Assessing vaccine safety during a pandemic: Recent experience and lessons learned for the future.

During the roll out of vaccines during a pandemic, questions regarding vaccine safety often arise. This was surely true during the SARS-CoV-2 pandemic. Different tools and capabilities exist during the pre-authorization phase and post introduction each with its strengths and limitations. Here we review the various tools and their strengths and limitations and discuss what functioned well in high income settings and the limitations that unequal vaccine safety pharmacovigilance capacity imposed upon middle and low income countries.

The critical role of background rates of possible adverse events in the assessment of COVID-19 vaccine safety.

Beginning in December of 2019, a novel coronavirus, SARS-CoV-2, emerged in China and is now a global pandemic with extensive morbidity and mortality. With the emergence of this threat, an unprecedented effort to develop vaccines against this virus began. As vaccines are now being introduced globally, we face the prospect of millions of people being vaccinated with multiple types of vaccines many of which use new vaccine platforms. Since medical events happen without vaccines, it will be important to know at what rate events occur in the background so that when adverse events are identified one has a frame of reference with which to compare the rates of these events so as to make an initial assessment as to whether there is a potential safety concern or not. Background rates vary over time, by geography, by sex, socioeconomic status and by age group. Here we describe two key steps for post-introduction safety evaluation of COVID-19 vaccines: Defining a dynamic list of Adverse Events of Special Interest (AESI) and establishing background rates for these AESI. We use multiple examples to illustrate use of rates and caveats for their use. In addition we discuss tools available from the Brighton Collaboration that facilitate case evaluation and understanding of AESI.

Consensus summary report for CEPI/BC March 12-13, 2020 meeting: Assessment of risk of disease enhancement with COVID-19 vaccines.

A novel coronavirus (CoV), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in late 2019 in Wuhan, China and has since spread as a global pandemic. Safe and effective vaccines are thus urgently needed to reduce the significant morbidity and mortality of Coronavirus Disease 2019 (COVID-19) disease and ease the major economic impact. There has been an unprecedented rapid response by vaccine developers with now over one hundred vaccine candidates in development and at least six having reached clinical trials. However, a major challenge during rapid development is to avoid safety issues both by thoughtful vaccine design and by thorough evaluation in a timely manner. A syndrome of "disease enhancement" has been reported in the past for a few viral vaccines where those immunized suffered increased severity or death when they later encountered the virus or were found to have an increased frequency of infection. Animal models allowed scientists to determine the underlying mechanism for the former in the case of Respiratory syncytial virus (RSV) vaccine and have been utilized to design and screen new RSV vaccine candidates. Because some Middle East respiratory syndrome (MERS) and SARS-CoV-1 vaccines have shown evidence of disease enhancement in some animal models, this is a particular concern for SARS-CoV-2 vaccines. To address this challenge, the Coalition for Epidemic Preparedness Innovations (CEPI) and the Brighton Collaboration (BC) Safety Platform for Emergency vACcines (SPEAC) convened a scientific working meeting on March 12 and 13, 2020 of experts in the field of vaccine immunology and coronaviruses to consider what vaccine designs could reduce safety concerns and how animal models and immunological assessments in early clinical trials can help to assess the risk. This report summarizes the evidence presented and provides considerations for safety assessment of COVID-19 vaccine candidates in accelerated vaccine development.

Analysis of safety data in children after receiving two doses of ProQuad® (MMRV).

BACKGROUND: In randomized clinical studies, over 11,800 children, 12 months to 6 years of age, were administered ProQuad(®), a combination measles, mumps, rubella, and varicella vaccine (MMRV). This paper describes the safety following a 2-dose regimen of MMRV administered to children in the second year of life. METHODS: Safety data from five clinical studies were combined for all children who were scheduled to receive two doses of MMRV ∼3-6 months apart. All vaccinated children were followed for safety following each dose of MMRV. RESULTS: Of 3112 children who received a first dose of MMRV, 2780 (89.3%) received a second dose of MMRV. Overall, 70.5% and 57.7% of children reported ≥1 adverse experiences following first and second doses of MMRV, respectively. Injection-site redness was statistically significantly higher postdose 2 than postdose 1, while injection-site pain/tenderness was statistically significantly higher postdose 1 compared to postdose 2. Rashes were statistically significantly lower postdose 2 compared to postdose 1. Ten febrile seizures (8 postdose 1, 2 postdose 2) were reported following MMRV vaccination. The incidence of febrile seizures postdose 1 of MMRV was 0.26% (8/3019) compared to 0.07% (2/2695) postdose 2 of MMRV. CONCLUSIONS: Administration of two doses of MMRV has an acceptable safety profile in children 12 to 23 months of age. There is a small increase in the risk of febrile seizures following the first dose of MMRV as compared to the component vaccines, but the risk for any individual child is relatively low.

Meningococcal disease from the public health policy perspective.

The incidence and serogroup distribution of meningococcal disease vary by country and over time. In the United States, the annual incidence has been 0.5-1.1/100,000 or about 1400-2800 cases annually with the highest incidence being in infants less than six months of age [1]. Given the availability of conjugate vaccines against serogroups A, C, W-135 and Y and the possible future availability of a group B vaccine, there is now the potential to effectively control meningococcal disease globally. The question then arises as to how public health policy can best serve this goal. MCV-D (Menactra) is not immunogenic in the first six months of life. For this reason, it has been proposed that immunization with this vaccine begin at nine months of age with a second dose at 12 months. This proposal would rely upon indirect or "herd protection" to protect young infants with the highest disease incidence. A second vaccine, MCV-CRM (Menveo), is immunogenic in the first months of life and is under consideration by the FDA for use in infants two months of age and older. MCV-CRM could provide direct protection of this high risk group, but three primary doses plus a toddler booster are required for this approach. In developing public health recommendations to protect infants, policy makers must weigh the additional cost of immunizing with four doses versus the possibility that relying on herd protection using a lower cost immunization schedule beginning at nine months of age may leave young infants unprotected. Optimal control of meningococcal disease will require both the public will and public policy to best serve this goal. The decision as to what ages to target and which schedules to use should not only take into account the cost of the program, but also the severity of the disease and the high level public concern regarding meningococcal disease.

Paralytic syndromes in children: epidemiology and relationship to vaccination.

Acute flaccid paralysis is a standard outcome for detection of poliomyelitis globally and an ongoing potential vaccine-associated adverse event concern for polio, influenza, and meningococcal vaccines. No systematic population-based data on the epidemiologic and clinical features of this condition, or its potential association with immunization, have been reported from the United States. The present retrospective cohort study of acute flaccid paralysis in the Southern and Northern California Kaiser Permanente Health Care Plans was conducted using computerized diagnosis data and medical record review of potential cases among children aged 1 month to <15 years and diagnosed from January 1, 1992 through December 31, 1998. In all, 3297 potential cases were identified; of these, 2682 cases (81%) did not meet the case definition, and of the remaining 615 cases, 245 (7% of the total) were included. The incidence of disease was 1.4 per 100,000 children/year (95% confidence interval = 1.2-1.6); predicting approximately 844 children/year in the United States. Disease incidence did not vary with season or sex, varied inversely with age, and declined 28% during the study period. No cases of vaccine-associated acute flaccid paralysis were identified. In nonendemic countries, ongoing acute flaccid paralysis surveillance is often conducted, because of the risk of poliovirus importation, but this practice may be difficult to justify, given low disease incidence and breadth of clinical presentation.

Human papilloma virus immunization in adolescent and young adults: a cohort study to illustrate what events might be mistaken for adverse reactions.

BACKGROUND: The large-scale implementation of human papilloma virus (HPV) immunization will be followed by cases of autoimmune diseases occurring in temporal association with immunizations. To anticipate events that might be mistakenly assumed to be caused by immunization, their prevalence was monitored before vaccine introduction. METHOD: Cohort study carried out within a database of female adolescents (n = 214,896) and young adults (n = 221,472) followed in the pre-HPV vaccine era (2005), computing rates of emergency consultations, hospitalizations and outpatient consultations, and estimation of risks of coincident associations. RESULTS: Immune-mediated conditions were a frequent cause (10.3%) of emergency room consultation by adolescent girls. Nonallergic immune-mediated conditions affected 86 per 100,000, diabetes ranking first. In 2005, 53 per 100,000 adolescents and 389 per 100,000 women were hospitalized for diseases of presumed autoimmune origin, thyroiditis being the most frequent diagnosis. If HPV immunization had been used with 80% coverage, 3 per 100,000 adolescents would have required emergency care for asthma/allergy within 24 hours and 2 per 100,000 for diabetes within 1 week of an injection. The risks of hospitalization in temporal association with immunization are 4 times higher for thyroiditis than for multiple sclerosis or Guillain-Barré's syndrome, and more than 20 times higher in young women than in adolescents. CONCLUSION: The distinction between HPV vaccine-caused adverse reactions and events only observed by chance in temporal association is difficult. The prior use of population-based data allows for identification of issues of potential concern, for monitoring the impact of large-scale interventions and for addressing rapidly vaccine-safety issues that may compromise vaccine programs.

Comparison of the safety and immunogenicity of a refrigerator-stable versus a frozen formulation of ProQuad (measles, mumps, rubella, and varicella virus vaccine live).

OBJECTIVE: A refrigerator-stable formulation of ProQuad has been developed to expand the utility of ProQuad to areas in which maintenance of a frozen cold chain (-15 degrees C or colder) during storage and transport may not be feasible. The objective of this study was to demonstrate that the immunogenicity and safety profiles of a refrigerator-stable formulation of ProQuad are similar to the recently licensed frozen formulation. METHODS: In this double-blind, randomized, multicenter study, healthy 12- to 23-month-old children with negative vaccination and clinical histories for measles, mumps, rubella, varicella, and zoster were vaccinated with either the refrigerator-stable formulation of ProQuad (N = 1006) or the frozen formulation of ProQuad (N = 513). Patients were followed for 42 days after vaccination for adverse experiences. Immunogenicity was evaluated 6 weeks after vaccination. RESULTS: The refrigerator-stable formulation of ProQuad was generally well tolerated. The incidence of adverse experiences was similar between groups. No vaccine-related serious adverse experiences were reported. For both groups, the response rate was > or = 97.7% for measles, mumps, and rubella, and the percentage of patients with a varicella zoster virus antibody titer of > or = 5 U/mL glycoprotein antigen-based enzyme-linked immunosorbent assay after vaccination was > or = 88.8%. The geometric mean titers for all antigens were numerically slightly higher in patients who received the refrigerator-stable formulation. CONCLUSIONS: The refrigerator-stable formulation of ProQuad is generally well tolerated, highly immunogenic, and noninferior in terms of postvaccination antibody responses. This refrigerator-stable formulation may improve ease of vaccine administration, increase use of the vaccine throughout the world because of its improved storage conditions, and replace the frozen formulation of ProQuad or any dose of M-M-RII and Varivax in routine practice.

Hepatitis B vaccine and risk of autoimmune thyroid disease: a Vaccine Safety Datalink study.

PURPOSE: Hepatitis B vaccine has been postulated as a possible cause of autoimmune disorders, including autoimmune thyroid diseases (ATD). Cases of Graves' disease and Hashimoto's thyroiditis, following hepatitis B vaccine have been reported to the Vaccine Adverse Events Reporting System (VAERS). To test the hypothesis that hepatitis B vaccine increases the risk of ATD, we conducted a case-control study, within the Vaccine Safety Datalink project. METHODS: We identified potential cases of Graves' disease and Hashimoto's thyroiditis, among persons aged 18-69 years from administrative data recorded by three health maintenance organizations (HMOs) and verified cases by medical record review. Controls were frequency-matched to cases by birth year, sex, and study site. Vaccine information was collected from administrative records, chart review, and telephone interviews with study subjects. We enrolled 355 Graves' disease cases, 418 Hashimoto's thyroiditis cases, and 1102 controls. We assessed the association between ever-receipt of hepatitis B vaccine, as well as receipt of hepatitis B vaccine less than 1 year, 1-5 years and at least 5 years prior to the index date, and the risk of ATD. RESULTS: Ever-receipt of hepatitis B vaccine was not associated with risk of Graves' disease (odds ratio (OR), 0.90; 95% confidence interval (CI), 0.62-1.32) or Hashimoto's thyroiditis (OR, 1.23; 95%CI, 0.87-1.73). There was also no association between the time interval since receipt of hepatitis B vaccination and either outcome. CONCLUSIONS: We did not observe an increased risk of Graves' disease or Hashimoto's thyroiditis, following receipt of hepatitis B vaccine.

Safety of trivalent inactivated influenza vaccine in children 6 to 23 months old.

CONTEXT: Beginning with the winter season of 2004-2005, influenza vaccination has been recommended for all children 6 to 23 months old in the United States. However, its safety in young children has not been adequately studied in large populations. OBJECTIVE: To screen for medically attended events in the clinic, emergency department, or hospital after administration of trivalent inactivated influenza vaccine in children 6 to 23 months old. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort using self-control analysis, with chart review of significant medically attended events at 8 managed care organizations in the United States that comprise the Vaccine Safety Datalink. Participants were all children in the Vaccine Safety Datalink cohort 6 to 23 months old who received trivalent inactivated influenza vaccine between January 1, 1991, and May 31, 2003 (45,356 children with 69,359 vaccinations). MAIN OUTCOME MEASURE: Any medically attended event significantly associated with trivalent inactivated influenza vaccine in risk windows 0 to 3 days, 1 to 14 days (primary analysis), 1 to 42 days, or 15 to 42 days after vaccination, compared with 2 control periods, one before vaccination and the second after the risk window. All individual ICD-9 codes as well as predefined aggregate codes were examined. RESULTS: Before chart review, only 1 diagnosis, gastritis/duodenitis, was more likely to occur in the 14 days after trivalent inactivated influenza vaccine (matched odds ratio [OR], 5.50; 95% confidence interval [CI], 1.22-24.81 for control period 1, and matched OR, 4.33; 95% CI, 1.23-15.21 for control period 2). Thirteen medically attended events were less likely to occur after trivalent inactivated influenza vaccine, including acute upper respiratory tract infection, asthma, bronchiolitis, and otitis media. After chart review, gastritis/duodenitis was not significantly associated with trivalent inactivated influenza vaccine (matched OR, 4.00; 95% CI, 0.85-18.84 for control period 1; matched OR, 3.34; 95% CI, 0.92-12.11 for control period 2). CONCLUSIONS: In the largest population-based study to date of the safety of trivalent inactivated influenza vaccine in young children, there were very few medically attended events, none of which were serious, significantly associated with the vaccine. This study provides additional evidence supporting the safety of universally immunizing all children 6 to 23 months old with influenza vaccine.

Cost-effectiveness of pneumococcal conjugate vaccine: evidence from the first 5 years of use in the United States incorporating herd effects.

BACKGROUND: Pneumococcal conjugate vaccine (PCV) has been in routine use in the United States for 5 years. Prior U.S. cost-effectiveness analyses have not taken into account the effect of the vaccine on nonvaccinated persons. METHODS: We revised a previously published model to simulate the effects of PCV on children vaccinated between 2000 and 2004, and to incorporate the effect of the vaccine in reducing invasive pneumococcal disease (IPD) in nonvaccinated persons during those years. Data from the Active Bacterial Core Surveillance of the Centers for Disease Control and Prevention (2000-2004) were used to estimate changes in the burden of IPD in nonvaccinated adults since the introduction of PCV (compared with the baseline years 1997-1999). Results combined the simulated effects of the vaccine on the vaccinated and nonvaccinated populations. RESULTS: Before incorporating herd effects in the model, the PCV was estimated to have averted 38,000 cases of IPD during its first 5 years of use at a cost of dollar 112,000 per life-year saved. After incorporating the reductions in IPD for nonvaccinated individuals, the vaccine averted 109,000 cases of IPD at a cost of dollar 7500 per life-year saved. When the herd effect was assumed to be half that of the base case, the cost per life-year saved was dollar 18,000. CONCLUSIONS: IPD herd effects in the nonvaccinated population substantially reduce the cost, and substantially improve the cost-effectiveness, of PCV. The cost-effectiveness of PCV in actual use has been more favorable than predicted by estimates created before the vaccine was licensed.

Immunogenicity and safety of measles-mumps-rubella, varicella and Haemophilus influenzae type b vaccines administered concurrently with a fourth dose of heptavalent pneumococcal conjugate vaccine compared with the vaccines administered without heptavalent pneumococcal conjugate vaccine.

BACKGROUND: Prevnar [heptavalent pneumococcal conjugate vaccine (PCV7)] is licensed in the United States for routine administration in infants and may be coadministered with other infant vaccines. Safety and immunogenicity data on the coadministration of the fourth dose of PCV7 with measles-mumps-rubella (MMR), varicella and Haemophilus influenzae type b (Hib) vaccines are limited. METHODS: Children 12-15 months of age received either MMR with PCV7 (group 1) or MMR without PCV7 (group 2). All subjects received Hib and varicella vaccines. Group 2 received PCV7 6-9 weeks after MMR vaccination. Sera for analysis of all non-PCV7 antibodies were collected just before administration of MMR vaccine and 6 weeks later. Optimal antigen responses were assessed with the use of predetermined antibody titers. The primary end point was >90% response rate (all antigens). Noninferiority was defined as <10% difference between groups. Local and systemic reactions and postvaccination adverse events were monitored and compared between groups. RESULTS: A total of 694 subjects (347 per group) were enrolled. After immunization with MMR plus PCV7 concurrently, or MMR followed 6 weeks later by PCV7, the percentages of subjects seroconverting were significantly greater than 90% for all antigens. The difference between the 2 groups was significantly less than 10%. CONCLUSION: The immune response to MMR, Hib and varicella vaccines, when administered concurrently with a 4th (booster) dose of PCV7, was noninferior to that of these vaccines when given without PCV7. These results support concomitant administration of PCV7 with MMR, varicella and Hib as part of the recommended immunization schedule for children 12-15 months of age.

Safety and efficacy of a pentavalent human-bovine (WC3) reassortant rotavirus vaccine.

BACKGROUND: Rotavirus is a leading cause of childhood gastroenteritis and death worldwide. METHODS: We studied healthy infants approximately 6 to 12 weeks old who were randomly assigned to receive three oral doses of live pentavalent human-bovine (WC3 strain) reassortant rotavirus vaccine containing human serotypes G1, G2, G3, G4, and P[8] or placebo at 4-to-10-week intervals in a blinded fashion. Active surveillance was used to identify subjects with serious adverse and other events. RESULTS: The 34,035 infants in the vaccine group and 34,003 in the placebo group were monitored for serious adverse events. Intussusception occurred in 12 vaccine recipients and 15 placebo recipients within one year after the first dose including six vaccine recipients and five placebo recipients within 42 days after any dose (relative risk, 1.6; 95 percent confidence interval, 0.4 to 6.4). The vaccine reduced hospitalizations and emergency department visits related to G1-G4 rotavirus gastroenteritis occurring 14 or more days after the third dose by 94.5 percent (95 percent confidence interval, 91.2 to 96.6 percent). In a nested substudy, efficacy against any G1-G4 rotavirus gastroenteritis through the first full rotavirus season after vaccination was 74.0 percent (95 percent confidence interval, 66.8 to 79.9 percent); efficacy against severe gastroenteritis was 98.0 percent (95 percent confidence interval, 88.3 to 100 percent). The vaccine reduced clinic visits for G1-G4 rotavirus gastroenteritis by 86.0 percent (95 percent confidence interval, 73.9 to 92.5 percent). CONCLUSIONS: This vaccine was efficacious in preventing rotavirus gastroenteritis, decreasing severe disease and health care contacts. The risk of intussusception was similar in vaccine and placebo recipients. (ClinicalTrials.gov number, NCT00090233.)

Compliance with national immunization guidelines for children younger than 2 years, 1996-1999.

OBJECTIVES: To evaluate compliance with national immunization guidelines among a large cohort of children cared for at health maintenance organizations (HMOs) and to examine effects on immunization status. METHODS: A cohort study of 176134 children born between January 1, 1994, and December 31, 1997, and monitored from birth to the second birthday was performed. Subjects belonged to the Vaccine Safety Datalink Project, a study of children enrolled in 1 of 4 HMOs. Children were continuously enrolled in a HMO for the first 2 years of life. Prevailing recommendations regarding optimal ages of immunization and intervals between doses were applied to define appropriate immunization timing and immunization status. Noncompliance was defined as having a missing or late immunization or an immunization error. Immunization errors included invalid immunizations (too early to be acceptable), extra immunizations (superfluous immunizations or make-up immunizations for invalid immunizations), and missed opportunities resulting in late or missing immunizations. RESULTS: Although 75.4% of children in these HMOs were up to date for all immunizations at 2 years, only 35.6% of children were fully compliant with recommended immunization practices. Less than 8% of children received all immunizations in accordance with strict interpretation of recommended guidelines. Fifty-one percent of children had at least 1 immunization error by age 2 years; 29.7% had a missed opportunity with subsequent late or missing immunization, 20.4% had an invalid immunization, and 11.6% had an extra immunization. Common reasons for noncompliance included missed opportunities for the fourth Haemophilus influenzae type b vaccine (14.6%), invalid fourth diphtheria-tetanus-pertussis/acellular pertussis immunizations (11.0%), and superfluous polio immunizations (9.8%). CONCLUSIONS: Approximately 35.6% of children were compliant with prevailing childhood immunization recommendations from 1996 to 1999. Efforts to improve compliance with guidelines are recommended, to optimize childhood infectious disease prevention.

Safety of the trivalent inactivated influenza vaccine among children: a population-based study.

BACKGROUND: To our knowledge, there are no published population-based studies on the safety of the inactivated trivalent influenza vaccine among children. OBJECTIVE: To screen a large population of children for evidence of increased medical visits in the 2 weeks after influenza vaccination compared with 2 control periods. Secondary analyses included shorter risk periods and restricted age categories. DESIGN: Self-control screening analysis. Children vaccinated from January 1, 1993, through December 31, 1999, were randomly divided into 2 equal groups. In group 1, risks of outpatient, emergency department, and inpatient visits during the 14 days after vaccination were compared with the risks of visits in 2 control periods. Significant plausible medically attended events identified in group 1 were then analyzed in group 2, using the same 2 control periods. Medically attended events significant in both groups were considered potentially associated with vaccination and were assessed by medical record review. SETTING: Five managed care organizations in the United States. PARTICIPANTS: Children younger than 18 years who received an influenza vaccination in one of the managed care settings (N = 251 600). MAIN OUTCOME MEASURE: Among vaccinated children seen for a medically attended event, the odds of the visit occurring in the 2 weeks after vaccination vs during 1 of the 2 control periods. RESULTS: Study participants incurred 1165, 230, and 489 different diagnoses during the 14 days after vaccination according to the outpatient, emergency department, and inpatient data, respectively. Four diagnoses were positively associated with the vaccine in both groups 1 and 2: impetigo, dermatitis, uncomplicated diabetes mellitus, and ureteral disorder not otherwise specified. After medical record review, impetigo (9 cases) in children 6 to 23 months old remained significantly associated with vaccination. CONCLUSION: This large screening safety study did not reveal any evidence of important medically attended events associated with pediatric influenza vaccination.

Safety, efficacy, and effectiveness of live, attenuated, cold-adapted influenza vaccine in an indicated population aged 5-49 years.

BACKGROUND: Three important studies have supported licensure of live, attenuated, cold-adapted influenza vaccine (CAIV-T [FluMist; MedImmune Vaccines]): (1) a pediatric efficacy trial involving children 15-71 months of age, (2) a large safety study of medically attended events occurring among children 1-17 years of age, and (3) an effectiveness trial involving healthy working adults 18-64 years of age. METHODS: During the United States Food and Drug Administration (FDA) review for the approval of CAIV-T for use in healthy persons, additional subgroup analyses were conducted to evaluate the safety, efficacy, and effectiveness of the vaccine, by use of various age subsets not prespecified by the original protocols. CAIV-T is currently approved by the FDA for use in healthy persons 5-49 years of age. In this article, we present data from some of the aforementioned subanalyses. RESULTS: The efficacy of CAIV-T in children >or=5 years of age (age range of the children in year 1 of the study, 60-71 months; age range of the children in year 2 of the study, 60-83 months) was similar to that reported for the entire cohort in year 1 (90.6%; 95% confidence interval [CI], 70.3%-97.1%). In year 2 of the study, efficacy was 86.9% (95% CI, 70.8%-94.1%), despite the presence of antigenically drifted influenza type A/Sydney/5/97 (H3N2), which caused most illnesses that occurred in year 2. Safety outcomes for children 5-17 years of age revealed no significant difference between vaccine recipients and placebo recipients, with regard to acute respiratory events, acute gastrointestinal events, systemic bacterial infection, or rare events possibly related to influenza. Effectiveness among adults 18-49 years of age was similar to that reported for the entire cohort--for example, for occurrence of severe febrile illness, there was a 19.5% reduction (P=.02) in adults. CONCLUSIONS: The present reanalysis summarizes data on the indicated uses for CAIV-T in the indicated population aged 5-49 years.

Effectiveness of influenza vaccine during pregnancy in preventing hospitalizations and outpatient visits for respiratory illness in pregnant women and their infants.

The Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention recommends influenza vaccination for women who will be in the second or third trimester of pregnancy during the influenza season. We analyzed hospital admissions with principal diagnoses of influenza or pneumonia and influenza-like illness (ILI) outpatient visits to study the effectiveness of influenza vaccine during pregnancy in protecting women and infants from influenza-related morbidity. Estimates of influenza vaccine effectiveness across five flu seasons (Fall 1997 to Spring 2002) were calculated using Cox proportional hazards models for women and infant study populations in Kaiser Permanente Northern California. Outpatient utilization outcomes included physician visits with a diagnosis of upper respiratory infection, pharyngitis, otitis media, asthma, bronchial asthma, viral infection, pneumonia, fever, cough, or wheezing associated with respiratory illness. Inpatient outcomes included hospitalizations with principal diagnoses of influenza or pneumonia. Women who received influenza vaccine during pregnancy had the same risk for ILI visits compared with unvaccinated women, adjusting for women's age and week of delivery. When asthma visits were excluded from the outcome measure, we also found no difference in the risk of outpatient visits for vaccinated and unvaccinated women. Hospital admissions for influenza or pneumonia for women in the study population were quite rare and no women died of respiratory illness during pregnancy. Infants born to women who received influenza vaccination had the same risks for influenza or pneumonia admissions compared with infants born to unvaccinated women, adjusting for infant's gender, gestational age, week of birth, and birth facility. Maternal influenza vaccination was also not a significant determinant of risk of ILI (excluding otitis media) outpatient visits for infants, nor did it significantly affect the risk of otitis media visits. Influenza vaccination during pregnancy did not significantly affect the risk of cesarean section, adjusting for the woman's age. It also did not affect the risk of preterm delivery. Although the immunogenicity of influenza vaccination in pregnancy in mother and infant has been well documented, in this study, we were unable to demonstrate the effectiveness of influenza vaccination with data for hospital admissions and physician visits. One possible interpretation of these findings is that typical influenza surveillance measures based on utilization data are not reliable in distinguishing influenza from other respiratory illness. Hospitalizations for respiratory illness were uncommon in both vaccinees and nonvaccinees.

Safety of thimerosal-containing vaccines: a two-phased study of computerized health maintenance organization databases.

OBJECTIVE: To assess the possible toxicity of thimerosal-containing vaccines (TCVs) among infants. METHODS: A 2-phased retrospective cohort study was conducted using computerized health maintenance organization (HMO) databases. Phase I screened for associations between neurodevelopmental disorders and thimerosal exposure among 124 170 infants who were born during 1992 to 1999 at 2 HMOs (A and B). In phase II, the most common disorders associated with exposure in phase I were reevaluated among 16 717 children who were born during 1991 to 1997 in another HMO (C). Relative risks for neurodevelopmental disorders were calculated per increase of 12.5 micro g of estimated cumulative mercury exposure from TCVs in the first, third, and seventh months of life. RESULTS: In phase I at HMO A, cumulative exposure at 3 months resulted in a significant positive association with tics (relative risk [RR]: 1.89; 95% confidence interval [CI]: 1.05-3.38). At HMO B, increased risks of language delay were found for cumulative exposure at 3 months (RR: 1.13; 95% CI: 1.01-1.27) and 7 months (RR: 1.07; 95% CI: 1.01-1.13). In phase II at HMO C, no significant associations were found. In no analyses were significant increased risks found for autism or attention-deficit disorder. CONCLUSIONS: No consistent significant associations were found between TCVs and neurodevelopmental outcomes. Conflicting results were found at different HMOs for certain outcomes. For resolving the conflicting findings, studies with uniform neurodevelopmental assessments of children with a range of cumulative thimerosal exposures are needed.

Risk of anaphylaxis after vaccination of children and adolescents.

OBJECTIVE: To quantify the risk of anaphylaxis after vaccination of children and adolescents. METHODS: The study population consisted of children and adolescents who were enrolled at 4 health maintenance organizations that participated in the Vaccine Safety Datalink Project. For the period 1991-1997, we identified potential cases by searching for occurrences of International Classification of Diseases, Ninth Revision (ICD-9) code 995.0 (anaphylactic shock), E948.0 through E948.9 (adverse reaction from bacterial vaccines), and E949.0 through E949.9 (adverse reaction from other vaccines and biological substances). At 1 study site, we also included a range of other allergy codes. We restricted to diagnoses on days 0 to 2 after vaccination (ICD-9 995.0) or day 0 (all other ICD-9 codes). We then reviewed the medical record to confirm the diagnosis. RESULTS: We identified 5 cases of potentially vaccine-associated anaphylaxis after administration of 7 644 049 vaccine doses, for a risk of 0.65 cases/million doses (95% confidence interval: 0.21-1.53). None of the episodes resulted in death. Vaccines that were administered before the anaphylactic episodes were generally given in combination and included measles-mumps-rubella, hepatitis B, diphtheria-tetanus, diphtheria-tetanus-pertussis, Haemophilus influenzae type b, and oral polio vaccine. One case of anaphylaxis followed measles-mumps-rubella vaccine alone. At the site at which we reviewed additional allergy codes, we identified 1 case after 653 990 vaccine doses, for a risk of 1.53 cases/million doses (95% confidence interval: 0.04-8.52). CONCLUSIONS: Patients and health care providers can be reassured that vaccine-associated anaphylaxis is a rare event. Nevertheless, providers should be prepared to provide immediate medical treatment should it occur.

A retrospective cohort study of the association of varicella vaccine failure with asthma, steroid use, age at vaccination, and measles-mumps-rubella vaccination.

OBJECTIVE: Varicella breakthrough, the occurrence of varicella disease >42 days after vaccination, is indicative of vaccination failure. A sevenfold increased risk of breakthrough among vaccinated children with asthma was observed in a 1996 varicella outbreak in a child care center. More recent outbreak investigations have also identified age at vaccination as a potential risk factor for breakthrough. We assessed the association of varicella breakthrough with asthma, steroids, age at varicella vaccination, and timing of measles-mumps-rubella (MMR) vaccination. METHODS: We performed a retrospective cohort study among children born after 1993 and followed up through 1999 at 2 health maintenance organizations ([HMOs] A and B) in the United States. Information was obtained from automated vaccination, clinic, hospital discharge, and pharmacy records. RESULTS: We identified 268 and 97 breakthrough cases among 80 584 and 8181 children vaccinated against varicella at HMOs A and B, respectively. Varicella breakthrough was not associated with asthma, inhaled steroids prescribed at any time, and oral steroids prescribed before vaccination. An increased risk of varicella breakthrough was found in the 3 months immediately after prescription for oral steroids at HMO A (adjusted relative risk [aRR]: 2.4; 95% confidence interval [CI]: 1.3-4.4) and HMO B (aRR: 2.8; 95% CI: 1.0-7.8), when varicella vaccine was given before 15 months of age at HMO A (aRR: 1.4; 95% CI: 1.1-1.9), and when varicella vaccination followed MMR vaccine within 28 days at HMO A (aRR: 3.1; 95% CI: 1.5-6.4). CONCLUSIONS: Varicella vaccine failure in children was not associated with asthma or the use of inhaled steroids, but with the use of oral steroids. Administration of varicella vaccine before the age of 15 months may be associated with a slightly increased risk of breakthrough disease. As currently recommended, varicella vaccination should not be administered for 28 days after MMR vaccination.