Researchers race to stem pandemics

Moving target: the influenza virus. Image courtest CDC.

Still, they face an ongoing challenge, particularly among diseases like influenza that are spread as easily as a cough, and that can mutate quickly. “I’m most concerned about the ones that are spread by ways [such as aerosoliaed] that are not easily handled by behavioural changes,” Anthony Fauci, director of the US National Institute of Allergy and Infectious Diseases (NIAID) and an expert on AIDS, said at a seminar on Monday (23 April) at the Whitehead Institute in Cambridge, Massachusetts.

Fauci pointed to the strides made in treating AIDS with multi-drug cocktails, emphasising that behavioural changes in sexual and injection drug habits also had a big impact. But an effective HIV vaccine remains elusive. HIV now is the leading cause of microbial death in the world, surpassing tuberculosis.

Challenges

“The most challenging problem we face with HIV is that good vaccines mimic closely natural infection,” he said. “But you wouldn’t want to mimic the natural immune response to HIV, because it [the immune response by the human body] isn’t that good.” He said researchers are moving forward with experimental recombinant adenovirus (rAd) and DNA AIDS vaccines that target the immune response.

“Much has been accomplished, but much remains to do,” he said, referring to the 25th anniversary last year of AIDS being acknowledged as a major global disease. And that’s with some of the highest US medical research dollars, about 11 per cent of the National Institute of Health’s budget of $28 billion, going to HIV/AIDS research. More than 39 million people worldwide are living with AIDS, and there were 4.3 million new HIV infections in 2006, including more than half a million in children younger than age 15.

Fauci said that 24 HIV drugs are approved by the US Food and Drug Administration, more than the sum total of all other antivirals for all other viral diseases combined. And this year more HIV/AIDS new medicines may be approved to combat the rising resistance to therapies, he said. “The RNA [HIV] virus mutates fast, so there is resistance to therapy,” he said.

Fighting flu

Influenza is another major killer of about half a million people worldwide a year. Influenza kills about 34,000 people a year in the United States, about the same as the number of people killed by handguns. Some 230,000 people are hospitalised in the United States each year with influenza, and 500 million are worldwide.

There is no cure for influenza. The 1918 pandemic killed more than 40 million people worldwide, 500,000 of them in the United States. Flu vaccines can help high risk groups like the elderly avoid the flu, provided the annual vaccine targets the particular strains that emerge in a given region in a given year. A bigger worry is the mutations of influenza that vaccines don’t target.

“We would like to develop new antivirals to treat influenza, and we would like to develop new drugs to prevent it,” said Hidde Ploegh, a researcher at the Whitehead. He and his colleagues helped elucidate how certain glycoproteins – molecules that help the immune system recognise invaders – are put together and delivered to the right destination to help trigger an immune response. They also discovered a new mechanism by which viruses evade the immune system.

Influenza has been a difficult target because of errors made when the virus copies itself, a phenomenon that evolves as an infection spreads.

The influenza virus undergoes two different changes: antigenic drift and antigenic shift. Antigenic drift is a series of mutations that occurs over time and causes a gradual evolution of the virus. This happens with seasonal flu epidemics. Of more concern is antigenic shift, in which proteins in the changes cause new subtypes of a virus that might cause a pandemic, such as the worries about the H5N1 avian flu strain that has moved from birds and pigs to humans in Hong Kong, The Netherlands, Vietnam, Turkey and elsewhere on and off since 1997. The US Agency for International Development (USAID) has developed a map of pandemic risk.

One of the challenges, Ploegh said, is that few animal models predict whether a particular strain of flu will infect humans, and scientists still are learning about how infection occurs in cells. Also the flu virus is very effective; a single virus can infect people within two feet of a sneeze by someone who is sick.

Ploegh described the battle with influenza and the human immune system as an “intricate song and dance between cells in the immune system and an infectious agent”. The technology to fight flu still is old: inactivated viruses are grown in chicken eggs, purified and inactivated. They induce short-lived antibody responses to hemagglutinin and neuraminidase, the two molecules in a virus. Eight strands of RNA specify the 10 proteins that make up a virus. The RNA virus is segmented into 15 hemagglutinins and 8 neuraminidases that can be expressed on the surface of the virus. In the case of the avian flu, there are five hemagglutinins and one neuraminidase, or H5N1.

In Europe, purified hemagglutinin and neuraminidase components are used in vaccines, Ploegh said. “The live influenza viruses work better,” to combat the flu, he said.

Scientists are also using novel adjuvant approaches to improve immunogenicity, essentially kick starting a strong immune response. But so far these have caused massive inflammations, so very few have been approved for humans.

Resistant bugs

Current therapeutics against particularly strong flus include Tamiflu, which inhibits neuraminidase. But resistant viruses to Tamiflu have emerged. The ability of viruses to change and become resistant to therapies remains a big challenge, and one that requires novel approaches.

“It’s very telling in this day and age that vaccines still are produced in chicken eggs,” said Ploegh. “Cell culture-based techniques like those used in Europe are faster.”

A side story to seasonal flu epidemics is the number of people who die of secondary bacterial infections, which account for about 25 percent of all deaths during seasonal flu epidemics, said Vincent Fischetti, chairman of the Laboratory of Bacterial Pathogenesis and Immunology at Rockefeller University in New York.

“During flu pandemics, secondary bacterial infections account for 70 to 90 per cent of deaths,” he said. Current methods to control colonizing pathogens include topical antibiotics. System antibiotics are used sparingly because of the risk of antibiotic resistance.

Fischetti’s lab is focusing on bacteriophage lytic enzymes, which he describes as a technology that falls between vaccines and antibiotics. Using the technology, a virus infects a bacterium and injects itself into the DNA of the host cell, where it multiplies. The lytic enzymes eat a hole through the cell wall, causing the damaging contents to essentially explode out and release phage progeny.

“We have exploited the rapid and lethal action of these enzymes to destroy pathogenic and biological warfare bacteria [anthrax] on mucous membranes and in blood,” he said. The enzymes are specific for the species or strain from which they were produced, thus avoiding destruction of the surrounding normal organisms on mucosal surfaces that can happen with other forms of treatment.

So far he and his colleagues have developed enzymes for S. pyogenes, S. pheumoniae, B. anthracis, S. aureus, E. faecalis/E.faecium and group B streptococci.

While Russian scientists have pretty much kept phage therapy alive, it is now coming back into the mainstream with the increase in antibacterial resistance, especially in hospitals. Fischetti has licensed his technology to a start-up company called Enzobiotics, which he said could file an investigational new drug application with the FDA for a group B lysin drug in one year.