The contribution of neighbours to an individual's risk of typhoid outcome.

An individual's risk of infection from an infectious agent can depend on both the individual's own risk and protective factors and those of individuals in the same community. We hypothesize that an individual's exposure to an infectious agent is associated with the risks of infection of those living nearby, whether their risks are modified by pharmaceutical interventions or by other factors, because of the potential for transmission from them. For example, unvaccinated individuals living in a highly vaccinated community can benefit from indirect protection, or living near more children in a typhoid-endemic region (where children are at highest risk) might result in more exposure to typhoid. We tested this hypothesis using data from a cluster-randomized typhoid vaccine trial. We first estimated each individual's relative risk of confirmed typhoid outcome using their vaccination status and age. We defined a new covariate, potential exposure, to be the sum of the relative risks of all who live within 100 m of each person. We found that potential exposure was significantly associated with an individual's typhoid outcome, and adjusting for potential exposure affected estimates of vaccine efficacy. We suggest that it is useful and feasible to adjust for spatially heterogeneous distributions of individual-level risk factors, but further work is required to develop and test such approaches.

Household transmissibility of avian influenza A (H7N9) virus, China, February to May 2013 and October 2013 to March 2014.

To study human-to-human transmissibility of the avian influenza A (H7N9) virus in China, household contact information was collected for 125 index cases during the spring wave (February to May 2013), and for 187 index cases during the winter wave (October 2013 to March 2014). Using a statistical model, we found evidence for human-to-human transmission, but such transmission is not sustainable. Under plausible assumptions about the natural history of disease and the relative transmission frequencies in settings other than household, we estimate the household secondary attack rate (SAR) among humans to be 1.4% (95% CI: 0.8 to 2.3), and the basic reproductive number R0 to be 0.08 (95% CI: 0.05 to 0.13). The estimates range from 1.3% to 2.2% for SAR and from 0.07 to 0.12 for R0 with reasonable changes in the assumptions. There was no significant change in the human-to-human transmissibility of the virus between the two waves, although a minor increase was observed in the winter wave. No sex or age difference in the risk of infection from a human source was found. Human-to-human transmissibility of H7N9 continues to be limited, but it needs to be closely monitored for potential increase via genetic reassortment or mutation.

Assessing the impact of travel restrictions on international spread of the 2014 West African Ebola epidemic.

The quick spread of an Ebola outbreak in West Africa has led a number of countries and airline companies to issue travel bans to the affected areas. Considering data up to 31 Aug 2014, we assess the impact of the resulting traffic reductions with detailed numerical simulations of the international spread of the epidemic. Traffic reductions are shown to delay by only a few weeks the risk that the outbreak extends to new countries.

Recent developments in theories of pathogenesis of AIDS.

Experimental and theoretical progress in HIV research includes an improved resolution of the spatial heterogeneity and the dynamics (time course and turnover rates) of virus and CD4+ cells. Some of these advances have resulted from the joint work of experimental and theoretical groups, demonstrating that interdisciplinary research can be fruitful.

Seven challenges for model-driven data collection in experimental and observational studies.

Infectious disease models are both concise statements of hypotheses and powerful techniques for creating tools from hypotheses and theories. As such, they have tremendous potential for guiding data collection in experimental and observational studies, leading to more efficient testing of hypotheses and more robust study designs. In numerous instances, infectious disease models have played a key role in informing data collection, including the Garki project studying malaria, the response to the 2009 pandemic of H1N1 influenza in the United Kingdom and studies of T-cell immunodynamics in mammals. However, such synergies remain the exception rather than the rule; and a close marriage of dynamic modeling and empirical data collection is far from the norm in infectious disease research. Overcoming the challenges to using models to inform data collection has the potential to accelerate innovation and to improve practice in how we deal with infectious disease threats.

Measures of the effects of vaccination in a randomly mixing population.

Vaccine efficacy in the field is often derived from the relative attack rates in the vaccinated and unvaccinated after an outbreak. In this paper, vaccine efficacy is defined in terms of the probability that the infectious agent is transmitted from an infected to a susceptible person, and a method for estimating it from the usual attack rate data is given. We explore two mechanisms of vaccine action defined by Smith et al, but include an underlying dynamic epidemic model of an acute directly transmitted disease. We show analytically that under the model in which the vaccine mechanism reduces the probability of infection given a certain exposure, vaccine efficacy based on the relative attack rates underestimates the protective effect of the vaccine based on the relative transmission probabilities. Under the other model in which the vaccine mechanism offers complete protection to a certain proportion of those vaccinated, and no protection to the other vaccinated proportion, the vaccine efficacy based on the relative attack rates will equal that based on the transmission probabilities. Parameters for the effectiveness of a vaccination programme are defined in terms of the direct and indirect benefit to a single person as well as the total and average benefit to the entire population, and derived from the dynamic model for an outbreak of an acute directly transmitted disease. These effects can also be estimated without an actual separate unvaccinated population, independent of assumptions about the vaccine mechanism. The variation of these measures as functions of the fraction of vaccinated people in the population is explored numerically.

On individual and population effectiveness of vaccination.

BACKGROUND: The protective effect of a vaccine following an outbreak is often measured by the vaccine efficacy statistic, namely one minus the ratio of attack rates in vaccinees and non-vaccinees. This quantity is not an adequate measure of the population-level benefits of the vaccine. METHODS: We discuss two measures of the effectiveness of a vaccination programme. The first is the commonly used vaccine efficacy statistic. This is called here the individual vaccination effectiveness. The second measure, called the population effectiveness, is defined as one minus the ratio of the overall (or average) attack rate in the population when the vaccination programme is implemented to the expected attack rate in the same population without vaccination. We outline a method for computing the population effectiveness following an outbreak of a directly transmitted acute infectious disease in a closed heterogeneous population. We then explore and compare the behaviour of the two measures of vaccination effectiveness under various conditions. RESULTS: The population vaccination effectiveness is more robust than individual effectiveness to factors that may interfere with the evaluation of the performance of vaccination. Such factors are non-uniform vaccination, changes in contact patterns by vaccinees, and the ability of the vaccine to reduce infectiousness. CONCLUSION: The population vaccination effectiveness is a more adequate measure of the population-level benefits of a vaccination programme. The main disadvantage of this measure is that it cannot be readily calculated from observed attack rates.

Assessment of the direct effectiveness of BC meningococcal vaccine in Rio de Janeiro, Brazil: a case-control study.

BACKGROUND: Meningococcal disease is still a serious public health problem in many countries. A vaccine produced by Cuba was the first product against B meningococcus available on a large scale. In an attempt to control the increasing incidence of this serogroup in greater Rio de Janeiro, Brazil, the vaccine was used in 1990 in children aged 6 months-9 years. About 1.6 million children were vaccinated. METHODS: In order to assess the direct effectiveness of the vaccine in preventing disease, we conducted a case-control study during the first year after vaccination. Using a hospital-based census, we selected all children hospitalized with meningococcal disease and sampled the control group among children hospitalized with other types of meningitis. Vaccine effectiveness was estimated from the relationship, 1-OR, where OR (odds ratio) was the exponential of the logistic regression coefficient for the association between meningococcal disease and previous vaccination. RESULTS: A total of 275 cases and 279 controls were selected between September 1990 and October 1991. The summary adjusted measure of protection against serogroup B was 54% (95% confidence interval [CI]: 20-74%). Estimated protection varied among different age strata and place of residence, being high among children aged > or = 4 years, 71% (95% CI: 34-87%), and among those who lived in the City of Rio de Janeiro, 74% (95% CI: 42-89%). CONCLUSIONS: The results suggest that the vaccine produced by Cuba may offer protection against serogroup B meningococcal disease, but its effects may not be homogeneous.

PIP: Meningococcal disease is still a serious public health problem in many countries. A vaccine produced by Cuba was the first product against B meningococcus available on a large scale. In an attempt to control the increasing incidence of this serogroup in greater Rio de Janeiro, Brazil, the vaccine was used in 1990 in children 6 months-9 years old. About 1.6 million children were vaccinated. In order to assess the direct effectiveness of the vaccine in preventing disease, a case-control study was conducted during the first year after vaccination. Using a hospital-based census, all children hospitalized with meningococcal disease caused by Neisseria meningitidis were selected, and the control group came from children hospitalized with other types of meningitis at the Sao Sebastiao State Infectology Institute. Vaccine effectiveness was estimated, using ordinary logistic regression, from the relationship, 1 - OR, where OR (odds ratio) was the exponential of the logistic regression coefficient for the association between meningococcal disease and previous vaccination. A total of 275 cases and 279 controls were selected between September 1990 and October 1991. 57% of the total cases belonged to serogroup B and 7% to serogroup C. The case fatality rate was 11%. Of the 279 controls, 46% were related to viral meningitis, 34% were related to meningitis caused by bacteria other than N. meningitidis, 13% were related to postmumps meningitis, 5% to tuberculosis meningitis, and 2% to other diseases. The summary-adjusted measure of protection against serogroup B was 54% (95% confidence interval [CI]: 20-74%). The combined vaccine effectiveness for 230 cases and 232 controls amounted to 58% (95% CI: 31-74%). Estimated protection varied among different age strata and place of residence, being high among children or= 4 years old, 71% (95% CI: 34-87%), and among those who lived in the City of Rio de Janeiro, 74%, (95% CI: 42-89%). The results suggest that the vaccine produced by Cuba may offer protection against serogroup B meningococcal disease, but its effects may not be homogeneous.

A case-control study of the effectiveness of BCG vaccine for preventing leprosy in Yangon, Myanmar.

BACKGROUND: Five randomized trials, a follow-up study, and six case-control investigations of BCG vaccine's effectiveness (VE) for preventing leprosy have been conducted internationally, with widely varying estimates of VE. Because of the difficulty of generalizing from disparate results, local estimates of VE are needed for health planning purposes and are currently particularly relevant, given the World Health Organization's (WHO) goal to eliminate leprosy by the year 2000. METHODS: We conducted a case-control study in Yangon, Myanmar. Residents of Yangon between the ages of 6 years and 24 years who were listed in the National Leprosy Registry as being on active treatment for leprosy between December 1992 and April 1993 were eligible to participate in the study as cases. Control subjects were matched to the cases on age, sex, and neighbourhood. RESULTS: One or more doses of BCG were associated with a VE of 66%. The results show a significant trend of increasing VE with increasing number of BCG doses (one dose, VE = 55%; two doses, VE = 68%; three doses, VE = 87%). One dose of BCG vaccine appeared to provide protection substantially higher than that found in an earlier vaccine trial in Myanmar, but consistent with results from case-control studies in other countries. CONCLUSIONS: These data suggest that BCG reduces the risk of leprosy in Myanmar, and that BCG vaccination of infants, along with early case-finding and treatment, should be considered an important part of the leprosy intervention strategy.

The behaviour of common measures of association used to assess a vaccination programme under complex disease transmission patterns--a computer simulation study of malaria vaccines.

Case-control studies have been evoked as important alternatives to randomized clinical trials in the evaluation of infectious disease interventions. Using computer simulations, we compare the behaviour of common measures of association derived from case-control studies in the context of a malaria vaccine programme administered under complex transmission conditions. Several simplifying assumptions of previous workers have been relaxed and the simulated conditions are endemic rather than epidemic. The common estimators of association used in case-control studies remain unbiased only in limited circumstances. The term dependent happenings, first defined by Ross in 1916, is resurrected. Since the number of people becoming infected is dependent on the number of people already infected, control programmes in infectious diseases produce direct as well as indirect effects. Three different study designs with different pairs of comparison populations are defined. The choice of comparison population can be used to differentiate direct from indirect effects. In order to clarify the direct effects of a vaccination programme the comparison groups must be subjected to identical transmission intensities. In contrast, the referent group must remain unaffected by consequences of the intervention to determine indirect effects.

Epidemiologic effects of varicella vaccination.

For a plausible range of values for the different efficacy characteristics of the live varicella (Oka) vaccine at different levels of coverage, modeling results suggest that routine immunization of preschool children would greatly reduce the number of primary varicella cases, whereas the shift in age distribution of cases would not result in increased overall morbidity as measured by number of hospitalizations. Although information about some of the vaccine assumptions is scanty, the combinations of assumptions leading to an increase in morbidity seem unlikely. A catch-up program in older children who have not yet had chickenpox will be important. The number and age distribution of the cases in vaccinees are sensitive to assumptions about the vaccine, especially the degree and distribution of partial protection against infection, relative residual infectiousness, and waning of immunity. Responsiveness to boosting by wild-type VZV infection was especially important in reducing the number of older cases. The advantage conferred by responsiveness to boosting depends on the level of transmission. The direct and indirect effects of vaccines and vaccination programs interact. Understanding how a vaccine works at the individual level is important for the vaccinated individual, but it also influences the overall public health benefits of an immunization programs. Lieu et al based a cost-effectiveness analysis of varicella vaccines on this model of varicella dynamics and assumptions about how the vaccines work. Models cannot replace biologic understanding. The purpose of such models is not to predict the number of cases of varicella, but to examine some possible consequences of introducing a vaccine into the routine immunization schedule of preschool children in the United States, effects of different vaccination strategies, and the benefits of a temporary catch-up program for older children. Modeling exercises of this sort force us to formalize our thinking, for instance about the vaccine mechanisms, and to admit our uncertainties, such as about the vaccine efficacy assumptions. Such models also show where more data need to be collected, for example, on boosting and waning of immunity and relative residual infectiousness. Improvements in the design of vaccine efficacy studies are necessary to provide the input to these models for looking at the long-term effects of vaccination programs. Frailty models can be used to analyze the data in the presence of heterogeneities in susceptibility. Waning can also be estimated using appropriate methods. Relative infectiousness of vaccinees with breakthrough cases can be measured by comparing the relative secondary attack rates when the index infected person is vaccinated and when the index infected person is unvaccinated. More studies are needed to understand how to evaluate responsiveness to boosting. Vaccine efficacy studies in the field should be designed to obtain better estimates of residual susceptibility, residual infectiousness, duration of protection, and the effects of boosting by reinfection with wild-type VZV.

Population biology, evolution, and immunology of vaccination and vaccination programs.

The purpose of prophylactic vaccination is to reduce morbidity and mortality in a population. Many questions related to the design of vaccines and vaccination programs require a population standpoint for their sharp formulation and laboratory and field studies to understand their immunologic background. Practical suggestions of the workshop included increased studies of age-specific immunity, better immunoepidemiologic surveillance, better design of efficacy studies, and more systematic sampling of parasite strains to study the evolutionary pressure exerted by vaccines. Theoretical immunology has much to contribute. One of the realizations of the workshop was the value of a strong interdisciplinary approach in vaccine development, utilizing relevant contributions from immunology, population biology, mathematical modeling, epidemiology, molecular biology, and virology.

Epidemiologic effects of vaccines with complex direct effects in an age-structured population.

Vaccines can alter the dynamic interaction of an infectious agent with a host in complex ways. The effect of routine childhood immunization on age-specific cases was studied in an age-structured population, assuming different vaccine effects at the individual level. Assumptions about vaccine efficacy include partial protection to infection and disease, reduction in infectiousness, waning of protection, and boosting of the level and duration of protection by natural infection. The concept of relative pathogenicity is introduced to describe the effect of a vaccine on the development of disease conditional on being infected. The concepts of the immunologically naive susceptible, naive susceptible equivalent, and relative residual infection potential are introduced in the context of defining the reproduction number of a population vaccinated with a partially protective vaccine. Sensitivity to boosting has a particularly pronounced effect in reducing the number of older vaccinated cases. Near the threshold for eliminating transmission, the dynamic behavior and number as well as age distribution of cases is very sensitive to the degree of protection and relative residual infectiousness. The number of unvaccinated cases is more sensitive to the level of coverage than to the type of vaccine, while the number of vaccinated cases is very sensitive to assumptions about vaccine efficacy.

Modeling malaria vaccines. II: Population effects of stage-specific malaria vaccines dependent on natural boosting.

Population effects of malaria vaccination programs will depend on the stage specificity of the vaccine, its duration of effectiveness, whether it is responsive to natural boosting, the proportion vaccinated, and the preexisting endemic conditions. This paper develops models of infection-blocking (sporozoite), disease-modifying (merozoite), and transmission-blocking (gametic) vaccines. It explores numerically their different effects on prevalence of infection and disease when utilized in different types of immunization programs at various levels of coverage. Simulations show that possible qualitative consequences of malaria vaccination programs include decreased prevalence of infection and disease and decreased prevalence of infection without a corresponding decrease in prevalence of disease. Epidemics, either one-time or cyclical, could occur. These effects could be accompanied by changes in the age distribution of disease. Finally, vaccination could contribute to elimination of transmission. The duration of effectiveness of the malaria vaccine relative to the duration of natural immunity could have important consequences for the unvaccinated. The problem of predicting a threshold for elimination of transmission is discussed.

Modeling malaria vaccines. I: New uses for old ideas.

Starting from a modification of the model of malaria transmission developed for the Garki project, this paper develops a model containing variables relevant to the stimulation of malaria vaccination programs. Modifications include (1) integration of maintenance of immunity dependent on boosting and the possibility of loss of immunity; (2) introduction of a boosting factor distinct from susceptibility to infection; (3) reinterpretation of the epidemiological compartments of positive immunes and nonimmunes in terms of severity of disease rather than just infection; (4) interpretation of the different stage-specific levels of immunity; (5) discrimination between different susceptibilities for the immune and nonimmune classes; (6) reformulation of the expression for acquisition of immunity to be biologically more acceptable. Simulations using the Garki model, Nedelman's modification of it, and our Basic model compare the similarities and differences in the predictive behavior of the models. Simulations using the Basic model reproduce observed periodic fluctuations of malaria attributed to the interplay of transmission-blocking immunity and loss of immunity in the absence of boosting in areas of unstable malaria transmission.

Estimation of vaccine efficacy from epidemics of acute infectious agents under vaccine-related heterogeneity.

A stochastic epidemic model is formulated for the study of the protective effects of vaccination in a population that is stratified by vaccine-related factors. The epidemic model is transformed into a counting process, and then martingale-based methods are used to provide estimators of vaccine efficacy and their variances. Following an example, various extensions of the model are discussed.

On the distribution of vaccine protection under heterogeneous response.

We assume that individuals in a vaccinated cohort respond heterogeneously and acquire a continuous spectrum of effective protection against an environmental exposure to infection that can be varying in time. The notion of dynamical invariants is applied to a proportional hazard model with an unvaccinated or placebo cohort as baseline. The hazard is expressed as a susceptibility factor times a measure of environmental exposure to infection. Using the time-evolving information for the aggregated vaccinated cohort and the unvaccinated cohort, it is possible to reconstruct the distribution of effective protection imparted by the vaccination at the beginning of observation. Efficacy is defined in terms of the hazard ratio at the beginning of observation.

Malaria vaccines: lessons from field trials.

Malaria vaccine candidates have already been tested and new trials are being carried out. We present a brief description of specific issues of validity that are relevant when assessing vaccine efficacy in the field and illustrate how the application of these principles might improve our interpretation of the data being gathered in actual malaria vaccine field trials. Our discussion assumes that vaccine evaluation shares the same general principles of validity with epidemiologic causal inference, i.e., the process of drawing inferences from epidemiologic data aiming at the identification of causes of diseases. Judicious exercise of these principles indicates that, for meaningful interpretation, measures of vaccine efficacy require definitions based upon arguments conditional on the amount of exposure to infection, and specification of the initial and final states in which one believes the effect of interest takes place.