AIDS vaccine testing at crossroads

By, David Brown, Washington Post, March 26, 2008

The leaders of the federal government's effort to develop an AIDS vaccine said yesterday that more of their budget needs to be spent on basic lab research and less on testing the current crop of vaccines, none of which has proved useful in human trials.

The declaration made at a "summit meeting" is tantamount to an admission that almost no progress has been made in the search for an AIDS vaccine in the past 25 years and that something close to new start is necessary.

The conference, held at the National Institutes of Health in Bethesda, was called after a much-touted vaccine tested in half a dozen countries not only failed to benefit people who received it but also may have actually increased their chance of becoming infected with HIV, the virus that causes AIDS.

"We need to turn the knob toward [basic scientific] discovery -- nobody should be unclear about that," said Anthony S. Fauci, head of the National Institute of Allergy and Infectious Diseases.

One of the co-chairmen of the meeting, Warner C. Greene of the University of California at San Francisco, was more definitive in his assessment. "There is no question the AIDS vaccine enterprise is in need of a major mid-course correction," he told the gathering of about 300 scientists, who came from as far away as South Africa and Kenya for the one-day meeting.

Carl W. Dieffenbach, the head of the NIH's Division of AIDS, acknowledged that "this summit does mark a change in our approach."

The meeting was called after two studies testing the same vaccine were stopped in September. The vaccine, made by the pharmaceutical giant Merck, used a crippled version of a common respiratory virus, called adenovirus type 5, to deliver a selection of HIV proteins to the immune system in the hope of inducing protection.

The studies were stopped when early results suggested that people receiving the vaccine were two to three times as likely to become infected with HIV than people receiving placebo injections. The reason is unknown and the subject of intensive scientific study.

NIH is spending $497 million on AIDS vaccine research this year, with about $476 million going to researchers outside its campus. About 47 percent of the money funds basic research and 38 percent funds testing "candidate vaccines" in humans. Fauci said the ratio needs to be tipped more steeply in favor of basic research.

Although researchers have tested numerous AIDS vaccines on small groups of volunteers, only three vaccines have gone to large clinical trials with thousands of volunteers.

Earlier this decade, one product, called AIDSVAX, was found to be ineffective. The Merck vaccine, which showed promising results in monkeys, may have been harmful. A third vaccine, being tested in an experiment nearing completion in Thailand, is given little hope of working by most researchers, 21 of whom wrote a letter to the journal Science several years ago saying that the study should not even begin.

The search for an AIDS vaccine has proved difficult for several reasons.

Source: http://www.washingtonpost.com/wp-dyn/content/article/2008/03/25/AR2008032503153.html

Chinese scientists developing new HIV vaccine

By, Thaindian News, January 23, 2008

Scientists are developing a new AIDS vaccine with the ability to ward off three variants of HIV sweeping across Hong Kong, Taiwan, and western areas of China.

Chen Zhiwei, director of the new AIDS Institute in Hong Kong, has revealed that gene sequencing is being to determine how track how HIV viruses on the mainland are evolving, and their geographical spread.

He says that two closely related HIV variants have been spreadone to as far as Xinjiang in the northwest and the second to Guangdong in the south, from southwestern Yunnan Provinceby intravenous drug users (IDUs).

According to him, the third variant, which is present in Yunnan and southern Guangxi province, passes mainly through heterosexual sex.

Chen has revealed that US and Chinese scientists have developed a vaccine based on the two HIV variants spreading among IDUs, which they hope to test on animals by the end of the year.

“If you want to make a vaccine, it is better to have a local strain as a target to work on,” the China Daily quoted him as saying.

Chen has also revealed that the HIV variants circulating in south and west China are similar to the ones found in India, Myanmar, Vietnam, Cambodia and Thailand, as well as in Taiwan and Hong Kong.

“The epidemic in China has evolved over time. Previously, the major risk factors were IDUs and the tragic story of blood donation in central China. But after these people got infected, they passed it on and it is now in the general population,” Chen said.

“After 2006, heterosexual sex has been playing the major role in transmission of the virus. Infections have gone up in the general population and from mother to child,” he added.

The researcher believes that the presence of such variants in Taiwan and Hong Kong may also be a telltale sign of the travelling routes of drug users in the region.

The AIDS Institute hopes to help set up HIV screening centres in China, which is estimated to have about 700,000 people living with HIV/AIDS. (ANI)

Source: http://www.thaindian.com/newsportal/health/chinese-scientists-developing-new-hiv-vaccine_10014062.html

HIV/AIDS vaccination 'within a decade'

By, Todd Cardy, The Advertiser, September 19, 2007

Vaccinations will be created for each of the "big three" killers - HIV/AIDS, tuberculosis and malaria - within the next decade, world health crusader Sir Gustav Nossal said today.

Sir Gustav, Australian of the Year in 2000, said scientists were making real progress on the creation of the potentially life-saving vaccines.

"I have no doubt that vaccinations for the big three will be found in the next decade,'' Sir Gustav said.

The Florey Medical Research Foundation is a fundraising arm of the university's medical division.

The Austrian-born scientist is well known for his humanitarian work, promoting Aboriginal reconciliation and projects for the World Health Organisation and the Bill and Melinda Gates Foundation.

He holds an array of international scientific awards and doctorates, including a breakthrough in modern immunology for which he was knighted in 1977.

Sir Gustav said the health standards of developing nations were improving, particularly in nations with burgeoning economies such as China, India and Brazil.

The number of children aged under five who died annually from preventable diseases in the developing world had dropped from 13 million children in 1990 to 9.5 million, he said.

In the treatment of tuberculosis in Africa, Sir Gustav said a decade ago a rare few received adequate medicine to treat the disease compared with a quarter of people now.

He said practical measures to prevent malaria, such as insect repellent nets, were also being delivered, but the rate of HIV/AIDS infections was decreasing.

"The position is bad, but less bad than it was 10 years ago,'' he said.

Sir Gustav said the increase in health standards could be directly linked with the large injections of money from world governments, including Australia, and major foundations.

He credited the Gates Foundation, set up by billionaire Microsoft founder Bill Gates, with galvanising the world's attention on the health crisis, especially the epidemic of AIDS in Africa.

Sir Gustav said world health efforts must concentrate on helping the world's poorest people, who lived in the "basket-case nations'' of sub-Saharan Africa and the sub-continent, namely Bangladesh and Pakistan.

"That is where we should be putting our most attention and resources,'' he said.

"It's where most of the disasters are.''

Source: http://www.news.com.au/adelaidenow/story/0,22606,22446023-5005962,00.html?from=public_rss

Global: Encouraging news in vaccine development

By, IRIN PlusNews, August 31, 2007

The long road to developing an effective HIV vaccine has been fraught with false leads and disappointing outcomes, but promising preliminary results from a vaccine study conducted in South Africa and the United States suggest scientists may finally be on the right path.

The phase II study was designed to test for evidence that the vaccine could trigger an immune response - the body's natural defence against infection - and also that it would be safe.

According to Prof Gavin Churchyard of the Aurum Institute for Health Research, which conducted the South African arm of the trial, most participants who received the vaccine rather than a placebo demonstrated a strong immune response.

The results are sufficiently positive to support future trials investigating whether the vaccine can actually lower the likelihood of contracting HIV or, at the very least, slow the progression of HIV infection to AIDS.

"It's going to take us many more years to find an effective vaccine, but this is important news that we're on the right path," Churchyard told journalists at a briefing in Johannesburg on Friday, hosted by the South African AIDS Vaccine Initiative (SAAVI), a coordinating body for vaccine research funded mainly by the government.

In South Africa, 240 people at three different sites participated in the study, known as HVTN 204, which was sponsored by the US National Institutes of Health (NIH).

The vaccine was given in four doses: the first three contained genes from the three most prevalent strains of the HI virus - "the genes we want the body to mount an immune response to", explained Churchyard. The fourth injection contained a modified version of a virus called Adenovirus 5, which causes the common cold. The adenovirus acts as a "vector" to carry synthetic versions of HIV genes matching those in the three immunising shots.

Vaccines that can trigger an immune response are the new hope. According to Prof Lynn Morris, head of the HIV unit at the National Insitute of Communicable Diseases in South Africa, vaccines that help the body generate anti-bodies against HIV, the most commonly used method, have so far had disappointing results because of the HI viruses' ability to mutate rapidly.

"We don't know what type of immune response clears the virus, but we do know that a strong cellular immune response can control the virus," said Morris. "This type of vaccine is probably unlikely to prevent infection; it's more likely it will help control the virus in people who become infected."

Reducing the amount of virus in an HIV-infected person's system could have a significant indirect impact on the spread of the epidemic, added Dr Glenda Gray, of the University of the Witwatersrand Perinatal HIV Research Unit (PHRU), in Soweto. The lower someone's "viral load", the less likely they are to infect others.

While the main goal of most vaccines is preventative, Dr Efthyhia Vardas, also of the PHRU, presented preliminary findings from a trial of a therapeutic vaccine designed to help slow the progression of the virus in the estimated 40 million infected people worldwide.

HIV-positive trial participants who received this vaccine, developed by Finnish company FIT Biotech Plc, demonstrated significantly lower viral loads than those who received the placebo, but whether or not the effects would be long-lasting was not yet known, said Vardas.

The PHRU and the Aurum Institute are also recruiting 3,000 participants for a joint phase IIb HIV vaccine trial, the first of its kind in South Africa. The study will provide preliminary data on the efficacy of a vaccine known as HVTN 503, also designed to stimulate an immune response against HIV.

HVTN 503 will help researchers answer questions about the effect of gender on immune response, and whether a vaccine designed for sub-type B of the HI virus can protect people in Africa and other regions where sub-type C is most prevalent. Depending on the results, the next stage could be a much larger Phase III efficacy trial, the final stage before a vaccine could be manufactured and distributed.

"There's a whole pipeline of vaccines in development," said Churchyard, "and only a select few will make it into effectiveness trials."

South Africa is the only developing country involved in vaccine development but, according to Gray, a lack of local capacity to manufacture vaccines has prevented the country from becoming a "global player".

An international vaccine conference in Cape Town in 2008, when the annual meeting will be held outside of Europe and the United States for the first time, is likely to put the spotlight on South Africa's role in HIV vaccine research.

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The quest for an effective HIV vaccine presents new possibilities, challenges

By, Kathy Stover, EurekAlert, May 16, 2007

A vaccine that prevents HIV infection remains an important goal in the fight against AIDS, but the current top HIV vaccine candidates may not work in this way, say scientists at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH). Rather, the first successful preventive HIV vaccines, if administered prior to HIV infection, may reduce HIV levels in the body, thereby delaying the progression to AIDS and the need to start antiretroviral drugs. These vaccines may also reduce the chance that a person infected with HIV would pass the virus on to other people, according to NIAID Director Anthony S. Fauci, M.D., and Margaret I. Johnston, Ph.D., director of NIAID’s Vaccine Research Program in the Division of AIDS.

In a review article in the May 17 issue of the New England Journal of Medicine, Drs. Johnston and Fauci examine the daunting challenges posed by HIV, the evolution of HIV vaccine research, the role T cells may play in HIV vaccine effectiveness, and how the first successful HIV vaccine may fit into a comprehensive HIV/AIDS prevention effort.

Vaccines typically work by mimicking the effects of natural exposure to a specific microbe. Because of initial exposure, the immune system develops the ability to recognize the specific microbe and can protect the human body against it if it reappears. HIV, however, has thwarted scientists’ efforts thus far to develop a classic preventive vaccine for the virus because of its ability to integrate into target cells and evade clearance by the immune system. The interaction between HIV and the immune system is complex, and how different HIV-specific immune responses help to control infection is only partially understood.

"The development of an HIV vaccine is a complex research challenge because the virus is unusually well-equipped to elude immune defenses," says Dr. Fauci. "Much progress has been made; however, we must continue research efforts to improve our understanding of HIV and how it evades the immune system, to design new vaccine candidates and to assess the most promising ones in clinical trials."

Dr. Johnston adds, "An important research challenge is to determine if these so-called T-cell vaccines that primarily induce a cellular immune response can have a beneficial effect by reducing viral levels and preserving critical cells needed to control infection. There will be a tremendous public health challenge as well, in an HIV vaccine that does not completely prevent the virus from establishing itself in the body."

Once HIV enters the body, it infects crucial CD4+ T cells, replicates, spreads throughout the body and establishes HIV reservoirs in lymphatic tissues. Within weeks of exposure, virus levels peak and then decline to levels that may remain low for months or years. It is believed that CD8+ T cells--so-called killer T-cells--are responsible for this reduction in HIV levels; however, their ability to continue to suppress the virus declines over time as the virus mutates and the immune system is progressively destroyed.

The infection of CD4+ T cells occurs very early in HIV disease, and virus persists indefinitely. Other viruses also replicate robustly but, unlike HIV, most do not establish a permanent reservoir of infected cells in the body. The window of opportunity to prevent long-term HIV infection may close permanently once a pool of latently infected cells is in place, Drs. Johnston and Fauci note. Neutralizing antibodies, which can attach to and eliminate free virus, only appear after HIV levels have declined substantially. Further, the effectiveness of these antibodies is stymied because of the rapid genetic changes that occur in HIV’s outer envelope protein, which allow the virus to escape detection.

While early efforts to develop an HIV vaccine focused on the viral envelope, an improved understanding of how HIV causes disease has brought increased attention to the role that T cells could play in an HIV vaccine by spurring cellular immunity. Numerous animal and human studies have confirmed how important cellular immunity is in the early and later stages of HIV infection, even though the virus is never completely eliminated. Vaccines that induce strong cellular immune responses may have some benefits, say the authors. In non-human primate models of HIV infection, T-cell vaccines have reportedly decreased the total amount of virus produced during early infection, caused a reduction in virus levels following the acute stage of infection, or produced some combination of these effects. In many of these animals, disease progression was also delayed.

Based on the scientific evidence, several questions remain, say Drs. Johnston and Fauci: Can a vaccine that does not prevent HIV infection but reduces virus levels and preserves a segment of uninfected CD4+ T cells from destruction benefit the immunized individual" Might people immunized with T-cell vaccines before HIV exposure remain disease-free for a prolonged period once they are infected"

Additionally, T-cell vaccines may reduce secondary HIV transmission if they can help the immune system keep viral replication at a very low level for a long time. Studies have suggested that people with high levels of virus--namely those in the early and late stages of infection--are most likely to infect their sexual partners. A preventive vaccine given before exposure to HIV might stifle the initial burst of virus, better control virus levels and potentially reduce that person’s ability to infect other people, Drs. Johnston and Fauci assert.

Vaccines of this type present several complications, however. T-cell-mediated control of HIV infection may not stave off disease forever. Additional human studies would be needed to determine if the vaccine also reduces the spread of HIV. Finally, an HIV vaccine that delays but does not completely prevent disease could not stand alone as a preventive measure; the public health community would need to include it as part of a broader HIV prevention program, so that recipients would minimize, or ideally, not engage in high-risk behaviors, according to the authors.

Currently, several vaccines that induce primarily T-cell responses are in or will soon enter expanded human clinical trials to determine if they impact HIV infection. Researchers also continue to give high priority to creating an HIV vaccine that induces broadly neutralizing antibodies, which might prevent the establishment of HIV infection. Although rare, such antibodies do exist, giving hope to scientists that a vaccine to induce such antibodies can be designed.

Drs. Johnston and Fauci conclude that a vaccine that prevents HIV infection by clearing the virus before cells become latently infected remains the goal. In addition, they believe that even a vaccine that does not prevent infection could prove beneficial if it prolongs the disease-free period and possibly even reduces virus transmission. If such a vaccine is shown to be successful and is eventually licensed, it would need to be delivered as part of a comprehensive, multifaceted HIV prevention program.

###
NIAID is a component of the National Institutes of Health. NIAID supports basic and applied research to prevent, diagnose and treat infectious diseases such as HIV/AIDS and other sexually transmitted infections, influenza, tuberculosis, malaria and illness from potential agents of bioterrorism. NIAID also supports research on basic immunology, transplantation and immune-related disorders, including autoimmune diseases, asthma and allergies.

The National Institutes of Health (NIH)--The Nation's Medical Research Agency--includes 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

Reference: MI Johnston and AS Fauci. An HIV vaccine--evolving concepts. The New England Journal of Medicine DOI: 10.1056/NEJMra066267 (2007).

News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov.


Source: http://www.eurekalert.org/pub_releases/2007-05/nioa-tqf051007.php

Analysis: Advances in HIV, TB vaccines

By, Adrianne Appel, United Press International, May 9, 2007

Scientists are zeroing in on discovering vaccines to control malaria, tuberculosis and HIV in poorer nations, say health experts involved in the effort.
The diseases kill more than 6 million people each year and impact hundreds of millions of lives, many of them children in Latin America, Africa, Asia and Eastern Europe, Tadataka Yamada, president of the Bill and Melinda Gates Foundation, told United Press International.

"Knowing the impact of the death of one child on one family, it is too much," Yamada said at the BIO International Convention held this week in Boston.

Within a couple of years, vaccines against malaria and TB will be brought to the developing world for final-stage testing, while advanced trials of a few HIV vaccines are already under way in Africa and China, experts said.

The vaccines are specific for the strains of HIV found locally in those regions, said Seth Berkley, president and founder of the International AIDS Vaccine Initiative.

"We are most proud of our clinical trials in Zambia, Rwanda and India. We are seeing extraordinary enrollment rates," Berkley said.

The treatments are likely to be only moderately effective, he said. But given the large number of people with HIV and the devastation of the disease, even a small reduction in its incidence is worth going forward, he added.

In the meantime, scientists will keep searching for a more potent vaccine. In the laboratory, they have their sights on a form of a simian immunodeficiency virus, which attacks monkeys, that is altered to be harmless.

"We know it works better than anything else so far. We should have focused on it long ago," Berkley said.

Non-profit foundations, rather than the private sector, are largely leading and funding the vaccine effort against malaria, HIV and TB, said Christian Loucq, interim director of the Malaria Vaccine Initiative.

Big drug companies see the small profits to be made on vaccines in developing nations and thus have not taken the initiative to develop them, Loucq said.

"It's viewed as a problem of no market," Loucq said. Malaria is especially challenging in attracting private companies, he noted.

"It's a slightly bigger problem to raise interest in malaria because it doesn't affect the developed world; it's mainly (a disease of) poor people."

However, the non-profit groups are moving to fill the gap, having raised and spent hundreds of millions of dollars so far.

The Malaria Vaccine Initiative has raised about $275 million from the Gates Foundation, the Rockefeller Foundation and USAID. The initiative gives the funds to drug companies such as GlaxoSmithKline to develop the vaccines.

Within a year the initiative is preparing to bring a malaria-prevention vaccine to 16,000 children in Africa, Loucq said. It is one of 10 possible anti-malaria vaccines in various stages of development.

Malaria, a blood parasite transmitted by mosquitoes, infects 300 million to 500 million people each year and causes the death of 1 million, mostly children.

The group's goal is to have a vaccine by 2015 that prevents malaria in 50 percent of people for at least one year, he said.

On the TB front, the group hopes to have that disease under "global control" within 15 to 20 years, said Jerald Sadoff, president and chief executive officer of Aeras Global TB Vaccine Foundation.

To that end, the foundation will bring a tuberculosis vaccine for final testing to South Africa and the south of India by 2008, Sadoff said.

TB is an airborne bacterial disease that infects 8 million people a year and kills 2 million, many who also have HIV, he said.

Sadoff noted that some TB strains have become resistant to treatment, including the deadly XDR strain. It was found in South Africa last year, when 51 of 52 people infected with it died within 20 days, he said.


Source: http://www.upi.com/Health_Business/Analysis/2007/05/09/analysis_advances_in_hiv_tb_vaccines/

Beefing Up the Arsenal Against AIDS

By, www.time.com, March 2, 2007

If you're a drug developer, HIV is nothing but a thief. All the virus wants to do is break inside a healthy cell, steal its genetic machinery, and start profiting from the intrusion. To stop a thief, you need to throw a monkey wrench — or several — into his plans.

That's exactly what anti-HIV drugs, known as antiretrovirals (ARVs), are designed to do: interrupt the virus at various points along its nefarious journey. The FDA has approved four different classes of ARVs, each of which blocks a separate step in HIV's life cycle. The strategy is to build up a security detail of pharmacological agents that together thwart the virus at every turn, making sure that every receptor, protein and enzyme that the virus co-opts to sneak into a cell is covered.

But nearly 20 years after the epidemic began, maintaining this drug defense is getting harder. As patients live longer on the life-saving ARVs, their virus is more likely to mutate and become resistant to the therapies. The number of patients close to running out of their pharmaceutical options continues to grow. That's why this week's news out of the annual Conference on Retroviruses and Opportunistic Infections in Los Angeles was greeted with such enthusiasm by doctors and patients alike. Drug makers reported promising results with experimental agents in two entirely new classes of ARVs, the first potential new weapons against HIV since 2003.

Currently available ARVs work at both the beginning and the end of the HIV life cycle; the most recently approved class in 2003, called fusion inhibitors, start early, working to block HIV's attempt to bind and infect healthy cells to begin with. Next come the two oldest classes of drugs, which prevent the virus from transforming its genetic material from RNA to DNA. And finally, jumping to the very end of HIV's mission, the protease inhibitor drugs keep the virus from making its final protein coat, which it needs to re-emerge from the infected cell in order to start infecting additional cells.

Pfizer's maraviroc, one of the two new compounds described this week, steps in just after HIV has successfully bound to a healthy cell; called an entry inhibitor, it blocks the virus from entering the cell and integrating its viral genetic material into the host cell's genome. In a study of more than 1000 patients who had developed resistance to at least three of the four ARV classes, twice the number of patients given maraviroc versus those taking placebo enjoyed undetectable levels of virus after eight months. The results were enough to convince Pfizer to apply for approval to the Food and Drug Administration, which will begin its review next month.

If approved, maraviroc would be the first anti-HIV drug that targets the immune cell — by blocking the proteins that the cell uses to open the door for HIV — instead of the virus.

The second drug, an integrase inhibitor from Merck, aims to tackle HIV where it hurts the most — by blocking the integrase enzyme, which the virus uses to insert its genes into a host cell's genome and hijack the machinery to churn out more copies of itself. Called isentress, the experimental agent helped 75% of patients reduce their viral load of HIV to acceptable levels, compared with only 40% of patients given placebo.

All of this good news on the ARV front, however, is in stark contrast to the slower progress being made on an AIDS vaccine. "What we're seeing now with ARVs is the result of investments that were made 10 years ago," says Dr. Seth Berkley, president and CEO of the International AIDS Vaccine Initiative, a leading HIV vaccine developer. "Funding for vaccine research has always fallen far short of that devoted to drug development, and for a period, there was very little happening in the vaccine field. Had there been a sustained vaccine effort simultaneous with the drug effort, we probably would have a vaccine by now."

Still, Berkley and others say that the wider range of drug options can only help vaccine makers, giving them a larger well of knowledge upon which they can draw. Yet, even as newer classes of ARVs arrive, drugs cannot be the only answer to AIDS. Already, says Dr. Roy Steigbigel of State University of New York at Stony Brook, and one of the leading investigators of Merck's isentress, volunteers have begun to develop resistance to the integrase inhibitor — a drug that hasn't even yet been approved by the FDA.

Source: http://www.time.com/time/health/article/0,8599,1595377,00.html?xid=rss-topstories