U.S. Navy crew member having an influenza vaccination
|Target disease||influenza virus|
|Trade names||Fluarix, Fluzone, other|
|IM, intranasal, intradermal|
Influenza vaccines, also known as flu shots or jabs, are vaccines that protect against influenza. A new version of the vaccine is developed twice a year as the influenza virus rapidly changes. While their effectiveness varies from year to year, most provide modest to high protection against influenza. They decrease the number of missed days of work by a half day on average. Vaccinating children may protect those around them. The effectiveness in those under two years old and over 65 years old is unknown due to the low quality of the research.
The World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC) recommends yearly vaccination for nearly all people over the age of six months, especially those at high risk. The European Centre for Disease Prevention and Control also recommends yearly vaccination of high risk groups. These groups include pregnant women, the elderly, children between six months and five years of age, those with other health problems, and those who work in healthcare.
The vaccines are generally safe. In children, fever occurs in five to ten per cent, as may muscle pains or feeling tired. In certain years, the vaccine causes Guillain–Barré syndrome in older people in about one per million doses. It should not be given to those with severe allergies to eggs or to previous versions of the vaccine. The vaccines come in both inactive and weakened viral forms. The inactive version should be used for those who are pregnant. They come in forms that are injected into a muscle, sprayed into the nose, or injected into the middle layer of the skin.
Vaccination against influenza began in the 1930s with large scale availability in the United States beginning in 1945. It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system. The wholesale price in the developing world is about $5.25 USD per dose as of 2014. In the United States, it costs less than $25 USD.
- 1 Medical uses
- 2 Safety
- 3 Injection versus nasal spray
- 4 Recommendations
- 5 Uptake
- 6 Manufacturing
- 7 History
- 8 Society and culture
- 9 Research
- 10 Veterinary use
- 11 References
- 12 External links
The Centers for Disease Control and Prevention, recommend the flu vaccine as the best way to protect people against the flu and prevent its spread. The flu vaccine can also reduce the severity of the flu if a person contracts a flu strain that the vaccine did not contain. It takes about two weeks following vaccination for protective antibodies to form.
A 2012 meta-analysis found that flu vaccination was effective 67 percent of the time; the populations that benefited the most were HIV-positive adults ages 18 to 55 (76 percent), healthy adults ages 18 to 46 (approximately 70 percent), and healthy children ages six to 24 months (66 percent).
A vaccine is assessed by its efficacy; the extent to which it reduces risk of disease under controlled conditions, and its effectiveness, the observed reduction in risk after the vaccine is put into use. In the case of influenza, effectiveness is expected to be lower than the efficacy because it is measured using the rates of influenza-like illness, which is not always caused by influenza. Influenza vaccines generally show high efficacy, as measured by the antibody production in animal models or vaccinated people. However, studies on the effectiveness of flu vaccines in the real world are difficult; vaccines may be imperfectly matched, virus prevalence varies widely between years, and influenza is often confused with other influenza-like illnesses. However, in most years (16 of the 19 years before 2007), the flu vaccine strains have been a good match for the circulating strains, and even a mismatched vaccine can often provide cross-protection.
Trials of both live and inactivated influenza vaccines against seasonal influenza have been summarized in several 2012 meta-analyses. Studies on live vaccines have very limited data, but these preparations may be more effective than inactivated vaccines. The meta-analyses examined the efficacy and effectiveness of inactivated vaccines against seasonal influenza in adults, children, and the elderly.
The CDC recommend that everyone except infants under the age of six months should receive the seasonal influenza vaccine. Vaccination campaigns usually focus special attention on people who are at high risk of serious complications if they catch the flu, such as pregnant women, children over six months, the elderly, and people living with chronic illness or those with weakened immune systems, as well as those to whom they are exposed, such as health care workers.
As the death rate is also high among infants who catch influenza, the household contacts and caregivers of infants should be vaccinated to reduce the risk of passing an influenza infection to the infant.
In children, vaccines again showed high efficacy, but low effectiveness in preventing "flu-like illness". In children under the age of two, the data are extremely limited, but vaccination appeared to confer no measurable benefit.
In unvaccinated adults, 16% get symptoms similar to the flu, while about 10% of vaccinated adults do. Vaccination decreased confirmed cases of influenza from about 2.4% to 1.1%. No effect on hospitalization was found.
In working adults a review by the Cochrane Collaboration found that vaccination resulted in a modest decrease in both influenza symptoms and working days lost, without affecting transmission or influenza-related complications. In healthy working adults, influenza vaccines can provide moderate protection against virologically confirmed influenza, though such protection is greatly reduced or absent in some seasons.
In health care workers, a 2006 review found a net benefit. Of the eighteen studies in this review, only two also assessed the relationship of patient mortality relative to staff influenza vaccine uptake; both found that higher rates of health care worker vaccination correlated with reduced patient deaths. A 2014 review found benefits to patients when health care workers were immunized, as supported by moderate evidence based in part on the observed reduction in all-cause deaths in patients whose health care workers were given immunization compared with comparison patients in which the health care workers were not offered vaccine.
Evidence for an effect in adults over 65 years old is unclear. Systematic reviews examining both randomized controlled and case control studies found a lack of high-quality evidence. Reviews of case control studies found effects against laboratory-confirmed influenza, pneumonia, and death among the community-dwelling elderly.
The group most vulnerable to non-pandemic flu, the elderly, benefits least from the vaccine. There are multiple reasons behind this steep decline in vaccine efficacy, the most common of which are the declining immunological function and frailty associated with advanced age. In a non-pandemic year, a person in the United States aged 50–64 is nearly ten times more likely to die an influenza-associated death than a younger person, and a person over age 65 is over ten times more likely to die an influenza-associated death than the 50–64 age group.
There is a new high-dose flu vaccine specifically formulated to provide a stronger immune response. Available evidence indicates that vaccinating the elderly with the high-dose vaccine leads to a stronger immune response against influenza than the regular-dose vaccine.
Vaccinating health care workers who work with elderly people is recommended in many countries, with the goal of reducing influenza outbreaks in this vulnerable population. While there is no conclusive evidence from randomized clinical trials that vaccinating health care workers helps protect the elderly people from influenza, there is tentative evidence of benefit.
As well as protecting mother and child from the effects of an influenza infection, the immunization of pregnant women tends to increase their chances of experiencing a successful full-term pregnancy.
While side effects of the flu vaccine may occur, they are usually minor and the safety of flu vaccines is high. The flu vaccine can cause serious side effects, including an allergic reaction, but this is rare. Furthermore, the common side effects and risks of inoculation are mild and temporary when compared to the risks and severe health effects of the annual influenza epidemic's well-documented toll of illness, hospitalization, and death.
Flu vaccination may lead to side effects such as runny nose and sore throat, which can last for up to several days. Egg allergy may also be a concern, since flu vaccines are typically made using eggs; however, research into egg-allergy and influenza vaccination has led some advisory groups to recommend vaccine for those with mild allergies and monitored vaccination for those with severe. A large study of nearly 800 children in the UK with egg allergy, including over 250 with previous anaphylactic reactions, had zero systemic allergic reactions when given the live attenuated flu vaccine. On January 17, 2013, the U.S. FDA approved Flublok, a faster-turnaround influenza vaccine which is the first grown in insect cells instead of eggs. Since eggs are not used in its production, it avoids any problem with egg allergies.
Although Guillain–Barré syndrome had been feared as a complication of vaccination, the CDC states that most studies on modern influenza vaccines have seen no link with Guillain–Barré. Infection with influenza virus itself increases both the risk of death (up to 1 in 10,000) and increases the risk of developing Guillain–Barré syndrome to a far higher level than the highest level of suspected vaccine involvement (approximately 10 times higher by 2009 estimates).
Although one review gives an incidence of about one case of Guillain–Barré per million vaccinations, a large study in China, reported in The New England Journal of Medicine covering close to 100 million doses of vaccine against the 2009 H1N1 "swine" flu found only eleven cases of Guillain–Barré syndrome, (0.1 per million doses) total incidence in persons vaccinated, actually lower than the normal rate of the disease in China, and no other notable side effects; "The risk-benefit ratio, which is what vaccines and everything in medicine is about, is overwhelmingly in favor of vaccination." Several studies have identified an increased incidence of narcolepsy among recipients of the pandemic H1N1 influenza ASO3-adjuvanted vaccine, efforts to identify a mechanism for this suggest that narcolepsy is autoimmune, and that the ASO3-adjuvanted H1N1 vaccine may mimic hypocretin, serving as a trigger.
Some injection-based flu vaccines intended for adults in the United States contain thiomersal (also known as thimerosal), a mercury-based preservative. Despite some controversy in the media, the World Health Organization's Global Advisory Committee on Vaccine Safety has concluded that there is no evidence of toxicity from thiomersal in vaccines and no reason on grounds of safety to change to more-expensive single-dose administration.
Injection versus nasal spray 
Flu vaccines are available either as
- a trivalent or quadrivalent injection (TIV or QIV), which contains the inactivated form of the virus.
- a nasal spray of live attenuated influenza vaccine (LAIV, Q/LAIV), which contains the attenuated or weakened form of the virus.
TIV induces protection after injection (typically intramuscular, though subcutaneous and intradermal routes can also be protective) based on an immune response to the antigens present on the inactivated virus, while cold-adapted LAIV works by establishing infection in the nasal passages.
Various public health organizations, including the World Health Organization, have recommended that yearly influenza vaccination be routinely offered, particularly to people at risk of complications of influenza and those individuals who live with or care for high-risk individuals, including:
- the elderly (UK recommendation is those aged 65 or above)
- people with chronic lung diseases (asthma, COPD, etc.)
- people with chronic heart diseases (congenital heart disease, chronic heart failure, ischaemic heart disease)
- people with chronic liver diseases (including cirrhosis)
- people with chronic kidney diseases (such as the nephrotic syndrome)
- people who are immunosuppressed (those with HIV or who are receiving drugs to suppress the immune system such as chemotherapy and long-term steroids) and their household contacts
- people who live together in large numbers in an environment where influenza can spread rapidly, such as prisons, nursing homes, schools, and dormitories.
- healthcare workers (both to prevent sickness and to prevent spread to patients)
- pregnant women. However, a 2009 review concluded that there was insufficient evidence to recommend routine use of trivalent influenza vaccine during the first trimester of pregnancy. Influenza vaccination during flu season is part of recommendations for influenza vaccination of pregnant women in the United States.
World Health Organization
- Highest priority:
- Pregnant women
- Priority (in no particular order):
- Children aged 6–59 months
- Individuals with specific chronic medical conditions
- Health-care workers
In 2008, the National Advisory Committee on Immunization, the group that advises the Public Health Agency of Canada, recommended that everyone aged two to 64 years be encouraged to receive annual influenza vaccination, and that children between the age of six and 24 months, and their household contacts, should be considered a high priority for the flu vaccine. The NACI also recommends the flu vaccine for:
- People at high risk of influenza-related complications or hospitalization, including the morbidly obese, healthy pregnant women, children six to 59 months, the elderly, aboriginals, and people suffering from one of an itemized list of chronic health conditions
- People capable of transmitting influenza to those at high risk, including household contacts and healthcare workers
- People who provide essential community services
- Certain poultry workers
The European Center for Disease Prevention and Control recommends vaccinating the elderly as a priority, with a secondary priority people with chronic medical conditions and healthcare workers.
The influenza vaccination strategy is generally that of protecting vulnerable people, rather than limiting influenza circulation or totally eliminating human influenza sickness. This is in contrast with the high herd immunity strategies for other Infectious diseases such as polio and measles. This is also due in part to the financial and logistics burden associated with the need of an annual injection.
According to the CDC, the live attenuated virus (which comes in the form of the nasal spray in the US) should be avoided by:
- Children younger than two years
- Adults 50 years and older
- People with a history of severe allergic reaction to any component of the vaccine or to a previous dose of any influenza vaccine
- People with asthma
- Children or adolescents on long-term aspirin treatment.
- Children and adults who have chronic pulmonary, cardiovascular (except isolated hypertension), renal, hepatic, neurologic/neuromuscular, hematologic, or metabolic disorders
- Children and adults who have immunosuppression (including immunosuppression caused by medications or by HIV)
- Pregnant women
Within its blanket recommendation for general vaccination in the United States, the Centers for Disease Control and Prevention (CDC), which began recommending the influenza vaccine to health care workers in 1981, emphasizes to clinicians the special urgency of vaccination for members of certain vulnerable groups, and their caregivers:
- Vaccination is especially important for people at higher risk of serious influenza complications or people who live with or care for people at higher risk for serious complications. In 2009, a new high-dose formulation of the standard influenza vaccine was approved. The Fluzone High Dose is specifically for people 65 and older; the difference is that it has four times the antigen dose of the standard Fluzone.
The U.S. government requires hospitals to report worker vaccination rates. Some U.S. states and hundreds of U.S. hospitals require health-care workers to either get vaccinations or wear masks during flu season. These requirements occasionally engender union lawsuits on narrow collective bargaining grounds, but proponents note that courts have generally endorsed forced vaccination laws affecting the general population during disease outbreaks.
Vaccination against influenza is especially important for members of high-risk groups who would be likely to have complications from influenza, for example pregnant women and children and teenagers from six months to 18 years of age;
- In raising the upper age limit to 18 years, the aim is to reduce both the time children and parents lose from visits to pediatricians and missing school and the need for antibiotics for complications
- An added benefit expected from the vaccination of children is a reduction in the number of influenza cases among parents and other household members, and of possible spread to the general community.
Furthermore, health care personnel who care for severely immunocompromised persons should receive injections (TIV or QIV) rather than LAIV.
At risk groups
Uptake of flu vaccination, both seasonally and during pandemics, is often low. Systematic reviews of pandemic flu vaccination uptake have identified several personal factors that may influence uptake, including gender (higher uptake in men), ethnicity (higher in people from ethnic minorities) and having a chronic illness. Beliefs in the safety and effectiveness of the vaccine are also important.
Frontline healthcare workers are often recommended to get seasonal and any pandemic flu vaccination. For example, in the UK, all healthcare workers involved in patient care are recommended to receive the seasonal flu vaccine and were also recommended to receive the swine flu vaccine during the 2009 pandemic. However, uptake is often low. During the 2009 pandemic, low uptake by healthcare workers was seen in countries including the UK, Italy, Greece, and Hong Kong.
In a 2010 survey of United States healthcare workers, 63.5% reported that they received the flu vaccine during the 2010–11 season, an increase from 61.9% reported the previous season. US Health professionals with direct patient contact had higher vaccination uptake, such as physicians and dentists (84.2%) and nurse practitioners (82.6%).
The main reason to vaccinate healthcare workers is to prevent staff from spreading flu to their patients and to reduce staff absence at a time of high service demand, but the reasons healthcare workers state for their decisions to accept vaccination or not may more often be to do with perceived personal benefits.
Flu vaccine is usually grown by vaccine manufacturers in fertilized chicken eggs. In the Northern hemisphere, the manufacturing process begins following the announcement (typically in February) of the WHO recommended strains for the winter flu season. Three strains (representing an H1N1, an H3N2, and a B strain) of flu are selected and chicken eggs inoculated separately, these monovalent harvests are then combined to make the trivalent vaccine.
As of November 2007[update], both the conventional injection and the nasal spray are manufactured using chicken eggs. The European Union has also approved Optaflu, a vaccine produced by Novartis using vats of animal cells. This technique is expected to be more scalable and avoid problems with eggs, such as allergic reactions and incompatibility with strains that affect avians like chickens. Research continues into the idea of a "universal" influenza vaccine that would not require tailoring to a particular strain, but would be effective against a broad variety of influenza viruses. However, no vaccine candidates had been announced by Nov 2007.
A DNA-based vaccination, which is hoped to be even faster to manufacture, is as of 2011 in clinical trials, determining safety and efficacy.
In a 2007 report, the global capacity of approximately 826 million seasonal influenza vaccine doses (inactivated and live) was double the production of 413 million doses. In an aggressive scenario of producing pandemic influenza vaccines by 2013, only 2.8 billion courses could be produced in a six-month time frame. If all high- and upper-middle-income countries sought vaccines for their entire populations in a pandemic, nearly 2 billion courses would be required. If China pursued this goal as well, more than 3 billion courses would be required to serve these populations. Vaccine research and development is ongoing to identify novel vaccine approaches that could produce much greater quantities of vaccine at a price that is affordable to the global population.
Methods of vaccine generation that bypass the need for eggs include the construction of influenza virus-like particles (VLP). VLP resemble viruses, but there is no need for inactivation, as they do not include viral coding elements, but merely present antigens in a similar manner to a virion. Some methods of producing VLP include cultures of Spodoptera frugiperda Sf9 insect cells and plant-based vaccine production (e.g., production in Nicotiana benthamiana). There is evidence that some VLPs elicit antibodies that recognize a broader panel of antigenically distinct viral isolates compared to other vaccines in the hemagglutination-inhibition assay (HIA).
Influenza vaccines are produced in pathogen-free eggs that are 11 to 12 days old. The top of the egg is disinfected by wiping it with alcohol and then the egg is candled to identify a non-veinous area in the allantoic cavity where a small hole is poked to serve as a pressure release. A second hole is made at the top of the egg, where the influenza virus is injected in the allantoic cavity, past the chorioallantoic membrane. The two holes are then sealed with melted paraffin and the inoculated eggs are incubated for 48 hours at 37 degrees Celsius. During incubation time, the virus replicates and newly replicated viruses are released into the allantoic fluid 
After the 48 hour incubation period, the top of the egg is cracked and the 10 milliliters of allantoic fluid is removed, from which about 15 micrograms of the flu vaccine can be obtained. At this point, the viruses have been weakened or killed and the viral antigen is purified and placed inside vials, syringes, or nasal sprayers. Done on a large scale, this method is used to produce the flu vaccine for the human population.
Each year, three strains are chosen for selection in that year's flu vaccination by the WHO Global Influenza Surveillance Network. The chosen strains are the H1N1, H3N2, and Type-B strains thought most likely to cause significant human suffering in the coming season. Starting with the 2012–2013 Northern Hemisphere influenza season (coincident with the approval of quadrivalent influenza vaccines), the WHO has also recommended a 2nd B-strain for use in quadrivalent vaccines. The World Health Organization coordinates the contents of the vaccine each year to contain the most likely strains of the virus to attack the next year.
- "The WHO Global Influenza Surveillance Network was established in 1952. The network comprises four WHO Collaborating Centres (WHO CCs) and 112 institutions in 83 countries, which are recognized by WHO as WHO National Influenza Centres (NICs). These NICs collect specimens in their country, perform primary virus isolation and preliminary antigenic characterization. They ship newly isolated strains to WHO CCs for high level antigenic and genetic analysis, the result of which forms the basis for WHO recommendations on the composition of influenza vaccine for the Northern and Southern Hemisphere each year."
The Global Influenza Surveillance Network's selection of viruses for the vaccine manufacturing process is based on its best estimate of which strains will predominate the next year, amounting in the end to well-informed but fallible guesswork.
Formal WHO recommendations were first issued in 1973. Beginning in 1999 there have been two recommendations per year: one for the northern hemisphere (N) and the other for the southern hemisphere (S).
Historical annual reformulations of the influenza vaccine are listed in a separate article. Recent[update] WHO seasonal influenza vaccine composition recommendations:
2016–2017 Northern Hemisphere influenza season
The composition of trivalent virus vaccines for use in the 2016–2017 Northern Hemisphere influenza season recommended by the World Health Organization on February 25, 2016 was:
- an A/California/7/2009 (H1N1)pdm09-like virus†
- an A/Hong Kong/4801/2014 (H3N2)-like virus
- a B/Brisbane/60/2008-like virus
The WHO recommends that quadrivalent vaccines containing two influenza B viruses contain the above three viruses and a B/Phuket/3073/2013-like virus.
2016 Southern Hemisphere influenza season
The composition of virus vaccines for use in the 2016 Southern Hemisphere influenza season recommended by the World Health Organisation on September 24, 2015 was:
- an A/California/7/2009 (H1N1)pdm09-like virus†
- an A/Hong Kong/4801/2014 (H3N2)-like virus
- a B/Brisbane/60/2008-like virus
WHO recommended that quadrivalent vaccines containing two influenza B viruses should contain the above three viruses and a B/Phuket/3073/2013-like virus.
2017 Southern Hemisphere influenza season
The composition of virus vaccines for use in the 2017 Southern Hemisphere influenza season recommended by the World Health Organisation on September 29, 2016 was:
- an A/Michigan/45/2015 (H1N1)pdm09-like virus†
- an A/Hong Kong/4801/2014 (H3N2)-like virus
- a B/Brisbane/60/2008-like virus
WHO recommended that quadrivalent vaccines containing two influenza B viruses should contain the above three viruses and a B/Phuket/3073/2013-like virus.
Vaccines are used in both humans and nonhumans. Human vaccine is meant unless specifically identified as a veterinary, poultry or livestock vaccine.
Origins and development
In the worldwide Spanish flu pandemic of 1918, "Physicians tried everything they knew, everything they had ever heard of, from the ancient art of bleeding patients, to administering oxygen, to developing new vaccines and sera (chiefly against what we now call Hemophilus influenzae—a name derived from the fact that it was originally considered the etiological agent—and several types of pneumococci). Only one therapeutic measure, transfusing blood from recovered patients to new victims, showed any hint of success."
In 1931, viral growth in embryonated hens' eggs was reported by Ernest William Goodpasture and colleagues at Vanderbilt University. The work was extended to growth of influenza virus by several workers, including Thomas Francis, Jonas Salk, Wilson Smith and Macfarlane Burnet, leading to the first experimental influenza vaccines. In the 1940s, the US military developed the first approved inactivated vaccines for influenza, which were used in the Second World War. Hen's eggs continued to be used to produce virus used in influenza vaccines, but manufacturers made improvements in the purity of the virus by developing improved processes to remove egg proteins and to reduce systemic reactivity of the vaccine. Recently, the US FDA has approved influenza vaccines made by growing virus in cell cultures and influenza vaccines made from recombinant proteins have been approved, with plant-based influenza vaccines being tested in clinical trials.
According to the CDC: "Influenza vaccination is the primary method for preventing influenza and its severe complications. [...] Vaccination is associated with reductions in influenza-related respiratory illness and physician visits among all age groups, hospitalization and death among persons at high risk, otitis media among children, and work absenteeism among adults. Although influenza vaccination levels increased substantially during the 1990s, further improvements in vaccine coverage levels are needed".
The egg-based technology (still in use as of 2005) for producing influenza vaccine was created in the 1950s. In the U.S. swine flu scare of 1976, President Gerald Ford was confronted with a potential swine flu pandemic. The vaccination program was rushed, yet plagued by delays and public relations problems. Meanwhile, maximum military containment efforts succeeded unexpectedly in confining the new strain to the single army base where it had originated. On that base a number of soldiers fell severely ill, but only one died. The program was canceled, after about 24% of the population had received vaccinations. An excess in deaths of twenty-five over normal annual levels as well as 400 excess hospitalizations, both from Guillain–Barré syndrome, were estimated to have occurred from the vaccination program itself, illustrating that vaccine itself is not free of risks. The result has been cited to stoke lingering doubts about vaccination. In the end, however, even the maligned 1976 vaccine may have saved lives. A 2010 study found a significantly enhanced immune response against the 2009 pandemic H1N1 in study participants who had received vaccination against the swine flu in 1976.
Society and culture
Evaluation of evidence
Tom Jefferson, who has led Cochrane Collaboration reviews of flu vaccines, has called clinical evidence concerning flu vaccines "rubbish" and has therefore declared them to be ineffective; he has called for placebo-controlled randomized clinical trials. His views on clinical trials are considered unethical by mainstream medicine and his views on the efficacy of vaccines are rejected by medical institutions including the CDC and the National Institutes of Health, and by key figures in the field like Anthony Fauci.
Michael Osterholm who has led the Center for Infectious Disease Research and Policy 2012 review on flu vaccines recommends getting the vaccine but criticizes its promotion "We have overpromoted and overhyped this vaccine...it does not protect as promoted. It's all a sales job: it's all public relations".
The cost-effectiveness of seasonal influenza vaccination has been widely evaluated for different groups and in different settings. In the elderly (aged over 65 years) the majority of published studies have found that vaccination is cost saving, with the cost savings associated with influenza vaccination (e.g. prevented health care visits) outweighing the cost of vaccination. In older adults (aged 50–64 years), several published studies have found that influenza vaccination is likely to be cost-effective, however the results of these studies were often found to be dependent on key assumptions used in the economic evaluations. The uncertainty in influenza cost-effectiveness models can partially be explained by the complexities involved in estimating the disease burden, as well as the seasonal variability in the circulating strains and the match of the vaccine. In healthy working adults (aged 18–49 years), a 2012 review found that vaccination was generally not cost-saving, with the suitability for funding being dependent on the willingness to pay to obtain the associated health benefits. In children, the majority of studies have found that influenza vaccination was cost-effective, however many of the studies included (indirect) productivity gains, which may not be given the same weight in all settings. Several studies have attempted to predict the cost-effectiveness of interventions (including prepandemic vaccination) to help protect against a future pandemic, however estimating the cost-effectiveness has been complicated by uncertainty as to the severity of a potential future pandemic and the efficacy of measures against it.
Influenza research includes molecular virology, molecular evolution, pathogenesis, host immune responses, genomics, and epidemiology. These help in developing influenza countermeasures such as vaccines, therapies and diagnostic tools. Improved influenza countermeasures require basic research on how viruses enter cells, replicate, mutate, evolve into new strains and induce an immune response. The Influenza Genome Sequencing Project is creating a library of influenza sequences that will help us understand what makes one strain more lethal than another, what genetic determinants most affect immunogenicity, and how the virus evolves over time. Solutions to limitations in current[when?] vaccine methods are being researched.
A different approach is where Internet content is used to estimate the impact of an influenza vaccination campaign. More specifically, researchers have used data from Twitter and Bing, and proposed a statistical framework which, after a series of operations, maps this information to estimates of the percentage of influenza-like illness in areas, where vaccinations have been performed. Their impact estimates were in accordance with estimations from Public Health England.
Rapid response to pandemic flu
The rapid development, production, and distribution of pandemic influenza vaccines could potentially save millions of lives during an influenza pandemic. Due to the short time frame between identification of a pandemic strain and need for vaccination, researchers are looking at novel technologies for vaccine production that could provide better "real-time" access and be produced more affordably, thereby increasing access for people living in low- and moderate-income countries, where an influenza pandemic may likely originate, such as live attenuated (egg-based or cell-based) technology and recombinant technologies (proteins and virus-like particles). As of July 2009, more than 70 known clinical trials have been completed or are ongoing for pandemic influenza vaccines. In September 2009, the US Food and Drug Administration approved four vaccines against the 2009 H1N1 influenza virus (the 2009 pandemic strain), and expected the initial vaccine lots to be available within the following month.
Quadrivalent vaccines for seasonal flu
A quadrivalent flu vaccine administered by nasal mist was approved by the U.S. Food and Drug Administration (FDA) in March 2012. Fluarix Quadrivalent was approved by the FDA in December 2012.
Universal flu vaccines
A "universal vaccine" that would not have to be designed and made for each flu season in each hemisphere would be useful, in order to stabilize the supply and to ensure against error in the design or escape of the circulating strains by mutation. Such a vaccine has been the subject of research for decades.
One promising approach is using broadly neutralizing antibodies that unlike the vaccine used today, which provoke the body to generate an immune response, instead provide a component of the immune response itself. The first neutralizing antibodies were identified in 1993 via experimentation; with time researchers understood that the flu neutralizing antibodies were binding to the stalk of the Hemagglutinin protein; later researchers identified antibodies that could bind to the head of those proteins. Later yet, researchers identified the highly conserved M2 proton channel as a potential target for broadly neutralizing antibodies.
The challenges for researchers have been identifying single antibodies that could neutralize many subtypes of the virus, so that they could be useful in any season, and that target conserved domains that are resistant to antigenic drift.
Another approach has been taking the conserved domains identified from these projects, and delivering groups of these antigens to provoke an immune response; various approaches with different antigens, presented different ways (as fusion proteins, mounted on virus-like particles, on non-pathogenic viruses, as DNA, and others), are under development.
Efforts have also been undertaken to develop universal vaccines that specifically activate a T-cell response, based on clinical data showing that people with a strong, early T-cell response have better outcomes when infected with influenza and because T-cells respond to conserved epitopes. The challenge for developers is that these epitopes are on internal protein domains that are only mildly immunogenic.
Along with the rest of the vaccine field, people working on universal vaccines have been experimenting with vaccine adjuvants to improve the ability of their vaccines to create a sufficiently powerful and enduring immune response.
"Vaccination in the veterinary world pursues four goals: (i) protection from clinical disease, (ii) protection from infection with virulent virus, (iii) protection from virus excretion, and (iv) serological differentiation of infected from vaccinated animals (so-called DIVA principle). In the field of influenza vaccination, neither commercially available nor experimentally tested vaccines have been shown so far to fulfill all of these requirements."
Horses with horse flu can run a fever, have a dry hacking cough, have a runny nose, and become depressed and reluctant to eat or drink for several days but usually recover in two to three weeks. "Vaccination schedules generally require a primary course of two doses, 3–6 weeks apart, followed by boosters at 6–12 month intervals. It is generally recognized that in many cases such schedules may not maintain protective levels of antibody and more frequent administration is advised in high-risk situations."
It is a common requirement at shows in the United Kingdom that horses be vaccinated against equine flu and a vaccination card must be produced; the International Federation for Equestrian Sports (FEI) requires vaccination every six months.
Poultry vaccines for bird flu are made inexpensively and are not filtered and purified like human vaccines to remove bits of bacteria or other viruses. They usually contain whole virus, not just hemagglutinin as in most human flu vaccines. Purification to standards needed for humans is far more expensive than the original creation of the unpurified vaccine from eggs. There is no market for veterinary vaccines that are that expensive. Another difference between human and poultry vaccines is that poultry vaccines are adjuvated with mineral oil, which induces a strong immune reaction but can cause inflammation and abscesses. "Chicken vaccinators who have accidentally jabbed themselves have developed painful swollen fingers or even lost thumbs, doctors said. Effectiveness may also be limited. Chicken vaccines are often only vaguely similar to circulating flu strains — some contain an H5N2 strain isolated in Mexico years ago. 'With a chicken, if you use a vaccine that's only 85 percent related, you'll get protection,' Dr. Cardona said. 'In humans, you can get a single point mutation, and a vaccine that's 99.99 percent related won't protect you.' And they are weaker [than human vaccines]. 'Chickens are smaller and you only need to protect them for six weeks, because that's how long they live till you eat them,' said Dr. John J. Treanor, a vaccine expert at the University of Rochester. Human seasonal flu vaccines contain about 45 micrograms of antigen, while an experimental A(H5N1) vaccine contains 180. Chicken vaccines may contain less than one microgram. 'You have to be careful about extrapolating data from poultry to humans,' warned Dr. David E. Swayne, director of the agriculture department's Southeast Poultry Research Laboratory. 'Birds are more closely related to dinosaurs.'"
Researchers, led by Nicholas Savill of the University of Edinburgh in Scotland, used mathematical models to simulate the spread of H5N1 and concluded that "at least 95 percent of birds need to be protected to prevent the virus spreading silently. In practice, it is difficult to protect more than 90 percent of a flock; protection levels achieved by a vaccine are usually much lower than this." The Food and Agriculture Organization of the United Nations has issued recommendations on the prevention and control of avian influenza in poultry, including the use of vaccination.
A filtered and purified Influenza A vaccine for humans is being developed[when?] and many countries have recommended it be stockpiled so if an Avian influenza pandemic starts jumping to humans, the vaccine can quickly be administered to avoid loss of life. Avian influenza is sometimes called avian flu, and commonly bird flu.
Swine influenza has been recognized as a major problem since the outbreak in 1976. Evolution of the virus has resulted in inconsistent responses to traditional vaccines. Standard commercial swine flu vaccines are effective in controlling the problem when the virus strains match enough to have significant cross-protection. Customised (autogenous) vaccines made from the specific viruses isolated, are made and used in the more difficult cases. The vaccine manufacturer Novartis claims that the H3N2 strain (first identified in 1998) has brought major losses to pig farmers. Abortion storms are a common sign and sows stop eating for a few days and run a high fever. The mortality rate can be as high as 15%.
In 2004, influenza A virus subtype H3N8 was discovered to cause canine influenza. Because of the lack of previous exposure to this virus, dogs have no natural immunity to this virus. However, a vaccine is now available.
- "Influenza Virus Vaccine Inactivated". The American Society of Health-System Pharmacists. Retrieved Jan 8, 2015.
- "Vaccines against influenza WHO position paper – November 2012." (PDF). Wkly Epidemiol Rec. 87 (46): 461–76. Nov 23, 2012. PMID 23210147.
- Manzoli L, Ioannidis JP, Flacco ME, De Vito C, Villari P (July 2012). "Effectiveness and harms of seasonal and pandemic influenza vaccines in children, adults and elderly: a critical review and re-analysis of 15 meta-analyses". Hum Vaccin Immunother. 8 (7): 851–62. doi:10.4161/hv.19917. PMC . PMID 22777099.
- Demicheli, Vittorio; Jefferson, Tom; Al-Ansary, Lubna A; Ferroni, Eliana; Rivetti, Alessandro; Di Pietrantonj, Carlo (2014). "Vaccines for preventing influenza in healthy adults". Cochrane Database of Systematic Reviews (3): CD001269. doi:10.1002/14651858.CD001269.pub5. PMID 24623315.
- Osterholm, MT; Kelley, NS; Sommer, A; Belongia, EA (Jan 2012). "Efficacy and effectiveness of influenza vaccines: a systematic review and meta-analysis.". The Lancet. Infectious diseases. 12 (1): 36–44. doi:10.1016/S1473-3099(11)70295-X. PMID 22032844.
- Jefferson, T; Di Pietrantonj, C; Al-Ansary, LA; Ferroni, E; Thorning, S; Thomas, RE (Feb 17, 2010). "Vaccines for preventing influenza in the elderly". The Cochrane database of systematic reviews (2): CD004876. doi:10.1002/14651858.CD004876.pub3. PMID 20166072.
- Jefferson T, Rivetti A, Di Pietrantonj C, Demicheli V, Ferroni E (2012). "Vaccines for preventing influenza in healthy children". Cochrane Database Syst Rev. 8: CD004879. doi:10.1002/14651858.CD004879.pub4. PMID 22895945.
- "Who Should Get Vaccinated Against Influenza". U.S. Centers for Disease Control and Prevention. 2015-11-04. Retrieved 2015-12-08.
- "Factsheet for the general public". ecdc.europa.eu. Retrieved 30 December 2016.
- Compans, Richard W. (2009). Vaccines for pandemic influenza. Dordrecht: Springer. p. 49. ISBN 9783540921653.
- Vaccine Analysis: Strategies, Principles, and Control. Springer. 2014. p. 61. ISBN 9783662450246.
- "WHO Model List of Essential Medicines (19th List)" (PDF). World Health Organization. April 2015. Retrieved 8 December 2016.
- "Vaccine, influenza". International Drug Price Indicator Guide. Retrieved 6 December 2015.
- Hamilton, Richart (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. p. 314. ISBN 9781284057560.
- Center for Disease Control and Prevention. "Key Facts About Seasonal Flu Vaccine". Retrieved 7 February 2013.
- "Key Facts About Seasonal Flu Vaccine"
- Osterholm, Michael T; Kelley, Nicholas S; Sommer, Alfred; Belongia, Edward A (2012). "Efficacy and effectiveness of influenza vaccines: A systematic review and meta-analysis". The Lancet Infectious Diseases. 12 (1): 36–44. doi:10.1016/s1473-3099(11)70295-x. PMID 22032844.
- Fedson, D. S. (1998). "Measuring protection: Efficacy versus effectiveness". Developments in biological standardization. 95: 195–201. PMID 9855432.
- Stephenson, I.; Zambon, M. C.; Rudin, A.; Colegate, A.; Podda, A.; Bugarini, R.; Del Giudice, G.; Minutello, A.; Bonnington, S.; Holmgren, J.; Mills, K. H. G.; Nicholson, K. G. (2006). "Phase I Evaluation of Intranasal Trivalent Inactivated Influenza Vaccine with Nontoxigenic Escherichia coli Enterotoxin and Novel Biovector as Mucosal Adjuvants, Using Adult Volunteers". Journal of Virology. 80 (10): 4962–70. doi:10.1128/JVI.80.10.4962-4970.2006. PMC . PMID 16641287.
- Jefferson, T. (2006). "Influenza vaccination: Policy versus evidence". BMJ. 333 (7574): 912–5. doi:10.1136/bmj.38995.531701.80. PMC . PMID 17068038.
- "2007-2008 Influenza (Flu) Season". CDC. June 26, 2008.
- CDC - Key Facts About Seasonal Flu Vaccine
- Treanor, John J; Kotloff, Karen; Betts, Robert F; Belshe, Robert; Newman, Fran; Iacuzio, Dominick; Wittes, Janet; Bryant, Martin (1999). "Evaluation of trivalent, live, cold-adapted (CAIV-T) and inactivated (TIV) influenza vaccines in prevention of virus infection and illness following challenge of adults with wild-type influenza A (H1N1), A (H3N2), and B viruses". Vaccine. 18 (9–10): 899–906. doi:10.1016/S0264-410X(99)00334-5. PMID 10580204.
- Jefferson, Tom; Di Pietrantonj, Carlo; Al-Ansary, Lubna A; Ferroni, Eliana; Thorning, Sarah; Thomas, Roger E (2010). "Vaccines for preventing influenza in the elderly". Cochrane Database of Systematic Reviews (2): CD004876. doi:10.1002/14651858.CD004876.pub3. PMID 20166072.
- Jefferson, T; Rivetti, D; Rivetti, A; Rudin, M; Di Pietrantonj, C; Demicheli, V (2005). "Efficacy and effectiveness of influenza vaccines in elderly people: A systematic review". The Lancet. 366 (9492): 1165–74. doi:10.1016/S0140-6736(05)67339-4. PMID 16198765.
- "Influenza (Seasonal)". World Health Organization. November 2016.
- Burls, A; Jordan, R; Barton, P; Olowokure, B; Wake, B; Albon, E; Hawker, J (2006). "Vaccinating healthcare workers against influenza to protect the vulnerable—Is it a good use of healthcare resources? A systematic review of the evidence and an economic evaluation". Vaccine. 24 (19): 4212–21. doi:10.1016/j.vaccine.2005.12.043. PMID 16546308.
- Ahmed, F.; Lindley, M. C.; Allred, N.; Weinbaum, C. M.; Grohskopf, L. (2013). "Effect of Influenza Vaccination of Healthcare Personnel on Morbidity and Mortality Among Patients: Systematic Review and Grading of Evidence". Clinical Infectious Diseases. 58 (1): 50–7. doi:10.1093/cid/cit580. PMID 24046301.
- Griffin, M. R. (2013). "Editorial Commentary: Influenza Vaccination of Healthcare Workers: Making the Grade for Action". Clinical Infectious Diseases. 58 (1): 58–60. doi:10.1093/cid/cit590. PMID 24046312.
- Simonsen, Lone; Viboud, Cecile; Taylor, Robert J.; Miller, Mark A.; Jackson, Lisa (2009). "Influenza vaccination and mortality benefits: New insights, new opportunities". Vaccine. 27 (45): 6300–4. doi:10.1016/j.vaccine.2009.07.008. PMID 19840664.
- Darvishian, Maryam; Bijlsma, Maarten J; Hak, Eelko; Van Den Heuvel, Edwin R (2014). "Effectiveness of seasonal influenza vaccine in community-dwelling elderly people: A meta-analysis of test-negative design case-control studies". The Lancet Infectious Diseases. 14 (12): 1228–39. doi:10.1016/S1473-3099(14)70960-0. PMID 25455990.
- Nichol, Kristin L.; Nordin, James D.; Nelson, David B.; Mullooly, John P.; Hak, Eelko (2007). "Effectiveness of Influenza Vaccine in the Community-Dwelling Elderly". New England Journal of Medicine. 357 (14): 1373–81. doi:10.1056/NEJMoa070844. PMID 17914038.
- Simonsen, Lone; Taylor, Robert J; Viboud, Cecile; Miller, Mark A; Jackson, Lisa A (2007). "Mortality benefits of influenza vaccination in elderly people: An ongoing controversy". The Lancet Infectious Diseases. 7 (10): 658–66. doi:10.1016/S1473-3099(07)70236-0. PMID 17897608.
- Thompson, William W.; Shay, D. K.; Weintraub, E; Brammer, L; Cox, N; Anderson, L. J.; Fukuda, K (2003). "Mortality Associated with Influenza and Respiratory Syncytial Virus in the United States". JAMA. 289 (2): 179–86. doi:10.1001/jama.289.2.179. PMID 12517228.
- "High Dose Flu Vaccine for the Elderly « Science-Based Medicine". Sciencebasedmedicine.org. Retrieved October 17, 2013.
- "CDC – Seasonal Influenza (Flu) – Q & A: Fluzone High-Dose Seasonal Influenza Vaccine". Cdc.gov. August 13, 2013. Retrieved October 17, 2013.
- Haverkate, M; d'Ancona, F; Giambi, C; Johansen, K; Lopalco, P. L.; Cozza, V; Appelgren, E; VENICE project gatekeepers contact points (2012). "Mandatory and recommended vaccination in the EU, Iceland and Norway: Results of the VENICE 2010 survey on the ways of implementing national vaccination programmes". Euro surveillance. 17 (22). PMID 22687916.
- Field, R. I. (2009). "Mandatory vaccination of health care workers: Whose rights should come first?". P & T. 34 (11): 615–8. PMC . PMID 20140133.
- Kassianos, George (2015). "Willingness of European healthcare workers to undergo vaccination against seasonal influenza: Current situation and suggestions for improvement". Drugs in Context. 4: 212268. doi:10.7573/dic.212268. PMC . PMID 25657810.
- Thomas, Roger E; Jefferson, Tom; Lasserson, Toby J (2016). "Influenza vaccination for healthcare workers who care for people aged 60 or older living in long-term care institutions". Cochrane Database of Systematic Reviews (6): CD005187. doi:10.1002/14651858.CD005187.pub5. PMID 27251461.
- Fell, Deshayne B.; Sprague, Ann E.; Liu, Ning; Yasseen, Abdool S.; Wen, Shi-Wu; Smith, Graeme; Walker, Mark C. (2012). "H1N1 Influenza Vaccination During Pregnancy and Fetal and Neonatal Outcomes". American Journal of Public Health. 102 (6): e33–40. doi:10.2105/AJPH.2011.300606. PMC . PMID 22515877.
- Madhi, Shabir A.; Cutland, Clare L.; Kuwanda, Locadiah; Weinberg, Adriana; Hugo, Andrea; Jones, Stephanie; Adrian, Peter V.; Van Niekerk, Nadia; Treurnicht, Florette; Ortiz, Justin R.; Venter, Marietjie; Violari, Avy; Neuzil, Kathleen M.; Simões, Eric A.F.; Klugman, Keith P.; Nunes, Marta C. (2014). "Influenza Vaccination of Pregnant Women and Protection of Their Infants". New England Journal of Medicine. 371 (10): 918–31. doi:10.1056/NEJMoa1401480. PMID 25184864.
- "Key Facts About Seasonal Flu Vaccine". cdc.gov. Center for Disease Control. Retrieved 26 September 2014.
- CDC – Inactivated Influenza Vaccine 2007–2008 – What You Need To Know
- Flu – LAIV
- Gagnon, Remi; Primeau, Marie Noel; Des Roches, Anne; Lemire, Chantal; Kagan, Rhoda; Carr, Stuart; Ouakki, Manale; Benoît, Mélanie; De Serres, Gaston (2010). "Safe vaccination of patients with egg allergy with an adjuvanted pandemic H1N1 vaccine". Journal of Allergy and Clinical Immunology. 126 (2): 317–23. doi:10.1016/j.jaci.2010.05.037. PMID 20579720.
- National Advisory Committee on Immunization (August 2012). "Statement on Seasonal Influenza Vaccine for 2012–2013" (PDF). Canadian Communicable Disease Report. 38. Retrieved 18 July 2013.[dead link]
- Turner, Paul J; Southern, Jo; Andrews, Nick J; Miller, Elizabeth; Erlewyn-Lajeunesse, Michel (2015). "Safety of live attenuated influenza vaccine in young people with egg allergy: Multicentre prospective cohort study". BMJ. 351: h6291. doi:10.1136/bmj.h6291. PMC . PMID 26645895.
- Greenhawt, Matthew (2015). "Live attenuated influenza vaccine for children with egg allergy". BMJ. 351: h6656. doi:10.1136/bmj.h6656. PMID 26657778.
- Andrew Pollack, "Rapidly Produced Flu Vaccine Wins F.D.A. Approval", The New York Times, January 16, 2013
- Haber, Penina; Sejvar, James; Mikaeloff, Yann; Destefano, Frank (2009). "Vaccines and Guillain-Barré Syndrome". Drug Safety. 32 (4): 309–23. doi:10.2165/00002018-200932040-00005. PMID 19388722.
- Kaplan, J. E. (1982). "Guillain-Barre syndrome in the United States, 1979-1980 and 1980-1981. Lack of an association with influenza vaccination". JAMA. 248 (6): 428. doi:10.1001/jama.248.6.698. PMID 25996397.
- Stowe, J.; Andrews, N.; Wise, L.; Miller, E. (2008). "Investigation of the Temporal Association of Guillain-Barre Syndrome with Influenza Vaccine and Influenzalike Illness Using the United Kingdom General Practice Research Database". American Journal of Epidemiology. 169 (3): 382–8. doi:10.1093/aje/kwn310. PMID 19033158.
- Sivadon‐Tardy, Valérie; Orlikowski, David; Porcher, Raphaël; Sharshar, Tarek; Durand, Marie‐Christine; Enouf, Vincent; Rozenberg, Flore; Caudie, Christiane; Annane, Djillali; Van Der Werf, Sylvie; Lebon, Pierre; Raphaël, Jean‐Claude; Gaillard, Jean‐Louis; Gault, Elyanne (2009). "Guillain‐Barré Syndrome and Influenza Virus Infection". Clinical Infectious Diseases. 48 (1): 48–56. doi:10.1086/594124. PMID 19025491.
- Vellozzi, Claudia; Burwen, Dale R.; Dobardzic, Azra; Ball, Robert; Walton, Kimp; Haber, Penina (2009). "Safety of trivalent inactivated influenza vaccines in adults: Background for pandemic influenza vaccine safety monitoring". Vaccine. 27 (15): 2114–20. doi:10.1016/j.vaccine.2009.01.125. PMID 19356614.
- Steven Reinberg (February 2, 2011). "Last Year's H1N1 Flu Vaccine Was Safe, Study Finds". U.S. News & World Report.
- TECHNICAL REPORT: Narcolepsy in association with pandemic influenza vaccination (PDF). Stockholm, Sweden: European Centre for Disease Prevention and Contro. 2012. ISBN 978-92-9193-388-4.
- Yong, Ed (2013). "Narcolepsy confirmed as autoimmune disease". Nature. doi:10.1038/nature.2013.14413.
- Offit, Paul A. (2007). "Thimerosal and Vaccines — A Cautionary Tale". New England Journal of Medicine. 357 (13): 1278–9. doi:10.1056/NEJMp078187. PMID 17898096.
- Global Advisory Committee on Vaccine Safety (2006-07-14). "Thiomersal and vaccines". World Health Organization. Retrieved 2007-11-20.
- Plotkin & Mortimer (1988). Vaccines. Philadelphia: W.B. Saunders Company. ISBN 0-7216-1946-0.[page needed]
- Product Monograph: Flumist, Astrazeneca Canada Inc., 2011
- Fiore, A. E.; Shay, D. K.; Broder, K; Iskander, J. K.; Uyeki, T. M.; Mootrey, G; Bresee, J. S.; Cox, N. J.; Centers for Disease Control Prevention. (2009). "Prevention and control of seasonal influenza with vaccines: Recommendations of the Advisory Committee on Immunization Practices (ACIP), 2009". MMWR. Recommendations and reports. 58 (RR-8): 1–52. PMID 19644442.
- To, K.W.; Lai, A.; Lee, K.C.K.; Koh, D.; Lee, S.S. (2016). "Increasing the coverage of influenza vaccination in healthcare workers: Review of challenges and solutions". Journal of Hospital Infection. 94 (2): 133–42. doi:10.1016/j.jhin.2016.07.003. PMID 27546456.
- Rubin, G. James; Potts, Henry W.W.; Michie, Susan (2011). "Likely uptake of swine and seasonal flu vaccines among healthcare workers. A cross-sectional analysis of UK telephone survey data". Vaccine. 29 (13): 2421–8. doi:10.1016/j.vaccine.2011.01.035. PMID 21277402.
- Skowronski, Danuta M.; De Serres, Gaston (2009). "Is routine influenza immunization warranted in early pregnancy?". Vaccine. 27 (35): 4754–70. doi:10.1016/j.vaccine.2009.03.079. PMID 19515466.
- Health Care Guideline: Routine Prenatal Care. Fourteenth Edition.[dead link] By the Institute for Clinical Systems Improvement. July 2010.
- "Vaccine use". World Health Organization. Retrieved 2017-01-15.
- "Influenza (Seasonal) Fact sheet". World Health Organization. November 2016. Retrieved 2017-01-15.
- "U.S. panel recommends all kids get the flu shot". CTV. February 27, 2008.
In Canada, the National Advisory Committee on Immunization (NACI), the group that advises the Public Health Agency of Canada, currently says that children between the age of six and 24 months should be considered a high priority for the flu vaccine.[dead link]
- "Statement on Seasonal Influenza Vaccine for 2013–2014 – CCDR Vol.39 ACS-4 – Public Health Agency of Canada". Phac-aspc.gc.ca. 2013-11-14. Retrieved 2014-07-24.
- "Influenza vaccination". ecdc.europa.eu. Retrieved 24 December 2016.
- "ECDC Reviews - New WHO recommendations on seasonal influenza...". ecdc.europa.eu. Retrieved 25 December 2016.
- "ECDC GUIDANCE: Priority risk groups for influenza vaccination (p. 7-8)" (PDF). European Centre for Disease Prevention and Control. Retrieved 25 December 2016.
- Fiore, AE; Uyeki; Broder, K; Finelli, L; Euler, GL; Singleton, JA; Iskander, JK; Wortley, PM; et al. (August 2010). "Prevention and control of influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2010" (PDF). MMWR Recomm Rep. 59 (RR–8): 1–62. PMID 20689501.
- Centers for Disease Control Prevention (CDC). (August 2012). "Prevention and control of influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP) – United States, 2012–13 influenza season" (PDF). MMWR Morb. Mortal. Wkly. Rep. 61 (32): 613–8. ISSN 0149-2195. PMID 22895385.
- "Children, the Flu, and the Flu Vaccine"
- "Who Should Get Vaccinated Against Influenza". Centers for Disease Control. Retrieved 14 January 2014.
- CDC – Influenza (Flu) | Vaccination: Summary for Clinicians
- Couch, Robert B.; Winokur, Patricia; Brady, Rebecca; Belshe, Robert; Chen, Wilbur H.; Cate, Thomas R.; Sigurdardottir, Bryndis; Hoeper, Amy; Graham, Irene L.; Edelman, Robert; He, Fenhua; Nino, Diane; Capellan, Jose; Ruben, Frederick L. (2007). "Safety and immunogenicity of a high dosage trivalent influenza vaccine among elderly subjects". Vaccine. 25 (44): 7656–63. doi:10.1016/j.vaccine.2007.08.042. PMC . PMID 17913310.
- Tanner, Lindsey (2013-01-13). "Hospitals crack down on workers who refuse flu shots". NBC News. Retrieved 2014-07-24.
- Centers for Disease Control Prevention (CDC). (2010). "Seasonal influenza and 2009 H1N1 influenza vaccination coverage among pregnant women--10 states, 2009-10 influenza season". MMWR. Morbidity and mortality weekly report. 59 (47): 1541–5. PMID 21124293.
- Altman, Lawrence K. (February 28, 2008). "Panel Advises Flu Shots for Children Up to Age 18". The New York Times.
- "CDC Press Releases". CDC. Retrieved 2016-11-26.
- "Immunization Schedules". CDC. Center for Disease Control and Prevention. Retrieved 4 November 2014.
- Han, You Kyung Julia; Michie, Susan; Potts, Henry W.W.; Rubin, G. James (2016). "Predictors of influenza vaccine uptake during the 2009/10 influenza a H1N1v ('swine flu') pandemic: Results from five national surveys in the United Kingdom". Preventive Medicine. 84: 57–61. doi:10.1016/j.ypmed.2015.12.018. PMC . PMID 26757401.
- Bish, Alison; Yardley, Lucy; Nicoll, Angus; Michie, Susan (2011). "Factors associated with uptake of vaccination against pandemic influenza: A systematic review". Vaccine. 29 (38): 6472–84. doi:10.1016/j.vaccine.2011.06.107. PMID 21756960.
- Brien, Stephanie; Kwong, Jeffrey C.; Buckeridge, David L. (2012). "The determinants of 2009 pandemic A/H1N1 influenza vaccination: A systematic review". Vaccine. 30 (7): 1255–64. doi:10.1016/j.vaccine.2011.12.089. PMID 22214889.
- La Torre, G; Di Thiene, D; Cadeddu, C; Ricciardi, W; Boccia, A (2009). "Behaviours regarding preventive measures against pandemic H1N1 influenza among Italian healthcare workers, October 2009". Euro surveillance. 14 (49). PMID 20003908.
- Amodio, Emanuele; Anastasi, Giovanna; Marsala, Maria Grazia Laura; Torregrossa, Maria Valeria; Romano, Nino; Firenze, Alberto (2011). "Vaccination against the 2009 pandemic influenza A (H1N1) among healthcare workers in the major teaching hospital of Sicily (Italy)". Vaccine. 29 (7): 1408–12. doi:10.1016/j.vaccine.2010.12.041. PMID 21199700.
- Chor, J. S Y; Ngai, K. L.; Goggins, W. B; Wong, M. C S; Wong, S. Y S; Lee, N.; Leung, T.-f.; Rainer, T. H; Griffiths, S.; Chan, P. K S (2009). "Willingness of Hong Kong healthcare workers to accept pre-pandemic influenza vaccination at different WHO alert levels: Two questionnaire surveys". BMJ. 339: b3391. doi:10.1136/bmj.b3391. PMC . PMID 19706937.
- Coverage in healthcare workers
- Centers for Disease Control Prevention (CDC) (2011). "Influenza vaccination coverage among health-care personnel --- United States, 2010-11 influenza season". MMWR. Morbidity and mortality weekly report. 60 (32): 1073–7. PMID 21849963.
- Centers for Disease Control Prevention (CDC) (2012). "Influenza vaccination coverage among health-care personnel: 2011-12 influenza season, United States". MMWR. Morbidity and mortality weekly report. 61: 753–7. PMID 23013720.
- how it's made[dead link]
- New and Old Ways to Make Flu Vaccines, November 8, 2007, National Public Radio.
- WHO:Influenza vaccine viruses and reagents
- "Recommendations for the production and control of influenza vaccine (inactivated)" (PDF). World Health Organization. Retrieved 27 May 2013.
- "Priming with DNA vaccine makes avian flu vaccine work better (NIH News)". October 3, 2011.
- "Novartis receives FDA approval for Flucelvax, the first cell-culture vaccine in US to help protect against seasonal influenza" (Press release). Novartis. November 20, 2012.[dead link]
- "FDA approves first seasonal influenza vaccine manufactured using cell culture technology"
- "November 20, 2012 Approval Letter- Flucelvax"
- "Seqirus receives FDA approval for Flucelvax Quadrivalent (Influenza Vaccine) for people four years of age and older" (Press release). Seqirus. May 23, 2016.
- "FDA approves first seasonal influenza vaccine manufactured using cell culture technology" (Press release). U.S. Food and Drug Administration (FDA). November 20, 2012.
- PATH, Oliver Wyman. Influenza Vaccine Strategies for Broad Global Access. 2007. http://www.path.org/files/VAC_infl_publ_rpt_10-07.pdf
- Bright, Rick A.; Carter, Donald M.; Daniluk, Shannon; Toapanta, Franklin R.; Ahmad, Attiya; Gavrilov, Victor; Massare, Mike; Pushko, Peter; Mytle, Nutan; Rowe, Thomas; Smith, Gale; Ross, Ted M. (2007). "Influenza virus-like particles elicit broader immune responses than whole virion inactivated influenza virus or recombinant hemagglutinin". Vaccine. 25 (19): 3871–8. doi:10.1016/j.vaccine.2007.01.106. PMID 17337102.
- Racaniello, Vincent (Dec 2009). "Influenza virus growth in eggs". Virology Blog.
- Izzat, Fakhrul (Apr 2012). "Viral Cultivation in Chicken Embryo". Youtube.
- "How Influenza (Flu) Vaccines Are Made". Centers for Disease Control and Prevention. May 2014.
- WHO[dead link] article Global influenza surveillance[verification needed]
- Brown, David (2008-02-18). "Keeping ahead of flu comes down to guessing game". Knoxville News Sentinel. The Washington Post. Archived from the original on 2009-01-11. Retrieved 2015-12-22.
- WHO Report on Global Surveillance of Epidemic-prone Infectious Diseases (pdf)
- WHO | Recommended composition of influenza virus vaccines for use in the 2016–2017 northern hemisphere influenza season
- WHO | Recommended composition of influenza virus vaccines for use in the 2016 southern hemisphere influenza season.
- Centers for Disease Control Prevention (CDC) (2009). "Update on influenza A (H1N1) 2009 monovalent vaccines". MMWR. Morbidity and mortality weekly report. 58 (39): 1100–1. PMID 19816398.
- WHO | Recommended composition of influenza virus vaccines for use in the 2017 southern hemisphere influenza season.
- The Threat of Pandemic Influenza: Are We Ready? Workshop Summary (2005) (free online book) page 62
- Plotkin, S.L. and Plotkin, S.A. "A short history of vaccination." In: Vaccines, Stanley A. Plotkin, Walter A. Orenstein, Paul A. Offit, eds. Elsevier Health Sciences, 2008, pp. 6–7.
- Artenstein, A.W. "Influenza" In: Vaccines: A Biography Andrew W. Artenstein, ed. pp. 191–205.
- Hampson, A. W. (2008). "Vaccines for pandemic influenza. The history of our current vaccines, their limitations and the requirements to deal with a pandemic threat". Annals of the Academy of Medicine, Singapore. 37 (6): 510–7. PMID 18618064.
- USFDA FDA approves first seasonal influenza vaccine manufactured using cell culture technology. November 20, 2012.
- USFDA FDA approves new seasonal influenza vaccine made using novel technology. Jan. 16, 2013.
- Landry, Nathalie; Ward, Brian J.; Trépanier, Sonia; Montomoli, Emanuele; Dargis, Michèle; Lapini, Giulia; Vézina, Louis-P. (2010). "Preclinical and Clinical Development of Plant-Made Virus-Like Particle Vaccine against Avian H5N1 Influenza". PLoS ONE. 5 (12): e15559. Bibcode:2010PLoSO...515559L. doi:10.1371/journal.pone.0015559. PMC . PMID 21203523.
- CDC report Prevention and Control of Influenza published April 12, 2002.
- Osterholm, Michael T. (2005). "Preparing for the Next Pandemic". New England Journal of Medicine. 352 (18): 1839–42. doi:10.1056/NEJMp058068. PMID 15872196.
- The Sky is Falling: An Analysis of the Swine Flu Affair of 1976[dead link]
- McCullers, Jonathan A.; Van De Velde, Lee‐Ann; Allison, Kim J.; Branum, Kristen C.; Webby, Richard J.; Flynn, Patricia M. (2010). "Recipients of Vaccine against the 1976 "Swine Flu" Have Enhanced Neutralization Responses to the 2009 Novel H1N1 Influenza Virus". Clinical Infectious Diseases. 50 (11): 1487–92. doi:10.1086/652441. PMC . PMID 20415539.
- Brownlee, Shannon (1 November 2009). "Does the Vaccine Matter?". The Atlantic. Retrieved 8 December 2014.
- Rabin, Roni Caryn. "Reassessing Flu Shots as the Season Draws Near". New York Times. Retrieved 30 December 2016.
- Jit, Mark; Newall, Anthony T.; Beutels, Philippe (2014). "Key issues for estimating the impact and cost-effectiveness of seasonal influenza vaccination strategies". Human Vaccines & Immunotherapeutics. 9 (4): 834–40. doi:10.4161/hv.23637. PMC . PMID 23357859.
- Postma, Maarten J; Baltussen, Rob PM; Palache, Abraham M; Wilschut, Jan C (2014). "Further evidence for favorable cost-effectiveness of elderly influenza vaccination". Expert Review of Pharmacoeconomics & Outcomes Research. 6 (2): 215–27. doi:10.1586/1473718.104.22.168. PMID 20528557.
- Newall, Anthony T.; Kelly, Heath; Harsley, Stuart; Scuffham, Paul A. (2009). "Cost Effectiveness of Influenza Vaccination in Older Adults". PharmacoEconomics. 27 (6): 439–50. doi:10.2165/00019053-200927060-00001. PMID 19640008.
- Newall, A. T.; Viboud, C.; Wood, J. G. (2009). "Influenza-attributable mortality in Australians aged more than 50 years: A comparison of different modelling approaches". Epidemiology and Infection. 138 (6): 836–42. doi:10.1017/S095026880999118X. PMID 19941685.
- Newall, Anthony T.; Dehollain, Juan Pablo; Creighton, Prudence; Beutels, Philippe; Wood, James G. (2013). "Understanding the Cost-Effectiveness of Influenza Vaccination in Children: Methodological Choices and Seasonal Variability". PharmacoEconomics. 31 (8): 693–702. doi:10.1007/s40273-013-0060-7. PMID 23645539.
- Newall, Anthony T.; Scuffham, Paul A (2011). "Uncertainty and variability in influenza cost-effectiveness models". Australian and New Zealand Journal of Public Health. 35 (6): 576; author reply 576–7. doi:10.1111/j.1753-6405.2011.00788.x. PMID 22151168.
- Gatwood, Justin; Meltzer, Martin I.; Messonnier, Mark; Ortega-Sanchez, Ismael R.; Balkrishnan, Rajesh; Prosser, Lisa A. (2012). "Seasonal Influenza Vaccination of Healthy Working-Age Adults". Drugs. 72 (1): 35–48. doi:10.2165/11597310-000000000-00000. PMID 22191794.
- Newall, Anthony T.; Jit, Mark; Beutels, Philippe (2012). "Economic Evaluations of Childhood Influenza Vaccination". PharmacoEconomics. 30 (8): 647–60. doi:10.2165/11599130-000000000-00000. PMID 22788257.
- Newall, Anthony T.; Wood, James G.; Oudin, Noemie; MacIntyre, C. Raina (2010). "Cost-effectiveness of Pharmaceutical-based Pandemic Influenza Mitigation Strategies1". Emerging Infectious Diseases. 16 (2): 224–30. doi:10.3201/eid1602.090571. PMC . PMID 20113551.
- "Influenza Genome Sequencing Project – Overview". National Institutes of Health – National Institute of Allergy and Infectious Diseases. Retrieved 27 May 2013.[dead link]
- Lampos, Vasileios; Yom-Tov, Elad; Pebody, Richard; Cox, Ingemar J. (2015). "Assessing the impact of a health intervention via user-generated Internet content". Data Mining and Knowledge Discovery. 29 (5): 505. doi:10.1007/s10618-015-0427-9. PMID 26811110.
- World Health Organization. Acyte Respiratory Infections: Influenza. 2009. http://www.who.int/vaccine_research/diseases/ari/en/index1.html
- World Health Organization. Tables on the Clinical trials of pandemic influenza prototype vaccines. July 2009. http://www.who.int/vaccine_research/immunogenicity/immunogenicity_table.xls
- US Food & Drug Administration. FDA Approves Vaccines for 2009 H1N1 Influenza Virus Approval Provides Important Tool to Fight Pandemic. September 15, 2009. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm182399.htm
- "First Quadrivalent Vaccine Against Seasonal Flu Wins FDA Approval"
- "FDA approves first quadrivalent vaccine to prevent seasonal influenza"
- "December 14, 2012 Approval Letter- Fluarix Quadrivalent"
- Cho, Alice; Wrammert, Jens (2016). "Implications of broadly neutralizing antibodies in the development of a universal influenza vaccine". Current Opinion in Virology. 17: 110–5. doi:10.1016/j.coviro.2016.03.002. PMC . PMID 27031684.
- Soema, Peter C.; Kompier, Ronald; Amorij, Jean-Pierre; Kersten, Gideon F.A. (2015). "Current and next generation influenza vaccines: Formulation and production strategies". European Journal of Pharmaceutics and Biopharmaceutics. 94: 251–63. doi:10.1016/j.ejpb.2015.05.023. PMID 26047796.
- Deng, Lei; Cho, Ki; Fiers, Walter; Saelens, Xavier (2015). "M2e-Based Universal Influenza a Vaccines". Vaccines. 3 (1): 105–36. doi:10.3390/vaccines3010105. PMC . PMID 26344949.
- Gottlieb, Tanya; Ben-Yedidia, Tamar (2014). "Epitope-based approaches to a universal influenza vaccine". Journal of Autoimmunity. 54: 15–20. doi:10.1016/j.jaut.2014.07.005. PMID 25172355.
- Toussi, Deana; Massari, Paola (2014). "Immune Adjuvant Effect of Molecularly-defined Toll-Like Receptor Ligands". Vaccines. 2 (2): 323. doi:10.3390/vaccines2020323. PMID 26344622.
- Influenza Report (online book) chapter Avian Influenza by Timm C. Harder and Ortrud Werner
- UAE Equestrian & Racing Federation[dead link]
- FEI guidelines
- McNeil, Donald G. Jr. (May 2, 2006). "Turning to Chickens in Fight With Bird Flu". The New York Times.
- SciDev.Net article Bird flu warning over partial protection of flocks published August 16, 2006
- FAO Recommendations on the Prevention, Control and Eradication of Highly Pathogenic Avian Influenza (HPAI) in Asia http://www.fao.org/docs/eims/upload/246982/aj126e00.pdf
- Yen, Hui-Ling; Peiris, Joseph Sriyal Malik (2012). "Virology: Bird flu in mammals". Nature. 486 (7403): 332–3. Bibcode:2012Natur.486..332Y. doi:10.1038/nature11192. PMID 22722190.
- National Hog Farmer article Swine Flu Virus Turns Endemic published September 15, 2007
- livestock.novartis.com Custom Vaccines: Swine
- Karaca, Kemal; Dubovi, Edward J.; Siger, Leonardo; Robles, Amy; Audonnet, Jean-Christophe; Jiansheng, Yao; Nordgren, Robert; Minke, Jules M. (2007). "Evaluation of the ability of canarypox-vectored equine influenza virus vaccines to induce humoral immune responses against canine influenza viruses in dogs". American Journal of Veterinary Research. 68 (2): 208–12. doi:10.2460/ajvr.68.2.208. PMID 17269888.