HIV vaccine


An HIV vaccine can be either a preventive vaccine or a therapeutic vaccine, which means it can either protect individuals from being infected with HIV or treat HIV-infected individuals. And it can either induce an immune response against HIV or consist of preformed antibodies against HIV.
There is currently no licensed HIV vaccine on the market, but multiple research projects are trying to find an effective vaccine. Evidence observed from humans shows that a vaccine may be possible: Some, but certainly not all, HIV-infected individuals naturally produce broadly neutralizing antibodies which keep the virus suppressed, and these people remain asymptomatic for decades. Potential broadly neutralizing antibodies have been cloned in the laboratory and are being tested in passive vaccination clinical trials.
Many trials have shown no efficacy, but one HIV vaccine regimen, RV 144, has been shown to prevent HIV in some individuals in Thailand.
The urgency of the search for a vaccine against HIV stems from the AIDS-related death toll of over 35 million people since 1981. In 2002, AIDS became the primary cause of death due to an infectious agent in Africa.
Alternative medical treatments to a vaccine exist. For the treatment of HIV-infected individuals, highly active antiretroviral therapy medication has been demonstrated to provide many benefits to HIV-infected individuals, including improved health, increased lifespan, control of viremia, and prevention of transmission to babies and partners. HAART must be taken lifelong without interruption to be effective, and cannot cure HIV. Options for the prevention of HIV infection in HIV-uninfected individuals include safer sex, antiretroviral strategies and medical male circumcision. Vaccination has proved a powerful public health tool in vanquishing other diseases, and an HIV vaccine is generally considered as the most likely, and perhaps the only way by which the HIV pandemic can be halted. However, HIV remains a challenging target for a vaccine.

Difficulties in development

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 approach that is successful in the control of other viral diseases - priming the adaptive immunity to recognize the viral envelope proteins - did not work against HIV. Many factors make the development of an HIV vaccine different from other classic vaccines:
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 neutralizing antibodies.
The ineffectiveness of previously developed vaccines primarily stems from two related factors:
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.
Another response to the challenge has been to create a single peptide that contains the least variable components of all the known HIV strains.

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. Some vaccines based on the virus envelope have protected chimpanzees or macaques from homologous virus challenge, but in clinical trials, humans who were immunised with similar constructs became infected after later exposure to HIV-1.
There are some differences between SIV and HIV that may introduce challenges in the use of an animal model. The animal model can be extremely useful but at times controversial.
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.
NIAID-funded SIV research has shown that challenging monkeys with a cytomegalovirus -based SIV vaccine results in containment of virus. Typically, virus replication and dissemination occurs within days after infection, whereas vaccine-induced T cell activation and recruitment to sites of viral replication take weeks. Researchers hypothesized that vaccines designed to maintain activated effector memory T cells might impair viral replication at its earliest stage.

Clinical trials

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 is 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. 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 challenging 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 including more genes/epitopes has increased the percent of volunteers that have detectable CTL to a greater extent than did increase the dose of the viral vector. 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. Besides, 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. The canarypox vector 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. In 2015, a Phase I trial called HVTN 100, chaired by two South African researchers, tested the combination of a canarypox vector ALVAC and a gp120 protein adapted for the subtype C HIV common in sub-Saharan Africa, with the MF59 adjuvant. Those who received the vaccine regimen produced strong immune responses early on and the regimen was safe.
Other strategies that have progressed to phase I trials in uninfected persons include peptides, lipopeptides, DNA, an attenuated Salmonella vector, p24, etc. Specifically, candidate vaccines that induce one or more of the following are being sought:
In 2011, researchers in National Biotech Centre in Madrid unveiled data from the Phase I clinical trial of their new vaccine, MVA-B. The vaccine induced an immunological response in 92% of the healthy subjects.
In 2016, results were published of the first Phase I human clinical trial of a killed whole-HIV-1 vaccine, SAV001. HIV used in the vaccine was chemically and physically deadened through radiation. The trial, conducted in Canada in 2012, demonstrated a good safety profile and elicited antibodies to HIV-1. According to Dr. Chil-Yong Kang of Western University's Schulich School of Medicine & Dentistry in Canada, the developer of this vaccine, antibodies against gp120 and p24 increased to 8-fold and 64-fold, respectively after vaccination.

Phase II

Preventive HIV vaccines
Therapeutic HIV vaccines
Biosantech developed a therapeutic vaccine called Tat Oyi, which targets the tat protein of HIV. It was tested in France in a double-blind Phase I/II trial with 48 HIV-positive patients who had reached viral suppression on Highly Active Antiretroviral Therapy and then stopped antiretrovirals after getting the intradermal Tat Oyi vaccine.

Phase III

Preventive HIV vaccines
There have been no passive preventive HIV vaccines to reach Phase III yet, but some active preventive HIV vaccine candidates have entered Phase III.
Therapeutic HIV vaccines
No therapeutic HIV vaccine candidates have reached phase 3 testing yet.

Economics

A July 2012 report of the HIV Vaccines & Microbicides Resource Tracking Working Group estimates that $845 million was invested in HIV vaccine research in 2011.
Economic issues with developing an AIDS vaccine include the need for advance purchase commitment because after an AIDS vaccine has been developed, governments and NGOs may be able to bid the price down to marginal cost.

Classification of possible vaccines

Theoretically, any possible HIV vaccine must inhibit or stop the HIV virion replication cycle. The targets of a vaccine could be the following stages of the HIV virion cycle:
Therefore, the following list comprises the current possible approaches for an HIV vaccine:

Filtering virions from blood (Stage I)

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:
Inhibiting the life functions of infected cells:
There have been reports that HIV patients coinfected with GB virus C, also called hepatitis G virus, can survive longer than those without GBV-C, but the patients may be different in other ways. GBV-C is potentially useful in the future development of an HIV vaccine.
Live attenuated vaccines are highly successful against polio, rotavirus and measles, but has not been tested against HIV in humans. Reversion to live virus has been a theoretical safety concern that has to date prevented clinical development of a live attenuated HIV-1 vaccine. Scientists are researching novel strategies to develop a non-virulent live attenuated HIV-1 vaccine. For example, a genetically modified form of HIV has been created in which the virus's codons are manipulated to rely on an unnatural amino acid for proper protein translation, which allows it to replicate. Because this amino acid is foreign to the human body, the virus cannot reproduce.