no antibodies to the VS3 region, however, the serovariant-specific antigens are to be found in VS1 and VS2 or the more broadly reacting antigens of VS4.
Synthetic (linear) peptides from these regions elicit a strong immune response, both independently and in expression vectors such as poliovirus and vaccinia. Relatively little of this response confers on the organism, however, so there is no microbiologic protection. An increasing amount of data suggest that conformational-dependent determinants are important for this target molecule. In VS1, for example, a given 12-amino-acid sequence yields a peptide that is sometimes recognized in linear form but by other serovariants only in circular form. Similar variance occurs in VS2, in which there is good antiserologic response to circular peptides, but not linear.
CD4 and T-cell help is also essential for protection and resolution of infection. A variety of proteins can elicit stimulation for CD4 cells, including MOMP. Animal models also suggest that CD8 cells and cytotoxicity are also important in resolving infection, and possibly in protection. Recent studies have detected CD8-killing of chlamydia-infected epithelial cells in vitro, but it is unknown whether this involves MHC class IA or IB presentation. Research in this area is ongoing.
Issues in Vaccine Development. Unlike some of the viral infections, there are several animal models for chlamydia, including mice, guinea pigs, and monkeys. Murine models include respiratory, systemic, and even genital tract models, including infection with human strains of the pathogen. The guinea pig model is limited to a strain that is a natural pathogen to guinea pigs. Both ocular and genital tract models have been developed in monkeys.
At present, however, there is a need for a better understanding of the cellmediated immune mechanism, the role of CTLs and antibodies. There also needs to be a clearly differentiated understanding of the role of conformation determinants, the exact nature of the antigenic targets, and how to deliver them. And one of the biggest challenges is to find a way to genetically transform and manipulate these organisms, which currently cannot be grown in the quantities needed to support research.
In response to questions, Dr. Stephens added the following:
The time frame for developing a vaccine against either MOMP or the adhesion ligand is entirely a function of money. Most of the problems are fairly straightforward; given enough money, the time frame would be quite reasonable.
Differences in immune response to chlamydia peptides suggest that a small difference in primary sequence may result in a very large difference in the tertiary or quaternary structure of the molecules. In the guinea pig model, protection is totally dependent on conformational determinants. This suggests that researchers need to be more sophisticated in how they look at and present the antigens.
The hypothesis that heat shock protein 60 (HSP-60) plays a role in the pathogenesis of chlamydia has been called into question by recent experiments showing that immunization with HSP-60 makes no difference in response to