Mucosal Immunity: New Methods for Contraception and Disease Protection
Our “Mucosal Protection Laboratory” is developing barrier methods for protecting against sexually transmitted diseases (STDs) and unwanted pregnancy, methods that will be far more appealing to use than condoms. Microbicides being developed for this purpose must not only be highly effective at blocking the infectious entry of STD pathogens they must also be very safe to use repeatedly on Mucosal surfaces, and they must not disturb the healthy microflora of the vagina (lactobacilli). Research in the Mucosal Protection Laboratory helped create “BufferGel”, a spermicidal microbicide now entering major Phase III efficacy trials (funded by NIH) for contraception and for preventing HIV infections. The basic mechanism of protection is quite simple: The vagina is mildly acidic (~pH 4), sufficiently acidic to protect against many types of pathogens. But semen is alkaline, and the ejaculate abolishes the protective acidity of the vagina for many hours after intercourse since sperm are acid-sensitive and would otherwise be killed, within seconds, by vaginal acidity (within seconds). Many STD pathogens, including HIV, HSV, syphilis, and chlamydia, are also acid sensitive, so the alkaline action of semen helps many pathogens, not just sperm, to survive in the vagina. BufferGel, by rapidly acidifying semen, is expected to protect against both sperm and a wide range of STD pathogens while not disturbing the lactobacilli that acidify the vagina (see Boskey et al, 2001). Research on BufferGel and other microbicides is being performed in part through an ongoing Research Agreement with ReProtect, LLC, the JHU-associated company that is pursuing commercial development of BufferGel.
A long-range goal in the Mucosal Protection Lab is to develop monoclonal human antibodies to protect genital skin and epithelia by topical passive immunization. Mucus secretions contain large amounts of antibodies that are highly specific and potent agents for preventing the infectious entry of pathogens. Secreted Mucosal antibodies also help maintain healthy bacterial flora on our mucosal surfaces. Mucosal antibodies (sIgA, sIgM) are polyvalent and hence bind with high avidity to pathogens. Monoclonal antibodies against sperm, HIV, and other STD pathogens can be applied directly to genital skin and epithelia for protection. This use of antibodies will closely mimic the normal function of antibodies in the mucosal immune system, e.g., antibodies in a mother's milk help protect the mucosal surfaces of the mouth, nose, eyes, and entire digestive tract of her baby. Our results to date indicate that monoclonal antibodies delivered to the vagina can help prevent pregnancy as well as sexual transmission of two incurable diseases, genital herpes, and AIDS. We are investigating the molecular interactions between antibodies and mucins, the fibrous proteins that form the mucus gel. Our evidence suggests that antibodies form low affinity bonds with mucins, bonds with such low affinity that they slow, but do not stop, the diffusion of individual antibody molecules through mucus (see Olmsted et al, 2001). However, when antibodies diffusing through mucus bind to, and accumulate on the surface of a pathogen, this “coat” of antibodies can form large numbers of low-affinity bonds with the mucins and thereby trap (“glue”) the pathogen to the gel.
Most antibodies synthesized by the immune system are secreted into mucus (not into blood), and perhaps the primary role of secreted antibodies is simply to trap pathogens in mucus, preventing pathogens from contacting their target cells. We would like to identify and characterize the low-affinity binding sites that link antibodies to mucins.
- Cone, R.A., T. Hoen, X. Wong, R. Abusuwwa, D.J. Anderson, and T.R. Moench. (2006) Vaginal Microbicides: Detecting toxicities in vivo that paradoxically increase pathogen transmission. BMC Infect. Dis. 6:90.
- Olmsted, S.S., K.V. Khanna, E.M. Ng, S.T. Whitten, O.N. Johnson 3rd, R.B. Markham, R.A. Cone, and T.R. Moench. (2005) Low pH immobilizes and kills human leukocytes and prevents transmission of cell-associated HIV in a mouse model. BMC Infect. Dis. 5:79.
- Cone, R.A. (2005) Mucus. In Handbook of Mucosal Immunology, Third Edition, ed. by Mestecky, Lamm, Strober, Bienenstock, and McGhee, 49-72. London: Academic Press.
- Boskey, E.R., T.R. Moench, P.S. Hees and R.A. Cone. (2003) A self-sampling method to obtain large volumes of undiluted cervicovaginal secretions. Sex. Transm. Dis. 30:107-109.
- Castle, P.E., D.A. Karp, L. Zeitlin, B. Garcia-Moreno E., T.R. Moench, K.J. Whaley and R.A. Cone. (2002) Human monoclonal antibody stability and activity at vaginal pH. J. Reprod. Immunol. 56:61-76.
- Achilles, S.L., P.B. Shete, K.J. Whaley, T.R. Moench and R.A. Cone. (2002) Microbicide efficacy and toxicity tests in a mouse model for vaginal transmission of Chlamydia trachomatis. Sex. Transm. Dis. 29:655-664.
- Khanna, K.V., K.J. Whaley, L. Zeitlin, T.R. Moench, K. Mehrazar, R.A. Cone, Z. Liao, J.E. Hildreth, T.E. Hoen, L. Shultz and R.B. Markham. (2002) Vaginal transmission of cell-associated HIV-1 in the mouse is blocked by a topical, membrane-modifying agent. J. Clin. Invest. 109:205-211.
- Olmsted, S.S., J.L. Padgett, A.I. Yudin, K.J. Whaley, T.R. Moench, and R.A. Cone. (2001) Diffusion of macromolecules and virus-sized-particles in human cervical mucus. Biophys. J. 81:1930-1937.
- Boskey E.R., R.A. Cone, K.J. Whaley, and T.R. Moench. (2001) Origin of vaginal acidity: High D/L lactate ratio is consistent with bacteria being the primary source. Hum. Reprod. 16:1809-1813.
- Castle, P.E., K.J. Whaley, T.E. Hoen, T.R. Moench, and R.A. Cone. (1997) Contraceptive effect of sperm-agglutinating monoclonal antibodies in rabbits. Biol. of Reprod. 56:153-159.
- Cone, R.A., and K.J. Whaley. (1994) Monoclonal antibodies for reproductive health: Preventing sexual transmission of disease and pregnancy with topically applied antibodies. Am. J. Reprod. Immunol. 32/2:114-131.