Live-attenuated tetravalent dengue vaccines: The needs and challenges of post-licensure evaluation of vaccine safety and effectiveness

Since December 2015, the first dengue vaccine has been licensed in several Asian and Latin American countries for protection against disease from all four dengue virus serotypes. While the vaccine demonstrated an overall good safety and efficacy profile in clinical trials, some key research questions remain which make risk-benefit-assessment for some populations difficult. As for any new vaccine, several questions, such as very rare adverse events following immunization, duration of vaccine-induced protection and effectiveness when used in public health programs, will be addressed by post-licensure studies and by data from national surveillance systems after the vaccine has been introduced. However, the complexity of dengue epidemiology, pathogenesis and population immunity, as well as some characteristics of the currently licensed vaccine, and potentially also future, live-attenuated dengue vaccines, poses a challenge for evaluation through existing monitoring systems, especially in low and middle-income countries. Most notable are the different efficacies of the currently licensed vaccine by dengue serostatus at time of first vaccination and by dengue virus serotype, as well as the increased risk of dengue hospitalization among young vaccinated children observed three years after the start of vaccination in one of the trials. Currently, it is unknown if the last phenomenon is restricted to younger ages or could affect also seronegative individuals aged 9 years and older, who are included in the group for whom the vaccine has been licensed. In this paper, we summarize scientific and methodological considerations for public health surveillance and targeted post-licensure studies to address some key research questions related to live-attenuated dengue vaccines. Countries intending to introduce a dengue vaccine should assess their capacities to monitor and evaluate the vaccine’s effectiveness and safety and, where appropriate and possible, enhance their surveillance systems accordingly. Targeted studies are needed, especially to better understand the effects of vaccinating seronegative individuals.     

Childhood vaccines and Kawasaki disease,Vaccine Safety Datalink, 1996-2006

BackgroundKawasaki disease is a childhood vascular disorder of unknown etiology. Concerns have been raised about vaccinations being a potential risk factor for Kawasaki disease.MethodsData from the Vaccine Safety Datalink were collected on children aged 0–6 years at seven managed care organizations across the United States. Defining exposure as one of several time periods up to 42 days after vaccination, we conducted Poisson regressions controlling for age, sex, season, and managed care organization to determine if rates of physician-diagnosed and verified Kawasaki disease were elevated following vaccination compared to rates during all unexposed periods. We also performed case-crossover analyses to control for unmeasured confounding.ResultsA total of 1,721,186 children aged 0–6 years from seven managed care organizations were followed for a combined 4,417,766 person-years. The rate of verified Kawasaki disease was significantly lower during the 1–42 days after vaccination (rate ratio = 0.50, 95% CL = 0.27–0.92) and 8–42 days after vaccination (rate ratio = 0.45, 95% CL = 0.22–0.90) compared to rates during unexposed periods. Breaking down the analysis by vaccination category did not identify a subset of vaccines which was solely responsible for this association. The case-crossover analyses revealed that children with Kawasaki disease had lower rates of vaccination in the 42 days prior to symptom onset for both physician-diagnosed Kawasaki disease (rate ratio = 0.79, 95% CL = 0.64–0.97) and verified Kawasaki disease (rate ratio = 0.38, 95% CL = 0.20–0.75).ConclusionsChildhood vaccinations’ studied did not increase the risk of Kawasaki disease; conversely, vaccination was associated with a transient decrease in Kawasaki disease incidence. Verifying and understanding this potential protective effect could yield clues to the underlying etiology of Kawasaki disease.     

疫苗安全性评价文献数据仓库建立及应用前景初探

目的:建立可持续更新的全球疫苗安全性评价文献数据仓库,为疫苗安全性循证评价提供数据支持。方法:通过循证评价的标准操作步骤与人工智能技术的不断整合,实现文献数据仓库的半自动化构建和更新。检索包括英文数据库（OVID、Scopus、Web of Science、Cochrane Library、ClinicalTrails...     

流行病学方法在新型冠状病毒疫苗上市前后的应用

安全有效的疫苗是应对新型冠状病毒（新冠病毒）肺炎大流行的核心措施之一,从疫苗上市前安全性、保护效力的实验性研究到上市后安全性监测和人群保护效果的观察性研究,流行病学发挥了重要作用。本文通过列举国内外研究案例,系统介绍了临床试验、队列研究和病例对照研究设计在疫苗上市前后的应用及设计要素,以期丰富流行病学教学案例。另外,在...     

Evaluation of the feasibility of a state-based vaccine safety advice network

The vaccine safety advice network is a collaborative pilot project between Vanderbilt University Medical Center, the Tennessee Department of Health, and the Centers for Disease Control and Prevention to assess the feasibility of addressing vaccine safety questions posed by healthcare providers in near real-time. Using a two-tier response system and an electronic database for query submission, the pilot project received ten queries in three and one half months. Two of three pre-specified benchmarks for program evaluation, addressing queries within 24 h of receipt and 100% provider satisfaction, were met; one benchmark, the percentage of questions addressed by Tier 1 staff, was not met. Limitations included few submitted queries primarily involving children in the pilot period, “after-only” program evaluation, and limited geographic generalizability. The study demonstrates a successful partnership between federal, state and academic institutions and a feasible method to respond to healthcare provider inquiries about vaccine safety in near real-time.     

Background incidence rates of selected adverse events of special interest (AESI) to monitor the safety of COVID-19 vaccines

Background Determining background rates of medical conditions identified as adverse events of special interest (AESI) that may occur following COVID-19 vaccination is important for contextualising and investigating potential vaccine safety signals.MethodsWe conducted a retrospective population-based cohort study using linked emergency department, hospitalisation and death data for 2017 and 2018 from Australia’s most populous state, New South Wales. Incident cases of select neurological conditions, arterial or venous thromboembolic conditions, secondary thrombocytopenia, myocarditis/pericarditis, and unique events of anaphylaxis and generalised convulsions were identified using internationally agreed upon diagnostic (ICD-10) codes. State-specific rates per 100,000 person-years were calculated, with further stratification by age group and sex where clinically relevant to the condition, and the number of expected cases nationally in one and 6 weeks was estimated.ResultsBackground rates of selected neurological conditions were low with the exception of generalised convulsions for which 1,599–1,872 cases were estimated nationally in a 1-week period in the absence of vaccination. Using a narrow case definition, rates of Guillain-Barré Syndrome (3.9 per 100,000 person-years) were higher than international rates reported elsewhere. Thromboembolic and cerebral venous sinus thrombosis event rates increased with age. Myocarditis occurred more commonly in males, and was highest in males aged 18–24 years, with an estimated 1–4 cases expected nationally in a 1-week period.ConclusionsUsing routinely collected linked healthcare data provides localised estimates of background rates of new onset or periodic AESI which enables rapid estimation of observed-versus-expected rates of events reported following COVID-19 vaccination. This Australian-specific analysis contributes AESI background rates which can be compared with those from other countries to enhance understanding of geographic variability in the frequency of specific AESI in the absence of vaccination, and can be utilised for signal detection during program implementation.     

磁共振成像安全性和有效性评价

目的　评价MRI安全性和有效性 ,为制定大型医用设备发展政策提供重要依据。方法　应用流行病学中描述性方法评价MRI安全性 ,应用循证医学中疾病诊断标准评价体系评价MRI有效性。结果　MRI科室工作人员有轻微的自觉症状 ,患者在MRI检查、治疗过程无意外事件发生 ;MRI门诊诊断阳性率和住院诊断阳性率较高 ,分别达 83 6 0 %和 78 0 0 % ;MRI诊断与门诊前诊断和入院前诊断一致性较低 ,与“金标准”(出院诊断 )相比较一致性较高。结论　MRI是一种比较安全的大型医用设备 ,具有较高的临床诊断价值 ,对身体各部位疾病的诊断价值均高于CT。     

Safety of human papillomavirus (HPV) vaccines: A review of the international experience so far

Despite the advent of the Papanicolaou smear test almost 50 years ago, cervical cancer remains the second most common malignant disease in women and the leading cause of cancer death in developing countries. Thus the two prophylactic human papillomavirus (HPV) vaccines currently available have been greeted with enthusiasm internationally, as an emerging primary prevention strategy against cervical cancer. Prior to licensure the vaccines were trialed in over 60,000 women and assessed as safe, within the statistical constraints of the trials to detect very rare events. Post-licensure surveillance is underway as vaccination programs are undertaken. We reviewed published post-licensure surveillance data, as at January 2009, and concur with international advisory bodies that both HPV vaccines are safe, effective and of great importance for women's health. Ongoing monitoring is required to maintain confidence in the safety of the vaccines.     

探讨输尿管镜钬激光碎石治疗嵌顿输尿管结石的有效性和安全性

目的 探讨输尿管镜钬激光碎石治疗嵌顿输尿管结石的有效性和安全性.方法 分析2007年8月～2011年12月间某院输尿管镜下钬激光碎石治疗嵌顿输尿管结石85例患者临床资料,对碎石率、排石率和并发症等进行统计分析.结果 共行103侧输尿管镜钬激光碎石,碎石成功率为90.3％ (93/103),输尿管上段与中、下段结石碎石成功率分别为73.9％ (17/23)、95.0％ (76/80).随访3～18个月,结石排净率85.4％ (88/103).3例发现输尿管狭窄,并发症发生率2.9％ (3/103).结论 输尿管镜钬激光碎石治疗嵌顿输尿管结石安全、有效,尤其适用于中、下段输尿管结石.     

Planning for COVID-19 vaccines safety surveillance

COVID-19 vaccines are the most important tool to stem the pandemic. They are being developed with unprecedented global collaboration and accelerated timelines to achieve WHO Emergency Use Listing, while using regulatory pathways through national regulatory authorities. Alongside preparations to ensure equitable access to the vaccines among people globally, preparations must be made within countries for COVID-19 vaccines safety surveillance on an urgent basis. Safety surveillance must be capable of investigating adverse events of special interest (AESI) and adverse events following immunization to determine a change in the benefit-risk profile of the vaccine, and to be able to anticipate coincidental events that might be attributed to the vaccine.Active surveillance systems should calculate the incidence of background rates of AESI prior to vaccine roll out. These background rates vary tremendously across regions, populations and case ascertainment methods. Active surveillance systems must be established or strengthened now, (including in LMIC), to calculate the background rates. Utilizing standardized case definitions and global standards for AESI will help in harmonization. Vaccine safety communication plans should be developed. Expanding the global vaccine safety system to meet the needs of COVID-19 and other emergency and routine use vaccines is a priority currently.     

A systematic review and meta-analysis on the safety of newly adjuvanted vaccines among children

IntroductionNew adjuvants such as the AS- or the MF59-adjuvants improve vaccine efficacy and facilitate dose-sparing. Their use in influenza and malaria vaccines has resulted in a large body of evidence on their clinical safety in children.MethodsWe carried out a systematic search for safety data from published clinical trials on newly adjuvanted vaccines in children ≤10 years of age. Serious adverse events (SAEs), solicited AEs, unsolicited AEs and AEs of special interest were evaluated for four new adjuvants: the immuno-stimulants containing adjuvant systems AS01 and AS02, and the squalene containing oil-in-water emulsions AS03 and MF59. Relative risks (RR) were calculated, comparing children receiving newly adjuvanted vaccines to children receiving other vaccines with a variety of antigens, both adjuvanted and unadjuvanted.ResultsTwenty-nine trials were included in the meta-analysis, encompassing 25,056 children who received at least one dose of the newly adjuvanted vaccines. SAEs did not occur more frequently in adjuvanted groups (RR 0.85, 95%CI 0.75–0.96). Our meta-analyses showed higher reactogenicity following administration of newly adjuvanted vaccines, however, no consistent pattern of solicited AEs was observed across adjuvant systems. Pain was the most prevalent AE, but often mild and of short duration. No increased risks were found for unsolicited AEs, febrile convulsions, potential immune mediated diseases and new onset of chronic diseases.ConclusionsOur meta-analysis did not show any safety concerns in clinical trials of the newly adjuvanted vaccines in children ≤10 years of age. An unexplained increase of meningitis in one Phase III AS01-adjuvanted malaria trial and the link between narcolepsy and the AS03-adjuvanted pandemic vaccine illustrate that continued safety monitoring is warranted.     

U.S. Population-Based background incidence rates of medical conditions for use in safety assessment of COVID-19 vaccines

The Coronavirus Disease 2019 (COVID-19) pandemic has had a devastating impact on global health, and has resulted in an unprecedented, international collaborative effort to develop vaccines to control the outbreak, protect human lives, and avoid further social and economic disruption. Mass vaccination campaigns are underway in multiple countries and are expected worldwide once more vaccine becomes available. Some early candidate vaccines use novel platforms, such as mRNA encapsulated in lipid nanoparticles, and relatively new platforms, such as replication-deficient viral vectors. While these new vaccine platforms hold promise, limited safety data in humans are available. Serious health outcomes linked to vaccinations are rare, and some outcomes may occur incidentally in the vaccinated population. Knowledge of background incidence rates of these medical conditions is a critical component of vaccine safety monitoring to aid in the assessment of adverse events temporally associated with vaccination and to put these events into context with what would be expected due to chance alone. A list of 22 potential adverse events of special interest (AESI), including neurologic, autoimmune, and cardiovascular disorders, was compiled by subject matter experts at the U.S. Food and Drug Administration and the Centers for Disease Control and Prevention. The most recently available U.S. background rates for these medical conditions, overall and by age, sex, and race/ethnicity (when available), were sourced from reported statistics (data published by medical panels/ associations or federal government reports), and literature reviews in PubMed. This review provides estimates of background incidence rates for medical conditions that may be monitored or studied as AESI during safety surveillance and research for COVID-19 vaccines and other new vaccines.     

Vaccine safety evaluation: Practical aspects in assessing benefits and risks

Vaccines are different from most medicines in that they are administered to large and mostly healthy populations including infants and children, so there is a low tolerance for potential risks or side-effects. In addition, the long-term benefits of immunisation in reducing or eliminating infectious diseases may induce complacency due to the absence of cases. However, as demonstrated in recent measles outbreaks in Europe and United States, reappearance of the disease occurs as soon as vaccine coverage falls. Unfounded vaccine scares such as those associating the combined measles-mumps-rubella vaccine with autism, and whole-cell pertussis vaccines with encephalopathy, can also have massive impacts, resulting in reduced vaccine uptake and disease resurgence. The safety assessment of vaccines is exhaustive and continuous; beginning with non-clinical evaluation of their individual components in terms of purity, stability and sterility, continuing throughout the clinical development phase and entire duration of use of the vaccine; including post-approval. The breadth and depth of safety assessments conducted at multiple levels by a range of independent organizations increases confidence in the rigour with which any potential risks or side-effects are investigated and managed. Industry, regulatory agencies, academia, the medical community and the general public all play a role in monitoring vaccine safety. Within these stakeholder groups, the healthcare professional and vaccine provider have key roles in the prevention, identification, investigation and management of adverse events following immunisation (AEFI). Guidelines and algorithms aid in determining whether AEFI may have been caused by the vaccine, or whether it is coincidental to it. Healthcare providers are encouraged to rigorously investigate AEFIs and to report them via local reporting processes. The ultimate objective for all parties is to ensure vaccines have a favourable benefit-risk profile.     

流感嗜血杆菌结合疫苗临床安全性及免疫原性研究

目的评价国产流感嗜血杆菌结合疫苗的安全性和免疫原性。方法按整群随机抽样原则,以国产同类疫苗作为对照开展现场临床研究;比较试验和对照疫苗免后不良反应率、抗-Hib阳转率、保护率、免后抗-Hib水平（GMT）和免后抗-Hib较免前平均增长倍数。结果试验组及对照组接种后总体不良反应率分别为26．00％和22．67％,差异无统计学意义（P〉0．05）;在安全性观察期内,所观察到的不良反应以1、2级不良反应为主,未观察到3级以上不良反应。免后抗体总阳转率分别为98．52％和98．37％,试验疫苗和对照疫苗免后阳转率差异无统计学意义（P〉0．05）;两疫苗免后保护率、免后抗-HibGMT和免后抗-Hib较免前平均增长倍数差异均无统计学意义（P〉0．05）。结论受评的该国产流感嗜血杆菌结合疫苗总体不良反应与国产同类疫苗差异无统计学意义,免疫后抗体阳转率较高,抗体滴度上升幅度较大,具有良好的临床安全性和免疫原性。     

The Brighton Collaboration standardized template for collection of key information for benefit-risk assessment of inactivated viral vaccines

Inactivated viral vaccines have long been used in humans for diseases of global health threat and are now among the vaccines for COVID-19 under development. The Brighton Collaboration Viral Vector Vaccines Safety Working Group (V3SWG) has prepared a standardized template to describe the key considerations for the benefit-risk assessment of inactivated viral vaccines. This will help key stakeholders to assess potential safety issues and understand the benefit-risk of the vaccine platform. The standardized and structured assessment provided by the template would also help to contribute to improved communication and support public acceptance of licensed inactivated viral vaccines.     

The Brighton Collaboration standardized template for collection of key information for benefit-risk assessment of protein vaccines

Several protein vaccine candidates are among the COVID-19 vaccines in development. The Brighton Collaboration Viral Vector Vaccines Safety Working Group (V3SWG) has prepared a standardized template to describe the key considerations for the benefit-risk assessment of protein vaccines. This will help key stakeholders to assess potential safety issues and understand the benefit-risk of such a vaccine platform. The structured and standardized assessment provided by the template would also help contribute to improved public acceptance and communication of licensed protein vaccines.     

Monitoring the safety of influenza A (H1N1) vaccine using web-based intensive monitoring

Background

When adjuvant vaccines against the pandemic influenza A (H1N1) virus became available after an accelerated registration process, safety issues dominated the public debate. As part of the immunisation campaign, the Dutch government installed an active monitoring of possible adverse events following immunisation (AEFIs). As part of the monitoring we conducted an anonymous prospective cohort study to identify and quantify the occurrence of AEFIs related to pandemic vaccination among the population immunised in general practice.

Method

Adults aged 60 years and older or persons with a risk-elevating medical condition recommended for vaccination in general practice were eligible for participation. After receipt of the first pandemic vaccine the administrator handed over an information flyer of the web-based monitoring program. The patient could sign up for study participation online. Within one week, three weeks and three months after the first immunisation questions were asked about demographics and health, immunisations, injections site reactions and labeled reactions as well as other possible new AEFIs.

Results

In all, 3569 participants filled in the first questionnaire. Corresponding figures for the second and third questionnaires were 3395 (95.1%) and 3162 (88.6%). Mean age was 58 years (SD 15) and 50.1% was female. Main indication was 60 years or older followed by presence of pulmonary or cardiovascular disease. Of all participants, 1311 (37%) reported an AEFI. Unexpected serious reactions were not reported nor were there signals of possible new AEFIs. The occurrence of an AEFI was determined by gender, age and type of co-morbidity.

Conclusion

The web-based intensive monitoring system among patients immunised in general practice revealed AEFIs due to pandemic vaccination in one-third of participants. There were no unexpected serious adverse events in this population. This advanced methodology can be further developed to monitor real-time use and AEFIs of vaccines.     

Comparative evaluation of the effectiveness and safety of two regimens of levonorgestrel for emergency contraception in Nigerians

Emergency contraception was introduced in Nigeria over two decades ago, but few women have used this method even in emergency situations because of the side effects. To find an acceptable levonorgestrel regimen for emergency contraception in our community, the two-dose regimen 0.75-mg levonorgestrel 12 h apart (group A) and the single dose 1.5-mg levonorgestrel (group B) were studied in 1118 volunteers. Mild side effects such as nausea, vomiting, lower abdominal pains, menorrhagia, dizziness, headache, and breast tenderness were reported. Significantly more women in the high-dose group reported headache, breast tenderness, and heavy menstrual flow. Eleven pregnancies (1.0%) were reported (7 in group A and 4 in group B). The crude relative risk of pregnancies was similar in the two groups (RR = 0.71, 95% CI = 0.32-1.55; p > 0.05) [corrected]. On the other hand, the estimated effectiveness rate of 86.80% in group A was significantly lower than the 92.99% for group B (p < 0.05). The pregnancy rates increased with delay in starting treatment and if further acts of unprotected sexual intercourse took place after treatment. It was concluded that both regimens were effective and safe.