March 2009 36(3) Abstracts from the Supplement
Biomarkers for evaluating vaginal microbicides and contraceptives: discovery and early validation. Mauck CK. S73-S75.
A biomarker has been defined as "a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, pharmacological responses to a therapeutic intervention." Biomarkers can reduce the costs and time required to get a drug from discovery to market. Topical microbicides are new drugs designed to prevent HIV and other sexually transmitted infections (STIs). Biomarkers that may be important in microbicide development include biomarkers of semen exposure, biomarkers of cervicovaginal inflammation, and biomarkers of HIV and STIs. The development of biomarkers for use in microbicide development is a high priority.
This supplement reports on a meeting entitled "Biomarkers for Evaluating Vaginal Microbicides and Contraceptives: Discovery and Early Validation," held in Reston, VA on November 16 to 17, 2006. It was sponsored by CONRAD and the Alliance for Microbicide Development with funding from the Bill and Melinda Gates Foundation and the United States Agency for International Development (USAID). The meeting was convened to look at the ways in which biomarkers could be used to attenuate the challenges alluded to above. Availability of key biomarkers could expedite the development of microbicides, for which there is a pressing need, especially in developing countries where combinations of cultural and socioeconomic pressures on women constrain their ability to protect themselves from STIs. Although the meeting was held 2 years ago, the material reviewed and conclusions drawn are still relevant.
Biomarker discovery: validation and decision-making in product development. Niedbala RS, Mauck C, Harrison P, Doncel GF. S76-S80.
The conference on which this supplement reports was organized to bring together microbicide researchers with researchers in the areas of drug prophylaxis and therapeutics development. The goal of session 1 was to share methods used to validate markers of disease, elucidate the logic used to substantiate the performance of those markers, and identify ways to translate this experience into practical steps for developing microbicides. The experiences discussed ranged from de novo discovery of new therapeutics to qualification of biomarkers across all stages of development, and covered the complexity of biomarker identification, use, and assessment in the clinical areas of cancer and infectious disease.
This review is based on the presentations of Drs. Harsukh Parmar (AstraZeneca), Sudhir Srivastava (National Cancer Institute [NCI]), and Juan Leal (Exelixis Inc.), and the subsequent discussion led by Drs. Sam Niedbala (Lehigh University) and Thomas Moench (ReProtect) during a background session held at the conference entitled "Biomarkers for evaluation of vaginal microbicides and contraceptives: Discovery and early validation," organized by CONRAD and the Alliance for Microbicide Development in November 2006.
Biomarkers of semen exposure. Mauck CK. S81-S83.
Biomarkers of semen exposure have historically played their most important role in forensics, i.e., determining whether ejaculation took place in the course of a crime. However, it is becoming increasingly recognized that biomarkers of semen exposure can be useful in the development of new vaginal methods of HIV/sexually transmitted infections (STI) prevention and contraception. This review is based on the presentations of Drs. Michael Coppola (ContraVac, Inc.), Maurizio Macaluso (Centers for Disease Control and Prevention), Andrezej Kulczycki (University of Alabama at Birmingham), Christine Mauck (CONRAD), Robin Maguire (Population Council), and the subsequent discussion led by Drs. Susan Ballagh (CONRAD) and Johan Melendez (Johns Hopkins University) during a session entitled "Biomarkers of semen exposure" held during the conference entitled "Biomarkers for evaluation of vaginal microbicides and contraceptives: Discovery and early validation," organized by CONRAD and the Alliance for Microbicide Development in November of 2006.
Biomarkers of cervicovaginal inflammation for the assessment of microbicide safety. Cummins Jr JE, Doncel GF. S84-S91.
The human cervicovaginal mucosa is the primary target of HIV-1 infection during male to female transmission. This tissue contains the full spectrum of cell types and immune modulators that comprise both the innate and adaptive arms of the immune system. Mounting evidence indicates that mucosal epithelial cells are sentinels of the female reproductive tract, producing innate immune mediators that control the vaginal microflora under normal conditions. Recent studies, however, indicate that certain factors secreted in response to another pathogen or after exposure to a vaginal product may in fact enhance infection by HIV-1. Mucosal inflammation and CD4 cell activation as well as disruption of TLR function and epithelial integrity represent potential causes for such effect. It is therefore important to make sure that vaginal products, including microbicides, do not disrupt the structure or function of the cervicovaginal mucosa. Although a number of biomarkers have been linked to microbicide-induced cervicovaginal inflammation and many of these markers have been measured in preclinical and clinical assays, there are currently no data that demonstrate a correlation between any one marker and susceptibility to HIV-1 infection in humans. To date, the lack of a validated biomarker of cervicovaginal safety represents a gap in the knowledge base that hinders the rational and expeditious selection of microbicide candidates entering clinical trials. Current discovery efforts and preclinical assessment of microbicide safety use an integrated sequential evaluation system that includes cell-based models, explant-based models, and animal-based models. Relevant research in these areas is yielding new assays and biomarkers that, if validated, will be essential to the rational selection of microbicide candidates for efficacy trials.
Understanding basic mechanisms and optimizing assays to evaluate the efficacy of vaginal microbicides. Keller MJ, Herold BC. S92-S95.
The ideal microbicide or microbicide combination must have activity against cell-free and cell-associated primary HIV isolates representing multiple clades, must inhibit transmission to relevant cell types within the mucosa, and must retain activity in the presence of cervicovaginal fluid and when virus is introduced in semen or seminal plasma. This summary briefly reviews some of the basic concepts underlying the optimization of assays to evaluate the efficacy of candidate microbicides against HIV/STI. The review is based on the presentations of Drs. Stuart Turville (Population Council), Dan Barouch (Harvard University), Scott McCoombe (Northwestern University), Betsy Herold (Albert Einstein College of Medicine), Sam Niedbala (Lehigh University), and the subsequent discussion led by Drs. Robin Shattock (St. George's Hospital Medical School) and Jim Turpin (National Institutes of Health) during a session entitled "Biomarkers of HIV/STI" held at the conference entitled "Biomarkers for evaluation of vaginal microbicides and contraceptives: discovery and early validation," organized by CONRAD and the Alliance for Microbicide Development in November of 2006 as well as more recent published findings.