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Published in the
Bulletin of Experimental Treatments for AIDS September 1996 issue,
by the San Francisco AIDS Foundation.
September
1996 Table of Contents
Main Page
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HIV Vaccines
by Mark Bowers
Vaccination is the simplest, safest and most effective way to prevent
many diseases. Vaccines for many viral diseases are routinely given to
children and adults in all countries of the world. These vaccines, including
smallpox, polio and measles vaccines, are both cheap and effective. Yet
former Surgeon General C. Everett Koop told the American public not to
expect a vaccine for HIV before the end of the century, and Margaret Johnston,
PhD, who spearheads the new International AIDS Vaccine Initiative (IAVI),
told the XI International Conference on AIDS in Vancouver that current
research and development efforts are unlikely to yield an effective vaccine
for 6 more years. What is holding back research? Where are the candidate
vaccines that were so widely publicized in the early 1990s?
Drug companies have backed away from HIV vaccine research for the last
several years for a number of reasons. The failure of envelope glycoprotein
(gp) 120 subunit vaccines to neutralize primary isolates of the virus
(strains of HIV taken from the blood of infected individuals, rather than
developed in the laboratory) led to a pivotal decision in June 1994 not
to pursue wide-scale vaccine trials in the United States. In response,
biotechnology and pharmaceutical companies reduced their commitment to
vaccine research and development. Genentech, where vaccine researcher
Donald Francis, MD, for years has championed wider testing of his gp120
vaccine candidate, created a smaller, vaccine-focused company named Genenvax,
then backed away from AIDS vaccine research in general. Merck and Repligen
suspended work on their candidate vaccine in 1994. And MicroGeneSys, maker
of a controversial baculovirus-grown subunit gp 160 vaccine candidate,
ceased further vaccine research when that candidate failed to demonstrate
positive effect in clinical studies.
The focus of vaccine testing then shifted to the developing world. In
Thailand, increasing infection rates created the political will to test
candidate vaccines that certainly will not be 100% effective. However,
it is felt that even a modest rate of protection would have a major impact
on diminishing new infections. A wide-scale study of a Genenvax vaccine
candidate is slated for Thailand in 1997. Later this year, a Chiron gp120
subunit vaccine candidate based on the subtype of HIV prevalent in Thailand
will enter Phase I testing.
Primary concerns regarding the development of a vaccine intended for
wide use in developing countries are low cost and ease of administration.
A cheap and easily administered vaccine is considered the only possible
means of containing burgeoning infections in most third world nations.
Unfortunately, potential vaccine makers have chosen to direct their research
and development efforts elsewhere, fearing potential financial losses.
Also of concern is the huge variability of HIV, both in infected individuals
(more than 660 variants are known) and in infected populations (subtypes
or clades). HIV-1 has been classified in 2 groups, M and O; 9 subtypes
have been identified within group M, and only a few in group O. Subtypes
in a group differ genetically from one another by about 30%. A successful
HIV vaccine would need to elicit immunity to all the HIV subtypes to which
a vaccinee may be exposed.
Two major initiatives to bolster vaccine research were revealed at the
Vancouver conference. The director of the Office of AIDS Research at the
U.S. National Institutes of Health, William Paul, MD, announced an increased
allocation of funds for research on vaccines and a "restructured,
redirected vaccine research program." Moreover, efforts by Seth Berkley
at the Rockefeller Foundation in New York to raise $600 million over 7
years to fund the IAVI have borne fruit. IAVI, incorporated in January
1996, now has $5 million in its coffers for its first year of operation.
Under the leadership of scientific director Johnston, formerly deputy
director of the Division of AIDS, IAVI will support vaccine research and
development in areas where there are currently gaps. IAVI also plans to
work with the World Bank, governments, private industry, funders and regulatory
agencies to increase investment in vaccine research and development. Perhaps
the most important mission of IAVI is to foster the creation of coordinated
global vaccine efforts to make vaccines that can be effectively and cheaply
used in the developing world.
Preventive Vaccine Candidates
The AIDS Vaccine Evaluation Group (AVEG), sponsored by the National Institute
of Allergy and Infectious Diseases (NIAID), has conducted 25 clinical
studies of candidate HIV vaccines, involving more than 1,900 seronegative
adults. A table of completed, current and planned trials is shown below.
Results of AVEG 201, the only study in Phase II, were reported at the
Vancouver conference. A total of 296 adult heterosexuals, gay or bisexual
men and intravenous drug users received either 600 mg of the recombinant
gp120 MN vaccine candidate (made by Genenvax) in alum adjuvant, MF-59
adjuvant alone or alum alone, or 50 micrograms of the recombinant gp120
SF2 vaccine candidate in MF-59 adjuvant (made by Chiron Biocene). Comparisons
of neutralizing antibody were made between the groups, and it was concluded
that 4 rather than 3 immunizations may be the optimal dosing schedule
to elicit antibody responses. The participants in the study did not increase
their risk behaviors because they were in a vaccine study.
Also reported were the results of Phase I/II trials of a "prime/boost"
strategy employing a recombinant canarypox vaccine candidate designated
ALVAC-HIVgp160 (Virogenetics/Pasteur Merieux) as the prime followed by
the Chiron Biocene gp120 candidate as the boost. The strategy has proven
safe and capable of inducing not only neutralizing antibodies, but also
cytotoxic lymphocyte responses in vaccinees. This shows that the humoral
and cell-mediated (B-cell and T-cell) types of immunity can be induced
by intramuscular injection of the 2 candidate vaccines. Different doses
and dosing schedules were compared. Participants were vaccinated at baseline,
1 or 2 months later, 6 or 9 months later, and 12 months later. Ten participants
received 106 50% tissue culture infectious doses of ALVAC-HIVgp160 alone
while 9 also received 50 micrograms of Chiron's gp120; 18 received 107
50% tissue culture infectious doses of ALVAC-HIVgp160 alone while 29 also
received 50 micrograms of Chiron's gp120; and 9 participants received
only 50 micrograms of Chiron's gp120.
Those participants who received prime/boost developed antibodies that
could neutralize both the MN and SF2 strains of HIV. The 4-dose schedule
appeared to be better than the 3-dose schedule, and a current study will
assess if even higher doses enhance the immune responses that were found.
AIDS
Vaccine Evaluation Group Completed, Current and Planned Vaccine Trials
Completed
Trials
Envelope alone:
Product: gp160 IIIB
Sponsor*: MicroGeneSys
Number of volunteers: 128
Product: gp160 IIIB and MN
Sponsor*: Immuno-AG
Number of volunteers: 159
Product: gp 120 (yeast)
Sponsor*: Biocene
Number of volunteers: 78
Product: gp 120 IIIB
Sponsor*: Genentech
Number of volunteers: 28
Live pox virus ± envelope:
Product: Vaccinia -env ± envelope boosts
Sponsor*: Bristol-Myers
Number of volunteers: 217
Product: Vaccinia-env (gag)pol
Sponsor*: Therion
Number of volunteers: 14
Current
Trials
Envelope alone:
Product: gp 120 MN
Sponsor*: Genentech
Number of volunteers: 211
Product: gp 120 SF2
Sponsor*: Biocene
Number of volunteers: 205
Product: gp120 (new formulation)
Sponsor*: Biocene
Number of volunteers: 30
Product: gp120 + novel adjuvants
Sponsor*: Genentech/Biocene
Number of volunteers: 311
Live pox ± envelope:
Product: Canarypox env ± gp120
Sponsor*: PMC/Biocene
Number of volunteers: 131
Product: Low-dose canarypox env /gag ± gp120
Sponsor*: PMC/Biocene
Number of volunteers: 76
Peptide:
Product: V3 peptide
Sponsor*: UBI
Number of volunteers: 137
Method: intramuscular, intramuscular plus oral
Particle:
Product: p24 virus-like particle
Sponsor*: British Biotech
Number of volunteers: 36
Method: intramuscular plus mucosal
Planned
Trials
Live pox ± envelope:
Product: High dose canarypox env /gag ± gp120
Sponsor*: PMC/Biocene
Product: Canarypox env /gag mucosal
Sponsor*: PMC
Product: Canarypox env /gag/pol ± gp120
Sponsor*: PMC/Biocene
Product: Vaccinia-env /gag/pol
Sponsor*: Therion
Peptide:
Product: T-B peptide
Sponsor*: Lederle
Particle:
Product: Pseudovirion
Sponsor*: PMC
Live bacteria:
Product: Salmonella gp160
Sponsor*: University of Maryland
*Sponsors:
MicroGeneSys, Wallingford CT, USA
Immuno-AG, Vienna, Austria
Biocene, Emeryville, CA, USA
Genentech, South San Francisco, CA, USA
Bristol-Myers, Wallingford, CT, USA
PMC (Pasteur Murieux Connaught), Swiftwater, PA, USA
UBI (United Biomedical, Inc.) Hauppauge, NY, USA
British Biotech, Ltd., Cambridge, UK
Lederle/Praxis, Rochester, NY, USA
University of Maryland, Baltimore, MD, USA
BETA thanks Patricia Fast, MD, PhD, for permission to reprint this
chart.
Laboratory and Animal Studies
Considerable interest has been generated by the news shared at the international
AIDS conference by Robert Gallo, MD, of the Institute of Human Virology
in Baltimore. Gallo and Paolo Lusso, MD, of the San Raffaele Scientific
Institute, described 3 chemokines (pro-inflammatory chemicals made by
the immune system) that may play an important role in the way that HIV
infects cells. These chemokines, according to Daniel Zagury, MD, at the
Pierre and Marie Curie University in Paris, are more highly concentrated
in HIV positive non-progressors. Gallo argues that a strategy that can
artificially boost the chemokines (MIP-1a, MIP-1b and RANTES) or down-regulate
their receptors (designated cysteine-cysteine chemokine receptor 5, CKR5)
might protect against infection with HIV. The theory is so far untested,
but warrants closer scrutiny and research.
Several vaccine researchers have been pursuing "naked DNA"
approaches to vaccine development. Over the last 3 years, DNA vaccines
have increasingly been constructed and tested for HIV, as well as hepatitis
B, tuberculosis and influenza. Upon injection, DNA vaccines apparently
incorporate their genetic material into cells near the site of injection
and begin producing their gene products (proteins) more efficiently than
was predicted by tissue culture experiments. DNA vaccines can be simply
and cheaply produced in large quantities, and are free of contaminants.
Further, this type of vaccine remains very stable by comparison with other
vaccine modalities, increasing the likelihood that they can be transported
and utilized anywhere in the world.
Intramuscular injections of DNA expressing either gp120 or gp160 have
been found to induce significant titers both of neutralizing antibody
(a strong humoral response) and cytotoxic T-lymphocytes (cellular immunity).
According to a research team headed by Britta Wahren, MD, of the Karolinska
Institute in Stockholm, Sweden, immune responses to DNA that expresses
regulatory genes of HIV are stronger than the responses to DNA based on
HIV structural genes. Still, both types of genes may be needed to bring
forth the wide immune response to HIV challenge that may be necessary
to protect people from infection. Naked DNA vaccines are now established
as players in the field of HIV vaccine candidates, despite the fact that
little is known about the mechanisms by which they activate immune responses.
A collaboration between the University of Pennsylvania and Apollon, Inc.
of Malvern, PA, funded by a $4.2 million grant from NIAID, has yielded
a DNA vaccine candidate that expresses the envelope glycoprotein and rev
protein of HIVMN. The first clinical study of this vaccine candidate demonstrated
the safety of 3 doses (30, 100 and 300 micrograms) in 15 asymptomatic
HIV positive volunteers. The volunteers received 3 intramuscular injections
each at 10-week intervals. No trends were noted in CD4 or CD8 cell counts
or viral load. This study is the precursor to more elaborate planned studies;
it is thought that the immunogen may be useful as both a therapeutic and
prophylactic vaccine for HIV.
The most positive news in pre-clinical research on vaccines is data from
a study of an attenuated (weakened) version of simian immunodeficiency
virus (SIV) in monkeys. The vaccine was made by deleting the nef
gene and injecting it, followed by a challenge that consisted of high
intravenous doses of a lethal strain of SIV different from the one from
which the vaccine was made. While the monkeys were protected from infection,
control animals were not. Asakura Yusuke, PhD, and colleagues from Yokohama
University in Japan, who constructed the DNA, saw production of nef-specific
cytotoxic lymphocytes and no pathogenesis in vaccinated monkeys.
Burt Dorman, PhD, of Acrogen in Oakland, CA, believes that a whole inactivated
(killed) HIV vaccine candidate would be likely to generate wide-ranging
immune responses and might be as successful in reducing HIV infection
rates as the killed polio vaccine was 4 decades ago. Dorman's team has
proposed to identify appropriate strains of HIV, inactivate them, and
test them in pre-clinical settings. This research has not been done because
of the many attendant concerns that a vaccine based on whole HIV, if incompletely
inactivated, could lead to infection, and because of the associated liability
concerns. However, about one-third of all currently used viral vaccines
are based on "whole-killed" technology.
The proposal to identify and perform rigorous scientific testing on whole-killed
HIV vaccine candidates is currently the first proposal to be reviewed
by the Scientific Advisory Committee (SAC) of the IAVI. The SAC is enthusiastic
about advancing the concept of whole-killed HIV or another particle design
to Phase I studies. The SAC additionally felt that an approach to distinguish
between the vaccine strain of the virus and other HIV in an infected vaccinee
needs to be conceptualized before initiating development of a whole-killed
virus. This concern is shared by many potential HIV vaccine trial volunteers,
who worry that health insurance and employment may be out of reach if
a vaccinee cannot be distinguished from a person with active HIV infection.
Correlates of Protection
An effective preventive vaccine would have to protect people from transmission
of HIV by 2 very distinct routes: intravenous and sexual. Sexual transmission
can be further divided into transmission through oral, rectal and vaginal
mucosal surfaces. Can a single vaccine candidate protect against challenge
by both intravenous and sexual routes of transmission? Recently published
information shows that immunization that protects monkeys from SIV injected
directly into a vein does not protect against vaginal challenge. This
finding suggests that mucosal immunity differs from systemic immunity,
and supports the creation and testing of hybrid combinations of vaccine
candidates to induce immune protection from infection by both intravenous
and sexual routes of transmission.
These differences in transmission and in probable means of protection
help to highlight the importance of finding out what exactly does protect
people against HIV infection. Many researchers have attempted to find
correlations between various blood cells, cytokines and other factors
and protection against HIV infection by studying people who are at risk
for HIV infection, are frequently exposed to it, and yet never seroconvert.
Progress in answering this central question has been very slow. Studies
done at Chiang Mai University in Thailand and in Zambia reveal that there
are no apparent differences in CD4 cell counts, CD8 cell counts or CD4/CD8
percentages between people who are at risk but do not seroconvert and
people who do. Furthermore, levels of MIP-1a, MIP-1b and RANTES (the cytokines
recently described by Gallo), beta 2 microglobulin and neopterin levels
do not illuminate any fundamental differences between the groups. The
Chiang Mai University study did detect a statistically significant difference
in levels of natural killer (NK) cells, but this was the first report
of such a difference and needs to be independently validated. In summary,
according to the National Institute of Allergy and Infectious Diseases,
"whether a natural protective state against HIV can exist remains
unknown."
Future Plans
Much depends on public support for the development of an effective HIV
vaccine. The current lack of interest in HIV vaccine research at pharmaceutical
companies advances the field of vaccine research too slowly. On the other
hand, current efforts to attract more research and development funding
may offset the current lull. There are now only 4 major pharmaceutical
companies that make vaccines. Private funding may help open up the field
and bring more bright investigators into the crusade. With more investigators,
the chance of a new, unusual idea changing the landscape of vaccine research
increases, but the means to develop an effective HIV vaccine may already
be in hand. Whole-killed vaccine candidates have not been made (the technology
is now 40 years old) and no vaccine candidate has yet advanced to wide-scale
(Phase III) testing.
It is hoped that surveys of the preparedness of potential vaccine study
volunteers to participate in HIV vaccine trials, such as the survey currently
underway at the Center for AIDS Prevention Studies at the University of
California in San Francisco, will identify stumbling blocks and highlight
the concerns of AIDS-affected communities. It is clear that not enough
research is being devoted to this critically important area of AIDS research,
and that fundamental changes in funding research and development coupled
with community involvement will help.
Mark Bowers is Managing Editor of Treatment Publications at the San
Francisco AIDS Foundation.
References
Enger C and others. Survival from early, intermediate
and late stages of HIV infection. Journal of the American Medical Association
275(17): 1329-1334. May 1, 1996.
Gorse GJ and others. A dose-ranging study of a prototype
synthetic HIV-1MN V3 branched peptide vaccine. Journal of Infectious
Diseases 173: 330-339. February 1996.
Gorse GJ and others. Antibody to native human immunodeficiency
virus type 1 envelope glycoproteins induced by IIIB and MN recombinant
gp120 vaccines. Clinical and Diagnostic Laboratory Immunology 3(4):
378-386. July 1996.
Lehner T and others. Protective mucosal immunity elicited
by targeted iliac lymph node immunization with a subunit SIV envelope
and core vaccine in macaques. Nature Medicine 2(7): 767-775. July
1996.
Levine A and others. Initial studies on active immunization
of HIV-infected subjects using a gp120-depleted HIV-1 immunogen: long-term
follow-up. Journal of Acquired Immune Deficiency Syndromes and Human
Retrovirology 11(4): 351-364. 1996.
Miller CJ and others. Progress towards a vaccine to prevent
sexual transmission of HIV. Nature Medicine 2(7): 751-752. July
1996.
Pardoll DM and others. Exposing the immunology of naked
DNA vaccines. Immunity 3: 165-169. 1995.
Trauger R and others. Safety and immunogenicity of a gp120-depleted,
inactivated HIV-1 immunogen: results of a double-blind, adjuvant controlled
trial. Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology
10(Suppl. 2): S74-S82. 1995.
Wrin T and others. HIV-1MN recombinant gp120
vaccine serum, which fails to neutralize primary isolates of HIV-1, does
not antagonize neutralization by antibodies from infected individuals.
AIDS 8(11): 1622-1623. August 1994.
Page last updated 27 September 1996
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