Molecular Virology and Microbiology

Influenza (Flu)

 

The Agent

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.

Nearly everyone has experienced the fever, aches, and other symptoms of the seasonal flu outbreaks that afflict 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.

However, 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 death even in otherwise healthy people. These outbreaks can also lead to social disruption and economic loss.

Several years ago, scientists and public health officials feared that we might be on the brink of a new pandemic from 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.

Now, a new virus that has not been seen before has suddenly emerged. The novel virus is named influenza A (H1N1), but is commonly called swine flu. Unlike the avian H5N1 flu, the H1N1 swine flu is capable of being easily transmitted from person to person, although it is fortunately far less deadly than the H5N1 virus. In only a few weeks after emerging in North America, H1N1 spread around the globe. As a result of the rapid, global spread of H1N1, the first pandemic of the 21st century has been declared.

In this section, there is information on

• Different types of influenza virus
• What influenza viruses are made of
• How influenza viruses change
• Influenza epidemics and pandemics
• Avian Influenza
• Swine Influenza

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). Although many different combinations of these two proteins are possible, viruses with only a few of the possible combinations circulate through the human population at any one time. Currently, subtypes H1N1, H1N2, and H3N2 are found in people. Other subtypes can infect animals. The subtypes that circulate through the population change over time. The H2N2 subtype, which infected people between 1957 and 1968, no longer circulates among humans. 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.

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 and each is 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.

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.

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

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 happen every few decades. 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 this six phase pandemic alert system in 2005 in response to the potential threat of the H5N1 avian influenza virus. Prior to the emergence of the 2009 H1N1 influenza virus of swine origin, the alert level stood at Phase 3. 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 on June 11 and declared a full pandemic. This is the first time a pandemic has been declared since the “Hong Kong” flu pandemic of 1968. Phase 6 indicates sustained community-wide transmission in at least two regions of the world.

It is important to understand that the six-point alert system is based on the geographic spread of the virus. Although this system is useful is describing the spread of a disease, the existing rules do not take into account the severity of disease caused by the virus. By upgrading the alert status, the WHO has recognized the spread of H1N1 within different parts of the world. Declaration of an H1N1 pandemic, however, does not signify that the disease has become more severe. The WHO classifies the H1N1 flu as “moderate” in severity, although most cases are mild.

Declaration of a flu pandemic is expected to result in an acceleration of the process to produce a vaccine and prompt governments to take additional measures to contain the virus, but travel and trade bans are not anticipated at this time.

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.

The number of human cases of avian flu worldwide has topped 400 and there have been close to 260 deaths. Although no longer in the news following the emergence of the H1N1 swine flu , H5N1 is still circulating and has resulted in over 35 new cases in 2009, mostly in Egypt; 12 of these cases have been fatal. It is possible that additional 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.

Scientists have recently 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. However, H5N1 is currently the 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 the next pandemic has lessened.

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.

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, 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, and then spread rapidly throughout North America. Within a few weeks, the novel swine-origin H1N1 virus extended its reach into many regions of the world including Europe, Central and South America, Asia, and most recently, Africa. H1N1 cases have now been reported in more than 190 countries and territories. As a result of the global spread of the H1N1 virus, the WHO issued its first pandemic declaration of the 21st century and 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 has now become the dominant influenza strain in most parts of the world.

As of Oct. 25, the official number of laboratory-confirmed cases of H1N1 infection reported to the WHO was at least 440,000 with more than 5,700 deaths. However, because of the widespread and ever-growing increase in new infections, the WHO is no longer requiring countries to test and report individual cases, and these numbers greatly understate the actual number of cases. In the United States, most patients, especially those with mild cases, are not being tested and individual cases are no longer being counted. The number of Americans who have been infected with the H1N1 virus is estimated to be in the millions.

Currently, nearly all states are reporting widespread influenza activity. Such widespread influenza activity is unprecedented. Visits to doctors for influenza-like illness are now higher than that seen during the peak of many regular flu seasons and are still increasing. Hospitalization rates are higher than expected for this time of year and are climbing. The highest hospitalization rates are occurring in younger populations, with the highest hospitalization rate reported in children 0-4 years old. Deaths attributed to pneumonia and influenza are much higher than expected for this time of year. The CDC reports that there have been 114 laboratory-confirmed 2009 H1N1 pediatric deaths. The number of adult deaths has surpassed 1,000

The large majority of infections in the United States and most other countries have been mild, similar to that seen with seasonal flu. However, some people are at increased risk for severe and fatal illness. Especially vulnerable are pregnant women and individuals with certain underlying medical conditions, which include respiratory disease, notably asthma, cardiovascular disease, diabetes, and immunosuppression. Severe and fatal cases are also frequently associated with obesity. Some minority groups and indigenous populations are at higher risk of hospitalization and death, possibly due to poorer overall health and higher prevalence of underlying medical conditions. An analysis of fatal cases in children under the age of 18 years indicated that many had one or more high-risk medical conditions, most commonly neurodevelopmental disorders.

Experts caution that even the seasonal flu has a mortality rate of about 0.1 percent and can kill up to half a million people yearly worldwide, so deaths from a pandemic flu, even a mild one, are to be expected. The mortality rate of the H1N1 flu is currently about 0.5 percent, although it appears to be variable from country to country. This is similar to the 0.6 percent death rate seen with the Asian flu pandemic of 1957 and significantly less than the 1918 flu which killed about 2.5 percent of those infected. However, as flu pandemics usually occur in successive waves, it is too soon to know what the overall mortality rate of the new H1N1 flu will be.

Fortunately, the 2009 H1N1 virus does not appear to possess the genetic signature of highly lethal flu strains. Genetic characterization of highly pathogenic influenza viruses such as the 1918 H1N1 virus and the avian H5N1 virus has allowed scientists to identify genetic determinants of influenza viruses that increase their lethality. Several influenza proteins (including hemagglutinin, the “H” protein in the naming system of influenza viruses) are known to be involved in influenza pathogenicity through their ability to increase the replication ability of the virus or have effects on the human immune system. Genetic analysis of the 2009 H1N1 virus has indicated that the virus does not possess the markers that can make influenza viruses extremely lethal.

Pandemic H1N1 flu differs from seasonal flu

Although the 2009 H1N1 virus generally causes a relatively mild illness, the new H1N1 flu is not the same as seasonal flu. Unlike regular flu which causes few illnesses during the hot summer months, the H1N1 flu has continued to spread in the Northern Hemisphere during the summer, with intense local outbursts in some areas. In terms of symptoms, a much larger percentage of patients with swine-origin H1N1 report 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 difference between swine flu and seasonal flu is that the majority of cases of H1N1 infection, including severe and fatal cases, have 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.

Significantly, there are 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. In these patients, the virus directly infects the lungs causing respiratory failure and requiring highly specialized and often lengthy and costly care. Recent studies using animal models (ferrets, monkey, and mice) have also indicated that swine 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 is 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. Resistance to these drugs is being closing monitored, and to date only a handful of cases have been documented where Tamiflu was ineffective.

A vaccine to protect against the H1N1 virus has been tested and approved and became available in October 2009.  Due to the fact that the virus used to prepare the vaccine has grown more slowly than most seasonal flu viruses do, production of the vaccine has lagged and fewer doses than anticipated are currently available. Priority for the vaccine is being given to health care and emergency workers, pregnant women, everyone between the ages of 6 months to 24 years, adults up to age 64 with medical problems, and people caring for infants under 6 months old. A nasal spray version of the vaccine (also known as LAIV for “live attenuated influenza vaccine” or Flu Mist) is also available, but it is approved for use only in healthy people between the ages of 2 and 49 who are not pregnant. More doses of the H1N1 vaccine are expected to be distributed in the coming weeks, and ample supplies are expected to be available later in the year.

Because H1N1 is a new virus, it was anticipated that two doses would be required to provide full protection. However, the results of recent clinical trials indicate that one low dose appears to be protective for healthy adults and older children. Younger children will require two doses of the H1N1 vaccine. The H1N1 vaccine is needed in addition to the vaccine for regular seasonal flu.

Although some have concerns about the safety of the H1N1 vaccine, it is important to keep in mind that the process used to prepare the 2009 H1N1 vaccines - both the flu shot and the nasal spray - is the same as that used to prepare the seasonal flu vaccines. The seasonal flu vaccines have a very good safety record, and it is expected that the H1N1 vaccine will have a similar safety profile. To date, no serious adverse effects have been reported, and the safety record of the H1N1 vaccines will continue to be closely monitored.

While mild side effects from the 2009 H1N1 vaccine may occur similar to those experienced with the seasonal flu vaccines (including soreness at the site of injection, aches, and low-grade fever), 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 contains attenuated or weakened virus that is not able to cause the flu. Given the potential serious health outcomes from the 2009 swine-origin flu, especially for some 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. Now, for the first time in 40 years, and for the first time in the 21st century, an influenza pandemic has been declared. The 2009 H1N1 virus has spread to too many geographic locations too quickly to be effectively contained. 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. It has been estimated that up to 40 percent of Americans and as many as two billion people worldwide - or nearly one-third of the world’s population - could become infected over the next two years.

In most individuals, the 2009 H1N1 virus causes a mild illness similar to that seen with seasonal flu, and most people recover completely even without treatment. Complications, including pneumonia, can occur in people with underlying health conditions such as asthma, cardiovascular disease, autoimmune disorders, obesity, or pregnancy. One striking difference between the seasonal flu and the H1N1 flu is that the majority of H1N1 infections have occurred in people under the age of 25, and most of the severe cases have been in individuals between the ages of 30 and 50, a group not usually susceptible to severe illness with seasonal flu. Furthermore, the severity of illness caused by the virus may be greater in developing countries where the quality of healthcare is poor and many people may already be suffering from other diseases.

The major concern of influenza experts is that flu viruses are extremely unpredictable, and although the new H1N1 has been causing mild illness in most cases, it is possible that the virus could become more virulent over time. The flu strain that caused the 1918 pandemic was mild in the spring, but returned in a more lethal form in the fall and winter to infect about one-third of the world’s population and kill an estimated 50 million people. Pandemic flus usually last more than one season and take place in two or three waves.

Although there have been no indications that the virus has mutated, experts cannot predict at this time whether the new virus will remain a mild flu strain or become more dangerous with time. One worrisome scenario is that the new H1N1 virus could combine with the deadly H5N1 avian flu, especially as the H1N1 flu spreads into areas of the world where avian flu is endemic. Therefore, it is crucial to maintain vigilance and take steps to limit the spread of the virus.

Another concern of scientists is that the swine-origin H1N1 virus could become resistant to the antiviral drugs that are currently used to treat the flu. There are four different antiviral drugs, of two different classes, that are effective against influenza. However, influenza viruses can develop resistance to these drugs - as one of the main circulating seasonal viruses did this past year - so that the drugs can no longer be used to treat or prevent infections. The swine 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 sporadic reports of individuals infected with swine-origin H1N1 variants that are resistant to Tamiflu.

The vaccine to protect humans from the 2009 H1N1 swine influenza virus became available in October. However, because of difficulties in producing the vaccine (flu vaccines are traditionally produced using chicken eggs, and the H1N1 virus stock being used in vaccine production has yielded less from each egg than normally obtained for seasonal flu viruses), only limited supplies have been distributed to date. Priority for the vaccine is being given 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. Further doses of vaccine will continue to be produced and distributed, so it is expected that eventually there will be sufficient supply. However, with influenza activity already widespread in most states, there is concern that the H1N1 flu will peak before the vaccine is widely available to everyone. 

The 2009 H1N1 vaccine is needed in addition to the seasonal flu vaccine which does not provide protection against H1N1. Therefore most individuals will require two separate vaccinations (young children will require three because they need to have two doses of the H1N1 vaccine to produce a protective immune response).

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. They are currently in the process of testing several experimental vaccines against the 2009 H1N1 (swine) influenza.

Research is currently being conducted by MVM investigators on

• Epidemic 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

MVM investigators would like to better understand interpandemic influenza 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.

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 are currently testing vaccines against H5N1 and other potential pandemic flu strains and are analyzing the immune responses of different people to the vaccines.

Specific projects that are currently underway or planned for the near future 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.

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-ligand domain.  This domain is predicted to associate with a class of cellular proteins - termed PDZ proteins - that are typically involved in cell-cell contact, cellular migration, and signaling pathways. It is notable that the NS1 protein of the virulent influenza viruses, such as H5N1, contains the PDZ-ligand domain, while other less virulent influenza viruses lack this region. Dr. Rice and colleagues have identified a number of cellular targets of the NS1 PDZ-ligand domain. Their current research involves the investigation of signaling pathways that are affected by the interaction of NS1 with specific cellular PDZ proteins and how these pathways influence viral replication and pathogenesis. 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 are actively engaged in assessing the current outbreak of the 2009 H1N1 virus and keeping the public informed through local and national media outlets. Members of the Department are involved in the national effort to prepare a vaccine against H1N1 influenza and have begun testing candidate vaccines. They are also in the process of optimizing ways of collecting samples and testing for infection, analyzing immune responses, and working on epidemiological, pathogenesis, and treatment studies of the virus.

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 now begun to evaluate 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 are working 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 will be 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 is to determine the reactions and antibody protection responses following immunization with experimental influenza H1N1 vaccine when given with seasonal influenza vaccine. 200 adults will be enrolled in this trial, and 100 children aged 6 months to 17 years will be enrolled in a similar trial to begin shortly after the start of the adult trial. Study participants will receive a single strength of the 2009 H1N1 vaccine given in two doses and will also receive the seasonal flu vaccine either before, during, or after the time that they are inoculated with the swine flu vaccine. They hope to have information by September or October that would guide the appropriate use of the vaccines.

Members of the VTEU are monitoring vaccine recommendations made by the CDC and making suggestions. The CDC has 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 are concerned that this plan may result in too few people receiving vaccinations, and that some doses would go unused. They suggest 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 are developing a method to collect samples and isolate viruses so that they can assess the viruses and the immune responses against them. They are enrolling 200 patients with confirmed cases of H1N1 infection and collecting nasal, throat and/or blood samples. Researchers will use 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 will also be 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 will include 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.

In other projects, MVM researchers are preparing assays that will be 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 is setting up serologic assays for evaluation of immune responses.

As much is currently unknown about the 2009 H1N1 virus, this work will yield valuable information to help guide public health officials in determining the best course of action in dealing with, and hopefully minimizing the consequences of, this viral outbreak.

 

For more information:

• Swine Flu |
• Avian Flu |
• General Flu |
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