NIAID Prepares Response To Next Pandemic

This article appeared in U.S. Medicine (www.usmedicine.com) Vol. 42, No. 1, pp. 22-23, January, 2006.

In 2005, the National Institute of Allergy and Infectious Diseases made considerable progress in our mission to better understand, detect, prevent, and treat infectious and immunologic diseases. Efforts to decipher the basic mechanisms that underlie disease pathogenesis, as well as the development of promising new vaccine and drug candidates, contributed to advances in HIV/AIDS; immune-mediated diseases; biodefense; and established, emerging and re-emerging infectious diseases. In particular, during a year when the threat of a potential influenza pandemic garnered widespread attention among the general public, scientists, policy makers and public health officials throughout the world, NIAID-supported influenza researchers made important progress.

Preparing For Pandemic Influenza

Numerous outbreaks of the deadly H5N1 avian influenza virus in domestic poultry, particularly in South East Asia, and a growing number of H5N1 infections in people in that region have caused considerable concern. So far, pathogenic variants of the H5N1 virus have infected more than 125 people and killed 64 in at least four countries; and some 150 million to 200 million domestic fowl have been killed by the virus or were culled to slow H5N1 outbreaks. The virus has infected migratory birds, which appear to be spreading the virus over great distances, and also has infected non-human mammalian species such as domestic cats, tigers, leopards and pigs. Should the virus develop the capacity to be efficiently transmitted among humans while retaining its virulence, a worldwide pandemic could ensue.

NIAID researchers have devoted considerable effort and resources to develop new strategies to prevent and prepare for the possibility of a human influenza pandemic. For example, the Institute funded the development of an inactivated H5N1 vaccine and contracted with two pharmaceutical companies (Sanofi Pasteur and Chiron Corporation) to produce pilot lots of the vaccine for clinical trials. An initial trial to test the safety and immunogenicity of the Sanofi Pasteur vaccine, administered intramuscularly, was conducted in 451 healthy adult volunteers less than 65 years of age. Preliminary results indicate that the vaccine was well tolerated and induced an immune response predictive of protection, albeit at relatively high doses. The vaccine is now being tested in healthy volunteers over the age of 65, as well as in children. Studies of the Chiron H5N1 vaccine with and without adjuvant, a substance added to boost the immune response, are imminent. Preliminary results from a Phase I clinical trial of a vaccine against another avian influenza virus that has infected people—H9N2—indicate that use of an adjuvant can result in a substantial reduction in the dose required for a robust immune response.

Additional “dose-sparing” studies of inactivated H5N1 vaccines will assess other approaches to reducing the amount of vaccine needed to induce a protective immune response. Previous studies of the yearly influenza vaccine indicate that intradermal administration elicits a stronger immune response than intramuscular injection, suggesting that lower doses of antigen may be possible with the use of this alternative route of administration. A clinical trial conducted earlier this year compared these routes of administration using an H5N1 vaccine and we look forward to preliminary data shortly.

Researchers within the NIAID intramural research program have been pursuing another promising avenue of avian influenza vaccine development: cold-adapted, live-attenuated candidate vaccines. Live-attenuated vaccines tend to induce a more robust immune response than inactivated vaccines and may provide protection against a broader range of related viruses. Clinical trials of a live-attenuated H5N1 vaccine produced in collaboration with MedImmune, Inc., are planned for the spring of 2006. In addition, NIAID and MedImmune researchers are developing live-attenuated vaccines for each of the 16 hemagglutinin subtypes of avian influenza.

Other NIAID efforts have focused on the development and assessment of antivirals to treat both pandemic and seasonal influenza. Laboratory studies have shown that the neuraminidase inhibitors oseltamivir (trade name, Tamiflu), and zanamivir (trade name, Relenza), both licensed for use against seasonal influenza, have significant in vitro activity against H5N1 avian influenza isolates. NIAID researchers demonstrated recently that mice treated with oseltamivir were more likely to survive experimental infection with H5N1 virus compared to those receiving no drug.

Oseltamivir currently is licensed for use against seasonal influenza in individuals over the age of one year. Studies to evaluate the safety of the drug in children under the age of one year currently are being explored, with an eye toward having medications available to treat both seasonal and pandemic influenza in young infants. NIAID also is funding projects to develop improved antivirals. For example, a clinical trial planned for early 2006 will test a long-acting, “next-generation” neuraminidase inhibitor. In addition, studies are underway in animal models to assess whether combinations of existing antivirals are effective in reducing viral replication and the emergence of drug-resistant strains. Other studies are focusing on identifying novel drug targets such as inhibitors of viral entry, replication and hemagglutinin maturation.

Further efforts to prepare for pandemic influenza are directed toward influenza surveillance in wild birds, live bird markets, and pigs in Hong Kong, Vietnam, Thailand and Indonesia, and in wild birds and pigs in North America. A year ago, NIAID launched the Influenza Genome Sequencing Project, a collaborative effort with the National Library of Medicine, the Centers for Disease Control and Prevention (CDC), St. Jude Children’s Hospital, and other institutions. The goal of this project is to catalogue and make publicly available the full genomic sequence information of numerous influenza viruses to facilitate studies of how influenza viruses evolve, spread, and cause disease. Important publications have rapidly emerged from the project. For example, analyses of the complete genome sequences of human H3N2 viruses collected during influenza seasons from 1999 to 2004 showed that during the 2002-2003 flu season, distinctly different versions of the H3N2 flu virus mixed genetically to produce a strain that emerged late in the season and became the predominant flu virus the following year. The 2003-2004 influenza vaccine did not target the late-emerging virus, resulting in a less-than-optimal flu vaccine for that season, a situation that could be avoided in the future with the availability of influenza genomic sequence information.

NIAID-funded scientists also collaborated with researchers from CDC and the U.S. Armed Forces Institute of Pathology to study the influenza virus that emerged in 1918 to cause a worldwide pandemic that killed an estimated 40-50 million people. The 1918 virus was unusual because of its virulence, especially among young, healthy adults. In a short period of time, the virus infected one-third of the world’s population with death rates 50 times higher than seasonal influenza.

In their studies of the 1918 influenza virus, an H1N1 virus of avian origin, the researchers delineated the entire gene sequence of the virus and identified specific changes that might be used to predict whether other avian viruses are likely to spread among humans. The researchers found that some (but not all) of the specific amino acid residues thought to contribute to the lethality of the 1918 virus also are present in the currently circulating H5N1 avian influenza virus. Studies such as these are important as researchers continue their efforts to monitor the spread and understand the pathogenesis of the H5N1 viruses and other influenza viruses with pandemic potential.

Looking ahead, NIAID’s Office of Clinical Research is collaborating with Oxford University, the Wellcome Trust and the World Health Organization to establish a small network of clinical sites in Southeast Asia to conduct clinical research on avian influenza and other emerging infectious diseases. A key purpose of the effort is to build an independent clinical research capacity in these countries. Five sites in Vietnam, one site in Thailand and one in Jakarta will be established. An oseltamivir treatment protocol is being considered for 2006.

HIV/AIDS

Despite substantial progress in understanding the human immunodeficiency virus (HIV), the HIV/AIDS pandemic continues to devastate the world, particularly in developing nations, where 90 per cent of new infections occur. Nearly 40 million people throughout the world are living with HIV/AIDS, two-thirds of whom live in sub-Saharan Africa. In 2004, 3 million people died from AIDS and nearly 5 million adults and children were infected with the virus.

Although these figures are sobering, each year brings promising new approaches to preventing and treating HIV/AIDS. For example, NIAID-funded researchers recently have shown that anti-HIV compounds, administered alone or in combination as a vaginal gel (a so-called “topical microbicide”), protected monkeys against infection with a simian form of HIV. Developing woman-controlled approaches to prevent transmission of the virus is important because in many settings women frequently are unable to refuse sex or demand that their male partner use a condom. A large-scale NIAID-funded clinical trial to evaluate the safety and preliminary effectiveness of two candidate microbicides began this year at sites in the United States and abroad. Approximately 3,200 women will ultimately be enrolled in the trial, which is expected to last 30 months. To foster microbicide development, NIAID also has reached an agreement with the International Partnership for Microbicides to share information and expertise.

NIAID-funded scientists have made new discoveries that provide insight into the body’s natural mechanism for fighting viral infection. In one study, researchers found that people with a greater-than-average number of copies of a gene called CCL3LI were more likely to resist HIV infection. CCL3LI codes for an HIV-blocking protein that binds to the CCR5 HIV receptor. Those individuals with a low number of copies of the CCL3LI gene coupled with a specific CCR5 gene variation previously associated with AIDS progression are especially susceptible to HIV infection and progression to AIDS. The discovery could help researchers and clinicians to identify individuals at greater risk of infection and disease progression, and adapt treatment regimens and vaccine trials to optimize strategies to prevent and treat infection.

NIAID-supported scientists also have illuminated a defense mechanism, commonly used by plants, that has a role in human immunity to viruses. The mechanism, known as RNA silencing, effectively shuts down parts of the viral genome and leads to destruction of the virus. However, the Tat protein of HIV can suppress the silencing mechanism, allowing HIV to escape destruction. These studies may help in the development of new drugs or treatment strategies to combat HIV infection and other viruses.

The “holy grail” of HIV/AIDS research continues to be an effective vaccine that either prevents infection or slows disease progression. In preliminary trials, a vaccine that contains three HIV genes in a weakened adenovirus vector has been shown to be safe and to induce a cellular immune response against HIV in more than half of volunteers tested. The vaccine is now being tested in collaboration with the pharmaceutical company Merck in 1,500 volunteers in North America, South America, the Caribbean and Australia through NIAID’s multi-center HIV Vaccine Trials Network.

Another vaccine candidate, developed at NIAID’s Dale and Betty Bumpers Vaccine Research Center, is about to enter a phase II clinical trial. This vaccine combines synthetic versions of four HIV genes found in the A, B and C subtypes of the virus. These are the subtypes most commonly found in Africa, the Americas, Europe and parts of Asia and account for 85 per cent of HIV infections worldwide. The trial will rely on a “prime-boost” strategy in which two vaccine components are given at different times. One component, the “prime” consists of naked DNA containing HIV gene fragments, while the second component, the “boost” contains gene fragments in an adenovirus vector.

To speed novel approaches to HIV vaccine development, NIAID this year launched the Center for HIV/AIDS Vaccine Immunology (CHAVI), a consortium designed to address key immunological roadblocks to HIV vaccine development, and to design and test novel HIV vaccine candidates. The CHAVI consortium, led by Dr. Barton Haynes of Duke University, will focus on what happens during the earliest stages of HIV infection and how the immune systems of macaque monkeys fend off infection by SIV, the monkey equivalent of HIV. The consortium will also look at new approaches to designing HIV vaccines, including those that can stimulate an effective mucosal immune response.

Emerging, Re-emerging And Deliberately Emerging Infections

In addition to HIV and influenza viruses, other microbes continually plague mankind and will always continue to do so. Pathogens that have never been observed before may emerge and known pathogens can re-emerge with new properties or in atypical locations. Dangerous pathogens can also be released deliberately, such as the anthrax bioterror attacks of 2001.

To combat the ever-present microbial threat, NIAID has devoted considerable resources to understand the basic biological pathways of many common and uncommon pathogens and to develop technologies to detect, prevent and treat infection. Research into basic molecular pathways in both hosts and microbes is leading to a clearer understanding of how pathogens invade host cells, and may ultimately result in the development of new antimicrobial drugs. For example, new studies funded by NIAID last year revealed the mechanism by which the Nipah and Hendra viruses gain entry into human cells. The first outbreak of the Nipah virus occurred in 1998-1999 in Malaysia, where it infected 265 people and killed 105. Hendra virus first emerged in Australia when it spread from horses to humans. The new studies identified a specific cell-surface receptor, called Ephrin-B2, which is commonly found on neural cells and cells that line blood vessels. Both viruses bind to this surface protein to gain entrance to host cells. Other studies have identified two key cellular enzymes that the Ebola virus uses to replicate in host cells. These recent discoveries could lead to the development of new vaccines and treatments and to a better understanding of how viruses infect human cells.

In the area of therapeutics, a promising new drug that may be effective against both actively dividing and slow-growing forms of Mycobacterium tuberculosis has recently entered clinical trials. Researchers hope that the new drug, if proven safe and effective, may shorten the time to effectively treat tuberculosis, which claims over two million lives worldwide each year.

NIAID-supported scientists recently discovered that a poxvirus infection may be halted by a cancer drug aimed not at the virus, but at the human cellular machinery that the virus needs to spread from cell to cell. Although much work needs to be done on this concept, this research opens the possibility of providing a therapeutic approach to poxviruses such as smallpox, and also of circumventing the problem of antiviral drug resistance. This approach might also be applicable to other viruses. Researchers supported by NIAID also are investigating the use of antibodies that can bind to and block the action of toxins produced by the anthrax and botulinum bacteria.

In addition to conducting and supporting biodefense research initiatives, NIH has invested in several research infrastructure expansion programs. NIAID has established a nationwide network of Regional Centers of Excellence for Biodefense and Emerging Infectious Diseases Research (RCEs). These Centers are now conducting fundamental research on infectious diseases that could be used in bioterrorism; developing diagnostics, therapeutics and vaccines needed for biodefense, and providing training for future biodefense researchers. Two new RCE awards were announced on June 1, 2005, bringing to 10 the total number of RCEs nationwide. NIAID also supports five Cooperative Centers for Translational Research on Human Immunology and Biodefense to characterize human immune responses to disease-causing organisms, develop technologies to measure these responses, and apply this knowledge to design therapies that strengthen host immunity. In addition, NIAID is funding the construction of 13 Regional Biocontainment Laboratories (RBLs) with Biosafety Level 3 facilities, and two National Biocontainment Laboratories (NBLs) built to Biosafety Level 4 standards and therefore capable of safely containing any known pathogen. Ground was recently broken for the Galveston National Laboratory, the first of the two planned NBLs. This complex is the first of its size and scope undertaken in the United States on an academic campus and represents an unprecedented national resource. The new complex provides state-of-the-art facilities for research to fight emerging infectious disease threats, be they “natural” or manmade.

Immune-Mediated Diseases

Autoimmune diseases, allergic diseases, asthma and other immunologic diseases continue to contribute to chronic disease and disability in the United States and throughout the world. Autoimmune diseases affect 5 to 8 per cent of the U.S. population, while asthma and allergic diseases together are the sixth leading cause of chronic disease and disability in this country. In the past year NIAID-sponsored researchers made significant advances in understanding these common immune-mediated diseases. For example, researchers funded by NIAID have conducted “real-world” studies showing that home-based interventions could be effective at reducing childhood asthma. Home-based interventions aimed at reducing six major classes of allergens known to trigger asthma symptoms resulted in significant improvements in the health of children with asthma. Such interventions are simple to implement and are cost effective. Scientists also have engineered synthetic proteins that, based on tests in mice, could alleviate symptoms of allergy to cats and other possible allergens.

The portfolio of research conducted at NIAID and at NIAID-sponsored laboratories encompasses a broad array of basic, applied and clinical studies. By funding talented researchers and emphasizing a balance of basic studies and targeted research, we hope to continue to develop innovative technologies and treatments to combat a wide range of important diseases that afflict humanity.

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