This article is outdated. Please update this article to reflect recent events or newly available information. Please see the talk page for more information. (March 2011)

An HIV vaccine that protects vaccinated individuals from HIV infection is the goal of many HIV research programmes. Currently, there is no effective vaccine against HIV, the virus that causes AIDS. Vaccine development 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 prevention and awareness campaigns.

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. Potential candidates for antibodies and early stage results from clinical trials have been announced. However these are early results, and have not been developed to the point of human testing, or have not been replicated.

Overview[link]

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. Introduction of safer sex measures to halt the spread of AIDS has proven difficult in the worst affected countries.

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[link]

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[link]

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[link]

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 a 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[link]

This article is outdated. Please update this article to reflect recent events or newly available information. Please see the talk page for more information. (September 2009)

Several vaccine candidates are in varying phases of clinical trials.

Phase I[link]

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:

• neutralizing antibodies active against a broad range of HIV primary isolates;
• cytotoxic T cell responses in a vast majority of recipients;
• strong mucosal immune responses.

In 2011, researchers in National Biotech Centre in Madrid unveiled data from the Phase I clinical trial of their new vaccine. The study showed that the vaccine was effective 90% of the time.^[15]

Phase II[link]

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.^[16] 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 appeared associated with an increased risk of HIV infection in some recipients.^[17] 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)^[18] Additionally, it appears that V520 may have made some recipients more receptive to infection by HIV-1.^[19][20]

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.^[21] The results of the trial have caused some to call for a reexamination of vaccine development strategies.^[22]

Phase III[link]

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.^[23]

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%.^[23][24]

Further analysis presented at a 2011 AIDS conference in Bangkok revealed that participants receiving vaccines in the RV 144 trial who produced IgG antibodies against the V2 loop of the HIV outer envelope were 43% less likely to become infected than those who did not, while IgA production was associated with a 54% greater risk of infection than those who did not produce the antibodies (but not worse than placebo). Viruses collected from vaccinated participants possessed mutations in the V2 region. Tests of a vaccine for SIV in monkeys found greater resistance to SIV in animals producing antibodies against this region. For these reasons further vaccine development was expected to focus heavily on vaccines designed to provoke an IgG reaction against the V2 loop.^[25]

Planned clinical trials[link]

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[link]

A June 2005 study estimates that $682 million is spent on AIDS vaccine research annually.^[26]

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.^[27]

Classification of all theoretically possible HIV vaccines[link]

Any theoretically possible HIV vaccines must inhibit or stop the HIV virion replication cycle.^[28] 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 virions from blood (Phase I)[link]

• 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.

Approaches to catching the virion (Phase I-III, VI, VII)[link]

• 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

Approaches to destroying or damaging the virion or its parts (Phase I-VII)[link]

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 virion structure:
  • 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)[link]

• 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)[link]

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

[edit] Inhibiting the functionality of infected cells (Phase VI- VII)

Inhibiting the life functions of infected cells:

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

Future work[link]

According to Gary J. Nabel of the Vaccine Research Center, NIH, in Bethesda, Maryland, several hurdles must be overcome before scientific research will culminate in a definitive AIDS vaccine.^[29] 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 valuable in hastening this process.

A vaccine, SAV001, that has had success in animal subjects began Phase 1 human trials in London, Ontario in 2011.^[30]

Transgenic plants[link]

Transgenic plants can be a convenient and efficient way to obtain HIV vaccine. Plant-based vaccines, which are easy to produce and administer, and require no cold chain for their heat stability are, in principle, suited to such a strategy. More recently, it has been shown that even highly immunogenic, enveloped plant-based vaccines can be produced at a competitive and more efficient rate than conventional strategies. The high variability of HIV epitopes and the need to stimulate both humoral neutralizing antibodies and cellular immunity suggest the importance of using the plant system: it offers a wide range of possible strategies, from single-epitope to multicomponent vaccines, modulators of the immune response (adjuvants) and preventive molecules (microbicides), either alone or in association with plant-derived monoclonal antibodies, besides the potential use of the latter as therapeutic agents. Furthermore, plant-based anti-HIV strategies can be administered not only parenterally but also by the more convenient and safer oral route, which is a more suitable approach for possible mass vaccination.^[31] Plant-based HIV vaccines have already shown to be immonugenic ^[32]

See also[link]

• HIV Vaccine Trials Network
• World AIDS Vaccine Day

References[link]

External links[link]

• 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)
• U.S. Military HIV Research Program (MHRP)
• 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'