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Despite the existence of an impressive body of work on human immune responses against ¢larial infections, the occurrence of a protective response to infection remains unclear. Here, we use a combined modelling and comparative data analysis framework to address this issue for human infections with the ¢larial parasite, Wuchereria bancrofti. By analogy with previous work, the analysis involves the comparison of observed ¢eld patterns of infection with epidemiological patterns predicted by a mathematical model of parasite immunity. Unlike most other human helminths, which are transmitted by ingestion or dermal penetration, exposure to infection with lymphatic ¢lariasis can be measured explicitly in terms of vector mosquito biting rates, thereby also allowing, probably for the ¢rst time, examination of the suggested role of exposure in generating herd immunity to macroparasites. Observed ¢eld patterns in this study were derived from 19 di¡erent published studies, which gave parallel estimates of community exposure rates and the corresponding age^prevalence patterns of infection, while predictions of the epidemiological impact of herd immunity were obtained using a catalytic model framework. The results provide the ¢rst conclusive evidence to date that variations in the observed age^prevalence patterns of infection in ¢lar-iasis can be e¡ectively explained by the occurrence of an exposure-driven acquisition of herd immunity. We discuss this result in terms of implications for the new World Health Organization-led initiative for the global control of this parasitic disease.

Abstract. A major debate in infectious disease epidemiology concerns the relative importance of exposure and host factors, such as sex and acquired immunity, in determining observed age patterns of parasitic infection in endemic communities. Nonhomogeneous contact between hosts and vectors is also expected to increase the reproductive rate, and hence transmission, of mosquito-borne infections. Resolution of these questions for human parasitic diseases has been frustrated by the lack of a quantitative tool for quantifying the exposure rate of people in communities. Here, we show that the polymerase chain reaction (PCR) technique for amplifying and fingerprinting human DNA from mosquito bloodmeals can address this problem for mosquito-borne diseases. Analysis of parallel human and mosquito (resting Culex quinquefasciatus) samples from the same households in an urban endemic focus for bancroftian filariasis in South India demonstrates that a 9-locus radioactive short-tandem repeat system is able to identify the source of human DNA within the bloodmeals of nearly 80% of mosquitoes. The results show that a person's exposure rate, and hence the age and sex patterns of exposure to bites in an endemic community, can be successfully quantified by this method. Out of 276 bloodmeal PCR fingerprints, we also found that on average, 27% of the mosquitoes caught resting within individual households had fed on people outside the household. Additionally, 13% of mosquitoes biting within households contained blood from at least 2 people, with the rate of multiple feeding depending on the density of humans in the household. These complex vector feeding behaviors may partly account for the discrepancies in estimates of the infection rates of mosquito-borne diseases calculated parasitologically and entomologically, and they underline the potential of this tool for investigating the transmission dynamics of infection.

A striking feature of lymphatic filariasis is the considerable heterogeneity in infection burden observed between hosts, which greatly complicates the analysis of the population dynamics of the disease. Here, we describe the first application of the moment closure equation approach to model the sources and the impact of this heterogeneity for macrofilarial population dynamics. The analysis is based on the closest laboratory equivalent of the life cycle and immunology of infection in humans--cats chronically infected with the filarial nematode Brugia pahangi. Two sets of long-term experiments are analysed: hosts given either single primary infections or given repeat infections. We begin by quantifying changes in the mean and aggregation of adult parasites (inversely measured by the negative binomial parameter, kappa in cohorts of hosts using generalized linear models. We then apply simple stochastic models to interpret observed patterns. The models and empirical data indicate that parasite aggregation tracks the decline in the mean burden with host age in primary infections. Conversely, in repeat infections, aggregation increases as the worm burden declines with experience of infection. The results show that the primary infection variability is consistent with heterogeneities in parasite survival between hosts. By contrast, the models indicate that the reduction in parasite variability with time in repeat infections is most likely due to the 'filtering' effect of a strong, acquired immune response, which gradually acts to remove the initial variability generated by heterogeneities in larval mortality. We discuss this result in terms of the homogenizing effect of host immunity-driven density-dependence on macrofilarial burden in older hosts.

A total of 946 families with 2302 children was surveyed for microfilaraemia due to Wuchereria bancrofti. The prevalence of microfilaraemia among offspring born to microfilaraemic parents was significantly higher than in those born to amicrofilaraemic parents (P = 0.0049; relative risk = 3.40). However, there was no statistically significant difference between the prevalence of microfilaraemia in children born to microfilaraemic mothers or microfilaraemic fathers, suggesting that parental (not only maternal) infection is the important risk factor, and it may be exposure within the household which is important. Logistic regression analyses also confirmed that the risk of infection for offspring born to either microfilaraemic mothers or microfilaraemic fathers was higher than that for offspring born to amicrofilaraemic parents and indicated that infection in children < or = 20 years old was primarily dependent on parental infection status and minimally influenced by factors other than household exposure.

The effect of seasonal transmission on microfilaraemia, antigenaemia and filarial-specific antibody levels in individuals infected with Wuchereria bancrofti was investigated in a follow-up study in an endemic community in north-eastern Tanzania. The subjects were 37 adult male residents who were found to be positive for circulating filarial antigen (CFA) at the beginning of the study (26 of whom were also found microfilaraemic with W. bancrofti at this time). Blood samples were collected from each subject in July 1998, January 1999 and July 1999, during the seasons when transmission intensity was high, low and high, respectively. The mean intensities of microfilaraemia and the mean concentrations of CFA were each slightly higher during the low-transmission season than during the two high-transmission seasons but the differences were not statistically significant (P > 0.05). Similarly, the mean levels of filarial-specific IgG1, IgG2, IgG3, IgG4 or IgE did not differ to a statistically significant degree between the three examination times. Microfilaraemias and the levels of CFA and filarial-specific antibodies all therefore appeared to be remarkably stable and largely unaffected by the seasonal variation in transmission. That no variation in the mean IgG4/IgE ratio was observed over the study period may indicate that the level of resistance to W. bancrofti infection in the study subjects was also unaffected by the transmission season.

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