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Effector and memory T-cell differentiation: implications for vaccine development.

Recent work shows that after stimulation with antigen, CD4+ and CD8+ T cells embark on a programme of proliferation that is closely linked with the acquisition of effector functions and leads ultimately to memory-cell formation. Here, we discuss the signals required for commitment to this programme of development and the factors that might influence its progression. Models of the pathways of effector and memory T-cell differentiation are discussed, and we highlight the implications of this new understanding for the optimization of vaccine strategies.

Animals↗

Antigen processing: current issues, exceptional cases (Thy 1 alloantigen, MHC class-II-restricted cytolytic T cells), and implications for vaccine development.

A dogmatic view of antigen processing is presented in outline, followed by a survey of unresolved issues in the subject. The activity of Thy 1 as an alloantigen, and allospecific MHC Class-II-restricted cytolytic T cells offer examples of exceptional cases of antigen presentation. Implications for the design of vaccines are drawn.

Animals↗

Contribution of advances in immunology to vaccine development.

During the last 10 years, investigation of the bovine immune system has generated knowledge and reagents that can now be applied to study the mechanisms of immunity to disease and the identity of antigens recognized by protective immune responses. Such studies can indicate which antigens are likely to be effective in subunit vaccines and also highlight the type of antigen delivery system that will be required for a vaccine to induce a protective immune response. In the case of bovine RSV, studies of immune responses in the target host have demonstrated that both antibody and CTL responses play an important role in immunity. Both the F and G glycoproteins have been identified as targets of protective antibodies, and systems have been established that will allow the identification of the viral antigens recognized by CTL. Further studies of CD4+ T-cell responses to the virus are required to determine whether or not components of the response have the potential to enhance disease and, therefore, need to be avoided in vaccination strategies.

Allergy and Immunology↗

The implications of antigenic diversity for vaccine development.

The reactivity of human monoclonal and polyclonal anti-HIV-1 antibodies demonstrates that shared epitopes, including those that induce neutralizing antibodies, exist and are recognized by the human immune system. A priori, there is no reason why cross-clade neutralizing antibodies could not be induced by an appropriately constructed HIV vaccine. But to construct such a vaccine, it is critical to understand, as completely as possible, the antigenic structure of HIV, to establish and identify immunologic classifications for HIV, and to choose rationally the minimum number and types of viruses from these immunologic groupings that will induce the broadest protective responses.

AIDS Vaccines↗

Vaccine development against cutaneous leishmaniasis. Subcutaneous administration of radioattenuated parasites protects CBA mice against virulent Leishmania major challenge.

Experiments described in this paper were aimed at determining whether subcutaneous inoculation of live, avirulent Leishmania major would protect mice against infection by the virulent parasite. To this effect, promastigotes or amastigotes of a highly virulent strain of L. major (MRHO/IR/76), used in human trials of leishmanization, and which induces non-healing skin lesions in both CBA and BALB/c mice, were rendered non-pathogenic by gamma irradiation. A dose of 150 krad was required to abrogate the virulence of the parasite as tested on BALB/c mice. Strikingly, however, not all leishmanias were completely inactivated by this procedure since live parasites were detected in the footpads and/or the inguinal lymph nodes as long as 28 days (CBA) or 18 weeks (BALB/c) after injection. Furthermore, 150 krad-irradiated promastigotes retained the capacity to transform into amastigotes intracellularly in vitro. Subcutaneous inoculation of this irradiated 'vaccine' conferred onto CBA mice a high degree of protection against challenge by both the homologous and a heterologous (MRHO/SU/59/P) strains of L. major. Lymph node cells from protected animals acquired the capacity to activate infected macrophages in vitro to kill intracellular L. major. To allow for maximum development of immunoprotection, the irradiated promastigotes had to remain viable, perhaps reflecting a requirement for transformation into amastigotes in the vaccinated host.

Animals↗

Typhus vaccine developments from the First to the Second World War (on Paul Weindling's 'between bacteriology and virology...').

After the louse transmission of epidemic typhus had been established (1909), a small microorganism (thought to belong to a new genus, Rickettsia) was shown in enormous numbers in the guts of lice that had fed on human typhus victims. Attempts at cultivating this organism on inert media failed; transfer from louse to louse without loss of virulence for the vertebrate host was successful. Some scientists were not convinced of the etiologic role of Rickettsiae, because the presence of this microbe in blood and organs of victims or of experimentally infected animals was difficult to demonstrate. This uncertainty was dispelled in 1928, when in guinea pigs infected with material from the closely related disease Tabardillo (murine typhus) abundant Rickettsiae were revealed in the tunica vaginalis. Live vaccines, derived from strains of murine typhus and deployed in French North Africa, were considered by outside observers as unsafe. Killed vaccines were derived from the masses of Rickettsiae present in louse guts, in chick embryo yolk sacs or in vertebrate lungs. These developments were not spurned by any 'upswing of virology' but by the threat of typhus in endemic areas and, after 1938, in a war-torn world. Their basis was firmly anchored in bacteriological thought styles and techniques.

Animals↗