Bridging the gap between preclinical and clinical microbicide trials: blind evaluation of candidate gels in murine models of efficacy and safety

PLoS One. 2011;6(11):e27675. doi: 10.1371/journal.pone.0027675. Epub 2011 Nov 11.


Background: Despite significant protection in preclinical studies, cellulose sulfate (CS) failed to protect women against HIV-1/2 and was associated with a trend toward increased HIV-1 acquisition in one of the clinical trials. These results highlight the need for preclinical tests more predictive of clinical outcomes. The objective of this study was to test coded vaginal gels, including CS, in murine models of safety and efficacy to determine the models' utility for evaluating future products.

Methods: Four coded formulations, including 6% CS, 2% PRO 2000 and two placebo gels, were administered intravaginally to medroxyprogesterone-treated mice and their ability to prevent genital herpes (efficacy) or to alter the susceptibility to low dose HSV challenge (safety) was determined. Nonoyxnol-9 served as a positive toxicity control.

Results: CS and PRO 2000 significantly protected mice from genital herpes following infection with a laboratory or clinical isolate of HSV-2 introduced in buffer (p<0.001). However, protection was reduced when virus was introduced in seminal plasma. Moreover, mice were significantly more susceptible to infection with low doses of HSV-2 when challenged 12 h after the 7th daily dose of CS or nonoxynol-9 (p<0.05). The increased susceptibility was associated with alterations in epithelial architecture.

Conclusions: CS prevented genital herpes when present at the time of viral challenge, but increased the rate of infection when gel was applied daily for 7 days with a vaginal wash prior to viral inoculation. The findings presumably reflect altered epithelial architecture, which may have contributed to the trend towards increased HIV observed clinically.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Intravaginal
  • Animals
  • Anti-Infective Agents / administration & dosage
  • Anti-Infective Agents / adverse effects
  • Anti-Infective Agents / therapeutic use*
  • Cellulose / administration & dosage
  • Cellulose / adverse effects
  • Cellulose / analogs & derivatives
  • Cellulose / therapeutic use
  • Female
  • Herpes Genitalis / prevention & control*
  • Herpesvirus 2, Human / drug effects
  • Herpesvirus 2, Human / pathogenicity
  • Mice
  • Naphthalenesulfonates / administration & dosage
  • Naphthalenesulfonates / adverse effects
  • Naphthalenesulfonates / therapeutic use
  • Polymers / administration & dosage
  • Polymers / adverse effects
  • Polymers / therapeutic use
  • Vaginal Creams, Foams, and Jellies / administration & dosage*
  • Vaginal Creams, Foams, and Jellies / adverse effects
  • Vaginal Creams, Foams, and Jellies / therapeutic use*


  • Anti-Infective Agents
  • Naphthalenesulfonates
  • PRO 2000
  • Polymers
  • Vaginal Creams, Foams, and Jellies
  • Cellulose
  • cellulose sulfate