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HIV vaccine
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An HIV vaccine is a hypothetical vaccine against HIV, the virus that causes AIDS. As there is no known cure for AIDS, the search for a vaccine has become part of the struggle against the disease.

The urgency of the search for a vaccine against HIV stems from the AIDS-related death toll of over 25 million people since 1981.[1] Indeed, in 2002, AIDS became the primary cause of mortality due to an infectious agent in Africa.[2]

Alternative medical treatments to a vaccine do exist. Highly active antiretroviral therapy (HAART) has been highly beneficial to many HIV-infected individuals since its introduction in 1996 when the protease inhibitor-based HAART initially became available. HAART allows the stabilization of the patient’s symptoms and viremia, but they do not cure the patient of HIV, nor of the symptoms of AIDS. And, importantly, HAART does nothing to prevent the spread of HIV through people with undiagnosed HIV infections. Safer sex measures have also proven insufficient to halt the spread of AIDS in the worst affected countries, despite some success in reducing infection rates.

Therefore, an HIV vaccine is generally considered as the most likely, and perhaps the only way by which the AIDS pandemic can be halted. However, after over 20 years of research, HIV-1 remains a difficult target for a vaccine.

The human body can defend itself against HIV, as work with monoclonal antibodies (MAb) has proven. That certain individuals can be asymptomatic for decades after infection is encouraging.

Recently, in September 2009 it was announced by several companies and agencies working on an AIDS vaccine that two new AIDS antibodies, the broadly-neutralizing PG9 and PG16 antibodies, were discovered (the first AIDS-related antibodies to be discovered in quite some time). These new antibodies, while not solving the issue right now, are said to be very important to developing a vaccine that works against the many mutant strains of the virus, an important necessity in developing any vaccine with a realistic chance of working.[citation needed]

Also in September 2009, the results of a successful clinical trail in Thailand were released. The initial results are encouraging for scientists in search of a vaccine, but are not conclusive. The study involved 16,395 participants, 8917 of the participants were given an experimental vaccine consisting of two experimental vaccines targeting HIV types B and E, (not C, which is most prevalent in Africa) while 8918 were given a placebo. The participants were tested for HIV every six months for 3 years. After 3 years, those given the vaccine saw HIV infection rates reduced by more than 30% compared with those who had been given a placebo. It marks the first successful HIV vaccine trial in history. [3]

Contents
1 Difficulties in developing an HIV vaccine
1.1 HIV structure
1.2 Animal model
2 Clinical trials to date
2.1 Phase I
2.2 Phase II
2.3 Phase III
2.4 Planned clinical trials
3 Economics of vaccine development
4 Future work
5 See also
6 References
7 External links


Difficulties in developing an HIV vaccine
In 1984, after the confirmation of the etiological agent of AIDS by scientists at the U.S. National Institutes of Health and the Pasteur Institute, the United States Health and Human Services Secretary Margaret Heckler declared that a vaccine would be available within two years.

However, the classical vaccination approaches that have been successful in the control of various viral diseases by priming the adaptive immunity to recognize the viral envelope proteins have failed in the case of HIV-1. Some have stated that an HIV vaccine may not be possible without significant theoretical advances.[4]

There are a number of factors that cause development of an HIV vaccine to differ from the development of other classic vaccines:[5]

Classic vaccines mimic natural immunity against reinfection generally seen in individuals recovered from infection; there are almost no recovered AIDS patients.
Most vaccines protect against disease, not against infection; HIV infection may remain latent for long periods before causing AIDS.
Most effective vaccines are whole-killed or live-attenuated organisms; killed HIV-1 does not retain antigenicity and the use of a live retrovirus vaccine raises safety issues.
Most vaccines protect against infections that are infrequently encountered; HIV may be encountered daily by individuals at high risk.
Most vaccines protect against infections through mucosal surfaces of the respiratory or gastrointestinal tract; the great majority of HIV infection is through the genital tract.
[edit] HIV structure
The epitopes of the viral envelope are more variable than those of many other viruses. Furthermore, the functionally important epitopes of the gp120 protein are masked by glycosylation, trimerisation and receptor-induced conformational changes making it difficult to block with neutralising antibodies.

The ineffectiveness of previously developed vaccines primarily stems from two related factors.

First, HIV is highly mutable. Because of the virus' ability to rapidly respond to selective pressures imposed by the immune system, the population of virus in an infected individual typically evolves so that it can evade the two major arms of the adaptive immune system; humoral (antibody-mediated) and cellular (mediated by T cells) immunity.
Second, HIV isolates are themselves highly variable. HIV can be categorized into multiple clades and subtypes with a high degree of genetic divergence. Therefore, the immune responses raised by any vaccine need to be broad enough to account for this variability. Any vaccine that lacks this breadth is unlikely to be effective.
The difficulties in stimulating a reliable antibody response has led to the attempts to develop a vaccine that stimulates a response by cytotoxic T-lymphocytes.[6][7]

Another response to the challenge has been to create a single peptide that contains the least variable components of all the known HIV strains.[8]

Animal model
The typical animal model for vaccine research is the monkey, often the macaque. The monkeys can be infected with SIV or the chimeric SHIV for research purposes. However, the well-proven route of trying to induce neutralizing antibodies by vaccination has stalled because of the great difficulty in stimulating antibodies that neutralise heterologous primary HIV isolates.[9] Some vaccines based on the virus envelope have protected chimpanzees or macaques from homologous virus challenge,[10] but in clinical trials, individuals who were immunised with similar constructs became infected after later exposure to HIV-1.[11]

There are some differences between SIV and HIV that may introduce challenges in the use of an animal model.[12]

Clinical trials to date
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Several vaccine candidates are in varying phases of clinical trials.

Phase I
Most initial approaches have focused on the HIV envelope protein. At least thirteen different gp120 and gp160 envelope candidates have been evaluated, in the US predominantly through the AIDS Vaccine Evaluation Group. Most research focused on gp120 rather than gp41/gp160, as the latter are generally more difficult to produce and did not initially offer any clear advantage over gp120 forms. Overall, they have been safe and immunogenic in diverse populations, have induced neutralizing antibody in nearly 100% recipients, but rarely induced CD8+ cytotoxic T lymphocytes (CTL). Mammalian derived envelope preparations have been better inducers of neutralizing antibody than candidates produced in yeast and bacteria. Although the vaccination process involved many repeated "booster" injections, it was very difficult to induce and maintain the high anti-gp120 antibody titers necessary to have any hope of neutralizing an HIV exposure.

The availability of several recombinant canarypox vectors has provided interesting results that may prove to be generalizable to other viral vectors. Increasing the complexity of the canarypox vectors by inclusion of more genes/epitopes has increased the percent of volunteers that have detectable CTL to a greater extent than did increasing the dose of the viral vector. Importantly, CTLs from volunteers were able to kill peripheral blood mononuclear cells infected with primary isolates of HIV, suggesting that induced CTLs could have biological significance. In addition, cells from at least some volunteers were able to kill cells infected with HIV from other clades, though the pattern of recognition was not uniform among volunteers. Canarypox is the first candidate HIV vaccine that has induced cross-clade functional CTL responses. The first phase I trial of the candidate vaccine in Africa was launched early in 1999 with Ugandan volunteers. The study determined the extent to which Ugandan volunteers have CTL that are active against the subtypes of HIV prevalent in Uganda, A and D.

Other strategies that have progressed to phase I trials in uninfected persons include peptides, lipopeptides, DNA, an attenuated Salmonella vector, lipopeptides, p24, etc. Specifically, candidate vaccines that induce one or more of the following are being sought:

broadly neutralizing antibody against HIV primary isolates;
cytotoxic T cell responses in a vast majority of recipients;
strong mucosal immune responses.
[edit] Phase II
On December 13, 2004, the HIV Vaccine Trials Network (HVTN) began recruiting for the STEP study, a 3,000-participant phase II clinical trial of a novel HIV vaccine, at sites in North America, South America, the Caribbean and Australia.[13] The trial was co-funded by the National Institute of Allergy and Infectious Diseases (NIAID), which is a division of the National Institutes of Health (NIH), and the pharmaceutical company Merck & Co. Merck developed the experimental vaccine called V520 to stimulate HIV-specific cellular immunity, which prompts the body to produce T cells that kill HIV-infected cells. In previous smaller trials, this vaccine was found to be safe, because of the lack of adverse effects on the patients. The vaccine showed induced cellular immune responses against HIV in more than half of volunteers.[1]

V520 contains a weakened adenovirus that serves as a carrier for three subtype B HIV genes. Subtype B is the most prevalent HIV subtype in the regions of the study sites. Adenoviruses are among the main causes of upper respiratory tract ailments such as the common cold. Because the vaccine contains only three HIV genes housed in a weakened adenovirus, study participants cannot become infected with HIV or get a respiratory infection from the vaccine. It was announced in September 2007 that the trial for V520 would be discontinued after it determined that the vaccination was ineffective. Additionally, it appears that V520 may have made recipients more receptive to infection by HIV-1.[14][15]

The HVTN expected to finish the study in 2009, but ceased further treatment administration and declared the vaccine ineffective at preventing HIV-infection in September 2007.[16]

The results of the trial have caused some to call for a reexamination of vaccine development strategies.[17]

Phase III
In February 2003, Vaxgen announced that their AIDSVAX vaccine was a failure in North America as there was not a statistically significant reduction of HIV infection within the study population. In November 2003, it also failed clinical trials in Thailand for the same reason. These vaccines both targeted gp120 and were specific for the geographical regions.

The "RV 144" study in Thailand is the only one currently in phase III.[18] This study combines AIDSVAX with Aventis Pasteur ALVAC-HIV canarypox vector, known as "vCP1521". On September 24, 2009 it was announced that the combination succeeded in reducing the infection rate in trial, with 31.2% effectiveness.[19]

Planned clinical trials
Novel approaches, including modified vaccinia Ankara (MVA), adeno-associated virus, Venezuelan equine encephalitis (VEE) replicons, and codon-optimized DNA have proven to be strong inducers of CTL in macaque models, and have provided at least partial protection in some models. Most of these approaches are in, or will soon enter, clinical studies.

Economics of vaccine development
A June 2005 study estimates that $682 million is spent on AIDS vaccine research annually.[20]

Economic issues with developing an AIDS vaccine include the need for advance purchase commitment (or advance market commitments) because after an AIDS vaccine has been developed, governments and NGOs may be able to bid the price down to marginal cost.[21]

Future work
According to Gary J. Nabel of the Vaccine Research Center in Bethesda, Maryland, several hurdles must be overcome before scientific research will culminate in a definitive AIDS vaccine[22]. First, greater translation between animal models and human trials must be established. Second, new, more effective, and more easily produced vectors must be identified. Finally, and most importantly, there must arise a robust understanding of the immune response to potential vaccine candidates. Emerging technologies that enable the identification of T-cell-receptor specificities and cytokine profiles will prove invaluable in hastening this process.

A study that has had success in animal subjects is about to begin human trials in London, Ontario.[23]

See also
HIV Vaccine Trials Network
Subunit HIV vaccine
World AIDS Vaccine Day
[edit] References
^ a b Joint United Nations Programme on HIV/AIDS (UNAIDS) (December 2005). "AIDS epidemic update" (PDF). World Health Organization. http://www.unaids.org/html/pub/publication...2005_en_pdf.pdf. Retrieved 2006-01-20.
^ UNAIDS (2004) Report on the global AIDS epidemic, July 2004
^ BBC News (BBC) (September 2009). "HIV vaccine 'reduces infection'" (STM). BBC News. http://news.bbc.co.uk/2/hi/health/8272113.stm. Retrieved 2009-09-24.
^ Watkins DI (Mar 2008). "Basic HIV Vaccine Development". Top HIV Med 16 (1): 7–8. ISSN 1542-8826. PMID 18441377. http://www.iasusa.org/pub/topics/2008/issue1/7.pdf.
^ A. S. Fauci, 1996, An HIV vaccine: breaking the paradigms, Proc. Am. Assoc. Phys. 108:6.
^ Kim D, Elizaga M, Duerr A (March 2007). "HIV vaccine efficacy trials: towards the future of HIV prevention". Infect. Dis. Clin. North Am. 21 (1): 201–17, x. doi:10.1016/j.idc.2007.01.006. ISSN 0891-5520. PMID 17502236. http://linkinghub.elsevier.com/retrieve/pi...5520(07)00008-6.
^ Watkins DI (March 2008). "The hope for an HIV vaccine based on induction of CD8+ T lymphocytes--a review". Mem. Inst. Oswaldo Cruz 103 (2): 119–29. doi:10.1590/S0074-02762008000200001. ISSN 0074-0276. PMID 18425263. http://www.scielo.br/scielo.php?script=sci...nrm=iso&tlng=en.
^ Létourneau S, Im EJ, Mashishi T, et al. (Oct 2007). "Design and pre-clinical evaluation of a universal HIV-1 vaccine". PLoS ONE 2 (10): e984. doi:10.1371/journal.pone.0000984. PMID 17912361. PMC: 1991584. http://www.plosone.org/article/info:doi/10...al.pone.0000984.
^ Poignard P, Sabbe R, Picchio GR, et al. (April 1999). "Neutralizing antibodies have limited effects on the control of established HIV-1 infection in vivo". Immunity 10 (4): 431–8. doi:10.1016/S1074-7613(00)80043-6. ISSN 1074-7613. PMID 10229186.
^ Berman PW, Gregory TJ, Riddle L, et al. (June 1990). "Protection of chimpanzees from infection by HIV-1 after vaccination with recombinant glycoprotein gp120 but not gp160". Nature 345 (6276): 622–5. doi:10.1038/345622a0. ISSN 0028-0836. PMID 2190095.
^ Connor RI, Korber BT, Graham BS, et al. (February 1998). "Immunological and virological analyses of persons infected by human immunodeficiency virus type 1 while participating in trials of recombinant gp120 subunit vaccines". Journal of virology 72 (2): 1552–76. ISSN 0022-538X. PMID 9445059. PMC: 124637. http://jvi.asm.org/cgi/pmidlookup?view=long&pmid=9445059.
^ Morgan C, Marthas M, Miller C, et al. (August 2008). "The use of nonhuman primate models in HIV vaccine development". PLoS Med. 5 (8): e173. doi:10.1371/journal.pmed.0050173. ISSN 1549-1277. PMID 18700814. PMC: 2504486. http://medicine.plosjournals.org/perlserv/...al.pmed.0050173.
^ "STEP Study Locations". http://www.stepstudies.com/new/locations.shtml. Retrieved 2008-11-04.
^ Timberg, Craig (2007-10-25). "AIDS vaccine may have raised risk of infection". The Washington Post. http://seattletimes.nwsource.com/html/heal...431_aids25.html. Retrieved 2007-11-12.
^ Sekaly RP (January 2008). "The failed HIV Merck vaccine study: a step back or a launching point for future vaccine development?". J. Exp. Med. 205 (1): 7–12. doi:10.1084/jem.20072681. ISSN 0022-1007. PMID 18195078. PMC: 2234358. http://www.jem.org/cgi/pmidlookup?view=long&pmid=18195078.
^ "Failure of AIDS vaccine punctures soaring hopes". Seattle Times. 2007-11-08. http://seattletimes.nwsource.com/html/heal...vaccine08m.html. Retrieved 2008-10-29.
^ Iaccino E, Schiavone M, Fiume G, Quinto I, Scala G (Jul 2008). "The aftermath of the Merck's HIV vaccine trial". Retrovirology 5: 56. doi:10.1186/1742-4690-5-56. PMID 18597681. PMC: 2483718. http://www.retrovirology.com/content/5//56.
^ AIDS Vaccine Clearinghouse "Clinical Trials Around the World" (January 2008)
^ Donald G. McNeil Jr.. "For First Time, AIDS Vaccine Shows Some Success in Trials". http://www.nytimes.com/2009/09/25/health/r...rch/25aids.html.
^ "Tracking Funding for Preventive HIV Vaccine Research & Development: Estimates of Annual Investments and Expenditures 2000 to 2005". http://www.iavi.org/publications-resources...aspx?pubID=1251. Retrieved 2009-01-10.
^ "SSRN-Advanced Purchase Commitments for a Malaria Vaccine: Estimating Costs and Effectiveness by Ernst Berndt, Rachel Glennerster, Michael Kremer, Jean Lee, Ruth Levine, Georg Weizsacker, Heidi Williams". http://papers.ssrn.com/sol3/papers.cfm?abstract_id=696741. Retrieved 2009-01-10.
^ Nabel GJ. Challenges and opportunities for development of an AIDS vaccine. Nature 410, 1002 - 1007 (19 Apr 2001).
^ "Human trials approval sought for AIDS vaccine". http://communications.uwo.ca/com/western_n...20090630444536/. Retrieved 2009-06-30.
External links
Effective HIV Vaccine Announced
Vaccine Research Center (VRC)- Information concerning Preventive HIV vaccine research studies
NIAID HIV vaccine site (DAIDS)
Global Alliance for Vaccines and Immunization (GAVI)
International AIDS Vaccine Initiative (IAVI)
AIDS Vaccine Advocacy Coalition (AVAC)
The Pipeline Project - Vaccines in Development (Center for HIV Information at the University of California San Francisco and the HIV Vaccine Trials Network)
Capital Area Vaccine Effort (CAVE
Investigation of first candidate vaccine
Vaccines for Development
Be the Generation - Information on HIV Vaccine Clinical Research in 20 American Cities
Australian recruiter for HIV treatment studies
Aids Vaccine Integrated Project (European Union research programme)
AIDS.gov - The U.S. Federal Domestic HIV/AIDS Resource
HIVtest.org - Find an HIV testing site near you
[1]
- HIV vaccine 'reduces infection'
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#WHO-EM. ‡Withdrawn from market. CLINICAL TRIALS: †Phase III. §Never to phase III



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VaxGen
From Wikipedia, the free encyclopedia

VaxGen is a biopharmaceutical company based in the San Francisco Bay Area.

Contents
1 AIDSVAX
2 Current development
3 Anthrax vaccine
4 References
5 External links


AIDSVAX
In 1990s VaxGen developed, and began trials of, an AIDS vaccine called AIDSVAX. However, in 2003 it was announced that the preliminary trials of the vaccine, conducted in Thailand and Indianapolis, Indiana had been unsuccessful.[1][2]

Current development
VaxGen is currently attempting to develop vaccines to combat Smallpox, Anthrax and Meningitis B.[3]

Anthrax vaccine
Vaxgen had focused its recent efforts on a new form of Anthrax Vaccine, for which it was awarded a $877 million dollar contract. In December 2006, HHS unilaterally withdrew the $877 million dollar contract, sending the stock tumbling as low as $1.20 per share.

Bruce Edwards Ivins was a co-inventor of the patent for the vaccine. Some speculated that he stood to gain from government purchase of the vaccine.[4] This assertion has been discredited by anthrax researcher Meryl Nass, who pointed out that patent royalties go to the patent owners.[5] In this case, both patent 6316006[6] and 6387665[7] are owned by the US Army. Ivins was suspected of committing the 2001 anthrax attacks that killed five people but apparently committed suicide before he could be charged and tried.

References
^ "BBC News article on the failure of the AIDSVAX trial". http://news.bbc.co.uk/2/hi/health/3265089.stm.
^ "Community Medical Research Institute Begins Inoculations in AIDSVAX Trial". http://www.aegis.com/news/pr/1999/PR990313.html.
^ "BBC News article on VaxGen trials for an Anthrax vaccine". http://news.bbc.co.uk/2/hi/health/3652385.stm.
^ "Anthrax scientist Bruce Ivins stood to benefit from a panic". Los Angeles Times. August 2, 2008. http://articles.latimes.com/2008/aug/02/nation/na-anthrax2. Retrieved 2009-09-24.
^ http://anthraxvaccine.blogspot.com/2008/08/sourcing.html
^ http://www.wikipatents.com/6316006.html-1
^ http://www.wikipatents.com/6387665.html-1
External links
Company website
briandeer.com 'The VaxGen Experiment', The Sunday Times Magazine,October 3 1999
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