HIV vaccine
Encyclopedia
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 trial
s have been announced. However these are early results, and have not been developed to the point of human testing, or have not been replicated.
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
.
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, remains a difficult target for a vaccine.
, 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.
There are a number of factors that cause development of an HIV vaccine to differ from the development of other classic vaccines:
s 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.
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.
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, individuals 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.
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.
s.
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 titer
s 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 vector
s. 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, lipopeptide
s, DNA
, an attenuated Salmonella
vector, lipopeptides, 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. The study showed that the vaccine was effective 90% of the time.
(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. 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.
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. 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) Additionally, it appears that V520 may have made some recipients more receptive to infection by HIV-1.
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. The results of the trial have caused some to call for a reexamination of vaccine development strategies.
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.
(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.
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
.
So, the possible approaches for the HIV vaccine are the following (in the bracket specified the Phases were it is possible to do).
, NIH
, in Bethesda, Maryland, several hurdles must be overcome before scientific research will culminate in a definitive AIDS vaccine. 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 study that has had success in animal subjects is about to begin human trials in London, Ontario.
Vaccination
Vaccination is the administration of antigenic material to stimulate the immune system of an individual to develop adaptive immunity to a disease. Vaccines can prevent or ameliorate the effects of infection by many pathogens...
individuals from HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
infection is the goal of many HIV research programmes. Currently, there is no effective vaccine against HIV, the virus that causes AIDS
AIDS
Acquired immune deficiency syndrome or acquired immunodeficiency syndrome is a disease of the human immune system caused by the human immunodeficiency virus...
. Vaccine development is one of several strategies to reduce the worldwide harm from AIDS, with other approaches based upon antiviral
Antiviral drug
Antiviral drugs are a class of medication used specifically for treating viral infections. Like antibiotics for bacteria, specific antivirals are used for specific viruses...
treatments such as highly active antiretroviral therapy (HAART) and social approaches such as safe sex
Safe sex
Safe sex is sexual activity engaged in by people who have taken precautions to protect themselves against sexually transmitted diseases such as AIDS. It is also referred to as safer sex or protected sex, while unsafe or unprotected sex is sexual activity engaged in without precautions...
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 trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
s 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
The urgency of the search for a vaccine against HIVHIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
stems from the AIDS-related death toll of over 25 million people since 1981. Indeed, in 2002, AIDS
AIDS
Acquired immune deficiency syndrome or acquired immunodeficiency syndrome is a disease of the human immune system caused by the human immunodeficiency virus...
became the primary cause of mortality
Death
Death is the permanent termination of the biological functions that sustain a living organism. Phenomena which commonly bring about death include old age, predation, malnutrition, disease, and accidents or trauma resulting in terminal injury....
due to an infectious agent in Africa
Africa
Africa is the world's second largest and second most populous continent, after Asia. At about 30.2 million km² including adjacent islands, it covers 6% of the Earth's total surface area and 20.4% of the total land area...
.
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
Protease inhibitor
Protease inhibitor can refer to:* Protease inhibitor : a class of medication that inhibits viral protease* Protease inhibitor : molecules that inhibit proteases...
-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, 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 InstitutePasteur Institute
The Pasteur Institute is a French non-profit private foundation dedicated to the study of biology, micro-organisms, diseases, and vaccines. It is named after Louis Pasteur, who made some of the greatest breakthroughs in modern medicine at the time, including pasteurization and vaccines for anthrax...
, the United States Health and Human Services Secretary Margaret Heckler
Margaret Heckler
Margaret Mary Heckler is a Republican politician from Massachusetts who served in the United States House of Representatives for eight terms, from 1967 until 1983 and was later the Secretary of Health and Human Services and Ambassador to Ireland under President Ronald Reagan...
declared that a vaccine
Vaccine
A vaccine is a biological preparation that improves immunity to a particular disease. A vaccine typically contains an agent that resembles a disease-causing microorganism, and is often made from weakened or killed forms of the microbe or its toxins...
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
Viral envelope
Many viruses have viral envelopes covering their protein capsids. The envelopes typically are derived from portions of the host cell membranes , but include some viral glycoproteins. Functionally, viral envelopes are used to help viruses enter host cells...
proteins have failed in the case of HIV-1. Some have stated that an HIV vaccine may not be possible without significant theoretical advances.
There are a number of factors that cause development of an HIV vaccine to differ from the development of other classic vaccines:
- 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 epitopeEpitope
An epitope, also known as antigenic determinant, is the part of an antigen that is recognized by the immune system, specifically by antibodies, B cells, or T cells. The part of an antibody that recognizes the epitope is called a paratope...
s of the viral envelope are more variable than those of many other viruses. Furthermore, the functionally important epitopes of the gp120
Gp120
Envelope glycoprotein GP120 is a glycoprotein exposed on the surface of the HIV envelope. The 120 in its name comes from its molecular weight of 120 kilodaltons...
protein are masked by glycosylation
Glycosylation
Glycosylation is the reaction in which a carbohydrate, i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule . In biology glycosylation refers to the enzymatic process that attaches glycans to proteins, lipids, or other organic molecules...
, 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 (antibodyAntibodyAn antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
-mediated) and cellular (mediated by T cells) immunity. - Second, HIV isolates are themselves highly variable. HIV can be categorized into multiple cladeCladeA clade is a group consisting of a species and all its descendants. In the terms of biological systematics, a clade is a single "branch" on the "tree of life". The idea that such a "natural group" of organisms should be grouped together and given a taxonomic name is central to biological...
s 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
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
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 modelAnimal model
An animal model is a living, non-human animal used during the research and investigation of human disease, for the purpose of better understanding the disease without the added risk of causing harm to an actual human being during the process...
for vaccine research is the monkey, often the macaque
Macaque
The macaques constitute a genus of Old World monkeys of the subfamily Cercopithecinae. - Description :Aside from humans , the macaques are the most widespread primate genus, ranging from Japan to Afghanistan and, in the case of the barbary macaque, to North Africa...
. Monkeys can be infected with SIV
Simian immunodeficiency virus
Simian immunodeficiency virus , also known as African Green Monkey virus and also as Monkey AIDS is a retrovirus able to infect at least 33 species of African primates...
or the chimeric SHIV
Simian immunodeficiency virus
Simian immunodeficiency virus , also known as African Green Monkey virus and also as Monkey AIDS is a retrovirus able to infect at least 33 species of African primates...
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, individuals 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.
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.
Clinical trials to date
Several vaccine candidates are in varying phases of clinical trialClinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
s.
Phase I
Most initial approaches have focused on the HIV envelope protein. At least thirteen different gp120Gp120
Envelope glycoprotein GP120 is a glycoprotein exposed on the surface of the HIV envelope. The 120 in its name comes from its molecular weight of 120 kilodaltons...
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
Cytotoxic T cell
A cytotoxic T cell belongs to a sub-group of T lymphocytes that are capable of inducing the death of infected somatic or tumor cells; they kill cells that are infected with viruses , or are otherwise damaged or...
(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
Booster dose
In medicine, a booster dose is an extra administration of a vaccine after an earlier dose. After initial immunization, a booster injection or booster dose is a re-exposure to the immunizing antigen. It is intended to increase immunity against that antigen back to protective levels after it has been...
" injections, it was very difficult to induce and maintain the high anti-gp120 antibody titer
Titer
A titer is a way of expressing concentration. Titer testing employs serial dilution to obtain approximate quantitative information from an analytical procedure that inherently only evaluates as positive or negative. The titer corresponds to the highest dilution factor that still yields a positive...
s 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 vector
Viral vector
Viral vectors are a tool commonly used by molecular biologists to deliver genetic material into cells. This process can be performed inside a living organism or in cell culture . Viruses have evolved specialized molecular mechanisms to efficiently transport their genomes inside the cells they infect...
s. 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
PBMC
A peripheral blood mononuclear cell is any blood cell having a round nucleus. For example: a lymphocyte, a monocyte or a macrophage. These blood cells are a critical component in the immune system to fight infection and adapt to intruders. The lymphocyte population consists of T cells , B 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, lipopeptide
Lipopeptide
A lipopeptide is a molecule consisting of a lipid connected to a peptide. Bacteria express these molecules. They are bound by TLR 1, and other, Toll-like receptors.Certain lipopeptides are used as antibiotics....
s, DNA
DNA vaccination
DNA vaccination is a technique for protecting an organism against disease by injecting it with genetically engineered DNA to produce an immunological response. Nucleic acid vaccines are still experimental, and have been applied to a number of viral, bacterial and parasitic models of disease, as...
, an attenuated Salmonella
Salmonella
Salmonella is a genus of rod-shaped, Gram-negative, non-spore-forming, predominantly motile enterobacteria with diameters around 0.7 to 1.5 µm, lengths from 2 to 5 µm, and flagella which grade in all directions . They are chemoorganotrophs, obtaining their energy from oxidation and reduction...
vector, lipopeptides, p24, etc. Specifically, candidate vaccines that induce one or more of the following are being sought:
- neutralizing antibodiesNeutralizing antibodyA Neutralizing antibody, or NAb is an antibody which defends a cell from an antigen or infectious body by inhibiting or neutralizing any effect it has biologically...
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
Madrid
Madrid is the capital and largest city of Spain. The population of the city is roughly 3.3 million and the entire population of the Madrid metropolitan area is calculated to be 6.271 million. It is the third largest city in the European Union, after London and Berlin, and its metropolitan...
unveiled data from the Phase I clinical trial of their new vaccine. The study showed that the vaccine was effective 90% of the time.
Phase II
On December 13, 2004, the HIV Vaccine Trials NetworkHIV Vaccine Trials Network
The HIV Vaccine Trials Network is a non-profit organization which connects physicians and scientists with activists and community educators for the purpose of conducting clinical trials seeking a safe and effective HIV vaccine. Collaboratively, research professionals and laypeople review...
(HVTN) began recruiting for the STEP study
STEP Study
The STEP Study or Phambili Trial was a clinical trial which tested the efficacy of an HIV vaccine. Vaccination in the study ended suddenly and before it was scheduled to finish when pre-determined endpoints happened and indicated that the vaccine being tested certainly was not an effective tool...
, a 3,000-participant phase II clinical trial of a novel HIV vaccine, at sites in North America, South America, the Caribbean and Australia. The trial was co-funded by the National Institute of Allergy and Infectious Diseases
National Institute of Allergy and Infectious Diseases
The National Institute of Allergy and Infectious Diseases is one of the 27 institutes and centers that make up the National Institutes of Health , an agency of the United States Department of Health and Human Services...
(NIAID), which is a division of the National Institutes of Health
National Institutes of Health
The National Institutes of Health are an agency of the United States Department of Health and Human Services and are the primary agency of the United States government responsible for biomedical and health-related research. Its science and engineering counterpart is the National Science Foundation...
(NIH), and the pharmaceutical company Merck & Co.
Merck & Co.
Merck & Co., Inc. , also known as Merck Sharp & Dohme or MSD outside the United States and Canada, is one of the largest pharmaceutical companies in the world. The Merck headquarters is located in Whitehouse Station, New Jersey, an unincorporated area in Readington Township...
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.
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
Common cold
The common cold is a viral infectious disease of the upper respiratory system, caused primarily by rhinoviruses and coronaviruses. Common symptoms include a cough, sore throat, runny nose, and fever...
. 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. 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) Additionally, it appears that V520 may have made some recipients more receptive to infection by HIV-1.
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. The results of the trial have caused some to call for a reexamination of vaccine development strategies.
Phase III
In February 2003, VaxGenVaxGen
VaxGen is a biopharmaceutical company based in the San Francisco Bay Area.As of July 28, 2010, VaxGen Inc. was acquired by diaDexus, Inc., in a reverse merger transaction. VaxGen, Inc. does not have significant operations. The company seeks to enter into a strategic transaction or series of...
announced that their AIDSVAX
AIDSVAX
AIDSVAX is an experimental HIV vaccine that was developed originally at Genentech in San Francisco, California, and later tested by the VaxGen company, a Genentech offshoot. The development and trials of the vaccine received significant coverage in the international media, but American trials...
vaccine was a failure in North America
North America
North America is a continent wholly within the Northern Hemisphere and almost wholly within the Western Hemisphere. It is also considered a northern subcontinent of the Americas...
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
RV 144
RV 144, or the Thai trial, is the name of an HIV vaccine clinical trial combining two vaccines that failed on their own, vaccinating in Thailand over the course of 24 weeks in October 2003 then testing for HIV until July 2006, publicly releasing efficacy findings in September 2009...
beginning in 2003, with positive results. In both cases the vaccines targeted gp120
Gp120
Envelope glycoprotein GP120 is a glycoprotein exposed on the surface of the HIV envelope. The 120 in its name comes from its molecular weight of 120 kilodaltons...
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
Subtypes of HIV
One of the obstacles to treatment of the human immunodeficiency virus is its high genetic variability. HIV can be divided into two major types, HIV type 1 and HIV type 2 . HIV-1 is related to viruses found in chimpanzees and gorillas living in western Africa, while HIV-2 viruses are related to...
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
IGA
Iga or IGA may stand for:-Given name:* a female given name of Polish origin. The name originates from the female given name Jadwiga and stands for gia,or gina in the USA....
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
SIV
SIV or Siv may refer to:* Simian immunodeficiency virus, a virus found in primates and related to HIV* Siv, a character in the children's fiction book series Guardians of Ga'Hoole...
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 AnkaraModified vaccinia Ankara
Vaccinia viruses re-engineered to express foreign genes are robust vectors for production of recombinant proteins, the most common being a vaccine delivery system for antigens. Concerns about the safety of the vaccinia virus have been addressed by the development of vectors based on attenuated...
(MVA), adeno-associated virus
Adeno-associated virus
Adeno-associated virus is a small virus which infects humans and some other primate species. AAV is not currently known to cause disease and consequently the virus causes a very mild immune response. AAV can infect both dividing and non-dividing cells and may incorporate its genome into that of...
, 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.Economic issues with developing an AIDS vaccine include the need for advance purchase commitment (or advance market commitments
Advance market commitments
An advance market commitment is a binding contract, typically offered by a government or other financial entity, used to guarantee a viable market if a vaccine or other medicine is successfully developed. As a result of such a commitment, the market for vaccines or drugs for neglected diseases...
) because after an AIDS vaccine has been developed, governments and NGOs may be able to bid the price down to marginal cost
Marginal cost
In economics and finance, marginal cost is the change in total cost that arises when the quantity produced changes by one unit. That is, it is the cost of producing one more unit of a good...
.
Classification of all theoretically possible HIV vaccines
Any theoretically possible HIV vaccines must inhibit or stop the HIV virion replication cycle. 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)
- 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)
- 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)
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 gp41Gp41gp41 is a subunit of the envelope protein complex of retroviruses, including Human immunodeficiency virus and Simian-Human immunodeficiency virus. This glycoprotein subunit remains non-covalently-bound to gp120, and provides the second step by which HIV enters the cell...
(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 gp120Gp120Envelope glycoprotein GP120 is a glycoprotein exposed on the surface of the HIV envelope. The 120 in its name comes from its molecular weight of 120 kilodaltons...
. Hypothetically, it can be pieces of the CD4CD4CD4 is a glycoprotein expressed on the surface of T helper cells, monocytes, macrophages, and dendritic cells. It was discovered in the late 1970s and was originally known as leu-3 and T4 before being named CD4 in 1984...
cell membranes with receptors. Any chemical and organic alternative (with ability to bind the gp120Gp120Envelope glycoprotein GP120 is a glycoprotein exposed on the surface of the HIV envelope. The 120 in its name comes from its molecular weight of 120 kilodaltons...
) 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
- 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
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
According to Gary J. Nabel of the Vaccine Research CenterVaccine Research Center
The Dale and Betty Bumpers Vaccine Research Center, more commonly known as the Vaccine Research Center , is a department at the U.S. National Institutes of Health which was established to facilitate research in vaccine development...
, NIH
National Institutes of Health
The National Institutes of Health are an agency of the United States Department of Health and Human Services and are the primary agency of the United States government responsible for biomedical and health-related research. Its science and engineering counterpart is the National Science Foundation...
, in Bethesda, Maryland, several hurdles must be overcome before scientific research will culminate in a definitive AIDS vaccine. 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 study that has had success in animal subjects is about to begin human trials in London, Ontario.
External links
- Vaccine Research Center (VRC)- Information concerning Preventive HIV vaccine research studies
- NIAID HIV vaccine site (DAIDSDivision of Acquired Immunodeficiency SyndromeThe Division of Acquired Immunodeficiency Syndrome is a division of the National Institute of Allergy and Infectious Diseases which is part of the National Institutes of Health. It was formed in 1986 as a part of the to address the national research needs created by the advent and spread of the...
) - 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 UnionEuropean UnionThe European Union is an economic and political union of 27 independent member states which are located primarily in Europe. The EU traces its origins from the European Coal and Steel Community and the European Economic Community , formed by six countries in 1958...
research programme) - AIDS.gov - The U.S. Federal Domestic HIV/AIDS Resource
- HIVtest.org - Find an HIV testing site near you
- - HIV vaccine 'reduces infection'