Medical graduates and scientific research in Australia: a personal reflection.
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Biomedical subjects
Publications and source records attributed to G Ada.
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Abstract Viral and bacterial vaccines, especially for childhood use, are one of the most successful public health measures of the last two centuries and have a good safety record. However, there are still many diseases that are caused by infectious agents for which vaccines are not available. Our increasing ability to manipulate the immune system offers hope that, in the future, at least some of these infections may be prevented by vaccination. A surprising recent development is the use of vaccine technology to test whether a range of other generally non-communicable diseases can be prevented (or at least controlled) in this way. Investigation of these diseases is still mainly at the experimental level, however the list includes different types of cancers, allergies, drug addiction and neurodegenerative diseases.
Various pathogenic bacteria have coats of polysaccharide, many with repeating epitopes. Though polysaccharide vaccines have been available for some time, they induce mainly IgM production, and are only moderately protective in adults and ineffective in young children. It was originally shown in 1931 that the immunogenicity of polysaccharides could be enhanced by conjugating to a protein. The last two decades have witnessed the production and clinical testing of polysaccharide-protein conjugates specific for at least four different bacteria which normally cause considerable mortality and morbidity, especially in young children. In some cases, immunizing children from 4 months of age, with a booster early in the second year, has resulted in remarkably high success rates in protecting them from disease. For one pathogen, Haemophilus influenza type b, the success rate has been sufficiently high (> 95%) to suggest that this disease might, in time, be globally controlled in this way. The results of immunization with conjugate vaccines to Streptococcus pneumoniae, Neisseria meningiditis and Salmonella typhi are also very encouraging. More conjugate preparations are under development.
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Compared with the earlier incidence of acute infectious diseases, the introduction of vaccines has been one of the major public health success achievements. In contrast, vaccine development to control some persisting infections such as HIV remains a major challenge. There are many similarities with this task and that of controlling tumours by immunotherapy. Generating CTL responses by using pulsed dendritic cells has become a popular approach and has led to success with the mouse model. With viral antigens, priming with DNA plasmids and boosting with a chimeric live vector results in high levels of CTL activity, and is worth trying with cancer. A recent review highlights three other difficulties posed by tumours: epitope stability, maiming or killing of CTL by the tumour, and accessibility of the tumour vasculature to immune components. The new ability to label CTL by staining with specific tetrameric peptide/MHC complexes offers the possibility of effectively studying this third aspect. Our increased knowledge of tumour-associated antigens, viral or otherwise, and our growing ability to manipulate the immune system, offers hope that control of at least some human tumours may be within reach.
This article lists the vaccines current available for the control of both viral and bacterial infections. They may be attenuated live or inactivated whole microorganisms, or subunit preparations. Many more are in the pipeline and increasing attention is being given to establishing their safety before registration. Following the earlier eradication of smallpox, good progress is now being made toward the global eradication of poliomyelitis and a new program to eliminate measles from the Americas has begun. A variety of new approaches to vaccine development is now available. The hepatitis B virus surface antigen, made by DNA-transfected yeast or mammalian cells, is the basis of the first genetically engineered vaccine. Early in the 21st century, new vaccines based on oligopeptides, recombinant live viral or bacterial vectors (often existing live vaccines), or recombinant DNA plasmids are likely to be registered for human use. The efficacy of vaccines depends on the immune responses generated, and the recent substantial increase in our understanding of the mammalian immune system now offers great opportunities for manipulation to best obtain desired responses. These include mixing vaccine formulations to maximize immune responses, and combining vaccines to simplify their administration. Despite these advances, some persisting infections, such as those caused by HIV, plasmodia, and mycobacteria, still pose a great challenge to vaccine developers.
Early work on the roles of cytotoxic T lymphocytes (CTLs) in acute viral infections in animal models showed that i) the clearance of virus coincided with the increase in CTL activity rather than specific antibody levels, ii) transfer of CTLs after infection could protect from a lethal dose of virus, and iii) in primed, compared to naive, animals, CTL activity appeared 1-3 days earlier after a challenge infection. There is now a series of findings with individuals who have been exposed to HIV but are HIV-seronegative that suggest a protective role for CTLs. Usually after in vitro culture, HIV-specific CTLs have been isolated from i) infants born of infected mothers, ii) long-time partners of HIV-infected people, iii) some prostitutes in Africa, and iv). Most recently, 7/20 seronegative health care workers exposed once to HIV have been shown to possess HIV env-specific CTLs. The findings suggest that CTLs (a type I T cell response) may rapidly clear a low dose of HIV. Experiments with SIV are proposed that may provide more direct supporting data for this possibility.
The prospects for many children born in developing countries to reach adulthood has been transformed over the last 30 years by the activities of the Expanded Programme of Immunization (EPI) established by the World Health Organization (WHO) in 1974. By 1990, about 80% of children had been vaccinated against six common childhood diseases. The advent of new technologies provided a strong stimulus to those involved in vaccine design, development and delivery, and offered the possibility of improving current vaccines, developing new vaccines and simplifying vaccination practices. This in turn led to the formation of the Children's Vaccine Initiative (CVI) in the early 1990s. The worldwide emergence of new diseases such as HIV/AIDS and the re-emergence of old diseases such as tuberculosis and cholera present additional challenges.
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The efficacy of vaccines for prophylactic use is a function of the immune response elicited by activated lymphocytes. Based on the current understanding of these responses, their induction, and the most effective ways to obtain long-lived immunity, a novel protocol for the vaccination of children against seven childhood diseases, involving only two visits for vaccine administration, is proposed.
Twenty years ago, the terms 'altered self' and 'H-2 restriction', later modified to 'MHC-restriction', were coined to describe the finding by Peter Doherty and Rolf Zinkernagel that murine cytotoxic T cells (CTL) would lyse virus-infected target cells only if effector and target cells were H-2 compatible. This short review recalls those heady days and briefly recounts some of the later findings in three aspects of particular interest raised by the original finding: the nature of the T cell receptor, the composition and structure of the ligand on the target cell recognized by the TCR and the importance of CTL in the control and clearance of infections in general.
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A task force evaluated an in vitro antibody-mediated chlamydial neutralization assay for its utility as a method to assess functional correlates of antibody responses to Chlamydia trachomatis. Two monoclonal antibodies that recognize different major outer membrane protein (MOMP) epitopes for a C. trachomatis serovar B strain exhibit good in vitro neutralizing activity, with a maximum of 90% neutralization. Calculations based on the 50% neutralization point indicated that 100% neutralization could theoretically be achieved when only 10% of the MOMP molecules bound antibody. Monoclonal antibodies that recognized either a heterologous MOMP or the genus-specific chlamydial lipopolysaccharide did not produce neutralizing activity. The standardized assay will be useful to establish if in vitro neutralizing antibody responses are predictive of protective immunity and will aid in defining chlamydial antigens and epitopes that may be attractive vaccine candidates.
"Improbability of effective vaccination against human immunodeficiency virus ...", declares the title of a new paper by Dr Albert Sabin. But three immunologists see flaws in his argument.
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