What Is the Influenza (Flu) Vaccines?
Influenza (flu) vaccines are nasal sprays or injections currently composed either of live flu viruses that have been attenuated (rendered much less able to cause infection) or killed viruses or virus components (both are unable to reproduce) that, when administered to individuals, generate an immune response that will be strong enough to protect that individual from developing influenza disease. The design of the vaccine depends on how it is usually administered; the live attenuated vaccine is usually administered by a nasal spray (intranasal), while the killed virus is usually administered by an intramuscular injection (shot), usually into the deltoid (arm) muscle. There is a vaccine also available for intradermal injection. People cannot get the flu from the injected vaccine because the vaccine contains no live virus. However, nasal sprays use attenuated viruses (meaning that the viruses are live but cannot effectively cause disease) that, in some people (immunosuppressed people), may cause mild flu-like symptoms. (Note that nasal spray vaccines are currently not recommended because of poor immune responses as compared to those from the shots.)
Flu vaccines can be quite different based on the viral type (or strains of the flu virus) used to make the vaccine. For example, seasonal vaccines usually are now made up of a combination of four different influenza viruses (flu strains that differ in some of their surface molecules), although the trivalent (three flu strains) vaccine is still available. Experts choose the viruses in each year's vaccine because the chosen strains represent the most likely viruses to emerge in an upcoming flu season.
Pandemic flu vaccines are created in response to a specific strain of flu virus that is causing widespread disease. They differ from seasonal vaccines in several ways. First, the vaccines are usually made from new flu virus, not detected in previous flu seasons by flu experts and not included in the seasonal flu vaccines. These flu viruses are usually so new that they are not easily recognized by most human immune systems and quickly spread globally. Pandemic flu vaccines contain only a single strain of the pandemic virus (for example, H1N1 virus) instead of the usual three (trivalent) flu types used in a seasonal vaccine mixture. Seasonal vaccines are synthesized and distributed before the start of flu season (designated as October 4 each year until May of the following year) while pandemic vaccines, unfortunately, have to be synthesized and distributed only after the pandemic virus has been identified and started its global spread.
Until 2013, all commercially available flu vaccines were made from viruses cultivated in chicken eggs and then collected, purified, tested for safety and efficacy, and once approved, distributed to care providers. This process usually takes about six months to accomplish, which gives a pandemic flu virus a long time to circulate and infect populations before a vaccine can be developed. In 2013, Flublok was approved for use. This vaccine is a trivalent vaccine made from insect cells that have recombinant DNA that produces viral proteins in an egg-free system. Future vaccines may be synthesized differently like Flublok. Current techniques are time-consuming, expensive, and yield vaccines that usually protect against only those viral strains present in the vaccine; the protection does not extend to the wide spectrum of flu virus strains. This limited protection is the reason that new flu vaccines are developed each year
What Is the History of Flu Vaccine Development?
In 1933, researchers discovered that viruses (influenza virus types A, B, and rarely C) cause influenza (flu). Prior to 1933, a bacterium named Haemophilus influenzae was thought to cause the flu. In 1938, Jonas Salk and Thomas Francis developed the first vaccine against flu viruses. This first flu vaccine was used to protect the U.S. military forces against the flu during World War II. Dr. Salk used his experience with influenza vaccine to develop an effective polio vaccine in 1952. Vaccines produced from the 1940s to the 1960s were not as purified as more modern vaccines, and the impurities in vaccines were thought to contribute to side effects such as fever, aches, and fatigue. Since these symptoms were similar to those that accompanied the flu (flu symptoms usually were more severe and lasted longer), people mistakenly thought they got the flu from the vaccination. However, they did not get the flu from the vaccines since the vaccines used killed virus.
In a public vaccination program designed to prevent a pandemic swine flu outbreak in 1979, only a small percentage of people in the United States were vaccinated. Unfortunately, the 1979 vaccine was associated with a small increased risk of Guillain-Barré syndrome, a serious neurological condition, with the risk estimated to be one to nine excess cases per million doses of vaccine, but no cause for this increase in risk was ever discovered. Fortunately, no pandemic developed, and the vaccination program for that flu virus was cancelled. Since that time, vaccine purification has been improved, and millions of people have continued to be vaccinated every year. Currently, influenza viruses are inoculated into eggs, where they multiply. Afterward, they are harvested and separated from most egg particles and egg antigens. For years, the American Academy of Pediatrics and the ACAAI (American Academy of Allergy, Asthma and Immunology) recommended that egg-allergy patients avoid the vaccine. However, studies have revealed that the influenza vaccine does not contain enough egg protein to trigger an allergic reaction. Consequently, in the 2017-2018 flu season, there is no need to be concerned about allergic reactions to proteins according to the ACAAI and others. Attenuated viruses (for nasal spray like FluMist) are grown similarly, but strains are selected that only replicate under cool or cold temperatures so they can survive in the cool nasal passages long enough to stimulate an immune response but do not easily replicate and spread to warmer body regions like the lungs.
Because of the potential for widespread infection and deaths that the H1N1 pandemic virus strain seemed to possess, the H1N1 tests were accelerated so that the vaccine could be provided before the usual six-month timeline. However, all of the steps (cultivation, safety, efficacy, approval, and distribution) were done in the same way as for seasonal vaccines but over a shorter time period with fewer people involved in the initial trials. Tested and approved H1N1 vaccine started to become available in late September 2009 (in Europe) and in October 2009 in the Americas and Asia.
A major change in terminology (naming conventions for influenza vaccines) occurred in the 2014-2015 vaccine year. The new terminology (presented in bold type) is as follows:
- TIV (trivalent inactivated influenza vaccine) has been replaced with IIV (inactivated influenza vaccine) and has two subclasses; IIV3 which stands for egg-based and cell-culture-based trivalent inactivated influenza vaccines while IIV4 represents egg-based quadrivalent inactivated influenza vaccine.
- RIV is recombinant hemagglutinin influenza vaccine available as a trivalent form (RIV3).
- LAIV is live attenuated influenza vaccine, available as a quadrivalent formulation (LAIV4).
- The prefix cc means vaccine is cell-culture based (for example, ccIIV3).
- The older abbreviations LAIV, IIV, and RIV now indicate vaccine categories while the number at the end (suffix) represents the number of antigens in the vaccine (for example, IIV3 represents inactivated influenza vaccine with three antigens).
- Wash hands frequently with soap and water.
- Avoid touching one's eyes, nose, or mouth before washing one's hands.
- Avoid close contact with people who are ill.
- Do not share clothes or other personal items with another person during a flu outbreak.
- Those infected with influenza should stay at home for 24 hours after fevers have resolved.
The best means of preventing the flu is getting an influenza vaccination. The CDC recommends an annual flu vaccine for everyone 6 months of age and older. Two general types of vaccines are available. One is the injectable vaccine (known as the flu shot) made from inactivated virus. The flu shot contains only killed influenza viruses A and B. The other is a live attenuated, or weakened, virus that is squirted into the nose. This is called intranasal vaccine or nasal spray vaccine. The intranasal form is available for certain people who may prefer it to a shot, and it is approved for people from 2 through 49 years of age. It is not recommended for people who are immunosuppressed or have other conditions.
Why Are There New Flu Vaccines Each Year?
Although only a few different influenza virus strains circulate in human populations at any given time, people may continue to become ill with the flu throughout their lives. The reason for this continuing susceptibility is that the eight RNA strands that comprise the influenza virus genome are continually mutating through the mechanisms of antigenic shift and drift. Antigenic drift is a series of mutations that occurs over time and causes a gradual evolution of the virus. Antigenic shift is an abrupt change in the RNA genome that usually results in significant changes in the hemagglutinin and/or the neuraminidase proteins (surface components of the flu virus). In this case, a new subtype of the virus suddenly emerges. Influenza A virus mutates the most with both of the mechanisms, while influenza B changes mainly by the slower process of antigenic drift and doesn't cause pandemics like influenza A.
Each year, the seasonal vaccine is updated to include the most current influenza virus strains that are infecting people worldwide. The fact that influenza viral genes continually change is one of the reasons vaccine must be taken every year, because often the immune response to one flu viral strain will not protect against other flu strains. Another reason is that antibodies produced by the host in response to the vaccine decline over time, and antibody levels are often low one year after vaccination. However, within about two weeks of receiving the vaccine, most people are protected against the viral strains that compose the vaccine. Vaccines produce immunity that lasts for at least a year; some people are protected by the vaccine against the strains of viruses for many years. Although most individuals need only one vaccine administration (flu shot) per year, children aged 6 months to 8 years are recommended by the Centers for Disease Control and Prevention (CDC) to obtain two doses. Please see the section on viral strains and vaccine producers in this article for the current composition of flu strains used in the 2017-2018 seasonal flu vaccines.
What Are Indications for Intramuscular and
Intradermal Flu Vaccines?
The nasal spray vaccine was approved for use in healthy people 2-49 years of age who are not pregnant. The term FluMist is used for the seasonal flu nasal spray vaccine. LAIV does not contain thimerosal or other preservatives. Because of the poor performance as a vaccine, the FluMist nasal mist vaccine has not been recommended in recent years by the CDC and others.
What Are Indications for the Nasal-Spray Flu Vaccine (FluMist, Live Attenuated Influenza Virus or LAIV)?
The nasal spray is approved for use in healthy people 2-49 years of age who are not pregnant. The term FluMist is used for the seasonal flu nasal spray vaccine. LAIV does not contain thimerosal or other preservatives. According to the CDC, the following people should not get the nasal-spray vaccine:
- People less than 2 years of age
- People 50 years of age and over
- People with a medical condition that places them at high risk for complications from influenza, including those with chronic heart or lung disease, such as asthma or reactive airways disease
- People with medical conditions such as diabetes or kidney failure
- People with illnesses that weaken the immune system or who take medications that can weaken the immune system
- Children <5 years of age with a history of recurrent wheezing
- Children or adolescents receiving aspirin therapy
- People with a history of Guillain-Barré syndrome that occurred after receiving influenza vaccine
- Pregnant women
- People who are allergic to any of the components of the nasal-spray vaccine
In addition, the package insert states that people allergic to gentamicin (Gentak, Garamycin), arginine, or gelatin should not use the nasal spray. These recommendations also apply to the new quadrivalent vaccines.
What Are Potential Side Effects or Reactions to Flu Vaccines and Flu Vaccine Safety (Seasonal and Pandemic)?
In general, all medications, including intramuscular, intradermal, and nasal-spray vaccines, have side effects and the potential for allergic reactions. For most medicines and vaccines, the side effects or reactions are infrequent and are minimal if they do occur. Consequently, the pros far outweigh the cons for vaccination. The seasonal and pandemic vaccines (including nasal sprays and intradermal vaccine) are no different. What is different about the side effects of flu vaccines is that the occasional side effects seen with all flu vaccines usually resemble the flu disease; a few people experience mild side effects, such as headache, nasal congestion, low-grade fever, sore throat, or muscle cramps; some individuals may experience short-term (hours to about a day) dizziness, nausea, and/or soreness or a mild rash at the inoculation site as vaccination side effects. Although these are short-lived, some people think they contracted the flu from the vaccine. This is a myth. The intramuscular and intradermal vaccines contain no live virus, so the vaccine cannot transmit the disease. Although the nasal-spray vaccines contain live virus, it contains weakened (attenuated) virus. The vast majority of viruses that are attenuated (altered so they will not replicate or do so poorly) will not be able to cause influenza in people with normal immune systems and good health because the attenuated viruses replicate poorly or not at all in these people. These side effects are most likely to occur in children who have not been exposed to influenza virus in the past, but they can occur in some adults.
Some of those vaccinated develop soreness and occasional redness at the injection site. Allergic reactions are rare. Intramuscular vaccine shots are usually mildly painful when injected into muscle tissue. The new intradermal shots use a very small needle and require 40% less viral antigen, and most people find them to be far less painful than the intramuscular shots.
How Effective Are Seasonal and Pandemic Flu Vaccines?
Flu vaccine effectiveness is judged by the ability of the vaccine to generate an immune response (measured by a blood test known as a hemagglutination-inhibition assay; protection is deemed effective if assay titer of antibodies reaches 1:40 or greater). This applies to both seasonal and pandemic flu vaccines. A titer of 1:40 is considered to be protective 21 days after vaccination. Vaccine efficacy also varies from one person to another; one person's titer could be different from another person's titer, even if both were given vaccine from the same batch.
Previous studies of healthy young adults have shown influenza seasonal vaccine to be 70%-90% effective in preventing illness. In the elderly and those with certain chronic medical conditions such as HIV, the vaccine is often less effective in preventing illness. However, studies show the vaccine reduces hospitalization by about 70% and death by about 85% among the elderly who are not in nursing homes. Among nursing-home residents, vaccine can reduce the risk of hospitalization by about 50%, the risk of pneumonia by about 60%, and the risk of death by 75%-80%.
However, experience with the vaccine, studied each year, can show a wide variation in effectiveness. The 2014-2015 vaccine demonstrated this point. The vaccine was designed to protect against those major flu viruses that emerged in 2014. Unfortunately, new strains arose in late 2014 so that the vaccine synthesized for the 2014-2015 season was only about 23% effective. However, the CDC still recommended utilization of the vaccine as it seemed to reduce the severity of the flu in people who were vaccinated but still became infected with the flu virus.
Nasal-spray vaccines may provide effective protection to some individuals 2-49 years of age. The effectiveness is less in the older population. FluMist nasal spray is not currently recommended by the CDC and the ACIP (Advisory Committee on Immunization Practices) of the CDC..
Effectiveness and safety of vaccines are continuously being monitored by the cooperative efforts of the FDA, CDC, and other institutions in the U.S.
Viral Strains and Producers of the Seasonal Flu Vaccines for
The following is the composition of the 2017-2018 vaccines as recommended by the FDA:
- Trivalent formulation influenza vaccines for the U.S. 2015-2016 influenza season contain the following:
- A/Michigan/45/2015 (H1N1)pdm09-like virus (updated)
- A/Hong Kong/4801/2014 (H3N2)-like virus
- B/Brisbane/60/2008-like (B/Victoria lineage) virus
- The FDA also recommended that quadrivalent influenza vaccines contain the above three strains and the following additional B strain:
- B/Phuket/3073/2013-like (B/Yamagata lineage) virus.
An extensive table that lists all the various flu vaccines, their manufacturer, age indication, and antigen formulations compiled by the CDC is available at https://www.cdc.gov/mmwr/volumes/66/rr/rr6602a1.htm#T1_down.
Caregivers are strongly advised to read the package inserts to check for indications and contraindications before administering any type of vaccine, especially new vaccines, as sometimes the indications for use and contraindications change. Readers are advised to view an extensive table (http://www.cdc.gov/flu/protect/vaccine/
vaccines.htm) that the CDC developed for each vaccine type and producer to describe the individual features of each vaccine. In addition, there are updates made occasionally about who should get what type of vaccine.
In August 2014, the FDA approved use of a jet injector for flu vaccination. The jet injector uses high-pressure fluid to penetrate the skin instead of a hypodermic needle and can be powered by gas or springs. A trivalent vaccine (Afluria) is used in the injector and can be used in people 18-64 years of age.
Thimerosal and Mercury in Seasonal and Pandemic Vaccines
Thimerosal is a preservative that contains mercury and is used in multidose vials of conventional and pandemic flu vaccines to prevent contamination when the vial is repeatedly used to extract the vaccine. Although thimerosal is being phased out as a vaccine preservative, it is still used in flu vaccines in low levels. There is no data that indicate thimerosal in these vaccines has caused autism or other problems in individuals. Consequently, the FDA has indicated the following:
- There is no convincing evidence of harm caused by the small doses of thimerosal preservative in influenza vaccines, except for minor effects like swelling and redness at the injection site.
- A study of influenza vaccination examining over 2,000 pregnant women demonstrated no adverse fetal effects associated with influenza vaccine.
However, single-dose vials and the nasal-mist formulations of both the seasonal and pandemic vaccines contain no thimerosal. These vaccine options are available to individuals who still want thimerosal-free vaccine. In addition, the new intradermal vaccine has no thimerosal. For thimerosal levels in flu vaccines, the reader should see the CDC table in the reference http://www.cdc.gov/flu/protect/vaccine/
vaccines.htm under "mercury content."
What Is the Value for Individuals Getting Seasonal and Pandemic Vaccine?
The best chance for protection against seasonal (conventional) and pandemic flu is vaccination. The value for getting vaccinated is very high for many individuals and even for the world's population. For individuals, seasonal flu often causes about 12,000 to 56,000 deaths in the U.S., with about 140,000 to 710,000 people hospitalized every year. There are from 9.2 million to 35.6 million flu illnesses in the U.S. population gets the seasonal flu each year and misses school, work, and vacation time, while productivity nationwide can decline. Seasonal flu takes the lives of our population 65 years of age and older; about 90%-95% of seasonal flu deaths occur in this age group. Without yearly seasonal flu vaccine, the illness and death rates would likely be much higher.
Pandemic flu in some instances can be far worse on world populations than seasonal flu. For example, the Spanish flu or 1918 flu pandemic killed about 45 million to 100 million people from 1918-1920. Commerce, economic systems, and travel were shut down in many areas of the world for months at a time during those years. In the recent H1N1 pandemic that began in Mexico in April 2009, the disease caused deaths "out of the usual flu season" and caused a shutdown in travel to Mexico that brought the country economic hardship. For many individuals, pandemic H1N1 flu was just a nuisance that makes people feel feverish and tired with sneezing and coughing that lasts for about a week; they recovered without any problems. For others, the pandemic H1N1 flu was disastrous and deadly. The H1N1 virus has behaved quite differently from the seasonal flu. It began in April 2009 (near the end of the seasonal flu season) and spread worldwide by September. H1N1 flu affected a different population than the seasonal flu. It caused the hospitalization and deaths of a markedly younger population (pediatric population, pregnant individuals, and young adults). Worldwide, H1N1 vaccine became available in limited amounts in late September and early October 2009. The H1N1 vaccine was initially given to those people at highest risk for complications (pediatric/children, pregnant women, caregivers). Researchers suggest the H1N1 vaccine was effective in reducing the effects of this flu virus, even though it was not as deadly as first estimated.
Vaccination against seasonal flu and the infrequent pandemic flu (1918 [no vaccine], 1957, 1968, and 2009) has been improved since it was first tried in the 1940s. Vaccination provides the best chance (about 70%-90%) to prevent the symptoms and complications (including pneumonia) of influenza infection from developing; the value of vaccinations is in the numbers of people who live and do not get sick from the disease because they were successfully vaccinated.
In the future, vaccines may be made differently; however, the vaccine hastily made in 2009 to protect people from H1N1 was deemed successful and can serve as a vaccine synthesis method until newer and faster vaccine synthesis methods are widely accepted.
Where Can People Obtain the Flu Vaccine?
Seasonal vaccines are usually available at most physician offices, urgent care clinics, and in the past few years, from some pharmacies (usually associated with pharmacy chains and grocery stores). Availability for the new flu seasonal vaccine starts in the late summer or early fall and if demand is normal, supplies are available well into the spring of the following year. This is not the situation for pandemic flu. As seen with the 2009 H1N1 pandemic, vaccine was not readily available and was rationed out to specific distribution sites that were tasked to vaccinate the most susceptible individuals initially until vaccine production was adequate to allow broad distribution. It is possible such circumstances could reoccur. If you need or want a specific vaccine, it is best to call the clinic, doctor's office, pharmacy or other health care professional to determine if the vaccine you want is available.
In fact, another influenza A H3N2v strain was noted in 2012 to be transmitted from pigs to humans. Fortunately, it causes symptoms similar to the seasonal flu, but there is no current development into a strain that becomes easily transmitted from person to person.
Future Flu Vaccines
There are many researchers looking for ways to protect humans with vaccines against both seasonal and pandemic flu outbreaks. It is likely that new developments in vaccine synthesis and production will be used in the next few years, like the recombinant DNA Flublok vaccine introduced for the 2013-2014 flu season; it is available in both the trivalent and quadrivalent vaccine formulations in 2017. Hopefully, future vaccines will remain effective for many seasons.
Reviewed on 5/23/2018
Medically reviewed by Joseph Palermo, MD; Board Certified Internal Medicine/Geriatric Medicine
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