HIV vaccine

Overview
A HIV vaccine is a hypothetical vaccine against HIV, the etiological agent of 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. Indeed, in 2002, AIDS became the primary cause of mortality due to an infectious agent in Africa (UNAIDS, 2004).

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 stabilisation of the patient’s symptoms and viremia, but they do not cure the patient of HIV, nor of the symptoms of AIDS (Martinez-Picardo et al., 2000). 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, a HIV vaccine is generally considered as the most likely, 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 (Associated Press, 1984). However, the classical vaccination approaches that have been successful in the control of various viral diseases by priming the adaptive immunity to recognise the viral envelope proteins have failed in the case of HIV-1, as the epitopes of the viral envelope are too variable. 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. 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 (Francis et al., 2003). 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 (Billich et al., 2001).

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 systemic (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.

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 (Poignard et al., 1999). Some vaccines based on the virus envelope have protected chimpanzees or macaques from homologous virus challenge (Berman et al., 1990), but in clinical trials, individuals who were immunised with similar constructs became infected after later exposure to HIV-1 (Connor et al., 1998).

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.

Clinical trials to date
Several vaccine candidates are in varying phases of clinical trials. 17 vaccine candidates are in phase I trials and four in phase I/II. There is only one in phase III (the NIH/Department of Defense’s ALVAC vCP 1521 canary pox vector/AIDSVAX prime-boost vaccine trial now under way in Thailand).

Up to May 2000 over 60 phase I/II trials of candidate vaccines had been conducted worldwide.

Phase I
Most initial approaches 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. As canarypox is the first candidate HIV vaccine that has induced cross-clade functional CTL responses,

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.

Phase II
On December 13 2004, a large phase II clinical trial of a novel HIV vaccine began enrolling volunteers at sites in North America, South America, the Caribbean and Australia. The organizers were seeking 3,000 participants. The trial was co-funded by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), and the pharmaceutical company Merck & Co. Inc. 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 and to induce cellular immune responses against HIV in more than half of volunteers.

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. 

Organizers expected results in 2009, however in September 2007 declared the vaccine a failure. 

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.

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%.

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.

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 (CITE).

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 (CITE).

Conducting trials of HIV vaccines in the countries most affected by the epidemic is a challenge,[76] albeit one that has been successfully met in Thailand. When one or more HIV-1 vaccines are identified, the task will be just beginning. The next step will be ensuring access for populations where the need is the greatest. Currently, over 60 million people have become infected with HIV-1 and hundreds of millions are at risk. Many of these individuals have little access to medical care, no access to adult vaccinations and live in countries where the per capita expenditure on health care is a few dollars.

HIV-1 is poorly understood and often stigmatized. Diagnostic tests or algorithms may need to be altered. Education will be needed to convey not only the value but the anticipated limitations of the vaccines, so that other preventive strategies will be maintained. The role of community organizations in maintaining this balance will be critical (www.avac.org). Regulatory approvals in numerous countries will be required. The issues in the USA are complex.[77] Internationally, there are greater challenges. If a vaccine has not been demonstrated to be universally effective against every HIV-1 subtype, the standard paradigm of approval in one or more industrialized countries followed years or even decades later by acceptance in and distribution to developing countries will not apply. Both the governments of countries affected by HIV-1 and the international regulatory and health authorities must plan ahead for the advent of an HIV-1 vaccine to avoid unnecessary delays.

HIV-1 vaccines might induce antibody responses that would completely prevent HIV-1 infection by strains of virus that are sufficiently well matched to the vaccine. Unfortunately, HIV-1 evolves continuously both within an individual (the source of infection) and within human populations. Therefore, a vaccinated person might be protected initially, but later encounter a virus against which he or she is not immune. Multivalent vaccines or repeated immunization with an updated vaccine may be required for continued protection. Thus, eventually, one might imagine licensure not of a specific HIV-1 vaccine but of a method for producing the vaccine and its updated versions, somewhat analogous to the annual updates of influenza vaccine.

The scientific challenges involved in discovery of a safe and effective vaccine against HIV-1, although daunting, are only the prelude. The task of developing and deploying a vaccine against HIV-1 will be enormous (i.e. gaining licensure and scaling up to produce vaccine for worldwide distribution, developing distribution methods and establishing purchase mechanisms will require an unprecedented co-operative effort by governments, international agencies, philanthropic organizations and the private sector).[78] Recent recognition of the importance of controlling HIV-1 for public health, economic and political stability has been encouraging and there has been substantial growth in academic, government, nonprofit and pharmaceutical industry vaccine research, but the fight is not over. Stopping the march of the pandemic will conserve economic and human resources needed to care for those already infected. Ending the HIV-1 epidemic is critical to allow economic development and promote political stability in the developing world and to reduce loss of life and suffering worldwide.

Controversy
Some conservatives, such as Reginald Finger, M.D., M.P.H., a member of the Advisory Committee on Immunization Practices (ACIP) in the U.S., have stated that the Committee would have to carefully consider an HIV vaccine's effects on sexual activity. ACIP is a government committee linked to the Centers for Disease Control. ACIP is charged with advising the President on prevention of vaccine-related diseases. Dr. Finger's term expired in June, 2006.

Similar controversy has arisen in response to the recent introduction of the HPV vaccine, which prevents infection with certain strains of human papillomavirus, another sexually transmitted disease.

Transgenic plants
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.
 * Plant-based HIV vaccines have already shown to be immonugenic