Flu in the 21st Century

Written in collaboration with Brigitte Hurtubise and Sophie Turrell

Flights grounded, business interrupted, animals slaughtered, large gatherings discouraged, and quarantines enacted. Millions of people dead. While this may sound like a nightmare scenario scripted by Hollywood, these events have actually happened -- and may again as a result of a flu pandemic.

But it doesn't take a highly lethal form of flu to have a life-threatening impact. Since 1976, the seasonal flu (the effects of which vary greatly by season) has killed between 3,000 to 49,000 people (1) in the United States every year and as many as 500,000 annually worldwide, according to the Centers for Disease Prevention and Control (CDC) and the World Health Organization (WHO) (2,3).

Ninety percent of deaths from the flu are in persons aged 65 and older (4). In the 2009-2010 U.S. flu season, there were a total of 2,125 deaths from seasonal flu and an estimated 12,000 from H1N1 (5,6) -- a number that is comparable to the U.S. yearly death rate from AIDS (7). Every year 25 to 50 million people acquire influenza in the U.S. and 225,000 of them are hospitalized for the illness (8). A recent CDC report suggests that the number of flu cases is higher than expected in several states for this time in the season (9). The flu's economic impact is also significant, costing an estimated $87 billion annually in the United States, mostly due to lost wages and productivity (10). Clearly, this is not a disease that can be ignored.

Flu pandemics increase the health, economic and societal impact of this illness exponentially. Here's why: a pandemic is a massive, prolonged, and widespread disease outbreak on the global level. An influenza pandemic occurs when a new influenza virus strain emerges for which there is little or no immunity in the human population, causing illness and spreading easily from person-to-person. Pandemics can be relatively mild, like last year's HIN1 outbreak, or they can be catastrophic.

The 1918 "Spanish flu" pandemic killed an estimated 50-100 million people worldwide, far more fatalities -- soldiers and civilians -- than in all of WWI (11). Pandemic influenza viruses often do not follow the seasonal patterns of peaking in December through February in the northern hemisphere and in June through August in the southern hemisphere. Instead, pandemics can peak in both hemispheres during the same time period (12). Nor do they necessarily follow other epidemiological patterns of seasonal flu; last year's H1N1, for instance, had higher mortality rates in young adults than in older persons (13).

The economic impact of pandemics is much greater than for seasonal strains. Within a few days of the H1N1 influenza being declared a pandemic in 2009, public speculation about the potential impact of the illness caused crude oil prices, industrial metals, and hog futures to drop and sent stock markets tumbling. Schools closed, flights were cancelled, and tourism slowed. In today's era of globalization, the H1N1 outbreak underscored that an infectious disease is just a jet plane away threatening the health and economies of countries around the world.

Furthermore, flu pandemics are hardly a phenomenon of the past. In fact, a novel pandemic strain of the flu emerges about every 30 years. Just 1½ years ago, the 2009 flu season extended far beyond the usual winter months because of the H1N1 2009 pandemic strain, ending instead on August 10, 2010 (14). The virus infected millions and killed thousands, though so far, the death toll is far below what many health experts feared. However, since pandemic flu is known to outbreak in waves, which can be spread over months or years (as was the case with the Spanish Flu pandemic, consisting of four waves from 1918 to 1920, each increasing in lethality) (15), we must remain vigilant.

Small but can be deadly: the H1N1 virus.

Another alarming piece of news came in November 2010, when a woman was hospitalized with H5N1 avian flu in Hong Kong. The strain of H5N1 that is currently circulating is often referred to as "avian flu" because it is occurring in bird populations, killing most of the birds that contract it globally. On December 31, 2010, South Korea confirmed cases of H5N1 in poultry farms in two cities, although so far there have been no human cases reported there (17) . Japan went on high alert in December as several wild birds in different regions were found dead from a virus that appeared to be H5N1 (18).

Tens of thousands of birds have been slaughtered in meat prefectures where outbreaks of the virus have occurred this year (19). In January, 2011, the WHO confirmed four more cases of H5N1 human infection in Egypt. Health experts worry that the virus could enter the human species in the future through bird-to-human transmission most likely in a region of the world where humans and birds live in close proximity (20).

Many developing countries, where these new diseases often originate, have inadequate public health infrastructure and are limited in their ability to respond effectively to a flu pandemic because they lack adequate surveillance capabilities, sufficient numbers of health care workers, laboratories, vaccines, medications, and other resources. Since 1997, there have been 510 human H5N1 cases reported in fifteen countries in Asia, the Middle East, and Africa (21). Indonesia has reported 171 cases, the most of any nation worldwide, and seven countries have had fewer than five reported cases (22). Despite the relatively low-level of human infections, this strain of the virus is worrisome because of its high mortality rate: of the 516 confirmed cases globally, 306 (nearly 60 percent) have died (23).

This is why the recent news from Hong Kong is so worrisome. Fortunately, as of yet, sustained human-to-human transmission has not occurred with this avian flu strain. Scientists monitor circulating flu strains to determine which are the most prevalent in preparation for formulating the next year's mix for the flu vaccine. According to a recent article in Nature (24), work is now underway to prepare for a possible future resurgence in the H2N2 strain, which circulated widely in the 1950s and 60s.

This year, the primary form of flu in circulation worldwide is the "garden variety" seasonal flu, which in actuality is numerous different strains that change every year. Today, international influenza occurrence is generally low but increasing in Canada and Europe with a recent marked rise in rates in Mongolia, the Republic of Korea, Sri Lanka, Madagascar and Cameroon. In the U.S., flu activity, which typically peaks in late January to February, has risen since the early fall, but there is a lower incidence of the flu this year (particularly the H1N1 strain) than there was last year (25).

However, despite the disease's severe consequences in some people, the flu is still viewed by many as a fairly mild illness. This year, 1/3 of mothers did not plan to have their children vaccinated and 25 percent of health workers also decided to forgo the flu vaccine, according to an October survey (26). Many people do not get vaccinated, even though it is relatively inexpensive (around $25) and easily accessible in the United States in venues such as pharmacies, supermarkets, doctors' offices, and hospitals.

Each year's vaccine protects against the three flu virus strains that experts believe will be most likely to circulate for the season. Those strains included in the 2010-2011 vaccine are well matched to the circulating flu viruses causing illness so far this year (27). While usually only the very young, elderly, and the medically ill die from the flu, it is still important for everyone over the age of 6 months (except those with chicken egg allergies or who have had a severe reaction to previous flu vaccines) to get immunized (28).

In addition to protecting people from becoming ill, vaccination helps prevent the spread of the virus particularly in vulnerable populations who may not be able to obtain the vaccine themselves. Vaccination helps prevent illness which could possibly cause others to miss school, work, be hospitalized or even die. Under the new health care legislation passed this year, the flu vaccine is fully covered as a preventive service for certain population groups by "non-grandfathered" insurance plans.

However, given the flu's impact, vaccine development and production are in urgent need of innovation. This is reflected in the first goal of the 2010 National Vaccine Plan: develop new and improved vaccines (29). The flu vaccine, the primary strategy for prevention, is manufactured in the same manner as 50 years ago -- a process in which chicken eggs, taken from flocks that must be kept biosecure (to ensure they do not become contaminated with avian flu or any other disease), are used to "grow" the virus, which is then either inactivated (in 90 percent of cases) or attenuated (rendering the virus weakened so as to not cause illness, but still elicit an immune response) (30).

This method is slow, taking between 4-9 months to be available for distribution. Additionally, sometimes there can be a lower than expected yield of HA protein (the protein that signals the immune system to respond when attacked by the flu virus), resulting in fewer doses of vaccine initially. Furthermore, there is currently not enough production capacity in the U.S. or worldwide to make sufficient vaccine to protect the global population.

During the 2009-2010 flu season, while many doses of the H1N1 vaccine went unused in the U.S., other nations were left rationing the few flu shots that could be obtained, leaving most of their population unprotected. For seasonal flu as well, many countries are left unprepared. Given current resource limitations (the need for biosecure chicken flocks, the limited number of manufacturers, and the length of the clinical trial and approval processes for the vaccine) the ability to manufacture enough vaccine for "surge capacity" is currently inadequate and would leave 80-90 percent of the world's population without immunization (31,32,33). The effectiveness of both methods of flu vaccine vary depending on the match between the viruses in the vaccine and those that are circulating during a particular flu season as well as individual factors such as the recipient's age and health status.

Thankfully, research is now underway to develop faster, better ways of producing flu immunizations as well as to design delivery mechanisms that can be used across age groups (e.g., nose drops, preservative free multi-dose vials) to further promote their use and availability. To be licensed, a new flu immunization must be shown to be safe and effective, to elicit antibodies, and to prevent influenza. In a recent paper published in the New England Journal of Medicine (34), researchers from the National Institutes of Health (NIH) described eight different strategies that scientists are exploring to improve flu vaccines in the 21st century:

1. Growing inactivated influenza vaccines in mammalian cell cultures rather than chicken eggs. Mammalian cell-culture has several advantages to the current method of vaccine production that uses chicken eggs. In the event of an avian influenza outbreak among chicken flocks, there may be insufficient egg supply to produce large quantities of vaccine; the cell culture method overcomes this limitation, giving manufacturers greater control over the production process and allowing them to increase surge capacity for vaccine production in the event of a pandemic (35,36). However, this technique may not significantly reduce the amount of time it takes to produce vaccines. A cell cultured live attenuated vaccine is currently in late-stage pre-clinical development but more work must be done before it can advance to clinical testing.

2. Enhancing the effectiveness and reach of existing vaccines with adjuvants. Adjuvants are substances (e.g. oils or aluminum salts) (37,38) that are added to vaccines to amplify the body's immune response to an antigen (e.g. a foreign particle such as a flu virus). The body's immune response to certain influenza strains may not be robust enough to protect it from the health damaging effects of the flu virus; adjuvants help to overcome this by stimulating the production of high levels of antibodies that can defend the body against the virus's infection. Additionally, adjuvants may act to expand the amount of vaccine available, since less of the active ingredient is needed per dose of vaccine, allowing limited supplies of active ingredient (e.g. purified virus protein) to be stretched over a greater volume of doses (39). While adjuvant based vaccines have been approved for use in Europe, they have not been approved by the FDA for administration in the United States. Currently, next generation adjuvants using purified bacterial outer membrane proteins and toll-like receptors are in the early stages of clinical testing in America.

3. Developing new live attenuated vaccines. In contrast to vaccines that contain the inactivated (killed) influenza virus, live attenuated vaccines contain a live virus that scientists have altered so that it stimulates the immune response without doing harm to the body. A promising candidate for this type of vaccine is based on altering or deleting the influenza NS1 protein, which works to prevent the virus from replicating while it enhances the body's immune system defenses.

4. Creating next generation vaccines with DNA recombinant techniques. Producing vaccines with DNA recombinant technology eliminates the need for chicken eggs or mammalian cell cultures, thereby significantly speeding up production time (40). When the genetic sequence of a particular influenza virus's HA (its distinctive outer marker) is identified, scientists can use this information to more rapidly produce a vaccine without having to adapt viruses to grow in eggs. They can use the DNA to create HA proteins in the lab for use in vaccines. A clinical trial of such a DNA recombinant vaccine for seasonal flu has recently been completed for use in people over the age of 18 and is currently under review by the FDA.

5. Utilizing non-infectious virus-like particles for vaccine production. This technique uses recombinant viral vectors to produce proteins found in the influenza virus, which then self-assemble to form particles that resemble wild-type viruses themselves but are non-infectious. The method is still under development but has reached testing in phase-2 clinical trials.

6. Using other harmless "carrier" viruses as vectors to deliver influenza proteins to the immune system. Not every virus causes disease in humans. This novel vaccination method uses harmless viruses that are still capable of entering human cells, piggybacking them with influenza proteins so that they will help the body develop immunity to the wild influenza virus. Early trials of nasal spray and pill versions of this type of vaccine are showing promise.

7. Creating DNA-based vaccines. Injecting DNA directly into the muscles of animals, where it subsequently encodes the critical HA or NA influenza proteins, has resulted in positive immune responses. So far, this technique has not worked as well in humans. Further research must prove the efficacy of DNA based vaccines in human studies before researchers proceed to scale up this prevention method.

8. Developing a "universal" vaccine. This approach, the "Holy Grail" of vaccine development, involves the creation of a "universal vaccine" capable of conferring long lasting immunity across multiple strains of the influenza virus. The flu virus is a wily adversary that mutates often. It is this frequent genetic misspelling of the influenza virus that makes it so hard to conquer; because the virus changes so often, a new vaccine must be developed every year to prevent its widespread transmission. But certain highly conserved virus proteins (those that tend to survive most mutations and are present across strains) could be the targets for a universal vaccine, and these are now the subject of several clinical trials (41). The question of whether lifelong protection against all strains of flu could be achieved with a universal vaccine remains unanswered. That is why research should also pursue a vaccine strategy that would confer full or partial protection with periodic immunizations against seasonal strains as well as emerging pandemic ones.

Researchers at Oxford have recently found a promising candidate to provide universal protection against the flu (42). The vaccinate targets T-cell production in the body, elicited by a protein less susceptible to mutation that sits on the inside of the flu virus, rather than the external proteins that current flu vaccines use. Preliminary results also show that the vaccine is more effective in older people than the traditional vaccine, a great breakthrough that would help the segment of the population that has the highest mortality rate from influenza (43).

The good news is that research is currently underway to revolutionize flu vaccine technology in the 21st century. Given the impact of the seasonal flu every year and the potential health and economic threat posed by a pandemic, this must be a public health priority. However, the long term safety and effectiveness of new approaches must be determined before these techniques can be mainstreamed.

While scientists pursue these new advances, currently available flu vaccines and healthy habits will continue to be the best defense against influenza. Everyone over the age of 6 months (there are some exceptions) should get vaccinated for the seasonal flu annually (protection against H1N1 is included in this year's vaccine) and practice good hygiene such as washing your hands, sneezing/coughing into the crook of your arm, and staying away from others if you are sick. Hopefully, with more public awareness and investments in scientific research and innovation, the nightmare scenario of a global flu pandemic will be found only in the history books.

Listed below are some steps that individuals, businesses and communities can take to protect against the flu:

For Individuals:

Practice good hygiene.

Wash your hands often with soap and water, especially after you cough or sneeze. Using alcohol-based hand cleaners is also an effective alternative.

Cover your nose and mouth with a tissue when you cough or sneeze and dispose of them afterwards. If tissues are not immediately available, use the crook of your arm.

Avoid touching your eyes, nose or mouth. Germs spread this way.

Try to avoid contact with sick people.

If you get sick, stay at home and limit contact with others.

Be alert to your symptoms and get help. H1N1 flu symptoms include fever, body aches, sore throat, cough, runny nose, lethargy and some cases, vomiting and diarrhea. If you exhibit any of these symptoms, seek medical attention immediately

Develop an emergency plan for your family in case of a pandemic outbreak including having supplies at home such as food and medical supplies.

For Businesses and Communities:

Develop pandemic flu preparedness plans as you would for other public health emergencies.

Participate and promote public health efforts in your state and community.

Talk with your local public health officials and health care providers; they can supply information about the signs and symptoms of a specific disease outbreak.

Implement prevention and control actions recommended by your public health officials and health care providers.

Adopt business/school practices that encourage sick employees/students to stay home.

Anticipate how to function with a significant portion of the workforce/school population absent due to illness or caring for ill family members such as telecommuting.

Provide current and updated health information for your employees.

Stay Informed -- Helpful Internet Resources Include:

CDC Seasonal Influenza Information

World Health Organization Influenza Information

Emergency Preparedness Information

*Rear Admiral Susan Blumenthal, M.D., M.P.A. (ret.) is the Huffington Post Public Health Editor. She is also the Director of the Health and Medicine Program at the Center for the Study of the Presidency and Congress in Washington, D.C., a Clinical Professor at Georgetown and Tufts University Schools of Medicine, Chair of the Global Health Program at the Meridian International Center, and Senior Policy and Medical Advisor at amfAR, The Foundation for AIDS Research. Dr. Blumenthal served for more than 20 years in senior health leadership positions in the Federal government in the Administrations of four U.S. Presidents, including as Assistant Surgeon General of the United States, the first Deputy Assistant Secretary of Women's Health, as a White House Advisor on Health, and as Chief of the Behavioral Medicine and Basic Prevention Research Branch at the National Institutes of Health. Admiral Blumenthal has received numerous awards including honorary doctorates and has been decorated with the highest medals of the U.S. Public Health Service for her pioneering leadership and significant contributions to advancing health in the United States and worldwide. She is the recipient of the 2009 Health Leader of the Year Award from the Commissioned Officers Association. Admiral Blumenthal was recently named a 2010 Rock Star of Science.
Brigitte Hurtubise, a recent graduate of the University of Pennsylvania, served as a Health Policy Fellow at the Center for the Study of Presidency and Congress in Washington D.C.

Sophie Turrell, a recent graduate of Yale University, is a Health Policy Research Associate at the Center for the Study of the Presidency and Congress in Washington, D.C.