Influenza (Flu)
The Agent
Flu is a contagious respiratory illness that 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 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. These pandemics cause widespread illness, death (even in otherwise healthy people), social disruption, and economic loss. Scientists and public health officials fear that we may be on the brink of a new pandemic – the so-called avian or bird flu – that began circulating among poultry, ducks, and geese in Asia and has spread to Europe and Africa.
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
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 20 th century – the “Spanish flu” of 1918-19, the “Asian flu” of 1957-58, and the “Hong Kong flu” of 1968-69. The 1918 flu 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 World Health Organization ( WHO) has defined three main stages of a pandemic.
| Interpandemic period | No new influenza subtypes detected in humans |
|---|---|
| Pandemic alert period | New influenza subtype detected in humans but transmission from person to person is limited |
| Pandemic | New influenza subtype is easily transmitted from person to person and transmission is sustained |
Because of the emergence in 1997 of a new subtype of influenza, H5N1, that is capable of infecting humans, we are currently in a pandemic alert period for avian flu. The pandemic alert period is subdivided into three levels. We are now in level 3, the lowest of these three levels. Level 3 is described as having no or very little human-to-human transmission. The alert status would be increased to level 4 if there is evidence of increased human-to-human transmission and to level 5 if there is evidence of significant human-to-human transmission. Efficient and sustained human-to-human transmission would indicate that the world has entered the highest and most serious stage – a pandemic.
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.
To date, there have been around 350 cases of H5N1 infection in humans, with over 200 cases being fatal. It is possible, however, 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. Most human cases 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 the past several 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 it is known to mutate rapidly and cause severe illness in humans and because of its increasing and rapid geographic spread.
The Problem
Many experts believe that the world is currently closer to the next influenza pandemic than at any time since 1968 when the last pandemic occurred. Reasons for concern include the rapid spread and widespread geographic distribution of the H5N1 strain of avian influenza A, its high mortality rate, the difficulties with effective surveillance and lack of resources in containing outbreaks especially in the poorer countries of Asia and Africa, and the challenges of producing sufficient quantities of antiviral drugs and vaccines in a short period of time. Although most of the world’s attention is currently focused on the H5N1 strain, avian influenza A is comprised of a family of viruses, of which any strain could potentially cause a pandemic if it mutates to acquire the ability to pass easily through the human population.
Geographic Spread of Avian Influenza A H5N1
Since 1997, when the first outbreak of deadly avian influenza A H5N1 in poultry in farms in Hong Kong was reported, H5N1 has spread geographically. H5N1 initially spread through birds in southeastern Asia, but in the 2005 – 2006 season H5N1 moved westward at an alarming rate. H5N1 has been detected in birds in much of the Asian continent, many countries in Europe, as well as in several countries in the Middle East and Africa. H5N1 infections of humans reached outside of eastern Asia beginning in early 2006, with cases being reported in Turkey, Iraq, and Egypt. The spread continued in 2007, with human infections occurring for the first time in Laos, Myanmar, Nigeria, and Pakistan.
Much of the spread appears to be due to the migratory patterns of wild birds, but some of the spread of H5N1, particularly to Africa, is likely due to human trafficking of infected poultry.
In regions, such as Southeast Asia, where the virus is endemic, it will be very difficult to eradicate, and as the regions where H5N1 is established in the wild bird populations are extended, it is probable that the virus will continue to spread.
Lack of Surveillance and Resources
When birds become infected with avian influenza, rapid detection is critical, so that animals can be culled and humans in the region can be advised to avoid direct contact with sick birds and observed for signs of infection. If infections are detected early, it is much more feasible to restrain the spread of the virus than once infection becomes more pervasive in an area. When surveillance is not in place to detect infection of birds or if governments are slow to react to outbreaks, the situation becomes more dire and the virus may become endemic in a region.
Reaction to human outbreaks must also be very rapid so that infected individuals can be quarantined and treated with antiviral drugs and their contacts monitored. In some cases, there have been reports of human infections in areas where no previous cases of bird flu had been reported, indicating failure of comprehensive surveillance mechanisms.
Unfortunately, in many of the regions of the world where bird flu is spreading, countries lack the resources or expertise with deal adequately with the situation. Especially in parts of rural Asia and in Africa, there is minimal veterinary and health care infrastructure, and distribution of accurate information is difficult. A large problem is the difficulty in conveying the seriousness of the outbreaks to farmers who depend on poultry for their food and refuse to allow their poultry to be culled, especially in the absence of sufficient compensation.
Until 2005, the highest number of human cases of H5N1 infection occurred in Vietnam. Following an aggressive campaign of culling birds, Vietnam was able to restrict the expansion of human infections, and no new cases were reported in 2006 although seven new cases were reported in 2007. Vietnam has since been surpassed by Indonesia in the number of human cases and deaths. The first human case in Indonesia occurred in 2005, and by the end of 2007 there were more than 100 cases with over 90 deaths. Indonesia is one of the world’s most populous nations and home to over a billion chickens spread over thousands of islands. It has a limited public health system. The government did not react quickly to the first avian outbreaks and failed to cull birds. It will be a major challenge for authorities to contain the further spread of H5N1 in this island nation where the virus is now endemic in Indonesian poultry.
Virus Mutations
The analysis of the reconstructed flu virus from the 1918 pandemic indicates that the virus responsible for the deadly 1918 outbreak was likely an avian virus that jumped directly from birds to humans. It is a rare event – with an apparently much more lethal outcome - when an avian virus can directly infect humans and cause sustained transmission from person to person. More commonly, pandemics occur when human flu strains pick up some avian genetic sequences. The 1918 avian flu strain appears to have mutated just enough to become easily transmissible in humans - without the need for any human flu genetic material. It is worrisome to scientists that the current H5N1 virus appears to have picked up some, although not all, of the same genetic mutations that allowed the 1918 flu to pass easily from person to person. However, scientists cannot predict whether the H5N1 will continue to acquire the mutations necessary for human transmission, when this might occur, or if the outcome would be as deadly as the 1918 pandemic.
A troubling development has been small clusters of human H5N1 infection, especially in Indonesia. In these cases, infections appear to have been transmitted from an infected individual to others having prolonged, close contact such as family members or caregivers. To date, only one of these cases has been confirmed as human-to-human transmission. Because all the cases involved close contact for an extended period of time, this situation, while worrisome, does not signal that the virus has mutated in such a way that allows it to spread easily through a community.
Although there have not been many cases where H5N1 is suspected of passing from person to person, the extreme changeability of influenza causes grave concern that the current form of H5N1 will mutate to a form that is easily transmitted. With each new case of human infection, the virus has the opportunity to acquire mutations that could allow it to spread more easily between people.
There is also concern that the virus may be becoming more pathogenic. In Vietnam, one of the first countries to report human H5N1 infections, the death rate was 45 percent. In Indonesia, which reported its first human case of H5N1 infection in 2005, the fatality rate is 80 percent. However, the higher mortality rate could reflect a limitation of resources in Indonesia.
If transmission of H5N1 among humans becomes sustained, it is likely that a pandemic would result. Because this is a new form of influenza virus that has not previously existed in the human population, people will have little immunity to H5N1, and high rates of illness and death could occur. The possibility that other avian flu strains, such as H7N2 or H9N2, could mutate and become more pathogenic and transmissible is also a concern. However, viruses usually become less pathogenic once they acquire the changes to let them spread more easily, so the mortality rate of H5N1 would likely be lower than it is now.
Antiviral Drugs and Vaccines
There are four different antiviral drugs that are effective against influenza, but sometimes influenza can become resistant to these drugs, so that the drugs are no longer effective. Some of the strains from people infected with H5N1 in Vietnam and Thailand are already resistant to two of these drugs. Furthermore, it is unclear if sufficient stockpiles of anti-influenza drugs can be produced in time to protect the population in the event of a pandemic. Although many countries, including the United States, are stockpiling antiviral drugs, in the event of an outbreak, the drugs would have to be distributed rapidly to sites of outbreaks. In cases of limiting amounts of antiviral drugs, decisions will have to be made as to how to prioritize the doses.
A vaccine has recently been shown to induce antibodies to the circulating strain of H5N1 at a level that may be protective, but high doses of the vaccine were required to do so. Vaccine production can be problematic even during normal influenza epidemics (as was apparent during the 2004 -2005 flu outbreak), so it is yet unclear if the vaccine could be produced rapidly enough and in sufficient quantities to protect people from H5N1 infection. Furthermore, changes in the virus could render the current vaccine ineffective. It is a challenge for the vaccine industry to produce large quantities of new vaccines very quickly or to be able to produce a vaccine that would be protective against different variants of the virus.
Surveillance and a rapid, coordinated response will be critical in controlling a new influenza pandemic. Antivirals and vaccines need to be rushed into areas where small outbreaks occur and administered quickly in an attempt to curb further spread of the virus. However, this is a very difficult undertaking, especially in rural and poor areas of Asia and Africa with limited resources and health facilities.
Historically, influenza pandemics occur about three to four times each century. Experts believe that another influenza pandemic is inevitable. Scientists do not know if the next pandemic is imminent or if it will be caused by H5N1 or another influenza strain. However, the world needs to be ready to use our current knowledge and technology to prevent a recurrence of the massive illness and death that occurred during the pandemic of 1918.
The Research
Investigators in the Department of Molecular Virology and Microbiology ( MVM ) at Baylor College of Medicine ( BCM ) have been studying influenza for many years with an Influenza Research Center first being established in 1974. A major focus of their effort is currently 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.
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, occasionally, 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. There is increasing concern that a new pandemic caused by avian flu will occur soon.
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.
Courtesy: CDC/
James Gathany
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.
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 , Thomas Cate, 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.
A newly initiated study by Dr. Andrew Rice and colleagues will investigate 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 and cellular migration. 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. Once the identities of the PDZ proteins are known, these investigators will study the functional consequence of the interaction between the avian influenza virus NS1 protein and the cellular PDZ proteins. A further goal 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.
For more information:
http://pandemicflu.gov/ - U.S. Government avian and pandemic flu information
http://www.cdc.gov/flu/avian/ - information on avian influenza from the Centers for Disease Control and Prevention (CDC)
http://www3.niaid.nih.gov/healthscience/healthtopics/Flu/default.htm - influenza information from the NIAID Division of Microbiology and Infectious Disease website
http://www.who.int/topics/influenza/en/ - information on influenza from the World Health Organization (WHO)
http://www.who.int/csr/disease/avian_influenza/updates/en/index.html - situation updates on avian influenza from the WHO
http://www.who.int/csr/disease/avian_influenza/country/en/ - reports on the cumulative number of confirmed human cases of avian influenza A/(H5N1) reported to the WHO
http://www.bcm.edu/news/features/item.cfm?newsID=746 - information from the Flu Center at Baylor College of Medicine
http://www.bcm.edu/findings/vol4/is6/06jun_n2.html - Answers to frequently asked avian flu questions from Dr. Paul Glezen.
http://www.declanbutler.info/Flumaps1/Timeseries.kml - Google Earth's time lapse of the spread of Avian Flu (Google Earth must be installed first)