Vaccine modeling, human immune system

Methods for assessing or modeling of the responses of the human immune system to vaccines are critical components of any effort to understand the relationship between immunogenicity and either a positive or a negative outcome of vaccination. Decades of research have yielded many useful in vitro methods that enable the isolation and molecular dissection of selected components (modulators or cell types) of an immune system, whether mouse or human. While of hmited scope biologically, these systems have elucidated the modulators and cell types responsible for certain facets of humoral or cellular immunity. These systems have also been employed to define the roles that modulators and specific cell types play in particular aspects of an immune response. Missing, until recently, was an in vivo setting in which to study the human immune system. 

It is generally accepted that two types of immune response are involved in the host defence against salmonellosis - cellular and humoral (41). In attempts to control salmonellosis by active immunization of humans, or of animals in experimental model systems, living vaccines have been superior to killed vaccines consequently, cellular immunity has been considered to be of greater importance for the host resistance (42, 43). 

Polymorphism in the human leukocyte antigen (HLA) s ystem also may be an obstacle to producing an effective vaccine. A potential model for this problem is the observation that T cells, including the cytotoxic T lymphocytes, in patients with HLA-B3S do not re.spond to certain. strains of the parasite. It appears that the combination of certain proteins produced by Plasmodium strains with HLA-B3S prevents a normal T-cell re.sponse. In other words, the immune system of these patients will respond to some Plasmodium strains and not others. The implication is that an effective vaccine will have to be very polyvalent. 

The described three cases address stimulation of the immune system by vaccines and/or adjuvants that could theoretically lead to adverse effects, including the potential induction of a systemic inflammatory response by new molecular adjuvants, T cell-mediated cytotoxicity by therapeutic vaccines, and autoimmunity by therapeutic cancer vaccines. In each case, the risk can be evaluated via appropriate assessments in nonclinical toxicity studies and by considerations of the relevance of the animal models to humans. 

PLGA microspheres containing encapsulated DNA vaccines are usually prepared using double-emulsion methods or by spray-drying, resulting in more or less even distribution of DNA throughout the bulk of the microspheres. These micro-spheres have been evaluated extensively in vitro and in cell culture to study DNA release and uptake by immune cells (see Refs. [40, 41]). In vivo studies of this system have also been conducted in animal models [42 14] and in human trials for... 

---