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Molecular Virology and Microbiology

Houston, Texas

BCM has 25 departments and more than 90 research and patient-care centers.
Department of Molecular Virology and Microbiology
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Influenza Virus (Flu)

The Agent

Nearly everyone has experienced the fever, aches, and other symptoms of seasonal flu that afflicts 5 – 20% 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 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.

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.

Because flu viruses change so easily and often, are unpredictable, and can be deadly, it is always a great concern when a new flu virus emerges, because the general population does not have immunity and nearly everyone is susceptible. 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 the influenza virus and to improve vaccine and drug development, will enable us to minimize the effects of future influenza outbreaks.

Stained transmission electron micrograph showing the ultrastructural details of an influenza virus particle

Courtesy: CDC
Cynthia Goldsmith, Dr. Erskine. L. Palmer;
Dr. M. L. Martin

In this section, there is information on:

Different Types of Influenza Virus

There are three different types of influenza virus – A, B, and C. Type A viruses infect humans and several types of animals, including birds, pigs, and horses. Type B influenza is normally found only in humans, and type C is mostly found in humans, but has also been found in pigs and dogs. Influenza pandemics are caused by type A viruses, and therefore these are the most feared type of influenza virus; neither types B or C have caused pandemics.

Type A influenza is further classified into subtypes depending on which versions of two different proteins are present on the surface of the virus. These proteins are called hemagglutinin (HA) and neuraminidase (NA). There are 16 different versions of HA and 9 different versions of NA. So, for example, a virus with version 1 of the HA protein and version 2 of the NA protein would be called influenza A subtype H1N2 (A H1N2, for short). The influenza A subtypes are further classified into strains, and the names of the virus strains include the place where the strain was first found and the year of discovery. Therefore, an H1N1 strain isolated in California in 2009 is referred to as A/California/07/2009 (H1N1).

Although many different combinations of the HA and NA proteins are possible, viruses with only a few of the possible combinations circulate through the human population at any given time. Currently, subtypes H1N1, H1N2, and H3N2 are found in people. Other subtypes are found in animals. The subtypes that exist within a population change over time. The H2N2 subtype, which infected people between 1957 and 1968, is no longer found in humans.

What Influenza Viruses are Made of

Influenza virus has a rounded shape (although it can also be elongated or irregularly shaped) and has a layer of spikes on the outside. There are two different kinds of spikes, each made of a different protein – one is the hemagglutinin (HA) protein and the other is the neuraminidase (NA) protein. The HA protein allows the virus to stick to a cell, so that it can enter into a host cell and start the infection process (all viruses need to enter cells in order to make more copies of themselves). The NA protein is needed for the virus to exit the host cell, so that the new viruses that were made inside the host cell can go on to infect more cells. Because these proteins are present on the surface of the virus, they are “visible” to the human immune system.

Influenza Flu particle showing HA and NA spikes.

Inside the layer of spikes, there are eight pieces, or segments, of RNA that contain the genetic information for making new copies of the virus. Each of these segments contains the instructions to make one or more proteins of the virus. So for example, segment 4 contains the instructions to make the HA protein, and segment 6 contains the instructions to make the NA protein (the segments are numbered in size order, with 1 being the largest). When new viruses are made inside the host cell, all eight segments need to be assembled into a new virus particle, so that each virus has the complete set of instructions for making a new virus. The danger occurs when there are two different subtypes of influenza A inside the same cell, and the segments become mixed to create a new virus.

How Influenza Viruses Change

Influenza virus is one of the most changeable viruses known. There are two ways that influenza virus changes – these are called drift and shift. Drifting, or antigenic drift, is a gradual, continuous change that occurs when the virus makes small “mistakes” when copying its genetic information. This can result in a slight difference in the HA or NA proteins. Although the changes may be small, they may be significant enough so that the human immune system will no longer recognize and defend against the altered proteins. This is why you can repeatedly get the flu and why flu vaccines must be administered each year to combat the current circulating strains of the virus.

Shifting, or antigenic shift, is an abrupt, major change in the virus, which produces a new combination of the HA and NA proteins. These new influenza virus subtypes have not been seen in humans (or at least not for a very long time), and because they are so different from existing influenza viruses, people have very little protection against them. When this happens, and the newly created subtype can be transmitted easily from one person to another, a pandemic could occur.

Virus shift can take place when a person or animal is infected with two different subtypes of influenza. Take the case, for example, where there are two different subtypes of influenza circulating at the same time, one in humans and one in ducks. The human subtype is able to infect humans and pigs, but not ducks, while the duck subtype is able to infect ducks and pigs, but not humans. Consider what can happen when a pig becomes infected with both the human and duck influenza subtypes at the same time. Inside an infected cell, the segments of both viruses are scrambled or reassorted, so that a human virus particle is assembled that contains the duck HA segment instead of the human HA segment. A new virus subtype has been created. This new subtype can infect humans, but because it has the new duck version of the HA protein, the human immune system would not be able to defend an infected person against the new virus subtype. The virus may continue to change to allow it to spread more easily in its new host, and widespread illness and death could result.

Reassortment of the genetic material of two different influenza subtypes within an infected cell to produce a new virus subtype.

Reassortment of the genetic material of two different influenza subtypes
within an infected cell to produce a new virus subtype.

Virus shift can also occur when an avian strain becomes adapted to humans, so that the avian virus is easily transmitted from person to person. In this case, the avian strain jumps directly from birds to humans, without mixing or reassortment of the genetic material of influenza strains from different species.

Influenza Epidemics and Pandemics

Seasonal flu or influenza epidemics occur annually and are the most common emerging infection among humans. These epidemics have major medical impacts and are known as interpandemic epidemic influenza.

Pandemics, on the other hand, happen once every few decades on average. They occur when a new subtype of influenza A arises that

  • has either never circulated in the human population or has not circulated for a very long time (so that most people do not have immunity against the virus)
  • causes serious illness
  • can spread easily through the human population.

There were three influenza pandemics in the 20th century – the “Spanish” flu of 1918-19, the “Asian” flu of 1957-58, and the “Hong Kong” flu of 1968-69. The 1918 flu, caused by a strain of H1N1, was by far the most deadly. More than 500,000 people died in the United States as a result of the Spanish flu, and up to 50 million people may have died worldwide. Nearly half of those of those deaths were among young, otherwise healthy individuals. The 1957 pandemic was due to a new H2N2 strain of influenza virus and killed two million people, while the 1968 pandemic resulted from an H3N2 strain and killed one million.

The WHO established a six phase pandemic alert system in 2005 in response to the potential threat of the H5N1 avian influenza virus. The alert system is based on the geographic spread of the virus, not necessarily the severity of disease caused by the virus. Although a disease may be “moderate” in severity, during widespread outbreaks, declaration of a pandemic is beneficial because it accelerates the vaccine production and prompts governments to take extra measures to contain the virus. Travel and trade bans may be implemented in some cases, although if the disease is already widespread, these may not be considered effective

The World Health Organization (WHO) has defined six phases of a pandemic.

Phase 1 No influenza viruses circulating in animals reported to cause infections in humans
Phase 2 Influenza virus circulating in animals reported to cause infection in humans
Phase 3 Small clusters of infections in humans, but no human-to-human transmission
Phase 4 Human-to-human transmission resulting in community-wide outbreaks
Phase 5 Human-to-human transmission in at least two countries within one WHO region
Phase 6 Human-to-human transmission in at least two countries within one WHO region

Prior to the emergence of the 2009 H1N1 virus, the alert level stood at Phase 3 based on the circulation of the H5N1 virus. On April 27, 2009, after the H1N1 flu virus was recognized to be passing from person to person in Mexico, the alert level was raised to Phase 4. Two days later, on April 29, the WHO again increased the alert level, this time to Phase 5, reflecting the sustained transmission of the novel H1N1 virus in the United States. As H1N1 continued to spread worldwide and infect people in over 70 countries, the WHO raised the alert to Phase 6 – the highest level - on June 11, 2009, the first full pandemic since the “Hong Kong” flu of 1968. Over the next few months, H1N1 spread to more than 200 countries and territories worldwide. The Phase 6 alert of the 2009 H1N1 pandemic was declared by the WHO to have ended on August 10, 2010, and the world is now in a post-pandemic phase. H1N1 activity will continue, probably for some years to come, at low levels or in localized areas, with a behavior similar to that of seasonal influenza virus.

Avian Flu

Influenza naturally infects wild birds all around the world. Wild birds do not usually become ill from influenza, but it is very contagious and when domesticated birds, such as chickens, ducks, or turkeys become infected, they can become ill and die.

Humans do not generally become infected with avian flu. This is why news of humans contracting avian influenza during an outbreak of bird flu in poultry in 1997 in Hong Kong was alarming. It indicated that the virus had changed to allow it to directly infect humans. The virus that caused this outbreak is influenza A subtype H5N1.

Since 1997, H5N1 infections in birds have spread. H5N1 initially spread in birds throughout Asia. Wild birds have since brought H5N1 to countries along their migratory routes – first Russia and Eastern Europe and then to countries in Western Europe. H5N1 infections in birds have now been reported in most countries of Europe including the United Kingdom, Spain, Greece, Italy, Germany, and France. H5N1 has also been detected in Turkey, Iraq, Iran, Pakistan, and India and in countries on the African continent, including Egypt, Sudan, and Nigeria.

There have been about 500 laboratory-confirmed cases of H5N1 infections in humans, in 15 different countries, and close to 300 deaths. Although no longer in the news following the emergence of the H1N1 swine flu, H5N1 is still circulating and caused some 70 cases in 2009, mostly in Egypt and Indonesia; 32 were fatal. By mid-2010, 30 additional cases were reported, with 13 deaths. It is possible that other infections have occurred that were unreported or unconfirmed or did not produce symptoms of infection, so the actual death rate may be lower than it appears.

Most human cases of H5N1 influenza have been traced to direct contact with infected poultry, but there have been a few cases where person-to-person transmission is suspected, particularly in clusters where multiple family members became infected. In June 2006, the first case of human-to-human transmission was confirmed by the WHO. This event occurred within a family in Indonesia. Another case of H5N1 transmission between two family members - this time in Pakistan - was confirmed by the WHO at the end of 2007. So far, infections in humans have not spread beyond persons with close, prolonged contact with an infected individual.

Scientist conducting an experiment with the H5N1 virus in an enhanced BSL-3 facility

Courtesy:CDC
Taronna Maines and Greg Knobloch

Scientists have discovered one reason why avian H5N1 is not readily transmissible among people. As with other viruses, the influenza virus must attach to specific proteins called receptors on the outside of cells in order to gain entry into cells and cause an infection. It is the hemagglutinin, or HA, protein of the influenza virus that determines which cell type the virus can enter. Unlike human influenza viruses, which infect cells high in the respiratory tract, the H5N1 HA protein attaches to cells much lower in the respiratory track. The virus is so deep within the respiratory tract that it is not coughed up or sneezed out, and so it does not easily infect other people. If the HA protein of H5N1 were to mutate so that it could infect cells higher in the respiratory tract, then it would more likely be able to pass from person to person.

In addition to H5N1, other avian influenza strains have occasionally infected humans in recent years. These include the H7N2 strain which infected two individuals in the eastern United States in 2002 and 2003, and the H9N2 strain which has caused illness in several people in Asia in 1999 and 2003. The H5N1 virus was of greatest concern because of its rapid mutation rate, geographic spread, and ability to cause severe illness in humans. However, in the time since the H5N1 virus first emerged, it has not acquired the ability to spread easily within the human population, and so concern that this virus could cause a pandemic has eased.

In the spring of 2013, a new subtype of avian influenza was found to infect humans. This variant is known as influenza A (H7N9) and had previously been detected in birds, but never in humans. As of the end of May 2013, 132 cases and 37 deaths were reported to the WHO; all cases occurred in China. Human infection appears to result from exposure to infected poultry or contaminated environments. The virus does not appear to spread easily from person to person, but influenza viruses are highly mutable and it is possible that H7N9 could spread more readily over time. As with other newly emerged viruses, much is not yet known, including the source of the virus and the means by which it is transmitted.

Swine Flu

Swine influenza, or swine flu, is a very contagious respiratory disease of pigs. Swine flu viruses produce high levels of illness in pigs, but do not generally cause them to die. Pigs become infected year round, although the highest incidence of infection occurs in late fall and winter, similar to outbreaks in humans. In addition to infection with swine influenza viruses, pigs are also susceptible to infection by avian influenza or human seasonal influenza viruses. This can lead to a dangerous mixing or reassortment of different influenza types, resulting in the creation of new virus subtypes.

 Transmission electron micrograph of the 2009 swine flu virus

Courtesy:CDC
C. S. Goldsmith and A. Balish

Swine influenza viruses do not usually infect humans, except for occasional cases where a person has had close contact with an infected pig. In 1976, a highly publicized outbreak of swine flu occurred among soldiers in Fort Dix, New Jersey. The cause of this outbreak was a swine influenza virus that mutated in such a way to allow it to spread among humans. This virus caused disease and one death among otherwise healthy individuals. Fearing that a flu pandemic was imminent, officials rushed to produce a vaccine, but the vaccination drive was quickly halted after hundreds of people reported developing a paralyzing disorder called Guillain-Barre syndrome after getting immunized. There was limited transmission outside of the group of soldiers, and the virus disappeared after a short time.

A new “swine” flu emerges

In April of 2009, a new influenza virus that originated in swine was detected that is capable of infecting humans and spreading from person to person. This virus is called influenza A (H1N1), although it is commonly referred to as swine flu. It is distinct from the swine flu virus of 1976 and also from human seasonal H1N1 influenza viruses. Although it is called swine flu, the new H1N1 virus is transmitted from person to person, and not through contact with pigs or pork products.

The new H1N1 virus appears to be made up of a novel combination of segments from four different influenza virus strains - a Eurasian swine virus, a North American swine virus, and avian and human influenza virus segments (probably as a result of the mixing of a swine/avian/human triple assortment virus with the Eurasian swine virus, with H1 derived from a classical swine virus and N1 from the Eurasian virus).

Reassortment of segments from these different viruses has produced a unique virus that has not been seen before by the human population, although some of the pieces of the new virus may have been circulating in pigs as early as 1998. Whenever a new virus passes directly from animals to people, limited or no natural immunity is likely to exist in humans, and so therefore nearly everyone may be susceptible.

The 2009 H1N1 pandemic

The 2009 H1N1 influenza virus outbreak appears to have originated in Mexico, probably at least as early as February of 2009, and then spread rapidly throughout North America. Within a few weeks, the novel swine-origin H1N1 virus extended its reach around the globe. In June 2009, as a result of the global spread of the H1N1 virus, the WHO issued its first pandemic declaration of the 21st century - the first since the flu pandemic of 1968. The pandemic declaration acknowledged the inability to contain the virus and recognized its inevitable further spread within affected countries and into new countries. The new H1N1 virus became the dominant influenza strain in most parts of the world, including the United States.

Like other influenza pandemics, the 2009 H1N1 outbreak occurred in waves. The first wave took place in the spring of 2009 (although cases continued throughout the summer – an unusual occurrence for a flu virus). A second wave began in late August as children and college students returned to classes. The fall wave of H1N1 peaked in mid-October in the United States, with 48 states reporting widespread flu activity at that time. The high prevalence of influenza activity so early in the flu season was an unprecedented event, as flu season typically begins in December. By January 2010, flu activity had returned to below baseline levels, although new cases, hospitalizations, and deaths continue to occur at low levels. The H1N1 pandemic alert was declared to have ended in August of 2010, although the virus is likely to continue to circulate at low levels or in localized areas for some years to come. However, it is no longer the dominant influenza strain, and its behavior will more closely resemble a seasonal influenza virus than a pandemic flu.

Colorized transmission electron micrograph showing H1N1 influenza virus particles. Surface proteins on the virus particles are shown in black. Credit: NIAID

Credit: NIAID.

From the time the outbreak began in April 2009 through April 2010, the CDC estimates that about 60 million Americans became infected with the H1N1 virus. About 265,000 Americans are thought to have been hospitalized and approximately 12,000 deaths have resulted as a consequence of the 2009 H1N1 flu. The number of child deaths (aged 17 and under) is estimated to be around 1250. The highest hospitalization rates have occurred in younger populations, with the highest hospitalization rate reported in children 0-4 years old. Exact numbers are not known due to the widespread nature of the outbreak and because most patients, especially those with mild cases, were not tested and individual cases are no longer being counted.

The large majority of infections in the United States and most other countries were mild, although pregnant women and individuals with certain underlying medical conditions, including respiratory disease, cardiovascular disease, diabetes, and immunosuppression were at increased risk for severe and fatal illness.

Even though, for most people, the 2009 H1N1 virus caused an illness of severity similar to that of seasonal flu, there are differences between the pandemic H1N1 flu and regular, seasonal flu. First, the H1N1 flu continued to spread during the summer months, which is uncommon for seasonal flu. The H1N1 flu also inflicted a much larger percentage of patients with symptoms of vomiting and diarrhea. This may be explained by the finding that the swine flu virus, unlike seasonal flu viruses, appears to be capable of infecting cells deep within the lungs and into the intestines.

An important distinction between the H1N1 pandemic flu and seasonal flu is that the majority of cases of H1N1 infection, including severe and fatal cases, occurred in young and otherwise healthy individuals generally between the ages of 5 and 50, with relatively few deaths among the elderly. This is in contrast to the situation with seasonal flu which primarily afflicts the very young and the elderly, and where 90% of severe and lethal cases occur in people over the age of 65. Deaths among the elderly account for only 11% of H1N1 deaths. There were also more reports of severe respiratory disease, again mostly in young and otherwise healthy people, infected with the new H1N1 virus than with seasonal flu viruses. Recent studies using animal models (ferrets, monkey, and mice) have indicated that the H1N1 flu reproduces more aggressively, affects more areas of the lungs, and produces more severe disease than seasonal flu.

Treatment for H1N1 flu

Fortunately, the 2009 H1N1 flu was sensitive to two antiviral drugs used to treat influenza - Tamiflu® (oseltamivir) and Relenza® (zanamivir). The drugs act by inhibiting the essential neuraminidase protein (the “N” protein in the naming system). Proper use of these drugs can shorten the duration and lessen the severity of the sickness and reduce the chance of spreading the disease. The drugs reduce the risk of pneumonia - a major cause of death from influenza - and the need for hospitalization. To be most effective, the antiviral drugs should be administered as soon as possible after the onset of symptoms.

A vaccine to protect against the H1N1 virus was developed, tested, and approved and became available in October 2009. Due to the fact that the virus used to prepare the vaccine grew more slowly than most seasonal flu viruses do, production of the vaccine lagged and widespread distribution of the vaccine occurred later than anticipated. Priority for the vaccine was initially given to health care and emergency workers and individuals at high risk for severe disease, but by the winter of 2009-2010 availability was extended to the general population. Although some had concerns about the safety of the H1N1 vaccine, the process used to prepare the 2009 H1N1 vaccine was the same as that used to prepare the seasonal flu vaccines, and the vaccines have a very good safety profile.

While mild side effects, such as soreness at the site of injection, aches, and low-grade fever, may occur as a result of receiving a flu shot, it is not possible to get the flu (H1N1 or seasonal) from the vaccine. The flu shot, or inactivated vaccine, is made from only a portion of the virus – a purified protein that makes our immune system develop protection. Likewise, the nasal spray version of the flu vaccine contains attenuated or weakened virus that is not able to cause the flu. Given the potential serious health outcomes from the flu, especially for high-risk population groups, the benefits of vaccination as the best way to prevent influenza infection and its complications far outweigh the risk of relatively minor side effects from the vaccination.

The Problem

Historically, influenza pandemics occur about three to four times each century. The first pandemic of the 21st century was declared in June of 2009 – the first in about 40 years. The 2009 H1N1 “swine” flu spread to so many geographic locations so quickly that it could not be effectively contained. H1N1 spread around the globe faster than any virus in history, largely due to air travel.

The concern with pandemic flu strains is that nearly everyone is susceptible to infection, because there is limited or no natural immunity to novel flu strains. A high percentage of the population could become ill at any one time and overwhelm public health systems, and a large number of deaths could occur.

We were very fortunate in the case of the 2009 H1N1 pandemic. Most people suffered only a mild illness. H1N1 – at least in its current form - is not an especially virulent virus. The 2009 H1N1 virus has remained stable and has not mutated to a more deadly form or to a drug resistant form.

Other influenza strains have been far more lethal. The flu strain that caused the 1918 pandemic began in the spring as a mild flu, but returned as a more deadly version in the fall and winter to infect about one-third of the world’s population and kill an estimated 50 million people. The avian H5N1 virus, that is still circulating, has a mortality rate of near 60%, although it does not easily pass from person to person.

Electron Micrograph of 1918 Flu particles

Courtesy:CDC
C.S. Goldsmith, and T. Tumpey

There are drugs that are effective against influenza, but the possibility that a virus could acquire resistance to the drugs is a serious concern to scientists. There are four different antiviral drugs, of two different classes, that are effective against influenza. However, influenza viruses can and do develop resistance to these drugs - as one of the main circulating seasonal viruses did during a recent flu season - so that the drugs can no longer be used to treat or prevent infections. The 2009 H1N1 influenza virus is sensitive to the two neuraminidase inhibitor drugs Tamiflu (oseltamivir) and Relenza (zanamivir), but it is resistant to the second class of drugs, the adamantanes. There have been isolated reports of individuals infected with swine-origin H1N1 variants that are resistant to Tamiflu. There is a need to develop additional drugs that can prevent or alleviate flu symptoms.

Vaccines can be developed to protect humans from influenza viruses. However, as was strikingly obvious during the 2009 H1N1 pandemic, vaccine production takes many months. By the time a vaccine was developed, tested, produced, and distributed, many individuals had already been infected. Production of the 2009 H1N1 vaccine was especially slow because of difficulties in growing the virus used to produce the vaccine (flu vaccines are traditionally produced using chicken eggs, and the H1N1 virus stock used in vaccine production yielded less from each egg than normally obtained for seasonal flu viruses). Because of the delay in producing sufficient quantities of the vaccine, doses were initially restricted to healthcare workers and individuals from groups at high risk from severe disease and death, such as pregnant women and people with certain underlying medical conditions. Later, some doses went unused. Clearly, a more rapid method of vaccine development is needed.

The greatest fear is that a new pandemic influenza virus could emerge that could pass from person to person as easily as the H1N1 virus, but be as deadly as the H5N1 virus. Additional concerns are that an influenza virus could mutate into a form that would be resistant to anti-influenza drugs, such as Tamiflu, or that the virus could change so that a vaccine no longer afforded protection.

Even though the 2009 H1N1 pandemic was relatively mild, knowing how lethal and unpredictable influenza viruses can be, we must continue to remain alert and prepare for future pandemics.

The Research

Investigators in the Department of Molecular Virology and Microbiology (MVM) at Baylor College of Medicine have been studying influenza for many years, 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. Most recently, they have been involved in testing several experimental vaccines against the 2009 H1N1 (swine) influenza.

Research is currently being conducted by MVM investigators on

  • Epidemic (seasonal) influenza which occurs annually and is attributable to minor changes in genes that encode proteins on the surface of circulating influenza viruses. These are known as interpandemic epidemics.
  • Pandemic influenza which occurs when more significant changes in the influenza A virus arise when human virus strains acquire genes from influenza viruses of other animal species. When this happens, everyone in the world is susceptible to the new virus, and a worldwide epidemic - or pandemic - can result.
  • H1N1 (swine) influenza, a new flu virus that emerged in the spring of this year, which has been declared the cause of a global pandemic.

Epidemic Influenza Section Top

Patient receiving a vaccination

Courtesy:CDC

MVM investigators would like to better understand interpandemic influenza (seasonal flu) infections, disease, and vaccines with the goal of developing ways to better control these epidemics. Towards this goal, they are working on developing new improved vaccines against epidemic influenza strains and are trying to understand how the immune systems of different people respond to the influenza virus and influenza vaccines.

The following research projects are ongoing.

  • 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.

MVM researchers are also conducting a study (in collaboration with Kelsey-Seybold Clinics) to monitor the safety of inactivated influenza vaccine administered to pregnant women. They want to determine the effectiveness of the vaccine in protecting the women that are pregnant and whether these immunized women can pass on immunity against influenza, so that their infants would be protected from influenza during their first few months of life.

The top box depicts a community in which no one is immunized and an outbreak occurs. In the middle box, some of the population is immunized but not enough to confer community immunity. In the bottom box, a critical portion of the population is immunized, protecting most community members.

Credit: NIAID.

Another approach that is being used by MVM researchers 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) Piedra and colleagues are in the process of testing herd immunization in school-aged children in central Texas. In their initial study, they found that vaccination of 12 to 15% of children in selected communities resulted in an indirect protection to influenza infection in 8 to 18% of the adults in these communities. They are currently conducting a larger, school-based vaccination program with the goal of immunizing 50% 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. These results indicate that the use of Tamiflu may be particularly important in treating children with chronic medical conditions during the current H1N1 swine flu pandemic, especially until an effective vaccine is developed.

Pandemic Influenza

The most effective way to prevent the widespread infection and high mortality rate that a new influenza virus could inflict upon the human population would be to vaccinate people, so that the human immune system would be prepared to fight off an infection. MVM investigators are trying to identify the best way to prime the human immune system to defend against avian flu strains that could cause a pandemic. They have been testing vaccines against H5N1 and other potential pandemic flu strains and analyzing the immune responses of different people to the vaccines.

Specific projects include the following.

  • Studies of vaccines against different potential pandemic influenza virus strains (H5N1, H9N2, and others)
  • 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

The researchers in MVM conducting these studies - Drs. Robert Atmar , Robert Couch, Paul Glezen , Wendy Keitel , Innocent Mbawuike , Flor Munoz , and Pedro (Tony) Piedra - hope the results of these studies will identify the optimal and most effective dosages of vaccine to protect the public from a possible influenza pandemic.

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.

X-ray structure of the NS1 protein from a highly pathogenic H5N1 influenza virus Courtesy: Dr. B.V.V. Prasad

X-ray structure of the NS1 protein from a highly pathogenic H5N1 influenza virus
Courtesy: Dr. B.V.V. Prasad

The top panel shows the localization of the NS1 protein (green) and the PDZ protein Scribble (red) in human cells (colocalization of the two proteins is seen in yellow).  The bottom panel shows a version of the NS1 protein that is mutated in the PDZ-binding motif resulting in loss of colocalization with the Scribble protein.

The top panel shows the localization of the NS1 protein (green) and the PDZ protein Scribble (red) in human cells (colocalization of the two proteins is seen in yellow). The bottom panel shows a version of the NS1 protein that is mutated in the PDZ-binding motif resulting in loss of colocalization with the Scribble protein.
Courtesy: Dr. Andrew Rice

Dr. Andrew Rice and colleagues are studying an avian influenza virus protein called NS1 that has recently been shown to be associated with virulence. Proteins like NS1 that are involved in pathogenesis are important targets for novel antiviral therapeutics. The goal of this project is to identify cellular proteins that interact with NS1 and play a role in the pathogenesis of avian influenza virus infection. A critical feature of the avian NS1 protein is the presence of a protein domain at one end of the protein - the carboxyl terminus – that is termed the PDZ-Binding Motif, or PBM. The PBM is predicted to associate with a class of cellular proteins - termed PDZ proteins - that are typically involved in cell-cell contact, cellular polarity, and signaling pathways. It is notable that the NS1 protein of the virulent influenza viruses, such as H5N1, contains a PBM with the sequence ESEV, while other less virulent influenza viruses contain a different PBM sequence or lack this region entirely.

Dr. Rice and colleagues have identified a number of cellular targets of the NS1 PDZ-ligand domain: Dlg1, Scribble, MAGI-1, MAGI-2, and MAGI-3. Their current research involves the investigation of the functional significance of the interaction between NS1 with the ESEV PBM and these protein targets. Their results to date have shown that the ESEV PBM reduces apoptosis during infection and enhances the level of viral replication. They have also found that the ESEV PBM is involved in the disruption of cellular tight junctions during infection. A long-term goal of this project is to derive small molecules that can inhibit the interaction between the NS1 protein and its cellular PDZ protein targets, as such small molecules may be the basis for the development of novel therapeutics to treat avian influenza virus infection.

H1N1 (Swine) Influenza

MVM researchers have been actively engaged in assessing the outbreak of the 2009 H1N1 virus and keeping the public informed through local and national media outlets. Members of the Department were part of the national effort to prepare a vaccine against H1N1 influenza and test candidate vaccines. They have 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.

Image of a vial of influenza vaccine.

Courtesy: CDC/
James Gathany

MVM Department member Dr. Wendy Keitel directs the BCM Vaccine and Treatment Evaluation Unit (VTEU), one of eight federally funded centers in the nation established by the National Institute of Allergy and Infectious Diseases. The VTEU network conducts clinical trials that evaluate vaccines and treatments for a wide array of infectious diseases. They have previously tested vaccines to seasonal influenza and H5N1 influenza and have evaluated candidate vaccines against the new swine-origin H1N1 virus. An important strength of this established network is that it is able to efficiently and safely test new vaccines within a rapid time frame. Other members of the VTEU are Dr. Robert Atmar, Dr. Hana El Sahly, Dr. Paul Glezen, Dr. Flor Munoz-Rivas, Dr. Shital Patel, and Dr. Pedro Piedra.

MVM researchers have worked within the VTEU network to evaluate 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 of the study by the MVM researchers 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.

Members of the VTEU have also monitored vaccine recommendations made by the CDC and made suggestions. The CDC advised that priority for limited supplies of vaccine be given to pregnant women, household contacts of children younger than six months of age, healthcare workers, those within the range of six months to 24 yours of age, and non-elderly adults with underlying medical condition. MVM vaccine experts expressed concerned that this plan could result in too few people receiving vaccinations, and that some doses would go unused. They suggested more discussion about the possibility of expanding the supply of available vaccine by increasing the amount of live virus vaccine (made with weakened flu viruses and referred to as live attenuated influenza viruses as opposed to a second type of vaccine that contains killed virus and is known as inactivated vaccine), so that more universal coverage could be achieved. Research has shown that universal coverage of a vaccination helps protect high risk populations, as well as the rest of the community.

In another study, MVM scientists with the VTEU have worked on developing a method to collect samples and isolate viruses so that they can 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 will be banked and shared with researchers around the country. The goal of this study is to help guide the process of vaccine development and to give scientists an idea of what the response is to antiviral chemotherapy and analyze changes of the virus over time.

MVM researchers with the VTEU have also 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, such as those currently being developed against the H1N1 influenza virus, in pregnant women.

Dr. Terrence Tumpey (CDC, NCID), showed him examining reconstructed 1918 Pandemic Influenza Virus inside a specimen vial containing an orange-colored supernatant culture medium.

Courtesy:CDC
J. Gathany

In other projects, 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 has expanded its capabilities to include the swine-origin influenza A/H1N1 virus. In addition, Dr. Robert Couch has worked on setting up serologic assays for evaluation of immune responses.

Studies conducted by MVM researchers have helped guide public health officials in determining the best course of action in dealing with the 2009 H1N1 outbreak. 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. This work will provide valuable information in responding to this and future influenza outbreaks.

For more information:

General Flu Information Section Top

http://www.cdc.gov/flu/about/disease/index.htm - Basic seasonal flu information from the CDC

http://www.cdc.gov/flu/weekly/summary.htm - Summary and maps of weekly seasonal flu activity from the CDC

http://www.flu.gov/ - General flu information from the US Department of Health and Human Services

http://www.niaid.nih.gov/topics/Flu/understandingFlu/Pages/definitionsOverview.aspx - Flu information from the NIAID Division of Microbiology and Infectious Disease

http://www.google.org/flutrends/us/#US - US flu trend map from Google

http://www.bcm.edu/news/features/item.cfm?newsID=6675 - Flu information from experts at Baylor College of Medicine

Swine Flu Section Top

http://www.cdc.gov/h1n1flu/ - Health information and current information about cases numbers in the United States from the CDC

http://www.who.int/csr/disease/swineflu/en/index.html - Information about the H1N1 swine flu from the WHO including confirmed case numbers worldwide and pandemic phase alerts

Avian Flu Section Top

http://www.cdc.gov/flu/avianflu/h7n9-virus.htm Information about H7N9 avian influenza virus from the CDC

http://www.who.int/influenza/human_animal_interface/influenza_h7n9/en/index.html Information about H7N9 avian influenza virus from the WHO

http://www.who.int/influenza/human_animal_interface/influenza_h7n9/Data_Reports/en/index.html Number of confirmed human cases of avian influenza A(H7N9) reported to WHO

http://www.who.int/influenza/human_animal_interface/H5N1_cumulative_table_archives/en/ Cumulative number of confirmed human cases of avian influenza A/(H5N1) reported to the WHO

http://www.who.int/influenza/H5N1_avian_influenza_update_20121217b.pdf H5N1 avian influenza: Timeline of major events

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