Ac Ghani

Determination of the Processes Driving the Acquisition of Immunity to Malaria Using a Mathematical Transmission Model

Acquisition of partially protective immunity is a dominant feature of the epidemiology of malaria among exposed individuals. The processes that determine the acquisition of immunity to clinical disease and to asymptomatic carriage of malaria parasites are poorly understood, in part because of a lack of validated immunological markers of protection. Using mathematical models, we seek to better understand the processes that determine observed epidemiological patterns. We have developed an age-structured mathematical model of malaria transmission in which acquired immunity can act in three ways (“immunity functions”): reducing the probability of clinical disease, speeding the clearance of parasites, and increasing tolerance to subpatent infections. Each immunity function was allowed to vary in efficacy depending on both age and malaria transmission intensity. The results were compared to age patterns of parasite prevalence and clinical disease in endemic settings in northeastern Tanzania and The Gambia. Two types of immune function were required to reproduce the epidemiological age-prevalence curves seen in the empirical data; a form of clinical immunity that reduces susceptibility to clinical disease and develops with age and exposure (with half-life of the order of five years or more) and a form of anti-parasite immunity which results in more rapid clearance of parasitaemia, is acquired later in life and is longer lasting (half-life of >20 y). The development of anti-parasite immunity better reproduced observed epidemiological patterns if it was dominated by age-dependent physiological processes rather than by the magnitude of exposure (provided some exposure occurs). Tolerance to subpatent infections was not required to explain the empirical data. The model comprising immunity to clinical disease which develops early in life and is exposure-dependent, and anti-parasite immunity which develops later in life and is not dependent on the magnitude of exposure, appears to best reproduce the pattern of parasite prevalence and clinical disease by age in different malaria transmission settings. Understanding the effector mechanisms underlying these two immune functions will assist in the design of transmission-reducing interventions against malaria.

Identification of individuals with gonorrhoea within sexual networks: a population-based study

BACKGROUNDnMolecular typing of Neisseria gonorrhoeae and contact tracing provide a combined approach for analysis of sexual networks in metropolitan areas, although there are some difficulties in application. Our aim was to examine the application of high-throughput molecular approaches that can identify individuals in linked sexual networks.nnnMETHODSnWe characterised 2045 isolates of N gonorrhoeae from patients presenting at 13 major sexually transmitted infection clinics in London, UK, between June 1 and Nov 30, 2004. All isolates were assigned a sequence type (strain) on the basis of the sequences of internal fragments of two highly polymorphic loci, por and tbpB. These types were matched to demographic and behavioural data obtained at the clinic for each patient. We assessed the congruence in the demographic and behavioural characteristics of individuals infected with the same strain.nnnFINDINGSnWe identified 21 prevalent strains in this diverse gonococcal population, each infecting between 20 and 124 individuals. Seven of these strains were predominantly from men who have sex with men; the remaining 14 were predominantly from heterosexual people. No differences were recorded between the strains associated with men who have sex with men in the demographic or behavioural characteristics of infected individuals. By contrast, significant differences in age (p<0.0001), ethnicity (p=0.001), proportion of women (p=0.01), and HIV status (p=0.03) were noted between the 14 prevalent heterosexual-associated strains. Heterosexuals with strains not shared by others in the sample were significantly older (p=0.0005) and more likely to have had sex outside the UK (p<0.0001) than those sharing a strain with at least one other.nnnINTERPRETATIONnThe discriminatory high throughput strain characterisation method applied here identified localised transmission networks and suggests little bridging between networks of men who have sex with men and heterosexual networks.

Developing a realistic sexual network model of chlamydia transmission in Britain

BackgroundA national chlamydia screening programme is currently being rolled out in the UK and other countries. However, much of the epidemiology remains poorly understood. In this paper we present a stochastic, individual based, dynamic sexual network model of chlamydia transmission and its parameterisation. Mathematical models provide a theoretical framework for understanding the key epidemiological features of chlamydia: sexual behaviour, health care seeking and transmission dynamics.ResultsThe model parameters were estimated either directly or by systematic fitting to a variety of appropriate data sources. The fitted model was representative of sexual behaviour, chlamydia epidemiology and health care use in England. We were able to recapture the observed age distribution of chlamydia prevalence.ConclusionEstimating parameters for models of sexual behaviour and transmission of chlamydia is complex. Most of the parameter values are highly correlated, highly variable and there is little empirical evidence to inform estimates. We used a novel approach to estimate the rate of active treatment seeking, by combining data sources, which improved the credibility of the model results. The model structure is flexible and is broadly applicable to other developed world settings and provides a practical tool for public health decision makers.

Reduction of the HIV-1-infected T-cell reservoir by immune activation treatment is dose-dependent and restricted by the potency of antiretroviral drugs.

BackgroundTreatments combining T-cell activating agents and potent antiretroviral drugs have been proposed as a possible means of reducing the reservoir of long-lived HIV-1 infected quiescent CD4 T-cells. ObjectiveTo analyse the effect of such therapies on HIV-1 dynamics and T-cell homeostasis. Design and methodsA mathematical framework describing HIV-1 dynamics and T-cell homeostasis was developed. Three patients who were kept on a particularly potent course of highly active antiretroviral therapy (HAART) were treated with the anti-CD3 monoclonal antibody OKT3 and interleukin (IL)-2. Plasma HIV-RNA, and HIV-RNA and DNA in peripheral blood mononuclear cells and lymph node mononuclear cells were measured. These results and other published studies on the use of IL-2 alone were assessed using our mathematical framework. ResultsWe show that outcome of treatment is determined by the relative rates of depletion of the infected quiescent T-cell population by activation and of its replenishment through new infection. Which of these two processes dominates is critically dependent on both the potency of HAART and also the degree of T-cell activation induced. We demonstrate that high-level T-cell stimulation is likely to produce negative outcomes, both by failing to reduce viral reservoirs and by depleting the CD4 T-cell pool and disrupting CD4/CD8 T-cell homeostasis. In contrast, repeated low-level stimulation may both aid CD4 T-cell pool expansion and achieve a substantial reduction in the long-lived HIV-1 reservoir. ConclusionsOur analysis suggests that although treatment that activates T-cells can reduce the long-lived HIV-1 reservoir, caution should be used as high-level stimulation may result in a negative outcome.

The Transmissibility of Highly Pathogenic Avian Influenza in Commercial Poultry in Industrialised Countries

Background With the increased occurrence of outbreaks of H5N1 worldwide there is concern that the virus could enter commercial poultry farms with severe economic consequences. Methodology/Principal Findings We analyse data from four recent outbreaks of highly pathogenic avian influenza (HPAI) in commercial poultry to estimate the farm-to-farm reproductive number for HPAI. The reproductive number is a key measure of the transmissibility of HPAI at the farm level because it can be used to evaluate the effectiveness of the control measures. In these outbreaks the mean farm-to-farm reproductive number prior to controls ranged from 1.1 to 2.4, with the maximum farm-based reproductive number in the range 2.2 to 3.2. Enhanced bio-security, movement restrictions and prompt isolation of the infected farms in all four outbreaks substantially reduced the reproductive number, but it remained close to the threshold value 1 necessary to ensure the disease will be eradicated. Conclusions/Significance Our results show that depending on the particular situation in which an outbreak of avian influenza occurs, current controls might not be enough to eradicate the disease, and therefore a close monitoring of the outbreak is required. The method we used for estimating the reproductive number is straightforward to implement and can be used in real-time. It therefore can be a useful tool to inform policy decisions.

SARS-CoV antibody prevalence in all Hong Kong patient contacts.

A total of 1,068 asymptomatic close contacts of patients with severe acute respiratory (SARS) from the 2003 epidemic in Hong Kong were serologically tested, and 2 (0.19%) were positive for SARS coronavirus immunoglobulin G antibody. SARS rarely manifests as a subclinical infection, and at present, wild animal species are the only important natural reservoirs of the virus.

Investigating ethnic inequalities in the incidence of sexually transmitted infections: mathematical modelling study

Objectives: To investigate ethnic differences in rates of gonorrhoea using empirical sexual behaviour data in a simple mathematical model. To explore the impact of different intervention strategies in this simulated population. Methods: The findings from cross sectional studies of gonorrhoea rates and sexual behaviour in three ethnic groups in south east London were used to determine the parameters for a deterministic, mathematical model of gonorrhoea transmission dynamics, in a population stratified by sex, sexual activity (rate of partner change), and ethnic group (white, black African, and black Caribbean). We compared predicted and observed rates of infection and simulated the effects of targeted and population-wide intervention strategies. Results: In model simulations the reported sexual behaviours and mixing patterns generated major differences in the rates of gonorrhoea experienced by each subpopulation. The fit of the model to observed data was sensitive to assumptions about the degree of mixing by level of sexual activity, the numbers of sexual partnerships reported by men and women, and the degree to which observed data underestimate female infection rates. Interventions to reduce duration of infection were most effective when targeted at black Caribbeans. Conclusions: Average measures of sexual behaviour in large populations are inadequate descriptors for the epidemiology of gonorrhoea. The consistency between the model results and empirical data shows that profound differences in gonorrhoea rates between ethnic groups can be explained by modest differences in a limited number of sexual behaviours and mixing patterns. Targeting effective services to particular ethnic groups can have a disproportionate influence on disease reduction in the whole community.

Surrogate markers for disease progression in treated HIV infection

Objective: To characterize the relationships among highly active antiretroviral therapy (HAART), HIV‐1 RNA levels, immune system markers, and clinical outcome in a cohort of HIV‐1‐infected homosexual men. Patients: A total of 123 men enrolled in the Amsterdam cohort study of HIV‐1 infection and AIDS with a documented seroconversion for HIV‐1 antibodies and known date of seroconversion were included in this study. Methods: CD4+/CD8+ T‐cell counts and HIV‐1 RNA levels in plasma were measured approximately every 6 months. Dates of starting and stopping antiretroviral therapy were also recorded. The relationship between HIV‐1 RNA in plasma, CD4+/CD8+ T‐cell counts and HAART and their influence on clinical outcome were examined using a graphical chain modeling approach. Generalized estimating equations were used to examine correlations among the three disease markers. Hazards models with time‐dependent covariates were used to examine the influence of HAART and the disease markers on progression to AIDS. Results: HAART was significantly associated with reduced disease progression (relative hazard [RH] of AIDS, 0.20;, 95% confidence interval [CI], 0.05‐0.85). The most recent HIV‐1 RNA measurement and CD4+ T‐cell count are independently associated with disease progression (adjusted RH for HIV‐1 RNA 1.8 per log10 increase; 95% CI, 1.2‐2.6, p = .002; adjusted RH for CD4+ 0.48 per 100 × 106/L increase; 95% CI, 0.40‐0.58; p <.001). Depending on these measurements, HAART was no longer significantly associated with AIDS (adjusted RH, 0.81; 95% CI, 0.18‐3.6; p = .78). Conclusions: HIV‐1 RNA levels in plasma and CD4+ T‐cell counts are currently considered as effective surrogate markers for the effect of HAART on disease progression in this cohort.

Seroprevalence of IgG antibodies to SARS-coronavirus in asymptomatic or subclinical population groups

We systematically reviewed the current understanding of human population immunity against SARS-CoV in different groups, settings and geography. Our meta-analysis, which included all identified studies except those on wild animal handlers, yielded an overall seroprevalence of 0.10% [95% confidence interval (CI) 0.02-0.18]. Health-care workers and others who had close contact with SARS patients had a slightly higher degree of seroconversion (0.23%, 95% CI 0.02-0.45) compared to healthy blood donors, others from the general community or non-SARS patients recruited from the health-care setting (0.16%, 95% CI 0-0.37). When analysed by the two broad classes of testing procedures, it is clear that serial confirmatory test protocols resulted in a much lower estimate (0.050%, 95% CI 0-0.15) than single test protocols (0.20%, 95% CI 0.06-0.34). Potential epidemiological and laboratory pitfalls are also discussed as they may give rise to false or inconsistent results in measuring the seroprevalence of IgG antibodies to SARS-CoV.