**Read Ahead for FDA/VRBPAC Meeting 23 September 2004**

Prepared by:

U.S. Army Medical Materiel Development Activity

U.S. Army Medical Research and Materiel Command

Fort Detrick, MD

**Document Outline**

[Introduction]{.underline}

[Background]{.underline}

Joint HIV vaccine development

Summary of phase I/II clinical trial results

Rationale for advancement to phase III testing

Trial management

[Phase III Trial: Protocol (RV144) Summary]{.underline}

[Implementation and Oversight of Phase III Trial]{.underline}

[Attachments]{.underline}

Article describing phase II trial and results

> Article describing analysis of relationship between CTL response and
> HLA type
>
> Article summarizing associated research in Thailand

**Introduction**

The U.S. Army's Office of the Surgeon General is the sponsor of several
INDs with the U.S. Food and Drug Administration (FDA). IND \# 8795 is
the application for a combination of candidate HIV vaccines: ALVAC-HIV
vCP1521 (Aventis Pasteur) and AIDSVAX^®^ B/E gp120 (VaxGen). A phase III
trial of this vaccine combination has begun in collaboration with the
Ministry of Public Health of Thailand. The purpose of this document is
to provide information to the members of the Vaccine and Related
Biologic Products Advisory Committee of the U.S. FDA in association with
the trial update scheduled for September 23, 2004. The associated
research which provided the foundation for this trial has been recently
summarized (Brown and Nitayaphan, Milit Med 169:588, 2004; attached). An
earlier phase I/II trial was conducted under this IND and the clinical
study report was filed with the FDA in September 2003.

**Background**

[Joint HIV Vaccine Development]{.underline}

The U.S. Army Medical Research and Materiel Command (MRMC), through the
Walter Reed Army Institute of Research and its subsidiary laboratory in
Bangkok \[the Armed Forces Research Institute for Medical Sciences
(AFRIMS)\], has collaborated with Thai scientific and public health
leaders to jointly develop and evaluate candidate HIV vaccines. This
collaboration began in the early 1990s and includes the Royal Thai Army
Medical Department, Mahidol University and Chiang Mai University and
AFRIMS, forming the Thai AIDS Vaccine Evaluation Group (TAVEG). Industry
partners from VaxGen, Chiron Vaccines and Aventis Pasteur (AvP) joined
the collaboration and each developed candidate HIV vaccines with
components derived from the predominant strain (\>85% of isolates) of
HIV in Thailand, subtype E (CRF01_A/E). Gp120 Env subunit HIV vaccines
to T cell line adapted subtype B strains, developed for use in the
United States, were included in bivalent B/E vaccines, in an attempt to
mirror the dual subtype epidemiology of HIV in Thailand, where between 5
and 15% of infections may be due to subtype B HIV infection. Four
vaccine candidates resulted from these efforts and were assessed in
phase I/II trials carried out by the TAVEG. \[The VaxGen candidate was
assessed as a single vaccine thru phase II and III trials by the Bangkok
Vaccine Evaluation Group (BVEG).\] These clinical trials have placed
Thailand at its leadership position in HIV vaccine evaluation among the
less industrialized countries of the world, and led to AFRIMS becoming
the U.S. Department of Defense's lead platform for HIV vaccine
evaluation and testing.

A strategic plan has been followed which, in the absence of knowledge of
the mechanism of protective immunity or empirically derived correlates
of protection, has elected to optimize the likelihood of success by
utilizing vaccine combinations to stimulate the humoral and cellular
arms of the immune system. The joint testing and evaluation of candidate
vaccines in Thailand has progressed through phase I and II trials of
monomeric gp120 candidates alone to live vectored vaccines combined with
a number of soluble envelope proteins. In this unusual situation of
testing and evaluation of a candidate vaccine combinations with
individual products produced by different manufacturers, the INDs are
held by U.S. Army's Office of the Surgeon General. Following are the
candidate vaccines that have been tested in these phase I/II trials in
Thailand by the TAVEG. The first generation vaccines (1 & 2) were
designed to induce humoral immunity alone; the second generation vaccine
combinations (3a, 3b & 4) were designed to induce both humoral and
cellular immunity.

  ----------- ----------------------------------------- ----------------------------
              [Vaccine]{.underline}                     [Manufacturer]{.underline}

  1\.         Monomeric gp120 protein (B)               Chiron

  2\.         Monomeric gp120 protein (E)               Chiron

  3a.         ALVAC-HIV (vCP1521) + gp120 protein (B/E) Aventis Pasteur + Chiron

  3b.         ALVAC-HIV (vCP1521) + oligo gp160 protein Aventis Pasteur
              (E)                                       

  4\.         ALVAC-HIV (vCP1521) + AIDSVAX^®^ B/E      Aventis Pasteur + VaxGen
              gp120                                     

  Note:                                                 
  Studies 3a                                            
  and 3b                                                
  ("RV132")                                             
  were                                                  
  carried out                                           
  under IND                                             
  #8590;                                                
  study 4                                               
  ("RV135")                                             
  was carried                                           
  out under                                             
  IND #8795.                                            
  ----------- ----------------------------------------- ----------------------------

The phase I/II trials carried out by the TAVEG were performed at four
academic centers \[Chiang Mai University, Mahidol University (2 sites)
and Phramongkutklao Army Medical Center\], involving about 700
volunteers. Volunteers were HIV-negative Thai adults, selected to be at
low risk of HIV infection. All candidate vaccines were found to be safe
and well-tolerated, and no HIV infections occurred to volunteers during
the course of these trials.

The combination of ALVAC-HIV (vCP1521) and AIDSVAX B/E gp120 was chosen
for advancement to phase III evaluation based on a combination of the
safety and immunogenicity data of the vaccine candidates in humans, and
considerations related to manufacturing and supply of product necessary
to support the study. This vaccine combination was evaluated in a phase
II trial in Thailand (protocol RV135) with results presented to the U.S.
FDA as part of the "End of Phase II" package in Q3 2002. The results of
that trial are published (Nitayaphan, J Infect Dis 190:702, 2004;
attached); a separate analysis of the relationship of CTL response to
HLA class I type from both phase I/II trials with ALVAC-HIV (vCP1521) is
also published (Paris, Tissue Antigens 64:251, 2004; attached).

[Summary of Phase II Clinical Trial Results]{.underline}

ALVAC-HIV vCP1521 plus AIDSVAX B/E gp120 were tested in study RV135
(Nitayaphan, J Infect Dis 190:702, 2004) which evaluated this
combination with two doses of AIDSVAX B/E, 200 and 600 µg (two antigens
combined). Both vaccines are given as IM injections; ALVAC at 0, 1, 3
and 6 months, AIDSVAX at 3 and 6 months. Both vaccines were found to be
safe and well tolerated. The trial demonstrated that the higher dose of
'boosting' vaccine induced stronger immune responses. Thus, the
combination advanced to phase III evaluation utilized the higher dose of
AIDSVAX B/E.

Of 133 volunteers enrolled in RV135, 122 completed the trial. There were
no serious vaccine-related adverse events, nor were there any
intercurrent HIV infections. Lymphoproliferative responses to gp120 E
were detected in 31% of vaccine recipients after two doses of ALVAC
(pre-protein boost) and in 63% of vaccine recipients after the full
course of immunization. HIV-specific CD8 CTL responses were detected in
24% of vaccinees and 0% of placebo recipients. Antibody responses
increased in frequency and magnitude in association with the dose level
of AIDSVAX B/E. Binding and neutralizing antibodies to the MN strain
were induced in 100% and 98%, respectively, of the volunteers receiving
600 µg of AIDSVAX B/E, and such antibodies to E strains were induced in
96% and 71%, respectively, of these volunteers. Antibody-dependent
cellular cytotoxicity was detected against gp120 in 86% of these
vaccinees and 0% of placebo recipients.

The relationship to HLA type was explored in 187 volunteers who received
ALVAC-HIV vCP1521 in either of the two phase I/II trials (RV132 +
RV135). Precursor cytolytic CD8 T-cell responses were detected in 21% of
these vaccine recipients, and while there was a positive association
with HLA-B44 (odds ratio of 7.6), there were no statistically
significant negative associations. Thus, although larger studies will be
required, there appear to be no HLA-based limitations to the use of
ALVAC-HIV vCP1521.

[Rationale for Advancement to Phase III Testing]{.underline}

The U.S. Army MRMC has elected to move forward with a vaccine
combination that stimulates both the humoral and cellular arms of the
immune system. The collaborative effort in Thailand follows the
hypothesis that vaccine antigens should match the HIV subtypes
circulating in the region, and the candidate vaccines under assessment
utilize subtype E envelope antigens and B Gag/Pol antigens. Volunteer
safety is a prime concern. Although approximately 200 persons had
previously received the specific vCP1521 ALVAC-HIV construct, both
ALVAC-HIV and AIDSVAX have well documented safety profiles. ALVAC-HIV
has been tested in numerous variations in approximately 2500 persons and
with a variety of subtype B sequences. AIDSVAX B/E was recently tested
and found safe in more than 2500 Thai adults. Based on these factors,
criteria for progressing to phase III evaluation were that the subtype E
candidate vaccines demonstrate safety and an immunogenicity profiles
similar to subtype B (vCP205) ALVAC-HIV and AIDSVAX candidate vaccines.

Following review of the phase II trial results, the U.S. and Thai
governments, along with vaccine manufacturers, agreed to proceed to
phase III testing. For nearly two years prior to initiation, information
pertaining to RV144 was publicly presented. Eleven governmental and
academic scientific, ethical and regulatory review bodies in Thailand
and the United States, as well as the World Health Organization and the
Joint U.N. Programme on HIV/AIDS (WHO-UNAIDS) reviewed and endorsed this
clinical trial. The Category B-End of Phase 2 Meeting with the U.S. FDA
was held November 8, 2002.

[Trial Management]{.underline}

This multi-national collaboration includes a large number of partners.
Sponsorship is shared by the U.S. Army's Office of the Surgeon General
(IND holder) and the Division of AIDS of the National Institute of
Allergy and Infectious Diseases. The investigator team is led by Dr.
Supachai Rerks-Ngarm of the Department of Disease Control, Thai Ministry
of Public Health, in collaboration with the Royal Thai Army Medical
Department and the Faculty of Tropical Medicine, Mahidol University;
Aventis Pasteur and VaxGen are industry partners. These relationships
are formalized through an Interagency Agreement \[U.S. Army Medical
Research and Materiel Command (USAMRMC) and NIAID\], Cooperative
Research and Development Agreements (USAMRMC and each of the two
companies), a Cooperative Agreement (USAMRMC and the Henry M. Jackson
Foundation); and contracts (the Jackson Foundation and the investigator
institutions).

Trial-specific committees have been established for oversight, including
a Requirements and Obligations Committee within the sponsor agencies and
a Pharmacovigilence Committee with representatives of all the
collaborative partners. These committees meet regularly by
teleconference and information is shared among members by utilizing a
secure website. The sponsor has also established a Data and Safety
Monitoring Board (DSMB), chaired by Dr. Walter Dowdle, with five of its
10 members being designees of the National AIDS Commission of Thailand.
The DSMB plans to have meetings to monitor volunteer safety every six
months and as needed, and to have a single interim efficacy assessment
about two thirds of the way through the trial. The following paragraphs
summarize the trial protocol.

**Phase III Trial: Protocol (RV144) Summary**

TITLE: A Phase III Trial of Aventis Pasteur Live Recombinant ALVAC-HIV
(vCP1521) Priming With VaxGen gp120 B/E (AIDSVAX^^ B/E) Boosting in
HIV-uninfected Thai Adults

IND (# 8795) Holder: Office of The Surgeon General, U.S. Army Medical
Department

OBJECTIVES:

### 

### Primary Objective:

> To determine whether immunizations with an integrated combination of
> ALVAC-HIV (vCP1521) boosted by AIDSVAX^^ gp120 B/E prevent HIV
> infection in healthy Thai volunteers.

## Secondary Objectives: 

-   To determine whether immunization with this vaccine combination
    results in reduced HIV viral load among those acquiring HIV-1
    infection, comparing vaccine recipients to placebo recipients.

-   To determine whether immunization with this vaccine combination
    results in an increased CD4 count among those acquiring HIV-1
    infection, comparing vaccine recipients to placebo recipients.

-   To confirm the safety of this vaccine combination in Thai
    volunteers.

-   To evaluate whether participation in this HIV vaccine trial is
    associated with behavior change that may increase the risk of HIV
    infection.

SUBJECTS: 16,000 HIV-uninfected Thai subjects, male or female, aged 20
through 30 years (inclusive), available for 3.5 years of participation.
Subjects who are 18 or 19 years of age and married will also be eligible
for enrollment. \[Assumptions employed for sample size calculations
utilized results of HIV incidence and follow-up rates determined in
cohort studies carried out in the study area (Brown and Nitayaphan,
Milit Med 169:588-93, 2004).\]

STUDY SITES: Ministry of Public Health (MOPH) facilities in Chon Buri
and Rayong Provinces, Thailand, to include health centers, hospitals,
and Rayong STD Clinic.

PRODUCT DESCRIPTIONS:

> ALVAC-HIV (vCP1521), produced by Aventis Pasteur (Marcy L'Etoile,
> France), is a recombinant canarypox vector vaccine that has been
> genetically engineered to express subtype E HIV-1: gp120 (subtype E)
> linked to the transmembrane anchoring portion of gp41 (subtype B), and
> HIV-1 gag and protease (subtype B). ALVAC-HIV (vCP1521) is formulated
> at a dose of \>10^6^ CCID~50~. The diluent supplied for reconstitution
> of ALVAC-HIV (vCP1521) consists of sterile 0.4% NaCl.
>
> ALVAC Placebo (Aventis Pasteur) is supplied as a sterile, lyophilized
> product that consists of a mixture of virus stabilizer, and freeze
> drying medium. The diluent supplied for reconstitution of ALVAC
> Placebo consists of sterile 0.4% NaCl.
>
> AIDSVAX^^ B/E, produced by VaxGen, Inc. (Brisbane, CA), is a bivalent
> HIV gp120 envelope glycoprotein vaccine containing a subtype E
> envelope from the HIV-1 strain A244 and a subtype B envelope from the
> HIV-1 strain MN. The recombinant gp120s are produced in genetically
> engineered Chinese hamster ovary (CHO) cell lines. The envelope
> glycoproteins are coformulated and administered at a combined dose of
> 600 µg (300 µg of each antigen). AIDSVAX^^ B/E is formulated with 600
> µg of alum adjuvant.
>
> AIDSVAX Placebo (VaxGen, Inc.) is 600 µg alum adjuvant.

ROUTE OF ADMINISTRATION: Intramuscular into the deltoid muscle.

ALVAC-HIV or ALVAC Placebo (1 mL) into left deltoid

AIDSVAX^^ B/E or AIDSVAX Placebo (1 mL) into right deltoid.

SCHEDULE OF IMMUNIZATION:

  ------- ---------- --------------------- ------------ ---------------- ----------------
                     [Weeks]{.underline}                                 

  Group   Subjects   0                     4            12               24

  I       8,000      ALVAC Placebo         ALVAC        ALVAC Placebo +  ALVAC Placebo +
                                           Placebo      AIDSVAX Placebo  AIDSVAX Placebo

  II      8,000      ALVAC-HIV             ALVAC-HIV    ALVAC-HIV +      ALVAC-HIV +
                                                        AIDSVAX^^ B/E   AIDSVAX^^ B/E
  ------- ---------- --------------------- ------------ ---------------- ----------------

STUDY ENDPOINTS:

### Primary Endpoint

> The primary endpoint of the trial is acquisition of HIV infection as
> determined by repeatedly reactive EIA, positive Western blot and
> positive HIV nucleic acid testing (from two different blood
> collections).

## Secondary Endpoints 

> The secondary endpoints of the trial are the following:

-   Plasma viral load in volunteers developing HIV infection during the
    trial.

-   CD4 T cell count in volunteers developing HIV infection during the
    trial.

-   Safety assessment of this vaccine combination in Thai volunteers

-   Change in HIV risk behaviors associated with participation in the
    vaccine trial.

Overall Study Design:

This is a community-based, randomized (vaccine : placebo = 1:1),
multicenter, double-blind, placebo-controlled clinical trial. Screening
of potential volunteers, including HIV testing and counseling, is
carried out under a separate protocol entitled "Screening and evaluation
of potential volunteers for a trial in Thailand of a candidate
preventive HIV vaccine" (RV148). Eligible volunteers are being enrolled
over approximately two years. Vaccinations for each individual occur
over a 24-week period (at 0, 4, 12, 24 weeks). Women are tested for
pregnancy at each vaccination visit and volunteers testing positive are
not vaccinated. Blood is collected for plasma (for diagnostics and
HIV-specific antibodies) at 0, 24 and 26 weeks, and every 6 months
during the follow-up phase. The blood collection at 0, 6, 12 and 42
months is also used for cryopreservation and archiving of PBMCs (for
HIV-specific cellular immune responses). At week 24 and at each
six-month follow-up visit, volunteers have HIV testing, preceded by
pretest counseling and followed (approximately 2-3 weeks later) by
post-test counseling. Assessment of HIV risk behavior is be performed at
baseline, week 26 and at each 6-month follow-up visit. Education on risk
behavior reduction is given at each vaccination visit and at each
post-test counseling visit. Volunteers diagnosed with an HIV infection
based on the testing of blood collected at two separate time points are
counseled, referred to the specialized clinics for HIV care and
management in accordance with the National Guidelines of the Thai
Ministry of Public Health, and monitored with HIV viral load and CD4
cell quantitation.

**Implementation and Oversight of Phase III Trial**

Screening of potential volunteers began in September 2003 with the first
volunteers enrolled and vaccinated in the trial (RV144) in October 2003.
Screening and vaccination sites began enrollment in a phased and rolling
manner to allow optimal attention to performance of trial procedures and
logistics. After completion of the initial phase-in stages of the trial,
a meeting of all collaborators was held in February 2004, chaired by Dr.
Vallop Thaineua, the Permanent Secretary of the Ministry of Public
Health, and attended by senior representatives of the sponsor,
investigator and manufacturer organizations. At that time it was agreed
by all partners to move forward with full implementation of the trial
across all sites in the two provinces (47 screening sites and 8
vaccination sites).

The investigator team includes more than 500 staff in Thailand, among
whom more than 100 are dedicated fulltime to this trial. The majority of
staff are from the health care facilities in the study area. In
addition, full-time research teams from Mahidol University work in each
of the eight vaccination sites. Vaccine is stored centrally prior to
distribution to vaccination sites in a secure section of the Ministry of
Public Health's regional facility for EPI vaccines. Blood specimens are
processed and stored in a dedicated central laboratory in Chon Buri
Province from which aliquots for diagnostic testing are shipped to the
AFRIMS laboratory in Bangkok which is accredited by the College of
American Pathologists. Data from clinical report forms are forwarded
from each vaccination site to the Data Management Unit at Mahidol
University via a dedicated DataFax system. Oversight of the data
management is provided by the Walter Reed Army Institute of Research and
independent statistical analysis is performed by the EMMES Corporation.

As of 15 August 2004, more than 7,500 volunteers have been screened as
potential volunteers for the trial, and more than 4500 have been
enrolled and begun the vaccination series. At the current rate of
enrollment into the trial, completion of enrollment is projected to be
in the fourth quarter of 2005. The trial's Data and Safety Monitoring
Board held its organizational meeting by teleconference in January 2004
and a full face-to-face meeting in Thailand in July 2004. Subsequent to
the July review, the DSMB informed the sponsors and investigator team
that the trial should continue.

**Attachments**

Article describing phase I/II trial and results (Nitayaphan S,
Pitisuttithum P, Karnasuta,C, et al. J Infect Dis 190:702-6, 2004).

Article describing analysis of relationship between CTL response and HLA
type (Paris R, Bejrachandra S, Karnasuta C, et al. Tissue Antigens
64:251-6, 2004).

Article summarizing associated research in Thailand (Brown AE and
Nitayaphan S. Milit Med 169:588-93, 2004.