D

Part 1: Barrier Methods

Lourens J.D. Zaneveld, Ph.D., D.V.M.

Department of Obstetrics and Gynecology, Rush University,

Rush-Presbyterian-St. Luke's Medical Center

Deborah J. Anderson, Ph.D.

Fearing Research Laboratory, Department of Obstetrics,

Gynecology, and Reproductive Biology,

Brigham and Women's Hospital and Harvard Medical School

Kevin J. Whaley, Ph.D.

Department of Biophysics, The Johns Hopkins University

Introduction

This chapter has two parts. The first describes approaches to development of novel vaginal agents and formulations with potential for preventing both conception and STD transmission. To facilitate understanding of these approaches, we present background information on the nature of chemical formulations, the functional activity of spermatozoa, and the infective mechanisms of sexually transmitted pathogens. The second part of the chapter presents some of the theoretical underpinnings of mucosal immunity, an area that offers hope of bridging the large and present gap between contraception and prevention of sexually transmitted disease.

The need to focus on sexually transmitted diseases in connection with contraception reflects a growing, if reluctant, recognition of several large sociomedical facts: that the prevalence of these diseases is mounting in much of the world; that their transmission is not limited to small or distant populations engaging in aberrant sexual behavior; that their immediate and more remote sequelae can be dire; and that, biologically and behaviorally, contraception and disease prevention will be necessary partners, at least sometimes, for significant numbers of people and for the foreseeable future.

While effective contraceptive technology for females has been available for several decades, very few contraceptive methods—the condom and some vaginal



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--> D Part 1: Barrier Methods Lourens J.D. Zaneveld, Ph.D., D.V.M. Department of Obstetrics and Gynecology, Rush University, Rush-Presbyterian-St. Luke's Medical Center Deborah J. Anderson, Ph.D. Fearing Research Laboratory, Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women's Hospital and Harvard Medical School Kevin J. Whaley, Ph.D. Department of Biophysics, The Johns Hopkins University Introduction This chapter has two parts. The first describes approaches to development of novel vaginal agents and formulations with potential for preventing both conception and STD transmission. To facilitate understanding of these approaches, we present background information on the nature of chemical formulations, the functional activity of spermatozoa, and the infective mechanisms of sexually transmitted pathogens. The second part of the chapter presents some of the theoretical underpinnings of mucosal immunity, an area that offers hope of bridging the large and present gap between contraception and prevention of sexually transmitted disease. The need to focus on sexually transmitted diseases in connection with contraception reflects a growing, if reluctant, recognition of several large sociomedical facts: that the prevalence of these diseases is mounting in much of the world; that their transmission is not limited to small or distant populations engaging in aberrant sexual behavior; that their immediate and more remote sequelae can be dire; and that, biologically and behaviorally, contraception and disease prevention will be necessary partners, at least sometimes, for significant numbers of people and for the foreseeable future. While effective contraceptive technology for females has been available for several decades, very few contraceptive methods—the condom and some vaginal

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--> formulations and devices—also protect against sexually transmitted diseases (STDs) (Claypool 1994). Of these, only the condom offers protection against the whole spectrum of these diseases, including HIV, and only the female condom and vaginal formulations and devices can be controlled directly by women. Attempts to limit the spread of HIV and other STDs through behavioral modification, encouraging condom use and fewer sexual partners, for example, have proved insufficient to the large task of stemming transmission of these diseases (Stein 1993). Furthermore, understanding about alternative, nonpenetrative sexual practices (''outercourse") that are both protective and satisfying would appear to be limited, although recent empirical data in large population samples are lacking (Greenwood and Margolis 1981; Norman and Cornett 1995; Norsigian 1994). Women experience particular difficulties owing to underlying gender power inequalities that constrain their ability—sometimes severely—to protect themselves from HIV infection, given the absence of a protective technology they could use, if necessary, without a partner's consent (Stein 1990). New emphasis on developing contraceptive agents that have the additional, critical characteristic of preventing STDs is also being driven by the realization that sexually transmitted diseases other than HIV elevate the risk of HIV transmission (Berkley 1991; Wasserheit 1992); by the increasing rates of heterosexual transmission of HIV infection; by realization of women's greater vulnerability to infection (Mann et al. 1992; Stein 1993); and by women's need to control their own protection against infection and/or conception. Globally, most women are at greatest risk of acquiring HIV through heterosexual vaginal intercourse with an infected man (Mayer and Anderson 1995). To avoid infection via this route, a preventive method must establish an effective barrier between the infectious elements in genital secretions and those cells of the female reproductive tract that are susceptible to infection. Such a barrier may be physical (such as that provided by condoms), chemical (such as that provided by an intravaginal microbicide), some combination of a physical and a chemical barrier (such as a condom and an intravaginal microbicide), or immunologic (such as topically applied monoclonal antibodies or mucosal immunogens). The ideal vaginal microbicide should be colorless, odorless, tasteless, stable at room temperature with a long shelf life, easy to use, fast-acting for an appropriate duration after insertion, effective pre- and postcoition, affordable, available without prescription, and safe for use at least once or twice daily. While it would be desirable to develop some microbicides that do not kill sperm, because women who only sometimes want to prevent pregnancy will always want to prevent STD infection, this paper focuses on chemical barriers that may be able to block both conception and STD transmission, that is, "prophylactic contraception" (Cone and Whaley 1994). In so doing, however, there is no intention to disparage the present and future value of physical barrier methods. The diaphragm and cervical cap can provide some protection against disease transmission (Rosenberg et al. 1992) and are

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--> appropriate for use by some women, although much is unknown about their efficacy, utilization, and protective power (Stein 1993; Stratton and Alexander 1993). Vaginal topical formulations had received very little research attention until recently. Advances have relied on serendipitous discovery or relatively minor changes in existing methods and, overall, have failed to solve the most critical problems associated with these formulations. Nevertheless, scientists have accumulated much new knowledge about sperm and genital tract physiology over the past three decades. Combined with recent progress in biochemistry, pharmaceutics, and engineering, such knowledge should make it possible now to compensate for previous lack of progress in this increasingly critical area. Mechanisms of Fertilization by Spermatozoa During ejaculation, spermatozoa are often placed near the cervix, trapped within the seminal coagulum. As the coagulum liquefies, the spermatozoa are released and enter cervical mucus, a process of penetration that can occur as rapidly as 1.5 to 3 minutes after ejaculation. The primary mechanism whereby spermatozoa pass through cervical mucus appears to be their motility, although other factors such as enzymatic digestion of the mucus may also play a role. The amount of time viable spermatozoa remain in the vagina is not well studied but appears to vary from two to six hours. Successful sperm penetration into and through cervical mucus occurs primarily during the mid-cycle of the menstrual period, at which time the cervical mucus may contain micelles that guide spermatozoa toward the uterus. At other times in the cycle, particularly the luteal phase, cervical mucus is "hostile" to spermatozoa and does not allow penetration. Even at the optimal period, only about 0.1 to 1 percent of ejaculated spermatozoa pass through the cervix. Still, many spermatozoa become trapped in the cervical crypts and can be released at a later date, potentially providing a constant source of spermatozoa for about four days. Passage of spermatozoa through the uterus and fallopian tubes (oviducts) relies on sperm motility, contractions of the tract, and the motion of cilia on the endothelial surface. Because the uterotubal junction and the fallopian tube isthmus also present a barrier to sperm transport, only about 5,000 spermatozoa actually reach the site of fertilization. At the time of fertilization, an oocyte is surrounded by three layers. These are, from the outside inwards, the cumulus oophorus, the corona radiata, and the zona pellucida. The fertilizing spermatozoon has to pass through all these layers to contact the oocyte itself. In addition, it must penetrate the vitelline (egg plasma) membrane and decondense inside the ooplasm. Penetration through the oocyte's protective layers requires the use of lytic enzymes, associated with the acrosome of the spermatozoon. Good evidence suggests that hyaluronidase helps sperm pass through the cumulus; acrosin, a serine proteinase, helps it penetrate

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--> the zona pellucida. Sperm motility, ligand-receptor interactions, and other factors are also required for sperm penetration. Just before or just after it contacts the zona pellucida, the spermatozoon undergoes a morphologic change called the acrosome reaction. This extracellular or exocytotic event results in the disappearance of the sperm's outer acrosomal membrane and surrounding plasma membrane; dispersal of the acrosome proper; activation of proacrosin; and release of acrosomal contents, with acrosin being of particular importance. While sperm penetration through the cumulus oophorus can occur in the absence of the acrosome reaction—presumably because hyaluronidase is associated with the external membranes—sperm passage through the zona pellucida is not possible without this reaction. An early acrosome reaction, such as one that occurs in the vagina, will result in premature release of acrosomal contents and, most likely, in an inability of the spermatozoon to fertilize. Proper timing of the acrosome reaction is controlled by capacitation in the female genital tract, an activation process resulting in removal of inhibitory substances from the sperm surface; by possible modification of the sperm's plasma membrane; and by changes in motility patterns. Ejaculated spermatozoa cannot undergo the acrosome reaction unless they are capacitated. Capacitation can occur in all parts of the female genital tract, with the possible exception of the vagina, and requires at least four hours. However, it probably occurs as a continuous process while the spermatozoa are being transported through the cervix, uterus, and fallopian tubes, so that a spermatozoon is fully or mostly capacitated by the time it reaches the oocyte. Final steps in the capacitation process may occur during sperm passage through the cumulus oophorus. Recently, biochemical aspects of capacitation and the acrosome reaction have received significant attention as possible targets for intervention (Dunbar and O'Rand 1991; see also Appendixes B and C in this volume). The former appears to involve impeding maturation and the acrosome reaction by preventing changes in the sperm's plasma membrane or, in contrast, attempting to induce a premature acrosome reaction that would render sperm unable to meld with an egg. The acrosome reaction, like other exocytotic processes, requires certain physiological conditions such as ligand interaction with surface receptors, activation of second messenger systems, protein phosphorylation, ionic and osmotic changes, and, ultimately, membrane fusion, vesiculation, and disappearance. Mechanisms of Infection by Sexually Transmitted Pathogens Sexually transmitted diseases are caused by a variety of organisms, including bacteria (aerobic and anaerobic), chlamydia, mycoplasmas, ureaplasmas, spirochetes, fungi, flagellates, amoebae, worms, and viruses. Each of these organisms has different biologic properties, conferring widely diverse mechanisms of infection and pathogenesis (see Chapter 2 and Chapter 5).

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--> TABLE D-1 Susceptible Sites for Sexually Transmitted Disease Infection in the Lower Female Genital Tract   Vulva Vagina Endocervix WBCs of Vascular Origin Treponema pallidum X X X   Haemophilus ducreyi X X     Neisseria gonorrhoeae   X     Candida albicans   X     Trichomonas vaginalis   X     Chlamydia trachomatis   X     Cytomegalovirus       X Epstein Barr virus       X Herpes simplex virus X X X   Hepatitis B virus   X X   Human papillomavirus X X X   Human immunodeficiency virus, type 1 ? ? X X Source: Derived from: P Stratton, NJ Alexander. Prevention of sexually transmitted infections. Infectious Disease Clinics of North America 7(4):841-859, December 1993; W Cates, KM Stone. HIV, other STDs, and barriers. IN Barrier Contraceptives: Current Status and Future Prospects, CK Mauck, M Cordero, HL Gabelnick, et al., eds. New York: Wiley-Liss. 1994. The most common human STD pathogens and their primary sites of infection are listed in Table D-1. Effective vaginal microbicides must block infection by directly and efficiently killing these organisms or by blocking or inactivating molecular mechanisms underlying infection. Current detergent vaginal formulations have broad-spectrum cytolytic properties that may be effective against several STD pathogens but may also damage epithelial and other genital tract cells and disrupt normal vaginal flora. Ligand/receptor molecules located on the surface of STD pathogens and their host cells—which are responsible for pathogen attachment and entry—are obvious targets for microbicide action. While these molecular structures have not been fully characterized for most STD pathogens, researchers are intensively seeking them today, importantly including HIV-AIDS. Human Immunodeficiency Virus (HIV) Type 1 The infectiousness of HIV is highly variable and there are still surprising gaps in understanding of its transmission, including the factors affecting amount and timing of virus shedding, the roles of vaginal and seminal antibodies, and the effects of exogenous or endogenous hormones (Mayer and Anderson 1995; Stratton and Alexander 1994). Partner studies have provided much of the information we do have. They indicate that the following factors affect rates of HIV

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--> transmission: (1) mean numbers of sexual contacts and/or types of sexual practices; (2) differences in infectivity of partners depending on disease stage, symptomatology, and therapeutic drug status; (3) potential differences in infectivity of various clades of HIV-1; and (4) intrinsic biological differences between infecting or susceptible partners. Specific risk factors specific to heterosexual transmission of HIV-1 include: (1) sex during menstruation; (2) anal intercourse; (3) traumatic sex; (4) advanced HIV disease stage of infected partner; (5) zidovudine therapy (negative association); (6) age of the female partner; (7) choice of contraceptive method; and (8) concomitant STD infections (bacterial vaginosis, candidiasis, chancroid, chlamydia, gonorrhea, herpes simplex, human papilloma virus, syphilis, and trichomoniasis have all been associated with HIV transmission) (Mayer and Anderson 1995; Stratton and Alexander 1993). The cell biology and molecular mechanisms of HIV-1 sexual transmission are areas where much remains to be learned. It is known that HIV-1 is present in semen and cervicovaginal secretions, both in cell-free and cell-associated forms, and data from both in vitro and in vivo primate studies indicate that each of these forms may be capable of transmitting infection. Cell-free HIV-1 in genital-tract secretions may infect Langerhans cells, lymphocytes, and/or macrophages residing within the epithelial layer of mucosal surfaces in the vagina, foreskin, and penile urethra. Infection could occur via CD4, Fc, complement, or other receptors as yet unknown. If genital lesions or microabrasions are present, HIV-1-infected white blood cells (WBCs) in genital-tract secretions could infect by direct access to target cells in connective tissue (resident and extravasated WBCs). Furthermore, in vitro studies indicate that HIV-infected WBCs may have the capacity to adhere to mucosal epithelium and transmit HIV directly to these cells (Mayer and Anderson 1995). Numerous biologic variables can affect HIV levels in semen and cervicovaginal secretions and may also influence HIV transmission rates. Leukocytospermia (inflammation of the genital tract) in men has been associated with higher HIV-1 titres in semen. This phenomenon may be due to recruitment of HIV-1-infected cells to the genital tract; induction of edema and capillary dilation, both of which increase the potential for erosion and escape of blood lymphocytes and monocytes into the intravascular space and lumen; and/or activation of lymphocytes that could make them more capable of producing HIV- 1. In women, several variables can affect infectious HIV-1 titres in genital-tract secretions, including: (1) inflammation of the genital tract; (2) menstruation, which introduces infected peripheral blood cells into vaginal secretions; (3) factors elevating vaginal pH, which is normally acidic and confers protection against STDs, including HIV-1; (4) cervical ectopy; and (5) hormonal factors that influence the thickness of the epithelial layer and the production of protective mucus (Mayer and Anderson 1995). An open—and highly significant—question is whether HIV is carried solely by somatic cells in semen or whether it is carried by the sperm themselves. If the

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--> former is the case, contraception is not necessary for prevention of sexually transmitted infection, so that a primary technologic need is for a virucide/microbicide; individuals can then decide whether they wish to contracept as well, but it is a separate decision. However, if the latter is the case, contraception becomes an essential concomitant of disease prevention (Stein 1993). The healthy human vagina has several natural defense mechanisms against STD pathogens. The stratified squamous epithelium lining of the vagina and ectocervix is generally several cell layers thick, conferring physical protection against most invading organisms. Copious amounts of mucins produced during certain stages of the menstrual cycle also provide a physical barrier to pathogens. In addition, the vagina and cervix are both capable of mounting antibody and cell-mediated immune responses to genital tract infections, and cervicovaginal secretions contain a number of nonspecific antibacterial and antiviral defense agents, including lysozymes, polyamines, zinc, H202, lactoferrin, and B-defensins (Cohen et al. 1990). Finally but quite importantly, the predominant normal vaginal microflora—lactobacillus organisms—help to maintain low pH conditions that are hostile to most viral and bacterial pathogens (Voeller et al. 1992b). Unfortunately, a number of situations perturb these natural protective mechanisms. Menopause and progestin-dominated hormonal therapies, for example, cause thinning of the squamous epithelial layer and reduction in cervical mucus production. Intercourse and vaginal infections, whose coincidence is not uncommon, can cause an elevation in vaginal pH, disarming this effective protective mechanism. And, although currently marketed vaginal topical contraceptives may, in fact, be buffered at acidic pH, the buffering capacity of semen itself elevates the vaginal pH substantially (Masters and Johnson 1980). Approaches to the Development of Novel Vaginal Formulations Pivotal Issues The Balance Between Protection and Perturbation The functional activity of both spermatozoa and pathogenic microbes can be prevented by killing or inactivating them. The former strategy employs spermicides and microbicides. The latter relies on agents that inhibit the functional activity of spermatozoa and microbes so that they are unable to enter, respectively, the oocyte or the vaginal/cervical epithelium and target cells. Although these inactivating agents are more appropriately called spermistats and microbistats, the terms spermicide or microbicide are still frequently used for all antifertility and antimicrobial agents. Candidate classes of these compounds include detergents and surfactants, iodophores, carbohydrates, antibodies, antiviral drugs, defensins, and pyocins.

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--> Many of the chemical formulations that are currently available for use as vaginal contraceptives, in addition to their contraceptive properties, can confer some protection against such STD infections as Neisseria gonorrhea , Trichomonas vaginalis, and Chlamydia trachomatis (Rosenberg et al. 1987, 1992). However, like microbicides, spermicides act as cytotoxins, often destroying vaginal and cervical cell membranes (Patton et al. 1992). As a consequence, the protective capacity of these formulations erodes under frequent and/or prolonged use, largely because their potential effects on normal vaginal flora and on the vaginal/cervical epithelium create perturbations that can actually promote the possibility of STD transmission (Kreiss et al. 1992; Niruthisard et al. 1991, 1992). This means that, if vaginal formulations are to be used more often for STD prevention, they will have to be nonirritating, nontoxic, and not upset the normal vaginal environment. In other words, such formulations must produce no lasting impact on the normal vaginal flora and their work in maintaining the vaginal milieu and its naturally acidic pH, nor should they compromise the vaginal or cervical epithelium. Each formulation will therefore need to be rigorously tested for any proinflammatory effects that could promote transmission of STD pathogens, notably HIV-1. Efficacy A topical formulation used for purposes of vaginal contraception consists of one or more active ingredients and a base (carrier) to deliver them. Both are important and each presents particular challenges to researchers and users. Typically, an active ingredient makes up only about 5-10 percent of an entire formulation; at least this is the case for those products that are on today's market, primarily surfactants or detergents such as nonoxynol-9, octoxynol-9, menfegol, and benzalkonium chloride (Haslett 1990; Hatcher and Warner 1992; Mauck et al. 1994). The activity of these products resides in their ability to dissolve lipid components in the cell membrane or viral envelope. Since these agents have approximately the same properties and potency, marketed formulations differ primarily in their base composition—either jellies, creams, foams, suppositories, tablets, films, or sponges. Because the active ingredients in these formulations all act by immobilizing or killing spermatozoa, they are usually referred to as "spermicides." The contraceptive use-effectiveness of existing formulations varies greatly from study to study (Trussell 1994). Reported failure rates range from 2 percent to over 40 percent, with typical rates falling between 15 and 20 percent (Sobrero 1989), much higher than desirable. The limited efficacy of these formulations, their brief longevity after vaginal placement and effects on coital spontaneity, together with leakage and consequent "messiness," surely constrain consumer interest in available vaginal contraceptives. Although the relatively poor efficacy of available vaginal contraceptive for-

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--> mulations can be partly blamed on improper use, some animal experiments have shown that the efficacy of many current products may be low even with more reliable use (Homm et al. 1976; Zaneveld et al. 1977). This implies that either their active ingredients and/or their distribution/delivery systems are in some way ineffective; because good comparative studies are rare, it has been difficult to discern where, exactly, the primary limitations reside. Furthermore, because many pathogens—for instance, HIV, the herpes viruses, and chlamydial elementary bodies—are cell-associated, the margin between toxicity and efficacy is narrow. There is nothing unique about the membrane of an infected cell that permits a surfactant to distinguish it from the membrane of a healthy cell, though the cells of intact genital mucosa may be protected to some extent by a coating of mucus. Finally, in vitro spermicidal efficacy does not necessarily translate into in vivo contraceptive efficacy (Quigg et al. 1988). Thus, without in vivo studies, it is not possible to state with certainty whether an agent with spermicidal properties is also contraceptive (Zaneveld 1994a, 1994b), nor are in vitro spermicidal comparisons adequate to the task of assessing the relative contraceptive activity of different formulations. The Base Because an active ingredient is only as effective as its delivery system allows, the formulation's base requires careful attention. Not only can the nature of a given base "make or break" the active ingredients, but can, in itself contribute to prevention of STD infections and conception, an attribute that should enhance the overall acceptability of vaginal topicals to women. The following characteristics of a good base are particularly important: A good base should spread rapidly and evenly over the vaginal and cervical surface, forming a slightly adhesive film. Optimally, this film should be impenetrable to microbes and, if possible, spermatozoa. The film should remain in place for prolonged periods of time, including during intercourse, providing long-acting protection. Leakage and consequent "messiness" should be minimal. Finally, the formulation should be somehow buffered at an acidic pH so as to retain a pH below 4.5 even in the presence of semen. New Technologies Many complicated biochemical processes are required for successful fertilization. Inhibition of any of these processes can lead to infertility, providing a

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--> large number of potential attack sites for new contraceptive agents, both chemical and immunologic. Yet, to date, only a few researchers have taken advantage of advances in knowledge to develop novel vaginal contraceptives. New information can also be utilized to identify agents that can prevent both conception and STD infection. Tissue and/or cell invasion is required for both spermatozoa and pathogenic microbes to reach their target sites. Such invasion requires the activity of lytic enzymes, binding proteins, receptor-ligand interactions, fusion, endo- and exocytotic events, and a myriad of other processes. Each of these events is susceptible to inhibition, which would in turn prevent invasion. It is possible, if not likely, that spermatozoa and certain pathogenic microbes use some identical mechanisms of invasion. If so, the same agent could be used to prevent both occurrences (see Table D-2). Detergents and Surfactants Several detergents are already licensed in one country or another for intravaginal use as contraceptive agents. These include nonoxynol-9, the most commonly used, as well as menfegol, octoxynol, and benzalkonium chloride. Like the phospholipids that constitute cell membranes, detergents have hydrophobic and hydrophilic domains and exhibit activity that derives from their ability to dissolve lipid components in the cell membrane or viral envelope. Improvements on nonoxynol-9 may come from removing low molecular weight toxic components from the polydispersed N9 mixture (Klebanoff 1992; Walter et al. 1991a, 1991b), from improving dispersion/distribution, by providing for triggered release (Quigg 1991), or by lowering the detergent dose. In order to extend the spectrum of activity or longevity of action, low concentrations of nonoxynol-9 could be combined with other agents, for example, other detergents (Psychoyos 1994), beta-lactoglobulin (Neurath et al. 1996), antivirals (De Clercq 1993; Tsai et al. 1995), or zinc (Krieger and Rein 1992; Mardh et al. 1980; Williams 1980). Milk Fatty Acids Lipids found in human milk and epidermis display antibacterial and antiviral activity (Isaacs et al. 1990). Microbial killing by milk lipids is primarily due to the free fatty acids and monoglycerides that are released from milk triglycerides by lipases. At high concentrations, lipophilic molecules may be expected to have activity on sperm membranes that is similar to their activity on the membranes of other cells (Thormar et al. 1987). Chlorhexidine Chlorhexidine is a broad-spectrum antiseptic used in a prescription oral rinse. It is a positively charged molecule at physiological pH and binds to negative sites

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--> TABLE D-2 Potential Targets and Mechanisms for Agents that Prevent Pregnancy and/or Sexually Transmitted Diseases Target Mechanism Intended Effect Sperm     Nonoxynol-9 Surfactant Spermicidal C31G Surfactant Spermicidal Chlorhexidine Surfactant Spermicidal Peroxides Membrane active Spermicidal Antibody (MAb) Agglutination Decreased forward motility   Shaking phenomenon Decreased forward motility Magainin Pore formation Spermicidal Decapacitation factor Blocks capacitation No acrosome reaction Progesterone Activates calcium channels Premature acrosome reaction AGB Acrosin inhibitor Fertilization blocked Sulfonated polystyrene Acrosin inhibitor Fertilization blocked   Agglutination Decreased forward motility ZP mimics Blocks ZP binding Fertilization blocked Acidic buffer Maintains low pH Spermicidal Zinc Blocks capacitation Blocked fertilization Neem Membrane-active Spermicidal Squalamine Membrane-active Microbicidal Pathogen     Nonoxynol-9 Disrupts membrane/envelope Microbicidal C31G Disrupts membrane/envelope Microbicidal Chlorhexidine Disrupts membrane/envelope Microbicidal Milk fatty acids Disrupt membrane/envelope Microbicidal Peroxides Membrane-active Microbicidal Antibody Agglutination Immune exclusion Docosanol Disrupts membrane/envelope Microbicidal (enveloped viruses) CAM mimic Decoy Adhesion blocked Sulfated polymer Coats cells Adhesion blocked   Coats virus Fusion blocked AGB Protease inhibition Adhesion blocked Protegrins Pore-formation Microbicidal Acidic buffer Maintains low pH Microbicidal Zinc Binds proteins Microbicidal Neem Membrane-active Microbicidal Squalamine Membrane-active Microbicidal PMPA Reverse transcriptase inhibition Anti-HIV Cervicovaginal Environment     1. Mucus     Acidic buffer Lowers or maintains pH Microbicidal Lactoferrin Fe binding Inhibits Fe dependent pathogens Lysozyme Enzymatic bacteriolysis Bactericidal Zinc Protein binding Microbicidal Sulfonated polystyrene Increases viscosity Decreased sperm migration Chlorhexidine Increases viscosity Decreased sperm migration

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--> administered suppositories and a boosting effect might also be produced by reproductive processes themselves. Relatively little is known about cell-mediated immune (CMI) responses within the male or female genital tracts and their potential effects on fertility. Although chronic CMI responses may be associated with undesirable side effects such as delayed-type hypersensitivity and irreversibility, CMI responses to infrequent or low antigen exposures could provide a powerful adjunct mechanism for mucosally targeted immunization. More needs to be known about how secreted antibodies function in mucus to protect the human mucosal surfaces. Despite evidence that antibodies can be highly effective at blocking mucosal transmission of both infectious agents and sperm, both sperm and STD pathogens have evolved mechanisms for successful exchange between sexual partners—mechanisms that evade immune defenses in mucosal secretions—of which one of the most challenging is the common evasion mechanism of antigenic variability, which enables pathogens to stay a step ahead of host immune responses. A potential, though surely challenging, research direction would be to seek combinations of pathogen-specific monoclonal antibodies and pan-semen or other anti-human surface antigenic monoclonal antibodies that could defeat these evasive actions and ultimately provide effective broad-spectrum protection against STDs and pregnancy (Cone and Whaley 1994). References Abraham E, S Shah. Intranasal immunization with liposomes containing IL-2 enhances polysaccharide antigen-specific pulmonary secretory antibody response. Journal of Immunology 149:3719-3726, 1992. Ada GL. The induction of immunity at mucosal surfaces. IN Local Immunity in Reproductive Tract Tissues. PD Griffin, PM Johnson, eds. Oxford, UK: Oxford University Press. 1993. Alving CR, RL Richards. Liposomes containing lipid A: A potent nontoxic adjuvant for a human malaria sporozoite vaccine. Immunology Letters 25:275-279, 1990. Anderson DJ. Mechanisms of HIV-1 transmission via semen. Journal of NIH Research 4:104-108, 1992. Anderson DJ. Cell mediated immunity and inflammatory processes in male infertility. Archives of Immunology and Therapeutic Experiments 38:79-86, 1990. Anderson DJ, JA Hill. Cytokines in the reproductive tract that affect fertility. Mucosal Immunology Update 2:6-15, 1995. Anderson DJ, J Pudney. Mucosal immune defense against HIV-1 in the male urogenital tract. Vaccine Research 1:143, 1992. Anderson DJ, EJ Yunis. "Trojan Horse" leukocytes in AIDS. New England Journal of Medicine 309:984-985, 1983. Araujo FG, B Morein. Immunization with Trypanosoma cruzi epimastigote antigens incorporated into ISCOMS protects against lethal challenge in mice. Infectious Immunology 59:2909-2914, 1991. Beagley KW, JH Eldridge, F Lee, et al. Interleukins and IgA synthesis: Human and mouse IL-6 induce high rate of IgA secretion in IgA committed B cells . Journal of Experimental Medicine 169:2133-2148, 1989.

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