Nicolas Burdin

Immunological Foundations to the Quest for New Vaccine Adjuvants

Developing efficient adjuvants for human vaccines that elicit broad and sustained immune responses at systemic or mucosal levels remains a formidable challenge for the vaccine industry. Conventional approaches in the past have been largely empirical and — at best — partially successful. Importantly, recent advances in our understanding of the immune system, most particularly with respect to early proinflammatory signals, are leading to the identification of new biological targets for vaccine adjuvants. This review covers both the current status of adjuvant testing in humans, the residual needs for vaccines in development, and the emerging immunological foundations for adjuvant design. A better understanding of the biology of toll-like receptors, non-conventional T cell subpopulations, T and B cell memory, regulatory T cells, and mucosal immunity has profound implications for a modern approach to adjuvant screening and development. The future lies in the high throughput screening of synthetic chemical entities targeting well-characterized biological molecules. Used alone or in combination, such synthetic adjuvants will allow stimulation or modulation in a safe and efficient manner of strong effector, regulatory and memory immune mechanisms.

Functional CD40 on B lymphocytes and dendritic cells.

B lymphocytes, generated through a process called lymphopoiesis in foetal liver and bone marrow, migrate into peripheral lymphoid organs (lymph nodes, spleen, tonsils) as mature sIgD+ sIgM+ B cells which are also referred to as naive B cells. During antigen-specific immune responses, antigen-specific naive B cells undergo a cascade of events including activation, expansion, mutations, isotype switch, selections and differentiation into either antibodysecreting plasma cells or memory B cells. These antigen-dependent events occur in different areas of secondary lymphoid organs, as well as other nonlymphoid organs. This requires the interaction of B cells with antigens and numerous cell types including T cells, dendritic cells (DC) and follicular dendritic cells (FDC). These cells interact with B cells through different cell surface molecules and through the release of polypeptidic mediators called cytokines.

How Microarrays Can Improve Our Understanding of Immune Responses and Vaccine Development

The international symposium Microarrays, Immune Responses and Vaccines held in Veyrier du Lac, France, 26–29 May 2002, is the first to our knowledge to assess the impact of DNA microarray technology in the fields of immunology and vaccinology. It was based on the premise that the unfolding field of functional genomics has already proven its ability to provide new approaches that could be used to better unravel the complexity of immunology, with the challenge of extending it to vaccine development. Furthermore, it was felt that enough data have accumulated to serve as a basis for a fruitful discussion between scientists from different fields. The last two decades have seen a revolution in molecular biology due essentially to large scale DNA sequencing and gene expression profiling (measurement of the transcriptome, or the regulation of mRNA levels at the genomic level) and the development of tools which have facilitated the analysis of complex data. While several high-throughput methods are available for measuring gene expression, including qRT-PCR, SAGE, and DNA microarrays, the later offers the advantage of simplicity, at least in theory (microarrays are the reverse of Southern blots), sensitivity (down to the single cell level), flexibility (regarding the choice of genes to be analyzed), and power of analysis (in combination with bioinformatic tools). Robotics has now made it possible to array tens of thousands of distinct spots of DNA, each corresponding to a single gene, on glass slides or other supports such that complete genomes can be explored. With the description of the human genome, the way is now open for the creation of arrays covering the full spectrum of the human transcriptome. Among other things, this should open the way to:

Nouveaux vaccins à l'ère post-génomique

Limpact de la genomique sur le developpement de nouveaux vaccins est deja une realite tangible. La disponibilite de sequences genomiques issues dagents infectieux permet, par le biais dune analyse in silico, de selectionner une liste restreinte de molecules potentiellement antigeniques, qui pourront ensuite etre testees pour validation dans des modeles experimentaux animaux. Dans cette optique, lanalyse bio-informatique des sequences nucleotidiques doit etre completee par une strategie de criblage des antigenes preselectionnes impliquant un choix de methode dexpression approprie, lui-meme conditionne par la nature des reponses immunes souhaitees. La contribution de la genomique a la conception de nouveaux vaccins se manifeste - ou se manifestera - par une meilleure comprehension de la relation agents pathogenes-cellules hotes, ainsi que des mecanismes regulateurs et effecteurs impliques dans la reponse immunitaire. Lanalyse des profils dexpression de genes bacteriens pourrait permettre egalement de suivre certains procedes de fermentation industrielle. Au total, lapport de la genomique sintegre, a de multiples niveaux, dans une strategie de developpement de nouveaux vaccins parfaitement definis sur le plan moleculaire, presentant au systeme immunitaire des composants antigeniques minimaux et necessaires pour garantir une efficacite et une innocuite maximales. Une comprehension fine de lassociation entre une susceptibilite particuliere a certaines maladies et un polymorphisme genetique pourrait permettre denvisager dans le futur le developpement de vaccins a facon, concus specifiquement pour des sous-populations humaines presentant un profil genetique donne. Lavenir est-il a la vaccinogenomique ?