The first trial was a huge disappointment. The experimental vaccine, developed by U.S. drugmaker Merck, failed to prevent HIV infections so miserably, Merck halted the trial in September 2007. Two years later, results from the second trial were more promising. The trial was conducted in Thailand, involved more than 16,000 volunteers and used a combination of two vaccines. But three months after the results were released, questions persist whether the modest preventative effect of the Thai vaccine combo was real or due to chance.

Dr. Myron Cohen

Dr. Myron Cohen, a leading HIV/AIDS expert at the University of North Carolina, considers the results from the Thai vaccine trial “the first glimmer of hope” that there is a way to stop the spread of HIV/AIDS, particularly in poor countries.

Cohen, who also serves in a senior leadership position at the National Institutes of Health Center for HIV/AIDS Vaccine Immunology, also known as CHAVI, was one of two speakers Thursday at the N.C. Biotechnology Center in Research Triangle Park. The Triangle Global Health Consortium invited him and Kenneth Schulz, head of the biostatistics division at Family Health International in Durham, to give their takes on the Thai trial.

“Diseases come and go,” said Cohen. “There must be an end to the AIDS/HIV epidemic.” But he and Schulz agreed the Thai trial has yet to provide clues how to get there.

The failure of the Merck trial was such a great disappointment, because at the time the Merck vaccine was considered the best shot at preventing an HIV infection. It was designed to stimulate the production of white blood cells, or T-cells, and train them to attack and kill the AIDS virus once it entered the bloodstream. Researchers had invested much hope in the killer T-cell approach. Efforts to come up with a vaccine that stimulates neutralizing antibodies – an approach used in flu, polio and measles vaccines - had gone nowhere because of HIV’s ability to rapidly adapt.

The Thai trial appears to redirect researchers’ attention to the antibody approach, Cohen said. The vaccine combo was designed to first alert killer T-cells and then boost the antibody response. Volunteers who received the combo shots had about a 31 percent lower HIV infection rate than volunteers who received dummy shots. But the trial, which lasted three years and cost $105 million, doesn’t answer why.

Indeed, the Thai trial combined immune response boosters that either didn’t work in previous trials or had not been tested alone.

Dr. Alan Bernstein

So, do the Thai trial results matter, and how? Cohen said he might find answers as he evaluates blood samples from the trial, which will take about a year. But for now, nobody knows.

His concerns echo an assessment another AIDS vaccine expert made of the puzzling results two months ago at the AIDS Vaccine 2009 conference in Paris.

“It’s a sign of our own ignorance of what’s really going on scientifically and biologically and, therefore, the need to think deeply of how to go forward,” Dr. Alan Bernstein, executive director of the Global HIV Vaccine Enterprise in New York, said during a presentation at the conference.

There’s no doubt, research will continue to look for an HIV/AIDS vaccine that is safe and works. As a matter of fact, several are being tested now and researchers are looking into repeating the Thai trial in Africa.

More than 33 million people worldwide are HIV positive, including an estimated 1.2 million in the U.S., according to 2008 figures of the World Health Organization and UNAIDS, the United Nations Program on HIV/AIDS. Every day, more than 7,000 people worldwide are newly infected with HIV and about 5,500 die from AIDS.

About two dozen antiviral medicines are available to suppress HIV, but treatment to keep the virus in check is expensive and carries the risk of side effects. Without a cure, a vaccine that prevents HIV infection appears to be the best chance to stop HIV/AIDS in its tracks.

So what should HIV/AIDS vaccine researcher focus on next? The response to this question will not only determine key scientific opportunities but also where money for research goes, Bernstein said. For example, funding for two key initiative, CHAVI and the Collaboration for AIDS Vaccine Discovery, or CAVD, is up for renewal.

In 2006, CHAVI and CAVD received a total of more than $500 million from the NIH and the Bill and Melinda Gates Foundation over five years. UNC and Duke University play leading roles in both organizations.

HIV

It took a generation, but researchers now dare to speak of a cure for HIV, the virus that triggered the AIDS epidemic in the late 1970s.

A laboratory experiment with a special mouse gives them hope.

The experiment is described in a peer-reviewed journal the Public Library of Science published in January 2008.

Mice don’t usually get HIV infections. But the BLT (short for bone marrow/liver/thymus) mouse is different. It is specially bred and has human stem cells implanted. The cells infiltrate the BLT mouse’s organs and tissues, which allows the virus to take hold similarly to how it does in humans.

In the experiment, researchers gave BLT mice an HIV medicine called Truvada before they infected them with the virus. Truvada contains two drugs, Viread and Emtriva, that target the virus’ ability to get into the genetic information of a cell and hijack it. None of the mice on Truvada got sick.

Dr. Myron Cohen

“If you can cure a mouse, you can potentially cure a human,” said Dr. Myron Cohen, head of the division of infectious diseases at the University of North Carolina at Chapel Hill and director of the UNC Center for Infectious Diseases.

Cohen (photo at left) spoke Tuesday at the headquarters of the foundation that manages North Carolina’s Research Triangle Park. His talk was part of a World AIDS Day event that celebrated 30 years of HIV/AIDS research.

Much of the work was done in the RTP area, long a hotbed of research in infectious diseases.

AZT, the first HIV/AIDS drug that became available in 1987, was discovered and developed here. So were Fuzeon, the first drug to prevent HIV from entering a cell, and Emtriva, a drug developed by Triangle Pharmaceuticals in Durham. Both came to market in 2003.

GlaxoSmithKline, in whose RTP labs AZT was discovered, has formed a partnership with Pfizer to come up with new HIV/AIDS drugs, but GSK continues to center its HIV/AIDS drug research and development at its U.S. headquarters in RTP. Gilead Sciences, which became the leading HIV/AIDS drug developer after buying Triangle Pharmaceuticals six years ago, still maintains Triangle’s operations in Durham.

Cohen called the RTP area one of the focal points in HIV/AIDS research worldwide. In U.S. funding for HIV/AIDS research it comes in second only to the San Francisco Bay area, he said.

The RTP area is home to RTI International and Family Health International, research institutes trying to stem the spread of HIV in developing countries. UNC and Duke University run HIV/AIDS clinics in Africa and, with more than 1,500 patients each, two of the largest U.S. HIV/AIDS clinics.

UNC and Duke are also part of the Center for HIV/AIDS Vaccine Immunology, orCHAVI, a research consortium of universities and medical schools worldwide. Directed by Dr. Barton Haynes, head of Duke’s human vaccine institute, CHAVI stands to receive up to $483 million from the National Institutes of Health to overcome roadblocks in HIV vaccine development.

Lymphocyte (green) infected with HIV (red)

HIV is a master shapeshifter.

Once it has hijacked its host’s immune system, the virus’ genetic code begins to change almost immediately. The rapid-fire mutations can quickly make the virus resistant to medication and require changes in a patient’s drug regimen.

The mutations have also foiled many attempts to come up with a vaccine.

In the past five years, two RTP area companies have shelved ambitious HIV vaccine development projects. Two years ago, U.S. drugmaker Merck halted the first test of an experimental HIV vaccine in humans because the vaccine seemed to increase the risk of an HIV infection rather than decrease it.

Researchers in Thailand have had more luck. A study that tested a vaccine on 16,000 drug addict volunteers was the first with successful results. Study participants who received a series of shots were 31 percent less likely to get infected with HIV than those who , according to study results that were reported in September.

(More on the Thai HIV/AIDS vaccine study later. The study will be a topic of discussion Dec. 17 at the Triangle Global Health Consortium breakfast meeting.)

But the immunity lasted only about a year – a modest improvement at best considering about 30 million people worldwide are HIV positive and for every person who receives treatment six get infected with HIV.

Measuring twice the size of a Super Wal-Mart store, the plant (photo below) will be the first in the U.S. to use millions of factory-grown cells rather than millions of fertilized chicken eggs to make seasonal and pandemic flu vaccine. With a production capacity of up to 150 million doses per year and room for expansions on the 167-acre site, the Novartis vaccine manufacturing plant in Holly Springs will also be one of the largest.

Company officials expect that the first dose made in Holly Springs will be sold in 2011 – a milestone in U.S. flu vaccine manufacturing, which has relied on fertilized chicken eggs since the end of World War II.

On Tuesday, Novartis offered a rare look inside the facility. Gov. Beverly Perdue, Congressman David Price and Kathleen Sebelius, U.S. secretary of health and human services, toured the facility. Daniel Vasella, chief executive of Novartis, and Dr. Andrin Oswald, head of Novartis’ vaccines and diagnostics division, were on hand to host the guests.

“It’s the beginning of modern cell-based flu manufacturing,” Oswald (photo at right) said during a media briefing. “This facility is a promise for the next 20 to 40 years.”

Cells cultured in the laboratory and grown in a series of ever larger tanks have been used to make biotech medicines for more than a decade. The Triangle, the center of the North Carolina biotech hub, got its first commercial biotech manufacturing facility in 1997, when Boston drugmaker Biogen Idec opened its cell-based production plant in RTP.

Cell cultures are also used to make some vaccines, including those protecting against polio, hepatitis B and types of the human papilloma virus that can cause cervical cancer. But the handful of companies that make flu vaccines have long been reluctant to switch from chicken eggs to cell cultures.

Flu vaccines aren’t profitable enough to justify the large investment necessary to build cell-based production facilities, said Novartis CEO Vasella. (Photo at right)

The Holly Springs plant required more than $1 billion in investments – about $600 million from Novartis and $487 million from the U.S. Department of Health and Human Services.

Without the public-private partnership, Vasella said, “a $1 billion investment would be a real stretch” for Novartis.

Announced about 10 months ago, the partnership followed four years after Swiss-based Novartis bought Chiron, the second largest supplier of U.S. flu vaccine, for about $5 billion.

Like other large pharmaceutical companies, Novartis wanted to beef up its vaccine business. But the company also saw the Chiron deal as an opportunity to pursue cell-based production technologies, Vasella said.

In 2004, quality problems with Chiron’s egg-based production method caused a shortage of seasonal flu vaccine supplies in the U.S. The same year, the first avian flu virus to infect people emerged in Asia. The virus, also known as H5N1, killed half of the about 250 people it infected over the next two years before its advance stopped in Europe.

The 2004 shortage of U.S. seasonal flu vaccine supplies and the threat of a deadly avian flu epidemic alarmed federal public health officials and led to the partnership that made construction of the Holly Springs facility possible, Vasella said.

Novartis officials said they hope the H1N1 virus (photo at left), which arrived in the U.S. in April and has killed nearly 4,000 nationwide, will help them with an immune response booster, or adjuvant, they want to make at the plant.

The adjuvant not only reduces the amount of H1N1 pandemic vaccine needed per shot by 75 percent, clinical tests have shown it also gives better protection for young children and the elderly.

Like the cell-based pandemic flu vaccine, Novartis’ adjuvant still requires regulatory approval in the U.S. Both are approved in Europe, the adjuvant for more than a decade.

The Food and Drug Administration, long reluctant to consider approving a vaccine adjuvant because of safety concerns, now is at least talking about what it would take to bring it to market, Oswald said.

In the past year, Novartis has tested pandemic flu vaccine with an adjuvant in the U.S. and started collecting data from the tests, said Russell Thirsk, head of Novartis’ U.K. vaccine manufacturing site in Liverpool.

While FDA approvals for the cell-based vaccine and the adjuvant are far from guaranteed, Novartis officials said there is a chance.

Last week, Protein Sciences was sent looking for more safety data for its cell-based seasonal flu vaccine. But the Connecticut biotech company uses insect cells to grow the one crucial protein that produces an immune response. Novartis’ approach is less experimental, using canine kidney cells the company has long cultured in the lab and inactivated virus.

The current shortage of H1N1 pandemic vaccine – brought on by the virus’ slower-than-expected growth in chicken eggs – could also become a factor.

Cell cultures grow much faster than chicken embryos, are available on demand and don’t pose the risk of allergic reactions to the vaccine. Also, the virus produced in eggs is slightly altered.

At the Holly Springs plant the steps of making flu vaccines with the help of cells is spread across three floors: from growing the cells in tanks holding up to 5,000 liters, about 1,250 gallons, to infecting the cells, harvesting and inactivating the virus and filling up to 600 vials per minute on a packaging line that is equipped with the latest technology available.

The plant already employs about 200. The work force is projected to increase to 350 by 2013.