Vaccination in a community can reduce transmission producing effects beyond the direct protective effects in vaccinated individuals. The population effects of vaccination are primarily due to an increase in the population level of immune protection, also known as herd immunity (Fox and Elveback, 1975
; Fine, 1993
). Herd immunity describes the collective immunological status of a population of hosts, as opposed to an individual host, with respect to a given pathogen. Population-level effects of vaccination include indirect, total and overall effects (Halloran and Struchiner, 1991
). Indirect effects of a vaccination strategy are the effects in those individuals who were not vaccinated, or at least who were not vaccinated as part of the strategy of interest. The total effects are the combined population-level effects of the vaccination strategy and the direct protective effects of vaccination in those individuals who received the vaccine. The overall effect of a vaccination strategy is the average effect in the population in those who did and did not receive the vaccine compared to if the population had not had the vaccination strategy. In this paper we are concerned primarily with indirect effects.
The indirect effects of interest may be in subpopulations outside the target age groups, such as infants, or in whom it is believed the vaccine might not be efficacious, such as in elderly or immunocompromised people. For example, one might be interested in the effect of a strategy of vaccinating school-aged children with influenza vaccine in reducing incidence of influenza in pre-school children or in people over 65 years of age. Evidence that vaccine-induced herd immunity produces indirect protection has been demonstrated for several vaccines, including those against Haemophilius influenzae b
(Adegbola et al., 2005
), pneumococcal bacteria (Metlay et al., 2006
; Grijalva et al., 2007
), meningococcal C bacteria (Ramsay et al., 2003
), among others. Establishing indirect protection of vaccination in unvaccinated subpopulations can have implications for global vaccine policies. Population effects of vaccination could also be detrimental. In areas of high transmission of malaria, maintenance of partial direct protection against disease depends on repeated boosting of immunity to exposure to natural infection. Malaria vaccination could reduce transmission, thus lower boosting, resulting in unvaccinated individuals becoming susceptible to more severe disease again (Halloran et al., 1989
). Thus, interest in evaluating the indirect effects of vaccination programs has increased.
Heuristically, evaluation of the indirect effects of vaccination requires comparison of the outcomes in individuals who did not receive the vaccine in communities with the vaccination strategy and individuals who did not receive the vaccine in communities without the vaccination strategy (Halloran and Struchiner, 1991
; Struchiner et al., 1990
). In this situation, the indirect vaccine effect would generally be estimated as one minus the ratio of some measure of risk in unvaccinated individuals in the vaccinated communities compared to the unvaccinated individuals in the unvaccinated communities:
Ideally the communities would be randomized to receive either the vaccination strategy or a strategy using a control vaccine. Because vaccines are administered to individuals, randomization can occur at two stages, namely the group level and the individual level (Hudgens and Halloran, 2008
; VanderWeele and Tchetgen Tchetgen 2011b
). In a study with two levels of randomization, communities could be randomized to either receive the vaccination strategy or not, then individuals randomized to be vaccinated or not in the communities with the vaccination strategy and to receive control or not in the communities without the vaccination strategy. Then presumably those who did not receive vaccine in the vaccinated community would be comparable to those who did not receive control in the communities randomized to control. In general, assignment mechanisms that are not independent of the infection outcomes of interest could be in place at either or both of the two levels, making a study observational at either or both of the two levels. In these situations, the comparability of the unvaccinated individuals across the populations would need further examination.
One could also consider comparing two different vaccination strategies, say where one strategy vaccinated a certain proportion of the people and the other strategy vaccinated a different proportion of the people. If vaccination coverage varied over a range of values in a collection of communities, one could estimate how the indirect effect varied with the proportion of the population vaccinated.
Discussions of evaluating indirect effects in populations have generally been concerned with relatively large clusters (Halloran and Struchiner, 1991
; Moulton et al., 2001
; Hayes and Moulton, 2009
), although Hayes and Moulton (2009)
briefly mention small clusters such as households (pp. 51–52). However, in recent years, a number of studies have been conducted to assess indirect effects in smaller clusters such as households or other small transmission units. The transition from small transmission units, such as households, to units of extended families as in compounds in Niakhar, Senegal (Préziosi and Halloran, 2003
) or baris in Bangladesh (Ali et al., 2005
), to day care centers, to schools, and to villages is fairly continuous. In households, the indirect effect of vaccination could be estimated by
The measure of risk could be attack rates (cases per household members at risk) or incidence rates (cases per person-time at risk). The relative risk could be estimated by an odds ratio from a case-control study. Studies in smaller clusters have many similarities to studies in larger communities. However, studies in small transmission units do have differences compared to studies in larger clusters or groups. Thus, this type of study deserves its own characterization.
We propose the name of minicommunity design for studies of indirect effects in small clusters. Orenstein et al. (1988)
proposed that individuals in a small transmission unit exposed to an infectious case can be thought of as a minicohort
that has its own reference date for exposure to infection. When evaluating the indirect effects of vaccinating one or several individuals in a small transmission unit, the small transmission unit can be thought of as a minicommunity
, or minicluster or minigroup, in which to estimate indirect effects.
In this paper, we characterize minicommunity studies to estimate indirect effects of vaccination in small clusters or transmission units. To motivate the development, we first present several published examples of what we call mini-community studies to estimate indirect effects. The examples include studies of the indirect effects of pertussis, pneumococcal, influenza, and cholera vaccination. They illustrate diverse methodological considerations which we discuss. We compare the minicommunity design with studies for indirect effects in larger communities, as well as with studies based on temporal trends.