Arm Paralysis After Routine Childhood Vaccinations: Application of Advanced Molecular Methods to the Causality Assessment of an Adverse Event After Immunization.

Post-licensure surveillance for adverse events following immunizations (AEFI) can identify rare complications of vaccinations and rigorous vaccine adverse event causality assessments can help to identify possible causal relationships. We report the development of arm paralysis after varicella vaccination in a 1-year-old child. Paralysis was initially presumed to be due to vOka because of the temporal relationship between vaccination and onset of arm weakness; however, molecular studies identified wild-type varicella zoster virus VZV (WT-VZV) in the CSF, leading the authors to conclude that WT-VZV was the probable cause. This case illustrates the complexity of assessing AEFI causality, and the importance of careful and complete evaluations when determining the most likely cause of an AEFI.

Reflections of a Vaccinologist: Lessons Learned About What We Can Do to Improve Trust in Vaccines and Vaccine Programsa.

Public trust can be improved by learning from past mistakes, by establishing a standing forum for review of new concerns as they arise, and by maintaining a robust vaccine safety system. Developing standard guidelines for reporting causality assessment in case reports would help educate physicians and prevent future unnecessary concerns based on false assumptions of causal relationships.

United States private schools have higher rates of exemptions to school immunization requirements than public schools.

OBJECTIVE: To compare medical, religious, and personal belief immunization exemption rates between private and public schools in US. STUDY DESIGN: Exemption rates were calculated using the Centers for Disease Control and Prevention School Immunization Assessment Surveys for the 2009-2010 school year excluding states with incomplete survey data. Standardized exemption rates weighted on enrollments in public and private schools were calculated. Differences in exemption rates between public and private schools were tested using Wilcoxon signed rank test. RESULTS: The overall state exemption rate was higher in US private than public schools, 4.25% (SD 4.27) vs 1.91% (1.67), P = .0001 and private schools had higher exemption rates for all types of exemptions; medical 0.58% (0.71) vs 0.34% (0.34) respectively (P = .0004), religious 2.09% (3.14) vs 0.83% (1.05) respectively (P = .0001), and personal belief 6.10% (4.12) vs 2.79% (1.57), respectively (P = .006). Overall exemption rates were significantly higher in states that allowed personal belief exemptions. CONCLUSIONS: Exemption rates were significantly higher in US private than in public schools. Children attending private schools may be at higher risk of vaccine-preventable diseases than public school children.

Gender differences in immediate hypersensitivity reactions to vaccines: a review of the literature.

OBJECTIVE: To examine published studies of immediate hypersensitivity reactions (IHS) following vaccination and to determine whether women are at an increased risk of developing IHS after vaccination. DESIGN AND SAMPLE: PubMed was reviewed for vaccine articles reporting IHS by gender through June 2012. Data were abstracted on type of study, vaccine, hypersensitivity reaction, and statistic reported. MEASURES: Articles were included if they described experimental, quasi-experimental, correlational or descriptive studies and IHS was reported by gender. RESULTS: Of 847 articles found in PubMed, 11 met the inclusion criteria. In eight studies, more women than men reported IHS, in two studies more men than women reported IHS and in one study the count was even. CONCLUSION: Limited data from these studies suggest that women may have higher rates of IHS reactions following vaccination than men. Limitations to the available data include the lack of denominator data and that the definition of IHS was not consistent across the studies. Large-scale population-based studies are indicated to determine if there are differences in rates by gender and biologic basis for these differences.

Assessment of causality of individual adverse events following immunization (AEFI): a WHO tool for global use.

Serious illnesses or even deaths may rarely occur after childhood vaccinations. Public health programs are faced with great challenges to establish if the events presenting after the administration of a vaccine are due to other conditions, and hence a coincidental presentation, rather than caused by the administered vaccines. Given its priority, the Global Advisory Committee for Vaccine Safety (GACVS) commissioned a group of experts to review the previously published World Health Organization (WHO) Adverse Event Following Immunization (AEFI) causality assessment methodology and aide-memoire, and to develop a standardized and user friendly tool to assist health care personnel in the processing and interpretation of data on individual events, and to assess the causality after AEFIs. We describe a tool developed for causality assessment of individual AEFIs that includes: (a) an eligibility component for the assessment that reviews the diagnosis associated with the event and identifies the administered vaccines; (b) a checklist that systematically guides users to gather available information to feed a decision algorithm; and (c) a decision support algorithm that assists the assessors to come to a classification of the individual AEFI. Final classification generated by the process includes four categories in which the event is either: (1) consistent; (2) inconsistent; or (3) indeterminate with respect of causal association; or (4) unclassifiable. Subcategories are identified to assist assessors in resulting public health decisions that can be used for action. This proposed tool should support the classification of AEFI cases in a standardized, transparent manner and to collect essential information during AEFI investigation. The algorithm should provide countries and health officials at the global level with an instrument to respond to vaccine safety alerts, and support the education, research and policy decisions on immunization safety.

Review and assessment of poliovirus immunity and transmission: synthesis of knowledge gaps and identification of research needs.

With the intensifying global efforts to eradicate wild polioviruses, policymakers face complex decisions related to achieving eradication and managing posteradication risks. These decisions and the expanding use of inactivated poliovirus vaccine (IPV) trigger renewed interest in poliovirus immunity, particularly the role of mucosal immunity in the transmission of polioviruses. Sustained high population immunity to poliovirus transmission represents a key prerequisite to eradication, but poliovirus immunity and transmission remain poorly understood despite decades of studies. In April 2010, the U.S. Centers for Disease Control and Prevention convened an international group of experts on poliovirus immunology and virology to review the literature relevant for modeling poliovirus transmission, develop a consensus about related uncertainties, and identify research needs. This article synthesizes the quantitative assessments and research needs identified during the process. Limitations in the evidence from oral poliovirus vaccine (OPV) challenge studies and other relevant data led to differences in expert assessments, indicating the need for additional data, particularly in several priority areas for research: (1) the ability of IPV-induced immunity to prevent or reduce excretion and affect transmission, (2) the impact of waning immunity on the probability and extent of poliovirus excretion, (3) the relationship between the concentration of poliovirus excreted and infectiousness to others in different settings, and (4) the relative role of fecal-oral versus oropharyngeal transmission. This assessment of current knowledge supports the immediate conduct of additional studies to address the gaps.

Clinical assessment of serious adverse events in children receiving 2009 H1N1 vaccination.

BACKGROUND: Monovalent 2009 H1N1 influenza vaccines were licensed and administered in the United States during the H1N1 influenza pandemic between 2009 and 2013. METHODS: Vaccine Adverse Event Reporting System received reports of adverse events following immunization (AEFI) after H1N1 vaccination. Selected reports were referred to the Centers for Disease Control and Prevention's Clinical Immunization Safety Assessment network for additional review. We assessed causality using modified World Health Organization criteria. RESULTS: There were 3,928 reports of AEFI in children younger than age 18 years after 2009 H1N1 vaccination received by January 31, 2010. Of these, 214 (5.4%) were classified as serious nonfatal and 109 were referred to Clinical Immunization Safety Assessment for further evaluation. Ninety-nine (91%) had sufficient initial information to begin investigation and are described here. The mean age was 8 years (range, 6 months-17 years) and 38% were female. Median number of days between vaccination and symptom onset was 2 (range, -11 days to +41 days). Receipt of inactivated, live attenuated, or unknown type of 2009 H1N1 vaccines was reported by 68, 26 and 5 cases, respectively. Serious AEFI were categorized as neurologic events in 47 cases, as hypersensitivity in 15 cases and as respiratory events in 10 cases. At the time of evaluation, recovery was described as complete (61), partial (16), no improvement (1), or unknown (21). Causality assessment yielded the following likelihood of association with 2009 H1N1 vaccination: 8 definitely; 8 probably; 21 possibly; 43 unlikely; 17 unrelated; and 2 unclassifiable. CONCLUSIONS: Most AEFI in children evaluated were not causally related to vaccine and resolved without sequelae. Detailed clinical assessment of individual serious AEFI can provide reassurance of vaccine safety.

Causality assessment of serious neurologic adverse events following 2009 H1N1 vaccination.

BACKGROUND: Adverse events occurring after vaccination are routinely reported to the Vaccine Adverse Event Reporting System (VAERS). We studied serious adverse events (SAEs) of a neurologic nature reported after receipt of influenza A (H1N1) 2009 monovalent vaccine during the 2009-2010 influenza season. Investigators in the Clinical Immunization Safety Assessment (CISA) network sought to characterize these SAEs and to assess their possible causal relationship to vaccination. METHODS: Centers for Disease Control and Prevention (CDC) and Food and Drug Administration (FDA) physicians reviewed all SAE reports (as defined by the Code of Federal Regulations, 21CFR§314.80) after receipt of H1N1 vaccine reported to VAERS between October 1, 2009 and March 31, 2010. Non-fatal SAE reports with neurologic presentation were referred to CISA investigators, who requested and reviewed additional medical records and clinical information as available. CISA investigators assessed the causal relationship between vaccination and the event using modified WHO criteria as defined. RESULTS: 212 VAERS reports of non-fatal serious neurological events were referred for CISA review. Case reports were equally distributed by gender (50.9% female) with an age range of 6 months to 83 years (median 38 years). The most frequent diagnoses reviewed were: Guillain-Barré Syndrome (37.3%), seizures (10.8%), cranial neuropathy (5.7%), and acute disseminated encephalomyelitis (3.8%). Causality assessment resulted in classification of 72 events as "possibly" related (33%), 108 as "unlikely" related (51%), and 20 as "unrelated" (9%) to H1N1 vaccination; none were classified as "probable" or "definite" and 12 were unclassifiable (6%). CONCLUSION: The absence of a specific test to indicate whether a vaccine component contributes to the pathogenesis of an event occurring within a biologically plausible time period makes assessing causality difficult. The development of standardized protocols for providers to use in evaluation of adverse events following immunization, and rapid identification and follow-up of VAERS reports could improve causality assessment.

Overview of the Clinical Consult Case Review of adverse events following immunization: Clinical Immunization Safety Assessment (CISA) network 2004-2009.

BACKGROUND: In 2004 the Clinical Consult Case Review (CCCR) working group was formed within the CDC-funded Clinical Immunization Safety Assessment (CISA) Network to review individual cases of adverse events following immunizations (AEFI). METHODS: Cases were referred by practitioners, health departments, or CDC employees. Vaccine Adverse Event Reporting System (VAERS) searches and literature reviews for similar cases were performed prior to review. After CCCR discussion, AEFI were assessed for a causal relationship with vaccination and recommendations regarding future immunizations were relayed back to the referring physicians. In 2010, surveys were sent to referring physicians to determine the utility and effectiveness of the CCCR service. RESULTS: CISA investigators reviewed 76 cases during 68 conference calls between April 2004 and December 2009. Almost half of the cases (35/76) were neurological in nature. Similar AEFI for the specific vaccines received were discovered for 63 cases through VAERS searches and for 38 cases through PubMed searches. Causality assessment using the modified WHO criteria resulted in classifying 3 cases as definitely related to vaccine administration, 12 as probably related, 16 as possibly related, 18 as unlikely related, 10 as unrelated, and 17 had insufficient information to assign causality. The physician satisfaction survey was returned by 30 (57.7%) of those surveyed and a majority of respondents (93.3%) felt that the CCCR service was useful. CONCLUSIONS: The CCCR provides advice about AEFI to practitioners, assigns potential causality, and contributes to an improved understanding of adverse health events following immunizations.

Understanding the role of human variation in vaccine adverse events: the Clinical Immunization Safety Assessment Network.

The Clinical Immunization Safety Assessment (CISA) Network is a collaboration between the Centers for Disease Control and Prevention (CDC) and 6 academic medical centers to provide support for immunization safety assessment and research. The CISA Network was established by the CDC in 2001 with 4 primary goals: (1) develop research protocols for clinical evaluation, diagnosis, and management of adverse events following immunization (AEFI); (2) improve the understanding of AEFI at the individual level, including determining possible genetic and other risk factors for predisposed people and subpopulations at high risk; (3) develop evidence-based algorithms for vaccination of people at risk of serious AEFI; and (4) serve as subject-matter experts for clinical vaccine-safety inquiries. CISA Network investigators bring in-depth clinical, pathophysiologic, and epidemiologic expertise to assessing causal relationships between vaccines and adverse events and to understanding the pathogenesis of AEFI. CISA Network researchers conduct expert reviews of clinically significant adverse events and determine the validity of the recorded diagnoses on the basis of clinical and laboratory criteria. They also conduct special studies to investigate the possible pathogenesis of adverse events, assess relationships between vaccines and adverse events, and maintain a centralized repository for clinical specimens. The CISA Network provides specific clinical guidance to both health care providers who administer vaccines and those who evaluate and treat patients with possible AEFI. The CISA Network plays an important role in providing critical immunization-safety data and expertise to inform vaccine policy-makers. The CISA Network serves as a unique resource for vaccine-safety monitoring efforts conducted at the CDC.

Importance of background rates of disease in assessment of vaccine safety during mass immunisation with pandemic H1N1 influenza vaccines.

Because of the advent of a new influenza A H1N1 strain, many countries have begun mass immunisation programmes. Awareness of the background rates of possible adverse events will be a crucial part of assessment of possible vaccine safety concerns and will help to separate legitimate safety concerns from events that are temporally associated with but not caused by vaccination. We identified background rates of selected medical events for several countries. Rates of disease events varied by age, sex, method of ascertainment, and geography. Highly visible health conditions, such as Guillain-Barré syndrome, spontaneous abortion, or even death, will occur in coincident temporal association with novel influenza vaccination. On the basis of the reviewed data, if a cohort of 10 million individuals was vaccinated in the UK, 21.5 cases of Guillain-Barré syndrome and 5.75 cases of sudden death would be expected to occur within 6 weeks of vaccination as coincident background cases. In female vaccinees in the USA, 86.3 cases of optic neuritis per 10 million population would be expected within 6 weeks of vaccination. 397 per 1 million vaccinated pregnant women would be predicted to have a spontaneous abortion within 1 day of vaccination.

Disparities in preschool immunization coverage associated with maternal age.

Associations between maternal age and preschool immunization coverage are unclear. This study aimed to determine if maternal age is associated with preschool immunization coverage and the importance of maternal age compared with other factors affecting vaccination coverage. Data from the 2001-2003 National Immunization Survey (NIS) were used to estimate vaccine coverage. Children were considered up-to-date (UTD) if they received > or =4 doses of DTaP, > or =3 doses of polio, > or =1 doses of MMR, > or =3 doses of Hib and > or =3 doses of Hep B. Bivariate and multivariate relationships between UTD coverage and maternal, child and household factors were evaluated. Classification tree analysis assessed complex interactions between maternal, child and household factors associated with UTD coverage and isolated the most important factors in predicting UTD coverage. UTD coverage was significantly associated with maternal age: coverage increased as maternal age increased. Coverage among children with 17 year old mothers was 64%; coverage among children of mothers 17-26 years old increased by 16.3% overall (approximately 1.8% per year). After 26 years of age, coverage did not increase significantly as maternal age increased. The relationship between maternal age and UTD coverage remained statistically significant after adjusting for a broad range of maternal, child and household factors. Classification tree analysis suggested that maternal age is the most important factor associated with vaccine coverage. More research is needed to determine the reasons for underimmunization of children born to young mothers.

Geographic clustering of nonmedical exemptions to school immunization requirements and associations with geographic clustering of pertussis.

School immunization requirements are important in controlling vaccine-preventable diseases in the United States. Forty-eight states offer nonmedical exemptions to school immunization requirements. Children with exemptions are at increased risk of contracting and transmitting vaccine-preventable diseases. The clustering of nonmedical exemptions can affect community risk of vaccine-preventable diseases. The authors evaluated spatial clustering of nonmedical exemptions in Michigan and geographic overlap between exemptions clusters and clusters of reported pertussis cases. Kulldorf's scan statistic identified 23 statistically significant census tract clusters for exemption rates and 6 significant census tract clusters for reported pertussis cases between 1993 and 2004. The time frames for significant space-time pertussis clusters were August 1993-September 1993, August 1994-February 1995, May 1998-June 1998, April 2002, May 2003-July 2003, and June 2004-November 2004. Census tracts in exemptions clusters were more likely to be in pertussis clusters (odds ratio = 3.0, 95% confidence interval: 2.5, 3.6). The overlap of exemptions clusters and pertussis clusters remained significant after adjustment for population density, proportion of racial/ethnic minorities, proportion of children aged 5 years or younger, percentage of persons below the poverty level, and average family size (odds ratio = 2.7, 95% confidence interval: 2.2, 3.3). Geographic pockets of vaccine exemptors pose a risk to the whole community. In addition to monitoring state-level exemption rates, health authorities should be mindful of within-state heterogeneity.

Economic analysis of childhood pneumonia in Northern Pakistan.

OBJECTIVES: This study estimates household costs for treatment of pneumonia, severe pneumonia and very severe febrile disease. Combined with reported costs from the health care provider perspective, an estimate of the overall financial burden of these diseases has been developed for the Northern Areas of Pakistan. METHODS: Data on the duration and economic implications of the illnesses for households were collected from caretakers of children under 3 years of age enrolled in a surveillance study who sought care at a health facility. Trained study physicians and health workers identified children with pneumonia, severe pneumonia and very severe febrile disease--as defined by protocols for the Integrated Management of Childhood Illness (IMCI). RESULTS: From January to December 2002, 141 health facility visits for pneumonia (n = 41, 29%), severe pneumonia (n = 65, 46%) and very severe febrile disease (n = 35, 25%) were recorded for 112 children who sought care at various levels of health facilities in the Northern Areas of Pakistan. The total societal average cost per episode was US$22.62 for pneumonia, US$142.90 for severe pneumonia and US$62.48 for very severe febrile disease. For household expenditures, medicines constituted the highest proportion (40.54%) of costs incurred during a visit to the health facility, followed by meals (23.68%), hospitalization (13.23%) and transportation (12.19%). CONCLUSION: Pneumonia is one of the leading killers of children in Pakistan with a correspondingly high economic burden to society. The results of this study suggest that there is a strong economic justification for expanding the availability of existing interventions to fight pneumonia, and for introducing measures such as vaccines to prevent pneumonia episodes.

Haemophilus influenzae type b conjugate vaccine use and effectiveness.

Haemophilus influenzae type b (Hib) is an important cause of invasive bacterial disease in children, including meningitis and pneumonia. The introduction of Hib conjugate vaccines into routine vaccination schedules has contributed to a substantial reduction in the burden of Hib-related disease in many developed countries. However, introduction of Hib conjugate vaccines in developing countries has progressed more slowly. We review the worldwide use and effectiveness of Hib conjugate vaccines. At present, 119 countries have programmes for routine Hib immunisation. WHO estimates that in the developed world 92% of the eligible population is vaccinated against Hib; however, average coverage is 42% in developing countries and only 8% in the poorest countries. Africa and southeast Asia have the lowest rates of Hib vaccine introduction. Vaccine costs and debate about the burden of disease are obstacles to the global use of Hib conjugate vaccine. Even with new funding support, there are many ongoing challenges and vaccine use remains suboptimal, particularly in developing countries.

Vaccine knowledge and practices of primary care providers of exempt vs. vaccinated children.

OBJECTIVES: Compare vaccine knowledge, attitudes and practices of primary care providers for fully vaccinated children and children who are exempt from school immunization requirements. METHODS: We conducted a mailed survey of parent-identified primary care providers from four states to measure perceived risks and benefits of vaccination and other key immunization beliefs. Frequencies of responses were stratified by type of provider, identified by exempt versus vaccinated children. Logistic regression was used to calculate odds ratios for responses by provider type. RESULTS: 551 surveys were completed (84.3% response rate). Providers for exempt children had similar attitudes to providers for non-exempt children. However, there were statistically significant increased concerns among providers for exempt children regarding vaccine safety and lack of perceived individual and community benefits for vaccines compared to other providers. CONCLUSIONS: The great majority of providers for exempt children had similar attitudes about vaccine safety, effectiveness and benefits as providers of non-exempt children. Although providers for exempt children were more likely to believe that multiple vaccines weaken a child's immune system and were concerned about vaccine safety and less likely to consider vaccines were beneficial, a substantial proportion of providers of both exempt and vaccinated children have concerns about vaccine safety and believe that CDC underestimates the frequency of vaccine side effects. Effective continuing education of providers about the risks and benefits of immunization and including in vaccine recommendations more information on pre and post licensing vaccine safety evaluations may help address these concerns.

The cost of treatment for child pneumonias and meningitis in the Northern Areas of Pakistan.

Pneumonia, meningitis, and sepsis place a significant economic burden on health care systems, particularly in developing countries. This study estimates treatment costs for these diseases in health facilities in the Northern Areas of Pakistan. Health facility resources are organized by categories--including salaries, capital costs, utilities, overhead, maintenance and supplies--and quantified using activity-based costing (ABC) techniques. The average cost of treatment for an outpatient case of child pneumonia is dollar 13.44. For hospitalized care, the health system spent an average of dollar 71 per episode for pneumonia, dollar 235 for severe pneumonia, and dollar 2,043 for meningitis. These costs provide important background information for the potential introduction of the conjugate Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae vaccines in Pakistan.

Nonmedical exemptions to school immunization requirements: secular trends and association of state policies with pertussis incidence.

CONTEXT: School immunization requirements have played a major role in controlling vaccine-preventable diseases in the United States. Most states offer nonmedical exemptions to school requirements (religious or personal belief). Exemptors are at increased risk of acquiring and transmitting disease. The role of exemption policies may be especially important for pertussis, which is endemic in the United States. OBJECTIVE: To determine if (1) the rates of nonmedical exemptions differ and have been increasing in states that offer only religious vs personal belief exemptions; (2) the rates of nonmedical exemptions differ and have been increasing in states that have easy vs medium and easy vs difficult processes for obtaining exemptions; and (3) pertussis incidence is associated with policies of granting personal belief exemptions, ease of obtaining exemptions, and acceptance of parental signature as sufficient proof of compliance with school immunization requirements. DESIGN, SETTING, AND PARTICIPANTS: We analyzed 1991 through 2004 state-level rates of nonmedical exemptions at school entry and 1986 through 2004 pertussis incidence data for individuals aged 18 years or younger. MAIN OUTCOME MEASURES: State-level exemption rates and pertussis incidence. RESULTS: From 2001 through 2004, states that permitted personal belief exemptions had higher nonmedical exemption rates than states that offered only religious exemptions, and states that easily granted exemptions had higher nonmedical exemption rates in 2002 through 2003 compared with states with medium and difficult exemption processes. The mean exemption rate increased an average of 6% per year, from 0.99% in 1991 to 2.54% in 2004, among states that offered personal belief exemptions. In states that easily granted exemptions, the rate increased 5% per year, from 1.26% in 1991 to 2.51% in 2004. No statistically significant change was seen in states that offered only religious exemptions or that had medium and difficult exemption processes. In multivariate analyses adjusting for demographics, easier granting of exemptions (incidence rate ratio = 1.53; 95% confidence interval, 1.10-2.14) and availability of personal belief exemptions (incidence rate ratio = 1.48; 95% confidence interval, 1.03-2.13) were associated with increased pertussis incidence. CONCLUSIONS: Permitting personal belief exemptions and easily granting exemptions are associated with higher and increasing nonmedical US exemption rates. State policies granting personal belief exemptions and states that easily grant exemptions are associated with increased pertussis incidence. States should examine their exemption policies to ensure control of pertussis and other vaccine-preventable diseases.

Evaluation of non-specific effects of infant immunizations on early infant mortality in a southern Indian population.

OBJECTIVE: The aim of this study was to assess the relationship between receipt of routine childhood immunizations and infant mortality before 6 months of age. METHODS: This was an observational study of 10,274 infants, in a randomized trial of vitamin A supplementation, who received the study dose and survived to at least 1 week of age. The primary outcome was mortality before 6 months of age, analysed in Cox regression models as a function of vaccine receipt and gender. RESULTS: Receipt of Bacille Calmette Guerin (BCG) or diphtheria, tetanus, polio (DTP) vaccine was associated with significant reductions of one-half to two-thirds of mortality hazards; among girls, those who received both BCG and DTP experienced higher mortality than those who received only one of the two vaccines (hazards ratio 2.4; 95% confidence interval 1.2-5.0). CONCLUSION: The reduced mortality rate associated with receipt of BCG or DTP may be due to both biological and selection factors; the analyses regarding the combined effect of these vaccines and gender need to be replicated in other settings.