As our first line of defense against the majority of infections, mucosal surfaces in the genitourinary, oral, gastrointestinal, and respiratory systems are obvious sites for delivering protective agents for preventing infectious disease. Unfortunately, the technology for mucosal protection is severely limited; for example, the world community has had few options for preventing sexual transmission of HIV. With the report by Beninati et al. in this issue of Nature Biotechnology1, an additional option may be realized. The authors used a single-chain antibody fragment (scFv) for treating vaginal Candida albicans infections in a rat model. What makes this report distinctive is the combination of a novel use of an antibody (antiidiotype scFv) and a unique delivery system (transgenic commensal bacteria expressing the scFv).

Candida albicans, an opportunistic fungus, causes recurrent vaginal infections in a large percentage of women as well as oral and esophageal infections in the immunocompromised. By exploiting idiotypic networks, the investigators generated an scFv antiidiotype antibody (H6) that mimics the activity of a killer toxin from Pichia anomala2. The toxin has activity against a variety of fungal pathogens but is unsuitable for topical microbicides because of its instability at physiologic pH and temperatures. The investigators generated recombinant Streptococcus gordonii, an oral commensal bacteria, that either secreted or displayed H6 on the surface. These engineered bacteria were then used therapeutically to colonize the vaginas of rats with existing candidal infection. Although their study focused on Candida as an example, the authors point out that this technology may be broadly applicable to infections on all mucosal surfaces.

Delivery of agents such as antibodies and peptides to mucosal surfaces for hours to days of protection has been achieved using solutions, gels, aerosols, tablets, or films (Fig. 1A). In the vagina, antibodies have been incorporated into controlled-release devices for weeks to months of protection3. Alternatively, as described in this report, transgenic commensal bacteria can be used for sustained delivery (Fig. 1B). By this means, protection may last as long as the transgenic commensal remains. In this study, the transgenic commensals continued to colonize the rat vaginas for at least 15 days. It remains to be seen whether long-term colonization of the human vagina with S. gordonii can be maintained in the presence of intercourse, menses, and related daily fluctuations of vaginal flora4. It may prove preferable to use a vaginal commensal, e.g. Lactobacillus, that is adapted to the acidic pH of a healthy vagina. A further concern with the use of transgenic commensals that will need to be addressed is the stability of the antibody gene and its ability to transfect wild-type bacteria. This can at least in part be studied using green fluorescent protein as a reporter gene as described recently5. Finally, as with any new approach, the means for large-scale production must be developed and the regulatory pathway for transgenic commensals will need to be defined.

Figure 1: Protection afforded by different methods of delivery.
figure 1

© Bob Crimi

(A) Conventional delivery of a aersol or tablet formulation affords only hours to days of protections. (B) Transgenic microbe delivery to the mucus affords days to months of protection.

Full size image

The importance of developing microbicides for protecting mucosal surfaces, in particular the vaginal and cervical mucosa, was recently highlighted at the Microbicides 2000 Conference sponsored by national and international agencies6. The development of mucosal protectants for vaginal microbicides is starting to increase markedly. In fact, the authors of the current study reported on an HIV-inactivating protein expressed in S. gordonii for use as a vaginal microbicide7. According to the Alliance for Microbicide Development (Silver Spring, MD), at least 60 vaginal microbicidal products (antibodies, peptides, acidic buffers, sulfated polymers) are in various stages of development.

There are currently no vaccines available for preventing sexually transmitted diseases (with the exception of hepatitis B) or reproductive health ailments such as urinary tract and Candida infections. Interestingly, the investigators in the current study have also used this transgenic commensal for delivery of vaccine antigens to mucosal surfaces8. This use of transgenic commensals for active as well as passive immunization highlights the intersection between the science of antibody-based mucosal microbicides and mucosal vaccines. Some of the best characterized antibodies, discovered through vaccine development efforts, are the same ones being developed as mucosal protectants. Conversely, evaluating the efficacy of antibodies delivered to mucosal surfaces may help determine the mucosal antibody concentrations necessary for vaccines to be protective9.

One historic obstacle to evaluating the clinical efficacy of mucosal antibodies has been their high cost and limited production capacity. Now we can add the use of transgenic commensals to deliver therapeutic antibodies mucosally, to methods to produce antibodies in plants or animals10 that have been developed to overcome this limitation. Another recent report describing delivery of therapeutic peptides11 suggests that these reports are just the beginning of an exciting and potentially generally applicable strategy for delivery of a variety of protectants to mucosal surfaces.