Influenza Virus (Flu)

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 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 17 different versions of HA and 10 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 and H3N2 are in general circulation in people. Other combinations circulate in animals, such as the H5N1 virus found in birds. The subtypes that exist within a population change over time. For example, the H2N2 subtype, which infected people between 1957 and 1968, is no longer found in humans.

Influenza virus has a rounded shape (although it can 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.

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.

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. When a pig becomes infected with both the human and duck influenza subtypes at the same time, the segments of both viruses are scrambled or reassorted. inside an infected pig cell. As a result, a human virus particle could assemble that contains the duck HA segment instead of the human HA segment. A new virus subtype has been created. This new subtype could 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 could continue to change to allow it to spread more easily in its new host, and widespread illness and death could result.

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, also known as seasonal flu, occur annually and are the most common emerging infection among humans. These epidemics have major medical impacts, but they are generally not fatal except in certain groups such as the elderly.

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). The new subtype often causes serious illness and death, even among healthy individuals, and 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 that caused the deaths of two million people, while the 1968 pandemic resulted from an H3N2 strain that killed one million people.

One pandemic has occurred so far in the 21st century. This was due to the novel swine-origin H1N1 virus which emerged in 2009.

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.

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. 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 Aug. 10, 2010.

Influenza naturally infects wild birds all around the world, although they usually do not become ill. The virus is very contagious, however, and it can become a problem when the virus is transmitted to domesticated birds, such as chickens, ducks, or turkeys, because domesticated poultry can succumb to illness and death from influenza.

Humans generally do not become infected with avian flu. That 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 particular outbreak is influenza A subtype H5N1.

Since 1997, H5N1 infections in birds have spread, initially throughout Asia. Then as birds traveled along their migratory routes, H5N1 dispersed to Russia and Europe, and later to countries in the Middle East and on the African continent.

Most human cases of H5N1 influenza have been traced to direct contact with infected poultry, but there have been a few cases of person-to-person transmission, particularly in clusters where multiple family members became infected.

One reason why avian H5N1 is not readily transmissible among people has to do with the hemagglutinin, or HA, protein of the virus that determines which cell type the virus can enter. 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. 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.

As of July 2015, there have been some 840 laboratory-confirmed cases of H5N1 infections in humans, in 16 different countries, and close to 450 deaths. The countries with the overall highest case numbers are Egypt, where almost all cases in 2015 have occurred, followed by Indonesia and Vietnam.

H5N1 continues to circulate in poultry, and small and sporadic clusters of human infections are still occurring. However, H5N1 currently does not transmit easily between people, so the risk of a large outbreak is low at this time.

Highly pathogenic H5 avian virus infections were first reported in birds in the United States in December 2014. Over approximately the next six months, more than 200 findings of infection with H5N2, H5N8, and H5N1 viruses were confirmed, mostly in poultry including backyard and commercial flocks. More than 40 million birds in 20 states were either infected or exposed. No human infections by these H5 viruses have been reported in the United States, but their presence in birds makes it more likely than human H5 infections could occur in the United States. Individuals having close contact with live infected poultry or surfaces contaminated with the avian influenza viruses are at highest risk of infection in places where the viruses circulate. There have been no reports of infection occurring from eating properly cooked poultry.

In addition to the H5 viral subtypes, 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.

In March of 2013, a new subtype of avian influenza was found to infect humans. Influenza A (H7N9) had previously been detected in birds, but this particular variant had never been seen before in humans or animals. The initial wave of H7N9 infections occurred in the spring of 2013 in China, followed by a larger, second wave in the first half of 2014 in China and a few neighboring countries. As of February 2015, approximately 570 cases and 210 deaths have been reported to the WHO, mostly in China. People in the majority of cases had exposure to infected poultry or contaminated environments. The H7N9 virus causes a severe respiratory illness in most infected people, but it currently does not appear to spread easily from person to person.

Swine influenza, or swine flu, is a very contagious respiratory disease of pigs. Although pigs become ill, they generally do not die from swine flu viruses.

In April of 2009, an influenza virus originating in swine was discovered to be capable of infecting humans and spreading from person to person. The new virus is named influenza A (H1N1), although it is commonly referred to as swine flu. 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 is 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. Reassortment of segments from these different viruses produced a unique virus that had not been seen before by the human population. When novel viruses like this emerge, natural immunity is usually limited or nonexistent in humans.

The H1N1 influenza virus outbreak originated in Mexico in early 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, with a second wave commencing in late August as children and college students returned to classes. The outbreak peaked in October of 2009, with flu activity reported in all 50 states, as well as numerous other countries and territories. By January 2010, flu activity had returned to below baseline levels.

The H1N1 virus continues to circulate at low levels, but it is no longer the dominant influenza strain, and its behavior more closely resembles a seasonal influenza virus than a pandemic flu.

From the time the outbreak began in April 2009 through April 2010, the CDC estimated that about 60 million Americans became infected with the H1N1 virus, 265,000 Americans were hospitalized and 12,000 deaths occurred as a consequence of the 2009 H1N1 flu. The highest hospitalization rates occurred in young children. 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. 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 had an increased risk of severe and fatal illness.

There were some 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. Second, a much larger percentage of H1N1 patients exhibited symptoms of vomiting and diarrhea than is common with regular seasonal flu. There were also more reports of severe respiratory disease, especially in young and otherwise healthy people, infected with the new H1N1 virus than with seasonal flu viruses.

Significantly, 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 percent of severe and lethal cases occur in people over the age of 65. Deaths among the elderly accounted for only 11 percent of H1N1 deaths.

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. Later, some doses went unused.

Although some had concerns about the safety of the H1N1 vaccine, flu 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.

Historically, influenza pandemics arise about three to four times each century. The most recent pandemic, and the first of the 21st century, occurred in 2009, some 40 years after the previous pandemic. The 2009 H1N1 flu, commonly known as swine flu, spread around the globe faster than any virus in history, largely due to air travel.

Pandemic flu strains are of deep concern because there is no or only limited natural immunity to novel flu strains, and therefore nearly everyone is susceptible to infection. 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 was not an especially virulent virus. Further, the virus remained stable and did not mutate 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 of that year and went on 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.

Currently, there is concern about the new avian H7N9 virus. Most patients have experienced severe respiratory illness, with about one-third of the cases resulting in death. Although the virus does not appear to pass easily from person to person, there is always the worry that it could mutate into a form that is more transmissible.

There are drugs that are effective against influenza, but the possibility that a virus could acquire resistance to the drugs is a serious issue. 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. 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. Clearly, a more rapid method of vaccine development is needed. The goal of developing a universal flu vaccine, one that would provide durable protection against multiple flu strains, remains a challenging feat.

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.

MVM investigators would like to better understand epidemic 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.

Specifically, to gain this knowledge scientists are engaged in the following projects:

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 flu strains that could cause a pandemic.

Researchers have been testing vaccines against H1N1, H5N1, H7N9, and other potential pandemic flu strains and analyzing the immune responses of different people to the vaccines.

Specific projects include the following:

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.