Assessment of risk of intussusception after pilot rollout of rotavirus vaccine in the Indian public health system

BackgroundPre-licensure trials of ROTAVAC® were not adequately powered to assess risk of intussusception, a rare adverse event associated with other rotavirus vaccines in some settings. We examined the risk of intussusception after ROTAVAC® vaccination among Indian infants during pilot rollout of the vaccine in the public health system in three states - Himachal Pradesh, Maharashtra and Tamil Nadu.MethodsPassive surveillance for intussusception was set up in 35 sentinel health facilities covering 26.3 million population in the three states under monitoring of an Interministerial-Interagency Steering Committee. Clinical and immunization data were collected by independent teams. An expert committee blinded to vaccination status, classified intussusception cases using Brighton criteria. The self-controlled case-series method was used to estimate risk of intussusception (Brighton Level 1) after ROTAVAC® vaccination.Results151 intussusception cases were included in the analysis. The relative incidence (incidence during the risk period compared to the control period) 1–21 days after doses 1 and 2 combined was 1.56 (95% CI, 0.0–5.28) and that for three doses combined was 1.88 (95% CI, 0.76–4.30). Attributable risk 1–21 days after doses 1 and 2 combined was 0.11 (95% CI, 0.0–0.25) and that for 3 doses combined was 0.42 (95% CI, 0.0–0.70) per 100,000 doses.ConclusionsNo increased risk of intussusception within 21 days of receipt of the first two doses combined or all 3 doses combined of ROTAVAC® was detected.     

Adverse events following mRNA SARS-CoV-2 vaccination among U.S. nursing home residents

BackgroundThe devastating impact of the SARS-CoV-2 pandemic prompted the development and emergency use authorization of two mRNA vaccines in early 2020. Vaccine trials excluded nursing home (NH) residents, limiting adverse event data that directly apply to this population.MethodsTo prospectively monitor for potential adverse events associated with vaccination, we used Electronic Health Record (EHR) data from Genesis HealthCare, the largest NH provider in the United States. EHR data on vaccinations and pre-specified adverse events were updated daily and monitored for signal detection among residents of 147 facilities who received the first dose of vaccine between December 18, 2020 and January 3, 2021. For comparison, unvaccinated residents during the same time period were included from 137 facilities that started vaccinating at least 15 days after the vaccinating-facilities.ResultsAs of January 3, 2021, 8553 NH residents had received one dose of SARS-CoV-2 vaccine and by February 20, 2021, 8371 residents had received their second dose of vaccine; 11,072 were included in the unvaccinated comparator group. No significant associations were noted for neurologic outcomes, anaphylaxis, or cardiac events.ConclusionsNo major safety problems were detected following the first or second dose of the vaccine to prevent COVID-19 in the study cohort from December 18, 2020 through March 7, 2021.     

树状扫描统计量用于药品和疫苗安全性监测的综述

本综述系统梳理了国内外使用树状扫描统计量（TreeScan）方法开展的药物流行病学原始研究，总结TreeScan方法的发展与应用现状，阐述其方法学原理，为我国开展同类研究提供参考。通过系统检索英文文献数据库（Medline、Embase与Web of Science），最终纳入15项研究，其中9项为药物安全性监测研究，6项为疫苗安全性监测研究。研究中采用的TreeScan方法有3类：泊松概率模型、伯努利概率模型及树状时空扫描统计量模型。3类模型的差别主要体现在：在研究设计时是否预先设定了对照、是否考虑了暴露至出现不良事件间的风险期时长。部分研究比较了TreeScan方法与其他不良反应信号发掘方法的检出结果，或使用已知存在的不良反应，探讨了该方法对不良反应信号的检出能力。通过总结发现TreeScan是一种有效的药品安全性信号监测方法，国际上目前仍处于快速发展阶段，十分有必要推进TreeScan方法在我国药品、疫苗安全性监测和其他相关研究领域的探索与应用。     

部分突发公共卫生事件监测与现场处置关键技术遴选研究

目的 探索传染病、食物中毒、医院感染这三类突发公共卫生事件监测与现场处置中具有重要作用且需要完善与发展的关键技术,有效提高突发公共卫生事件监测与现场处置能力。方法 在文献研究与专家小组讨论的基础上构建传染病、食物中毒、医院感染监测与现场处置关键技术遴选框架,运用德尔菲专家咨询法以及逼近理想解排序法综合评价法,遴选三类事件监测与现场处置的关键技术。结果 构建了基于事件类别、事件处理周期、技术层次的关键技术遴选框架,选择来自公共卫生领域的26位专家进行2轮专家咨询,专家权威程度为0.796;遴选出对传染病、食物中毒、医院感染监测与现场处置具有重要意义的各10项关键技术,其中,预警制度是对三类事件均具有重要意义的关键技术,未知病原微生物检测、个人防护、基因测序与溯源、微生物分子分型和核酸检测技术是传染病与医院感染监测与现场处置均需要发展的关键技术,现场快速检测、预警预测以及数据安全与保密技术是传染病与食物中毒监测与现场处置均需要完善的关键技术。此外,传染病监测与现场处置的关键技术还包括数据交换,食物中毒监测与现场处置的关键技术还包括毒素检测等,医院感染监测与现场处置的关键技术还包括数据采集标准化等。结论 本研究通过科学的方法遴选出符合传染病、食物中毒、医院感染监测与现场处置需求的关键技术,在2轮专家咨询中,专家意见的权威程度较高,可保证遴选结果的可靠性,为关键技术的进一步研究与优先发展提供了科学依据。     

Using simulation to assess the sensitivity and specificity of a signal detection tool for multidimensional public health surveillance data

The objective of the work described in this paper is to develop a means for characterizing the validity of an empirical methodology for detecting signals potentially related to complicated adverse event (AE) coding terms in multidimensional public health surveillance data. The signal detection tool under evaluation is the multi-item gamma Poisson shrinkage (MGPS) estimation program. We were interested in its potential application to passive surveillance system monitoring, to screen for 'signals' of complicated adverse event coding terms (AE terms) in complex and noisy data. The research was to design and produce a flexible and user-friendly utility for probabilistically defining complicated signals in a database, iterating large numbers of applications of the MGPS detection algorithm and establishing proportions of correct detection events. We sought to establish the specificity of the MGPS by developing a random background using a gradient that ranged from rigorous (but not very relevant) to relevant (but noisy).To establish the sensitivity, signals were defined based on recognized public health issues of interest (such as the introduction of a new vaccine into the population). Methods of representing a signal included a simple pair-wise association consisting of a new vaccine and one AE term, as well as a more realistic complex of multiple AE terms comprising a 'syndrome'. A web application has been developed to create and insert signals with user-defined probabilities in multiple iterations of simulated random background data. Three forms of simulated data based on the vaccine adverse event reporting system (VAERS) cumulative spontaneous database were defined to serve as background noise against which to contrast introduced vaccine adverse event signals: (1) completely random associations between vaccines and AE terms, (2) random associations of vaccine sets and AE term sets preserving naturally observed vaccine co-occurrences and AE term co-occurrences and (3) samples from the actual VAERS data as reported. Rates of detection by the MGPS algorithm can be established for specific signal patterns at varying probabilistic intensities in a choice of random background data forms. Knowing these rates is important for determining the degree of response to an MGPS signal detection event in 'live' data.     

Disease-specific adverse events following nonlive vaccines: a paradoxical placebo effect or a nocebo phenomenon?

Vaccines can cause adverse reactions (AR), i.e. adverse events following immunization (AEFIs) due to the vaccine, such as local reactions or fever. In addition, live attenuated vaccines which replicate in vaccinees can cause disease-specific AR, e.g. measles-like rash following measles vaccination. However, nonlive vaccines because they are inactivated and they do not replicate in vaccinees, are not likely to cause disease-specific AR. The aim of the study was to assess whether safety signals could be generated by an undescribed bias in spontaneous reporting of disease-specific AEFIs with nonlive vaccines.All AEFIs of Sanofi Pasteur MSD vaccines spontaneously reported in France from January 2000 to June 2010, coded according to MedDRA terms and collected in the company's pharmacovigilance database were analyzed. Vaccine-event pairs of interest were selected a priori. The disproportionality reporting rate methodology was used, comparing the proportion of a given event reported following a given vaccine to its proportion reported following all other studied vaccines. The Reporting Odds Ratio (ROR) was used for signals detection for each vaccine-event pair selected.A total of 33,275 AEFIs were analyzed. The calculated ROR showed a statistically disproportionate reporting rate and generated false safety signals for almost all the pairs tested. Three nonlive vaccine pairs were striking: gynaecological symptoms and the quadrivalent human papillomavirus (qHPV) vaccine; trismus and tetanus vaccines; hepatobiliary disorders and hepatitis B vaccines. In conclusion we have identified a new vaccine AE spontaneous reporting bias: “disease-specific adverse events following nonlive vaccines”, showing that vaccinees and healthcare professionals tend to report preferentially the symptoms of the disease against which the nonlive vaccine was administered. We suggest that bias is subordinate to a paradoxical placebo effect and/or a nocebo phenomenon.     

Efficacy of m-Health for the detection of adverse events following immunization – The stimulated telephone assisted rapid safety surveillance (STARSS) randomised control trial

IntroductionPassive surveillance is recommended globally for the detection of adverse events following immunisation (AEFI) but this has significant challenges. Use of Mobile health for vaccine safety surveillance enables a consumer-centred approach to reporting. The Stimulated Telephone Assisted Rapid Safety Surveillance (STARSS) a randomised control trial (RCT) sought to evaluate the efficacy and acceptability of SMS for AEFI surveillance.MethodsMulti-centre RCT, participants were adult vaccinees or parents of children receiving any vaccine at a trial site. At enrolment randomisation occurred to one of two SMS groups or a control group. Prompts on days 2, 7 and 14 post-immunisation, were sent to the SMS group, to ascertain if a medical event following immunisation (MEFI) had occurred. No SMS’s were sent to the control participants. Those in the SMS who notified an MEFI were pre-randomised to complete a computer assisted telephone interview or a web based report to determine if an AEFI had occurred whilst an AEFI in the controls was determined by a search for passive reports. The primary outcome was the AEFI detection rate in the SMS group compared to controls.ResultsWe enrolled 6,338 participants, who were equally distributed across groups and who received 11,675 vaccines. The SMS group (4,225) received 12,675 surveillance prompts with 9.8% being non-compliant and not responding. In those that responded 90% indicated that no MEFI had been experienced and 184 had a verified AEFI. 6 control subjects had a reported AEFI. The AEFI detection rate was 13 fold greater in the SMS group when compared with controls (4.3 vs 0.3%).ConclusionWe have demonstrated that the STARSS methodology improves AEFI detection. Our findings should inform the wider use of SMS-based surveillance which is particularly relevant since establishing robust and novel pharmacovigilance systems is critical to monitoring novel vaccines which includes potential COVID vaccines.     

Safety of trivalent inactivated influenza vaccines in adults: Background for pandemic influenza vaccine safety monitoring

In preparation for pandemic vaccine safety monitoring, we assessed adverse events reported to the Vaccine Adverse Event Reporting System following receipt of trivalent inactivated influenza vaccines among adults from 1990 through 2005. We calculated reporting rates for nonserious, serious, and neurological adverse events. We reviewed reports of recurrent events and deaths, as well as reports identified through advanced signal detection. The most frequently reported events were local reactions and systemic symptoms. Guillain-Barré syndrome was the most frequently reported serious event (0.70 reports per million vaccinations). Adverse event reporting rates have been reasonably constant over time. No new safety concerns emerged after our review of 15 years of post-licensure surveillance data. These findings provide useful information if pandemic vaccine is rapidly distributed and pre-licensure data are limited.     

Concomitant administration of a liquid formulation of human rotavirus vaccine (porcine circovirus-free) with routine childhood vaccines in infants in the United States: Results from a phase 3, randomized trial

BackgroundIn response to the detection of porcine circovirus type 1 (PCV-1) in the human rotavirus vaccine (HRV), a PCV-free HRV (no detection of PCV-1 and PCV-2 according to the detection limit of tests used) was developed. Liquid (Liq) PCV-free HRV previously showed immunogenicity and safety profiles comparable to lyophilized (Lyo) HRV.MethodsThis was a phase 3a, randomized, single-blind study (NCT03207750) conducted in the United States. Healthy infants aged 6–12 weeks received 2 doses (0, 2 months) of either Liq PCV-free HRV or Lyo HRV with routine vaccines (0, 2, 4 months): diphtheria-tetanus-acellular pertussis, hepatitis B and inactivated poliovirus combination vaccine (DTaP-HBV-IPV), monovalent tetanus toxoid-conjugated vaccine against Haemophilus influenzae type b (Hib-TT), and 13-valent pneumococcal conjugate vaccine. Co-primary objectives were: (i) to assess non-inferiority of immune responses to routine vaccine antigens 1 month post-dose 3 following co-administration with Liq PCV-free HRV compared to Lyo HRV; (ii) to rule out a 10% decrease in seroresponse to pertussis antigens after dose 3. Other objectives were to evaluate immunogenicity and safety of HRV vaccines.ResultsOf 1272 vaccinated infants, 990 (489 in Liq PCV-free HRV and 501 in Lyo HRV group) were included in the per-protocol set. All statistical criteria were met, thus co-primary objectives were demonstrated. Seroprotection/seropositivity rates in both groups were high: 100% for diphtheria/tetanus, ≥99.3% for HBV, ≥99.8% for polio, ≥99.8% for each pertussis antigen, ≥90.8% for all pneumococcal serotypes except serotype 3 (≥69.1%), and ≥ 97.4% for Hib. Most infants seroconverted for anti-RV antibodies (76.3% of Liq PCV-free HRV and 78.9% of Lyo HRV recipients). Geometric mean concentrations/titers were comparable between groups. Incidences of adverse events and serious adverse events were similar between groups.ConclusionRoutine pediatric vaccines co-administered with Liq PCV-free HRV showed non-inferior immune responses and similar safety profiles to those following co-administration with Lyo HRV.     

Role of Oral Rabies Vaccines in the Elimination of Dog-Mediated Human Rabies Deaths

Domestic dogs are responsible for nearly all the »59,000 global human rabies deaths that occur annually. Numerous control measures have been successful at eliminating dog-mediated human rabies deaths in upper-income countries, including dog population management, parenteral dog vaccination programs, access to human rabies vaccines, and education programs for bite prevention and wound treatment. Implementing these techniques in resource-poor settings can be challenging; perhaps the greatest challenge is maintaining adequate herd immunity in free-roaming dog populations. Oral rabies vaccines have been a cornerstone in rabies virus elimination from wildlife populations; however, oral vaccines have never been effectively used to control dog-mediated rabies. Here, we convey the perspectives of the World Organisation for Animal Health Rabies Reference Laboratory Directors, the World Organisation for Animal Health expert committee on dog rabies control, and World Health Organization regarding the role of oral vaccines for dogs. We also issue recommendations for overcoming hesitations to expedited field use of appropriate oral vaccines.     

Bacillus Calmette–Guérin (BCG) vaccine safety surveillance in the Korea Adverse Event Reporting System using the tree-based scan statistic and conventional disproportionality-based algorithms

BackgroundSubstantial variations in the safety profiles of different formulations of the bacillus Calmette–Guérin (BCG) vaccine exist. Therefore, we aimed to detect safety signals of BCG vaccine for intradermal injection (BCG-ID) and percutaneous injection (BCG-PC) in the Korea Adverse Event Reporting System (KAERS).MethodsWe conducted a vaccine safety surveillance study from the adverse events (AEs) reported following BCG vaccine in the Korea Institute of Drug Safety and Risk Management KAERS Database (KIDS-KD) between 2005 and 2017. We used the tree-based scan statistic (TSS) and four disproportionality-based algorithms for signal detection: empirical Bayesian geometric mean; proportional reporting ratio; reporting odds ratio; and information component. The detected signals from each algorithm was compared with the known AEs of BCG vaccine (reference standard) to present positive predictive value (PPV) and area under the receiver operating curve (AUC).ResultsFrom the total of 52,191 vaccine-related AE pairs, 963 AE pairs were reported following the BCG vaccine, in which BCG-ID and –PC accounted for 71.1% and 28.9%, respectively. Overall, 97.2% of AE reports were non-serious; lymphadenopathy (583/963; 50.3%) and injection site discharge (193/963; 20.0%) were the most commonly reported AEs detected by all algorithms. Tuberculous osteitis was reported solely from BCG-PC (15/279; 5.4%), while most of the AEs from BCG-ID were related to injection site complications. The TSS demonstrated the best balance of the performance measures, with PPV and AUC of 66.7% and 63.1%, respectively.ConclusionsTSS was successfully applied in the KAERS to detect safety signals of BCG vaccine. In addition, difference in the safety profiles of BCG-ID and BCG-PC warrants further investigation to confirm our findings. Although TSS performed the best in our study, caution should be taken when interpreting the results owing to the lack of a robust “gold standard” and the relatively small number of reports for data mining.     

Safety of MF59-adjuvanted versus non-adjuvanted influenza vaccines in children and adolescents: An integrated analysis

We reviewed the safety of MF59-adjuvanted versus non-adjuvanted influenza vaccines in children and adolescents (aged 6 months–18 years) in an integrated analysis of all pediatric trials evaluating MF59-containing influenza vaccines completed to date (5 trials). In the MF59-adjuvanted group (n = 1181) versus the non-adjuvanted group (n = 545) there was no increase in the incidence of unsolicited adverse events and serious adverse events. As expected, solicited local or systemic reactions occurred more frequently in MF59-adjuvanted subjects; however, a majority of reactions were mild and transient. These data support the safety of MF59-adjuvanted influenza vaccines in the pediatric population.     

Vaxtracker: Active on-line surveillance for adverse events following inactivated influenza vaccine in children

Vaxtracker is a web based survey for active post marketing surveillance of Adverse Events Following Immunisation. It is designed to efficiently monitor vaccine safety of new vaccines by early signal detection of serious adverse events. The Vaxtracker system automates contact with the parents or carers of immunised children by email and/or sms message to their smart phone. A hyperlink on the email and text messages links to a web based survey exploring adverse events following the immunisation. The Vaxtracker concept was developed during 2011 (n = 21), and piloted during the 2012 (n = 200) and 2013 (n = 477) influenza seasons for children receiving inactivated influenza vaccine (IIV) in the Hunter New England Local Health District, New South Wales, Australia. Survey results were reviewed by surveillance staff to detect any safety signals and compare adverse event frequencies among the different influenza vaccines administered. In 2012, 57% (n = 113) of the 200 participants responded to the online survey and 61% (290/477) in 2013. Vaxtracker appears to be an effective method for actively monitoring adverse events following influenza vaccination in children.     

我国二类疫苗集中采购程序及核心要素分析

目的：分析二类疫苗集中采购的基础性政策,揭示疫苗采购的主要程序与核心要素,以期提出优化建议。方法：运用内容分析法,进行词频统计与共现网络构建,结合对比分析法,总结各省份二类疫苗采购的共性与差异。结果：我国二类疫苗集中采购程序包括规划、遴选、执行,共涉及采购目录、采购公告、疫苗接收与购入等17个核心要素。其中,集中采购周期以1年为主,疫苗报价大部分参考各省份的价格水平,定标时主要采取评审模式。结论：各省份二类疫苗集中采购程序与框架一致,采购环境趋于公开、规范,应完善二类疫苗监测与评价、深化遴选标准、健全评审人才队伍等,促进我国二类疫苗采购良性发展。     

Adverse events following vaccination with an inactivated,Vero cell culture-derived Japanese encephalitis vaccine in the United States, 2009–2012

BackgroundIn March 2009, the U.S. Food and Drug Administration licensed an inactivated, Vero cell culture-derived Japanese encephalitis vaccine (JE-VC [Ixiaro]) for use in adults. The vaccine was licensed based on clinical trial safety data in 3558 JE-VC recipients. It is essential to monitor post-licensure surveillance data to evaluate the safety of JE-VC because rare adverse events may not be detected until the vaccine is administered to a larger population.MethodsWe reviewed adverse events reported to the U.S. Vaccine Adverse Event Reporting System (VAERS) for adults (≥17 years) who received JE-VC from May 2009 through April 2012. Adverse event reporting rates were calculated using 275,848 JE-VC doses distributed.ResultsOver the 3 year period, 42 adverse events following vaccination with JE-VC were reported to VAERS for an overall reporting rate of 15.2 adverse events per 100,000 doses distributed. Of the 42 total reports, 5 (12%) were classified as serious for a reporting rate of 1.8 per 100,000 doses distributed; there were no deaths. Hypersensitivity reactions (N = 12) were the most commonly reported type of adverse event, with a rate of 4.4 per 100,000 doses distributed; no cases of anaphylaxis were reported. Three adverse events of the central nervous system were reported (one case of encephalitis and two seizures) for a rate of 1.1 per 100,000; all occurred after receipt of JE-VC with other vaccines.ConclusionsThese post-marketing surveillance data suggest a good safety profile for JE-VC consistent with findings from pre-licensure clinical trials. Post-licensure safety data should continue to be monitored for any evidence of rare serious or neurologic adverse events.     

Adverse events following vaccination with an inactivated,Vero cell culture-derived Japanese encephalitis vaccine in the United States, 2012–2016

BackgroundIn March 2009, the U.S. Food and Drug Administration licensed an inactivated Vero cell culture-derived Japanese encephalitis vaccine (JE-VC [IXIARO®]) for use in persons aged ≥17 years. In 2013, licensure was extended to include children aged ≥2 months. A previous analysis reviewed adverse events reported to the U.S. Vaccine Adverse Event Reporting System (VAERS) from May 2009 through April 2012.MethodsWe reviewed adverse events reported to VAERS following JE-VC administered from May 1, 2012 through April 30, 2016. Adverse event reporting rates were calculated using 802,229 doses distributed.ResultsDuring the 4-year period, 119 adverse event reports were received for a reporting rate of 14.8 per 100,000 doses distributed. Nine (8%) adverse events were classified as serious for a reporting rate of 1.1 per 100,000 distributed. The most commonly reported event was hypersensitivity (n = 24; 20%) for a rate of 3.0 per 100,000 doses distributed; 1 anaphylaxis event was reported. Ten (8%) neurologic events were reported for a rate of 1.2 per 100,000 doses distributed; 2 events were classified as seizures. Sixty-three (53%) adverse events occurred after a first dose of JE-VC. Eighty (67%) adverse events occurred after administration of JE-VC with other vaccines. Eleven (9%) adverse events were reported in children; 1 was considered serious.ConclusionsThese data continue to support the generally favorable safety profile of JE-VC. Reporting rates of adverse events were similar to those of the previous analysis. Although reporting rates of adverse events in children could not be calculated, there were low numbers of reported events in this age group. Post-licensure adverse event surveillance for this relatively new vaccine continues to be important to monitor adverse event reporting rates and identify possible rare serious events.     

Vaccination of active component US military personnel against Salmonella Typhi

IntroductionVaccination against Salmonella Typhi is one of the leading public health interventions reducing the risk of typhoid fever. There are two available licensed vaccines, Vivotif, oral live-attenuated, and Typhim Vi, intramuscular Vi capsular polysaccharide. The US military is a high risk travel population commonly vaccinated for S. Typhi. We describe the use of S. Typhi vaccination in this population and the acute reactogenicity profile of these vaccines.MethodsData were obtained from the Defense Medical Surveillance System and vaccination identified between 1998 and 2011 from vaccination codes. Clinical outcomes were assessed for four weeks post vaccination. Adverse event rates and odds ratios were estimated across the two vaccine types.ResultsA total of 1.9 million predominately male military personnel received 3.6 million S. Typhi vaccinations with 94.3% of vaccinees receiving the Vi capsule vaccine though variability in the vaccine administered was observed. Receipt of other vaccinations in the 6 months surrounding the S. Typhi vaccine was common. Rates of nausea (195 per 100,000 vaccinations), headache (13 per 100,000 vaccinations) and fever (40 per 100,000 vaccinations) were significantly higher following Vi capsule vaccination compared to receipt of Vivotif (130, 2, 10 per 100,000 vaccinations, respectively). In contrast the rates of rash and non-infectious diarrhea (186 and 426 per 100,000 vaccinations, respectively) were increased in those receiving Vivotif compared to the Vi capsule vaccine.DiscussionThe US military is a major consumer of S. Typhi vaccines. The parenterally administered vaccine appears to be more amenable, though we were limited in our ability to assess the reasons for its higher usage. While we observed a higher rate of several adverse events in subjects receiving the intramuscular vaccination, the overall rate of these events was low. Future studies assessing more long-term health outcomes are warranted.