Master Content Nearly everyone has experienced the fever, aches, and other symptoms of seasonal flu that
afflicts 5 – 20 percent of Americans each year. Although these yearly flu epidemics can be fatal in some people, such as the elderly, young children, and people with certain underlying heath conditions, flu is generally not a life-threatening disease in healthy individuals. Flu, or influenza, is a contagious respiratory illness that spreads from person to person through the air via coughs or sneezes or through contact with infected surfaces. It is caused by a group of continuously changing
viruses called influenza viruses. Influenza viruses change easily and often, they are unpredictable, and they can be deadly. It is always a great concern when a new flu virus emerges, because the general population does not have immunity and almost
everyone is susceptible to infection and disease. Every few decades or so, a new version of the influenza virus emerges in the human population that causes a serious global outbreak of disease called a pandemic. Pandemics are associated with
widespread illness - and sometimes death - even in otherwise healthy people. These outbreaks can also lead to social disruption and economic loss. About a decade ago, scientists and public health officials feared that we might be on the brink of a pandemic caused by the so-called avian or bird H5N1 flu that began circulating among poultry, ducks, and geese in Asia and spread to Europe and Africa. To date, the avian flu virus has not acquired to ability to spread easily from person to
person – a necessary step in order for a virus to cause a pandemic. In the spring of 2009, a different influenza virus - one that had never been seen before - suddenly appeared. The novel virus, commonly called swine flu, is named influenza A (H1N1). Unlike the avian H5N1 flu, the H1N1 swine flu is capable of being transmitted easily from person to person. Fortunately, however, H1N1 is far less deadly than the H5N1 virus. In only a few short weeks after emerging in North America, the new
H1N1 virus reached around the world. As a result of the rapid, global spread of H1N1, the first pandemic of the 21st century was declared in June of 2009. Although the 2009 H1N1 pandemic did not turn out to be as deadly as initially feared, the next pandemic flu virus could emerge at any time, and we must remain vigilant. Hopefully, the knowledge gained in response to the H5N1 and 2009 H1N1 outbreaks, and continued research to more completely understand influenza virus, as well as
improvements in vaccine and drug development, will enable us to minimize the effects of future influenza outbreaks. Content Investigators in the Department of Molecular Virology and Microbiology (MVM) have been studying influenza for several decades, with an Influenza Research Center first established in 1974. A major focus of the work is directed towards the development and testing of influenza
vaccines to find the most effective vaccination dosages, methods, and strategies to protect the population against this deadly disease. Other projects involve studying the structure and function of important influenza proteins. Research is ongoing on both
epidemic influenza (also referred to as seasonal or interpandemic influenza) and
pandemic influenza. Epidemic influenza occurs annually and is attributable to minor changes in
genes that encode
proteins on the surface of circulating influenza viruses. Pandemic influenza occurs when more significant changes in the influenza A virus arise as a result of the acquisition of genes from influenza viruses of other animal species by a human virus strain,
thus creating a novel virus. The latter carries a greater risk for the human population.
Notably, the department is home to the BCM Vaccine and Treatment Evaluation Unit (VTEU), one of nine federally funded centers in the nation established by the National Institute of Allergy and Infectious Diseases. It was previously led by Dr. Wendy Keitel and is currently under the direction of Dr. Hana El-Sahly. The VTEU network conducts clinical trials that evaluate vaccines and treatments for a wide array of infectious diseases. An important strength of this established network is that it is able to efficiently and safely test new vaccines within a rapid time frame.
The VTEU research group in the department has been involved in important studies that led to the licensure of live attenuated and high dose inactivated influenza virus vaccines. They have tested vaccines to seasonal influenza and they have performed many studies evaluating vaccines targeting pandemic influenza, including the swine-origin H1N1, and the H5N1, H9N2, and H7N9 viruses, among others. They have evaluated methods to improve vaccine immunogenicity, including delivery of vaccine by different routes of administration, different dosages, and with different adjuvant preparations.
Researchers involved in these studies include Drs. Robert Atmar, Robert Couch, Hana El Sahly, Paul Glezen, Wendy Keitel, Innocent Mbawuike, Flor Munoz-Rivas, Shital Patel, and Pedro (Tony) Piedra. Their hope is that the results of these studies will identify the optimal and most effective dosages of vaccine to protect the public from seasonal influenza, as well as from a possible influenza pandemic.
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- Developing new vaccines for induction of humoral and cell-mediated immune responses against influenza viruses that can prevent or modify infections.
- Identifying the optimal way to induce mucosal immune responses to influenza viruses that can increase resistance to infection at the site where infection initially occurs.
- Searching human genes for single nucleotide polymorphisms that determine the pattern and magnitude of immune response to influenza virus or provide an explanation for illness and its severity.
- Determining the role of immune responses directed toward the different proteins of influenza, including new candidates, for a beneficial role.
- Performing clinical trials of new and experimental vaccines as part of a program for development of improved influenza vaccines.
- Developing improved methods for measuring immune function in humans.
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In addition, MVM researchers with the VTEU have been evaluating the safety and immunogenicity of seasonal influenza vaccine in pregnant women. Because pregnant women are at higher risk for serious complications from the flu, it is important to develop strategies to protect these women from seasonal and pandemic influenza. The clinical trial includes up to 200 women recruited from nine sites across the nation and is headed by Dr. Shital Patel. It is one of the few studies that will evaluate antibody responses in pregnant women following vaccination. Evaluating the safety of seasonal inactivated influenza vaccine will yield vital information in anticipation of the need to test novel vaccines against possible future pandemic strains, in pregnant women.
Scientists are also conducting a study (in collaboration with Kelsey-Seybold Clinics) to determine the effectiveness of an inactivated influenza vaccine in protecting pregnant women and whether these immunized women can pass immunity against influenza to their infants, so that newborns would be protected from influenza during their first few months of life.
Another approach to protect against influenza epidemics is called herd immunity. The idea is to vaccinate a large percentage of school-age children to limit the spread of influenza without needing to vaccinate a larger percentage of the general population. The reasoning behind this idea is that school-age children are often the source of infection and pass the virus onto their friends, teachers, and family members. So preventing children from spreading influenza through large-scale vaccination of this group should protect the rest of the “herd” from influenza infection, even those who haven’t been vaccinated. This might be especially helpful to the elderly population who are at higher risk from influenza-related complications and whose immune systems may not mount as effective a response to influenza as younger individuals. Another advantage to this approach is that it might be possible to achieve high community protection from influenza with a limiting amount of vaccine.
Dr. Pedro (Tony) Piedraand colleagues are testing herd immunization in school-aged children in central Texas. In their initial study, they found that vaccination of 12 to 15 percent of children in selected communities resulted in an indirect protection to influenza infection in 8 to 18 percent of the adults in these communities. They are currently conducting a larger, school-based vaccination program with the goal of immunizing 50 percent of the children, and they will determine how effective this level of immunization is in preventing infection in adults. Dr. Piedra and co-workers want to know how many children need to be vaccinated in order to protect the adult population from influenza infection, and they would like to use this approach to control the spread of epidemic influenza. They also hope to use this approach as a model for combating pandemic influenza and bioterrorism.
Dr. Piedra has also investigated the effects of oseltamivir (commonly known as Tamiflu) on influenza-related complications in children with chronic medical conditions. Patients with underlying medical conditions are at higher risk of complications from both seasonal and pandemic flu. Dr. Piedra and his colleagues found that children with chronic medical conditions benefit from the use of Tamiflu if it is prescribed early in the disease process. Children and adolescents between the ages of 1 and 17 who were at high risk of influenza complications showed significant reductions in the risks of respiratory illnesses other than pneumonia, reduced risk of otitis media (a middle ear infection), and fewer hospitalizations in the 14 days after influenza diagnosis.
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- Studies of vaccines against different potential pandemic influenza virus strains (H5N1, H9N2, and H7N9)
- Studies of pandemic influenza vaccines given by different routes (intramuscularly, intradermally) and in different dosages
- Studies to determine whether immune responses are improved when a pandemic influenza virus vaccine strain is combined with an adjuvant
- Studies of pandemic influenza vaccines in different age groups
- Developing methods for measuring immune responses to these vaccines
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Members of the Department were part of the national effort to prepare a vaccine against H1N1 influenza and test candidate vaccines. MVM researchers within the VTEU network evaluated the safety and effectiveness of H1N1 candidate vaccines produced by two different manufacturers (Sanofi Pasteur and CSL Biotherapies). Several different parameters were tested: the number of doses required (one or two), different dosage amounts (15 or 30 micrograms), and different age groups (18 to 64 years old, age 65 and older, and healthy children). The goal was to determine the reactions and antibody protection responses following immunization with experimental influenza H1N1 vaccine when given with seasonal influenza vaccine. The trial enrolled healthy adults, and a similar trial was conducted with children aged 6 months to 17 years. Study participants received a single strength of the 2009 H1N1 vaccine given in two doses along with the seasonal flu vaccine given either before, during, or after the time that they were inoculated with the H1N1 vaccine.
Scientists in the department also examined ways to optimize the collection of samples and testing for infection, analyzing immune responses, and working on epidemiological, pathogenesis, and treatment studies of the virus. They worked on developing a method to collect samples and isolate viruses so that they could assess the viruses and the immune responses against them. They enrolled patients with confirmed cases of H1N1 infection and collected nasal, throat and/or blood samples. Researchers used these samples to isolate the virus for further characterization and study how the immune system responds. These samples were banked and shared with researchers around the country. The goal of this study was to help guide the process of vaccine development and to give scientists an idea of the response to antiviral chemotherapy and changes of the virus over time.
MVM researchers have been involved in preparing assays used to detect the virus and evaluate immune responses. The Respiratory Virus Diagnostic Research laboratory supports clinical trials on the epidemiology, immunology, pathogenesis, and vaccine prevention of important human respiratory pathogens and houses a cell culture lab for virus isolation and a polymerase chain reaction (PCR) lab for respiratory virus identification. Under the direction of Dr. Pedro Piedra, the lab tests for most of the known respiratory viral pathogens and expanded its capabilities to include the swine-origin influenza A/H1N1 virus. In addition, Dr. Robert Couch set up serologic assays for evaluation of immune responses.
Studies conducted by MVM researchers helped guide public health officials in determining the best course of action in dealing with the 2009 H1N1 outbreak. They monitored vaccine recommendations made by the CDC and made suggestions. They kept the general public informed through local and national media outlets. The scientists continue to study the H1N1 virus to gain a deeper understanding of the virus itself, its interactions with the immune system, and responses to the H1N1 vaccine.
Additionally, researchers within the VTEU have been working on other new influenza strains that have pandemic potential including the new avian H7N9 virus and investigating vaccine strategies. This work will provide valuable information in responding to future influenza outbreaks.
In more recent work, Dr. Robert Atmar and his colleagues have been conducting a phase 2 clinical trial to test a candidate for a universal flu vaccine known as M-001. Unlike other flu vaccines, which consist of a whole inactivated flu virus or an attenuated live virus, the M-001 vaccine is comprised of nine epitopes, short stretches of viral protein, that are common to many different influenza strains. Because these regions are shared between different strains, it is hoped that the vaccine would trigger the immune system to respond to multiple strains. Adult healthy volunteers will receive the experimental vaccine or a placebo and will be monitored over time to evaluate their immune responses.
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In a separate study, Dr. B.V. Venkataram Prasad and Zach Bornholdt, a graduate student in his laboratory, have determined the structure of a region of an important influenza protein called NS1. Their work may explain, in part, why the H5N1 virus causes such a severe and often fatal illness. NS1, a protein essential for influenza infection, antagonizes the cellular immune response and is thought to play a role in virulence. The lethal H5N1 strain has a different version of the NS1 protein than the NS1 protein of other strains of influenza. By knowing the structure of the NS1 protein, these investigators can surmise how variations in the H5N1 version of NS1 may alter its ability to interact with other molecules. They hypothesize that the mutations or changes in the H5N1 NS1 protein allow it to overcome the cellular immune response more effectively than the NS1 proteins of other strains of influenza. With detailed knowledge of the structure of the NS1 protein and how it interacts with other components of the cell, it will be easier to design drugs to specifically block these interactions and possibly disrupt the ability of the NS1 protein to interfere with the host’s protective immune response.
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