Case-control vaccine effectiveness studies: Data collection, analysis and reporting results.

The case-control methodology is frequently used to evaluate vaccine effectiveness post-licensure. The results of such studies provide important insight into the level of protection afforded by vaccines in a 'real world' context, and are commonly used to guide vaccine policy decisions. However, the potential for bias and confounding are important limitations to this method, and the results of a poorly conducted or incorrectly interpreted case-control study can mislead policies. In 2012, a group of experts met to review recent experience with case-control studies evaluating vaccine effectiveness; we summarize the recommendations of that group regarding best practices for data collection, analysis, and presentation of the results of case-control vaccine effectiveness studies. Vaccination status is the primary exposure of interest, but can be challenging to assess accurately and with minimal bias. Investigators should understand factors associated with vaccination as well as the availability of documented vaccination status in the study context; case-control studies may not be a valid method for evaluating vaccine effectiveness in settings where many children lack a documented immunization history. To avoid bias, it is essential to use the same methods and effort gathering vaccination data from cases and controls. Variables that may confound the association between illness and vaccination are also important to capture as completely as possible, and where relevant, adjust for in the analysis according to the analytic plan. In presenting results from case-control vaccine effectiveness studies, investigators should describe enrollment among eligible cases and controls as well as the proportion with no documented vaccine history. Emphasis should be placed on confidence intervals, rather than point estimates, of vaccine effectiveness. Case-control studies are a useful approach for evaluating vaccine effectiveness; however careful attention must be paid to the collection, analysis and presentation of the data in order to best inform evidence-based vaccine policies.

Case-control vaccine effectiveness studies: Preparation, design, and enrollment of cases and controls.

Case-control studies are commonly used to evaluate effectiveness of licensed vaccines after deployment in public health programs. Such studies can provide policy-relevant data on vaccine performance under 'real world' conditions, contributing to the evidence base to support and sustain introduction of new vaccines. However, case-control studies do not measure the impact of vaccine introduction on disease at a population level, and are subject to bias and confounding, which may lead to inaccurate results that can misinform policy decisions. In 2012, a group of experts met to review recent experience with case-control studies evaluating the effectiveness of several vaccines; here we summarize the recommendations of that group regarding best practices for planning, design and enrollment of cases and controls. Rigorous planning and preparation should focus on understanding the study context including healthcare-seeking and vaccination practices. Case-control vaccine effectiveness studies are best carried out soon after vaccine introduction because high coverage creates strong potential for confounding. Endpoints specific to the vaccine target are preferable to non-specific clinical syndromes since the proportion of non-specific outcomes preventable through vaccination may vary over time and place, leading to potentially confusing results. Controls should be representative of the source population from which cases arise, and are generally recruited from the community or health facilities where cases are enrolled. Matching of controls to cases for potential confounding factors is commonly used, although should be reserved for a limited number of key variables believed to be linked to both vaccination and disease. Case-control vaccine effectiveness studies can provide information useful to guide policy decisions and vaccine development, however rigorous preparation and design is essential.

Global invasive bacterial vaccine-preventable diseases surveillance--2008-2014.

Meningitis and pneumonia are leading causes of morbidity and mortality in children globally infected with Streptococcus pneumoniae (pneumococcus), Neisseria meningitidis, and Haemophilus influenzae causing a large proportion of disease. Vaccines are available to prevent many of the common types of these infections. S. pneumoniae was estimated to have caused 11% of deaths in children aged <5 years globally in the pre-pneumococcal conjugate vaccine (PCV) era. Since 2007, the World Health Organization (WHO) has recommended inclusion of PCV in childhood immunization programs worldwide, especially in countries with high child mortality. As of November 26, 2014, a total of 112 (58%) of all 194 WHO member states and 44 (58%) of the 76 member states ever eligible for support from Gavi, the Vaccine Alliance (Gavi), have introduced PCV. Invasive pneumococcal disease (IPD) surveillance that includes data on serotypes, along with meningitis and pneumonia syndromic surveillance, provides important data to guide decisions to introduce PCV and monitor its impact.

Priorities for research on meningococcal disease and the impact of serogroup A vaccination in the African meningitis belt.

For over 100 years, large epidemics of meningococcal meningitis have occurred every few years in areas of the African Sahel and sub-Sahel known as the African meningitis belt. Until recently, the main approach to the control of these epidemics has been reactive vaccination with a polysaccharide vaccine after an outbreak has reached a defined threshold and provision of easy access to effective treatment but this approach has not prevented the occurrence of new epidemics. Meningococcal conjugate vaccines, which can prevent meningococcal carriage and thus interrupt transmission, may be more effective than polysaccharide vaccines at preventing epidemics. Because the majority of African epidemics have been caused by serogroup A meningococci, a serogroup A polysaccharide/tetanus toxoid protein conjugate vaccine (PsA-TT) has recently been developed. Results from an initial evaluation of the impact of this vaccine on meningococcal disease and meningococcal carriage in Burkina Faso have been encouraging. To review how the research agenda for meningococcal disease in Africa has been changed by the advent of PsA-TT and to define a new set of research priorities for study of meningococcal infection in Africa, a meeting of 41 scientists was held in Dakar, Senegal on April 24th and 25th 2012. The research recommendations developed during the course of this meeting are presented in this paper. The need for enhanced surveillance for meningitis in defined populations with good diagnostic facilities in African countries at risk of epidemics was identified as the highest priority. This is needed to determine the duration of protection against serogroup A meningococcal disease provided by PsA-TT and to determine the risk of disease and carriage caused by meningococci of other serogroups. Other research areas given high priority included identification and validation of serological correlates of protection against meningococcal disease and carriage, development of improved methods for detecting carriage and epidemiological studies aimed at determining the reasons underlying the peculiar epidemiology of meningococcal disease in the African meningitis belt. Minutes and working papers from the meeting are provided in supplementary tables and some of the presentations made at the meeting are available on the MenAfriCar consortium website (www.menafricar.org) and on the web site of the Centers for Disease Control (www.cdc.gov).

Investigating outbreaks: practical guidance in the Indian scenario.

The new international Health Regulations, 2005, which came into force in 2007, establish a national focal point in each country to manage public health emergencies of international concern, including outbreaks. Investigating outbreaks is a challenging task. Often, pressure from decision-makers to hasten investigation may preclude proper evidence-based conclusions. Furthermore, the task of outbreak investigation is given to senior staff, who have limited time for field activities. The classical 10-step approach includes 4 main stages of (i) confirmation of the presence of the outbreak and of diagnosis using laboratory tests, (ii) generation of hypotheses regarding causation using descriptive epidemiology findings, (iii) hypothesis-testing using analytical epidemiology techniques, and (iv) institution of prevention measures. Peer-review at all stages of the investigation and reporting is the keystone of the quality assurance process. It is important to build capacity for outbreak Investigation. Two Field Epidemiology Training Programmes in India are trying to do this. In these programmes, epidemiologists-in-training take a lead in investigating outbreaks, while learning the ropes, with full technical support from the faculty. This training should spawn a culture of generating and using evidence for decision-making in the context of public health, and help strengthen health systems even beyond the domain of outbreaks.

Federal role in early detection preparedness systems.

This report discusses CDC's role in the early detection of threats to public health, including linkage of detection to other preparedness functions, and provides an update on recent progress in improving these capabilities. CDC's role has been fivefold: 1) identifying and adopting information system standards; 2) providing funding; 3) defining critical surveillance functionalities; 4) accelerating Internet-based surveillance systems and electronic reporting of laboratory results; and 5) implementing BioSense, a secure, Internet-accessible, national early detection system that includes syndromic surveillance. Ongoing iterative efforts and consultation are needed to ensure future progress.

Public Health Information Network--improving early detection by using a standards-based approach to connecting public health and clinical medicine.

Public health departments and their clinical partners are moving ahead rapidly to implement systems for early detection of disease outbreaks. In the urgency to develop useful early detection systems, information systems must adhere to certain standards to facilitate sustainable, real-time delivery of important data and to make data available to the public health partners who verify, investigate, and respond to outbreaks. To ensure this crucial interoperability, all information systems supported by federal funding for state and local preparedness capacity are required to adhere to the Public Health Information Network standards.

Statutory basis for public health reporting beyond specific diseases.

Statutory authority for public health surveillance is necessarily broad as previously uncharacterized diseases are regularly discovered. This article provides specific information about general disease reporting provisions in each state. The intent of these reporting laws and the Health Insurance Portability and Accountability Act Privacy Rule is to support this critical disease surveillance function for the benefit of the entire population.

Comparison of Three Selective Enrichment Methods for the Isolation of Listeria monocytogenes from Naturally Contaminated Foods.

Three selective enrichment procedures-the U.S. Food and Drug Administration (FDA) method, the U.S. Department of Agriculture (USDA) method, and the Netherlands Government Food Inspection Service (NGFIS) method-were compared for isolating Listeria monocytogenes from contaminated foods. The foods were obtained from the refrigerators of patients with culture-proven listeriosis who were identified through multistate active surveillance in a U.S. population of 19 million. The study was designed to identify foods that may be important in transmission of L. monocytogenes in sporadic cases of human listeriosis. Of 899 foods analyzed by all three methods, 121 were positive for L. monocytogenes by at least one method. The three enrichment methods detected L. monocytogenes in 65% (FDA), 74% (USDA), and 74% (NGFIS) of the foods shown to contain L. monocytogenes . The differences among the three methods were not statistically significant. However, the recovery of L. monocytogenes by a combination of any two methods (USDA-FDA 88%, USDA-NGFIS 91%, FDA-NGFIS 87%) was significantly better than that by one method alone (p < 0.02). The differences among the combinations of methods were not statistically significant. These results suggest that at least two enrichment methods must be used in combination to recover L. monocytogenes from contaminated foods with a success rate near 90%. Correlations were observed between negative results and low (<0.3 CFU/g) level of L. monocytogenes contamination for the USDA (p << 0.001) and NGFIS (p << 0.001) methods. A similar but somewhat weaker association was observed for the FDA method (p < 0.06).

Listeria monocytogenes Contamination of Turkey Franks: Evaluation of a Production Facility.

A facility which produced turkey franks that had been microbiologically linked to a case of human listeriosis was evaluated to establish prevalence of contamination and identify potential points for intervention. Listeria monocytogenes was isolated from only two of 41 environmental samples obtained in the plant. Among production line product samples analyzed by the Centers for Disease Control, 0 to 8% of samples from the production stages before the peeler-conveyor belt apparatus were positive for the case strain of L. monocytogenes , whereas 12 of 14 (86%) samples collected from this apparatus were positive (p <0.001). The most probable number (MPN) of L. monocytogenes in finished product purchased from a retail outlet was less than 0.3 per gram; however, the opened package of franks from the case patient's refrigerator had an MPN of >1100 per gram. These data suggest that systematic culturing and analysis of products and production facilities may help identify appropriate interventions to reduce L. monocytogenes contamination in food processing plants and contribute to control of L. monocytogenes in ready-to-eat meat products.