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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]].<ref name="urlSSRN-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">{{cite web |url=http://papers.ssrn.com/sol3/papers.cfm?abstract_id=696741 |title=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 |format= |work= |accessdate=2009-01-10}}</ref>
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]].<ref name="urlSSRN-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">{{cite web |url=http://papers.ssrn.com/sol3/papers.cfm?abstract_id=696741 |title=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 |format= |work= |accessdate=2009-01-10}}</ref>

==Classification of all theoretically possible HIV vaccines==
Any theoretically possible HIV vaccines must inhibit or stop the HIV virion replication cycle.<ref>Collier pp. 75–91</ref>So, the targets of the vaccine are the following phases of the HIV virion cycle:
* Phase I. Free state
* Phase II. Attachment
* Phase III. Penetration
* Phase IV. Uncoating
* Phase V. Replication
* Phase VI. Assembling
* Phase VII. Releasing

So, the possible approaches for the HIV vaccine are the following (in the bracket specified the ''Phases'' were it is possible to do).

===Filtering of the virions from blood (Phase I)===
* Biological approach for removing the HIV virions from the blood.
* Chemical approach for removing the HIV virions from the blood.
* Physical approach for removing the HIV virions from the blood.

===Different approaches to catch the virion (Phase I-III, VI, VII)===
* [[Phagocytosis]] of the HIV virions.
* Chemical or organic based capture (creation of any skin or additional membrane around the virion) of HIV virions
* Chemical or organic attachments to the virion

===Different approaches to destroy or damage the virion or its parts (Phase I-VII)===
Here, “damage” means inhibiting or stopping the ability of virion to process any of the ''Phase II-VII''. Here are the different classification of methods:
* By nature of method:
* Physical methods (''Phase I-VII'')
* Chemical and biological methods (''Phase I-VII'')
* By damaging target of the [[HIV#Structure_and_genome|HIV virion structure]]:
* Damaging the [[Envelope_glycoprotein_GP120|Docking Glycoprotein gp120]] (''Phase I-III, VI, VII'')
* Damaging the [[Gp41|Transmembrane Glycoprotein gp41]] (''Phase I-III, VI, VII'')
* Damaging the virion matrix (''Phase I-III, VI, VII'')
* Damaging the virion Capsid (''Phase I-III, VI, VII'')
* Damaging the Reverse Transcriptase (''Phase I-VII'')
* Damaging the RNA (''Phase I-VII'')
===Blocking the replication (Phase I)===
* Insertion into blood chemical or organic compounds which binds to the [[gp120]]. Hypothetically, it can be pieces of the [[CD4]] cell membranes with receptors. Any chemical and organic alternative (with ability to bind the [[gp120]]) of this receptors also can be used.
* Insertion into blood chemical or organic compounds which binds to the receptors of the CD4 cells.
===Inhibiting process of phases (drugs already used for this approach)===
* Biological, chemical or physical approach to inhibit the ''Attachment''
* Biological, chemical or physical approach to inhibit the ''Penetration''
* Biological, chemical or physical approach to inhibit the ''Uncoating'' including introducing the mutation into the HIV
* Biological, chemical or physical approach to inhibit the ''Replication'' including introducing the mutation into the HIV
* Biological, chemical or physical approach to inhibit the ''Assembling'' including introducing the mutation into the HIV
* Biological, chemical or physical approach to inhibit (capping) the ''Releasing''
===Methods of the inhibiting of the functionality of the infected cell (''Phase VI- VII'')===
Inhibiting the life functions of the infected cell:
* Inhibiting the metabolism of the infected cell
* Inhibiting the energy exchange of the infected cell


==Future work==
==Future work==

Revision as of 22:11, 21 November 2010

An HIV vaccine is the theoretical vaccine which would be given to persons without HIV in order to vaccinate them against getting HIV, the virus which causes AIDS. No effective vaccine against HIV exists. As there is no known cure for AIDS, the search for a vaccine has become part of medical approaches against the disease.

It has been known for many years that HIV is an extremely difficult virus to render harmless, and no cure presently exists. Research into a vaccine is one of several strategies to reduce the worldwide harm from AIDS, with other approaches based upon antiviral treatments such as highly active antiretroviral therapy (HAART), and social approaches such as safe sex.

There is evidence that a vaccine may be possible. Work with monoclonal antibodies (MAb) has proven that the human body can defend itself against HIV, and certain individuals remain asymptomatic for decades after HIV infection. More recently in 2009, a number of potential candidates for antibodies and early stage results from clinical trials have been announced by various teams. However these are early results, and have either not been developed to the point of human testing, or not fully peer reviewed and replicated by other teams, at this time.

Overview

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.

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.[3]

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.

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. 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]

As published on 27 November 2009 in Journal of Biology, there is new animal model strongly resembling that of HIV in humans. Generalized immune activation as a direct result of activated CD4+ T cell killing - performed in mice allows new ways of testing HIV behaviour.[13][14]

Clinical trials to date

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:

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.[15] 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 (gag / pol / nef). 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. The foremost issue facing the rAd5 adenovirus that was used is the high prevalence of the adenovirus-specific antibodies as a result of prior exposure to the virus. Adenovirus vectors and many other viral vectors currently used in HIV vaccines, will induce a rapid memory immune response against the vector. This results in an impediment to the development of a T cell response against the inserted antigen (HIV antigens)[16] Additionally, it appears that V520 may have made some recipients more receptive to infection by HIV-1.[17][18]

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.[19] The results of the trial have caused some to call for a reexamination of vaccine development strategies.[20]

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. This same vaccine was retested in Thailand within a vaccine regimen called RV 144 beginning in 2003, with positive results. In both cases the vaccines targeted gp120 and were specific for the geographical regions. The Thai trial was the largest AIDS vaccine trial to date when it started.[21]

In October 2009, the results of the RV 144 trial were published. Initial results, released in September 2009 prior to publication of complete results, were encouraging for scientists in search of a vaccine. The study involved 16,395 participants who did not have HIV infection, 8197 of whom were given treatment consisting of two experimental vaccines targeting HIV types B and E that are prevalent in Thailand, while 8198 were given a placebo. The participants were tested for HIV every six months for three years. After three years, the vaccine group saw HIV infection rates reduced by more than 30% compared with those in the placebo group. However, after taking into account the seven people who had HIV infections at the time of their vaccination (two in the placebo group, five in the vaccine group) the percentage dropped to 26%. [21][22]

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.[23]

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.[24]

Classification of all theoretically possible HIV vaccines

Any theoretically possible HIV vaccines must inhibit or stop the HIV virion replication cycle.[25]So, the targets of the vaccine are the following phases of the HIV virion cycle:

  • Phase I. Free state
  • Phase II. Attachment
  • Phase III. Penetration
  • Phase IV. Uncoating
  • Phase V. Replication
  • Phase VI. Assembling
  • Phase VII. Releasing

So, the possible approaches for the HIV vaccine are the following (in the bracket specified the Phases were it is possible to do).

Filtering of the virions from blood (Phase I)

  • Biological approach for removing the HIV virions from the blood.
  • Chemical approach for removing the HIV virions from the blood.
  • Physical approach for removing the HIV virions from the blood.

Different approaches to catch the virion (Phase I-III, VI, VII)

  • Phagocytosis of the HIV virions.
  • Chemical or organic based capture (creation of any skin or additional membrane around the virion) of HIV virions
  • Chemical or organic attachments to the virion

Different approaches to destroy or damage the virion or its parts (Phase I-VII)

Here, “damage” means inhibiting or stopping the ability of virion to process any of the Phase II-VII. Here are the different classification of methods:

  • By nature of method:
   * Physical methods (Phase I-VII)
   * Chemical and biological methods (Phase I-VII)

   * Damaging the Docking Glycoprotein gp120 (Phase I-III, VI, VII)
   * Damaging the Transmembrane Glycoprotein gp41 (Phase I-III, VI, VII)
   * Damaging the virion matrix (Phase I-III, VI, VII)
   * Damaging the virion Capsid (Phase I-III, VI, VII)
   * Damaging the Reverse Transcriptase (Phase I-VII)
   * Damaging the RNA (Phase I-VII)

Blocking the replication (Phase I)

  • Insertion into blood chemical or organic compounds which binds to the gp120. Hypothetically, it can be pieces of the CD4 cell membranes with receptors. Any chemical and organic alternative (with ability to bind the gp120) of this receptors also can be used.
  • Insertion into blood chemical or organic compounds which binds to the receptors of the CD4 cells.

Inhibiting process of phases (drugs already used for this approach)

  • Biological, chemical or physical approach to inhibit the Attachment
  • Biological, chemical or physical approach to inhibit the Penetration
  • Biological, chemical or physical approach to inhibit the Uncoating including introducing the mutation into the HIV
  • Biological, chemical or physical approach to inhibit the Replication including introducing the mutation into the HIV
  • Biological, chemical or physical approach to inhibit the Assembling including introducing the mutation into the HIV
  • Biological, chemical or physical approach to inhibit (capping) the Releasing

Methods of the inhibiting of the functionality of the infected cell (Phase VI- VII)

Inhibiting the life functions of the infected cell:

  • Inhibiting the metabolism of the infected cell
  • Inhibiting the energy exchange of the infected cell

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.[26] 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.[27]

See also

References

  1. ^ a b Joint United Nations Programme on HIV/AIDS (UNAIDS) (2005). "AIDS epidemic update" (PDF). World Health Organization. Retrieved 2006-01-20. {{cite web}}: Unknown parameter |month= ignored (help) [dead link]
  2. ^ UNAIDS (2004) Report on the global AIDS epidemic, July 2004
  3. ^ Shilts, Randy (1987). And the Band Played On: Politics, People, and the AIDS Epidemic. (2007 ed.). St. Martin's Press. ISBN 0312241356. p. 451
  4. ^ Watkins DI (2008). "Basic HIV Vaccine Development" (PDF). Top HIV Med. 16 (1): 7–8. ISSN 1542-8826. PMID 18441377. {{cite journal}}: Unknown parameter |month= ignored (help)
  5. ^ A. S. Fauci, 1996, An HIV vaccine: breaking the paradigms, Proc. Am. Assoc. Phys. 108:6.
  6. ^ Kim D, Elizaga M, Duerr A (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  7. ^ Watkins DI (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. {{cite journal}}: Unknown parameter |month= ignored (help)
  8. ^ Létourneau S, Im EJ, Mashishi T; et al. (2007). "Design and pre-clinical evaluation of a universal HIV-1 vaccine". PLoS ONE. 2 (10): e984. doi:10.1371/journal.pone.0000984. PMC 1991584. PMID 17912361. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  9. ^ Poignard P, Sabbe R, Picchio GR; et al. (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. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  10. ^ Berman PW, Gregory TJ, Riddle L; et al. (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. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  11. ^ Connor RI, Korber BT, Graham BS; et al. (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. PMC 124637. PMID 9445059. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  12. ^ Morgan C, Marthas M, Miller C; et al. (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. PMC 2504486. PMID 18700814. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  13. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1186/jbiol194, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1186/jbiol194 instead.
  14. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1186/jbiol198, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1186/jbiol198 instead.
  15. ^ "STEP Study Locations". Retrieved 2008-11-04.
  16. ^ Sekaly, R. P. (2008). The failed HIV Merck vaccine study: a step back or a launching point for furture vaccine development? Journaly of Cell Biology, 205, (1), 7-12
  17. ^ Timberg, Craig (2007-10-25). "AIDS vaccine may have raised risk of infection". The Washington Post. Retrieved 2007-11-12.
  18. ^ Sekaly RP (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. PMC 2234358. PMID 18195078. {{cite journal}}: Unknown parameter |month= ignored (help)
  19. ^ Song, Kyung M.; Ostrom, Carol M. (2007-11-08). "Failure of AIDS vaccine punctures soaring hopes". Seattle Times. Retrieved 2008-10-29.
  20. ^ Iaccino E, Schiavone M, Fiume G, Quinto I, Scala G (2008). "The aftermath of the Merck's HIV vaccine trial". Retrovirology. 5: 56. doi:10.1186/1742-4690-5-56. PMC 2483718. PMID 18597681. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  21. ^ a b Harmon, Katherine (16 November 2009). "Renewed Hope". Scientific American. News Scan. Vol. 302, no. 1. Scientific American, Inc. (published January 2010). pp. 15–16. doi:10.1038/scientificamerican0110-15. ISSN 0036-8733. Archived from the original on 23 December 2009. Retrieved 23 December 2009.{{cite news}}: CS1 maint: date and year (link)
  22. ^ Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S; et al. (2009). "Vaccination with ALVAC and AIDSVAX to Prevent HIV-1 Infection in Thailand". N. Engl. J. Med. 361 (23): 2209–2220. doi:10.1056/NEJMoa0908492. PMID 19843557. Archived from the original on 23 December 2009. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  23. ^ "Tracking Funding for Preventive HIV Vaccine Research & Development: Estimates of Annual Investments and Expenditures 2000 to 2005". Retrieved 2009-01-10.
  24. ^ "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". Retrieved 2009-01-10.
  25. ^ Collier pp. 75–91
  26. ^ Nabel, G. J. (2001). "Challenges and opportunities for development of an AIDS vaccine". Nature. 410 (6831): 1002–1007. doi:10.1038/35073500. PMID 11309631..
  27. ^ "Human trials approval sought for AIDS vaccine". Retrieved 2009-06-30.

External links

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