Post-licensure Vaccine Safety Research Articles

Active Postlicensure Safety Surveillance for Recombinant Zoster Vaccine Using Electronic Health Record Data.

Recombinant zoster vaccine (RZV) (Shingrix; GlaxoSmithKline, Brentford, United Kingdom) is an adjuvanted glycoprotein vaccine that was licensed in 2017 to prevent herpes zoster (shingles) and its complications in older adults. In this prospective, postlicensure Vaccine Safety Datalink study using electronic health records, we sequentially monitored a real-world population of adults aged ≥50 years who received care in multiple US Vaccine Safety Datalink health systems to identify potentially increased risks of 10 prespecified health outcomes, including stroke, anaphylaxis, and Guillain-Barré syndrome (GBS). Among 647,833 RZV doses administered from January 2018 through December 2019, we did not detect a sustained increased risk of any monitored outcome for RZV recipients relative to either historical (2013-2017) recipients of zoster vaccine live, a live attenuated virus vaccine (Zostavax; Merck & Co., Inc., Kenilworth, New Jersey), or contemporary non-RZV vaccine recipients who had an annual well-person visit during the 2018-2019 study period. We confirmed prelicensure trial findings of increased risks of systemic and local reactions following RZV. Our study provides additional reassurance about the overall safety of RZV. Despite a large sample, uncertainty remains regarding potential associations with GBS due to the limited number of confirmed GBS cases that were observed.

Smartphone-based active vaccine safety surveillance (SmartVax) at a Swiss adult vaccination clinic - a pilot study.

Post-licensure surveillance of adverse events following immunisation (AEFI) is critical for detecting rare but severe AEFI. SmartVax software, using smartphone technology, actively solicits reports of AEFI via automated, opt-out SMS surveys to vaccine recipients in the days following immunisation. We report on a pilot study to test the feasibility and acceptance of SmartVax in Switzerland. Between February and September 2020, consecutive subjects immunised at an adult immunisation clinic and the employee health service at the University Hospital of Basel were screened. Participants included three subgroups: healthcare workers (HCW), subjects with immune-mediated inflammatory diseases (IMID) and clients of the regular adult immunisation clinic. Three days after vaccination, participants received an SMS inquiring if they had any AEFI. In the case of an AEFI, subjects received an automated SMS with a link to an online survey assessing the type and temporal evolution of the AEFI. Descriptive statistics of response rate, time-to-response, frequency and type of AEFI by vaccine and clinical subgroup were performed. Of 293 subjects screened, 276 were included (46.6% routine vaccination check-up visits, 33.3% HCW, 20.1% IMID patients) receiving 625 vaccinations during 360 immunisation visits. The SMS response rate was high (90.3%), with a median time-to-respond of 47 minutes (interquartile range11-205). After 29.8% of immunisation visits at least one AEFI was reported. There were no differences in frequency or type of AEFI between the three clinical subgroups. The recombinant, adjuvanted zoster vaccine Shingrix® was associated with the highest rate of local and systemic reactions. Monitoring post-licensure vaccine safety using the active SMS-based surveillance system SmartVax is feasible in Switzerland. We observed a high acceptance in the diverse study population, including healthcare workers and IMID patients. High response rates in the elderly and reliable monitoring almost in real-time make SmartVax a promising tool for COVID-19 vaccine safety monitoring.

Myocarditis After SARS-CoV-2 Vaccination: True, True, and… Related?

Myocarditis After SARS-CoV-2 Vaccination: True, True, and… Related?

Challenges in Phase 4 post-licensure safety studies using real world data in the United States: Hepatitis B vaccine example

Post-licensure vaccine safety studies are essential to identify adverse events that may not have been detected in pre-licensure clinical trials and to address questions that arose during the pre-licensure phase. These studies are increasingly conducted using real-world data collected as part of routine health care delivery. However, design of post-licensure vaccine safety studies involves many pragmatic and scientific decisions, which must be made while balancing diverse stakeholder opinions. Challenges include selecting exposure and comparison groups, deciding on the most appropriate outcome, determining sample size and length of follow-up time, and other analytic considerations. As an example of this process and to inform other post-licensure vaccine safety studies in real-world settings, we discuss our experience with design of an FDA-required Phase 4 post-licensure safety study of a hepatitis B vaccine in a large integrated health care organization in the United States.

Postapproval Vaccine Safety Surveillance for COVID-19 Vaccines in the US

This Viewpoint reviews systems in place to monitor postlicensure vaccine safety, and recommends harmonizing end points and protocols across vaccine trials and surveillance systems to enable timely identification and reliable evaluation of potential adverse events.

Use of routinely collected electronic healthcare data for postlicensure vaccine safety signal detection: a systematic review

BackgroundConcerns regarding adverse events following vaccination (AEFIs) are a key challenge for public confidence in vaccination. Robust postlicensure vaccine safety monitoring remains critical to detect adverse events, including those not...

Knowledge and Perceptions of Adverse Events Following Immunization among Healthcare Professionals in Africa: A Case Study from Ghana.

The spontaneous reporting of suspected adverse events following immunization (AEFI) by healthcare professionals (HCPs) is vital in monitoring post-licensure vaccine safety. The main objective of this study was to assess the knowledge and perceptions of AEFIs among healthcare professionals (HCPs) in Africa, using the situation in Ghana as a case study. The study was of a cross-sectional quantitative design, and was carried out from 1 July 2017 to 31 December 2017 with doctors, pharmacists, and nurses as the study participants. A 28-item paper-based questionnaire, delivered by hand to study participants, was the data collection tool in the study. The study was conducted in 4 hospitals after ethical approval was granted. The desired sample size was 686; however, 453 consented to partake in the study. Data were analyzed using SPSS (software version 22, IBM, Armonk, NY, USA), and chi-square and binary logistic regression tests were used for tests of association between HCPs’ characteristics and their knowledge and perceptions. Detailed knowledge of AEFIs was ascertained with a set of 9 questions, with 8 or 9 correctly answered questions signifying high knowledge, 5 to 7 correctly answered questions signifying moderate knowledge, and below 5 correctly answered questions signifying low knowledge. A set of 10 questions also ascertained HCPs’ positive and negative perceptions of AEFI. Results revealed that knowledge of AEFIs was high in 49 (10.8%) participants, moderate in 213 (47.0%) participants, and low in 191 (42.2%) participants. There was no statistically significant correlation between AEFI knowledge and professions. The highest negative perception was the lack of desire to learn more about how to diagnose, report, investigate, and manage AEFI, whereas the lowest was the lack of belief that surveillance improves public trust in immunization programs. There was a general awareness of AEFIs among HCPs in this study. However, negative perceptions and the lack of highly knowledgeable HCPs regarding AEFIs were possible setbacks to AEFI diagnosis, management, prevention, and reporting. More training and sensitization of HCPs on AEFIs and vaccine safety will be beneficial in improving the situation. Future research should focus on assessing the training materials and methodology used in informing HCPs about AEFIs and vaccine safety.

Safety of 9-valent human papillomavirus vaccine administration among pregnant women: Adverse event reports in the Vaccine Adverse Event Reporting System (VAERS), 2014–2017

Introduction9-valent human papillomavirus vaccine (9vHPV) was approved by the Food and Drug Administration (FDA) in December 2014. 9vHPV is not recommended during pregnancy, but some women of childbearing age may be inadvertently exposed. This study aims to evaluate reports submitted to the Vaccine Adverse Event Reporting System (VAERS) of pregnant women exposed to 9vHPV. MethodsWe searched the VAERS database, a national post-licensure vaccine safety surveillance system, for reports of pregnant women vaccinated with 9vHPV in the United States between December 10, 2014 and December 31, 2017. Disproportionate reporting of adverse events (AEs) was assessed using proportional reporting ratios (PRRs). ResultsA total of 82 pregnancy reports were identified. Sixty reports (73.2%) did not describe an AE and were submitted only to report the vaccine exposure during pregnancy. The most frequently reported pregnancy-specific AE was spontaneous abortion (n = 3; 3.7%), followed by vaginal bleeding (n = 2; 2.4%). Among non-pregnancy-specific AEs, injection site reaction (n = 3; 3.7%) was most common. No disproportionate reporting of any AE was found. DiscussionNo unexpected AEs were observed among these pregnancy reports.

Timeliness of recording in the Clinical Practice Research Datalink (CPRD) – an initial step in the implementation of near real-time vaccine safety surveillance

ABSTRACTObjectiveNear real-time vaccine safety surveillance (NRTVSS) using electronic health records (EHR) is an option for post-licensure vaccine safety assessment. NRTVSS requires timely recording of outcomes in the database used. Our study aimed to examine recording delays in the Clinical Practice Research Datalink (CPRD) to inform the feasibility of implementing NRTVSS in England using these data. 
 ApproachTo examine delays we selected 4 outcomes of interest for NRTVSS: Guillain-Barre syndrome (GBS), Bell’s palsy (BP), optic neuritis (ON), and seizures for the period January 2005 to July 2015. Timeliness of CPRD records was assessed in two ways: 1) Using linked CPRD-hospital episode (HES) data to compare the hospital diagnosis date with the date the record was entered in CPRD (system date), 2) Looking at delays in recording (e.g. due to feedback from specialist referral) in stand-alone CPRD. For the latter the event date was compared with the system date. However, system dates can be changed when practice software is updated or there is mass transfer of a patient’s records. After investigation, we excluded these uninformative system dates by excluding records from patients who had more than 100 records with the system date on the same day.
 Results67813 patients were identified in CPRD (GBS:n=1081, BP:n=15835, ON:n=2236, seizures:n=48866), 64527 in HES (GBS:n=1680, BP:n=8468, ON:n=1746, seizures:n=53080) and 14104 in both databases (GBS:n=356, BP:n=1511, ON:n=226, seizures:n=12036). For the CPRD-HES comparison, 11843 patients with a diagnosis of interest both in CPRD and HES were included (GBS:n=321, BP:n=1374, ON:n=190, seizures:n=9976). Of these, the majority had a record in CPRD before or within 1 month of the HES record (GBS:49.5%, BP:83.8%, ON:66.8%, seizures:69.8%). For 6 months the corresponding percentage was more than 85% for all conditions examined (GBS:85.4%, BP:92.9%, ON:90.0%, seizures:86.6%). For stand-alone CPRD 57317 patients were included (GBS:n=972, BP:n=14275, ON:n=1958, seizures:n=40327). The majority had a record within one month of the event date (GBS:67.9%, BP:89.3%, ON:71.8%, seizures:83%). More than 87% of records occurred within 6 months of the event date (GBS:87.9%, BP:94.4%, ON:91.6%, seizures:94.9%).
 ConclusionThis work shows that most diagnoses examined were recorded with a delay of ≤30 days, making NRTVSS possible. The distribution of the delays was condition-specific and the weekly delay distribution could be used to adjust for delays in the NRTVSS analysis. CPRD can be a viable data source to use in this kind of analysis; next steps will include trial implementation of the system using these data.

Kawasaki disease and immunisation: A systematic review

BackgroundKawasaki disease is a complex and potentially serious condition. It has been observed in temporal relation to immunisation. MethodsWe conducted a systematic literature review using various reference sources to review the available evidence published in the literature. ResultsWe identified twenty seven publications reporting a temporal association between immunisation and Kawasaki disease. We present a systematic review of data drawn from randomised controlled trials, observational studies, case series and reports, and reviews. Overall there was a lack of standardised case definitions, making data interpretation and comparability challenging. ConclusionsAlthough a temporal relationship between immunisation and Kawasaki disease is suggested, evidence for an increased risk or a causal association is lacking. Implementation of a standardised Kawasaki disease case definition would increase confidence in the findings and add value to future studies of pre- or post-licensure vaccine safety studies.

Assessing recording delays in general practice records to inform near real-time vaccine safety surveillance using the Clinical Practice Research Datalink (CPRD)

PurposeNear real‐time vaccine safety surveillance (NRTVSS) is an option for post‐licensure vaccine safety assessment. NRTVSS requires timely recording of outcomes in the database used. Our main objective was to examine recording delays in the Clinical Practice Research Datalink (CPRD) for outcomes of interest for vaccine safety to inform the feasibility of NRTVSS using these data. We also evaluated completeness of recording and further assessed reporting delays for hospitalized events in CPRD.MethodsWe selected Guillain–Barré syndrome (GBS), Bell's palsy (BP), optic neuritis (ON) and febrile seizures (FS), from January 2005 to June 2014. We assessed recording delays (e.g. due to feedback from specialist referral) in stand‐alone CPRD by comparing the event and system dates and excluding delays >1 year. We used linked CPRD‐hospitalization data to further evaluate delays and completeness of recording in CPRD.ResultsAmong 51 220 patients for the stand‐alone CPRD analysis (GBS: n = 830; BP: n = 12 602; ON: n = 1720; and FS: n = 36 236), most had a record entered within 1 month of the event date (GBS: 73.6%; BP: 93.4%; ON: 76.2%; and FS: 85.6%). A total of 13 482 patients, with a first record in hospital, were included for the analysis of linked data (GBS: n = 678; BP: n = 4060; ON: n = 485; and FS: n = 8321). Of these, <50% had a record in CPRD after 1 year (GBS: 41.3%; BP: 22.1%; ON: 22.4%; and FS: 41.8%).ConclusionThis work shows that most diagnoses in CPRD for the conditions examined were recorded with delays of ≤30 days, making NRTVSS possible. The pattern of delays was condition‐specific and could be used to adjust for delays in the NRTVSS analysis. Despite low sensitivity of recording, implementing NRTVSS in CPRD is worthwhile and could be carried out, at least on a trial basis, for events of interest. © 2017 The Authors. Pharmacoepidemiology & Drug Safety Published by John Wiley & Sons Ltd.

Evaluating efficiency and statistical power of self-controlled case series and self-controlled risk interval designs in vaccine safety

ABSTRACTThe self-controlled case series (SCCS) and self-controlled risk interval (SCRI) designs have recently become widely used in the field of post-licensure vaccine safety monitoring to detect potential elevated risks of adverse events following vaccinations. The SCRI design can be viewed as a subset of the SCCS method in that a reduced comparison time window is used for the analysis. Compared to the SCCS method, the SCRI design has less statistical power due to fewer events occurring in the shorter control interval. In this study, we derived the asymptotic relative efficiency (ARE) between these two methods to quantify this loss in power in the SCRI design. The equation is formulated as (a: control window-length ratio between SCRI and SCCS designs; b: ratio of risk window length and control window length in the SCCS design; and : relative risk of exposed window to control window). According to this equation, the relative efficiency declines as the ratio of control-period length between SCRI and SCCS methods decreases, or with an increase in the relative risk . We provide an example utilizing data from the Vaccine Safety Datalink (VSD) to study the potential elevated risk of febrile seizure following seasonal influenza vaccine in the 2010–2011 season.

Active Surveillance for Adverse Events After a Mass Vaccination Campaign With a Group A Meningococcal Conjugate Vaccine (PsA-TT) in Mali.

Background. The monovalent meningococcal A conjugate vaccine (PsA-TT, MenAfriVac) was developed for use in the “meningitis belt” of sub-Saharan Africa. Mali was 1 of 3 countries selected for early introduction. As this is a new vaccine, postlicensure surveillance is particularly important to identify and characterize possible safety issues.Methods. The national vaccination campaign was phased from September 2010 to November 2011. We conducted postlicensure safety surveillance for PsA-TT in 40 government clinics from southern Mali serving approximately 400 000 people 1–29 years of age. We conducted analyses with individual-level data and population-level data, and we calculated rates of adverse events using the conditional exact test, a modified vaccine cohort risk interval method, and a modified self-controlled case series method for each outcome of interest, including 18 prespecified adverse events and 18 syndromic categories.Results. An increased rate of clinic visits for fever within 3 days after vaccination was found using multiple methods for all age groups. Although other signals were found with some methods, complete assessment of all other prespecified outcomes and syndromic categories did not reveal that PsA-TT was consistently associated with any other health problem.Conclusions. No new safety concerns were identified in this study. These results are consistent with prelicensure data and other studies indicating that PsA-TT is safe. The approach presented could serve as a model for future active postlicensure vaccine safety monitoring associated with large-scale immunization campaigns in low-income countries.

Unmasking in an observational vaccine safety study: Using type 2 diabetes mellitus as an example

BackgroundIn observational vaccine safety studies, diagnosis codes assigned prior to or on the day of vaccination (Day 0) are often excluded from analysis of safety signals since they usually represent pre-existing conditions. The limitations of this approach have been described for autoimmune conditions but not for other chronic conditions. We draw on our experience in a post-licensure quadrivalent human papillomavirus vaccine (HPV4) safety study to examine the effectiveness of exclusion of pre-existing and Day 0 diagnoses of type 2 diabetes mellitus (T2DM) in excluding prevalent T2DM. MethodsSubjects included all 117,402 females ages 9–26 years who received HPV4 August 2006–March 2008 in Kaiser Permanente Southern California. We identified potential incident T2DM cases using ICD9 code 250.xx associated with inpatient and emergency room visits during the 60 days following each HPV4 dose, excluding those with this code prior to their first HPV4 dose. Electronic medical records were reviewed to determine the dates of symptom onset, diagnostic labs, vaccine administration and T2DM diagnosis. ResultsOf 33 potential incident T2DM cases identified using automated data, 4 (12%) were confirmed to have new onset T2DM after medical record review. Nineteen cases were excluded that did not have T2DM or had T2DM diagnosed before Day 0; nine had an abnormal fasting blood sugar (FBS) ordered on Day 0, prompting subsequent evaluation and diagnosis of T2DM; and one had elevated FBS and glucosuria prior to the first dose of HPV4 but T2DM diagnosed at a visit following vaccination. ConclusionThese results suggest that among adolescents and young adults, the workup and subsequent diagnosis of pre-existing conditions may result from a visit at which a vaccination is administered. This “unmasking” phenomenon is not entirely eliminated by exclusion of pre-existing and Day 0 diagnoses. Medical record review should be considered in the evaluation of potential safety signals.

Demographic characteristics of members of the Vaccine Safety Datalink (VSD): A comparison with the United States population

BackgroundThe Vaccine Safety Datalink (VSD) is a collaboration between CDC and nine integrated health care systems that serves as a cornerstone of US post-licensure vaccine safety monitoring. Given concerns that potential differences between the insured VSD population and the US population could limit the generalizability of VSD study findings, we performed a comparison of the demographic characteristics between the two populations. MethodsWe collected data from medical records and administrative files at VSD sites in 2010 to compare sex, age, race, ethnicity, income, and educational attainment to the 2010 US Census population. We also compared data on the 2012 VSD Medicaid population to 2012 US Medicaid data. ResultsThe VSD population included over eight million individuals in 2010, which represented 2.6% of the total US population. All major demographic groups were represented in the VSD. We found no major differences in comparing sex, race, ethnicity, and educational attainment between the VSD and the US population. Middle income populations were comparable between the VSD and the US. While the percentage of lower income populations was less in the VSD compared to the US, the VSD had over two million individuals in this group. Additionally, there were over 600,000 Medicaid members in the VSD in 2012, which represented 1.1% of the US Medicaid population. ConclusionsWe found that the VSD population is representative of the general US population on several key demographic and socioeconomic variables. Despite a few specific groups being underrepresented in the VSD compared to the US, the absolute number of VSD members is large enough to ensure significant representation of these groups in vaccine safety studies that use VSD data.

Surveillance of adverse events following immunization with meningococcal group C conjugate vaccine: Tuscany, 2005-2012.

Post-licensure vaccine safety studies are essential to identify uncommon events that may be difficult to assess during pre-licensure studies. The aim of our study was to evaluate the safety of serogroup C meningococcal conjugate (MCC) vaccine in Tuscany from 2005 to 2012. All adverse events (AEs) to MCC vaccine notified from 2005 to 2012 were obtained from the regional health authority. Following 451,570 doses administered, 110 suspected AEs were notified (mean annual reporting rate: 2.8/10,000 doses). The most frequently AE reported was fever (60%), followed by swelling at the injection site (11%) and febrile seizures (10%). Overall, 77.3% of cases were not severe, while 21.8% required hospitalization. Almost four months after the receipt of the vaccine, a one-year-old infant was diagnosed with a pervasive developmental disorder with disturbance of speech, but any link with the vaccinations received was refuted. Most AEs (80.9%) occurred after co-administration with other vaccines, especially with MMR or MMRV vaccines (42.7%) or the DTPa-HBV-IPV/Hib vaccine (33.7%). Our study confirmed the high level of safety of MCC vaccine in Tuscany: AEs proved rare and all cases had only temporary and self-resolving consequences. As usually only the most severe suspected AEs are reported, the true proportion of AEs requiring hospitalization was most probably overestimated, and it is plausible that most of these cases were in fact only temporally related.

Vaccine Adjuvant Informatics: From Data Integration and Analysis to Rational Vaccine Adjuvant Design

GENERAL COMMENTARY article Front. Immunol., 03 February 2014Sec. Vaccines and Molecular Therapeutics https://doi.org/10.3389/fimmu.2014.00032

Healthcare providers’ knowledge, experience and challenges of reporting adverse events following immunisation: a qualitative study

BackgroundHealthcare provider spontaneous reporting of suspected adverse events following immunisation (AEFI) is central to monitoring post-licensure vaccine safety, but little is known about how healthcare professionals recognise and report to surveillance systems. The aim of this study was explore the knowledge, experience and attitudes of medical and nursing professionals towards detecting and reporting AEFI.MethodsWe conducted a qualitative study, using semi-structured, face to face interviews with 13 Paediatric Emergency Department consultants from a tertiary paediatric hospital, 10 General Practitioners, 2 local council immunisation and 4 General Practice nurses, recruited using purposive sampling in Adelaide, South Australia, between December 2010 and September 2011. We identified emergent themes related to previous experience of an AEFI in practice, awareness and experience of AEFI reporting, factors that would facilitate or impede reporting and previous training in vaccine safety. Thematic analysis was used to analyse the data.ResultsAEFI reporting was infrequent across all groups, despite most participants having reviewed an AEFI. We found confusion about how to report an AEFI and variability, according to the provider group, as to the type of events that would constitute a reportable AEFI. Participants’ interpretation of a “serious” or “unexpected” AEFI varied across the three groups. Common barriers to reporting included time constraints and unsatisfactory reporting processes. Nurses were more likely to have received formal training in vaccine safety and reporting than medical practitioners.ConclusionsThis study provides an overview of experience and beliefs of three healthcare professional groups in relation to identifying and reporting AEFI. The qualitative assessment reveals differences in experience and awareness of AEFI reporting across the three professional groups. Most participants appreciated the importance of their role in AEFI surveillance and monitoring the ongoing safety of vaccines. Future initiatives to improve education, such as increased training to health care providers, particularly, medical professionals, are required and should be included in both undergraduate curricula and ongoing, professional development.

Physicians' confidence in vaccine safety studies

ObjectivesTo ascertain, through two separate surveys among nationally representative networks of pediatricians (Peds) and family physicians (FM): 1) physicians' reported level of confidence in pre- and post-licensure vaccine safety studies; and 2) changes in reported level of confidence from 2007 to 2010/11. MethodsTwo surveys were conducted in August to October 2007 and in November 2010 to January 2011. The survey response rates were 81% (FM, 79%, Peds, 84%, p=0.07) for the 2007 survey (691/848) and 66% (FM, 61%, Peds, 70%, p=0.003) for the 2010/11 survey (532/811). ResultsOne in three family physicians compared to one in ten pediatricians in both surveys reported little or no confidence in pre-licensure vaccine safety studies (p<0.001). Compared to pre-licensure studies, higher percentages of both specialties reported a great deal of confidence in post-licensure vaccine safety studies in both years, and more physicians from both specialties reported a great deal of confidence in 2010/11 than in 2007. ConclusionWhile most family physicians and pediatricians report confidence in post-licensure vaccine safety studies, one third of family physicians report little or no confidence in pre-licensure studies. More research is needed to better understand the reasons behind some physicians' lack of confidence in vaccine safety studies.

Adapting Group Sequential Methods to Observational Postlicensure Vaccine Safety Surveillance: Results of a Pentavalent Combination DTaP-IPV-Hib Vaccine Safety Study

To address gaps in traditional postlicensure vaccine safety surveillance and to promote rapid signal identification, new prospective monitoring systems using large health-care database cohorts have been developed. We newly adapted clinical trial group sequential methods to this observational setting in an original safety study of a combination diphtheria and tetanus toxoids and acellular pertussis adsorbed (DTaP), inactivated poliovirus (IPV), and Haemophilus influenzae type b (Hib) conjugate vaccine (DTaP-IPV-Hib) among children within the Vaccine Safety Datalink population. For each prespecified outcome, we conducted 11 sequential Poisson-based likelihood ratio tests during September 2008-January 2011 to compare DTaP-IPV-Hib vaccinees with historical recipients of other DTaP-containing vaccines. No increased risk was detected among 149,337 DTaP-IPV-Hib vaccinees versus historical comparators for any outcome, including medically attended fever, seizure, meningitis/encephalitis/myelitis, nonanaphylactic serious allergic reaction, anaphylaxis, Guillain-Barré syndrome, or invasive Hib disease. In end-of-study prespecified subgroup analyses, risk of medically attended fever was elevated among 1- to 2-year-olds who received DTaP-IPV-Hib vaccine versus historical comparators (relative risk = 1.83, 95% confidence interval: 1.34, 2.50) but not among infants under 1 year old (relative risk = 0.83, 95% confidence interval: 0.73, 0.94). Findings were similar in analyses with concurrent comparators who received other DTaP-containing vaccines during the study period. Although lack of a controlled experiment presents numerous challenges, implementation of group sequential monitoring methods in observational safety surveillance studies is promising and warrants further investigation.