Ecological aspects in vaccine trials

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“Failure to consider the geographic dimension in vaccine trials ... trials. The methods available in graphic information systems .... Cartography (2nd Edition).
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Ecological aspects in vaccine trials Expert Rev. Vaccines 7(3), 279–281 (2008)

Mohammad Ali, PhD Author for correspondence

Translation Research Division, International Vaccine Institute, SNU Research Park, San 4-8 Bongcheon-7 dong, Kwanak-gu, Seoul 151-818, Korea Tel.: +82 2881 1127 Fax: +82 2881 2803 [email protected]

John D Clemens International Vaccine Institute, SNU Research Park, San 4-8 Bongcheon-7 dong, Kwanak-gu, Seoul 151-818, Korea Tel.: +82 2881 1100 Fax: +82 2881 2803 [email protected]

“Failure to consider the geographic dimension in vaccine trials may lead to inadequate planning, conduct and analysis of the trials. The methods available in graphic information systems offer public-health practitioners a valuable new toolbox to incorporate ecological aspects in vaccine trials.” Vaccines have become a centerpiece in public-health practice because they have helped to reduce the incidence and prevalence of many diseases and have been responsible for the eradication of smallpox from the world [1]. It has been estimated that, currently, over 350 vaccine candidates against nearly 100 different infectious diseases are in the development pipeline [2]. Currently available vaccines are the result of research in which vaccine trials play an essential role. Recent conceptual and methodological advances in geographical analysis have greatly enhanced our ability to design and execute vaccine trials. Methods for incorporating a geographic dimension into field research on human disease and interventions against disease, through geographic information systems (GIS), have advanced greatly in recent years. GIS is a powerful automated system for the capture, storage, retrieval, analysis and display of spatial data that can be loaded on most computers [3]. Within a GIS database, spatial data, which may include geopolitical boundaries, rivers, roads, health facilities, sources of risk and human settlements, are stored.

“…graphic information systems may help to define the clusters to be vaccinated each day of vaccination…” Perhaps the most obvious utility of GIS for vaccine trials is in the planning of such trials. A vaccine trial requires a study area with sufficient disease burden, adequate healthcare centers to detect the target disease, and a system for transportation of www.future-drugs.com

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vaccines, frequently within a cold chain. Knowledge regarding the population, physical characteristics of the area and barriers to movement are essential prerequisites for selecting a trial site. Of the three important components of a vaccine trial, preparation, vaccination campaign and follow-up, the vaccination campaign perhaps requires the most intense effort. The participants to be vaccinated have to be distributed among teams in a fashion that allows the teams to achieve their assigned goals. The size of their catchment area, rather than the size of catchment population, is closely associated with the performance of staff [4]. The use of geographic data assists in planning by facilitating the creation of geographically informed work schedules for the team. If vaccines are administered in the community and not at a central site where vaccines are stored, the daily vaccine requirement has to be predicted accurately to allow shipping of the correct number of study vaccines within the cold chain. Shipping too few vaccine doses may result in disappointed volunteers and shipping too many vaccines requires the return of vaccine doses at risk of breaking the cold chain. The GIS may help to define the clusters to be vaccinated each day of vaccination and the target population residing within the clusters. Commonly, specimens such as serum are collected from study participants on the day of vaccination to compare the immunogenicity of the candidate vaccine with the control. The GIS may be used to estimate the distance between the specimen collection centers and the center for storage (vaccination control center) of the specimens.

© 2008 Future Drugs Ltd

ISSN 1476-0584

279

Editorial

Ali & Clemens

The GIS can also help in monitoring the success of recruitment in a vaccine trial. Refusals and absentees are a common problem in vaccine trials. Identifying areas with low coverage during a vaccine campaign can help investigators to target these areas for sensitization prior to a next day/round of vaccination. Distance to health facilities may play a vital role in healthcare-seeking behavior, particularly in low-income countries, where mobility is limited [5]. In a vaccine trial, the target patients are usually enrolled in hospital-based passive-surveillance systems. If a person lives far away from the target health facilities, they will be less likely to report to these facilities, which could lead to detection bias. It is important to ensure that health facilities are within reach of the subjects of the trial area. Establishing health facilities requires knowledge of the spatial distribution of the population, existing health facilities, barriers to movements and spatial barriers to the establishment of health facilities. Using the GIS, suitable sites for health facilities can be established. In addition, by using the GIS, we are now able to determine spatial metrics (e.g., simple cost and network distances) of movements and to evaluate spatial factors and impediments for the uptake of healthcare. For instance, a well-developed road may accelerate and a water body may impede our movements, which can be evaluated through a GIS when determining accessibility of the target health facilities. When resource constraints do not allow the establishment of new health facilities, GIS can provide the spatial information needed to delineate and create trial areas and, subsequently, to analyze the trial data.

these individuals, and from herd protective effects, which may protect nonvaccinated neighbors of vaccinees and may also enhance the protection of vaccinees who reside in the neighborhood of other vaccinees [10–14]. Protection of nonvaccinees in this fashion is termed ‘indirect’ vaccine protection, whereas the enhanced protection of vaccinees is termed ‘total’ vaccine protection, both in distinction to direct vaccine protection. For instance, the introduction of conjugate Haemophilus influenzae type b vaccines in the USA, and later in The Gambia, demonstrated such indirect protection [15]. The use of cluster-randomized trials has been proposed as a design to measure these herd protective effects [16]. In this design, geographic clusters of individuals are randomized to the vaccine under study or the control agent. Contrasting the rates of the target infection among vaccinated individuals in the vaccinated clusters versus recipients of the control agent in the control clusters is thought to measure total vaccine protection, whereas contrasting the rates among nonvaccinated individuals in vaccinated clusters versus nonrecipients of the control agent in the control clusters measures indirect vaccine protection. However, the use of cluster-randomized trials to measure herd effects is dependent on several assumptions: • The target infection must be transmitted from person to person (directly or indirectly); • The clusters that are randomized must correspond to epidemiological units of transmission of the infection, in the sense the transmission must occur within clusters but be negligible between clusters;

“…in any individually randomized trial there will

• The clusters must be demographically stable.

be geographic differences in vaccine coverage of the target population…”

The second and third assumptions require antecedent data on the geography of infection transmission and population movement, data that require earlier studies on geographically mapped populations. While individually randomized trials of vaccines are thought to measure only direct vaccine protection, in practice, in any individually randomized trial there will be geographic differences in vaccine coverage of the target population owing to chance variations in randomized assignments and to different rates of eligibility and participation. In addition, if suitable geographic clusters can be identified and there is sufficient variation in vaccine coverage among these clusters, vaccine herd effects can be assessed by evaluating the correlation of disease incidence with levels of vaccine coverage in these clusters. As an example, although the oral cholera vaccine was found to be efficacious from the data of an individually randomized, placebo-controlled trial in Bangladesh in 1985, until 2005 it was unknown that the vaccine conferred a significant level of herd protection to nonvaccinees, as well as enhanced protection to the vaccinees living in the high vaccine coverage areas [17]. It was also unknown that, by vaccinating mothers and caregivers, the risk of cholera in infants and young children (