Distinguishing vaccine efficacy and effectiveness

Background

Mathematical models of disease transmission and vaccination typically assume that protective vaccine efficacy (i.e. the relative reduction in the transmission rate among vaccinated individuals) is equivalent to direct effectiveness of vaccine. This assumption has not been evaluated.

Methods

We used dynamic epidemiological models of influenza and measles vaccines to evaluate the common measures of vaccine effectiveness in terms of both the protection of individuals and disease control within populations. We determined how vaccine-mediated reductions in attack rates translate into vaccine efficacy as well as into the common population measures of ‘direct’, ‘indirect’, ‘total’, and ‘overall’ effects of vaccination with examples of compartmental models of influenza and measles vaccination.

Results

We found that the typical parameterization of vaccine efficacy using direct effectiveness of vaccine can lead to the underestimation of the impact of vaccine. Such underestimation occurs when the vaccine is assumed to offer partial protection to every vaccinated person, and becomes worse when the level of vaccine coverage is low. Nevertheless, estimates of ‘total’, ‘indirect’ and ‘overall’ effectiveness increase with vaccination coverage in the population. Furthermore, we show how the measures of vaccine efficacy and vaccine effectiveness can be correctly calculated.

Conclusions

Typical parameterization of vaccine efficacy in mathematical models may underestimate the actual protective effect of the vaccine, resulting in discordance between the actual effects of vaccination at the population level and predictions made by models. This work shows how models can be correctly parameterized from clinical trial data.     

Direct and indirect effects in a survival context

A cornerstone of epidemiologic research is to understand the causal pathways from an exposure to an outcome. Mediation analysis based on counterfactuals is an important tool when addressing such questions. However, none of the existing techniques for formal mediation analysis can be applied to survival data. This is a severe shortcoming, as many epidemiologic questions can be addressed only with censored survival data. A solution has been to use a number of Cox models (with and without the potential mediator), but this approach does not allow a causal interpretation and is not mathematically consistent. In this paper, we propose a simple measure of mediation in a survival setting. The measure is based on counterfactuals, and measures the natural direct and indirect effects. The method allows a causal interpretation of the mediated effect (in terms of additional cases per unit of time) and is mathematically consistent. The technique is illustrated by analyzing socioeconomic status, work environment, and long-term sickness absence. A detailed implementation guide is included in an online eAppendix (http://links.lww.com/EDE/A476).     

Direct and indirect effects of education on health

In virtually every study by economists considering the determinants of an individual's health, years of schooling has stood out as an important regressor. Yet there is little agreement among economists concerning the mechanisms through which schooling affects health. This study is a first attempt to test for the direct and indirect effects of education on an individual's health. Education is assumed to enhance health directly by, for example, allowing wise use of medical care and indirectly through encouraging healthy habits and caution in the choice of occupation. Evidence from two national surveys indicates that the indirect dominate the direct effects.     

Measuring indirect effects of rotavirus vaccine in low income countries

Widespread introduction of rotavirus vaccines has led to major reductions in the burden of rotavirus gastroenteritis worldwide. Vaccine effectiveness is diminished, however, in low income countries, that harbour the greatest burden of rotavirus attributed morbidity and mortality. Indirect effects of rotavirus vaccine (herd immunity and herd protection) could increase population level impact and improve vaccine cost effectiveness in such settings. While rotavirus vaccine indirect effects have been demonstrated in high and middle income countries, there are very little data from low income countries where force of infection, population structures and vaccine schedules differ. Targeted efforts to evaluate indirect effects of rotavirus vaccine in low income countries are required to understand the total impact of rotavirus vaccine on the global burden of rotavirus disease.     

Direct and indirect cellular effects of aspartame on the brain

The use of the artificial sweetener, aspartame, has long been contemplated and studied by various researchers, and people are concerned about its negative effects. Aspartame is composed of phenylalanine (50%), aspartic acid (40%) and methanol (10%). Phenylalanine plays an important role in neurotransmitter regulation, whereas aspartic acid is also thought to play a role as an excitatory neurotransmitter in the central nervous system. Glutamate, asparagines and glutamine are formed from their precursor, aspartic acid. Methanol, which forms 10% of the broken down product, is converted in the body to formate, which can either be excreted or can give rise to formaldehyde, diketopiperazine (a carcinogen) and a number of other highly toxic derivatives. Previously, it has been reported that consumption of aspartame could cause neurological and behavioural disturbances in sensitive individuals. Headaches, insomnia and seizures are also some of the neurological effects that have been encountered, and these may be accredited to changes in regional brain concentrations of catecholamines, which include norepinephrine, epinephrine and dopamine. The aim of this study was to discuss the direct and indirect cellular effects of aspartame on the brain, and we propose that excessive aspartame ingestion might be involved in the pathogenesis of certain mental disorders (DSM-IV-TR 2000) and also in compromised learning and emotional functioning.     

Direct and indirect effects of a potential aquatic contaminant on grazer-algae interactions

Contaminants have direct, harmful effects across multiple ecological scales, including the individual, the community, and the ecosystem levels. Less, however, is known about how indirect effects of contaminants on consumer physiology or behavior might alter community interactions or ecosystem processes. We examined whether a potential aquatic contaminant, an ionic liquid, can indirectly alter benthic algal biomass and primary production through direct effects on herbivorous snails. Ionic liquids are nonvolatile organic salts being considered as an environmentally friendly potential replacement for volatile organic compounds in industry. In two greenhouse experiments, we factorially crossed four concentrations of 1-N-butyl-3-methylimidazolium bromide (bmimBr; experiment 1: 0 or 10 mg/L; experiment 2: 0, 1, or 100 mg/L) with the presence or absence of the snail Physa acuta in aquatic mesocosms. Experimental results were weighted by their respective control (no bmimBr or P. acuta) and combined for statistical analysis. When both bmimBr and snails were present, chlorophyll a abundance and algal biovolume were higher than would be expected if both factors acted additively. In addition, snail growth rates, relative to those of controls, declined by 41 to 101% at 10 and 100 mg/L of bmimBr. Taken together, these two results suggest that snails were less efficient grazers in the presence of bmimBr, resulting in release of algae from the grazer control. Snails stimulated periphyton primary production in the absence, but not in the presence, of bmimBr, suggesting that bmimBr also can indirectly alter ecosystem function. These findings suggest that sublethal contaminant levels can negatively impact communities and ecosystem processes via complex interactions, and they provide baseline information regarding the potential effects of an emergent industrial chemical on aquatic systems.     

Components of the indirect effect in vaccine trials: identification of contagion and infectiousness effects

Vaccination of one person may prevent the infection of another either because the vaccine prevents the first from being infected and from infecting the second, or because, even if the first person is infected, the vaccine may render the infection less infectious. We might refer to the first of these mechanisms as a contagion effect and the second as an infectiousness effect. In the simple setting of a randomized vaccine trial with households of size two, we use counterfactual theory under interference to provide formal definitions of a contagion effect and an unconditional infectiousness effect. Using ideas analogous to mediation analysis, we show that the indirect effect (the effect of one person's vaccine on another's outcome) can be decomposed into a contagion effect and an unconditional infectiousness effect on the risk difference, risk ratio, odds ratio, and vaccine efficacy scales. We provide identification assumptions for such contagion and unconditional infectiousness effects and describe a simple statistical technique to estimate these effects when they are identified. We also give a sensitivity analysis technique to assess how inferences would change under violations of the identification assumptions. The concepts and results of this paper are illustrated with hypothetical vaccine trial data.     

The impact of indirect benefits of vaccination on postlicensure vaccine effectiveness estimates: A scenario analysis

Vaccine efficacy is measured in randomized, prelicensure clinical trials where vaccination typically affords only direct protection to the vaccinated individual. Vaccine effectiveness is measured in postlicensure observational studies where vaccination might provide indirect benefits to a population as a whole in addition to directly protecting the vaccinated individual. The potential discrepancy in effectiveness and efficacy estimates would depend on the postlicensure study design. We developed a mathematical model to assess the impact of indirect benefits on vaccine effectiveness as measured by the common cohort study design under scenarios of homogenous and heterogenous vaccine allocation. We found that under the cohort design, effectiveness estimates equaled efficacy if either the indirect effects were assumed to be negligible or vaccine allocation in the community was homogenous. However, in presence of indirect benefits, effectiveness estimates would be biased upward compared with vaccine efficacy if one of the two sub-populations in the same study had a higher rate of vaccination. Because of indirect effects of vaccination, even in studies where other biases can be eliminated, the presence of distinct sub-populations with varying rates of vaccination can lead to discrepancies between effectiveness and efficacy estimates.     

Implications and measurement of herd protection (indirect effects) for enteric vaccine development

Diarrhea remains one of the top five causes of disease and death among young children in developing nations. Fortunately, scientists are making progress developing vaccines against enterotoxigenic E. coli (ETEC) and Shigella, two of the leading diarrhea pathogens. As vaccine developers start to consider field efficacy trials of these vaccines, they should be aware of the importance of evaluating not only vaccine direct effects on the immunized, but also the herd effects that vaccination can afford to the unimmunized in a community. In a workshop held at the conference titled “Vaccines against Shigella and ETEC (VASE)”, we described to participants what herd effects are and we presented on methods used in cholera and rotavirus studies that could be useful for future ETEC and Shigella vaccine trials conducted in low and middle-income nations. We also presented evidence on the effects of vaccine herd effects for estimates of vaccine cost-effectiveness.     

Direct and indirect immunofluorescence studies in congestive myocardial diseases

Immunfluorescence examinations were made on 118 patients with congestive cardiomyopathy. Standard techniques of direct immunfluorescence (DIF) were employed on myocardial biopsy material in 61 cases, and of indirect immunfluorescence (IIF) on the serum in 89 cases. On the basis of the assumed aetiologies, the patients were classified into 6 groups: definitely alcoholic, presumably alcoholic, familial, peripartum, chronic myocarditic and idiopathic; studies were then made of the frequencies of pathological immunological processes in the individual groups. The highest incidences of DIF-positive cases were observed in the familial, peripartum, chronic myocarditic and idiopathic groups (67-87%). In the presumably alcoholic group the corresponding incidence was 37%, and in the definitely alcoholic group it was 25%, in contrast with expectations. Interestingly, very strong IIF-positive reactions too were observed in these alcoholic groups. It is possible that, besides the effect of alcohol, the fact that the immune background becomes pathological is also a significant factor in the emergence of the congestive cardiomyopathy in the alcoholic groups.     

Direct and indirect effects of routine vaccination of children with 7-valent pneumococcal conjugate vaccine on incidence of invasive pneumococcal disease--United States, 1998-2003

Streptococcus pneumoniae (pneumococcus) is a leading cause of pneumonia and meningitis in the United States and disproportionately affects young children and the elderly. In 2000, a 7-valent pneumococcal conjugate vaccine (PCV7) was licensed in the United States for routine use in children aged <5 years. Surveillance data from 2001 and 2002 indicated substantial declines in invasive pneumococcal disease (IPD) in children and adults compared with prevaccine years . This report updates assessment of the impact of PCV7 on IPD through 2003 by using population-based data from the Active Bacterial Core surveillance (ABCs) of the Emerging Infections Program Network, a cooperative surveillance program conducted by several state health departments and CDC. The results of this analysis indicated that 1) routine vaccination of young children with PCV7 continued to result in statistically significant declines in incidence of IPD through 2003 in the age group targeted for vaccination and among older children and adults, 2) the vaccine prevented more than twice as many IPD cases in 2003 through indirect effects on pneumococcal transmission (i.e., herd immunity) than through its direct effect of protecting vaccinated children, and 3) increases in disease caused by pneumococcal serotypes not included in the vaccine (i.e., replacement disease) occurred in certain populations but were small compared with overall declines in vaccine-serotype disease. Ongoing surveillance is needed to assess whether reductions in vaccine-serotype IPD are sustained and whether replacement disease will erode the substantial benefits of routine vaccination.     

Varicella breakthrough infection and vaccine effectiveness in Taiwan

We performed this nationwide retrospective investigation among the recipients of varicella vaccine to evaluate the breakthrough varicella infection rate, factors associated with breakthrough infection and the vaccine effectiveness. The recipients of these vaccinations were identified through Taiwan's National Immunization Information System and data on breakthrough infections among these recipients were collected by using Taiwan's National Health Insurance Claims Database. From 2000 to 2007, 1,057,345 persons received varicella vaccinations in Taiwan. Varicella breakthrough infection occurred among 22,640 (2.1%) vaccinees and 170 (0.016%) required hospitalization for varicella disease. Annual breakthrough infection rates ranged from 0.12% to 2.04%. The mean age of vaccination was 1.6 years (median 1.3 years) and the mean age at breakthrough infection was 3.9 years. The mean interval between vaccination and the breakthrough infection was 2.3 years. The rate was significantly lower in regions where free varicella vaccinations were available than in regions where they were not (P < 0.001). Varicella breakthrough infection was significantly more likely to occur at 5 and 6 years of age among the vaccinees, who received vaccination between 12 months and 23 months of age (P < 0.001). The vaccine effectiveness against varicella was 82.6% and against varicella-related hospitalization was 85.4% from 2000 to 2005.     

Cost effectiveness analysis of heptavalent pneumococcal conjugate vaccine in Germany considering herd immunity effects

Background  In Germany the heptavalent pneumococcal conjugate vaccine (PCV7) has been recommended as a general infant vaccination since 2006. Data from similar programmes in the USA have reported a reduction of pneumococcal diseases in both vaccinated and unvaccinated populations, suggesting herd immunity effects. This study analyses the cost-effectiveness of a general vaccination with PCV7 in Germany based on these findings. Methods  A Markov model adapts efficacy and herd immunity data to the German population. Further main model inputs are incidence, vaccination uptake, serotype distribution, case fatality rates, and vaccination and health-care costs. Results  A general vaccination with PCV7 would avoid about 232,000 pneumococcal infections and 1,879 premature deaths per year in Germany. From the health-care payer's perspective, direct cost savings would outweigh vaccination expenditures by a ratio of 1:1.16. The sensitivity analysis shows that these estimates are quite conservative. Conclusion  Based on the health-economic evaluation, the authors recommend the continuation of the general recommendation of PCV7 according to the 3 + 1 schedule within the German Statutory Health Insurance.     

Protective effectiveness of hantavirus vaccine

A case-control study in the Republic of Korea evaluated the protective effectiveness of the hantavirus vaccine. Point estimates showed increasing effectiveness with increasing numbers of doses received: 25% for one dose, 46% for two doses, and 75% for three doses. All 95% confidence intervals overlapped zero; therefore, the findings could be due to chance.