Biomedical subjects
Publications and source records attributed to M E Woolhouse.
A comprehensive analysis of the bovine spongiform encephalopathy (BSE) epidemic in cattle in Great Britain assesses past, present and future patterns in the incidence of infection and disease, and allows a critical appraisal of different culling policies for eradication of the disease.
Ebert (1994) has proposed the rule that parasites are, with few exceptions, more infective to sympatric hosts than to allopatric hosts. We test this rule using field data for schistosome infections of planorbid snails and find that, although sympatric parasite-host combinations do tend to be more compatible, there are exceptions where particular allopatric parasite-host populations are significantly more compatible. We develop a mathematical model of the dynamics of the parasite-host interaction where parasite infectivity and host susceptibility are defined by the matching of genotypes in a diploid system, The model predicts dynamic polymorphisms where parasite allele frequencies track host allele frequencies but with a lag. Because of this lag, it is possible for allopatric combinations to be more compatible than sympatric combinations. Any 'rule' that precludes this possibility is unlikely to prove robust.
A cross-sectional parasitological study of a population of wild olive baboons (Papio cynocephalus anubis), consisting of 5 troops, was conducted in Gombe Stream National Park. Baboons were individually recognizable. Information on age, sex, troop membership, reproductive status, social rank and life-history of each individual baboon could be related to parasite infection. Seven helminth taxa and 2 protozoan taxa were found. All baboons were parasitized by at least 1 taxon. Distributions of helminths were aggregated among hosts. There were significant differences among troops in the prevalence of all but 2 of the recorded helminths. Age had a significant impact on the prevalence and intensity of Strongyloides sp. No significant effect of sex on the prevalence of infection could be detected. There was some indication that female reproductive status was related to Trichuris egg output. In contrast to a previous study, no significant correlations between parasite infection and social rank could be found. Troop membership constituted the predominant factor contributing to heterogeneity of prevalence of infection. This suggests that spatial location and/or genetics may be important in determining levels of parasite infection.
Outbreaks of foot-and-mouth disease persist in dairy cattle herds in Saudi Arabia despite revaccination at intervals of 4-6 months. Vaccine trials provide data on antibody responses following vaccination. Using this information we developed a mathematical model of the decay of protective antibodies with which we estimated the fraction of susceptible animals at a given time after vaccination. The model describes the data well, suggesting over 95% take with an antibody half-life of 43 days. Farm records provided data on the time course of five outbreaks. We applied a 'SLIR' epidemiological model to these data, fitting a single parameter representing disease transmission rate. The analysis provides estimates of the basic reproduction number R(0), which may exceed 70 in some cases. We conclude that the critical intervaccination interval which would provide herd immunity against FMDV is unrealistically short, especially for heterologous challenge. We suggest that it may not be possible to prevent foot-and-mouth disease outbreaks on these farms using currently available vaccines.
Existing estimates of the basic reproduction number, Ro, for human schistosomes are mostly in the range 1-4, implying that schistosomes should be relatively easy to eliminate from endemic areas, which is contrary to practical experience. An estimate of Ro for a site in Zimbabwe is obtained here using a mathematical model explicitly incorporating two features believed to be epidemiologically significant; age-dependent exposure and acquired immunity. Parameter estimates are, as far as possible, obtained independently, but the coefficients representing man-snail and snail-man transmission, as well as parameters representing effects of acquired immunity, must be estimated indirectly by fitting the model to field data. Heterogeneity in human exposure and contamination is crudely incorporated by considering "wormy' and non-wormy' fractions of the population. The results suggest Ro to be in the range 4-5 or more, higher than previous estimates and despite only moderate levels of infection at this site. It is shown that this estimate is sensitive to the form of the underlying model. The application of less realistic models may lead to less reliable estimates of Ro.
A simulation model of African horse sickness in Spain was developed to investigate what factors affect the likelihood of an epidemic after the introduction of the virus. The model included 2 host species (horses and donkeys) and 1 vector species (Culicoides imicola Kieffer). Latin hypercube sampling was used for sensitivity analysis of the model, to include uncertainty in parameter estimates. In general, if an epidemic occurred most hosts were infected. The peak prevalence in midges was low, and never exceeded 3%. Midge population size, the recovery rate in horses, and the time of year when the virus was introduced were the most significant factors in determining whether or not an epidemic occurred. The uncertainty in interbloodmeal interval, removal rate (mortality and recovery) of infectious horses, midge population size, and transmission rates were significant factors in the size of the epidemic. These factors should be priorities for empirical research, and should be considered in the design of control strategies in areas at risk of virus introduction.
The basic reproduction number, R0, can be used to determine factors important in the ability of a disease to invade or persist. We show how this number can be derived or estimated for vector-borne diseases with different complicating factors. African horse sickness is a viral disease transmitted mainly by the midge Culicoides imicola. We use this as an example of such a vector-transmitted disease where latent periods, seasonality in vector populations, and multiple host types may be important. The effect of vector population dynamics which are dependent on either host or vector density are also addressed. If density-dependent constraints on vector population density are less severe, R0 is more sensitive to vector mortality and the virus development rate. Host-dependent vector dynamics change the relationship between R0 and host population size. Seasonality can either increase or decrease the estimate of R0, depending on the lag between the peak of the midge population and the infective host population. The relative abundance of two host types is a factor in the ability of a disease to invade, but the strength of this factor depends on the differences between the hosts in recovery from infection, mortality and transmission. Removal of a reservoir host may increase R0.
Over 10 000 Glossina pallidipes tsetse flies were collected during two field studies in the Zambezi Valley, Zimbabwe and one in the Luangwa Valley, Zambia. These were screened for mature trypanosome infections and 234 dot-blot preparations were made of infected midguts, which were screened using DNA probes or PCR with primers specific to different species or types of the trypanosome subgenus Nannomonas. Over 70% of midgut infections were successfully identified as either Trypanosoma godfreyi, T. simiae or three types of T. congolense, savannah, riverine-forest and Kilifi. The relative abundance of species and types did not vary significantly between study locations, habitat, season or tsetse age or sex, although there were differences between DNA probe and PCR results. Mixed species and/or mixed type infections were common and were more often detected using PCR. The distribution of infections among flies was highly aggregated, but there was no tendency for multiple infections to accumulate in older flies, implying that sequential superinfection may be uncommon. Possible explanations for these patterns are discussed.
Mathematical models are potentially valuable aids to a quantitative understanding of schistosome epidemiology and to the design of control programs. A basic theoretical framework is described that is developed to incorporate the impact of acquired immunity, heterogeneous transmission rates, and the effects of control measures. Models that assume that acquired immunity acts to moderate the rate of human infection make predictions consistent with age-intensity data from different human populations. Models incorporating heterogeneous water contact behavior can be applied to suitable field data and used to predict the potential efficacy of targeted chemotherapy or focal molluscicide application. More complex and detailed models can be used in simulation studies to assist with the design of field trials and in the interpretation of data from these trials. These applications of mathematical models suggest several areas requiring further theoretical development and also indicate areas in which adequate field data are still lacking.
Populations of Bulinus globosus were sampled from two rivers, 60 km apart, in northern Zimbabwe, and offspring from each geographic strain reared in the laboratory. Schistosomes were harvested from each strain and also maintained in the laboratory. Cross-infection experiments were conducted, whereby snails of both geographic strains were exposed to parasites of both geographic strains. Compatibility was found to be related to: (i) the geographic origin of the snail, and (ii) an interaction between the geographic origin of snail and parasite, such that sympatric combinations of snails and parasites produced a greater proportion of compatible infections than allopatric combinations. Cercarial output of infected snails was found to be related to the geographic origin of the parasite, but not of that of the snail. It is suggested that, as the snails used were laboratory bred and naive to schistosome infection, differences in snail-schistosome compatibility were genetically determined, rather than an adaptive response. This study supports earlier work which suggests the existence of geographic compatibility amongst natural populations of snails and trematodes, indicative of either increased infectivity by the parasite, or decreased resistance by the snail.
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The potential outcomes of a Phase II schistosomiasis vaccine trial are explored using mathematical models which assume some natural immunity and a vaccine providing partial protection for a limited time. Analyses suggest that vaccination may have only a limited impact on life-long cumulative worm burdens and may lead to increased susceptibility and higher worm burdens at some ages, a "rebound" effect which results reduced opportunity to acquire natural immunity. There is a trade-off between the degree and duration of vaccine-induced protection; long-lived vaccines may be preferable to vaccines giving greater protection but for a shorter time.
In this paper we describe the relationship between antibodies to Necator americanus stage-specific antigens and parasite burden in an endemically-infected population in Papua New Guinea. Using an age-structured analysis, we show that the correlation coefficient between levels of IgG against adult worm excretory-secretory (ES) antigen and parasite burden declined significantly with host age from positive in younger hosts to significantly negative in older hosts. A trend towards similar patterns was present for anti-larval IgG both pretreatment and after reinfection, and for anti-ES IgM and anti-ES IgE pretreatment. These patterns are consistent with a role for these isotypes in a protective immune response, although parasite-induced immunosuppression may provide an alternate explanation. This is another demonstration of possibly protective responses to N. americanus infection.
Trypanosome infections of Glossina pallidipes were investigated at a site in the Luangwa Valley, Zambia between June 1991 and September 1992. Almost 3700 flies were captured, dissected, screened for trypanosome infection, and aged using both wing fray and (for females) ovarian categories. DNA probes were used to identify midgut infections. Prevalences of mature infections were 6.2% Trypanosoma vivax-type and 3.1% T. congolense-type (including low prevalances of T. brucei, T. simiae and another Nannomonas species). The prevalence of infection increased with age. For both types of infection this relationship could be described by a simple 'catalytic' model which generates estimates of per capita rates of infection. Prevalences varied significantly with time independently of any changes in the age structure of the tsetse population. This may reflect temporal variation in the per capita rates of infection.
Much is known about human immune responses to schistosome infection, but it has proved difficult to determine the impact of these responses on schistosome epidemiology in the field. In this paper, Mark Woolhouse compares epidemiological patterns from field data with the predictions o f simple mathematical models of different immunological processes. The comparison gives some indications as to which types of immune response may be important, and of their strength and duration. The results are consistent with a significant impact of a process similar to 'concomitant' immunity, with a possible role for anti-fecundity effects.
Epidemiological evidence is widely cited in support of the hypothesis that certain antibody responses to human helminth, especially schistosome, infection exhibit blocking activity. This evidence includes positive correlations between antibody levels and the rate of re-establishment of infection following chemotherapy, antibody levels which peak in younger and more susceptible age classes, lower ratios of blocking antibodies to others in older and less susceptible age classes. In this paper simple mathematical models are used to explore expected age-specific relationships between antibody levels, parasite burdens and re-establishment rates for different combinations of protective, neutral and blocking immune responses. In general, all the above cited patterns may be generated without invoking blocking activity, especially if the abilities to produce different antibody responses have different immunological memories, i.e. persist for different lengths of time in the absence of continued exposure to antigen. None of these patterns, including a positive correlation between antibody levels and rates of re-establishment following chemotherapy, offers unambiguous evidence for blocking activity. Blocking activity is also predicted to affect the shape of the age-intensity curve and the relationship between susceptibility to infection and age in ways which are not necessarily consistent with the epidemiological evidence. The importance of the blocking activity, which has been convincingly demonstrated in vitro, to population level immunoepidemiological patterns in the field therefore remains uncertain.
A simulation study is used to examine the statistical behaviour of estimators of parameters of parasite infection in relation to variation in sample size, the degree of parasite aggregation, and mean parasite burden. The most important patterns to emerge are the associations between estimates of parameters and sample size (= number of host individuals). As sample size decreases values of sample mean parasite burden, its associated variance, and the level of parasite aggregation are all systematically underestimated. The geometric mean of parasite burden and the prevalence of infection appear to be independent of associations with other parasite parameters. Estimates of parameter values may also depend on the underlying frequency distribution, but appear insensitive to variation in the population mean parasite burden. Results are discussed in relation to the interpretation of data derived from field-based studies. In particular, establishing the form of the relationship between host age and mean parasite burden and/or the degree of parasite aggregation. It is typical for sample size to decline as a function of host age within cross-sectional field data. This may give rise to artefactual patterns in the shape of age-aggregation curves in which sample sizes are unequal among host age classes.
The negative binomial distribution (NBD) is widely used to describe the distribution of parasitic helminths in a number of host individuals and has proved a useful, though possibly overused, empirical and theoretical device. It is therefore important that the limits to the applicability of the NBD be clearly defined. In this paper, Alan Grafen and Mark Woolhouse consider applications of the NBD in situations where either the host or parasite population can be divided into subpopulations of different types (eg. by age, sex or genotype), and they describe the relationships between the frequency distributions relevant to the different subpopulations and those relevant to the total population.