 days or missing following a complete RZV vaccination schedule). The O/E analysis of 1928 reports assessed as possible VZV reactivations indicated that the observed number of cases was lower than that expected in the general population. Additionally, 810 reports of non-HZ vesicular and bullous cutaneous eruptions were identified, including injection site rashes attributed to the vaccine's reactogenicity. CONCLUSION: This review of spontaneously reported post-marketing data did not raise safety concerns regarding the occurrence of vesicular and bullous cutaneous eruptions following vaccination with RZV.
Shingles is a disease caused by reactivation of the chickenpox virus. It mostly affects adults aged 50 years and older and patients of all ages who have an impaired immune system. Diagnosis of shingles is often based only on the presence of symptoms such as a typical rash and pain. However, rashes can have various other causes (e.g., allergies, autoimmune diseases, and infections). Consequently, rashes with other causes may be misdiagnosed as shingles. Adults at increased risk of shingles and/or aged 50 years and older may be vaccinated with Shingrix (GSK, Belgium) to protect them from shingles and its complications. Since Shingrix became available in Germany, blister-like skin rashes have been reported that occurred shortly after vaccination. We searched the GSK safety database for reports of blister-like skin rashes that occurred following vaccination with Shingrix and that were spontaneously reported from countries where Shingrix was first marketed. To analyse these reports of rashes, we described the reports that we retrieved, we performed a statistical analysis to quantify whether the number of events assessed as reactivations of the chickenpox virus following Shingrix vaccination was higher than the number of reactivations that would be expected in the general population, and we described possible explanations for the observed rashes and underlying disease mechanisms. Our analyses did not raise safety concerns related to the onset of these rashes after vaccination with Shingrix. This paper raises awareness about the varying causes of rashes since a shingles-like rash that onsets shortly after vaccination with Shingrix is not necessarily caused by vaccination. In conclusion, this analysis shows that caution is needed when evaluating rashes in older adults and that all potential contributing factors (e.g., pre-existing diseases, medication, vaccination) should be considered.
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Vacuna contra el Herpes Zóster , Herpes Zóster , Herpes Zóster/epidemiología , Vacuna contra el Herpes Zóster/efectos adversos , Herpesvirus Humano 3 , Humanos , Vacunación/efectos adversos , Vacunas Sintéticas/efectos adversosRESUMEN
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.
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Vacuna contra el Herpes Zóster , Herpes Zóster , Huésped Inmunocomprometido , Adulto , Ensayos Clínicos como Asunto , Herpes Zóster/prevención & control , Vacuna contra el Herpes Zóster/efectos adversos , Herpesvirus Humano 3 , Humanos , Vacunas Sintéticas/efectos adversosRESUMEN
BACKGROUND: CoV2 preS dTM is a stabilised pre-fusion spike protein vaccine produced in a baculovirus expression system being developed against SARS-CoV-2. We present interim safety and immunogenicity results of the first-in-human study of the CoV2 preS dTM vaccine with two different adjuvant formulations. METHODS: This phase 1-2, randomised, double-blind study is being done in healthy, SARS-CoV-2-seronegative adults in ten clinical research centres in the USA. Participants were stratified by age (18-49 years and ≥50 years) and randomly assigned using an interactive response technology system with block randomisation (blocks of varying size) to receive one dose (on day 1) or two doses (on days 1 and 22) of placebo or candidate vaccine, containing low-dose (effective dose 1·3 µg) or high-dose (2·6 µg) antigen with adjuvant AF03 (Sanofi Pasteur) or AS03 (GlaxoSmithKline) or unadjuvanted high-dose antigen (18-49 years only). Primary endpoints were safety, assessed up to day 43, and immunogenicity, measured as SARS-C0V-2 neutralising antibodies (geometric mean titres), assessed on days 1, 22, and 36 serum samples. Safety was assessed according to treatment received in the safety analysis set, which included all randomly assigned participants who received at least one dose. Neutralising antibody titres were assessed in the per-protocol analysis set for immunogenicity, which included participants who received at least one dose, met all inclusion and exclusion criteria, had no protocol deviation, had negative results in the neutralisation test at baseline, and had at least one valid post-dose serology sample. This planned interim analysis reports data up to 43 days after the first vaccination; participants in the trial will be followed up for 12 months after the last study injection. This trial is registered with ClinicalTrials.gov, NCT04537208, and is ongoing. FINDINGS: Between Sept 3 and Sept 29, 2020, 441 individuals (299 aged 18-49 years and 142 aged ≥50 years) were randomly assigned to one of the 11 treatment groups. The interim safety analyses included 439 (>99%) of 441 randomly assigned participants (299 aged 18-49 years and 140 aged ≥50 years). Neutralising antibody titres were analysed in 326 (74%) of 441 participants (235 [79%] of 299 aged 18-49 years and 91 [64%] of 142 aged ≥50 years). There were no vaccine-related unsolicited immediate adverse events, serious adverse events, medically attended adverse events classified as severe, or adverse events of special interest. Among all study participants, solicited local and systemic reactions of any grade after two vaccine doses were reported in 81% (95% CI 61-93; 21 of 26) of participants in the low-dose plus AF03 group, 93% (84-97; 74 of 80) in the low-dose plus AS03 group, 89% (70-98; 23 of 26) in the high-dose plus AF03 group, 95% (88-99; 81 of 85) in the high-dose plus AS03 group, 29% (10-56; five of 17) in the unadjuvanted high-dose group, and 21% (8-40; six of 29) in the placebo group. A single vaccine dose did not generate neutralising antibody titres above placebo levels in any group at days 22 or 36. Among participants aged 18-49 years, neutralising antibody titres after two vaccine doses were 13·1 (95% CI 6·40-26·9) in the low-dose plus AF03 group, 20·5 (13·1-32·1) in the low-dose plus AS03 group, 43·2 (20·6-90·4) in the high-dose plus AF03 group, 75·1 (50·5-112·0) in the high-dose plus AS03 group, 5·00 (not calculated) in the unadjuvanted high-dose group, and 5·00 (not calculated) in the placebo group. Among participants aged 50 years or older, neutralising antibody titres after two vaccine doses were 8·62 (1·90-39·0) in the low-dose plus AF03 group, 12·9 (7·09-23·4) in the low-dose plus AS03 group, 12·3 (4·35-35·0) in the high-dose plus AF03 group, 52·3 (25·3-108·0) in the high-dose plus AS03 group, and 5·00 (not calculated) in the placebo group. INTERPRETATION: The lower than expected immune responses, especially in the older age groups, and the high reactogenicity after dose two were probably due to higher than anticipated host-cell protein content and lower than planned antigen doses in the formulations tested, which was discovered during characterisation studies on the final bulk drug substance. Further development of the AS03-adjuvanted candidate vaccine will focus on identifying the optimal antigen formulation and dose. FUNDING: Sanofi Pasteur and Biomedical Advanced Research and Development Authority.
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Adyuvantes Inmunológicos/administración & dosificación , Vacunas contra la COVID-19/administración & dosificación , COVID-19/prevención & control , Inmunogenicidad Vacunal , Proteínas Recombinantes/administración & dosificación , SARS-CoV-2/inmunología , Adulto , Anticuerpos Neutralizantes/efectos de los fármacos , Anticuerpos Antivirales/efectos de los fármacos , Vacunas contra la COVID-19/inmunología , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteínas Recombinantes/inmunología , Glicoproteína de la Espiga del Coronavirus , Estados Unidos/epidemiologíaRESUMEN
A diligent, systematic, regular review of aggregate safety data is essential, particularly early after vaccine introduction, as this is when safety signals not identified during clinical development may emerge. In October 2017, the US Centers for Disease Control and Prevention Advisory Committee on Immunization Practices recommended the adjuvanted recombinant zoster vaccine (RZV; Shingrix, GSK) as the preferred vaccine for preventing herpes zoster (HZ) and related complications in immunocompetent adults aged ≥ 50 years. Subsequently, GSK experienced an unprecedented high demand for RZV. In this methodology paper, we summarize the enhanced measures undertaken to assess RZV safety during its early post-marketing experience in the USA, Canada and Germany. In addition to the routine signal-detection methods already in place for all vaccines, GSK established tailored and enhanced safety monitoring for RZV based on aggregate data of spontaneous reports and manufacturing data. Proactive, near real-time detection and evaluation of signals was a key objective. A dedicated in-house signal-detection tool customized for RZV was employed on a weekly (rather than the routine monthly) basis, allowing for a centralized, more frequent review of data on a single web-based platform. We also identified the background incidence rates of preselected medical events of interest in the first countries to introduce RZV (USA, Canada and Germany) to perform observed-to-expected analyses. This approach may offer a solution to the challenges associated with the assessment and monitoring of vaccine safety in an efficient and timely manner in the context of high vaccine uptake.
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Sistemas de Registro de Reacción Adversa a Medicamentos , Vacuna contra el Herpes Zóster/efectos adversos , Farmacovigilancia , Vacunas Sintéticas/efectos adversos , Canadá/epidemiología , Alemania/epidemiología , Humanos , Estados Unidos/epidemiologíaRESUMEN
BACKGROUND: The adjuvanted recombinant zoster vaccine (RZV) received its first marketing authorization in October 2017, for prevention of herpes zoster in individuals aged ≥50 years. METHODS: We summarized safety information, following RZV administration, received by GSK via spontaneous adverse event (AE) reports submitted by healthcare providers, vaccine recipients and other reporters. Observed-to-expected (O/E) analyses were performed for selected outcomes: reports of death, Guillain-Barré syndrome and Bell's palsy. Standard case definitions were used to assess individual case reports. Data mining, using proportional reporting ratio and time-to-onset signal detection methods, was employed to identify RZV-AE pairs with disproportionate reporting or unexpected time-to-onset distribution. RESULTS: Between October 13, 2017 and February 10, 2019, an estimated 9.3 million doses were distributed and GSK received 15,638 spontaneous AE reports involving RZV. Most reports were classified as non-serious (95.3%) and originated from the United States (81.7%), where the majority of doses were distributed. Among reports with age or sex reported, individuals were mainly 50-69-year-olds (62.1%) and female (66.7%). Of all reports, 3,579 (22.9%) described vaccination errors, of which 82.7% were without associated symptoms. Of all vaccination error reports, most described errors of vaccine preparation and reconstitution (29.7%), inappropriate schedule or incomplete course of administration (26.7%), incorrect route of administration (16.4%), and storage errors (12.9%). The most commonly reported symptoms were consistent with the known RZV reactogenicity profile observed in clinical trials, including injection site reactions, pyrexia, chills, fatigue, headache. O/E analyses for selected outcomes and data mining analyses for all reported AEs did not identify any unexpected patterns. CONCLUSIONS: Review of the initial data from the post-marketing safety surveillance showed that the safety profile of RZV is consistent with that previously observed in pre-licensure clinical trials. Other studies are ongoing and planned, to continue generating real-world safety data and further characterize RZV.
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Vacuna contra el Herpes Zóster , Herpes Zóster , Anciano , Femenino , Herpes Zóster/prevención & control , Vacuna contra el Herpes Zóster/efectos adversos , Herpesvirus Humano 3 , Humanos , Masculino , Mercadotecnía , Persona de Mediana Edad , Estados Unidos , Vacunas Sintéticas/efectos adversosRESUMEN
BACKGROUND: Women living with HIV (WLWH) are at higher risk of acquisition and progression of human papillomavirus (HPV) infection. Evidence on effect of HPV vaccination in this population is limited. METHODS: This phase IV randomized controlled observer-blind study assessed immunogenicity and safety of two HPV vaccines (AS04-HPV-16/18â¯vs. 4vHPV) given in WLWH (stage 1) and HIV- females aged 15-25 years. Co-primary endpoints were to demonstrate, in WLWH subjects, non-inferiority (and if demonstrated, superiority) of AS04-HPV-16/18â¯vs. 4vHPV for HPV-16 and HPV-18 by pseudovirion-based neutralization assay (PBNA) at month 7 and safety. Non-inferiority criteria was lower limit (LL) of the 95% confidence interval (CI) of the GMT ratio AS04-HPV-16/18/4vHPV above 0.5, in the according to protocol population. NCT01031069. FINDINGS: Among 873 subjects recruited between 26-Oct-2010 and 14-May-2015, 546 were randomized (1:1) and received at least one vaccine dose (total vaccinated cohort, TVC): 257 were WLWH (129 AS04-HPV-16/18; 128 4vHPV) and 289 were subjects without HIV (144 AS04-HPV-16/18; 145 4vHPV). Baseline CD4 cell count in WLWH was at least 350 cells/mm3.At month 7, AS04-HPV-16/18 showed immunological superiority to 4vHPV in WLWH. Neutralizing anti-HPV-16 and HPV-18 antibody GMTs were 2·74 (95% CI: 1·83; 4·11) and 7·44 (95% CI: 4·79; 11·54) fold higher in AS04-HPV-16/18â¯vs. 4vHPV (LL of the GMT ratio >1 in TVC, p<0·0001), respectively. Similar results were observed by ELISA up to month 24.Solicited local and general symptoms were in line with product labels. The number of reported serious adverse events (SAEs) was balanced throughout the study. INTERPRETATION: Both vaccines showed an acceptable safety profile in all subjects. Despite the absence of an immunological correlate of protection for HPV, differences in immune responses elicited by the vaccines especially for HPV-18 may translate into longer lasting or more robust protection against cervical cancer with the AS04-HPV-16/18 vaccine in WLWH.
RESUMEN
Adjuvant Systems (AS) are combinations of immune stimulants that enhance the immune response to vaccine antigens. The first vaccine containing an AS (AS04) was licensed in 2005. As of 2018, several vaccines containing AS04, AS03 or AS01 have been licensed or approved by regulatory authorities in some countries, and included in vaccination programs. These vaccines target diverse viral and parasitic diseases (hepatitis B, human papillomavirus, malaria, herpes zoster, and (pre)pandemic influenza), and were developed for widely different target populations (e.g. individuals with renal impairment, girls and young women, infants and children living in Africa, adults 50â¯years of age and older, and the general population). Clearly, the safety profile of one vaccine in one target population cannot be extrapolated to another vaccine or to another target population, even for vaccines containing the same adjuvant. Therefore, the assessment of adjuvant safety poses specific challenges. In this review we provide a historical perspective on how AS were developed from the angle of the challenges encountered on safety evaluation during clinical development and after licensure, and illustrate how these challenges have been met to date. Methods to evaluate safety of adjuvants have evolved based on the availability of new technologies allowing a better understanding of their mode of action, and new ways of collecting and assessing safety information. Since 2005, safety experience with AS has accumulated with their use in diverse vaccines and in markedly different populations, in national immunization programs, and in a pandemic setting. Thirteen years of experience using antigens combined with AS attest to their acceptable safety profile. Methods developed to assess the safety of vaccines containing AS have progressed the way we understand and investigate vaccine safety, and have helped set new standards that will guide and support new candidate vaccine development, particularly those using new adjuvants. FOCUS ON THE PATIENT: What is the context? Adjuvants are immunostimulants used to modulate and enhance the immune response induced by vaccination. Since the 1990s, adjuvantation has moved toward combining several immunostimulants in the form of Adjuvant System(s) (AS), rather than relying on a single immunostimulant. AS have enabled the development of new vaccines targeting diseases and/or populations with special challenges that were previously not feasible using classical vaccine technology. What is new? In the last 13 years, several AS-containing vaccines have been studied targeting different diseases and populations. Over this period, overall vaccine safety has been monitored and real-life safety profiles have been assessed following routine use in the general population in many countries. Moreover, new methods for safety assessment, such as a better determination of the mode of action, have been implemented in order to help understand the safety characteristics of AS-containing vaccines. What is the impact? New standards and safety experience accumulated over the last decade can guide and help support the safety assessment of new candidate vaccines during development.
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Adyuvantes Inmunológicos , Vacunas/inmunología , Animales , Composición de Medicamentos , Humanos , Concesión de Licencias , Vigilancia de la Población , Enfermedades Prevenibles por Vacunación/epidemiología , Enfermedades Prevenibles por Vacunación/etiología , Enfermedades Prevenibles por Vacunación/prevención & control , Vacunas/administración & dosificación , Vacunas/efectos adversos , Vacunas/químicaRESUMEN
Reactogenicity represents the physical manifestation of the inflammatory response to vaccination, and can include injection-site pain, redness, swelling or induration at the injection site, as well as systemic symptoms, such as fever, myalgia, or headache. The experience of symptoms following vaccination can lead to needle fear, long-term negative attitudes and non-compliant behaviours, which undermine the public health impact of vaccination. This review presents current knowledge on the potential causes of reactogenicity, and how host characteristics, vaccine administration and composition factors can influence the development and perception of reactogenicity. The intent is to provide an overview of reactogenicity after vaccination to help the vaccine community, including healthcare professionals, in maintaining confidence in vaccines by promoting vaccination, setting expectations for vaccinees about what might occur after vaccination and reducing anxiety by managing the vaccination setting.
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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.
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Vacunas contra la Influenza/efectos adversos , Polisorbatos/efectos adversos , Escualeno/efectos adversos , Vacunación/efectos adversos , alfa-Tocoferol/efectos adversos , Adyuvantes Inmunológicos/administración & dosificación , Adyuvantes Inmunológicos/efectos adversos , Animales , Anticuerpos Antivirales/sangre , Ensayos Clínicos como Asunto , Combinación de Medicamentos , Pruebas de Inhibición de Hemaglutinación , Humanos , Subtipo H1N1 del Virus de la Influenza A , Vacunas contra la Influenza/administración & dosificación , Narcolepsia/etiología , Farmacovigilancia , Polisorbatos/administración & dosificación , Escualeno/administración & dosificación , Vacunas de Productos Inactivados/administración & dosificación , Vacunas de Productos Inactivados/efectos adversos , alfa-Tocoferol/administración & dosificaciónRESUMEN
BACKGROUND: The ZOE-50 (NCT01165177) and ZOE-70 (NCT01165229) phase 3 clinical trials showed that the adjuvanted recombinant zoster vaccine (RZV) was ≥90% efficacious in preventing herpes zoster in adults. Here we present a comprehensive overview of the safety data from these studies. METHODS: Adults aged ≥50 (ZOE-50) and ≥70 (ZOE-70) years were randomly vaccinated with RZV or placebo. Safety analyses were performed on the pooled total vaccinated cohort, consisting of participants receiving at least one dose of RZV or placebo. Solicited and unsolicited adverse events (AEs) were collected for 7 and 30â¯days after each vaccination, respectively. Serious AEs (SAEs) were collected from the first vaccination until 12â¯months post-last dose. Fatal AEs, vaccination-related SAEs, and potential immune-mediated diseases (pIMDs) were collected during the entire study period. RESULTS: Safety was evaluated in 14,645 RZV and 14,660 placebo recipients. More RZV than placebo recipients reported unsolicited AEs (50.5% versus 32.0%); the difference was driven by transient injection site and solicited systemic reactions that were generally seen in the first week post-vaccination. The occurrence of overall SAEs (RZV: 10.1%; Placebo: 10.4%), fatal AEs (RZV: 4.3%; Placebo: 4.6%), and pIMDs (RZV: 1.2%; Placebo: 1.4%) was balanced between groups. The occurrence of possible exacerbations of pIMDs was rare and similar between groups. Overall, except for the expected local and systemic symptoms, the safety results were comparable between the RZV and Placebo groups irrespective of participant age, gender, or race. CONCLUSIONS: No safety concerns arose, supporting the favorable benefit-risk profile of RZV.