Future Directions

The measurement of vaccine antigen content and development of T-cell responses has proved a useful guide in the evaluation ofvaccine immunogenicity and efficacy in animal model systems, where laboratory strains of pathogen can be used as antigen/challenge. However, these parameters have proved much less secure for evaluating candidate preventive vaccines for clinical use in humans [118]. Here, the course of infectious diseases that vaccines are aimed at preventing are more variable and the "wild" strains of pathogens are often rapidly mutating so that the immune system is less effective in counteracting and eliminating them. Vaccines are, therefore, required to boost the immune defenses more than that normally occurring during natural infections. Ideally, they should boost both CD4+ helper T cells and CD8+ CTLs, generate the development of durable memory T cells, and elicit longlasting neutralizing antibody production. Such tests to quantify these functions can, at present, only be carried out post-vaccination, and involve the removal of blood and lymphoid cells from animals or humans. Both animal usage and the variability of such testing would be reduced if vaccine functions/ activities could be modeled in artificially created cell-based systems in vitro. Today, investigations are ongoing into the creation of synthetic lymphoid tissue-like organoids, which may find uses for this purpose. For example, a tissue-engineered, lymphoid tissue-like organoid, which was constructed by transplanting stromal cells embedded in biocompatible scaffolds into the renal subcapsular space in mice, had an organized tissue structure comparable to that of secondary lymphoid organs [110]. Compartmentalized B-cell and T-cell clusters, high endothelial venule-like vessels, germinal centers and follicular dendritic cell networks were all present in the organoid. Furthermore, IgG antibody formation could be induced by antigenic stimulation. Although this organoid was transplantable into naive normal or severe immunodeficiency (SCID) mice, maintenance ex vivo in a fully functioning form would be the next logical step for establishing a system to test vaccines. Another example is that of a tissue-engineered thymic organoid [111]. In this case, a three-dimensional framework of a tantalum-coated carbon matrix was seeded with murine thymic stroma in an attempt to provide a structure that supports the reconstitution of functioning thymic tissue. When seeded with human bone marrow-derived hematopoietic progenitor cells, the thymic organoid environment reproducibly generated mature functional T cells within 14 days. The thymic organoid may, with further developments, also lead to test systems for determining the immunogenicity of vaccines.

It is clear that much remains to be done to create artificial, synthetic organoids capable of providing valid test systems to quantify the immunogenicity/potency of preventive vaccines. Perhaps, this enterprise could be aided by computer modeling of immune functions. For instance, "model system heuristics" integrate known characteristics and processes of cells, pathogens, antigens, antibodies, and cytokines; the system may then generate qualitative simulations of primary immune responses to bacterial and viral infections [112]. Such a technique could, therefore, serve as a tool for testing assumptions about cellular functions in immune responses in silica, which may be informative for creating appropriate organoids for vaccine testing.

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