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A R McLean

Publications and source records attributed to A R McLean.

47 records · Page 3Linked to original sources

A mathematical model of vaccination against HIV to prevent the development of AIDS.

Vaccination and post-exposure immunization against the human immunodeficiency viruses (HIV-1 and HIV-2) faces the problem of the extensive genetic and antigenic variability of these viruses. This raises the question of what fraction of all possible antigen strains of the virus must be recognized by the immune response to a vaccine to prevent development of acquired immunodeficiency disease (AIDS). The success of a vaccine can depend on the variability of the target epitopes. The different HIV variants must be suppressed faster than new escape mutants can be produced. In this paper the antigenic variation of HIV during an individual infection is described by a stochastic process. The central assumption is that antigenic drift is important for the virus to survive immunological attack and to establish a persistent infection that leads to the development of AIDS after a long incubation period. The mathematical analysis reveals that the fraction of antigenic variants recognized by the immune response, that is induced by a successful immunogen, must exceed 1-1/R, where R is the diversification rate of the virus population. This means that if each HIV strain can produce, on average, five new escape mutants, then more than 80% of the possible variants must be covered by the immunogen. A generic result of the model is that, no matter how immunogenic a vaccine is, it will fail if it does not enhance immune attack against a sufficiently large fraction of strains. Furthermore, it is shown that the timing of the application of post-exposure immunization is important.

AIDS Vaccines↗

Antigenic diversity thresholds and the development of AIDS.

Longitudinal studies of patients infected with HIV-1 reveal a long and variable incubation period between infection and the development of AIDS. Data from a small number of infected patients show temporal changes in the number of genetically distinct strains of the virus throughout the incubation period, with a slow but steady rise in diversity during the progression to disease. A mathematical model of the dynamic interaction between viral diversity and the human immune system suggests the existence of an antigen diversity threshold, below which the immune system is able to regulate viral population growth but above which the virus population induces the collapse of the CD4+ lymphocyte population. The model suggests that antigenic diversity is the cause, not a consequence, of immunodeficiency disease. The model is compared with available data, and is used to assess how the timing of the application of chemotherapy or immunotherapy influences the rate of progress to disease.

Acquired Immunodeficiency Syndrome↗

Mixing ecology and epidemiology.

Mixing matrices can be used to describe subgroup interactions in mathematical models which have heterogeneity in population structure. A discussion is presented of two different approaches to the formulation of such mixing matrices. The relation between the two different methods is discussed, using examples based upon models of the transmission dynamics of HIV. There follows a discussion of the application of the mixing matrix approach to other areas in population biology, and a complementary overview of recent advances in theoretical ecology that may have applications in theoretical epidemiology.

Ecology↗

Model-based comparisons of measles immunization strategies using high dose Edmonston-Zagreb type vaccines.

The World Health Organization has recently made a new recommendation for measles immunization in areas with very high rates of transmission. The new policy will involve a switch to the high potency Edmonston-Zagreb (E-Z) vaccine (a strain with improved efficacy in the presence of maternally-derived, specific antibody), targeting immunization at six-month-old infants. We present a mathematical model of measles transmission that can be used to assess the likely impact of cohort immunization on the incidence of infection using the new strain of vaccine. Data requirements of the model are discussed, with special reference to the critical issue of age-specific vaccine efficacy. Currently available information on seroconversion rates achieved with the new strain are summarized. Results are presented which endorse the new WHO recommendations, predicting considerable benefits, in particular, to those most at risk of measles morbidity and mortality. Furthermore, integration of E-Z with the third diphtheria, pertussis, tetanus (DPT) dose at three-four months should be considered as an alternative option, particularly if combined with some additional coverage at nine months of age.

Humans↗

Population dynamics of HIV within an individual after treatment with zidovudine.

A new mechanism is proposed for the apparent breakthrough of HIV that occurs approximately 6 months after the commencement of therapy with zidovudine (AZT). Using a simple mathematical model of the interacting population dynamics of HIV and its major host cell in the circulation (the CD4+ lymphocyte), predicted patterns of HIV plasma viraemia in the weeks following treatment with zidovudine are generated. These are in close agreement with observed patterns despite the fact that the model contains no mechanisms for the development of drug-resistant strains of virus. It is suggested that the patterns of viral abundance observed during the first 6 months after treatment may be the result of non-linearities in the interactions between HIV and CD4+ cells, and that it is only after the first post-treatment burst of viral production that drug resistance plays an important role.

AIDS-Related Complex↗

A model of human immunodeficiency virus infection in T helper cell clones.

We present a mathematical model of the activation and proliferation of a clone of T helper cells in response to a replicating antigen. This is able to show types of behaviour akin to persistent infection and to immune memory. This model is expanded to include the infection and destruction of activated T helper cells by human immunodeficiency virus and the growth of a population of circulating human immunodeficiency virus. The resulting model is used to investigate the circumstances under which the human immunodeficiency virus can destabilize persistent infections and destroy immune memory, and to illustrate the impact of antigenic stimulation of infected T helper cell clones upon human immunodeficiency virus replication rates.

Acquired Immunodeficiency Syndrome↗

Measles immunization strategies for countries with high transmission rates: interim guidelines predicted using a mathematical model.

This study addresses the problem of measles immunization in communities experiencing unacceptably high numbers of cases in young infants, under circumstances where high dose Edmonston-Zagreb vaccine is not yet available. Where the continued use of standard potency vaccines (eg Schwarz) is unavoidable we have investigated the merits of new policies which aim to offer better protection to children below the currently recommended vaccination age of nine months. These policies are intended for implementation in communities with intense measles transmission. Predictions, spanning five years, using a previously developed mathematical model are presented for two types of potential new policies: a 'switch' to a younger target age, or a 'two-dose' strategy incorporating vaccination at a younger age in addition to the current schedule at nine months. We conclude that a switch in immunization policy to a younger age is of doubtful worth, but that supplementary vaccination at around six months in addition to existing coverage at nine months (ie two-dose policy) is a desirable option.

Age Factors↗

Possible demographic consequences of AIDS in developing countries.

Simple mathematical models of the transmission dynamics of HIV that incorporate demographic and epidemiological processes to assess the potential impact of AIDS on human population growth and structure in developing countries suggest that AIDS is capable of changing population growth rates from positive to negative values over timescales of a few decades. The disease is predicted to have little if any impact on the dependency ratio of a population, defined as the number of children below age 15 years and elderly people over 64 years, divided by the number of adults between 15 to 64 years.

Acquired Immunodeficiency Syndrome↗

Measles in developing countries. Part I. Epidemiological parameters and patterns.

This paper presents a review of published data concerning the epidemiology of measles in developing countries. Simple mathematical models provide a framework for data analysis and interpretation. The analyses highlight differences and similarities in the patterns of transmission of the measles virus in developed and developing countries. Whilst the rate of loss of maternally derived immunity to measles is broadly similar, the average age at infection is much lower, and case fatality rates are much higher in developing countries. Data analysis also serves to illustrate inter-relationships between different kinds of epidemiological data. Thus, for example, in order to correctly interpret an age stratified serological profile from a developing country it is necessary to have information on the rate of decay of maternal antibodies and age specific case fatality rates. To determine the probable impact of a given vaccination programme, information on the birth rate in the community concerned is also required. A discussion is given of the epidemiological data required in order to effectively design a community based vaccination programme aimed at the eradication of measles.

Adolescent↗

Measles in developing countries. Part II. The predicted impact of mass vaccination.

A mathematical model is developed to mimic the transmission dynamics of the measles virus in communities in the developing world with high population growth rates and high case fatality rates. The model is used to compare the impacts of different mass vaccination programmes upon morbidity and mortality arising from infection by measles virus. Analyses identify three conclusions of practical significance to the design of optimal vaccination programmes. First, there is no single optimum age at which to vaccinate children for all urban and rural communities in developing countries. For a given community the best age at which to vaccinate depends critically on the age distribution of cases of infection prior to the introduction of control measures. Second, numerical studies predict that the introduction of mass vaccination will induce a temporary phase of very low incidence of infection before the system settles to a new pattern of recurrent epidemics. Mass vaccination acts to lengthen the inter-epidemic period in the post-vaccination period when compared with that prevailing prior to control. Third, numerical simulations suggest that two-phase and two-stage vaccination programmes are of less benefit than one-stage programmes (achieving comparable coverage) aimed at young children. The paper ends with a discussion of the needs for: improved programmes of data collection; monitoring of the impact of current vaccination programmes; and the development of models that take account of viral transmission dynamics, host demography and economic factors.

Adolescent↗

An assessment of the effects of internal neurolysis on a chronically compressed rat sciatic nerve.

Chronically compressed nerves were treated with three surgical modalities. Simple decompression was compared to internal neurolysis with and without the addition of extrafascicular steroid. Electrophysiologic, histologic, and morphometric assessments were performed. Compressed control nerves demonstrated changes compatible with severe nerve compression (Wallerian degeneration). With simple decompression, improvement in histologic and electrophysiologic parameters occurred. When internal neurolysis was added to the decompression, further improvement in histologic and electrophysiologic parameters was noted. There was no added improvement with the addition of steroids.

Animals↗