|
HIV/AIDS
Vaccines Pose Economic, Demographic, and Scientific
Challenges
By
Vicki
Glaser
Contributing
Editor, Pharma DD
September 27, 2006
Development
and release of an effective commercial HIV vaccine is still years away, even as the
need continues to increase and more candidate vaccines
work their way through the R&D pipeline.
Significant
scientific
challenges stand in the way of an effective HIV vaccine, and include the virus’ regional
diversity and remarkable ability to mutate and evolve
rapidly, as well as challenges inherent in trying to
manipulate and stimulate the highly complex human immune
system. On top of this are the historical issues that
plague the large-scale
manufacture of vaccines.
Putting
these challenges aside for a moment, even if
such a vaccine were available, its successful
implementation would face hurdles related to economic
feasibility, distribution and access, and acceptance.
These obstacles would include the potentially high cost of
a vaccine. Furthermore, the possibility that the first
generation of vaccines may only confer partial protection
against infection could limit their acceptance (Hecht
and Suraratdecha 2006).
Defining
the Market
In
2005, an estimated 40 million people worldwide were
infected with HIV (UNAIDS/WHO 2005). Approximately 95% of people
living with HIV/AIDS are in developing countries (Hecht
and Suraratdecha 2006).
Despite
the development of highly effective antiretroviral drugs
that can control viral load, preserve immune function, and
extend survival, approximately three million people still die from
AIDS each year (Hecht
and Suraratdecha 2006). An even greater number than
that acquire HIV, with more than 13,000 people globally
becoming newly infected with the virus each day (Hecht
and Suraratdecha 2006).
If
an HIV vaccine could be manufactured cost effectively in
large enough quantities to meet worldwide demand, it would
have blockbuster potential (CNN Money 2006).
For
vaccines overall, however, companies have much more
incentive to invest in discovery of a potential
blockbuster drug than in vaccine R&D, as the
discrepancy in market size can be as great as billions of
dollars for a successful drug compared with approximately $500
million a year for a vaccine in developing countries (Zandonella
2005).
Vaccines
have at least one strategic advantage over drugs: Their
complex design and manufacturing demands make them much
more difficult to copy, reducing the threat from
counterfeiters and generic drug makers (CNN Money 2006).
The
International AIDS Vaccine Initiative (IAVI) has
emphasized the need to generate a market sufficiently
large to encourage industry to invest in HIV vaccine
development (Zandonella
2005). Total investments in AIDS vaccine research rose
from $160 million in 1996 to approximately $690 million in 2004,
but only 10% of that funding came from the private sector.
The field got a big boost this year when, in July, the
Bill and Melinda Gates Foundation announced grants
totaling $287 million to support HIV vaccine research (Altman
2006).
When
establishing a pricing structure, producers of HIV
vaccines will no doubt take into account the enormous
global demand for a vaccine—potentially as high as
several hundred million doses in developing countries
initially—while also factoring in their manufacturing
and R&D costs.
Studies
in Africa,
Mexico, and
Thailand
have described a high level of demand (>75%) for an
HIV vaccine, even if people would have to pay for it
themselves, at a reasonable price point (Hecht
and Suraratdecha 2006). Willingness to be
vaccinated was even higher if a vaccine were to be offered
free of charge. As the proposed price of a vaccine
increases, willingness to pay for the vaccine out of
pocket drops, with less than 25% of respondents willing to
pay for a vaccine that would cost $500, even it if were
95% effective. Thus, there will be substantial pressure on
vaccine manufacturers to keep vaccine prices low and even
to provide the vaccine free of charge in developing
nations.
In
addition to the enormous market size and demand, another
factor driving mounting industry interest in HIV vaccine
development is the potential for applying advances in
vaccine design and manufacturing technology to other areas
of vaccine research and being able to evaluate these novel
strategies in large-scale clinical studies.
Vaccines
in the Clinic
The
table (below) lists many of the companies with HIV
vaccines in clinical development. To date, only one
vaccine has completed clinical testing—VaxGen’s
Aidsvax—and it failed in 2003. Big Pharma leads the
effort, with vaccines in development at Merck,
Sanofi-Aventis, Wyeth, Novartis Vaccines, and
GlaxoSmithKline. Merck initiated a Phase II study of its
adenoviral vector-based HIV vaccine in 2005. Vical,
Pharmexa, AlphaVax, GeoVax, CytRx, and Bavarian Nordic are
some of the other companies testing preventive HIV
vaccines in the clinic.
The
first human trial of an AIDS vaccine in
China
has yielded promising results. According to the Chinese
government, the vaccine, which was administered to 49
volunteers, induced immunity against HIV-1 without causing
any adverse effects (Cheng 2006).
Researchers
in
Sweden
recently reported an immune response in more than 90% of
healthy subjects who received an HIV DNA vaccine
administered with a needle-free injection device. The
Phase I trial involved delivering the vaccine on three
occasions, followed by a fourth immunization with a
vaccinia-based HIV DNA vaccine (Medical News Today
2006).
The
prime-boost strategy being evaluated in Vical Inc.’s
Phase I trial in uninfected subjects was well-tolerated
and was shown to stimulate broad T-cell immunity. The
regimen involved priming an immune response by giving
subjects three doses of a plasmid DNA vaccine and then
boosting the response with a single dose of an adenoviral
vector-based vaccine incorporating modified versions of
HIV gag, pol, nef, and env genes. The NIH
initiated a Phase II trial of the vaccine in October 2005
and plans to start a larger Phase II trial in 2007.
Novartis
Vaccines’ (formerly Chiron Vaccines) strategy delivers
DNA in microparticles to prime the immune response and
then administers a recombinant boost vaccine that contains
oligomeric, engineered HIV envelope protein.
A
prototype HIV vaccine incorporating the HIV gag
gene and based on AlphaVax’s modified alphavirus
technology yielded promising findings in a Phase I trial,
with the results announced in September. AlphaVax reported
that the vaccine induced an antibody response in 100% of
recipients at the highest dose tested and in the majority
of recipients at a 10-fold lower dose. The company is
developing a second-generation multigene HIV vaccine that
is also in clinical trials.
GeoVax
announced the launch of Phase I human trials in
HIV-negative volunteers with its prime-boost DNA/rMVA
(recombinant modified vaccinia
Ankara
) poxvirus vaccine strategy in May. The vaccine expresses
the HIV-1 Gag, Pol, Env, Tat, Rev, and Vpu proteins. The
company published initial trial results in July (Mulligan et al. 2006).
CytRx
completed a Phase I trial of its DP6-001 prime/boost
vaccine approach in July and reported both HIV-specific
T-cell and antibody immune responses. The DNA vaccine
prime regimen followed by a protein boost vaccine that
delivers HIV Env and Gag proteins was tested in 34 healthy
volunteers.
Bavarian
Nordic is developing both prophylactic and therapeutic
AIDS vaccines. The company’s MVA nef vaccine
expresses the HIV Nef protein and is in Phase II testing
as a therapeutic vaccine. MVA-BN polytope, based on
the company’s MVA-BN virus system, is in preclinical
development as both a therapeutic vaccine and a
prophylactic vaccine (in partnership with IDM Pharma).
MVA-BN multiantigen is also in preclinical testing.
Pharmexa-Epimmune’s
EP1233 DNA vaccine is used together with Bavarian
Nordic’s MVA-BN32 viral vector-based vaccine for HIV
prophylaxis in a prime-boost regimen. The company
initiated a Phase Ib trial in the
US
in August of its EP1090 therapeutic vaccine. Delivered to
HIV-infected patients via the Biojector 2000 needle-free
injection device, the epitope-based DNA vaccine is
intended to activate a cytotoxic T-lymphocyte response.
Results are expected in the third quarter of 2007.
Adenoviral-vector
technology and a prime-boost approach are at the core of
GenVec’s vaccine program. GenVec’s therapeutic HIV
vaccine candidate entered its first human study in 15
HIV-positive patients in August 2006.
Promising
Early-Stage Results
Two
NIH-sponsored studies in monkeys suggest that even if an
HIV vaccine were to offer less than complete protection
against virus transmission, it could still provide
immunized individuals with a significant survival
advantage after infection. Monkeys vaccinated against
simian immunodeficiency virus (SIV) that then became
infected following exposure to SIV survived significantly
longer than unvaccinated animals (Mattapallil
et al. 2006).
An
oral HIV vaccine developed by Bio-Bridge Science that is
undergoing preclinical testing in China demonstrated no
toxicity and induced HIV-1 gp41-specific serum IgG
antibodies, intestinal and vaginal sIgA antibodies, and
gag-specific T cells in immunized monkeys.
A
preventive HIV vaccine containing virosome-gp41 peptides
developed by Switzerland-based Mymetics Corp. stimulated
production of anti-gp41 IgG and IgA antibodies in
preclinical studies in nonhuman primates.
Researchers
at Baylor College of Medicine in Texas are exploiting interfering
RNA (RNAi) gene-silencing techniques to stimulate a
patient’s immune response to HIV. Using RNAi to shut
down production of SOCS1, a molecule that plays a role in
antigen presentation by dendritic cells, combined with HIV
DNA vaccination, the researchers have demonstrated
enhanced potency of the vaccine (Song et al. 2006).
|
Table:
Companies with Prophylactic or Therapeutic HIV
Vaccines in Clinical Trials
|
|
AlphaVax
Bavarian Nordic
CytRx
GeoVax
GlaxoSmithKline
Merck
Novartis Vaccines
Pharmexa
Sanofi-Aventis
Vical
Wyeth
|
Source:
Vicki Glaser
References
Altman
LK. Gateses to finance HIV vaccine search. The New York
Times. July 20, 2006.
Cheng
AT.
China
calls AIDS vaccine ‘effective’ in early test. Bloomberg
News. Aug. 22, 2006.
CNN
Money. http://money.cnn.com/2006/03/09/news/companies/aids/
Hecht
R and Suraratdecha C. Estimating the demand for a
preventive HIV vaccine: why we need to do better. PloS
Med. 2006;3(10):e398 (pp 1–5).
Mattapallil
JJ et al. Vaccination preserves CD4 memory T cells during
acute simian immunodeficiency virus challenge. J
Experimental Med. 2006;203(6):1533–1541.
Medical
News Today.
Sept.
1, 2006. http://www.medicalnewstoday.com/medicalnews.php?newsid=50849.
Mulligan
MJ et al. Excellent
safety and tolerability of the human immunodeficiency
virus type 1 pGA2/JS2 plasmid DNA priming vector vaccine
in HIV type 1 uninfected adults. AIDS Research and
Human Retroviruses. 2006;22(7):678–683.
Song
XT et al. An alternative and effective HIV vaccination
approach based on inhibition of antigen presentation
attenuators in dendritic cells. PloS Med.
2006;3(1):e37.
UNAIDS/WHO.
Adults and children estimated to be living with HIV as of
the end of 2004. “The Global HIV/AIDS Vaccine
Enterprise
: Scientific Strategic Plan.” PloS Med. 2005;2(2):e25.
Zandonella
C. If you build it, they will pay: a novel incentive
called an Advance Market Commitment could help spur
private sector investment in AIDS vaccine research and
development. IAVI Report. 2005;9(3): http://www.iavireport.org/Issues/Issue9-3/apc.asp.
Copyright
2006, All Rights Reserved. Cambridge Healthtech Institute.
|
