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Epidemiological Studies of the 'Non-Specific Effects' of Vaccines

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Epidemiological Studies of the 'Non-Specific Effects' of Vaccines Tropical Medicine and International Health doi:10.1111/j.1365-3156.2009.02301.x volume 14 no 9 pp 969–976 september 2009 Epidemiological studies of the ‘non-specific effects’ of vaccines: I – data collection in observational studies Paul E. M. Fine1, Thomas N. Williams2,3,4, Peter Aaby5,6, Karin Ka¨llander7,8, Lawrence H. Moulton9, Katie L. Flanagan10, Peter G. Smith1 and Christine S. Benn5,6 on behalf of the Working Group on Non-specific Effects of Vaccines* 1 London School of Hygiene & Tropical Medicine, London, UK 2 Kenya Medical Research Institute Centre for Geographic Medicine Research Coast, Kilifi District Hospital, Kilifi, Kenya 3 Nuffield Department of Medicine, John Radcliffe Hospital, Oxford, UK 4 Department of Paediatrics, John Radcliffe Hospital, Oxford, UK 5 Proje´cto de Sau´ de Bandim, Indepth Network, Bissau, Guinea-Bissau 6 Bandim Health Project, Danish Epidemiology Science Centre, Statens Seruminstitut, Copenhagen, Denmark 7 Division of International Health, Karolinska Institutet, Stockholm, Sweden 8 Makerere University School of Public Health, Kampala, Uganda 9 Department of International Health, Johns Hopkins University, Baltimore, MD, USA 10 Medical Research Council Laboratories, Fajara, The Gambia Summary Routine vaccination programmes have led to substantial declines in the incidence of most of the target diseases. In these circumstances, vaccine effects beyond those on the target diseases may become evident. Several studies have suggested that certain vaccines may influence mortality in low income settings in ways that cannot be attributed to effects on target diseases. Trials of such ‘non-specific’ effects are difficult if not impossible to organise; and observational studies of them are prone to serious confounding, because those who do or do not receive vaccines are likely to differ in many ways, some of which relate to their subsequent risk of early death, independent of vaccination. They are also prone to other biases, including the selective loss of vaccination records for children who die. We review these potential sources of bias and suggest what and how data may be collected to optimise the validity of such studies. keywords vaccines, mortality, non-specific effects, study design DTP vaccines might be associated with mortality increases Introduction (Anonymous 1981; Clemens et al. 1988; Holt et al. 1990; Routine childhood vaccination was introduced with the Koenig et al. 1990; Chen et al. 1994; Aaby et al. 1995, intention of reducing morbidity and mortality attributable 2003; Kumar et al. 2000; Kabir et al. 2003; Miller et al. to specific target diseases. It has been immensely successful 2003; Roth et al. 2006, Steenhuis et al. 2008). These in this regard, and most of these target diseases are now at observations have attracted attention to the possibility of historically low levels throughout the world. Under important vaccine effects beyond those on the target circumstances of high vaccination coverage and low target diseases (often called ‘non-specific effects’). If true, these disease frequency, there may be an opportunity for vaccine observations raise many issues, both immunological (for effects that are not specific to the target diseases to become example, they may indicate ‘biasing’ of the immune system evident. Indeed, several studies suggest that certain routine in ways not previously appreciated) and programmatic vaccines may influence child mortality in ways which (they may suggest ways in which current vaccines or cannot be ascribed to the presence or absence of the target vaccine schedules could be improved). diseases. For example, measles and BCG vaccines may The assessment of such ‘non-specific’ vaccine effects is reduce mortality to a larger degree than expected due to not straight-forward. Although the most rigorous way to prevention of measles and tuberculosis deaths, and under test them would be through randomised trials, such an some circumstances (e.g. the near absence of pertussis) approach is not always possible. For example, where a vaccine is recommended both nationally and internation- *The members of Working Group on Non-specific Effects of ally, and current low levels of the target disease are Vaccines are given in the Appendix. dependent upon maintaining high vaccine coverage, it is ª 2009 Blackwell Publishing Ltd 969 Tropical Medicine and International Health volume 14 no 9 pp 969–976 september 2009 P. E. M. Fine et al. Data collection in observational studies of non-specific effects of vaccines likely to be considered unethical to randomise children to the context of vaccine studies, it is important that child receive no vaccine. For this reason, most of the studies on identifiers be assigned and recorded at the time a birth is these effects have been observational. registered in the HDSS, whether the birth occurs in a health Observational studies of such vaccine effects are difficult facility or at home. A vaccination card should be allocated to design and to interpret, being prone to serious biases. In or examined on this occasion and all vaccinations received this study, we outline some of the methodological issues should be recorded in detail, including a record if no surrounding data collection for observational studies on vaccinations have yet been given. Study identity number non-specific vaccine effects, with particular emphasis on (ID) should be recorded on the vaccination card in a way studies with mortality outcomes. that will make it clear on subsequent follow-up if the initial card has been lost and replaced. Some HDSSs include the registration of pregnancies in their routine surveillance. In The value of health and demographic surveillance such circumstances a study ID may be pre-assigned to the systems foetus and noted on the pregnancy card as this may make it While studies of non-specific vaccine effects on morbidity easier to identify the children after delivery in a maternity [e.g. the possible association of vaccination with allergic ward in which vaccines are administered. conditions (Steenhuis et al. 2008)] may be conducted in high income countries with well-developed health infor- Vaccination data mation systems, most of the mortality-studies have been carried out in low income countries. This is in part for Vaccination data collected in HDSSs may be complete and historical reasons (several key studies were carried out in correct, or they may be wrongly recorded, or missing, in West Africa), but it may be that the high prevalence and whole or in part. This will depend upon the method and variety of infectious diseases in low income settings make care with which they are gathered. There are five general them particularly prone to multiple effects of vaccines. ways in which vaccination data can be collected: Furthermore, the high background mortality risks in such • Through continuous recording by dedicated project settings means that small proportional increases are more staff members at the point of vaccination. This easily seen than they would be against a low background. method is ideal but is the most labour and resource As such countries commonly lack comprehensive data on intensive. Its feasibility should be evaluated by inves- vaccinations and mortality, these studies have typically tigators conducting studies of vaccine effects. There been conducted within health and demographic surveil- are issues of ensuring the correct identification of each lance systems (HDSSs) in which defined populations are child, but these may be minimized by disciplined use followed longitudinally for births, deaths and migrations of vaccination cards with an ID and by asking and which may include collection of information on appropriate questions (name, birth date, residence, vaccination status. Much of the following discussion thus etc.) of the adult accompanying the child (typically the relates to the data collection possibilities within HDSSs. mother). It should be recognised that an illiterate The ideal would be to collect complete data on both mother having several children with vaccination cards vaccination and mortality, including precise dates of may not have brought the correct card for the child vaccination and death, along with data on causes of death being presented for vaccination. and relevant confounding variables, for all individuals in This approach requires placing project staff in all the population under surveillance. However, while mor- vaccination clinics serving the study population. In tality data are collected in all HDSSs, cause of death addition, there need to be methods for capturing information is generally poor. Similarly, while vaccination information on vaccinations performed outside the data may be collected in some HDSSs, they are often study area. This information may (and should) be recorded in ways which are not well suited for analysis in recorded on a child’s vaccination card, but is sometimes relation to subsequent mortality. on separate pieces of paper. Mothers should thus be asked routinely if the child has been vaccinated Methodological issues in the conduct of observational elsewhere, and if these vaccinations were recorded. studies of vaccines • Through periodic review of vaccination centre records. The quality of routine records in busy Identification vaccination clinics is often poor, and it may be Each HDSS develops methods for identifying individual difficult to ensure accurate identification of children residents that are appropriate for its own circumstances. In (Luman et al. 2008). In some HDSSs measures may be 970 ª 2009 Blackwell Publishing Ltd Tropical Medicine and International Health volume 14 no 9 pp 969–976 september 2009 P. E. M. Fine et al. Data collection in observational studies of non-specific effects of vaccines taken to improve such record keeping, for example by should be recorded in full at each visit. The date when encouraging use of project IDs in their registers. Such the card is seen is critical, as this is the date which is records may be used to validate or complement data used in landmark analysis [see companion paper on vaccinations collected in household visits. (Farrington et al. 2009)].
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