No immunological interference or concerns about safety when seasonal quadrivalent influenza vaccine is co-administered with a COVID-19 mRNA-1273 booster vaccine in adults: A randomized trial.

The objective of the study was to assess the safety and immunogenicity of mRNA-1273 COVID-19 booster vaccination when co-administered with an egg-based standard dose seasonal quadrivalent influenza vaccine (QIV). This was a phase 3, randomized, open-label study. Eligible adults aged ≥ 18 years were randomly assigned (1:1) to receive mRNA-1273 (50 µg) booster vaccination and QIV 2 weeks apart (Seq group) or concomitantly (Coad group). Primary objectives were non-inferiority of haemagglutinin inhibition (HI) and anti-Spike protein antibody responses in the Coad compared to Seq group. 497/498 participants were randomized and vaccinated in the Seq/Coad groups, respectively. The adjusted geometric mean titer/concentration ratios (95% confidence intervals) (Seq/Coad) for HI antibodies were 1.02 (0.89-1.18) for A/H1N1, 0.93 (0.82-1.05) for A/H3N2, 1.00 (0.89-1.14] for B/Victoria, and 1.04 (0.93-1.17) for B/Yamagata; and 0.98 (0.84-1.13) for anti-Spike antibodies, thus meeting the protocol-specified non-inferiority criteria. The most frequently reported adverse events in both groups were pain at the injection site and myalgia. The 2 groups were similar in terms of the overall frequency, intensity, and duration of adverse events. In conclusion, co-administration of mRNA-1273 booster vaccine with QIV in adults was immunologically non-inferior to sequential administration. Safety and reactogenicity profiles were similar in both groups (clinicaltrials.gov NCT05047770).

What is the context? Updated booster shots against COVID-19 disease are likely to offer more protection as the virus is changing over time.It is important for doctors, other healthcare providers and patients to know whether COVID-19 booster vaccines can be given at the same time as other vaccines recommended for adults.What is new? The results of our study showed that an mRNA-based COVID-19 booster vaccine could be given at the same time as the seasonal influenza vaccine.When given together, both vaccines led to immune responses and had side effects that were similar to those observed when they were given at separate times.What is the impact? The potential benefits of administering more than 1 vaccine during a healthcare visit include improved coverage and a reduced number of doctor visits needed to receive all vaccines.Co-administration of COVID-19 booster vaccines and influenza vaccines could be an attractive option for patients and healthcare professionals.

Real-world effectiveness of recombinant zoster vaccine in self-identified Chinese individuals aged ≥50 years in the United States.

We evaluated the vaccine effectiveness (VE) of two doses of recombinant zoster vaccine (RZV) against herpes zoster (HZ) and postherpetic neuralgia (PHN) in Chinese adults at Kaiser Permanente Southern California (KPSC). Chinese KPSC members were identified based on self-reported ethnicity or self-reported preferred spoken/written language. Those aged ≥50 years who received two doses of RZV 4 weeks to ≤ 6 months apart were matched 1:4 to RZV unvaccinated Chinese members and followed through June 2022; second doses were accrued 6/1/2018-12/31/2020. We estimated incidence and adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) comparing outcomes (HZ and PHN). Adjusted VE (%) was calculated as (1-aHR)×100. 3978 RZV vaccinated Chinese members were matched to 15,912 RZV unvaccinated Chinese members. The incidence per 1000 person-years (95% CI) of HZ in the vaccinated group was 1.5 (0.9-2.5) and 10.9 (9.8-12.1) in the unvaccinated group; aHR (95% CI) was 0.12 (0.07-0.21). Adjusted VE (95% CI) was 87.6% (78.9-92.7) against HZ. We identified 0 PHN cases in the vaccinated group and 19 in the unvaccinated group. Among Chinese adults aged ≥50 years, two doses of RZV provided substantial protection against HZ and PHN supporting the real-world effectiveness of the vaccine in this population.

Post-Marketing Safety Surveillance for the Adjuvanted Recombinant Zoster Vaccine: Methodology.

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.

Enabling social listening for cardiac safety monitoring: Proceedings from a drug information association-cardiac safety research consortium cosponsored think tank.

This white paper provides a summary of the presentations and discussions from a think tank on "Enabling Social Listening for Cardiac Safety Monitoring" trials that was cosponsored by the Drug Information Association and the Cardiac Safety Research Consortium, and held at the White Oak headquarters of the US Food and Drug Administration on June 3, 2016. The meeting's goals were to explore current methods of collecting and evaluating social listening data and to consider their applicability to cardiac safety surveillance. Social listening is defined as the act of monitoring public postings on the Internet. It has several theoretical advantages for drug and device safety. First, these include the ability to detect adverse events that are "missed" by traditional sources and the ability to detect adverse events sooner than would be allowed by traditional sources, both by affording near-real-time access to data from culturally and geographically diverse sources. Social listening can also potentially introduce a novel patient voice into the conversation about drug safety, which could uniquely augment understanding of real-world medication use obtained from more traditional methodologies. Finally, it can allow for access to information about drug misuse and diversion. To date, the latter 2 of these have been realized. Although regulators from the Food and Drug Administration and the United Kingdom's Medicines and Healthcare Products Regulatory Agency participated in the think tank along with representatives from industry, academia, and patient groups, this article should not be construed to constitute regulatory guidance.

Adjuvanted (AS03) A/H1N1 2009 Pandemic Influenza Vaccines and Solid Organ Transplant Rejection: Systematic Signal Evaluation and Lessons Learnt.

INTRODUCTION: We investigated a signal of solid organ transplant (SOT) rejection after immunisation with (AS03) A/H1N1 2009 pandemic influenza vaccines. METHODS: Potential immunological mechanisms were reviewed and quantitative analyses were conducted. The feasibility of pharmacoepidemiological studies was explored. RESULTS: Overall results, including data from a pharmacoepidemiological study, support the safety of adjuvanted (AS03) pandemic influenza vaccination in SOT recipients. The regulatory commitment to evaluate the signal through a stepwise investigation was closed in 2014. CONCLUSION: Lessons learned highlight the importance of investigating plausible biological mechanisms between vaccines and potentially associated adverse outcomes, and the importance of selecting appropriate study settings and designs for safety signal investigations.

Social Media Listening for Routine Post-Marketing Safety Surveillance.

INTRODUCTION: Post-marketing safety surveillance primarily relies on data from spontaneous adverse event reports, medical literature, and observational databases. Limitations of these data sources include potential under-reporting, lack of geographic diversity, and time lag between event occurrence and discovery. There is growing interest in exploring the use of social media ('social listening') to supplement established approaches for pharmacovigilance. Although social listening is commonly used for commercial purposes, there are only anecdotal reports of its use in pharmacovigilance. Health information posted online by patients is often publicly available, representing an untapped source of post-marketing safety data that could supplement data from existing sources. OBJECTIVES: The objective of this paper is to describe one methodology that could help unlock the potential of social media for safety surveillance. METHODS: A third-party vendor acquired 24 months of publicly available Facebook and Twitter data, then processed the data by standardizing drug names and vernacular symptoms, removing duplicates and noise, masking personally identifiable information, and adding supplemental data to facilitate the review process. The resulting dataset was analyzed for safety and benefit information. RESULTS: In Twitter, a total of 6,441,679 Medical Dictionary for Regulatory Activities (MedDRA(®)) Preferred Terms (PTs) representing 702 individual PTs were discussed in the same post as a drug compared with 15,650,108 total PTs representing 946 individual PTs in Facebook. Further analysis revealed that 26 % of posts also contained benefit information. CONCLUSION: Social media listening is an important tool to augment post-marketing safety surveillance. Much work remains to determine best practices for using this rapidly evolving data source.

Safety of AS03-adjuvanted inactivated split virion A(H1N1)pdm09 and H5N1 influenza virus vaccines administered to adults: pooled analysis of 28 clinical trials.

Clinical trials have shown that AS03-adjuvanted H5N1 and A(H1N1)pdm09 vaccines are highly immunogenic, although with an increased reactogenicity profile relative to non-adjuvanted vaccines in terms of the incidence of common injection site and systemic adverse events (AEs). We evaluated pooled safety data from 22,521 adults who had received an AS03-adjuvanted H5N1 or A(H1N1)pdm09 influenza or control vaccine with the purpose to identify medically-attended AEs (MAEs), including subsets of serious AEs (SAEs), potentially immune-mediated diseases (pIMDs), and AEs of special interest (AESI), and to explore a potential association of these AEs with the administration of an AS03-adjuvanted influenza vaccine. For participants who had received an AS03-adjuvanted vaccine, the relative risks (RRs) for experiencing a MAE or a SAE compared to control group (participants who had received a non-adjuvanted vaccine or saline placebo) were 1.0 (95% confidence interval [CI]: 0.9; 1.1) and 1.1 (95% CI: 0.9; 1.4), respectively. The overall RRs for experiencing an AESI or a pIMD (AS03-adjuvanted vaccine/control) were 1.2 (95% CI: 0.9; 1.6) and 1.7 (95% CI: 0.8; 3.8), respectively. Thirty-8 participants in the AS03-adjuvanted vaccine group had a pIMD reported after vaccine administration, yielding an incidence rate (IR) of 351.9 (95% CI: 249.1; 483.1) per 100,000 person-years. The estimated IRs in the AS03-adjuvanted vaccine group were greater than the literature reported rates for: facial paresis/VIIth nerve paralysis, celiac disease, thrombocytopenia and ulcerative colitis. These results do not support an association between AS03-adjuvanted H5N1 and A(H1N1)pdm09 vaccines and the AEs collected in the trials included in the analysis.

Assessment of safety in newborns of mothers participating in clinical trials of vaccines administered during pregnancy.

A panel of experts convened by the Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, developed proposed guidelines for the evaluation of adverse events in newborns of women participating in clinical trials of maternal immunization in the United States.

Manufacturers' postmarketing safety surveillance of influenza vaccine exposure in pregnancy.

Pregnant women are at increased risk for hospitalization and death with influenza infection. The limited data on safety and effectiveness of influenza immunization in pregnancy emphasizes the importance of developing new and well-designed studies and of enhancing safety surveillance in pregnant women who are vaccinated with licensed influenza vaccines. Pregnancy exposure registries aim to collect and maintain data on the effects of marketed drugs and vaccines, when prescribed in pregnancy or during breastfeeding, on the women themselves and their children. Women who are prescribed a medication or vaccine as part of their routine clinical care can be enrolled directly or through reporting health care providers on a voluntary basis. Such registries generally are established for products that are intended for use by adolescents and adults and are a key component of the safety monitoring of licensed products. This article reviews some of the pregnancy registries that have been established for US-licensed vaccines, which includes influenza vaccines, and other postlicensure safety surveillance efforts for monitoring safety in vaccinated pregnant women.

Anaphylaxis following H1N1 pandemic vaccines: safety data in perspective.

We present here a detailed analysis of anaphylaxis cases reported to GlaxoSmithKline safety database following vaccination with its H1N1 pandemic influenza vaccines, Pandemrix™ and Arepanrix™. Cases were assessed according to the Brighton Collaboration Case Definition (BCCD) as either confirmed diagnosis (97/395, 24.6%), insufficient information to fulfil the minimal criteria of the case definition (117/395, 29.6%) or anaphylaxis excluded (181/395, 45.8%). There was no evidence that the rate of anaphylaxis following vaccination with Pandemrix™ or Arepanrix™ is increased with respect to the rates of anaphylaxis for other vaccines. Our analysis also highlighted the challenges of reliably determining the rate of anaphylaxis as an adverse event in the postmarketing setting following mass vaccination, as anaphylaxis was excluded in 45.8% of reported cases.

Quantitative signal detection for vaccines: effects of stratification, background and masking on GlaxoSmithKline's spontaneous reports database.

Disproportionality analyses are increasingly gaining acceptance as signal detection tools for drug adverse events. Their application to vaccine adverse events has not been well evaluated. Disproportionality analyses based on the Multi-Item Gamma Poisson Shrinkage principle (MGPS) were applied to spontaneous adverse events reports for five vaccines with different reporting profiles. Sensitivity analyses were used to assess the potential impact of changing key parameters. We used the Company's in-house spontaneous adverse events database. We evaluated the impact of stratification, the comparator dataset and the potential for masking. We conducted a semi-quantitative assessment by comparing the changes in the disproportionality scores and the number of vaccine-event pairs that exceeded an arbitrary threshold as a measure of the impact of any of these choices. The results show that stratification by age and region has a significant impact. The effect of the comparator dataset was dependent on the vaccine being evaluated. The potential for a masking effect was only weakly noticeable. In conclusion, we opt to start with a conservative approach in which we will supplement our primary stratification against the vaccine database with unstratified analyses as well as analyses against the entire database. We recommend that similar studies be performed before introducing disproportionality analyses to a new vaccine adverse events database.

Database size and power to detect safety signals in pharmacovigilance.

Most regulatory agencies and pharmaceutical companies focus the majority of their pharmacovigilance on safety signal identification in large databases. GlaxoSmithKline (GSK) has > 100 drugs marketed worldwide. In order to determine which database has the highest statistical power to detect safety signals in three large global databases, ten GSK marketed drugs were randomly selected for review in the three databases. At the time of data lock, the FDA database (Adverse Event Reporting System [AERS]) contained approximately 6.2 million total records of adverse drug reactions (ADRs). The WHO database (VIGIBASE) contained 7.2 million total records of ADRs. GSK's global safety database (OCEANS) contained approximately 2 million total ADRs for all of its marketed drugs. For the ten drugs selected, there was an average of 7566 reports found in AERS, 8661 reports found in VIGIBASE and 15,496 reports in OCEANS. The information from all three databases was used in pairs (AERS/OCEANS; AERS/VIGIBASE; and OCEANS/VIGIBASE) to calculate power using the maximum likelihood estimation. The OCEANS database contained more ADRs for all 10 drugs than AERS. OCEANS also contained more ADRs for 8/10 drugs than VIGIBASE. The highest statistical power to detect safety signals was determined by the pair of databases which had the greatest number of reports for the given drug. Based on this data, it was concluded that the highest power may be achieved by combining those databases with the most drug-specific data. It is also believe that early safety signal detection should involve the use of multiple large global databases because this permits the use of the largest number of reports for a given drug, and that reliance on a single database may reduce statistical power and diversity of ADRs.

Female gender increases the risk of death during hospitalization for pediatric cardiac surgery.

OBJECTIVES: The study objective was to determine whether gender is a determinant of in-hospital mortality after surgery to repair congenital heart disease in patients aged 20 years or less. Secondary objectives were to determine other factors associated with increased risk of death and whether female gender is associated with increased length of stay or total charges. METHODS: The study included a retrospective cohort consisting of all records indicating cardiac operations within the Healthcare Cost and Utilization Project Kids' Inpatient Database for the year 2000. Logistic regression was used to simultaneously evaluate the effect of gender on the risk of death while adjusting for all other factors being considered. Logistic regression was then used to evaluate possible differences in length of stay or total charges. RESULTS: Female gender was associated with increased risk of in-hospital death when all of the other measured factors were taken into consideration (odds ratio 1.31, 95% confidence interval 1.02-1.69). Other factors that were significantly associated with increased in-hospital mortality after pediatric cardiac surgery included the number of days between admission and operation; African American race; young age (neonates and infants compared with children aged > or =1 year); pulmonary hypertension; and the Norwood operation. There were no significant gender differences in risk-adjusted length of stay or total charges. CONCLUSIONS: In-hospital mortality after pediatric cardiac surgery seems to be associated with patient gender but not with the type of insurance or ability to access higher-volume pediatric facilities or teaching hospitals.

Perspectives on the use of data mining in pharmaco-vigilance.

In the last 5 years, regulatory agencies and drug monitoring centres have been developing computerised data-mining methods to better identify reporting relationships in spontaneous reporting databases that could signal possible adverse drug reactions. At present, there are no guidelines or standards for the use of these methods in routine pharmaco-vigilance. In 2003, a group of statisticians, pharmaco-epidemiologists and pharmaco-vigilance professionals from the pharmaceutical industry and the US FDA formed the Pharmaceutical Research and Manufacturers of America-FDA Collaborative Working Group on Safety Evaluation Tools to review best practices for the use of these methods.In this paper, we provide an overview of: (i) the statistical and operational attributes of several currently used methods and their strengths and limitations; (ii) information about the characteristics of various postmarketing safety databases with which these tools can be deployed; (iii) analytical considerations for using safety data-mining methods and interpreting the results; and (iv) points to consider in integration of safety data mining with traditional pharmaco-vigilance methods. Perspectives from both the FDA and the industry are provided. Data mining is a potentially useful adjunct to traditional pharmaco-vigilance methods. The results of data mining should be viewed as hypothesis generating and should be evaluated in the context of other relevant data. The availability of a publicly accessible global safety database, which is updated on a frequent basis, would further enhance detection and communication about safety issues.

Adverse events after protamine administration following cardiopulmonary bypass in infants and children.

UNLABELLED: We performed this study to determine the incidence of and risk factors for adverse events (AEs) in infants and children after the IV administration of protamine after cardiopulmonary bypass. In a retrospective cohort study, all relevant anesthesia records from a 3-yr period were examined to identify AEs after protamine. The AEs were then grouped into three categories by applying increasingly strict criteria. Among 1249 anesthesia records, there were no documented episodes of isolated or hypotension-associated right-sided cardiac failure or acute pulmonary dysfunction. The incidence of systemic hypotension after protamine was between 1.76% (95% confidence interval [CI], 1.11%-2.65%) and 2.88% (95% CI, 2.03%-3.97%), depending on the strictness of case definition. To identify risk factors, we performed a nested case-control study in which unmatched controls were randomly selected from the parent cohort at a 4:1 ratio to cases. Cases of hypotension after protamine were more likely during operations on girls (odds ratio [OR], 6.47; 95% CI, 1.66-32.8), after larger doses of protamine (OR, 1.88; 95% CI, 1.03-3.63), or after smaller doses of heparin (OR, 0.49; 95% CI, 0.17-0.67). IMPLICATIONS: Systemic hypotension after protamine administration occurred in 1.76%-2.88% of pediatric patients having cardiac surgery. Female sex, larger protamine dose, and smaller heparin dose were each associated with increased risk. The development of protamine alternatives or prophylactic therapies may be useful for reducing the frequency of these events.