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Biomedical subjects

A R McLean

Publications and source records attributed to A R McLean.

At least 19 recordsLinked to original sources
PubMed1998

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.

Animals↗
PubMed1997

Resource competition as a mechanism for B cell homeostasis.

Cellular competition for survival signals offers a cogent and appealing mechanism for the maintenance of cellular homeostasis [Raff, M. C. (1992) Nature (London) 356, 397-400]. We present a theoretical and experimental investigation of the role of competition for resources in the regulation of peripheral B cell numbers. We use formal ecological competition theory, mathematical models of interspecific competition, and competitive repopulation experiments to show that B cells must compete to persist in the periphery and that antigen forms a part of the resources over which B cells compete.

Animals↗
PubMed1997

AIDS: decline and fall of immune surveillance?

Recent observations cast doubt on the view that cytotoxic T cells play a key role in keeping HIV-1 infection in check, and that it is the decline in this mechanism of immune surveillance that permits progression to AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Vaccination, evolution and changes in the efficacy of vaccines: a theoretical framework.

The evolution of vaccine-resistant strains of infectious agents is potentially a huge problem for their control by immunization. Yet, for many infectious diseases, it has been possible to drive them to the verge of extinction without vaccine escape mutants arising. This paper establishes a theoretical framework within which to ask why this should be so, what properties of vaccines allow this situation and what might happen in situations where vaccine escape mutants do arise.

Child↗
PubMed1995

Modelling HIV vaccination.

Relatively recently, mathematical models have been applied to issues r elated to HIV vaccination. Significant progress has been made towards understanding how rather ineffective vaccines will perform in trials and in the community, but some areas still need research.

AIDS Vaccines↗
PubMed1995

The regulation of malaria parasitaemia: parameter estimates for a population model.

Classical studies of non-immune individuals infected with Plasmodium falciparum reveal that the infection may be regulated for long periods at a relatively stable parasite density, despite the enormous growth potential of a parasite that continually replicates within host erythrocytes. This suggests that the parasite population may be controlled by density-dependent mechanisms, and in theory the most obvious of these is competition between parasites for host erythrocytes. Here we evaluate the role of this mechanism in the regulation of parasitaemia, by modelling the basic population interaction between parasites and erythrocytes in a form that allows all the essential parameters to be estimated from clinical data. Our results show that competition cannot account for the total regulation of P. falciparum, but when combined with immune mechanisms it may play a more important role than is generally supposed. Further analysis of the model indicates that in the long term, parasite replication at low parasite densities can contribute significantly to the high degree of anaemia observed in natural infection, a conclusion which is not obvious from simple clinical observation.

Anemia↗
PubMed1995

The intrinsic transmission dynamics of tuberculosis epidemics.

In developed countries the major tuberculosis epidemics declined long before the disease became curable in the 1940s. We present a theoretical framework for assessing the intrinsic transmission dynamics of tuberculosis. We demonstrate that it takes one to several hundred years for a tuberculosis epidemic to rise, fall and reach a stable endemic level. Our results suggest that some of the decline of tuberculosis is simply due to the natural behaviour of an epidemic. Although other factors must also have contributed to the decline, these causal factors were constrained to operate within the slow response time dictated by the intrinsic dynamics.

Disease Outbreaks↗
PubMed1994

Modelling T cell memory.

A new mathematical model of T helper-cell activation and proliferation is investigated. The model incorporates recent data and theories about memory T cells. It accounts for the interacting population dynamics of resting, activated and memory T helper cells, interleukin 2 and replicating antigen, and is able to mimic a broad range of available data on T helper-cell proliferation and the effects of interleukin 2. The model is tested against existing in vitro data. It is then used to make novel interpretations of some recent experimental findings and predictions about the outcome of further experiments. Predictions made by the model fall into three groups concerning persistent infections, cell transfer experiments, and the return of memory cells to the resting state. The model predicts the existence of a group of persistent infections which result from slow growing replicating antigens and can be cleared by a boosting dose of antigen. A threshold is derived for the number of cells that must be transferred in order to transfer long-term immune memory from one animal to another. The existence of such a threshold implies that when small numbers of cells are transferred, or the transferred cells are in the resting state, cells alone cannot confer long-term memory on a recipient animal. However, if enough activated cells are transferred, it is possible to transfer long-term immune memory without antigen. The biological significance of a pathway whereby memory cells can lose their phenotypic and functional differences to return to the resting state is studied. A threshold concerning the rate of that return is derived; and it is only if the rate of return is above that threshold is there any impact on the response to a replicating antigen.

Animals↗
PubMed1994

Prophylactic vaccines, risk behavior change, and the probability of eradicating HIV in San Francisco.

Theory is linked with data to assess the probability of eradicating human immunodeficiency virus (HIV) in San Francisco through the use of prophylactic vaccines. The necessary vaccine efficacy levels and population coverage levels for eradication are quantified. The likely impact of risk behavior changes on vaccination campaigns is assessed. The results show it is unlikely that vaccines will be able to eradicate HIV in San Francisco unless they are combined with considerable reductions in risk behaviors. Furthermore, if risk behavior increases as the result of a vaccination campaign, then vaccination could result in a perverse outcome by increasing the severity of the epidemic.

AIDS Vaccines↗
PubMed1994

Modelling the impact of mass vaccination against hepatitis B. I. Model formulation and parameter estimation.

A new model of the transmission dynamics of hepatitis B virus in countries with high transmission rates is presented. The model is age and sex stratified, and includes details of host demography. Details of hepatitis B natural history, such as the existence of infectious and non-infectious carriers, are included. The biological assumptions of the model are discussed in full and related to the model's equations. Hepatitis B epidemiological data is reviewed with special emphasis on the estimation of model parameter values from field data. A full set of model parameter values are derived. Possible uses of the model in the assessment of strategies of mass vaccination are discussed.

Adolescent↗
PubMed1994

Quasispecies dynamics and the emergence of drug resistance during zidovudine therapy of HIV infection.

OBJECTIVE: To investigate the roles of mutation, competition and population dynamics in the emergence of drug resistant mutants during zidovudine therapy. DESIGN: A mathematical model of the population dynamics of the viral quasispecies during zidovudine therapy was investigated. METHODS: The model was used to simulate changes in the numbers of uninfected and infected cells and the composition of the viral quasispecies in the years following initiation of therapy. Resulting scenarios in asymptomatic and AIDS patients were compared. The model was also used to investigate the efficacy of a treatment regimen involving alternating zidovudine and dideoxyinosine therapy. RESULTS: The behaviour of the model can be divided into three stages. Before therapy, mutation maintains a small pool of resistant mutants, outcompeted to very low levels by sensitive strains. When therapy begins there is a dramatic fall in the total viral load and resistant strains suddenly have the competitive advantage. Thus, it is resistant strains that infect the rising number of uninfected CD4+ cells. During this second stage the rapid effects of population dynamics swamp any effects of mutation between strains. When the populations of infected and uninfected cells approach their treatment equilibrium levels, mutation again becomes important in the slow generation of highly resistant strains. CONCLUSIONS: The short-term reduction in viral replication at the initiation of therapy generates a pool of uninfected cells which cause the eventual increase in viral burden. This increase is associated with (but not caused by) a rise in frequency of resistant strains which are at a competitive advantage in the presence of the drug. When therapy is ceased, reversion of resistance is slow as resistant strains are nearly as fit as sensitive strains in the absence of drug.

CD4-Positive T-Lymphocytes↗
PubMed1994

Germinal centre destruction as a major pathway of HIV pathogenesis.

Human immunodeficiency virus (HIV)-induced destruction of follicular dendritic cells (FDCs), which are important in immunological memory, may be a major pathway of HIV pathogenesis. We use a mathematical model to investigate this hypothesis and conclude that a low level of FDC destruction could ultimately result in loss of control of HIV. Their slow turnover makes them good candidates for the part of the immune system that fails during the long period of HIV infection. As FDC destruction is essentially a misdirected immune response, too much immunotherapy may be detrimental. Our model shows how to estimate this critical level of immunotherapy. We derive an expression for the time taken to the loss of immune control. Transient changes in the viral growth rate before the immune system fails do not affect this time, providing a possible explanation for the results of the Concorde trial. We suggest that inducible B cell function is a good potential marker of disease progression, indicating the functional ability of the FDC network. Finally, we rereview data in the light of the FDC theory, paying particular attention to data on CD4+ numbers and function that are inconsistent with the classical view of HIV pathogenesis.

Antigen-Presenting Cells↗
PubMed1993

Imperfect vaccines and herd immunity to HIV.

A number of prophylactic vaccines against human immunodeficiency virus (HIV) have passed through phase I clinical trials, and phase II clinical trials are now being planned. These vaccines are not expected to be perfect and might fail in a number of different ways. This paper shows how to equate different aspects of imperfection in a prophylactic vaccine in terms of impact upon levels of herd immunity, and hence upon the vaccine coverage required for eradication. Such comparisons reveal that an otherwise perfect vaccine that gives protection which wanes with a half-life of 10 years is only as good as a vaccine that works in 30% of people giving them complete, lifelong protection. The paper goes on to compare predicted patterns of seroconversion that would be observed in clinical trials and in community-wide vaccination campaigns for vaccines that confer the same levels of herd immunity but are imperfect in different ways.

AIDS Vaccines↗
PubMed1993

The balance of power between HIV and the immune system.

There are several theories of the pathogenesis of HIV that attempt to explain the long and variable delay between infection and disease. Here, each theory is reviewed within the context of a simple mathematical model of the interactions between HIV and the immune system. From this model, a theoretical index of progression has been derived that combines elements from each proposed mechanism.

HIV↗
PubMed1992

Models of interactions between HIV and other pathogens.

We investigate possible interactions between HIV and other pathogens that would arise if HIV replication were enhanced by the activation of T helper cells specific to other pathogens. Using mathematical models of the population dynamics of T helper cells, HIV and other pathogens we address three facets of the interactions between HIV and other pathogens: enhanced HIV replication due to immune stimulation by other pathogens; modified immune control of other pathogens due to immunosuppression by HIV; and the vicious circle formed by positive feedback between these two effects. The models predict that there is a correlation between higher levels of activated TH cells and disease progression and that there is a threshold number of activated TH cells above which the HIV infected immune system is unable to control pre-established pathogens. This threshold marks the boundary between a suppressed but still functioning immune system and the vicious circle of CD4 cell depletion that marks the final stages of AIDS.

Acquired Immunodeficiency Syndrome↗