U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health

National Institute of Allergy and Infectious Diseases

Protective Efficacy

Product Acceptability

Safety

September 2

g

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health

National Institute of Allergy and Infectious Diseases

NIH Publication No. 03-7138

September 2003

www.niaid.nih.gov

Protective Efficacy

Product Acceptability

Safety

September 2

g

The Organizational Framework for Microbicide Research and Development . . . . . . . 

NIAID Strategy for Microbicide Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 

Comprehensive Microbicide Program . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 

Organization of the NIAID Topical Microbicide Program . . . . . . . . . . . . . . . . . . . . . . 

Basic Biomedical Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 

Preclinical Product Development and Selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 

Phase I Through Phase III Clinical Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 

Social and Behavioral Research on Microbicides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 

Criteria for Advancement of Candidate Microbicides . . . . . . . . . . . . . . . . . . . . . . . . . . 

Entry into Clinical Efficacy Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 

NIAID Topical Microbicide Program – 5-Year Scientific Priorities . . . . . . . . . . . . . . . . . 

Basic Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 

Preclinical Product Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 

Clinical Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 

NIAID Topical Microbicide Strategi
Clinical Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .34

Microbicide Research and Development: Scientific Opportunity and Response . . . . . . . .35

Limitations of Existing Strategies to Avert Sexual Transmission of HIV . . . . . . . . . . . .35

The Potential for Topical Microbicides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .35

Plausibility of Topical Microbicides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .36

Progress to Date . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .36

Scientific Progress in Microbicide Development Can be Accelerated 

at All Phases: Discovery, Preclinical Development, and Clinical Evaluation . . . . . . . . . .44

Basic Biomedical Research: Expanding Knowledge of Fundamental Mechanisms of 

HIV/STD Mucosal Transmission and of Protection From Sexual Infection . . . . . . . .44

Preclinical Development: Improving the Likely Predictive Power of In Vitro, 

Ex Vivo, and Animal Models for Safety and Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . .45

Phase I Through Phase III Clinical Evaluation: Establishing Sufficient Capacity to 

Efficiently Advance Meritorious Products into and Through Proof-of-Concept Trials . .48

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .51

Attachment 1: NIAID TopMic Group Membership . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .52

End Notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .53

Photo Descriptions & Credits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .55

ii NIAID Topical Microbicide Strategic Plan
PART A: 

DISCOVERY,

DEVELOPMENT,

AND

EVALUATION

infections (STIs), both because HIV infection 

is a fatal STI and because other STIs are risk

factors for sexual transmission of HIV. Without

effective measures to prevent sexual transmission

of HIV and other STIs, HIV incidence will

continue to rise. In addition, STIs other than

HIV cause significant morbidity and mortality,

accounting for more than 17 billion dollars in

costs annually in the United States alone. 

A consensus has emerged that safe, effective,

accessible topical microbicides are needed to

prevent sexually transmitted HIV infection as

well as other STIs. Such products – foams, gels,

creams, suppositories, etc. – would be designed

for intravaginal or intrarectal use where they

would inactivate or block sexually transmitted

pathogens such as HIV and other STIs. In

addition to the greatest achievable efficacy

against HIV and other STIs, an ideal microbicide also would be 

• Completely safe for daily use 

• Fast acting and long lasting 

• Acceptable and appealing to both 

sexual partners

• Inexpensive and available 

without prescription 

Goals

The long-term goal of the National Institute of

Allergy and Infectious Diseases (NIAID) is to 

identify safe and effective microbicides to prevent

HIV/AIDS and other STIs. NIAID’s near-term

goal is to establish proof-of-concept (i.e., safety and

effectiveness) of at least one candidate microbicide

against HIV/AIDS. Once this proof-of-concept 

has been established, NIAID’s focus will shift to 

product optimization in relation to the broad 

criteria listed previously for an ideal product. 

To achieve this goal, NIAID’s strategy is to 

support an integrated extramural program 

consisting of three complementary components:

basic biomedical research, preclinical product

development, and clinical evaluation, including

behavioral research. In general, investigatorinitiated grants provide funding for basic

research that requires scientific creativity and

innovation. Contracts support development

through efficient, responsive, often highthroughput standardized product evaluation

and pilot lot manufacturing processes.

Cooperative agreements support clinical

research, providing a mechanism for integrating

extramural investigator leadership in study

design and conduct with facilitation by Federal

program officers and medical officers. Program

The long-term goal of the National Institute of Allergy and Infectious Diseases (NIAID)

is to identify safe and effective microbicides to prevent HIV/AIDS and other STIs. 

NIAID Topical Microbicide Strategic 
microbicide design and evaluation, help expand

and diversify the microbicide pipeline, identify

safe and acceptable formulations, and foster

improved methods for the preclinical and clinical

evaluation of microbicide candidates. Current

priorities are to

• Define the molecular basis and chronology

of the early steps in the infectious processes

of HIV and other STI pathogens to identify

multiple points at which the process of

infection may be interrupted 

• Characterize cervicovaginal and rectal

microbial ecology and the natural defense

mechanisms of cervicovaginal and rectal tissues 

• Establish new and improved in vitro, 

ex vivo, and in vivo models to evaluate

microbicide safety and efficacy 

• Determine the optimal characteristics and

mode of delivery of topical formulations

Preclinical Product Development of

Topical Microbicides

In general, the private sector is best equipped 

to carry out product development. Because the

private sector has been reluctant to fully engage

in microbicide development, however, public

sector support is needed to facilitate critical work

that is currently unsupported or partially supported.

A broadly active agent or combination of agents

where they are suitable for human testing.

NIAID will

• Facilitate identification of the safest and

potentially most efficacious candidate 

topical microbicides through laboratory 

and animal testing against HIV and other

STIs, including

 In vitro testing

 Animal vaginal irritation and other 

animal safety studies

 Animal efficacy

• Manufacture and, if necessary, formulate 

in amounts suitable for early phase clinical

testing, selected, promising microbicide 

candidates that have proven safe in preclinical

studies and that have activity against HIV,

with preference given to those that have the

broadest activity profile 

• Work with sponsors and regulatory authorities

to encourage and expedite testing of the

most promising products, alone and/or

in combination

Clinical Evaluation of Topical

Microbicides Integrated with

Behavioral Research

This stage of microbicide development is

extremely challenging and complicated. Clinical

evaluation must be conducted vigorously to

2 NIAID Topical Microbicide Strategic Plan
duy

and efficacy/effectiveness against HIV

infection in humans

• Support Phase I, II, and III clinical trials of

selected, highly promising candidate topical 

HIV microbicides 

• Help characterize critical factors associated

with microbicide acceptability

• Identify strategies for improving the conduct

of effective and ethical clinical trials

Future Plans

A 5-year implementation plan is proposed to

support the nearer-term goal of establishing

proof-of-concept for at least one microbicide

candidate while simultaneously supporting basic

and applied programs, which are expected to

lead to a more robust and diverse pipeline of

microbicide candidates for future testing as 

well as improved and enhanced technologies to

expedite development (e.g., new and promising

preclinical models for evaluating both HIV and

STI safety and efficacy, new STI diagnostics).

Once the nearer-term goal of identifying and

establishing the safety and effectiveness of at least

one candidate product has been demonstrated

clinically, NIAID will expand its focus, especially

through partnerships with other agencies involved

in microbicide development and dissemination, to

products that have proven safe and ef

• Support long-term follow-up of volun

to evaluate long-term effectiveness an

• Link with others to foster relevant soc

behavioral research, whenever approp

NIAID Topical Microbicide Strategic 
4 NIAID Topical Microbicide Strategic Plan

g

whom were infected perinatally. Of 5 million

new infections in 2001, 2 million (40 percent)

occurred among women. The vast majority 

of these infections were acquired through

unprotected sexual intercourse. Unless effective

prevention measures to stop sexual transmission

of HIV are implemented, the number of AIDS

cases will continue to grow. 

The HIV pandemic has focused attention on

sexually transmitted infections (STIs), both

because HIV infection is a fatal STI and

because other STIs are risk factors for sexual

transmission of HIV. Separate from the HIV

epidemic, STIs cause significant morbidity and

mortality and contribute greatly to increasing

health care costs. In the United States, where

more than 65 million people are infected with

an incurable STI, an estimated 15 million new

cases occur each year, with teenagers accounting

for approximately 25 percent of these new

infections.1 Excluding HIV, these infections

cost in excess of $17 billion in 1994 in

lost wages and health care expenditures.2

Furthermore, in several major U.S. cities,

unsafe sexual practices are on the rise, as

indicated by both behavioral surveillance and

increases in rectal gonorrhea and syphilis cases. 

ppy

or avert infection of susceptible cells, or block

dissemination from initial target cells. The

development of a microbicide for HIV (or any

other STI) that meets requirements for U.S.

Food and Drug Administration (FDA) 

licensure is a daunting task. Not only must it

be effective against HIV, but also the spectrum 

of effectiveness against other STIs must be

known, including the potential to increase 

susceptibility to one or more sexually transmitted

agents. In addition, the short-term and

longer-term safety must be well documented

with sufficient follow up in Phase III studies.

Furthermore, combination products, using

multiple strategies to block infection, may 

represent the most promising approach but

may require that each individual active 

component as well as the combination be

proven safe. These factors impose substantial

requirements upon the design and cost of 

clinical trials. 

The compelling near-term need is to establish

the plausibility of at least one candidate agent.

Identifying a safe and even partially efficacious

product would then shift the emphasis from

proof-of-concept to product optimization. 

The following considerations guide NIAID’s

perspective on efficacy and effectiveness trials.

The compelling near-term need is to establish the plausibility of at least one

candidate agent.
NIAID Topical Microbicide Strategic 

• Safety, both short term and longer term 

for the user and the user’s partner(s),

is paramount. 

• A partially efficacious product could provide

insights into factors associated with effective

blocking of sexual transmission: so-called

correlates of effectiveness. In turn, knowledge

of one or more correlates of effectiveness

could accelerate identification and development

of improved agents and formulations.

Iterative processes like this offer the best

chance to develop an optimal product. 

• Demonstration of the safety and efficacy of a

topical product in preventing HIV infection

or any other STI (i.e., proof-of-concept)

would likely remove an important barrier to

increased industry investment in product

development, particularly if concurrent

efforts have been made to assure the existence

of markets for effective products and to

address concerns about corporate liabili

during and after the conduct of trials. 

If the first product shown to be effective 

only partial protection or fails to meet all 

criteria that would be desirable in an opt

product (Table 1), new insights into corr

of effectiveness, together with findings rega

product acceptability from field experien

during large-scale efficacy and effectivene

trials, can inform the development of add

products and formulations and thereby s

optimization for increased efficacy, utility

and acceptability. 

This strategic plan elaborates the approac

NIAID to microbicide discovery, develop

and evaluation as it supports the near-ter

of proof-of-concept of at least one candid

in effect

• Be acceptable to both sexual partners

or completely unobtrusive

• Be available in both contraceptive 

and non-contraceptive formulations

• Be suitable for both vaginal and 

rectal application

• Act potently against HIV and/or other

STIs in both ejaculate and cervicovaginal secretions to provide 

bi-directional protection for both partners

store and transport

• Be messy or leaky

• Cause burning or itching

• Be costly or require a prescription 

• Require use of an uncomfortable, 

cumbersome, or otherwise 

unacceptable applicator

• Upset the vaginal (or rectal) 

microbial ecology (e.g., kill

Lactobacilli or enhance overgrowth 

by other pathogens)
positioned to address in comparison 

with other organizations 

• Sets out plans for addressing those needs

through expansion of existing resources 

and development of new programs 

• Outlines general and specific decision criteria

to be used at critical junctures to select

products for prioritized development using

NIAID-supported resources 

Part B of this plan addresses some of the

important scientific challenges associated 

with basic, preclinical, and clinical phases 

of microbicide development, and approaches

that may be used to address those scientific

challenges. Specifically, Part B

• Describes the current status of microbicide

development including

 Limitations of existing strategies to 

prevent sexual transmission

 Progress thus far in

microbicide development 

 Reasons for expecting microbicides to

be an effective prevention strategy

• Elaborates remaining challenges in 

microbicide research and development

development has remained the mission of

domestic and international public sector 

organizations and foundations. Moreover, 

public support has only recently begun to 

gain momentum. Total Federal support for

microbicide research in fiscal year (FY) 2001

was approximately $61,300,000, as shown in

Figure 1. (The fiscal year runs from October 1

through September 30.) 

The major funding agency for microbicide

research and development is the National

Institutes of Health (NIH), part of the U.S.

Department of Health and Human Services,

with approximately $47 million devoted to 

topical microbicides in FY 2001. This figure is

expected to increase to almost $56 million in

FY 2002. The U.S. Agency for International

Development (USAID) was tasked by Congress

in FY 2001 to establish a microbicide research

and development program and allocated a

budget of $12.0 million. The U.S. Centers for

Disease Control and Prevention (CDC) has

developed a topical microbicide program with

particular emphasis on Phase I studies and

development of international infrastructure 

for clinical testing of microbicides. A total of

approximately $2,200,000 FY 2001 funds were

committed to this effort.

The major funding agency for microbicide research and development is the

National Institutes of Health (NIH).

6 NIAID Topical Microbicide Strategic Plan
NIAID Topical Microbicide Strategi

CDC
Institute on Drug Abuse (NIDA), National

Institute of Mental Health (NIMH), Fogarty

International Center (FIC), Office of Research

on Women’s Health (ORWH), and Office of

Behavior and Social Science Research (OBSSR). 

In response to a congressional mandate, OAR,

in collaboration with other NIH institutes,

CDC, USAID, and outside domestic and 

international experts, has developed a strategic

plan for microbicide research. The microbicide

component of the NIH Plan for HIV-Related

Research (NIH Microbicide Plan), coordinated

by OAR, identifies and establishes objectives

and priorities and formulates policy statements

to guide the conduct of NIH AIDS research

related to microbicides. This plan has been 

formally integrated into the NIH Plan for 

HIV-Related Research for FY 2003 as a Special

Area of Interest. 

NIAID supports the most extensive microbicide

effort at NIH, with a FY 2001 budget for topical

microbicides of $27 million that increased from

$19 million in FY 2000 (Figure 2). Other

contributors, predominantly non-governmental,

include the following organizations

• The International Partnership for Microbicides

(IPM) – supported by a founding award from

the Rockefeller Foundation – has secured

donations from five European governments,

candidates, expansion of worldwide capacity

to conduct efficacy trials, and access-related

initiatives in regulatory harmonization, pricing

policy, and public and policymaker awareness

to improve product availability once determined

to be effective against HIV transmission.

Financial commitments currently exceed

$70 million over a 5-year period.

• The Contraceptive Research and

Development Program (CONRAD), 

partially funded by USAID and NICHD,

has exploited its expertise in developing

vaginal methods that prevent pregnancy 

to expand its mission to include the 

development of topical microbicides. 

 A project of CONRAD, the Consortium

for Industrial Collaboration in

Contraceptive Research (CICCR),

awards grants to collaborative groups

consisting of industry and nonprofit

investigators, for research and development

of vaginal methods that prevent STIs.

 More recently, the Global Microbicide

Project (GMP) has been established 

by CONRAD, through a $25 million

grant awarded in 2000 from the Bill

and Melinda Gates Foundation, to 

support development of microbicides

lacking contraceptive activity over 

8 NIAID Topical Microbicide Strategic Plan
NIAID Topical Microbicide Strategi

Research (amfAR) initiated a targeted 

microbicide program in December 1999 

with the award of ten 1-year grants totaling

$875,000. Following re-release of the request

for proposals in February 2001, five 1-year

awards were made totaling $445,000. The

Foundation has committed to awarding a

total of 100 1-year grants of between $75,000

and $90,000 over a period of 5 years.

• The Alliance for Microbicide

Development is a consortium representing

pharmaceutical companies, investigators

from nonprofit institutions and advocacy

groups dedicated to the development of

topical microbicides. Funded by the

William and Flora Hewlett Foundation,

the Moriah Fund, IPM, and private contributors, the Alliance seeks

to advance microbicide research and

development through coordination,

education, and advocacy.

As these and other programs expand microbicide

research and development, careful coordination

will be necessary to maximize the unique 

contributions each program can make to the goal

of developing and commercializing microbicides

that can reverse the advancing global burden 

of morbidity and mortality from HIV and other

STIs. A formal process for coordination 

of governmental agencies’ microbicide programs 

is being developed through the OAR.

Once this proof-of-concept has been establi

NIAID’s primary focus will shift to prod

optimization in relation to the broad crit

listed in Table 1 for an ideal product.

To achieve the primary and near-term go

of identifying and establishing the safety 

effectiveness of at least one candidate pro

and to support post proof-of-concept obj

NIAID will

• Support a strong basic biomedical rese

program to identify opportunities to b

cervicovaginal and anorectal infection 

dissemination of HIV and other STIs,

thereby better understanding previousl

identified targets and potentially ident

new targets against which a microbicid

be developed

• Refine/develop and utilize in vitro, ex v

and in vivo preclinical screening and 

evaluation models/tools to improve an

expand preclinical data on the likely sa

and potential efficacy of various candid

or combinations 

• Provide targeted support for preclinic

evaluation, formulation, and producti

assure that absence or limitations of in

sponsorship are not barriers to advanci

most promising candidates or combin

• Identify and provide targeted support f

the most promising candidates represe
process and prevent infection with other STIs

that may potentiate HIV transmission

• Develop clinical capacity and capabilities 

to establish proof-of-concept in humans by

evaluating promising candidates in human

trials to determine safety, efficacy/effectiveness,

and acceptability of candidate vaginal

and rectal topical microbicides in diverse

populations in domestic and international

settings, particularly in populations where

HIV is spreading most rapidly

• Facilitate social and behavioral research to

support effective and ethical conduct of 

clinical trials

Once proof-of-concept has been

demonstrated clinically

• Evaluate the most meaningful correlates of

safety and effectiveness in preclinical models

of safety and efficacy, in turn facilitating

more efficient product optimization

• Optimize protective efficacy and product

acceptability through continued development

and formulation of more effective second

and third generation products, including

combination microbicides

The comprehensive NIAID microbicide strategic plan is configured to address,

through programs and workshops, the scientific challenges that span basic,

preclinical, clinical, and behavioral research.

10 NIAID Topical Microbicide Strategic Plan
NIAID Topical Microbicide Strategic 

pqppp

This section describes established programs and

opportunities for their expansion, as well as

new programs that could accelerate the field.

The latter includes a novel public-private

program that uses milestone-driven funding to

expeditiously advance promising microbicide

concepts through preclinical testing and into

early clinical development. This section

also defines current capacities and analyzes

opportunities for increased capacity in critical areas.

Organization of the NIAID

Topical Microbicide Program

The NIAID topical microbicide program seeks

to advance microbicide research and development

across the microbicide development pathway.

Accordingly, the program does not manage a

specific portfolio of candidate microbicides or

seek to function solely as a “virtual pharmaceutical

company.” Rather, the overall strategy depends

on a broad overview of the field that assumes

the full spectrum of research – from basic

through clinical – requires support, but that

NIAID resources should be focused on particular

areas where a unique contribution can be made.

In some cases, that contribution will be through

support of basic scientific research through grants

that underwrite fundamental studies that lack

other sources of support such as pharmaceutical

research and development investment or other

public sponsors. In other cases, NIAID provides

gg

Because the NIAID topical microbicide p

ranges across basic, preclinical, and clinic

components of microbicide research and

development, it draws on a correspondin

of staff expertise from basic and applied s

as well as clinical investigation. Because i

to evaluate the potential activity of micro

against both HIV and other STIs, it inte

staff from the NIAID Division of AIDS

(DAIDS) and Division of Microbiology 

Infectious Diseases (DMID). 

To integrate staff across programs and div

into an effectively coordinated, functiona

the NIAID Topical Microbicide Working

Group (NIAID TopMic Group), consisti

of all NIAID staff with substantial involv

in microbicide research and development 

Attachment 1: NIAID TopMic Group

Membership), has met no less than mont

several years under the leadership of the T

Microbicide Team Leader in DAIDS. TopM

Group meetings include presentations by spo

of preclinical data to support prioritizatio

candidates for access to developmental

resources, identification and specification 

new initiatives to address potential gaps i

program, and integration of NIAID activ

within the framework of the NIH Micro

Plan and the mission of other Federal an

Federal stakeholders in microbicide resea
coordination and program management without

sacrificing important collegial and professional

interactions with the parent programmatic areas

in which individual staff are situated. For example,

separating those TopMic staff in DMID from

their DMID colleagues in a separate administrative

unit might make it more difficult to integrate into

the microbicide effort state-of-the-art knowledge

of STI transmission, infection, pathogenesis,

and diagnosis, without providing an offsetting

benefit in improved coordination and

management of microbicide-specific research

and development activities. 

Utilization of Preclinical Contract Resources

Another important principle of TopMic

management relates to the utilization of contract

resources, especially in the area of preclinical

development. Responsible management of scarce

contract resources – including mandatory Federal

guidelines that require official approval to allocate

funds for specific subtasks, and contracts that

specify Federal officials as the recipients of contract

deliverables – requires ongoing involvement 

of project officers in the oversight of activities

supported by preclinical development contracts

and in interactions between product sponsors 

and developmental resource contractors. 

With a planned expansion of preclinical 

contract resources, NIAID plans to create a 

new standing review group of external experts

pp 

two areas where increased coordination might

accelerate progress: technology transfer and 

regulatory review. 

Although Federal grants and research and 

development contracts contain provisions that

favor commercial development of innovative

concepts and products, promising designs and

candidate molecules may languish in the

research literature and laboratories of inventors

without specific incentives to move these

approaches into commercial development. 

This may be especially true in the area of 

topical microbicides where there is minimal

active involvement from the pharmaceutical

industry to commercialize promising candidates.

To expedite transfer of promising technologies

into a development framework, the TopMic

Group has begun to initiate meetings with

NIAID staff responsible for facilitating technology

transfer, especially from university and research

institute settings, into commercialization

frameworks, to identify incentives and other

strategies to foster this transition. 

In addition, a new Development Resource

Master Contract (see below) includes a subtask

in which contractor staff will facilitate technology

transfer for specific microbicide candidates.

DMID and DAIDS have increased the number

of staff with substantial experience at FDA. 

12 NIAID Topical Microbicide Strategic Plan
NIAID Topical Microbicide Strategic 

Basic Biomedical Research

A strong basic biomedical research program 

represents the foundation upon which microbicide

design and evaluation is based. The identification

of a promising microbicide candidate is facilitated

by understanding the molecular basis and

chronology of early steps in the infectious

processes of HIV and other STIs in the context

of cervicovaginal and rectal tissue ecology and

natural defense mechanisms. NIAID supports

this research predominantly through investigatorinitiated grants that include studies to

• Define the HIV and STI entry processes

and identify the first cell infected

• Understand the role of different cell types

and host factors in facilitating transmission

and spread (e.g., co-receptor and DC-SIGN

expression and utilization); compartmentalization of HIV genital secretions

• Elucidate the role of STIs and local

inflammatory processes and cytotoxic 

T lymphocytes in transmission

• Determine the impact of therapy on viral

load in genital secretions and transmission

• Characterize viral diversity at the time of

infection in women and the role of sex 

hormones and hormonal contraceptives 

in transmission

topical formulations. Grants focused on m

development encompass projects on in vi

models using continuous cell lines and p

cells in the presence of additional compo

to mimic genital secretions, ex vivo tissue

models, and in vivo murine, feline, and

nonhuman primate models, including a 

transmission model. Grants focused on form

science include projects to evaluate the trans

and activity of microbicide formulations

(e.g., alterations of tissue permeability an

effect on microbicide efficacy) and distrib

of microbicide/formulation in vivo. 

To further stimulate new approaches for 

microbicides, NIAID recently launched a

innovation grant program in AIDS researc

This program supports early, high-risk, sho

term projects that may be able to move a n

approach to the point where it can success

compete for support via more conventiona

grant mechanisms (e.g.,R01). Specific areas 

targeted under the current program that be

on microbicides include

• Viral and cellular processes involved i

transmission, local propagation, and 

spread of HIV

• Processes for cervicovaginal and recta

transmission of HIV

• Improved methods of formulation

and delivery
• Preclinical systems to test microbicide 

safety and efficacy

Preclinical Product Development and

Selection

Although, in general, product development is

most efficiently executed by the private sector,

public sector support is needed to facilitate 

critical work that academic and smaller 

industrial sponsors lack sufficient resources 

and mechanisms to address. In addition, a

broadly active agent or combination of agents

that prevents transmission of HIV and other

STIs simultaneously will be most commercially

attractive in garnering the largest market share

and is therefore the ultimate goal. A focus on

HIV prevention will most likely yield products

14 NIAID Topical Microbicide Strategic Plan

Safety

Rabbit Vaginal Irritation Test

Unformulated 2 4

Formulated 2 3 12

Vaginal Absorption 1 4 9

Analytical Methods 1 2 4

Process

Formulation Development 0 0 3

Clinical Product Manufacture 0 0 2

In vivo HSV-2 testing

Mouse 25 32 64

Guinea pig 0 8 16

Nonhuman Primate Testing

Safety 3 7

Chlamydia efficacy 0 3 8

SIV/SHIV efficacy

Vaginal 2 2

Rectal Not available 2 4

Additional Toxicity Testing

Chronic Toxicity Not available

Reproductive Toxicity

Segment I Not available

Segment II Not available

Segment III Not available

Carcinogenicity Not available
NIAID Topical Microbicide Strategic 

In Vitro Screening Against HIV

An NIAID-supported contract designed to support

microbicide and therapeutic development provides

microtiter-based, high-throughput assays to

evaluate uncharacterized compounds for activity

against HIV. The testing algorithm is initiated

with separate primary screening assays that 

separately target CD4-independent and 

CD4-dependent cell-to-cell virus transmission.

Compounds found to be active in either or

both of the primary screens (criteria defined on

page 24) proceed to the second phase of the

testing algorithm. The second phase includes:

(i) repetition of the primary screens in the 

presence of mucopoly-saccharides to mimic the

vaginal environment; (ii) evaluation of the effect

of the compound on several species of

Lactobacillus that represent beneficial natural

flora in the vagina; and (iii) secondary assays to

measure inhibition of virus-cell attachment

(CD4-gp120 interactions) and cell-cell fusion.

A CD4-independent assay was recently developed

to monitor the activity of potential topical

microbicides in the pH transition range of 4.5

to 7.4 to mimic the vaginal conditions during

coitus. This assay will soon be integrated into

the testing algorithm as a secondary screen.

Should a microbicide candidate meet all the

of evaluations per year and not the numb

of distinct agents per year [e.g., varied

formulations or doses of the same agent m

be tested]).

In Vitro Screening Against Human Herpes

Simplex Virus (HSV)-2

A contract for therapeutic and microbicid

development provides two levels of in vit

screening against HSV-2. A primary scree

measures inhibition of cytopathic effect (

following pretreatment of human foreski

fibroblast (HFF) cells with an uncharacte

microbicide candidate. Candidates with a

in the primary screen are subjected to a sec

in vitro screen using the more reliable an

labor-intensive plaque reduction assay in 

cells. Those compounds with microbicide 

documented in preliminary evaluations b

outside investigators are evaluated directl

the plaque reduction assay. Capacity (Tab

which is 100 evaluations per year, curren

exceeds the level of requests for testing. 

NIAID preclinical development resources have been established to help address

needs in several key areas.
vaginalis, and Chlamydia trachomatis. Testing

resources for these pathogens are not currently

available but have been identified as a potential

area for expansion in the proposed 5-year plan.

In Vivo Animal Safety Testing 

A contract to conduct preclinical toxicology and

pharmacokinetic evaluations for therapeutics

and microbicides provides several different types

of general and specialized safety testing on

microbicide products. Both bulk drug substance

and final clinical product are evaluated for their

potential to irritate the vaginal surface using a

standardized animal model, the rabbit vaginal

irritation model (RVI), accepted and recommended

by FDA for testing of vaginal products.3 Results

are expressed as a numerical value representing

an index of both incidence and severity of irritation.

Absorption into the blood and distribution to

other tissues also are routinely measured. Model

development studies have been conducted to

evaluate the rate and extent of distribution of

test compounds throughout the vagina and

associated reproductive/excretory organs. If needed,

systemic toxicity studies can be conducted for

agents that are absorbed systemically. Standard

genetic and immunologic toxicity studies can be

conducted routinely on candidate microbicides.

Capacity significantly exceeds current use of this

resource. Twelve RVI evaluations and nine 

vaginal absorption studies per year can be

toxicity to cervical/vaginal tissues after repeated

application in pigtailed macaques (Macaca

nemestrina).

4 Although this model is not 

considered a critical path for microbicide 

development, the similarity of the M. nemestrina

cervicovaginal anatomy, microflora, and pH 

to that of humans may make the pigtailed

macaque a more relevant model than the RVI.

The Topical Microbicide Program Projects 

have supported promising preliminary studies

to establish a M. nemestrina model to evaluate

toxicity profiles for rectal microbicide candidates.

Expansion of contract resources would be

required to make this rectal model available to

microbicide sponsors. The contract is currently

able to meet needs at the existing capacity,

which is 8 to 10 vaginal safety or efficacy 

evaluations per year (Table 2).

The ability of these methodologies to predict

what will happen in humans in controlled 

clinical trial settings and subsequently, their 

relevance to real-world product use where 

patterns of frequency and duration may vary

widely is unknown. This gap in understanding

presents an opportunity to learn from other

areas, such as ophthalmic products and the 

cosmetic industry, where the safety of frequently

applied products may be evaluated in the rabbit

eye irritation test. Additional research on the

applicability of such models for evaluating

microbicide safety has been identified as a

potential area for expansion in the 5-year plan. 

16 NIAID Topical Microbicide Strategic Plan
NIAID Topical Microbicide Strategic 

Mouse and Guinea Pig Models of Genital

HSV-2 Infection

A contract provides mouse and guinea pig models

of human herpes virus disease, including genital

herpes.5 Capacity exceeds current use of this

resource, which is 64 mouse and 16 guinea pig

evaluations per year (Table 2).

Nonhuman Primate Model of Chlamydia

Once a microbicide candidate has been shown 

to be safe in the M. nemestrina model, the potential

efficacy of the microbicide to prevent chlamydial

infection of the cervix is evaluated in M. nemestrina

through the STDP-PU.6 The contract is currently

able to meet needs at the existing capacity, which is

8 to 10 safety or efficacy evaluations per year

(Table 2).

Nonhuman Primate Models of HIV

The capacity and expertise for evaluating the

efficacy of candidate HIV microbicides in 

nonhuman primates are distributed among several

contracts.7 Because there is no information yet

as to which model most closely parallels results

in humans, and because each testing facility is

generally focused on a single macaque species

and on only one well-characterized, relevant SIV

and/or SHIV strain, several models are currently

being used. The models are

SHIV strains generally are more susceptib

entry inhibitors and must be used to evalu

microbicide candidates with this proposed

mechanism of action. In order to detect a 

protective effect afforded by the candidate 

topical microbicide, all untreated animals 

study must be infected after exposure to v

To enhance susceptibility to viral infection 

ensure infection of 100 percent of contro

animals, a single dose of progesterone is typ

administered one month prior to the vagi

administration of virus. Nonhuman prim

models can be used to optimize dose and 

of microbicide application and to enhanc

understanding of microbicide mechanism 

action. For example, a microbicide candid

that acts by inhibiting reverse transcriptio

require absorption into mucosal tissue, pro

a longer interval between application of p

and exposure to HIV than a product that 

directly by inactivating virus. Contract su

for evaluating the safety and efficacy of to

microbicides in the nonhuman primate m

will continue to help identify microbicide

candidates with the ability to block vagin

and SHIV infection in macaques, and pro

parallel evaluations of microbicides that h

already advanced into human clinical tria

Current capacity is four evaluations per y

(Table 2).
18 NIAID Topical Microbicide Strategic Plan

Efforts are underway to refine the nonhuman

primate models to more meaningfully simulate

the real-world process of infection using the 

following approaches

• Dual HIV/STI infection

• Multiple low-dose virus inoculations in concert

with repeated applications of microbicide

• More relevant viral strains that represent

the dominant phenotype in recently

infected individuals

• Chinese-origin rhesus and

cynomolgus macaques

To address limitations of in vitro and animal

model systems, NIAID proposes to utilize 

distinct, but redundant, preclinical test

systems for each critical step in the discovery

and development pathway, so that as products

complete safety and efficacy evaluations in

human clinical trials, results from a range of

preclinical test systems will be available for

comparison with clinical results to determine

which of the preclinical systems correlated most

closely with the clinical results. In turn, the

will be needed to ensure the continued utilization

of animal models to prioritize microbicide

candidates suitable for advancement using public

sector support. 

Production of Reagents and Products

for Preclinical and Clinical Evaluation

Chemical Synthesis

A contract to provide synthesis of pure chemicals

for preclinical discovery and development and for

clinical trials of microbicides, tuberculosis drugs,

and HIV drugs is currently funded at slightly

more than $400,000 per year, with a waiting list

of several months for availability. In the past 

2 years, synthesis of eight compounds for early

microbicide discovery studies (Table 2) has been

undertaken. As microbicide discovery and

screening efforts increase, additional resources

will be required.

Formulation Development

A contract to provide clinically acceptable 

formulations or delivery vehicles – for both

water-soluble and lipid-soluble microbicides –

includes all of the standard preformulation

studies that any drug requires before a concerted

formulation development effort begins.8

In the past 2 years, no microbicide formulation

work has been conducted (Table 2) but, should
to promising candidates in the pipeline – remains

a high priority. The NIAID TopMic Group will

seek to establish a partnership with IPM and

others working in this area to maximize 

the most efficient and expeditious use of

available resources. 

Clinical Product Manufacture 

The formulation contract described above also

provides capacity to manufacture products in

amounts and to specifications required by law

for Phase I/II clinical trials. This contract is

shared by all clinical trial programs supported

by DAIDS, however, with the effort focusing

principally on meeting ongoing requirements

for oral medications for therapeutics research.

Should this resource be required for future

microbicide development plans, additional

contract support and resources would be required.9

Expanded Product Evaluation and 

Development Capacity

Based on recognition of needs for increased 

preclinical development resources and more

flexible and responsive mechanisms for securing

resources as needs and opportunities become

clear, NIAID has initiated two new mechanisms

expanding product research and development

efforts: first, a master contractor and, second, a

contracted program to expedite preclinical

development and initial clinical evaluation of

selected candidates. 

and data management. 

This contractor would have the administ

capacity to rapidly evaluate, qualify, selec

and enter into subcontracts with preclini

development contractors that can provid

resources for all phases of preclinical develop

including product development, clinical 

production, formulation, preclinical enab

studies, and associated tasks leading to th

of IND applications.

In addition, this contract would support 

scientific staff who have advanced trainin

sufficient to qualify them to interpret an

summarize preclinical product data – includ

the details of methodologies used among 

different laboratories and algorithms to s

outcomes – and to establish databases and g

reports that can facilitate decision-makin

among program staff. 

Microbicide Design and Development

Team Contracts

NIAID has received concept approval to

adapt a strategy that has expedited HIV

vaccine development, which would imple

microbicide design and development team

contracts. Although expediting product

development can be facilitated by targeted 

for specific individual requirements such a

preclinical testing or GMP manufacture o

pilot clinical lots, successful HIV vaccine

NIAID Topical Microbicide Strategic 
following peer review for scientific merit and

budget appropriateness – to sponsors who 

provide persuasive evidence of the microbicide

candidate’s potential efficacy and safety, and

who propose a clear, focused plan for moving

products through the development process. 

The contracts would be structured to provide

for release of additional increments of funding

upon achievement of specific developmental

milestones, thereby maintaining continuity in 

a development program while assuring program

participation in the determination of satisfactory

progress. This approach would have the further

advantage of focusing resources on IND-enabling

studies and GMP process manufacture required

to qualify a candidate for clinical trials, without

diverting resources to fundamental research

issues that can be more appropriately supported

by separate unsolicited grants or other programs.

Phase I Through Phase III

Clinical Evaluation

NIAID supports the full range of clinical

microbicide trials, from pilot Phase I safety

evaluations through large-scale efficacy and

effectiveness trials. 

The pilot Phase I evaluations are supported by

the Integrated Preclinical-Clinical Program on

HIV Topical Microbicides (IPCP-HTM). By

design, this program supports iterative research

in which the findings from small pilot clinical

highest priorities.10 

Products thought to have efficacy against STIs

other than HIV enter into trials through the

Sexually Transmitted Diseases Clinical Trial

Unit program supported by DMID. To date,

no microbicide candidates have successfully

completed the preclinical testing necessary for

evaluation in this program. 

Phase I trials are conducted to collect early 

safety data of increasing dosage and frequency

of application. Typically, such studies begin

with women at lowest risk of HIV and STI

exposure – either sexually abstinent or in a

mutually monogamous relationship with a 

low-risk partner. Once a maximum safe 

dosage and/or daily frequency of application is

established, additional Phase I studies are carried 

out to evaluate product use by small numbers 

of sexually active HIV-infected women.11

Initial Acceptability Findings

The earliest users of new products, in Phase I

studies, may provide preliminary information

on major considerations related to product

acceptability. In addition, Phase I trials may

support focus groups among the male partners

of trial participants who – although advised

to use a condom to avoid exposure to the

investigational agent – give some early indications

as to how the partners of users in larger trials

might respond to use of the product by their

20 NIAID Topical Microbicide Strategic Plan
Male Tolerance Studies

As clinical trials enroll women at higher risk –

with multiple and/or casual partners – requiring

all consenting male partners to use condoms or

explaining the risk of exposure to an investigational

product ceases to be feasible. In addition, products

that appear to be free of vaginal toxicity would

be undesirable if found to cause lesions to

penile epithelium or mucosa. Accordingly,

Phase I trials now include “male tolerance”

studies that evaluate up to twice daily exposure

of the circumcised and uncircumcised male

penis to investigational microbicides. These

studies are designed to assure that products that

advance into Phase II trials are free of clinically

significant side effects such as macroscopic lesions.

Rectal Safety Studies

Topical microbicides are currently being 

developed primarily for use in preventing HIV

transmission during penile-vaginal intercourse.

It is understood however, that eventually users

may generalize findings of vaginal effectiveness

to assume such products may be safe and 

effective if applied rectally. Accordingly, product

development has begun to assess rectal toxicity

of products initially designed for vaginal use,

and initial clinical work is now underway under

entry of products deemed feasible and pl

for rectal protection into trials evaluating 

effectiveness for that indication. 

Expediting Clinical Efficacy/

Effectiveness Trials

Conventionally, the clinical development

process would next proceed to Phase II tr

that enroll larger populations at higher ri

infection representative of those who wou

included in large-scale efficacy or effectiv

trials, to collect expanded safety data whi

evaluating biological indicators of the plau

of protective efficacy. However, no defini

biological correlates of effectiveness again

have been determined for topical microb

although rates of acquisition of other ST

be indicative of potential anti-HIV activit

the case of broader spectrum microbicides

Consequently, to expedite the product eva

process,12 the separate Phase II trial has b

eliminated in the current testing paradigm

Now the first subgroup (10 percent of parti

in Phase III trials will be rigorously assesse

any adverse responses to the candidate micr

following a visit schedule, including inten

clinical assessments such as colposcopy tha

otherwise would be employed in a Phase 

Issues related to the dose and schedule –

NIAID supports the full range of clinical microbicide trials, from pilot Phase I

safety evaluations through large-scale efficacy and effectiveness trials.

NIAID Topical Microbicide Strategic 
• A global network of clinical trial sites 

offering access to a diverse array of at-risk

populations, permitting multicenter 

evaluations of candidate products 

• A multidisciplinary and interdisciplinary 

scientific leadership structure to facilitate

cross-fertilization of ideas among investigators

with diverse areas of expertise, and 

an effective integration of basic, clinical, 

epidemiologic, social, and behavioral 

scientific expertise 

• Procedures for continuous assessment of the

integrity of trial conduct, data collection,

and data management – together with 

provisions for on-site remedial training as

needed – which complements the oversight

responsibilities of an independent Vaccine

and Prevention Data and Safety Monitoring

board convened by DAIDS to monitor

Phase III trials

As elaborated in Part B, substantially expanded

capacity for global efficacy and effectiveness 

trials will be necessary, even with a parsimonious

approach to product selection. Important 

considerations include a need to evaluate multiple

products in diverse high risk populations so that

• Safety is rigorously assessed in relatively

large and diverse populations using

the product under varied conditions of

background health, STI exposure, usefrequencies, etc. 

potential impact of reduction in condom

coverage can be assessed relative to

product effectiveness

• The first product shown to be safe and

efficacious will likely confer only partial 

protection and may not necessarily meet 

all other criteria (e.g., availability in both 

contraceptive and non-contraceptive 

formulations, efficacy against other STI

pathogens). Iterative cycles of efficacy and

effectiveness testing will guide optimization 

of microbicide candidates and further testing.

However, with partially effective products 

(as well as condoms) employed as controls –

rather than an inert placebo – substantially

larger populations will be required to measure

even relatively large additional gains in efficacy

In turn, developing an adequate clinical research

infrastructure will require a substantial investment

in capacity-building, especially in resource-poor

countries where the need is greatest. Pivotally

important needs include

• New construction or renovation together with

necessary equipment 

• Scientific training at all levels 

• Community education and mobilization efforts 

• Adequate preparatory work will insure that,

especially for large trials, the investment of

financial resources and the voluntary efforts of

thousands of trial participants lead to reliable 

22 NIAID Topical Microbicide Strategic Plan
and interpretable findings. Before large-scale

trials begin, the responsible organizations

should have established their capacity to

• Accrue study cohorts efficiently 

• Retain very high proportions of study

participants over long periods of follow-up 

• Adhere to the highest ethical and operational

standards for trial conduct, data collection,

and clinical and laboratory assessment 

To enhance clinical research capacity, particularly

in developing countries, NIH supports a variety

of targeted and general programs.

• In order to maximize the flexibility and available

resources for clinical trials, NIAID has issued a

request for proposals for a clinical research

organization or consortium of organizations

capable of implementing, managing, and

monitoring global HIV prevention and

therapeutic trials. This resource can – depending

on need, opportunity, and available resources –

be expanded to enlarge worldwide capacity to

advance promising microbicide candidates

prioritized by NIAID into all stages of

clinical trials. 

clinical research capacity, including exp

in the design and conduct of clinical t

• OAR provided $2.7 million in FY 20

enhance research facilities and equipme

developing-country clinical sites in the H

• FIC supports a variety of programs to in

the scientific and logistical capacity o

developing countries in support of cl

and epidemiological research.13

• DAIDS supports independent contract

monitor the conduct of all DAIDS-spo

clinical trials, including both those con

within networks such as the HPTN an

conducted through investigator-initiated 

Upon demonstration of the efficacy and

effectiveness of microbicides in global cli

trials, their long-term safety – for the micr

user, the user’s partner(s), and children bo

a microbicide user – must be established. 

the limited timeframe of grant and contr

support available through NIAID, the In

will explore partnerships with other agen

with demonstrated expertise and capacity 

long-term surveillance (e.g., CDC) to pro

for continuing follow-up of trial voluntee

evaluate long-term safety. 

NIAID Topical Microbicide Strategic 
scientific leadership structure of the HPTN 

facilitates these efforts.

In addition to the programs just mentioned,

other NIH programs complement these efforts and

those supported through investigatorinitiated projects.15

The economics of microbicide development –

the market potential for effective products, 

subsidy mechanisms, and means of addressing 

concerns about intellectual property and liability –

remain inadequately addressed. This gap, ideally,

might be addressed by the non-profit sector,

including IPM, which may adopt strategies similar

to those developed by the international AIDS

Vaccine Initiative (IAVI) to call attention to the

need to increase private sector investment in vaccine

development and address product access. 

Criteria for Advancement of

Candidate Microbicides

Although expansion of specific programs will be

necessary to enlarge the pipeline of promising

microbicide candidates, priorities must be set at

specific junctures in the development process

to assure efficient use of resources. As outlined in

the accompanying discussion of scientific challenges,

the need to prioritize products becomes particularly

acute for large-scale clinical trials where even

For advancement into Phase I trials, NIAID wil

actively support further development only of

those colorless or lightly colored candidates that

meet the following criteria during initial 

in vitro screening

• IC90 less than or equal to 50 μg/ml in a 

primary screen; priority will be given to 

candidates meeting this criteria in both 

primary screens

• IC90 less than two-fold decrease when tested

in secondary screens to evaluate effect of pH

and mucin 

• Therapeutic index greater than or equal to 50 

A microbicide candidate that satisfies these 

criteria may be advanced to preclinical safety

testing in the RVI model following formulation

in a generic vehicle such as K-Y jelly. Mechanism

of action studies of previously uncharacterized

candidates can be conducted simultaneously. 

Safety in the RVI model must be demonstrated

in order to qualify for further development,

using NIAID preclinical resources. With a 

composite score range of 0 to 16, acceptable 

candidates score in the 0 to 8 range, the 9 to 10

range is considered borderline and a score ranging

from 11 to 16 is unacceptable. Nonoxynol-9 

(N-9) generally scores between 8 to 12. Those

24 NIAID Topical Microbicide Strategic Plan

Priorities must be set at specific junctures in the development process to assure

efficient use of resources.
NIAID Topical Microbicide Strategic 

candidates that score as poorly as the N-9 standard

(1.0 ml of Conceptrol), run in parallel, will not

be considered for further advancement.

Candidates that score better than N-9, between 1

and 4 (as described in Eckstein et al. J. Reprod.

Fertil. 20: 85 [1969]) will be given highest priority

while those with a score more than 4 but less than

the score for the N-9 standard will be advanced in

priority order based on additional considerations,

such as mechanism of action, potential cost, etc. In

addition, cost and breadth of activity are factors

considered throughout the development process.

A product development plan to advance a 

compound through preclinical development and

clinical evaluation must be customized to take

into account the specific physicochemical 

(e.g., immunogenicity or hypersensitivity potential)

and biological (e.g., mechanism of action, potential toxicities) characteristics of the active agent.

For example, a microbicide candidate that acts

intracellularly must be absorbed in order to

prevent infection. Systemic absorption and

toxicities must then be closely monitored to

address safety concerns.16

Because in vitro and ex vivo and preclinica

correlates of safety among human product 

recipients remain incompletely characterize

overall strategy for advancement from prec

to clinical testing will seek to advance prod

into human trials as expeditiously as possib

obtain readouts of human safety. 

Additional preclinical methods to evaluate 

are emerging from new ex vivo and animal 

of safety and efficacy, newly developed as

evaluate proinflammatory cytokine induc

and/or assays previously established in oth

disciplines (e.g., cosmetic safety testing). As 

from unvalidated model systems such as 

are gathered and compared with results f

established preclinical testing systems (su

the RVI model) and, optimally, from clinic

decisions can be made as to the added va

from these systems. As clinical trial exper

especially with larger trials, grows, this ite

process is expected to yield more reliable pre

indicators of probable safety in human tr

that, in turn, can provide more effective g

in prioritizing among multiple potential can
full support for manufacture of sufficient product

to support a Phase III study, (ii) agreements to

facilitate access by poorer populations in

exchange for manufacture, (iii) agreements for

technology transfer to developing countries

with a specific number of doses negotiated and

tiered pricing, or (iv) provision of lots of product

shown to be efficacious to communities

involved in the testing. 

Entry into Clinical Efficacy Trials

Beginning with the NIAID-funded HIV

Network for Prevention Trials (HIVNET) and

continuing with the HPTN, investigators have

established a selection process for determining

which candidates would enter into screening 

or efficacy trials, by enlisting an independent

advisory panel that consists of

• An industry representative, from an

organization with no microbicide-related

product development plans, who

has experience in development of

topical products

• Two representatives with expertise in 

preclinical development of pharmaceuticals 

for infectious diseases, particularly expertise 

in safety and efficacy testing in animal models 

• A virologist with expertise in development

of resistance to antiviral drugs

• A regulatory expert

• A DAIDS representative

evaluated. Only products supported by a 

majority of the independent advisory panel 

are advanced to Phase III testing.

Nonhuman primate efficacy testing is

recommended if it is feasible to evaluate the

selected microbicide candidate in a nonhuman

primate model (i.e., mechanism of action is

relevant and activity against the SIV or SHIV

to be used in vivo has been confirmed in vitro).

Should efficacy studies be conducted in nonhuman

primates, interpretation of the results should take

into account the constraints imposed by (i) the

specific conditions (e.g., progesterone pretreatment

and/or single high dose viral exposure) under which

the microbicide candidate is tested; and, (ii) the

statistical significance of the studies.

To support this decision-making process, 

microbicide candidates currently undergoing

Phase I testing in humans will be given priority

in an NIAID-supported nonhuman primate

model. Comparative primate trials to compare

preclinical efficacy are not contemplated; they

require large numbers of animals to perform

and are uncertain indicators of relative clinical

efficacy. On the other hand, favorable findings

in a nonhuman primate model would be 

considered as supportive evidence in favor 

of advancing a product into efficacy trials. 

At the conclusion of a Phase III trial, it may

also be possible to evaluate the utility of 

nonhuman primate models for predicting

efficacy in humans.

26 NIAID Topical Microbicide Strategic Plan
any given point in time may be a result of a set

of unforeseeable contingencies, such as having

been subject to fewer delays or setbacks that

cause otherwise equally plausible products to be

at an earlier stage of development. Accordingly,

alongside the specific comparative preclinical

characteristics of candidate products, the

advancement of suitably qualified candidates

into effectiveness trials may also take into

account such practical considerations as clinical

trial capacity, product availability, the overall

regard to likely clinical safety and effectiv

intermediate-sized or screening trials may 

considered as a way to select the most prom

candidate to advance into definitive trials

Thus far, NIAID’s clinical evaluation cap

within the HPTN – in the context of cli

trial plans supported by other organizatio

has been sufficient to advance those prod

for which an IND has been filed and for 

which sufficient quantities are available o

can be produced to support Phase I testin

NIAID Topical Microbicide Strategic 
28 NIAID Topical Microbicide Strategic Plan

Basic Research

• Develop and refine in vitro and in vivo models

to aid in the identification of microbicides

active against HIV and other STI pathogens,

as needed

• Explore novel approaches to prevention of

infections while improving safety profiles

• Stimulate formulation research to understand

the characteristics of individual formulation

components that lead to formulations that are

safe and acceptable

• Continue to facilitate efforts to understand

the similarities/differences in the factors

associated with cervicovaginal and anorectal

HIV transmission relevant to microbicide

discovery and development

Preclinical Product Development

• Facilitate partnerships between academia and

industry focused on product development

through outreach to developers of candidate

agents and potential sponsors

• Ensure advancement of promising candidates

through milestone-driven development plans

• Evaluate microbicide formulations in animal

models through partnership agreements

• Compare preclinical results – from in vitro,

ex vivo tissue-based, and in vivo animal

model systems for evaluating microbicide

• Assess anti-STI activity of microbicides

developed to inhibit HIV transmission

• Evaluate – as a follow-up to an initial June

2001 workshop on rectal microbicide

research and development – important 

considerations for developing and qualifying

products to protect against rectal

sexual transmission 

Clinical Trials

• Maintain core capacity of specialized

domestic and international clinical trial 

sites for the conduct of Phase I and Phase II

topical microbicide trials

• Identify, develop, and qualify additional

efficacy and effectiveness trial sites in 

developing country settings that offer 

appropriate populations for Phase III trials –

including community-randomized trials – 

of new candidate microbicides

• Explore partnerships with other agencies

with expertise and capacity in surveillance

(e.g., CDC) to evaluate long-term safety
NIAID Topical Microbicide Strategic P

PART B:

MICROBICIDE

DEVELOPMENT:

OPPORTUNITY

AND

SCIENTIFIC

CHALLENGES
accessible topical microbicides – foams, gels,

creams, suppositories, etc. – applied intravaginally

or intrarectally to block HIV or other STIs

would be a useful tool to prevent new infections. 

The long-term goal of NIAID is to identify safe

and effective microbicides against HIV/AIDS

and other STIs. NIAID’s nearer-term goal is

establishing proof-of-concept (i.e., safety and

effectiveness) of at least one candidate microbicide

against HIV/AIDS. Once this proof-of-concept

has been established, NIAID’s focus will shift 

to product optimization in relation to the 

broad criteria listed in Part A, Table 1, for an

ideal product. 

To achieve this goal, NIAID supports an integrated

extramural microbicide program consisting of

three complementary components. 

• Basic science as the foundation for discovery

and development of innovative approaches,

novel protective mechanisms, and improved

preclinical evaluation tools 

• Preclinical to clinical translational research 

• Clinical trials 

After a brief overview of the principal challenges

in these stages of the research and development

process, this document reviews the overall scientific

rationale for microbicide development, then

elaborates on key scientific issues and opportunities

in each of the three areas in greater detail. 

Basic Science for Discovery of New

Agents and Improved Tools

Microbicide discovery has paralleled, but lagged

behind, HIV drug discovery. Until several years

ago, microbicide discovery was somewhat

opportunistic, a byproduct of screening large

panels of available agents for potential activity

against HIV. In addition, surfactants were

considered a source of potential candidates

because in general they were expected to be

capable of disrupting the viral envelope. However,

the readily identifiable and easily testable agents

that have so far emerged from this high throughput

screening approach have been limited in two ways.

First, the screens were limited to only a few distinct modes of action. Second, some of these

mechanisms – particularly membrane disruption

or non-specific blocking of receptor sites – raise

important concerns about potential toxicity. 

More recently, however, the concept of combination

therapeutics – elucidating distinct stages of the

HIV life cycle (specifically viral attachment, 

intracellular penetration, and cell-to-cell 

dissemination) and then simultaneously 

blocking multiple distinct stages – has been

applied to microbicide discovery and development.

Many now appreciate that the most effective

microbicides probably will employ combinations

of agents that block separate and distinct stages in

the processes that permit initial HIV acquisition

32 NIAID Topical Microbicide Strategic Plan
vault and anorectal canal.

Translational Research and

Product Development

Translational research – from bench to clinic 

and clinic to bench – is intended to be an iterative

process in which pilot clinical findings associated

with safety, putative efficacy, or acceptability in

turn guide further modifications of candidate

agents or formulations. The types of studies 

performed during this iterative process to qualify,

prioritize, and if possible, optimize microbicides

for clinical testing have increased in number and

complexity, moving from reliance on relatively

simplistic in vitro assays and generic toxicity

screens used for any drug or biological agent to

increasingly sophisticated models designed to

more closely approximate the molecular and

physiological characteristics of HIV transmission

and infection in humans.

Two major considerations have motivated this

transition. First, safety is paramount, particularly

for a product that higher risk individuals will

need to use at least daily for long periods of

time. Conventional toxicity screens have been

inadequate to accurately gauge the risk of 

products that have entered into human trials, 

with the expectation that one or more of 

separately or in combination, may provid

meaningful preclinical assessment of prod

toxicity and/or efficacy. 

With increasingly detailed knowledge of t

basic biology of mucosal HIV transmissio

development and utilization of multiple a

more sophisticated in vitro testing system

ex vivo models, and animal models has bec

priority. But all animal models remain im

analogues for sexual transmission among

humans. Multiple models already are avai

each with its own apparent limitations, an

efforts continue in developing models that 

competing priorities, such as mimicking a

specifically as possible the specific conditi

sexual transmission and infection in hum

minimizing the number of animals requir

conduct any single experiment. Such mod

elaboration will continue until efficacy tri

provide a means for selecting model(s) th

seem to provide the most meaningful insi

into likely safety and potential efficacy. 

In addition to a greater diversity of preclin

ex vivo and animal models, loss of mucosal in

of challenge stocks over extended periods o

(e.g., 3 to 4 years) require that the potency 

challenge stock must be well established pri

A consensus has emerged that safe, effective, accessible topical microbicides –

foams, gels, creams, suppositories, etc. – applied intravaginally or intrarectally

to block HIV or other STIs would be a useful tool to prevent new infections.

NIAID Topical Microbicide Strategic 
34 NIAID Topical Microbicide Strategic Plan

An increasing number of plausible candidate

agents are making their way through the preclinical

development pipeline. Comparative results from

sufficiently powered animal model efficacy studies

would help prioritize candidates, especially those

from the same class or representing a common

mode of action. Until efficacy in human trials

has been measured, however, the validity of all

such animal models will remain uncertain.

Although a single animal model with good

predictive value would provide useful guidance

during product selection and prioritization,

ultimately only human efficacy trials can provide

a definitive measure of efficacy. 

Second, sample size requirements for efficacy/

effectiveness trials have grown. The most 

appropriate target population for the bulk of

trial enrollees is women whose risk results from

moderate frequencies of sexual contact with a

spouse or with one or few sexual partners: the

same women who are likely to represent the

largest group of users of a licensed microbicide.

However, evaluation solely among women whose

risk is moderate may underestimate safety concerns

for women of higher risk. In contrast, microbicide

efficacy trials that recruit preferentially among the

highest incidence populations of women – 

sex workers having many partners and many

episodes per day of sexual contact – would

require fewer volunteers, but overestimate 

safety concerns for most eventual users. 

acceptability, field trials should be conducted

concurrently in multiple countries to provide

useful comparative data. 

Although the breadth of research challenges 

may seem daunting, investment in microbicide

research and development is well justified, as 

discussed below, by the limitations of existing

approaches to prevention of sexual transmission 

of HIV, together with various lines of evidence

suggesting such an approach is fully plausible and

feasible. Complementing investments by NIAID,

other governmental and non-governmental

organizations continue to expand their 

commitment to this effort, and new organizational

entities are being established with the intent of

addressing specific gaps in, or otherwise facilitating,

microbicide development. 
NIAID Topical Microbicide Strategic 

consistently and correctly, effectively blocks

transmission of HIV and gonorrhea, although 

it has a limited spectrum of efficacy for other

STIs. Importantly, the condom requires active

cooperation of the male partner and therefore

cannot be implemented at the independent 

discretion of the female. The female condom

requires partner acceptance, as well as correct

insertion and proper use. Also, studies have yet

to establish its efficacy in preventing viral and

bacterial STIs. 

Attempting abstinence or seeking male partners’

cooperation in using condoms is unrealistic

under circumstances of non-consensual sex.Nor

is negotiating condom use a reliable strategy in

the context of consensual sex with a partner whose

risky sexual practices may remain undisclosed.

Conversely, just as oral contraceptives dramatically

enhanced the ability of women of childbearing age

to avoid unwanted pregnancy, effective, femalecontrolled topical microbicides would empower

women of all ages – including older, postmenopausal women and adolescents –

to avoid STIs.

Although bacterial STIs can be treated effectively

and relatively inexpensively in countries where

antibiotics are readily accessible, these infections

often remain asymptomatic in women and

difficult to diagnose without appropriate laboratory

facilities. As a result, they may go untreated –

especially in settings with underdeveloped health

qpppy g

and cumbersome. HPV – as a causal agent 

cervical cancer – is associated with very hig

for diagnosis and treatment of dysplasia or 

advanced disease. 

In the absence of a safe and completely ef

HIV vaccine, additional strategies to prev

sexual transmission of HIV are among the 

priorities for prevention research. Even if 

partially effective vaccine were available,

supplementary methods against HIV, as w

as agents with broad-spectrum activity ag

multiple STIs, could confer additional prot

during and after immunization. 

The Potential for Topical Microbi

The goal of NIAID’s microbicide research 

program is to identify safe topical microb

effective against sexual transmission of HI

and other STIs. Notwithstanding the pot

benefit of topical microbicides active agai

multiple STIs, development of a safe and 

effective microbicide with activity against 

single sexually transmitted pathogen wou

represent a seminal achievement by

• Reducing morbidity and/or mortality 

• Improving insight into common fundam

aspects of microbicide development, 

as formulation, clinical trial design,

and acceptability 
36 NIAID Topical Microbicide Strategic Plan

delivery, and breastfeeding. Sparing women

the burden of other STIs in turn prevents

neonatal infections with gonococcal and

chlamydial conjunctivitis that may lead to

congenitally acquired blindness or chlamydial

pneumonia, a source of chronic respiratory

disease; congenitally acquired syphilis; and

neonatal herpes.

Plausibility of Topical Microbicides

Ample precedents exist to suggest the plausibility

of topical agents for protecting against vaginal

and rectal infection with HIV and other STIs.

• Over-the-counter topically applied antifungals

have been approved for treating vulvovaginal

candidiasis (moniliasis). 

• Mouth rinses containing antiseptics such as

chlorhexidine gluconate or pvp-iodine have

been shown to reduce bacterial-associated

plaque accumulation. 

• Topical vaginal estrogen has been used 

successfully to treat atrophic vaginitis caused

by estrogen deficiency in post-menopausal

women and is particularly effective because

it avoids the adverse consequences observed

with systemic estrogen therapy, including

endometrial hypertrophy and suppression

of ovarian function. 

estimate a failure rate of only about 20 percent

among “typical” couples for vaginally

applied spermicides in the form of foams,

creams, gels, jellies, suppositories and vaginal

film; randomized controlled clinical trials of

such products are only now in progress.

Given the high “susceptibility” to pregnancy

during the period of ovulation, this overall

level of contraceptive effectiveness is

highly suggestive of the potential of topical

microbicides to prevent transmission of

HIV and other STIs.

• Promising safety profiles in early phase trials

of new microbicidal agents, together with

high rates of self-reported microbicide use

among high-risk women participants in 

previous N-9 efficacy trials, lay encouraging

foundations for proof-of-concept trials of

the efficacy of new products. 

Progress to Date

Progress in microbicide development can be

measured by the entry and movement of products

through the development pipeline and – perhaps

more importantly – advances in basic, preclinical,

and clinical science that have broadened and

deepened the scientific foundations for rational

product development and evaluation. 

Approximately 50 to 60 distinct agents that show some promise as potential topical

microbicides have been identified.
Reverse Transcriptase

Inhibitor (RTI)- 4

Zn Finger Inhibitor (ZFI)- 1

Attachment, Fusion, Entry

(AFE)- 16

Natural Defense (ND)- 3

Unknown (U)- 9

DI- 10 AFE- 14

RTI- 2 ND- 2

ZFI- 0 U- 0

DI- 2 AFE- 4

RTI- 1 ND- 2

ZFI- 0 U- 0

The Pipeline

Approximately 50 to 60 distinct agents that show

some promise as potential topical microbicides

have been identified (Figure 1). A large 

proportion of these candidates cluster within 

a small group of distinct chemical classes 

(e.g., sulfated and sulfonated polymers). The

majority of candidates have yet to progress

through the comprehensive preclinical studies

required prior to clinical trials. Thus far, relatively

few microbicide candidates have successfully

qualified to enter clinical testing, and only those

products containing the detergent compound

N-9 have advanced to efficacy trials. N-9 acts by

disrupting the lipid bilayers of enveloped viruses,

including HIV, as well as the cellular membranes

of sperm. However, this mode of action is nonspecific and potentially disruptive of normal cell

membranes. Indeed, results from Phase III 

trials of N-9-containing products have been 

disappointing. In the vaginal formulations 

evaluated to date, N-9 does not provide

significant protection against sexual 

transmission of HIV. Furthermore, mucosa

erosions and lesions have been detected am

high frequency users. Also, a recent study 

documented shedding of rectal epithelial tis

within minutes of applying over-the-counte

lubricants containing relatively low concent

of N-9.18

However, it would be inappropriate to ov

generalize from the disappointing results 

studies. This compound entered trials bec

was readily available in multiple formulat

a spermicide and because it showed subst

virucidal activity using simple in vitro mode

HIV inactivation. Absence of protection has 

possible implications

• With a narrow therapeutic window betw

host toxicity and antimicrobial activity, 

detergent may erode vaginal and/or cer

epithelial cell membranes with frequent 

thus permitting direct entry of intact H

NIAID Topical Microbicide Strategic 
• Commercially available topical N-9 

formulations may have been inappropriate,

either insufficiently masking toxicity or else 

delivering subtherapeutic doses of N-9.

Although the concept of conferring protection

using a topical agent thus remains unproven in

humans, we have learned that definitive clinical

trials of such products are feasible and achievable.

They can be conducted successfully among diverse

populations of women at risk, during which

participants willingly use such products in the

context of sexual intercourse. There remains,

therefore, great potential to succeed through

developing new agents formulated specifically

for this purpose. 

Recent Progress in Basic, Preclinical, and

Clinical Science

Studies fully or partially supported by the NIAID

topical microbicide program in basic, preclinical,

and clinical microbicide research and development

have contributed to an improved understanding of

both the challenges and the opportunities associated

with microbicide development.

• Basic research projects have elucidated several

specific mechanisms and pathways through

which sexual transmission of HIV occurs,

gp

transmission. However, dynamic processes

of intercourse and their impact on such

preclinical measurements remain important

considerations. Particularly for nonhuman

primate models used to assess potential

efficacy, continued model refinement, and

further model development if necessary,

would increase the perceived relevance of

such outcomes to decisions on whether to

advance products in expanded human trials. 

• Clinical research has moved the first generation

of non-detergent microbicide candidates to a

stage where they are poised to enter efficacy

trials. The availability of a variety of candidates

for efficacy trials – difficult to prioritize for

advancement because of the absence of 

dramatic differences in preclinical findings –

does not appear problematic for the immediate

future. As additional candidates representing

multiple modes of action proceed through

preclinical development, however, more

sensitive ways to establish priorities among

candidates will become essential, given the

limitations on global efficacy trial capacity.

Expansion of efficacy trial capacity will

remain a critical need, however, even after

establishing more rigorous thresholds for the

advancement of products into large field trials.

Some of the many important findings associated with current concepts of HIV

transmission and pathogenesis have significant implications for targeted development

of novel microbicides.

38 NIAID Topical Microbicide Strategic Plan
pgp

of vaccines and anti-HIV agents, including

microbicides, have been identified in the course

of basic research on the molecular mechanism of

viral attachment to and entry into susceptible

cells. It is now known that HIV infection of 

target cells requires both the primary CD4

receptor and either of two co-receptors, CXCR4

or CCR5. The physical interaction of CCR5

and CD4 in the cell membrane must remain

undisturbed in order for HIV to enter the cell.

Pharmacologic modification of the CCR5-CD4

interaction could offer a strategy for specifically

blocking HIV entry. 

Studies of a unique variant HIV IIIBx have

demonstrated CXCR4-dependent infection 

of CD4 cells, suggesting the potential to block

infection by preventing interaction between

CCR5/CXCR4 and gp120 envelope.

Therapeutic or microbicidal agents might

employ small molecules that block the active

sites of these interactions. Or a vaccine might 

be formulated from a suitably presented antigen

that elicited antibody specific to the active site.19

Continuing population-based research on the

distribution of gene variants associated with CCR5

has extended the initial finding of a protective

effect of distinct genotypes. A specific CCR5

marker associated with greater susceptibility to

infection has also been shown to predict more

rapid disease progression following infection.

structural variants may lead to new insigh

into modes of protection from infection a

dissemination of viral particles from initia

target cells.

Prevention of Vaginal Transmission of SIV by E

Epidemiologic research initially suggested, 

continues to investigate, a mechanism tha

has been demonstrated in simian experim

showing that hormonal factors very likely m

susceptibility to HIV infection. Furtherm

this mechanism appears to be mediated b

effect of hormones on the thickness of the v

epithelium. These studies have facilitated 

development of a laboratory model for lo

at the efficacy of experimental microbicid

protection against pathogenic strains of SI

Also, although a variety of potential routes 

mucosal infection during vaginal exposur

been established in in vitro and ex vivo stu

these findings suggest that models of the re

importance of different potential routes of e

and infection should consider as salient th

integrity of the vaginal epithelium.

In observational studies, women whose es

levels have been depressed by treatment w

contraceptive depo-medroxyprogesterone 

(DMPA) have an increased risk of HIV inf

This association is consistent with estroge

in stimulating thickened vaginal mucosa. 

ovariectomized female macaques received 

NIAID Topical Microbicide Strategic 
has since been found to increase the sensitivity

and efficiency of nonhuman primate efficacy

models by assuring that all control animals

become infected. Topical estrogen also has been

suggested as a possible ingredient for a vaginal

microbicide. More generally, these studies 

support an emphasis on the compatability of

candidate microbicides with the maintenance 

of intact vaginal epithelium. 

A Novel Protein (DC-SIGN) on Dendritic Cells

Delivers HIV to T Cells.

One of the newest potential targets for microbicide

development has been identified during detailed

examination of the behavior of a type of

immune cell known as a dendritic cell in its

response to HIV. Studies of this cell type have

revealed what may be an important mechanism

for conveying HIV from the initial site of exposure

to large internal reservoirs of susceptible CD4

and other immune cells. 

Dendritic cells were of interest because they

appear to play the role of sentry in their

immune system role of patrolling skin and

mucosal surfaces such as the rectum, vagina, 

and cervix; identifying, capturing, digesting, 

and displaying fragments of foreign invaders,

such as microorganisms; and thereby alerting

other immune system cells, such as T cells to

mobilize. Studies of the effector molecule on 

the dendritic cell surface, DC-SIGN, revealed

vaccines, therapeutics, and microbicide development.22

HIV-1 Buds from Specialized Regions of Host

Cell Membrane.

As suggested previously, significant work has

focused on the mechanisms of HIV attachment

and infection of susceptible cell types. At the other

end of the HIV life cycle – the final assembly

and expulsion of new virions from host cells –

new findings with potential for exploitation in

microbicide development have emerged. 

Increased understanding of the process of HIV

budding has identified a specific cell structure

associated with this final stage of HIV replication.

As HIV-1 buds from the cell, it selectively

incorporates lipids localized in specialized

regions of the host cell membrane known as 

glycolipid-enriched membrane (GEM) domains

or lipid rafts – organized areas on the cell surface

enriched in cholesterol, sphingolipids, and 

glycosylphosphatidylinol (GPI)-linked proteins.23

Further elucidating mechanisms of HIV 

assembly and the role of host constituents in 

the HIV-1 life cycle may have implications in 

developing agents with microbicidal properties. 

Preclinical Product Development

In vitro models utilized during comparative 

preclinical evaluation of microbicide candidates

increasingly reflect the natural characteristics of

40 NIAID Topical Microbicide Strategic Plan
human vaginal ecology (e.g., the antiviral and

antibacterial effect of colonization by two strains

of peroxidase-producing Lactobacillus), the

nature of the infectious unit (cell-associated 

or cell-free virus), distinct potential routes of

infection (CD4-dependent and CD4-independent),

and the physiologic characteristics of mucosa

at different times during the menstrual cycle.

The most recent addition to the battery used to

screen and prioritize compounds with potential

microbicidal efficacy is a CD4-independent

assay effective over the normal, acidic pH range

of the healthy female vagina (4.5 to 7.4). 

Multiple nonhuman primate models have 

contributed suggestive findings regarding both

safety and efficacy. The pigtailed macaque has

been used to assess safety (effects on surface 

tissues and microenvironment of the cervix and

vagina) of 14 candidate agents. In general, too

few animals have been used to be able to quantify

protective efficacy or achieve high levels of

statistically significant protection, because scarcity,

technical feasibility, and expense have so far 

discouraged nonhuman primate studies with

numbers sufficiently large to achieve such

increased levels of precision. 

groups while 0.5 percent PRO2000 pro

complete protection from infection in

7 of 7 animals.25

• Over-the-counter, commercially availab

bioadhesive gels with 3.5 percent N-9

(Advantage 24) or without N-9 (Replen

were applied topically to adult female r

monkeys 15 minutes prior to intravagin

challenge with SIV. Four of five monke

the untreated control group became inf

after a single inoculation. Advantage 24 

protected four of five monkeys from in

Replens prevented infection in two out 

of five monkeys,26 implying that a phys

barrier alone may confer partial 

protective efficacy.

• Concurrent with its early clinical evalua

a therapeutic agent, PMPA,27 formulat

gel, was administered to adult female rh

monkeys in different concentrations an

intervals prior to SIV exposure. PMPA 

prevented vaginal acquisition of SIV in

when administered pre- and post-expos

in multiple applications, or as a single

application administered 15 minutes p

to viral exposure.28

• Three candidate microbicides have been

evaluated for efficacy against chlamydia

challenge in a pigtailed macaque model. 

of these microbicides are advancing int

safety or efficacy testing in human trials

NIAID Topical Microbicide Strategic 
Clinical Trials

Principally through its multi-center HIV 

prevention trial networks – previously the

HIVNET and currently the HPTN – and also

through investigator-initiated grants, NIAID has

funded early Phase I safety and initial acceptability

assessments of a variety of new microbicide 

candidates, as described below and summarized 

in Figure 2.

• PRO2000 (at concentrations of 2 percent and

4 percent administered once or twice daily)

was given to sexually active HIV-negative and

abstinent HIV-positive women at 2 U.S. and

South African sites during 14 consecutive

days. During this relatively brief period of

product exposure and use, it was well tolerated

by both the HIV negative and HIV positive

women, with no serious adverse events.

Adverse event rates were not significantly

associated with either HIV status or exposure

variables such as concentration or frequency of

use. All of the women indicated they would be

willing to use the product again if it were

shown to protect against HIV infection.29

• BufferGel, a non-detergent microbicide, is

expected to maintain normal, acidic vaginal

pH in the presence of semen, and thereby

inactivate HIV and other STI pathogens.

Results of a Phase I trial of low-risk women

in the United States showed that BufferGel

was non-toxic and well tolerated. A comparison

of responses to questionnaires on hypothetical

pre-trial predictors of acceptability indicated

that actual experience with the study product,

rather than attitudes prior to use, was associated

with willingness to use such products in the

future, suggesting that strategies encouraging

women to try unfamiliar products are

more likely to achieve acceptance than

educational campaigns designed to change

pre-existing attitudes.30

An expanded Phase I trial was then conducted

to examine the safety, acceptability, and use

of BufferGel in India, Thailand, Malawi,

and Zimbabwe. About half of the women in

42 NIAID Topical Microbicide Strategic Plan

BufferGel Phase I (penile) Complete

PRO2000/5 Gel (P) Phase I (penile) Complete

Tenofovir Gel Phase I (vaginal) In progress

Cellulose Sulfate Gel Phase I (vaginal/HIV+) In progress

PRO2000/5 Gel (P) Phase I — India (vaginal) In progress

PRO2000/5 Gel (P) Phase II/IIb (vaginal) Q2 2004

BufferGel Phase II/IIb (vaginal) Q2 2004
NIAID Topical Microbicide Strategic 

days) was high, as was overall acceptability,

except in India.31

• A randomized, placebo-controlled Phase I/II

trial to assess the safety and acceptability of

Carraguard, a lambda-carrageenan (PC515)

non-contraceptive sulfated polysaccharide

microbicide, has completed enrollment at

several sites in South Africa. Data analysis 

is ongoing.

• Despite the widespread presence of N-9 in

commercial sexual lubricants used by U.S.

men who have sex with men (MSM), high

doses or prolonged, frequent exposure may

cause tissue damage that in turn may

increase susceptibility to HIV infection. 

assessments included genital exam and 

leucocyte-esterase for insertive partner

Receptive partners underwent anosco

with colposcopy, rectal biopsies, and m

samples for semi-quantitative assays o

DNA, and in HIV-infected men, quant

HIV RNA PCR and HSV DNA PCR

before and after product use. Daily us

of this formulation of N-9 gel resulted i

minimal irritation at the time of the c

examinations (a minimum of at least 

hours after exposure).32
44 NIAID Topical Microbicide Strategic Plan

improved scientific understanding also expands

opportunities. For example, a more sophisticated

understanding of the biology of HIV infection

suggests new potential blocking mechanisms. A

richer appreciation of the complexity of vaginal

physiology can support more meaningful models

for preclinical evaluation and suggest additional

clinical markers of toxicity or tolerability. This

section further elaborates these challenges 

and opportunities. 

Basic Biomedical Research:

Expanding Knowledge of Fundamental

Mechanisms of HIV/STD Mucosal

Transmission and of Protection

From Sexual Infection

With limited understanding of the mechanisms

of mucosal HIV/STI infection, to screen 

compounds for potential microbicidal activity,

researchers initially adopted methods used 

previously to screen candidate agents in such

related fields as contraceptive research and HIV

therapeutic drug development. In vitro cell-based

assays for establishing anti-HIV activity and

cytotoxicity, as well as standard animal models

to study chemical vaginal irritation and systemic

toxicity, have constituted the preclinical discovery

and development paradigm for microbicides. 

HIV in sexual transmission remains unresolved.

Recent progress in fundamental research on

mechanisms of infection suggests a broader

range of potential blocking strategies. Continued

elucidation of the specific mechanisms of mucosal

HIV infection during sexual transmission –

characteristics of both pathogen and host,

including natural host defenses – also might

provide a basis for development of methods 

and models that can improve the sensitivity and

specificity of the preclinical screening process.

On the pathogen side, ejaculates from HIVinfected men may contain both cell-associated

and cell-free infectious HIV-1. Consequently,

both must be addressed. However, these two

presentations of HIV entail different initial steps in

infection: (i) entry of cell-free virus via infection or

association with macrophages or dendritic cells

(DC) in cervicovaginal or rectal epithelium,

(ii) viral entry via interaction of cell-associated

virus with susceptible target cells in vaginal or

rectal lining, and (iii) direct entry of cell-free 

or cell-associated virus into the bloodstream 

secondary to trauma. 

Although HIV cell entry appears to proceed

through a CD4-dependent path in the presence

of co-receptors, mounting evidence suggests that

CD4-independent entry via co-receptors also

may occur. Defining CD4 and co-receptor

Recent progress in fundamental research on mechanisms of infection suggests a

broader range of potential blocking strategies.
NIAID Topical Microbicide Strategic 

role for Langerhans cells which may extend 

cellular processes from the submucosa to the

intact mucosal surface, where a receptor similar

to DC-SIGN may serve as a receptor for HIV.

The effect of intercourse on cervicovaginal and

rectal physiology – in the presence and absence

of STIs associated with enhanced HIV

transmission – would help determine the relative

contributions of these distinct mechanisms 

of transmission.

Just as a combination of physical, microbiological,

and chemical barriers act synergistically to protect

the cervicovaginal mucosal surfaces from infection

and injury, similar mechanisms may also protect

the lower gastrointestinal tract including the rectal

mucosa. Exogenous topical microbicides should

not disrupt either natural defense mechanisms

or normal physiological processes. Nor should

their activity be affected by or interfere with 

normal physiological processes – such as exudation

of cervicovaginal secretions – that occur during

sexual arousal. Further elucidating the nature,

contributions, and mechanisms of innate defenses

would augment the array of potential concepts of

protection that could be a focus for development

of new candidates. Assays to evaluate the impact

of candidate agents and products on these

mechanisms will be relevant to both qualifying

and comparing new candidates. 

topical products is being reconsidered. M

for evaluating intrarectal efficacy and safe

recently been developed; these, too, remain 

by inadequate understanding of host and 

factors specifically involved in rectal transm

of HIV. Recent assay development has so

address two important considerations.

• The environment to which the microb

is added undergoes wide variations in

physicochemical properties across wh

agent must retain anti-HIV/STI activ

• Immortalized cell lines differ from cul

of fresh cells; they have undergone

transformation and may prove less

relevant than fresh cells with respect t

the molecular events in initial infectio

A successful topical microbicide candidate 

be stable and active in a dynamic environ

The viscosity of the vaginal mucosa chang

during the course of the menstrual cycle, 

variable addressed by devising in vitro ass

that are conducted in the presence and ab

of mucin. Variations in pH have been add

by a new cellular assay that simulates the 

transition to replace simple stability assess

at pH 4.0 and pH 7.0. 

Although immortalized cell lines grown a

monolayers are valued for their ease of us

vitro screens and their ability to be geneti

engineered to express relevant viral and ba
46 NIAID Topical Microbicide Strategic Plan

By requiring biopsy material, such ex vivo 

systems would be costly and time consuming if

used for high throughput screening. But limited

comparative testing of different candidates using

such a system is feasible.

The conventional rabbit vaginal irritation test –

a mainstay of preclinical toxicity testing for

other vaginally applied products – does not 

represent either the pH of the healthy human

vagina or the mechanical factors that become

relevant during coitus. The rabbit vagina is 

neutral (pH = 6 to 7), although it is not known

whether this limits the predictability of results

generated by the rabbit vaginal irritation model.

Mechanical effects of coitus (e.g., development

of microabrasions) on potential irritation are not

addressed in this model because the microbicide

candidate is deposited atraumatically in the 

vaginal vault.

In vitro models can estimate adhesion of various

preparations to vaginal mucosa; their dispersion,

distribution, and retention within the vagina;

and the release of active agents to appropriate

submucosal cells. However, available models

only imperfectly mimic human vaginal 

physiology and function. The effects of shear

forces, especially during intercourse, on viscosity

and bioadhesion will be challenging to estimate 

ex vivo. Little is known, even from in vitro models,

about the behavior of products administered

permitting the successive refinement of such models. 

Available nonhuman primate models have

imperfect reproducibility and uncertain 

predictability. In humans, multiple exposures 

to HIV may precede the event that leads to

established infection, whereas current nonhuman

primate models are designed to require only a

single high-dose exposure to the challenge virus

to achieve 100 percent infection. 

Animal models offer the best source of 

information about the likely efficacy of a 

candidate microbicide short of full-scale 

human efficacy trials. But they do so with 

many limitations. 

• No single model is germane to all potential

mechanisms of protective efficacy that 
• No primate model can parallel all salient

aspects of human vaginal/cervical biology.

For example, the nonhuman primate 

vagina is normally pH neutral, although 

the distribution of microflora does parallel

the human vaginal environment. Moreover,

there currently is no primate model for

infection by cell-associated virus, even

though this presentation of HIV may be

responsible for some portion of sexual 

transmission of HIV among humans. 

• Human infection is believed to result only

after multiple exposures; whereas, until very

recently, animal models have emphasized a

high-dose viral challenge (see below) that 

can engender infection upon a single exposure.

This requires progesterone pretreatment,

whereas women appear to be susceptible

during all phases of the menstrual cycle. 

A model that depends on successful infection

after a single challenge dose of HIV may be

too stringent, or simply not relevant, as a

criterion for a microbicide candidate. 

• Nonhuman primates, specifically macaques,

are not readily infected vaginally by SIV or

SHIV chimeras.33 Moreover, stocks prepared

independently from the same virus strain

can vary in efficiency of vaginal transmission.

Those virus strains/stocks that do infect via

the intravaginal route require a dose of virus

three to five logs higher than for the

intravenous route. These characteristics of

controls because they can reliably be in

If using as few animals as possible in an

given experiment, and getting results as 

as possible from such experiments are co

priorities, then a control strategy that d

on a multiple low-dose challenge will b

desirable than a challenge stock that 

reliably establish infection after a singl

vaginal challenge. 

To address the limitations identified abov

in vitro and animal models for screening

microbicides continue to be refined, keep

pace with advances in understanding of h

cervicovaginal and rectal transmission ma

Although the models do not comprehensive

recapitulate the nature of HIV transmissio

during sexual intercourse, each model can 

provide information as to the potential inh

and toxicity profile of microbicides under

specific biologic conditions. 

• Identification of in vitro inhibitory 

activity against cell-free virus can prov

a preliminary foundation for pursuin

microbicide candidate. 

• An efficacy evaluation in nonhuman p

based on achieving protection with a s

application of microbicide followed by 

high dose viral inoculum can provide p

of biologic plausibility under condition

which host susceptibility is optimized 

absence of cervicovaginal trauma. 

NIAID Topical Microbicide Strategic 
48 NIAID Topical Microbicide Strategic Plan

to characterize important considerations regarding

formulation as well as preclinical safety. Models

that use cell-associated virus as the infecting unit

would become a higher priority if it were known

that this is the principal vector of infection in

human sexual transmission.

The number of nonhuman primates required

for preclinical studies of microbicide efficacy will

depend on how outcomes of such studies will be

used to guide product development. Head-tohead comparison of all potential products is not

feasible. Among those candidates for which 

nonhuman primate efficacy studies are feasible,

the selection of a qualitative readout – some 

versus no protection or a quantitative readout

(e.g., more or less than 50 percent of challenged

animals resisted infection) will impact sample

size. Currently at most seven animals per arm

are used to detect some versus no protection. 

To distinguish quantitively among products 

(for instance multiple candidates using the 

same presumptive mode of action) might 

require twice this number per arm. 

Ultimately, the relevance and predictive value 

of such models for microbicidal efficacy and

vaginal/rectal irritation will require comparisons

with data from human clinical trials of microbicide

candidates that were also evaluated using these

preclinical systems. For example, establishing the

Evaluation: Establishing Sufficient

Capacity to Efficiently Advance

Meritorious Products into and

Through Proof-of-Concept Trials

Worldwide clinical trial capacity for microbicide

research has been sufficient to evaluate new

products in Phase I testing, and to assess 

N-9-containing products in efficacy trials.

However, to a large extent this reflects the relative

paucity of candidates that have completed 

preclinical and early clinical development (Figure 1). 

The Potential Product Pipeline Will Offer

Opportunities to Evaluate an Increased

Number of Candidates in Phase I Trials 

in 2 to 3 Years

The advancement of additional agents identified

through screening of therapeutic drugs will 

combine, beginning in 2 to 3 years, with the

maturation of microbicide-targeted preclinical

research and development programs that are

supporting at least a dozen single and combination

candidates. Currently, one or two new products

per year become available for Phase I trials. This

number is expected to more than double by the

middle of the decade. These newer agents –

many of them representing novel mechanisms 

of action – may show more promise than the

first non-detergent microbicides available in the

Currently, one or two new products per year become available for Phase I trials.

This number is expected to more than double by the middle of the decade.
NIAID Topical Microbicide Strategic 

preclinical safety hurdles and that meet regulatory

requirements will likely tax current Phase I capacity,

particularly once a large scale trial gets underway

at these same clinical sites.

The Number of Promising Candidates for

Phase III Trials Will Exceed Clinical Capacity –

Already Severely Challenged – by the Middle

of the Decade

At this time, it is not clear whether current

global capacity to implement efficacy or

effectiveness trials can accommodate current

demands imposed by a handful of products that

qualify based on FDA requirements for preclinical

safety and efficacy, plausibility of protection, and

in most cases, some evidence of preclinical

efficacy in an animal model. 

Few U.S. or developing country clinical settings

can readily manage trial cohorts larger than 250

to 500 participants, so multisite investigations are

a necessity. On the other hand, the benefit of 

conducting microbicide efficacy trials in multiple

countries is that they could provide important

comparative insights into the impact of social, 

cultural, and behavioral factors on the adoption 

of microbicides once they reach the market. 

In addition, to support U.S. licensure, FDA will

expect U.S. women at higher risk to be evaluated

at least for safety. Given current seroincidence

estimates in higher risk women’s cohorts –

between 1 and 1.5 per hundred person-years –

outcomes become available at the same ti

efficacy results, so economies cannot be a

by delaying this aspect of clinical investiga

A final consideration that may affect the req

size of efficacy trial cohorts is the prevalence 

rectal intercourse. Vaginal microbicide cand

may or may not be efficacious for rectal u

given the different anatomical, physiologi

and immunological properties of suscepti

rectal mucosa. They may not even be safe 

anorectal exposure, although rectal safety 

are being developed and rectal safety is lik

become a routine part of early clinical eva

of microbicide candidates. To the extent t

trial participants who become infected we

exposed rectally rather than vaginally, this 

reduce the sensitivity of the trial to detec

protective effects of vaginal microbicides. 

extent to which this factor will require sti

sample sizes is not known because data on

prevalence of anorectal intercourse in wor

populations are very limited. However, th

behavior has been sufficiently well docum

in the relatively few settings where quanti

or qualitative data have been carefully col

to suggest that further studies of the preva

and predictors of anal sex will help, at a min

in planning future microbicide efficacy trial
50 NIAID Topical Microbicide Strategic Plan

safety information related to the specific populations

within which the product will be tested and

among whom it is intended to be used once

approved, prior to full-scale Phase III

efficacy evaluation.

The current lack of enthusiasm for a separate

Phase II evaluation has resulted from the lack 

of any surrogate for protection, together with

the reasonable expectation that incorporating a

Phase II run-in to the first period of a planned

Phase III trial would increase efficiency and 

possibly reduce overall costs. However, there are

two important areas where stand alone Phase II

trials may come to play an important future role

in the development process: first, in obtaining

expanded safety data, especially among populations

with a high proportion of participants who

might use such a product several times a day 

or more; second, in providing comparative

information on product acceptability in 

varied settings. 

Although women who may need to use a 

protective product multiple times per day – such

as sex workers – may be a minority of the total

potential user population, they remain a very

important population for an effective womancontrolled protective method. Differences in the

relative safety of different products when used

multiple times per day or against the backdrop

of higher STI rates may turn out to be the

most important factor differentiating otherwise

similar products and therefore a useful guide to

products consistently and correctly is a major

consideration. In the absence of a definitive 

surrogate of protection, that might serve as a

primary outcome measure for Phase II trials,

and with preclinical efficacy an imperfect guide

to prioritization, acceptability among representative

populations of prospective users becomes a 

paramount consideration and an important 

outcome to examine in Phase II, especially if

multiple products are ready for comparative testing. 

Behavioral outcomes associated with adherence

and proper use can be assessed in relatively small

numbers of women (e.g., 50 to 100) in enough

clinical sites to represent the diversity 

of populations of women being invited to join

efficacy trials. The validity of the results will

depend on the extent of differential self-selection

between women who agree to enroll in such 

trials and the composition of subsequent largescale efficacy trial cohorts. Phase II trials offer,

simultaneously, operational benefits.

• Training opportunities for additional

research staff

• Early indicators of potential problems 

with enrollment or retention

• Potential to embed comparative evaluations

of different approaches to condom promotion

counseling and informed consent education

• Opportunity to refine any new procedures

related to specimen collection, processing,

storage, and/or diagnostic testing 
• As a guide to further product discovery, the

fundamental biology of sexual transmission

across genital and rectal mucosa and the

subsequent dissemination among susceptible

target cells has come to be seen as a major

source of innovation in development of

additional candidate agents specifically

designed to block well-characterized steps 

in the infection process. 

• Both expanded populations of nonhuman

primates and animal models that more

closely mimic the circumstances of sexual

exposure among humans have emerged as

high priorities in improving the guidance

provided by preclinical evaluation in selecting

the most promising products to advance

through human trials. 

• The scale and complexity of clinical trials

will increase as the pipeline of qualified

candidates and innovative approaches to

formulation and delivery diversifies.

Sponsors have increasingly appreciated that

communities experiencing relatively high

HIV incidence among general populations

of women are priority populations for

microbicide trials because they represent the

largest group of anticipated future users.

However, these populations often lead to

discovery and development – although sug

the need for more diversified or robust eff

certain areas – also offers the potential to ac

attainment of NIAID’s goal – safe and eff

microbicides against HIV/AIDS and other 

The scale and complexity of clinical trials will increase as the pipeline of qualified 

candidates and innovative approaches to formulation and delivery diversifies.

NIAID Topical Microbicide Strategic 
52 NIAID Topical Microbicide Strategic Plan ATTACHMENT 1 NIAID TOPMIC GROUP MEMBERSHIP AFFILIATION

Division AIDS Microb

Infectio

Program Basic Sciences Treatment Research Vaccine & Prevention Research

Topical Microbicide Team Leader PSB5Program Officer, Immunology PBRB1Program Officer/Project Officer 

Virology/AIDS 

Reference & Reagent Program PBRB

Project Officer, Nonhuman 

Primate Evaluation TIB2

Project Officer, Specialized In Vitro 

Virological Testing TIB

Branch Chief TIBAssociate Director OAD3Project Officer, In Vitro Virological Evaluation DDCSB4Project Officer, Formulations/Manufacturing; 

Pharmacology/Toxicology DDCSB

Project Officer, Chemical Resynthesis; NIAID

Chemistry Database DDCSB

Branch Chief DDCSBMedical Officer PSB

Branch Chief PSBMedical Officer STProject Officer, STD Clinical Trials Group SBranch Chief SProject Officer, In Vitro & In Vivo 

Virological Evaluation 

Virologist/Immunologist 

TITLE
Nevertheless, any model must achieve the best possible correlation with clinical outcome for validation.

4 The effects of a formulated microbicide candidate on cervicovaginal tissues and microenvironment are measured immedia

min.) and 24 hours following each daily application for 4 days. Recovery of tissues and flora is measured within 1 week o

application of microbicide candidate.

5 To test topical microbicides, animals receive a single intravaginal application of the testing compound (formulated or non-for

immediately – seconds or minutes – or several hours prior to intravaginal challenge with HSV-2. This approach will ident

effective microbicide that not only protects the animals from viral infection soon after drug application but also retains ac

the genital tract for a considerable period.

6 In this model, a single dose of the formulated microbicide candidate is applied 30 minutes prior to cervical challenge with 

human biotype of trachomatis that readily and reproducibly infects 100 percent of challenged animals.

7 In general, a single dose of a candidate vaginal microbicide is applied to block the establishment of viral infection 15 to 2

prior to the atraumatic administration of virus.

8 All formulations under development are tested for their effect on the integrity of latex condoms.

9 Both the NIAID Clinical Research Products Manufacturing Contract and HIV Prevention Trials Network discretionary fu

be used to support packaging and labeling of bulk product for dispensing to study participants.

10 Through these mechanisms, candidate microbicides that have reached a more mature stage of development, in which the p

of both the active agent and the formulation have been established, enter into clinical trials that ultimately may supp

licensure application.

11 Recently, HPTN investigators have arranged with CONRAD to coordinate Phase I trials of several novel microbicide ca

with CONRAD conducting Phase I trials among HIV-seronegative low-risk women and HPTN continuing these studie

HIV-infected women. 

12Periodic meetings of NIAID and FDA staff – sometimes including HPTN investigators – address a variety of issues assoc

microbicide clinical development strategy. Clinical Trial Agreements (CTAs) and an associated letter of understanding are ne

with each manufacturer concurrent with the development of trial concepts or early protocol development. NIAID typically 

IND for agents entering NIAID-funded clinical trials; in those cases where the pharmaceutical company prefers to hold the 

CTA specifies which responsibilities (e.g., safety reporting, study monitoring, etc.) the manufacturer delegates to NIAID 

its grantees or contractors. 

13This includes the AIDS International Training and Research Program to train developing country scientists by bringing 

scientists to U.S. institutions and in exchange supporting in-country activities by U.S. scientists, and the International B

Education and Career Development Award program to develop or expand current curricula in international bioethics rel

performing research in low- and middle-income nations.

14These contractors assure compliance with human subjects requirements, data integrity, and other standards of Good Clin

Practice. They also offer management and organizational expertise through optional consultation visits to clinical sites se

advice on how to improve study management and operations.

NIAID Topical Microbicide Strategic 
py pgpy p

systemic levels of such a candidate may result in selection for and transmission of drug-resistant isolates by users who are unaware

of their infected status. Thus, a formulation tailored to optimize activity and minimize irritation potential and systemic absorption

becomes a pivotal step for further advancement.

17 Other than HIV and human papilloma virus, sexually transmitted infections can be effectively treated with antibiotics or, as in

the case of HSV-2, suppressed. 

18 Absence of vaginal protection in clinical trials to evaluate other N-9 containing products argues against clinical evaluations to

determine whether N-9 in sexual lubricants enhances the risk of HIV transmission. However, the potential of this detergent to

disrupt epithelial surfaces at the time when exposure to HIV is most likely to occur raises an important concern for policy makers

and commercial manufacturers of sexual lubricants containing N-9. 

19 Xiao, X., et al. Proc. Natl. Acad. Sci. USA; 96:7469 (1999)

20 Mangano, A., et. al. J. Inf. Dis. 183:1574 (2001); Gonzalez, E., et. al. Proc. Nat. Acad. Sci. USA; 98:5199 (2001)

21 Smith S. M., et al. J Inf Dis. 182:708 (2000)

22 Geijtenbeek, T. B. H., et al. Cell. 100:587 (2000)

23 Nguyen, D. H. and Hildreth, J. E. F. J. Virology. 74:3264 (2000)

24 PRO 2000 is a synthetic naphthalene sulfonate polymer that inhibits HIV attachment and fusion.

25 M. G. Lewis Ref. Lewis M. G. et al: Abstract 721 presented at the 8th Conference on Retroviruses and Opportunistic Infections

in Chicago, IL (2001)

26 Pal, R. et al. Abstract presented at the NIAID Topical Microbicide Preclinical Evaluation Workshop in Atlanta, GA (1998)

27 PMPA has since been licensed as the antiretroviral nucleotide reverse transcriptase inhibitor Tenofovir, marketed as Viread.

28 Wyand, M. et al. Abstract # 11246; 12th World AIDS Conference Geneva, June 28 – July 3, 1998

29 Mayer, K. H., Karim, S. A., Kelly, C. et al. AIDS. 17:321 (2003)

30 Chesney, M. et al. Abstract presented at the 12th World AIDS Conference Geneva, June 28 – July 3, 1998

31 Bentley M. et al. Abstract TuPpC1170 presented at the XIIIth International AIDS Conference in Durban, South Africa (2000);

Van de Bijgert J. et al. Abstract ThPeC5291 presented at the XIIIth International AIDS Conference in Durban, South Africa (2000)

32 Celum, C. L. et al. Abstract presented at the International Congress of Sexually Transmitted Diseases, Seville, Spain,

October 19-22, 1997

33 SHIV contains the genetic code for HIV envelope embedded in an SIV DNA backbone that contains genes for other structural

and all enzymatic proteins. 

54 NIAID Topical Microbicide Strategic Plan
P. 23 — Schematic of HIV on a T cell. Courtesy of L.E. Henderson, National Cancer Institu

SAIC, AIDS Vaccine Program

P. 34 — Electron micrograph of Neisseria gonorrhoeae bacteria. Courtesy of Public Health

Image Library.

P. 41 — Schematic of an HIV virion. Courtesy of L.E. Henderson, National Cancer Institut

SAIC, AIDS Vaccine Program

P. 43 — Portrait of two men. Stock photo: Photodisc/Getty Images.

P. 46 — Schematic of the normal cervix, squamocolumnar junction and transformation zone

Coombs R.W. et al. AIDS 2003. 17:455 (2003). Reprinted by permission from pub

Lippincott Williams & Wilkins

P. 51 — Scientist Looking Through a Microscope. Stock photo: Photodisc/Getty Images.

Cover – Portrait of a man and a woman (right side of globe, between organism photos).

Stockphoto: Photodisc/Getty Images

NIAID Topical Microbicide Strategic 
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health

National Institute of Allergy and Infectious Diseases

NIH Publication No. 03-7138

September 2003

www.niaid.nih.gov