Vaccines and Related Biological Products Advisory Committee (VRBPAC)

Background Package for September 23, 2004 Meeting

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HIV-1 Recombinant Canarypox-Vectored Vaccine with Recombinant gp 120 B/E

Phase III studies of vaccines intended for the prevention of HIV/AIDS
require careful consideration of trial design and study endpoints. The
demonstration of efficacy from a HIV vaccine study that might result in
licensure by the U.S. Food and Drug Administration should follow a
series of formalized steps that include input from FDA Advisory
Committees.^1^ In this case, the Office of the Surgeon General of the
Army submitted to the IND study RV144, a phase III clinical trial of
ALVAC vCP1521 plus AIDSVAX B/E for the prevention of HIV infection to be
conducted exclusively in Thailand. A decision was made by the National
Institutes of Health not to proceed with a phase III trial of a similar
vaccine series, ALVAC vCP1452 plus AIDSVAX B/B.^2^ Scientific journals
have aired the differing opinions surrounding the Thai trial.^3,4,5,6^
The purpose of the brief presentations by a representative of FDA and a
representative of the sponsor is to inform the VRBPAC of the status of
the clinical trial and highlight regulatory concerns, including the
decision to allow the Thai trial to proceed.

The World Health Organization in the early 1990s designated Thailand as
a target country for the development of a vaccine for primary prevention
of HIV. At that time, Thailand experienced an alarming increase in HIV
infection rates among injection drug users and commercial sex workers.
Recent HIV prevalence data demonstrate that approximately 2% of Thai
women receiving antenatal care are infected with HIV.^7^ The vast
majority of HIV infections in Thailand are characterized as the
recombinant CRF01_AE, formerly known as clade E.^8^ The predominant
strain that circulates in the United States (U.S.) is clade B. Another
epidemiological consideration for the U.S. FDA is the number of
infections with CRF01_AE HIV among persons residing in the U.S. A survey
of newly infected U.S. military personnel between the years 1997 and
2000 identified 28 infections among 520 recent seroconverters as
non-subtype B; only 5 were characterized as CRF01_AE and four out of the
five originated from Southeast Asia.^9^

The vaccine series of ALVAC-HIV vCP1521 plus AIDSVAX B/E is the second
vaccine regimen for the prevention of HIV to enter phase III clinical
development. ALVAC-HIV vCP1521 is a canarypox-vectored vaccine
manufactured by Aventis-Pasteur, Inc. and AIDSVAX B/E is a recombinant
glycoprotein (rpg) 120 subunit protein manufactured by VaxGen, Inc.
ALVAC-HIV vCP1521 plus AIDSVAX B/E is intended to match the HIV strain
CRF01_AE that circulates in Thailand. A recent publication describes
ALVAC-HIV vCP1521 and AIDSVAX B/E as follows^8^:

ALVAC-HIV (vCP1521)...is a recombinant canarypox vector vaccine
expressing CRF01_AE HIV-1 gp120 (92TH023) linked to the
transmembrane-anchoring portion of subtype B gp41 (strain LAI) with a
deletion in the immunodominant region and also expressing HIV-1 Gag and
protease (strain LAI).

> *AIDSVAX B/E...is a bivalent HIV gp120 vaccine containing a B envelope
> from strain MN and a CRF01_AE envelope from strain A244.*

Thus, while both vaccines contain some clade B antigen components, the
vaccines were specifically designed to enhance the possibility that they
might elicit an immune response that would protect against the CRF01_AE
strain. The rationale for the consideration of a prime-boost strategy of
a canarypox-vectored vaccine with a protein subunit boost centers upon
the theoretical ability to elicit strong humoral and cellular immune
responses. Indeed, the initial immunogenicity studies of ALVAC vCP125
and ALVAC vCP205 suggested that the addition of a protein boost might
enhance neutralizing antibody responses.^4^ In general, the ALVAC-HIV
constructs combined with protein subunit boosts have been reported to
lack robust immunological responses in healthy volunteers.^3^
Nevertheless the correlates of immune protection against HIV remain
unknown and the sponsors are proceeding with the ALVAC vCP1521 plus
AIDSVAX B/E in study RV144. The following table summarizes the
immunological responses from the phase II study RV135:

Table 2: Study RV135, immunological responses to ALVAC vCP1521 plus two
doses of AIDSVAX B/E at the same regimen to be used in study RV144^8^:

+---------+---+------+------+----+----------+----+----------+-----+
| Vaccine | N | Neut |      | B  |          | B  |          | HIV |
| r       |   | rali |      | in |          | in |          | -sp |
| egimen: |   | zing |      | di |          | di |          | ec. |
| vCP1521 |   | anti |      | ng |          | ng |          | C   |
| plus    |   | body |      | Ab |          | Ab |          | D8+ |
| AIDSVAX |   | sub  |      | g  |          | g  |          | CTL |
|         |   | type |      | p1 |          | p1 |          |     |
|         |   | CRF0 |      | 20 |          | 20 |          |     |
|         |   | 1_AE |      | MN |          | A2 |          |     |
|         |   | str  |      |    |          | 44 |          |     |
|         |   | ains |      |    |          |    |          |     |
+---------+---+------+------+----+----------+----+----------+-----+
|         |   | C    | NPO3 | \% | GMT      | \% | GMT      |     |
|         |   | M244 |      |    |          |    |          |     |
|         |   |      |      |    | \[95%    |    | \[95%    |     |
|         |   |      |      |    | CI\]     |    | CI\]     |     |
+---------+---+------+------+----+----------+----+----------+-----+
| 200μg   | 5 | 44%  | 23%  | 9  | 3744     | 8  | 596      | 24% |
|         | 0 |      |      | 5% |          | 6% |          |     |
|         |   |      |      |    | \[216    |    | \[30     |     |
|         |   |      |      |    | 7-6469\] |    | 1-1180\] |     |
+---------+---+------+------+----+----------+----+----------+-----+
| 600μg   | 4 | 64%  | 31%  | 10 | 7730     | 9  | 1691     | 24% |
|         | 7 |      |      | 0% |          | 6% |          |     |
|         |   |      |      |    | \[4961-  |    | \[91     |     |
|         |   |      |      |    | 12,045\] |    | 8-3114\] |     |
+---------+---+------+------+----+----------+----+----------+-----+
| Placebo | 3 | 0%   | 0%   | 0% |          | 0% |          | 0%  |
|         | 1 |      |      |    |          |    |          |     |
+---------+---+------+------+----+----------+----+----------+-----+

The completed efficacy studies for AIDSVAX B/B and AIDSVAX B/E products,
conducted in the U.S. and in Thailand, respectively, were well described
in the public domain.^10^ No efficacy was demonstrated in the prevention
of HIV vaccine when these rgp120 subunit vaccines were administered
alone. These study results and preliminary immunogenicity results from
AVLAC vCP1521 plus AIDSVAX B/E have led some to question the likelihood
that this vaccine will protect against HIV infection.^3,6^ This
particular vaccine regimen had been administered to several hundred
volunteers without significant safety concerns^8^, and no important
safety issues have been identified among the thousands of healthy
volunteers who have received ALVAC-HIV products with or without protein
subunit boosts.^11^ Therefore, sufficient safety information was
available regarding the administration of ALVAC vCP1521 plus AIDSVAX B/E
that would not preclude the initiation of study RV-144.

The regulatory challenge generated with this trial is the consideration
of approving a vaccine strategy that is designed for the prevention of a
specific clade of HIV that does not circulate in the U.S. The FDA
approves products that are indicated for use in a U.S. population. There
are ongoing discussions between various regulatory agencies and
non-governmental organizations on how guidance might be provided for
approvals for developing countries.^12^ Another regulatory concern is a
study result of relatively low efficacy which might, nevertheless, be
sufficient to have a beneficial impact in Thailand where widespread use
of the vaccine series could slow an HIV epidemic of the CRF01_AE strain.
However, a low level of efficacy might not provide substantial
individual benefit for a person residing in the U.S. The licensed
indication for the use of a vaccine regimen with a relatively low level
of efficacy would require a different risk-benefit assessment for the
U.S. population than would be required for licensure in Thailand.

In summary, we view study RV144 as a "proof of concept" study that would
assess the preliminary efficacy of a canarypox vectored HIV-1 vaccine
administered in combination with a rgp120 protein boost. The study was
allowed to proceed given the current state of knowledge in HIV vaccine
research where a correlate of immune protection has not been elucidated,
as well as the apparent safety profile of the vaccine regimen.
Furthermore, it is worth mentioning that the study is the first study to
be conducted in a young adult population where primarily heterosexual
transmission of HIV would occur. The purpose of this VRBPAC presentation
is to inform the VRBPAC of the regulatory decision to allow the study to
proceed and to inform the VRBPAC of some of the regulatory challenges
that might arise based on future results of this clinical trial.
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**References:**

^1^Meeting Summary: AIDS Vaccine Trials, Considerations for Phase III
Trial Design and Endpoints. National Institutes of Health, NIAID,
November 16, 2001. Retrieved from the World Wide Web on August 3, 2004
at <http://www.niaid.nih.gov/vrc>.

^2^NIAID Phase III HIV vaccine trial to determine correlates of
protection will not proceed. NIAID News, February 25, 2002. Retrieved
from the World Wide Web on August 9, 2004 at
<http://www2.niaid.nih.gov/newsroom/releases/phase3hiv.htm>.

^3^Burton DR, Desrosiers RC, Doms RW, et al. Public health. A sound
rationale needed for phase III HIV-1 vaccine trials. Science
2004;303:316.

^4^McNeil JG, Johnston MI, Birx DL, Tramont EC. Policy rebuttal. HIV
vaccine trial justified. Science 2004;303:961.

^5^Trinvuthipong, D. Thailand's prime-boost HIV vaccine trial phase III.
Science 2004;303:954-5.

^6^Letters to the Editor. Science 2004;305:177-180.

^7^Tangcharoensathien V, Wiput P, Pitayarangsarit S, et al. The
potential demand for an AIDS vaccine in Thailand. Health Policy
2001;57:111-139.

^8^Nitayaphan S, Pitisuttithum P, Karnasuta C, et al. Safety and
immunogenicity of an HIV subtype B and E prime-boost vaccine combination
in HIV-negative Thai adults. Journal of Infectious Diseases
2004;190:702-6.

^9^Tovanabutra S, et al. Characterization of full-length HIV-1 genomes
from non-B subtype infections in U.S. military personnel. AIDS Vaccine
2003, New York, NY; Abstract number 463.

^10^McCarthy M. AIDS vaccine fails in Thai trial. Lancet. 2003 Nov
22;362(9397):1728.

^11^de Bruyn G, Rossini AJ, Chiu Y, et al. Safety profile of recombinant
canarypox HIV vaccines. Vaccine 2004;22:704-13.

^12^Klausner RD, Fauci AS, Corey L, et al. The need for a global HIV
vaccine enterprise. Science 2003;300:2036-39.