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Two quadrivalent meningococcal conjugate vaccines (MenACWY) that prevent invasive meningococcal disease caused by N. meningitidis serogroups A, C, Y, and W have been licensed in the U.S. in the past 10–15 years. We systematically reviewed published studies conducted in the U.S. to evaluate the real-world safety evidence of meningococcal conjugate vaccines. We performed a literature search in PubMed of publications from 01/01/2005 to 02/29/2020 and identified 18 studies meeting inclusion criteria. Populations included high-risk persons aged 2 months to 10 years, adolescents/adults aged ≥11 years, pregnant populations, and hematopoietic cell transplant recipients. We extracted information about study setting, study design, exposure, outcomes, comparison group, follow-up/look back period, study population, sample size, available demographic/indication information, results, key conclusion, and reference. These published studies found no new significant safety concerns related to MenACWY. Consideration for future research includes a post-licensure safety evaluation of a new MenACWY product approved in April 2020.

The study investigated the safety of 4-component meningococcal serogroup B vaccination (4CMenB) in routine care. 4CMenB exposure and seizures, febrile seizures and Kawasaki disease were identified from The Health Improvement Network (THIN) database of UK electronic primary healthcare records, 2015–2018. A self-controlled case series analysis was completed. Anaphylaxis, Guillain-Barre syndrome and acute disseminated encephalomyelitis were secondary outcomes. A total of 107,231 children aged 1–18 months received ≥1 doses of 4CMenB vaccination. Most 4CMenB exposure (93%) was on the same day as other vaccines within a complete national immunisation program stage. With day 0 as day of vaccination, 43 seizures occurred in days 0–6 after 239,505 doses, and 23 febrile seizures occurred in days 0–6, and 4 Kawasaki disease cases in days 1–28 after 194,929 4CMenB doses. Adjusted incidence rate ratios including all 4CMenB exposures were 1.43 (95%CI: 1.02–2.02) for seizures and 1.72 (95%CI: 1.08–2.75) for febrile seizures. There were insufficient cases to model Kawasaki disease, and no cases of the secondary outcomes in risk periods when they may be associated with the vaccination. This study shows few cases of the outcomes after vaccination including 4CMenB with an increased risk of seizures and febrile seizures. It is not possible to attribute the finding to one specific vaccination as the majority of 4CMenB was given with other vaccinations. Trial registration: NA.

Background The Sentinel Initiative was established in 2008 to monitor the safety of FDA-regulated medical products. We evaluated the positive predictive value (PPV) of ICD-9 codes for post-vaccination febrile seizures to identify optimal algorithms for use in post-market safety surveillance. Methods We identified ICD-9 diagnosis codes for fever and seizures in the emergency department or inpatient setting after vaccinations of interest from July 1, 2010 to June 30, 2011. Medical record review was conducted to verify febrile seizure events. Results Of 216 potential febrile seizures identified with one or more seizure codes (the broadest algorithm), 152 were chart-confirmed (i.e., documentation of fever within 24 h of seizure or clinician diagnosis of febrile seizure; PPV 70%, 95% CI 64, 76%). Two codes specific for febrile seizures produced the highest PPV (PPV 91%, 95% CI 85, 95%) and accounted for 140 confirmed febrile seizures. In the absence of febrile seizure codes, other seizure codes yielded much lower PPVs, regardless of the presence of fever codes. Conclusions Our results indicate that ICD-9 diagnosis codes in the inpatient and emergency department settings have high predictive value for identifying febrile seizures within the Sentinel Distributed Database. While the PPV of the algorithm based on any diagnosis code for seizure is moderate, the algorithm limited to febrile seizure codes has a high PPV (>90%) and captures the vast majority of confirmed cases identified by the broadest algorithm, suggesting that the narrower algorithm limited to febrile seizure codes may be preferred.

Rotavirus gastroenteritis is a major public health concern globally, estimated to cause 215,000 deaths among children < 5 years of age in 2013; with majority of mortality occurring in developing countries. In 2013, it was estimated that Nigeria was the second country with the highest number of rotavirus deaths. Monitoring of circulating rotavirus strains in Enugu, Nigeria is part of on-going rotavirus surveillance before the introduction of rotavirus vaccination. A total of 2694 stool samples were collected from enrolled under 5 years old children with diarrhoea between January 2011 and December 2016 and tested the virus using an antigen enzyme immunoassay. Randomly selected rotavirus positive samples were further characterized by rotavirus genotype methods to identify the G and P types circulating during the study period. Rotavirus was detected in 1242 (46%) of the 2694 samples collected over the six years period. Of these, 867 were randomly selected for genotyping. G and P types could be assigned for 832 samples (96%), while 31 (3.6%) could only be assigned either genotype G or P (partially typed) and 4 (0.4%) could not be assigned genotype G and P (untypeable). The most common G-genotypes detected during the entire study period were G12, G1 and G3 accounting for 27.6%, 21.0% and 16.3% respectively. Mixed G and P-genotypes were commonly detected. Ninety-one of the samples, representing 10.8% (91/839) had mixed G-genotype whilst 130 of the samples representing 15.2% (130/852) had mixed P-genotype. The most common P-genotypes detected were P[8], P[6] and P[4] representing 38.3%, 35.4% and 9.1% respectively. The predominant strain detected was G12P[8] (22.3%) followed by G3P[6] (14.5%), G1P[8] (9.2%) and G1P[6] (8.0%). These data are useful for making an informed decision about the introduction of rotavirus vaccine into the national routine immunization program and to monitor the impact of the vaccine post licensure.

Raltegravir became the first integrase inhibitor to gain FDA approval; but with limited evidence documenting long-term risks in real world care, especially for major health outcomes of interest.Assess raltegravir safety in clinical practice within an integrated health system.We conducted a cohort study of HIV-infected adults within Kaiser Permanente California from 2005 to 2013. We compared patients initiating raltegravir during the study period with two groups; a historical cohort (started new antiretroviral regimen [ART] 2005-2007) and a concurrent cohort that did not initiate raltegravir (2007-2013). We used multivariate Cox proportional hazard regression to obtain hazard ratios (HR) for pre-specified incident health outcomes, employing propensity scores to adjust for potential confounding.The population included 8,219 HIV-infected adults (raltegravir cohort N = 1,757; 4,798 patient-years), with greater years known HIV-infected among raltegravir patients. The raltegravir cohort had increased HR for AIDS-defining (HR 2.69 [1.53-4.71]; HR 1.85 [1.21-2.82]) and non-AIDS-defining malignancies (HR 2.26 [1.29-3.94]; HR 1.88 [1.26-2.78]) relative to both comparison cohorts. Compared to the historical cohort we found no significant difference in all-cause mortality; the raltegravir cohort experienced increased HR for all-cause mortality compared to concurrent (HR 1.53 [1.02-2.31]). Raltegravir appeared protective of lipodystrophy when compared to the historical cohort but associated with increased incidence compared to concurrent. There were no significant differences in the incidence of hepatic, skin, or cardiovascular events.The potentially elevated risk for malignancy and mortality with raltegravir and residual confounding merits further investigation. We demonstrate the value of observational cohorts for monitoring post-licensure medication safety.

Objectives To report the efficacy of Human Botulism Immune Globulin Intravenous (BIG-IV) in the first 12 years following its licensure in 2003 and to characterize its use nationwide in treating patients with infant botulism. Study design Medical records and billing information were collected for US patients treated with BIG-IV from 2003 to 2015. Length of hospital stay (LOS) and hospital charge information for treated patients were compared with the BIG-IV Pivotal Clinical Trial Placebo Group to quantify decreases in LOS and hospital charges. Results The use of BIG-IV reduced mean LOS from 5.7 to 2.2 weeks. This shortened hospital stay resulted in a mean decrease in hospital charges of $88 900 per patient. For all US patients 2003-2015, total decreases in LOS and hospital charges were 66.9 years and $86.2 million, respectively. The decrease in mean LOS was time dependent: BIG-IV treatment on hospital days 0-3 reduced mean LOS by 3.7 weeks ( P P P = NS). Since licensure, 1192 patients in 48 states and Washington, DC, have been treated with BIG-IV. Conclusions The use of BIG-IV since its licensure in 2003 treated approximately 93% of US patients with laboratory-confirmed infant botulism, and prevented >65 years in hospital stay and >$85 million in hospital charges from occurring. The greatest LOS reduction was achieved when BIG-IV was administered soon after hospital admission. Effective and appropriate use of BIG-IV in the US has continued in the postlicensure period.

Monoclonal antibody (mAb)-based therapeutics are playing an increasingly important role in the treatment or prevention of many important diseases such as cancers, autoimmune disorders, and infectious diseases. Multi-domain mAbs are far more complex than small molecule drugs with intrinsic heterogeneities. The critical quality attributes of a given mAb, including structure, post-translational modifications, and functions at biomolecular and cellular levels, need to be defined and profiled in details during the developmental phases of a biologics. These critical quality attributes, outlined in this review, serve an important database for defining the drug properties during commercial production phase as well as post licensure life cycle management. Specially, the molecular characterization, functional assessment, and effector function analysis of mAbs, are reviewed with respect to the critical parameters and the methods used for obtaining them. The three groups of analytical methods are three essential and integral facets making up the whole analytical package for a mAb-based drug. Such a package is critically important for the licensure and the post-licensure life cycle management of a therapeutic or prophylactic biologics. In addition, the basic principles on the evaluation of biosimilar mAbs were discussed briefly based on the recommendations by the World Health Organization.

Resume Objectif Decrire le profil et l’incidence des effets indesirables (EI) notifies avec Prevenar 13® depuis sa commercialisation. Methode Analyse de tous les effets indesirables notifies en France entre le 1er juillet 2010 et le 31 octobre 2014. Resultats En 4 ans et 4 mois, 376 declarations d’EI dont 252 graves (67 %) ont ete enregistrees, parmi lesquels 83 etaient survenus au decours d’une injection de Prevenar 13® seul. Il s’agissait de 39 EI cutanes et 16 neurologiques, de 4 malaises, de 9 fievres et d’une thrombopenie. L’evolution a ete favorable pour 88 % des EI graves et aucun des 12 deces rapportes n’a ete attribue a un EI de la vaccination. Cinquante-neuf cas d’infection pneumococcique faisant suspecter une inefficacite vaccinale ont ete rapportes, mais seuls 16 ont pu etre consideres comme un reel echec de la vaccination. Discussion Dans de nombreux cas, le Prevenar 13® avait ete administre le meme jour qu’un vaccin hexavalent avec lequel l’EI rapporte etait attendu. Le profil des EI rapportes au decours de l’injection de Prevenar 13® seul est similaire a celui observe avec le Prevenar 7®. Conclusion Le suivi de pharmacovigilance de Prevenar 13® mis en place en France depuis sa commercialisation en 2010 et qui porte a ce jour sur plus de 11 800 000 doses distribuees n’a pas mis en evidence de fait nouveau de securite.

Background The 13-valent pneumococcal conjugate vaccine (PCV13) was first recommended for use in adults aged ⩾19 years with immunocompromising conditions in June 2012. On August 2014, the Advisory Committee on Immunization Practices (ACIP) recommended routine use of PCV13 among adults aged ⩾65 years. Methods We assessed adverse events (AEs) reports following PCV13 in adults aged ⩾19 years reported to the Vaccine Adverse Event Reporting System (VAERS) from June 2012 to December 2015. VAERS is a national spontaneous reporting system for monitoring AEs following vaccination. Our assessment included automated data analysis, clinical review of all serious reports and reports of special interest. We conducted empirical Bayesian data mining to assess for disproportionate reporting. Results VAERS received 2976 US PCV13 adult reports; 2103 (71%) of these reports were from PCV13 administered alone. Fourteen percent were in persons aged 19–64 years and 86% were in persons aged ⩾65 years. Injection site erythema (28%), injection site pain (24%) and fever (22%) were the most frequent AEs among persons aged 19–64 years; injection site erythema (30%), erythema (20%) and injection site swelling (18%) were the most frequent among persons aged ⩾65 years who were given the vaccine alone. The most frequently reported AEs among non-death serious reports were injection site reactions and general malaise among persons 19–64 years old; injection site reactions, general malaise and Guillain-Barre syndrome among those ⩾65 years (Table 2). Data mining did not detect disproportional reporting for any unexpected AE. Conclusions The results of this study were consistent with safety data from pre-licensure studies of PCV13. We did not detect any new or unexpected AEs.

The efficacy of vaccines is typically estimated prior to implementation, on the basis of randomized controlled trials. This does not preclude, however, subsequent assessment post-licensure, while mass-immunization and nonlinear transmission feedbacks are in place. In this paper we show how cross-sectional prevalence data post-vaccination can be interpreted in terms of pathogen transmission processes and vaccine parameters, using a dynamic epidemiological model. We advocate the use of such frameworks for model-based vaccine evaluation in the field, fitting trajectories of cross-sectional prevalence of pathogen strains before and after intervention. Using SI and SIS models, we illustrate how prevalence ratios in vaccinated and non-vaccinated hosts depend on true vaccine efficacy, the absolute and relative strength of competition between target and non-target strains, the time post follow-up, and transmission intensity. We argue that a mechanistic approach should be added to vaccine efficacy estimation against multi-type pathogens, because it naturally accounts for inter-strain competition and indirect effects, leading to a robust measure of individual protection per contact. Our study calls for systematic attention to epidemiological feedbacks when interpreting population level impact. At a broader level, our parameter estimation procedure provides a promising proof of principle for a generalizable framework to infer vaccine efficacy post-licensure. sem patrocinadores explícitos no artigo.

In 1999, the first rhesus-human reassortant rotavirus vaccine licensed in the U.S. was withdrawn within a year of its introduction after it was linked with intussusception at a rate of ~1 excess case per 10,000 vaccinated infants. While clinical trials of 60,000–70,000 infants of each of the two current live oral rotavirus vaccines, RotaTeq (RV5) and Rotarix (RV1), did not find an association with intussusception, post-licensure studies have documented a risk in several high and middle income countries, at a rate of ~1–6 excess cases per 100,000 vaccinated infants. However, considering this low risk against the large health benefits of vaccination that have been observed in many countries, including in countries with a documented vaccine-associated intussusception risk, policy makers and health organizations around the world continue to support the routine use of RV1 and RV5 in national infant immunization programs. Because the risk and benefit data from affluent settings may not be directly applicable to developing countries, further characterization of any associated intussusception risk following rotavirus vaccination as well as the health benefits of vaccination is desirable for low income settings.

Intimate partner violence (IPV) has a 1 in 4 prevalence for women globally. Nursing programs are positioned to prepare students to address IPV screening and brief counselling policy recommendations within curricula. The purpose of this project was to refine the undergraduate nursing curriculum to better facilitate student comfort with and knowledge of IPV screening and intervention using simulation. Methods: We used a 4-item pre/posttest tool to evaluate nursing students’ comfort level with IPV screening and safety planning before and after an IPV simulation with a standardized patient as part of the formative assessment of the simulation. Results: Close to 80% of students (N = 133) reported feeling more comfortable with discussing IPV, screening for IPV, talking to people about IPV, and safety planning after completing the IPV simulation. Conclusion: Infusing IPV screening and intervention simulation into curricula gives students a hands-on opportunity to practice critical trauma-informed skills before encountering a patient exposed to violence. This exposure enhances student comfort with and increases knowledge of screening and intervening with families exposed to IPV and as a result may help to decrease known barriers to IPV screening and intervening post licensure.

BACKGROUND Trivalent adjuvanted influenza vaccine (aIIV3; Fluad®) was approved in the United States (U.S.) in 2015 for adults aged ≥65 years and has been in use since the 2016-17 influenza season. METHODS We analyzed U.S. reports for aIIV3 submitted from July 1, 2016 through June 30, 2018 to the Vaccine Adverse Event Reporting System (VAERS), a national spontaneous reporting system. Medical records were reviewed for serious reports. Among individuals ≥65 years of age, the relative frequency of the most commonly reported adverse events (AEs) after aIIV3 were compared with non-adjuvanted inactivated influenza vaccines given to adults aged ≥65 years, high-dose trivalent influenza vaccine (IIV3-HD) and trivalent or quadrivalent vaccines (IIV3/IIV4). Data mining analyses were undertaken to identify whether AEs for aIIV3 occurred disproportionately more than expected compared to all influenza vaccines. RESULTS VAERS received 630 reports after aIIV3, of which 521 (83%) were in adults aged ≥65 years; 79 (13%) in persons

Latin American countries were among the first to adopt rotavirus vaccines into national immunization programs; we reviewed one decade of their experience with rotavirus vaccination.We systematically reviewed manuscripts published January 1990-January 2018 to assess rotavirus vaccine effectiveness (VE) via meta-analysis; describe trends in rotavirus and acute gastroenteritis (AGE)-associated hospitalizations and mortality before and after vaccine introduction; and estimate annual hospitalizations and deaths averted by rotavirus vaccination in Latin American and Caribbean children5 years. Rotavirus vaccines demonstrated VE against rotavirus hospitalization of 76% (95% CI: 58-87) in low-mortality countries and 67% (95% CI: 54-76) in high-mortality countries for children1 year of age. Reductions of 64.0% (interquartile range (IQR): 49.9-69.2) were observed in rotavirus hospitalizations, 32.8% (IQR 29.0-40.3) in AGE hospitalizations, and 53.5% (IQR: 40.4-57.1) in AGE-related mortalities in children5 years. In 2015, an estimated 125,000 rotavirus-associated hospitalizations and 800 rotavirus-related deaths were prevented in countries that implemented rotavirus vaccines.Rotavirus vaccines remain an effective tool against diarrheal disease. The continued success of rotavirus vaccines provides evidence for adoption in Latin American and Caribbean countries that have not yet introduced it, and improvement within those with low coverage.

Background: Herpes zoster (HZ), or shingles, is caused by reactivation of varicella-zoster virus in latently infected individuals. Live-attenuated HZ vaccine (zoster vaccine live, ZVL) is approved in the United States for persons aged ≥50 years and recommended by the CDC for persons ≥60 years. Methods: We analyzed U.S. reports of adverse events (AEs) following ZVL submitted to the Vaccine Adverse Event Reporting System (VAERS), a spontaneous reporting system to monitor vaccine safety, for persons vaccinated May 1, 2006, through January 31, 2015. We conducted descriptive analysis, clinical reviews of reports with selected pre-specified conditions, and empirical Bayesian data mining. Results: VAERS received 23,092 reports following ZVL, of which 22,120 (96%) were classified as non-serious. Of reports where age was documented (n = 18,817), 83% were in persons aged ≥60 years. Reporting rates of AEs were 106 and 4.4 per 100,000 ZVL doses distributed for all reports and serious reports, respectively. When ZVL was administered alone among persons aged ≥50 years, injection site erythema (27%), HZ (17%), injection site swelling (17%), and rash (14%) were the most commonly reported symptoms among non-serious reports; HZ (29%), pain (18%), and rash (16%) were the most commonly reported symptoms among serious reports. Six reports included laboratory evidence of vaccine-strain varicella-zoster virus (Oka/Merck strain) infection; AEs included HZ, HZ- or varicella-like illness, and local reaction with vesicles. In our review of reports of death with sufficient information to determine cause (n = 46, median age 75 years), the most common causes were heart disease (n = 28), sepsis (n = 4), and stroke (n = 3). Empirical Bayesian data mining did not detect new or unexpected safety signals. Conclusions: Findings from our safety review of ZVL are consistent with those from pre-licensure clinical trials and other post-licensure assessments. Transient injection-site reactions, HZ, and rashes were most frequently reported to VAERS following ZVL. Overall, our results are reassuring regarding the safety of ZVL.

Therapeutic antibodies have been manufactured since the advent of intravenous immunoglobulin in the 1950s. Rituxan was the first recombinant monoclonal antibody approved for therapeutic use by the U.S. Food and Drug Administration (FDA) in 1997. Now, over 50 recombinant monoclonal antibodies have been licensed for commercial distribution [ 1 ]. Post-licensure manufacturing process changes provide opportunities to increase manufacturing capacity, improve product quality, consistency, or safety, and may be necessary upon process transfer to a new facility [ 2 ]. Yet, the complexity of global regulatory authority oversight and approval sets a high bar for manufacturing process changes for an approved parenteral protein therapeutic. This review examines the history of antibody production, focusing on purification process technology. Strategies for post-licensure changes are discussed, including regulatory considerations. Case studies are described for several antibody process purification changes. Finally, some speculations are shared about the potential future of purification process technology and post-licensure process changes for commercial therapeutic antibody production.

Complex regional pain syndrome (CRPS) is a chronic pain disorder that typically follows trauma or surgery. Suspected CRPS reported after vaccination with human papillomavirus (HPV) vaccines led to temporary suspension of proactive recommendation of HPV vaccination in Japan. We investigated the potential CRPS signal in relation to HPV-16/18-adjuvanted vaccine (Cervarix (R)) by database review of CRPS cases with independent expert confirmation; a disproportionality analysis and analyses of temporality; an observed versus expected analysis using published background incidence rates; systematic reviews of aggregate safety data, and a literature review. The analysis included 17 case reports of CRPS: 10 from Japan (0.14/100,000 doses distributed) and seven from the United Kingdom (0.08/100,000). Five cases were considered by independent experts to be confirmed CRPS. Quantitative analyses did not suggest an association between CRPS and HPV-16/18-adjuvanted vaccine. Observed CRPS incidence after HPV-16/18 vaccination was statistically significantly below expected rates. Systematic database reviews using search terms varying in specificity and sensitivity did not identify new cases. No CRPS was reported during clinical development and no unexpected results found in the literature. There is not sufficient evidence to suggest an increased risk of developing CRPS following vaccination with HPV16/18-adjuvanted vaccine. Post-licensure safety surveillance confirms the acceptable benefit-risk of HPV-16/18 vaccination. (C) 2015 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

BackgroundJapanese encephalitis is a mosquito-borne viral disease endemic in most countries in Asia. A recombinant live, attenuated Japanese encephalitis virus vaccine, JE-CV, is licensed in 14 countries, including Thailand, for the prevention of Japanese encephalitis in adults and children.MethodsThis was a prospective, phase IV, open-label, multicentre, safety study of JE-CV conducted from November 2013 to April 2015, to evaluate rare serious adverse events (AEs). JE-CV was administered to 10,000 healthy children aged 9months to

Background Leadership is a process by which an individual influences a group or individual to achieve a common goal, in this case health promotion for individuals with disabilities. Objectives (1) To examine the association between the transformational leadership behaviors of the Association of University Centers on Disabilities (AUCD) network professionals and their practice beliefs about health promotion activities, specifically cardiovascular fitness and healthy weight, for people with disabilities. (2) To determine if discipline and/or years of practice moderate the association between transformational leadership behaviors and practice beliefs regarding health promotion. Hypothesis There is a positive association between transformational leadership behaviors and health professionals practice beliefs regarding health promotion activities for persons with disabilities. Methods A quantitative cross-sectional web-based survey design was used to determine the association between leadership behaviors and practices beliefs regarding health promotion for people with disabilities. The Multifactor Leadership Questionnaire and an adapted version of the Role of Health Promotion in Physical Therapy Survey were used to measure leadership and practice beliefs, respectively. Multiple regression analysis was applied to determine the association of leadership behaviors with health promotion practice beliefs variables. Results Transformational leadership behaviors of the AUCD network professionals were positively associated with health promotion practice beliefs about cardiovascular fitness for people with disabilities. Years post licensure and discipline did not moderate the association between transformational leadership and practice beliefs regarding health promotion. Conclusion Transformational leadership may facilitate health professionals' health promotion practices for people with disabilities. Further research and training in leadership is needed.

A valid, reliable practice assessment is needed to support intervention on the public’s behalf when the pattern of a nurse’s performance results in or is likely to result in patient harm. A collaborative multiagency research team developed and tested a criterion-referenced competency assessment process, using high-fidelity clinical simulation based on the Taxonomy of Error Root Cause Analysis and Practice Responsibility and the Clinical Competency Assessment of Newly Licensed Nurses. The 41-item instrument includes nine competency categories essential for safe practice. Registered nurses volunteered to be tested three times in the simulation laboratory ( N = 21). Experienced nurses made significantly fewer errors ( M = − 0.86, S = 0.50) than inexperienced nurses ( M = − 1.52, S = 0.91, p

Rotavirus causes approximately 450,000 deaths annually among children less than 5 years of age worldwide, almost half of which occur in Africa. After the recent completion of successful trials of 2 new rotavirus vaccines, the World Health Organization has recommended these vaccines for all children worldwide. Because a previous rotavirus vaccine, Rotashield(®), was associated with intussusception, a form of intestinal obstruction among infants, the current rotavirus vaccines were tested in large clinical trials and found to be safe. However, due to the past Rotashield(®) experience, post licensure monitoring of intussusception is considered to be crucial after the introduction of future oral rotavirus vaccines. Thus, in planning for future introductions of rotavirus vaccine in Africa, a workshop of experts working on intussusception was convened by the World Health Organization in May 2004 in association with the Pan-African Association of Paediatric Surgeons (PAPSA) in Malawi. In brief, delegates from ten countries presented data from retrospective record reviews of intussusception events from 1993 to 2003 at selected hospitals in their respective countries. This review showed that age of intussusception onset during infancy varies markedly with peak prevalence between 4 and 6 months of life. Diagnostic modality (e.g., contrast enema, ultrasound) was employed in

Rotavirus gastroenteritis (RVGE) is the leading cause of severe diarrhea in children worldwide. This paper provides an overview of the development, clinical evaluation, and postlicensure impact of RotaTeq™(Rotavirus Vaccine, Live, Oral, Pentavalent, Merck & Co., Inc.). RotaTeq, an oral vaccine, is uniquely designed to contain five human-bovine reassortant rotavirus strains expressing the human serotypes G1, G2, G3, G4, and P1A[8], which represent the most common human rotavirus serotypes responsible for ∼85% of RVGE worldwide. The development required novel solutions for manufacturing, testing, and formulation for each of the reassortants. In one of the largest vaccine clinical trials conducted, the vaccine was shown to be well tolerated and highly efficacious against severe RVGE. Efficacy has also been demonstrated in lower-income countries. In large U.S. postlicensure studies, there have been no safety signals identified, and RotaTeq has had a significant impact on reducing RVGE and its associated medical costs since licensure in 2006.

Post-licensure evaluation of vaccines plays an important role in monitoring the progress of immunization programs, demonstrating population impact of vaccines, and providing data for ongoing policy decisions. Two human papillomovirus (HPV) vaccines are licensed and recommended for use in females in the United States, a quadrivalent human HPV vaccine, licensed in 2006 and a bivalent vaccine HPV vaccine licensed in 2009. HPV vaccination is recommended for females 11 or 12 years of age with catch-up vaccination through age 26 years. Post-licensure monitoring of the HPV vaccine program has included some of the same systems established for other vaccines, such as those for vaccine safety and coverage monitoring. However, monitoring HPV vaccine impact on infection and disease outcomes has required new efforts. While there are well established cancer registries in the United States, it will take decades before the impact of vaccine on cervical cancer is observed. More proximal measures of vaccine impact include outcomes such as prevalence of HPV vaccine types, incidence of cervical precancers and genital warts. We review systems in place or being established for post-licensure monitoring of HPV vaccine in the United States.

Evaluation of vaccine stability does not end with licensure of the product. An annual stability program helps assure continued quality of product throughout the dating period, while comparability studies are performed after a process or facilities change in order to demonstrate that the change has not impacted the stability characteristics of the product. Careful attention to the design and analysis of post licensure studies helps mitigate the risk of missing a meaningful shift in the degradation rate of a vaccine, as well as the possibility of incorrectly earmarking a stability shift when the product remains acceptable.

Background 23-Valent pneumococcal polysaccharide vaccine, trade name Pneumovax ® 23 (PPSV23), has been used for decades in the Unites States and has an extensive clinical record. However, limited post-licensure safety assessment has been conducted. Objective To analyze reports submitted to the Vaccine Adverse Event Reporting System (VAERS) following PPSV23 from 1990 to 2013 in order to characterize its safety profile. Methods We searched the VAERS database for US reports following PPSV23 for persons vaccinated from 1990 to 2013. We assessed safety through: automated analysis of VAERS data, crude adverse event (AE) reporting rates based on PPSV23 doses distributed in the US market, clinical review of death reports and reports involving vaccine administered to pregnant women, and empirical Bayesian data mining to assess for disproportional reporting. Results During the study period, VAERS received 25,168 PPSV23 reports; 92% were non-serious, 67% were in females and 86% were in adults aged ≥19 years. When PPSV23 was administered alone, fever (43%), injection site erythema (28%) and injection site pain (25%) were the most commonly reported non-serious AEs in children. Injection site erythema (32%), injection site pain (27%) and injection site swelling (23%) were the most commonly reported non-serious AEs in adults. Of serious reports (2129, 8% of total), fever was most commonly reported in both children (69%) and adults (39%). There were 66 reports of death, four in children and 62 in adults. Clinical review of death reports did not reveal any concerning patterns that would suggest a causal association with PPSV23. No disproportional reporting of unexpected AEs was observed in empirical Bayesian data mining. Conclusions We did not identify any new or unexpected safety concerns for PPSV23. The VAERS data are consistent with safety data from pre-licensure clinical trials and other post-licensure studies.

INTRODUCTION Interprofessional education (IPE) has been recognized by the World Health Organization (WHO) as one potential approach for improving health care delivery and outcomes. The premise is that effective IPE can lead to more effective collaborative practice among health professionals from different disciplines. This in turn can lead to better health care delivery. IPE has been shown in the literature to be associated with increased patient satisfaction, better health outcomes, shorter hospital stays, improved staff morale, and a range of other benefits. In addition, successful examples of IPE initiatives from around the world demonstrate that IPE and collaborative practice can be beneficial to health care in a variety of contexts.

Background Quadrivalent live attenuated influenza vaccine (LAIV4) was approved in 2012 for healthy persons aged 2–49 years. Beginning with the 2013–2014 influenza season, LAIV4 replaced trivalent live attenuated influenza vaccine (LAIV3). Methods We analyzed LAIV4 reports to VAERS, a national spontaneous reporting system. LAIV4 reports in 2013–2014 were compared to LAIV3 reports from the previous three influenza seasons. Medical records were reviewed for non-manufacturer serious reports (i.e., death, hospitalization, prolonged hospitalization, life-threatening illness, permanent disability) and reports of selected conditions of interest. We conducted Empirical Bayesian data mining to identify disproportional reporting for LAIV4. Results In 2013–2014, 12.7 million doses of LAIV4 were distributed and VAERS received 779 reports in individuals aged 2–49 years; 95% were non-serious. Expired drug administered (42%), fever (13%) and cough (8%) were most commonly reported in children aged 2–17 years when LAIV4 was administered alone, while headache (18%), expired drug administered (15%) and exposure during pregnancy (12%) were most common in adults aged 18–49 years. We identified one death report in a child who died from complications of cerebellar vascular tumors. Among non-death serious reports, neurologic conditions were common in children and adults. In children, seizures (3) and Guillain-Barre syndrome (2) were the most common serious neurologic outcomes. We identified three serious reports of asthma/wheezing following LAIV4 in children. Data mining detected disproportional reporting for vaccine administration errors and for influenza illness in children. Conclusions Our analysis of VAERS reports for LAIV4 did not identify any concerning patterns. The data mining finding for reports of influenza illness is consistent with low LAIV4 vaccine effectiveness observed for influenza A disease in children in 2013–2014. Reports of LAIV4 administration to persons in whom the vaccine is not recommended (e.g., pregnant women) indicate the need for education, training and screening regarding indications.

Our recent experience in a post-licensure safety study of autoimmune conditions following the quadrivalent human papillomavirus vaccine in 189,629 girls and young women ages 9-26 years led us to question the adequacy of the exclusion of Day 0 events to prevent the erroneous association of prevalent conditions with vaccination. Of the 18 confirmed cases of Graves' disease diagnosed in days 1-60 following vaccination, only 6 cases appeared to be truly new onset. Among the remaining 12 cases, 2 cases had abnormal thyroid stimulating hormone or thyroxine labs drawn prior to or on Day 0 but had no documented pre-existing symptoms. The other 10 cases had mention of symptoms of hyperthyroidism referencing a period prior to first HPV-4 dose. This 'unmasking' phenomenon, due to health care visits that include vaccination and new workups of preexisting symptoms, may not be adequately controlled through the exclusion of Day 0 events.

Background: In a previous clinical trial comparing COMVAX™ with its monovalent components, PedvaxHIB™ and RECOMBIVAX HB™, one of 92 comparisons of post-vaccination adverse experiences revealed a higher rate of unusual, high-pitched crying following the second, but not the first or third doses of COMVAX™ compared with two monovalent control vaccines. Rates of prolonged crying were similar between groups at each visit. Objectives: To compare the frequencies of unusual, high-pitched crying between recipients of COMVAX™ plus placebo and recipients of PedvaxHIB™ plus RECOMBIVAX HB™ following the second vaccine doses (primary) and to summarize the frequency of unusual, high-pitched crying and prolonged crying after each vaccination visit. Design: We enrolled 1215 healthy infants in a randomized, double blind, placebo-controlled study. Participating infants received study vaccines at 2 and 4 months of age and other routine childhood vaccines at 6–7 weeks and 3 months of age. Crying was evaluated via questionnaire at the time of enrollment (baseline) and daily from days 0 to 2 after each injection. Results: Reports of unusual, high-pitched crying and prolonged crying were uncommon (

Background In February 2010, the Food and Drug Administration (FDA) licensed the 13-valent pneumococcal conjugate vaccine (PCV13) for use in children aged 6 weeks through 59 months. The Advisory Committee on Immunization Practices (ACIP) recommended routine use of PCV13 for all children ages 2, 4, and 6 months with a booster at 12–15 months. For incomplete or unvaccinated children, catch-up vaccination should occur through age 59 months. Methods We searched the Vaccine Adverse Event Reporting System (VAERS), a U.S. passive surveillance system, for reports of adverse events (AEs) following PCV13 from February 24, 2010 through February 24, 2017, in children aged 6 weeks through 59 months. Signs and symptoms of AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA). Physicians reviewed the VAERS forms and available medical records of serious reports (death, life-threatening illness, hospitalization, prolongation of hospitalization and permanent disability) and reports of Kawasaki disease and anaphylaxis. Cause of death was ascertained by review of death certificate and/or autopsy report. Results VAERS received 10,007 reports after PCV13; 1,706 (17.0%) were serious. In 927 (9.3%), PCV13 was administered alone. The most frequently reported symptoms were pyrexia (26.4%), injection site erythema (15.3%) and irritability (14.6%). Injection site erythema (25.4%), injection site swelling (20.6%) and pyrexia (20.1%) were most frequent among children who were given PCV13 alone. Median time from vaccination to start of symptoms was 1 day (range: day of vaccination – 2,033 days). There were 222 (2.2%) death reports with sudden infant death syndrome as the most common cause (37.8%). Pyrexia (45.1%), irritability (40.4%), and vomiting (39.7%) were most commonly reported among non-death serious reports. There were 20 (0.2%) reports of Kawasaki disease and 20 (0.2%) reports of anaphylaxis. Conclusion AES reported to VAERS following PCV13 were consistent with AEs previously observed in pre-licensure clinical trials and other post-licensure studies of PCV13. No new or unexpected patterns of AEs were identified. Disclosures All authors: No reported disclosures.

Background Trivalent live attenuated influenza vaccine (LAIV3) was licensed and recommended for use in 2003 in children and adults 2–49 years of age. Post-licensure safety data have been limited, particularly in adults. Methods We searched Vaccine Adverse Event Reporting System (VAERS) for US reports after LAIV3 from July 1, 2005–June 30, 2013 (eight influenza seasons) in adults aged ≥ 18 years old. We conducted descriptive analyses and clinically reviewed serious reports (i.e., death, life-threatening illness, hospitalization, prolonged hospitalization, or permanent disability) and reports of selected conditions of interest. We used empirical Bayesian data mining to identify adverse events (AEs) that were reported more frequently than expected. We calculated crude AE reporting rates to VAERS by influenza season. Results During the study period, VAERS received 1207 LAIV3 reports in adults aged 18–49 years old; 107 (8.9%) were serious, including four death reports. The most commonly reported events were expired drug administered ( n = 207, 17%), headache ( n = 192, 16%), and fever ( n = 133, 11%). The most common diagnostic categories for non-fatal serious reports were neurological ( n = 40, 39%), cardiovascular ( n = 14, 14%), and other non-infectious conditions ( n = 20, 19%). We noted a higher proportion of Guillain–Barre syndrome (GBS) and cardiovascular reports in the Department of Defense (DoD) population compared to the civilian population. Data mining detected disproportional reporting of ataxia ( n = 15); clinical review revealed that ataxia was a component of diverse clinical entities including GBS. Conclusions Review of VAERS reports are reassuring, the only unexpected safety concern for LAIV3 identified was a higher than expected number of GBS reports in the DoD population, which is being investigated. Reports of administration of expired LAIV3 represent administration errors and indicate the need for education, training and screening regarding the approved indications.

Professionalism is a multi-dimensional concept that provides nurses with opportunities to grow personally andprofessionally. Nurses demonstrating the attributes of professionalism impact positively on patient satisfaction and healthoutcomes. The objective of this article is to explore and analyze the phenomenon of nursing professionalism. The conceptof professionalism will be explored by analyzing Miller’s model entitled the “Wheel of Professionalism in Nursing”.Factors determining professionalism in post-licensure nurses will be identified. The Registered Nurses Association ofOntario-Best Practice Guideline, “Professionalism in Nursing”, will be used to discuss strategies to foster professionalismin nurses. Relevance of professionalism in nursing and literature gaps will also be addressed.

The healthcare workers having seroprotection at 3 weeks (n = 127) following Pandemic H1N1 2009 influenza vaccination were followed up for antibody persistence. Seroprotection at 12 mo (60.2%) was significantly lower as compared with 3 weeks (74.7%), 3 mo (77.8%) and 6 mo (75.4%). The vaccine provided seroprotection up to one year.

Rotavirus causes one-third to one-half of severe diarrheal disease in children under the age of five years worldwide. In 2006 two rotavirus vaccines became available and, in the intervening years, approximately thirty countries have introduced them into their immunization programs, primarily in high-income and middle-income settings. Major reductions in rotavirus hospitalizations have been observed in a number of these locations, and in select countries, there have been impacts on gastroenteritis mortality associated with rotavirus vaccine introduction. In addition to these direct health benefits, reduced gastroenteritis risk has been documented in unvaccinated groups, including older children and adults, suggesting indirect benefits (i.e. herd immunity). In this paper, we summarize what has been learned from programs studying post-licensure vaccine effectiveness, impact on health-care utilization and death, safety issues (namely, intussception and the detection of adventitious viruses) and the potential selective pressure of vaccination on the diversity of rotavirus genotypes.

Purpose: The Advanced Clinician Practitioner in Arthritis Care (ACPAC) Program was developed to train experienced physical and occupational therapists within extended practice roles with the aim of facilitating optimal, timely, and appropriate delivery of health care to patients with arthritis. This paper presents (1) the development of the ACPAC Program and (2) performance across the programme, as well as early quantitative and qualitative changes in clinical practice roles for the 2006 through 2008 cohorts of ACPAC Program graduates (n=19). Methods: Measurement of change in skills and knowledge involved standardized baseline and end-of-programme examinations as well as self-evaluation of a number of areas of clinical competence. Practice-focused surveys issued at baseline, mid-programme, and end of programme, as well as at 6 and 12 months after graduation, evaluated the practitioners' integration of advanced knowledge and skills acquired during the ACPAC Program into their extended practice roles. Results: Participants significantly increased their scores on examinations of clinical knowledge (p Conclusion: Graduates of the ACPAC Program have demonstrated knowledge and skills for practising in extended roles that enhance the available human health resource pool for patients with arthritis.

Purpose: A rapid test for influenza viruses (Binax NOW® ) was evaluated. Materials and Methods: In season-1, 35 respiratory samples were tested retrospectively; in season-2, 45 samples were tested prospectively [gold-standard: viral culture in season-1, culture+ reverse transcriptase-polymerase chain reaction (RT-PCR) in season-2]. Results: Sensitivity for Binax for influenza A was 59.3 and 0% in season-1 and -2, respectively. Sensitivity was low for influenza B (33.3% in season-1, 26.1% in season-2). Samples having low viral load were more likely to have a negative Binax test. Specificity of Binax was high (100 and 94.7% with influenza A and B, respectively). Conclusion: Sensitivity information provided in the kit insert does not always reflect post licensure performance in clinical settings.

Numerous variations to a manufacturing process may take place during the life cycle of a vaccine. To support these variations, the regulator requires providing stability data according to the existing ICH guidelines; these have been designed for documenting the licence of a new vaccine. Comparative studies and adapted stability designs specific to the variation will give far more confidence to the manufacturer and the regulator than the classical model. The following case study applied to a change of a stopper illustrates this approach.

Stability studies represent a significant workload for both manufacturers and regulatory reviewers and therefore a careful selection of the study design and of the stability indicator test is required to make sure that the study will provide the relevant information. Moreover, alternatives to the existing regulatory approaches should be favoured in order to better or quicker analyze the impact of a specific change. In this article, examples of alternative approaches are given. For the stability monitoring study, emphasis is put on the bulk stability program. Concerning comparability stability study, two case studies illustrating how accelerated stability studies could be used to support manufacturing changes are presented.

By intention, there are similarities between ADVATE (ADVATE Antihemophilic Factor (Recombinant), Plasma/Albumin-Free Method (r-AHF-PFM) and its predecessor Recombinate (Recombinate Antihemophilic Factor [Recombinant][rAHF]). Both are manufactured utilizing a CHO-cell clone, with the ADVATE master cell bank being derived from a protein/albumin free culture medium-adapted Recombinate cell line. Consequently, both cell lines include the human FVIII and human von Willebrand Factor genes. In addition, the development of ADVATE for licensure showed that both recombinant FVIII proteins are very similar in structure and function. Thus it was not a surprise that the clinical research carried out on ADVATE demonstrated an almost identical pharmacokinetic (PK) profile to that of Recombinate. The Recombinate-ADVATE PK study showed a Recombinate mean +/–SD adjusted recovery of 2.59 +/– 0.52 with that of ADVATE being 2.41 +/– 0.50. Also the half-life in hours for Recombinate was 11.24 +/– 2.53 versus 11.98 +/– 4.28 for ADVATE [1]. Given the importance of inhibitor development to the person with hemophilia, it is appropriate to ask the question as to whether there are differences in the inhibitor profile between the two products. Here the comparison between them are not as straight forward, because a clinical research study to answer this question was not carried out. Nevertheless there is data on inhibitor incidence that has been generated by clinical research study on both products in previously treated patients (PTPs). There is data on PUPS for Recombinate, but the ADVATE PUP study is still ongoing and it is too early to make any comparison. However, there is data generated by pharmacovigilance reporting post-licensure with both products that can provide some insight as to inhibitor prevalence in clinical practice across all age groups. The information provided in Table 1 shows the inhibitor incidence that has been generated by the clinical research projects on ADVATE through January 2005. The study subject number in the Pivotal, Pediatric and Japan PTP studies amounted to 176 study subjects, with one non-persistent low titer inhibitor being documented in a single study subject. In addition, no study subjects who underwent surgery using ADVATE for hemostasis and no study subject entered into the Pivotal study who continued to receive ADVATE until licensure developed an inhibitor. This compares favorably with the situation in Recombinate with one low titer transient inhibitor being identified in 69 previously treated children and adult research subjects.

In this paper we scanned and summarized the empirical research evidence and found that the effects of pre-licensure interprofessional education on patient/client care are unknown. In contrast, for post-licensure collaboration interventions, there is a growing body of evidence suggesting positive effects on the delivery of care. The coverage of this latter evidence, however, is patchy, being especially weak in primary care. In interprofessional education, where policy level interventions have been value driven for the last half century, we have identified a base of evidence for the effectiveness of certain post-licensure collaboration interventions; this evidence is lacking for pre-licensure interprofessional education. If interventions and policies for both pre-licensure interprofessional education and post-licensure collaboration are implemented without accompanying rigorous evaluation research, we will remain mired in this same uncertainty into the future.

Adverse events following immunization, while rare, unfortunately do occur. And when they do, the public's faith in vaccines waves. It's a known fact, for example, that vaccine safety concerns are among the most important factors contributing to parents refusing vaccination for their children. How best, then, to tackle these concerns and increase public confidence in the vaccine safety system? In an effort to contribute to identifying the right mechanisms, the International Alliance for Biological Standardization organized an international symposium on "Post-Licensure Evaluation of Vaccine Safety" in Barcelona in early Spring. Delegates from 24 countries took a close look at the current status of this challenging problem and identified several practical measures which could help address the situation. They suggested an integrated vaccine safety program to be in place in all countries and standardized so that information and data can be exchanged on a routine basis. Another proposal was to put in place simple measures such as the use of bar codes on vaccine vials.

Initial data on safety and efficacy of new therapeutic agents are provided by formal clinical research studies. These provide information to permit licensure of the product by regulatory agencies. However, this initial therapeutic profile requires confirmation by the prospective collection and analysis of safety and efficacy information. These data are collected via pharmacovigilance activities, which are dependant on the reporting of adverse events by patients, physicians and other healthcare providers. The pharmaceutical license holder of the therapeutic has the regulatory obligation to continually collect, analyze and report this information at specified intervals during the first post-licensure year. The 12-month post-licensure anniversary is therefore an important milestone in the evaluation of a therapeutic agent. Antihemophilic factor (recombinant), plasma/albumin-free method (Advate), is a recombinant FVIII concentrate manufactured without added human or animal plasma proteins during the production process. This eliminates the risk of infection from viruses and infectious prions that may be carried in these plasma protein additives. Advate was first licensed in the US on July 25, 2003. All reported adverse events were prospectively collected together with the volume of therapeutic agent distributed. This has permitted the determination of adverse event (AE) incidence relative to the amount of the concentrate released for distribution. These data were compared with similarly collected information on Antihemophilic factor (recombinant) Recombinate, over the equivalent first year postlicensure of this product. For Advate, there was a total of 21 AEs of which 7 were serious (SAEs), including 6 reports of Factor VIII inhibitor formation. A total of 158.4 million units of Advate was distributed during this first year providing an incidence of 0.133 AE’s and an incidence of 0.038 inhibitor events per million units Advate distributed. During the equivalent period with Recombinate, there were 20 AEs of which 9 were SAEs with 8 being reports of an inhibitor. A total of 69.2 million IU of Recombinate was distributed during the first year post licensure, providing an incidence rate of 0.289 AE’s and 0.116 for inhibitors per million IU distributed, respectively. All new onset inhibitor reports with both products were associated with small children who, where information was available, had experienced fewer than 50 exposure days with factor VIII concentrates. This interval represents the period of greatest risk in the natural history of inhibitor development among patients with hemophilia A. One episode of anaphylaxis following Advate was reported in an adult patient who had previously successfully undergone immune tolerance for an inhibitor. The patient’s sera demonstrated a low titer inhibitor with IgG and IgE specific for Factor VIII. These antibodies were present prior to exposure to Advate and the patient demonstrated similar allergic responses to FVIII concentrates other than Advate. These data are reassuring with respect to the safety record generated by Advate during the first year post licensure and are particularly encouraging relative to the substantially lower incidence of inhibitor reports compared with the initial experience with Recombinate. Advate Recombinate *per million units distributed Product Distributed # million units 158.4 69.2 AE’s 21 20 SAE’s (Inhibitor) 7 (6) 8 (8) Incidence AE’s* 0.133 0.289 Incidence Inhibitor* 0.038 0.116

Phase III trials of vaccines may be holding back the benefits of, and increasing the costs of vaccines, to an extent that is harmful to society. The safety of a vaccine is assessed, in the main, in Phases I and II trials. Were Phase III trials to be rendered unnecessary, it would be desirable to more extensively and stringently examine the performance of the vaccine in the field as part of a post licensure Phase IV exercise. The acceptance of such costs (risk of disbenefit * the magnitude of the disbenefit) is discussed in relation to costs that are commonly incurred while engaged in a modern 21st century life.