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.

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.

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.

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.

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.

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.