Influenza vaccine

The influenza vaccine, also known as flu shot, is an annual vaccination using a vaccine that is specific for a given year to protect against the highly variable influenza virus.[1] Each seasonal influenza vaccine contains antigens representing three (trivalent vaccine) or four (quadrivalent vaccine) influenza virus strains: one influenza type A subtype H1N1 virus strain, one influenza type A subtype H3N2 virus strain, and either one or two influenza type B virus strains.[2] Influenza vaccines may be administered as an injection or as a nasal spray.

The U.S. Centers for Disease Control and Prevention recommend that everyone over the ages of 6 months should receive the seasonal influenza vaccine.[3] Vaccination campaigns usually focus on people who are at high risk of serious complications if they catch the flu, such as the elderly and people living with chronic illness or those with weakened immune systems, as well as health care workers.[3][4]

Most flu vaccines provide modest protection against contracting influenza, with the effect seasonably variable depending on antigenic drift.[5] Some studies have concluded that there is little evidence for efficacy among the elderly, while others concluded that efficacy ranges from "acceptable" to "high" depending on the specific vaccine formulation.[6][7]

Medical uses

According to the Centers for Disease Control and Prevention, the flu vaccine is 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 strain of the flu that the vaccine did not contain.[8] It takes about two weeks following vaccination for antibodies to protect against the flu.[2]

Influenza vaccine has been demonstrated to reduce disease, hospitalization, and death. The CDC reports that studies demonstrate that vaccination is a cost-effective counter-measure to seasonal outbreaks of influenza.[9]

A 2012 meta analysis found that flu shots were efficacious 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 6 to 24 months (66 percent).[10]

Effectiveness

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.[11] 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.[12] Influenza vaccines generally show high efficacy, as measured by the antibody production in animal models or vaccinated people.[13] 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.[14] However, in most years (16 of the 19 years before 2007), the flu vaccine strains have been a good match for the circulating strains,[15] and even a mis-matched vaccine can often provide cross-protection.[16]

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.[17] The meta-analyses examined the efficacy and effectiveness of inactivated vaccines against seasonal influenza in adults,[12] children,[18] and the elderly.[19][20]

Children

The CDC recommend that everyone except children under the age of six months should receive the seasonal influenza vaccine.[3] 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.[3][4]

As mortality is also high among infants who contract influenza, the household contacts and caregivers of infants should be vaccinated to reduce the risk of passing an influenza infection to the infant.[4]

In children, vaccines again showed high efficacy, but low effectiveness in preventing "flu-like illness".[18] In children under the age of two the data are extremely limited, but vaccination appeared to confer no measurable benefit.[18]

Adults

In adults, vaccines show a 75% reduction in risk of contracting influenza (4% influenza rate among the unvaccinated versus 1% among vaccinated persons) when the vaccine is perfectly matched to the virus and a one-half reduction (2% get flu without vaccine versus 1% with vaccine) when it is not, but only four trials examined the rate of hospitalization. Although each showed a trend toward reduced hospitalizations, the effect was not statistically significant.[12]

For healthy, working adults, influenza vaccines can provide moderate protection against virologically confirmed influenza, but such protection is greatly reduced or absent in some seasons.[21]

A review of eighteen studies likewise found a net benefit to health care workers.[22] Of these eighteen HCW studies, 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.[22]

In working adults the Cochrane Collaboration found that vaccination reduced both influenza symptoms and working days lost, without affecting transmission or influenza-related complications.[12]

Elderly

Evidence for an effect in adults over 65 years old is unclear.[23] Reviews of randomized controlled and observational studies have found a lack of high quality evidence.[21][24] Reviews of case control studies have found effects against laboratory-confirmed influenza, pneumonia, and death among the community-dwelling elderly.[25][26]

The group most vulnerable to non-pandemic flu, the elderly, is also the least to benefit 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.[27] 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.[28]

There is a new high-dose flu vaccine specifically formulated to provide a larger immune response.[29] Available evidence indicates that the high-dose vaccine produces a stronger immune response.[30]

A 2010 Cochrane review found that the same benefit did not extend to vaccinating health care workers working with elderly patients in long-term care facilities.[31]

Other

The trivalent inactivated influenza vaccine is protective in pregnant women infected with HIV.[32]

Safety

While side effects of the flu vaccine may occur, they will be minor and the safety of flu vaccines is high. Furthermore, the 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.[33]

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,[34][35] however research into egg-allergy and influenza vaccination [36] has led some advisory groups to recommend vaccine delivery protocols for egg allergic persons.[37] 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. It will be available in the 2013–14 season for people age 18–49, and avoids the problem with egg allergies.[38]

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.[39][40] Getting infected by influenza itself increases both the risk of death (up to 1 in 10,000) and increases the risk of developing Guillain-Barré syndrome to a much higher level than the highest level of suspected vaccine involvement (approx. 10 times higher by 2009 estimates).[41][42]

Although one review gives an incidence of about one case of Guillain-Barré per million vaccinations,[43] 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-Barre 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."[44][45] Several studies have identified an increased incidence of narcolepsy among recipients of the pandemic H1N1 influenza ASO3-adjuvanted vaccine,[46] efforts to identify a mechanism for this suggest that narcolepsy is autoimmune, and that the H1N1 vaccine may mimic hypocretin, serving as a trigger.[47]

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,[48] 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.[49]

Vaccination recommendations

U.S. Navy personnel receiving influenza vaccination

Various public health organizations, including the World Health Organization, have recommended that yearly influenza vaccination be routinely offered to people at risk of complications of influenza and those individuals who live with or care for high-risk individuals, including:

Both types of flu vaccines are contraindicated for those with severe allergies to egg proteins and people with a history of Guillain-Barré syndrome.[56]

As of 2013, the UN World Health Organization recommends vaccination for, in order of priority:[57]

  1. nursing-home residents (the elderly or disabled)
  2. people with chronic medical conditions
  3. elderly individuals
  4. other groups such as pregnant women, health care workers, those with essential functions in society, as well as children from 6 to 24 months.

According to the CDC, the live attenuated virus (which comes in the forum of the nasal spray in the US) should be avoided by:

Canada

In 2008, the National Advisory Committee on Immunization, the group that advises the Public Health Agency of Canada, recommended that everyone aged 2 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.[59] The NACI also recommends the flu vaccine for:[60]

United States

In the United States, "Routine influenza vaccination is recommended for all persons aged ≥ 6 months" since 2010.[61][62][63]

Within its blanket recommendation for general vaccination in the United States, the Centers for Disease Control and Prevention (CDC), who 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.[64] 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.[65]

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.[66]

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[61][67] and children and teenagers from six months to 18 years of age;[68]

Injection versus nasal spray

Flu vaccines are available either as

TIV induces protection after injection (typically intramuscular, though subcutaneous and intradermal routes can also be protective)[70] 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.[71]

LAIV is not recommended for individuals under age 2 or over age 50,[72] but might be comparatively more effective among children over age 2.[73] Furthermore, health care personnel who care for severely immunocompromised persons should receive TIV or QIV rather than LAIV.[74]

Usage

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. Health professionals with direct patient contact had higher vaccination uptake, such as physicians and dentists (84.2%) and nurse practitioners (82.6%).[75][76][77]

Manufacturing

Schematic of influenza vaccine creation

Flu vaccine is usually grown by vaccine manufacturers in fertilized chicken eggs.[78][79] In the Northern hemisphere, the manufacturing process begins following the announcement (typically in February) of the WHO recommended strains for the winter flu season.[78][80] 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.[81]

Avian flu vaccine development by reverse genetics technique

As of November 2007, both the conventional injection and the nasal spray are manufactured using chicken eggs.[79] The European Union has also approved Optaflu, a vaccine produced by Novartis using vats of animal cells.[79] 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.[79] 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.[79]

A DNA-based vaccination, which is hoped to be even faster to manufacture, is as of 2011 in clinical trials, determining safety and efficacy.[82]

On November 20, 2012, Novartis received FDA approval for the first cell-culture vaccine.[83][84][85]

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.[86] 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).[87]

Influenza vaccines are produced in pathogen-free eggs that are 11 to 12 days old.[88] 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.[89] 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.[88] During incubation time, the virus replicates and newly replicated viruses are released into the allantoic fluid [90]

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.[90] Done on a large scale, this method is used to produce the flu vaccine for the human population.

Annual reformulation

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 4 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."[91]

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.[92]

Formal WHO recommendations first issued in 1973; beginning 1999 there have been two recommendations per year, one for the northern hemisphere (N) and the other for the southern hemisphere (S).[93]

Historical annual reformulations of the influenza vaccine are listed in a separate article. Recent WHO seasonal influenza vaccine composition recommendations:

2015–2016 Northern Hemisphere influenza season

The composition of trivalent virus vaccines for use in the 2015–2016 Northern Hemisphere influenza season recommended by the World Health Organization on February 26, 2015 was:

The WHO recommends that quadrivalent vaccines containing two influenza B viruses contain the above three viruses and a B/Brisbane/60/2008-like virus.[94]

2015 Southern Hemisphere influenza season

The composition of virus vaccines for use in the 2015 Southern Hemisphere influenza season recommended by the World Health Organization September 25, 2014 was:

WHO recommended that quadrivalent vaccines containing two influenza B viruses should contain the above three viruses and a B/Brisbane/60/2008-like virus.[95]

†Strain A(H1N1)pdm09 is a newer name for the strain used in the 2009 flu pandemic vaccine.[96]

History

Vaccines are used in both humans and nonhumans. Human vaccine is meant unless specifically identified as a veterinary, poultry or livestock vaccine.

The first influenza pandemic was recorded in 1580.[97] However, the etiological cause of influenza, the orthomyxoviridae was discovered by the Medical Research Council (MRC) of the United Kingdom in 1933.[98]

Known flu pandemics[99][100]
Name of pandemic Date Deaths Case fatality rate Subtype involved Pandemic severity index
1889–1890 flu pandemic
(Asiatic or Russian Flu)[101]		 1889–1890 1 million 0.15% possibly H3N8
or H2N2		NA
1918 flu pandemic
(Spanish flu)[102]		 1918–1920 20 to 100 million 2%H1N1 5
Asian Flu 1957–1958 1 to 1.5 million 0.13%H2N2 2
Hong Kong Flu 1968–1969 0.75 to 1 million <0.1%H3N2 2
Russian flu 1977–1978 no accurate count N/A H1N1 N/A
2009 flu pandemic[103][104] 2009–2010 18,000† N/A(H1N1)pdm09

† Because of lack of laboratory confirmation and underreporting among other factors, reported cases are "likely to be a gross underestimation of the true number of fatalities associated with the [2009] pandemic."[104] The 18,000 cases are those officially confirmed. Two statistical analyses, using different methods but producing similar results, estimated that the actual number was likely to be about ten times higher.[105][106]

Origins and development

In the world wide 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."[107]

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.[108] In the 1940s, the US military developed the first approved inactivated vaccines for influenza, which were used in the Second World War.[109] 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.[110] Recently, the US FDA has approved influenza vaccines made by growing virus in cell cultures[111] and influenza vaccines made from recombinant proteins[112] have been approved, with plant-based influenza vaccines being tested in clinical trials.[113]

Acceptance

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".[114]

The egg-based technology (still in use as of 2005) for producing influenza vaccine was created in the 1950s.[115] 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.[116] 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.[117]

Cost-effectiveness

The cost-effectiveness of seasonal influenza vaccination has been widely evaluated for different groups and in different settings.[118] 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.[119] 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.[120] The uncertainty in influenza cost-effectiveness models can partially be explained by the complexities involved in estimating the disease burden,[121] as well as the seasonal variability in the circulating strains and the match of the vaccine.[122][123] 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.[124] 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.[125] 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.[126]

Research

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[127] 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 vaccine methods are being researched.

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).[128] As of July 2009, more than 70 known clinical trials have been completed or are ongoing for pandemic influenza vaccines.[129] 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.[130] A quadrivalent flu vaccine administered by nasal mist was approved by the U.S. Food and Drug Administration (FDA) in March 2012.[131][132] Fluarix Quadrivalent was approved by the FDA in December 2012.[133]

Universal flu vaccines

Many groups worldwide are pursuing development of a universal flu vaccine that does not require modification each year.[134] Companies pursuing the vaccine as of 2009 and 2010 include BiondVax,[135] Theraclone,[136] Dynavax Technologies Corporation,[137] VaxInnate,[138] Crucell NV,[139] Inovio Pharmaceuticals,[140] and Immune Targeting Systems (ITS)[141]

In 2008, Acambis announced work on a universal flu vaccine (ACAM-FLU-ATM) based on the less variable M2 protein component of the flu virus shell.[142] See also H5N1 vaccines.

In 2009, the Wistar Institute received a patent for using "a variety of peptides" in a flu vaccine, and announced it was seeking a corporate partner.[143]

In 2010, the National Institute of Allergy and Infectious Diseases (NIAID) of the U.S. NIH announced a breakthrough; the effort targets the stem, which mutates less often than the head of the virus.[144]

DNA vaccines, such as VGX-3400X (aimed at multiple H5N1 strains), contain DNA fragments (plasmids).[140][145] Inovio's SynCon DNA vaccines include H5N1 and H1N1 subtypes.[146]

In July 2011, researchers created an antibody, which targets a protein found on the surface of all influenza A viruses called haemagglutinin.[147][148][149] F16 is the only known antibody that binds (its neutralizing activity is controversial) to all 16 subtypes of the influenza A virus hemagglutinin and might be the lynchpin for a universal influenza vaccine.[147][148][149] The subdomain of the hemagglutinin that is targeted by FI6, namely the stalk domain, was actually successfully used earlier as universal influenza virus vaccine by Peter Palese's research group at Mount Sinai School of Medicine.[150]

Other vaccines are polypeptide based.[151]

By 2010 some universal flu vaccines had started early stage clinical trials.

Based on the results of animal studies, a universal flu vaccine may use a two-step vaccination strategy — priming with a DNA-based HA vaccine followed by a second dose with an inactivated, attenuated, or adenovirus-vector–based vaccine.[158]

Some people given a 2009 H1N1 flu vaccine have developed broadly protective antibodies, raises hopes for a universal flu vaccine.[159][160][161]

On February 13, 2013, U.S. Food and Drug Administration (FDA) Chief Scientist Jesse Goodman predicted that a universal flu vaccine was still 5 to 10 years away. When asked about the prospects of a universal flu vaccine in a hearing before House Energy and Commerce Subcommittee on Oversight and Investigations, Goodman replied "Nature is very tricky and as this is a very crafty virus, so I'd be very hesitant to predict... I think the earliest we'd begin to see something with clinical benefit might be 5 to 10 years."[162]

Veterinary use

"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."[163]

Horses

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 2 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."[164]

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.[165][166]

Poultry

Poultry vaccines for bird flu are made on the cheap 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 1 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.'"[167]

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."[168] 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.[169]

A filtered and purified Influenza A vaccine for humans is being developed 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.[170]

Pigs

Swine origin influenza virus (SoIV) vaccines are extensively used in the swine industry in Europe and North America. Most swine flu vaccine manufacturers include an H1N1 and an H3N2 SoIV strains.

Swine influenza has been recognized as a greater problem since the outbreak in 1976. Evolution of the virus has resulted in inconsistent responses to traditional vaccines. Standard commercial swine origin flu vaccines are effective in controlling the problem when the virus strains match enough to have significant cross-protection and custom (autogenous) vaccines made from the specific viruses isolated are created and used in the more difficult cases.[171] SoIV vaccine manufacture Novartis paints this picture: "A strain of swine origin influenza virus (SoIV) called H3N2, first identified in the US in 1998, has brought exasperating production losses to swine producers. Abortion storms are a common sign. Sows go off feed for two or three days and run a fever up to 106°F. Mortality in a naïve herd can run as high as 15%."[172]

Dogs

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.[173]

References

  1. ↑ Couch, RB (2008). "Seasonal Inactivated Influenza Virus Vaccines". Vaccine. 26 Suppl 4 (Suppl 4): D5–9. doi:10.1016/j.vaccine.2008.05.076. PMC 2643340. PMID 18602728.
  2. ↑ 2.0 2.1 "Key Facts About Seasonal Flu Vaccine"
  3. ↑ 3.0 3.1 3.2 3.3 [No authors listed] (2011-09-09). "Who Should Get Vaccinated Against Influenza". U.S. Centers for Disease Control and Prevention. Retrieved 2013-04-07.
  4. ↑ 4.0 4.1 4.2 World Health Organization. Seasonal Influenza
  5. ↑ 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 3495721. PMID 22777099.
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ Center for Disease Control and Prevention. "Key Facts About Seasonal Flu Vaccine". Retrieved 7 February 2013.
  9. ↑ Comparisons of LAIV and TAIV Efficacy Centers for Disease Control and Prevention (CDC)
  10. ↑ Osterholm, MT; Kelley, NS; Sommer, A; Belongia, EA (January 2012). "Efficacy and effectiveness of influenza vaccines: a systematic review and meta-analysis.". The Lancet. Infectious diseases 12 (1): 36–44. PMID 22032844.
  11. ↑ Fedson DS (1998). "Measuring protection: efficacy versus effectiveness". Dev Biol Stand 95: 195–201. PMID 9855432.
  12. ↑ 12.0 12.1 12.2 12.3 Jefferson T, Di Pietrantonj C, Rivetti A, Bawazeer GA, Al-Ansary LA, Ferroni E (2010). "Vaccines for preventing influenza in healthy adults". Cochrane Database Syst Rev (7): CD001269. doi:10.1002/14651858.CD001269.pub4. PMID 20614424.
  13. ↑ Stephenson, I.; Zambon, M. C.; Rudin, A.; Colegate, A.; Podda, A.; Bugarini, R.; Del Giudice, G.; Minutello, A. et al. (May 2006). "Phase I Evaluation of Intranasal Trivalent Inactivated Influenza Vaccine with Nontoxigenic Escherichia coli Enterotoxin and Novel Biovector as Mucosal Adjuvants, Using Adult Volunteers". J Virol 80 (10): 4962–70. doi:10.1128/JVI.80.10.4962-4970.2006. PMC 1472052. PMID 16641287.
  14. ↑ Jefferson, T. (October 2006). "Influenza vaccination: policy versus evidence". BMJ 333 (7574): 912–5. doi:10.1136/bmj.38995.531701.80. PMC 1626345. PMID 17068038.
  15. ↑ CDC – Influenza (Flu) | Q & A: 2007–08 Flu Season
  16. ↑ CDC – seasonal flu
  17. ↑ Treanor, J.; Kotloff, K.; Betts, R.; Belshe, R.; Newman, F.; Iacuzio, D.; Wittes, J.; Bryant, M. (December 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.
  18. ↑ 18.0 18.1 18.2 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.
  19. ↑ Jefferson T, Di Pietrantonj C, Al-Ansary LA, Ferroni E, Thorning S, Thomas RE (2010). "Vaccines for preventing influenza in the elderly". Cochrane Database Syst Rev (2): CD004876. doi:10.1002/14651858.CD004876.pub3. PMID 20166072.
  20. ↑ 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". Lancet 366 (9492): 1165–74. doi:10.1016/S0140-6736(05)67339-4. PMID 16198765.
  21. ↑ 21.0 21.1 Osterholm MT, Kelley NS, Sommer A, Belongia EA. (2012). "Efficacy and effectiveness of influenza vaccines: a systematic review and meta-analysis.". Lancet Infect Dis. 12 (1): 36–44. doi:10.1016/S1473-3099(11)70295-X. PMID 22032844.
  22. ↑ 22.0 22.1 Burls, A; Jordan, R; Barton, P; Olowokure, B; Wake, B; Albon, E; Hawker, J (8 May 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. PMID 16546308.
  23. ↑ Simonsen L, Viboud C, Taylor RJ, Miller MA, Jackson L (October 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.
  24. ↑ Jefferson, T; Di Pietrantonj, C; Al-Ansary, LA; Ferroni, E; Thorning, S; Thomas, RE (17 February 2010). "Vaccines for preventing influenza in the elderly.". The Cochrane database of systematic reviews (2): CD004876. PMID 20166072.
  25. ↑ Darvishian, M; Bijlsma, MJ; Hak, E; van den Heuvel, ER (December 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.
  26. ↑ Nichol, K.L.; Nordin, J.D.; Nelson, D.B.; Mullooly, J.D.; Hak, E. (2007). "Effectiveness of Influenza Vaccine in the community-dwelling elderly". The New England Journal of Medicine 357 (14): 1373–1381. doi:10.1056/NEJMoa070844. PMID 17914038.
  27. ↑ Simonsen, L.; Taylor, R.J.; Viboud, C.; Miller, M.A.; Jackson, L.A. (2007). "Mortality benefits of influenza vaccination in elderly people: An ongoing controversy". The Lancet Infectious Diseases 7 (10): 658–666. doi:10.1016/S1473-3099(07)70236-0. PMID 17897608.
  28. ↑ Thompson WW, Shay DK, Weintraub E, Brammer L, Cox N, Anderson LJ, Fukuda K (2003). "Mortality associated with influenza and respiratory syncytial virus in the United States". The Journal of the American Medical Association 289 (2): 179–186. doi:10.1001/jama.289.2.179. PMID 12517228.
  29. ↑ "High Dose Flu Vaccine for the Elderly « Science-Based Medicine". Sciencebasedmedicine.org. Retrieved October 17, 2013.
  30. ↑ "CDC – Seasonal Influenza (Flu) – Q & A: Fluzone High-Dose Seasonal Influenza Vaccine". Cdc.gov. August 13, 2013. Retrieved October 17, 2013.
  31. ↑ Thomas RE, Jefferson T, Lasserson TJ (2010). "Influenza vaccination for healthcare workers who work with the elderly". Cochrane Database Syst Rev (2): CD005187. doi:10.1002/14651858.CD005187.pub3. PMID 20166073.
  32. ↑ 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): 918–931. doi:10.1056/NEJMoa1401480. ISSN 0028-4793.
  33. ↑ "Key Facts About Seasonal Flu Vaccine". cdc.gov. Center for Disease Control. Retrieved 26 September 2014.
  34. ↑ CDC – Inactivated Influenza Vaccine 2007–2008 – What You Need To Know
  35. ↑ Flu – LAIV
  36. ↑ Gagnon, R; Primeau MN; Des Roches A; Lemire C; Kagan R; Carr S; Ouakki M; Benoît M; De Serres G (August 2010). "Safe vaccination of patients with egg allergy with an adjuvanted pandemic H1N1 vaccine.". The Journal of Allergy and Clinical Immunology 126 (2): 317–323. doi:10.1016/j.jaci.2010.05.037. PMID 20579720.
  37. ↑ 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.
  38. ↑ Andrew Pollack, "Rapidly Produced Flu Vaccine Wins F.D.A. Approval", The New York Times, January 16, 2013
  39. ↑ Haber P, Sejvar J, Mikaeloff Y, DeStefano F (2009). "Vaccines and Guillain-Barré syndrome". Drug Safety 32 (4): 309–23. doi:10.2165/00002018-200932040-00005. PMID 19388722.
  40. ↑ Kaplan JE, Katona P, Hurwitz ES, Schonberger LB (August 1982). "Guillain-Barré syndrome in the United States, 1979–1980 and 1980–1981. Lack of an association with influenza vaccination". JAMA 248 (6): 698–700. doi:10.1001/jama.248.6.698. PMID 7097920.
  41. ↑ Stowe J, Andrews N, Wise L, Miller E (February 2009). "Investigation of the temporal association of Guillain-Barre syndrome with influenza vaccine and influenzalike illness using the United Kingdom General Practice Research Database". Am. J. Epidemiol. 169 (3): 382–8. doi:10.1093/aje/kwn310. PMID 19033158.
  42. ↑ Sivadon-Tardy V; 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 (January 2009). "Guillain-Barré syndrome and influenza virus infection". Clin. Infect. Dis. 48 (1): 48–56. doi:10.1086/594124. PMID 19025491.
  43. ↑ Vellozzi C, Burwen DR, Dobardzic A, Ball R, Walton K, Haber P (March 2009). "Safety of trivalent inactivated influenza vaccines in adults: Background for pandemic influenza vaccine safety monitoring". Vaccine 27 (15): 2114–2120. doi:10.1016/j.vaccine.2009.01.125. PMID 19356614.
  44. ↑ Steven Reinberg (February 2, 2011). "Last Year's H1N1 Flu Vaccine Was Safe, Study Finds". U.S.News & World Report.
  45. ↑ Sivadon-Tardy V, Orlikowski D, Porcher R; Orlikowski D; Porcher R et al. (January 2009). "Guillain-Barré syndrome and influenza virus infection". Clinical Infectious Diseases 48 (1): 48–56. doi:10.1086/594124. PMID 19025491.
  46. ↑ 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.
  47. ↑ Yong, Ed (18 December 2013). "Narcolepsy confirmed as autoimmune disease". Nature. doi:10.1038/nature.2013.14413.
  48. ↑ Offit PA (September 2007). "Thimerosal and vaccines—a cautionary tale". N Engl J Med (PDF) 357 (13): 1278–9. doi:10.1056/NEJMp078187. PMID 17898096.
  49. ↑ Global Advisory Committee on Vaccine Safety (2006-07-14). "Thiomersal and vaccines". World Health Organization. Retrieved 2007-11-20.
  50. ↑ Morbidity and Mortality Weekly Report (PDF) (Centers for Disease Control) 58 (RR-8): 31. 2009 http://www.cdc.gov/mmwr/pdf/rr/rr5808.pdf. Students or other persons in institutional settings (e.g., those who reside in dormitories or correctional facilities) should be encouraged to receive vaccine to minimize morbidity and the disruption of routine activities during influenza epidemics Missing or empty |title= (help)
  51. ↑ "Immunization to Protect the US Armed Forces: Heritage, Current Practice, and Prospects". Epirev.oxfordjournals.org. 2006-06-08. Retrieved 2014-07-24.
  52. ↑ "MILVAX-VHCN – Influenza – Seasonal". Vaccines.mil. Retrieved 2014-07-24.
  53. ↑ Thomas RE, Jefferson TO, Demicheli V, Rivetti D (2006). "Influenza vaccination for health-care workers who work with elderly people in institutions: a systematic review". Lancet Infect Dis 6 (5): 273–279. doi:10.1016/S1473-3099(06)70462-5. PMID 16631547.
  54. ↑ Skowronski DM, De Serres G (2009). "Is routine influenza immunization warranted in early pregnancy?". Vaccine 27 (35): 4754–70. doi:10.1016/j.vaccine.2009.03.079. PMID 19515466.
  55. ↑ Health Care Guideline: Routine Prenatal Care. Fourteenth Edition. By the Institute for Clinical Systems Improvement. July 2010.
  56. ↑ CDC
  57. ↑ "WHO | World Health Organization". Who.int. Retrieved 2014-07-24.
  58. ↑ "Who Should Get Vaccinated Against Influenza". Centers for Disease Control. Retrieved 14 January 2014.
  59. ↑ "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.
  60. ↑ "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.
  61. ↑ 61.0 61.1 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.
  62. ↑ "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. August 2012. ISSN 0149-2195. PMID 22895385.
  63. ↑ "Children, the Flu, and the Flu Vaccine"
  64. ↑ CDC – Influenza (Flu) | Vaccination: Summary for Clinicians
  65. ↑ Couch, Robert B.; Patricia Winokur, Rebecca Brady, Robert Belshe, Wilbur H. Chen, Thomas R. Cate, Bryndis Sigurdardottir, Amy Hoeper, Irene L. Graham, Robert Edelman, Fenhua He, Diane Nino, Jose Capellan, Frederick L. Ruben (1 November 2007). "Safety and immunogenicity of a high dosage trivalent influenza vaccine among elderly subjects". Vaccine 25 (44): 7656. doi:10.1016/j.vaccine.2007.08.042.
  66. ↑ Tanner, Lindsey (2013-01-13). "Hospitals crack down on workers who refuse flu shots". NBC News. Retrieved 2014-07-24.
  67. ↑ Centers for Disease Control and Prevention (CDC) (December 2010). "Seasonal influenza and 2009 H1N1 influenza vaccination coverage among pregnant women – 10 states, 2009–10 influenza season" (PDF). MMWR Morb Mortal Wkly Rep 59 (47): 1541–5. PMID 21124293. Because pregnant women are at increased risk for severe disease associated with influenza infection, the American College of Obstetricians and Gynecologists and the Advisory Committee on Immunization Practices have recommended seasonal influenza vaccination for women while pregnant, regardless of trimester (1,2). In 2009, a novel strain of influenza A (H1N1) virus was identified (3), and pregnant women also were found at greater risk for influenza-related complications from this new virus (4). As a result, during the 2009–10 influenza season, two separate influenza vaccines were recommended to pregnant women: inactivated trivalent 2009–10 seasonal vaccine and influenza A (H1N1) 2009 monovalent vaccine (2,5)
  68. ↑ Fiore, AE; Shay, DK; Broder, K; Iskander, JK; Uyeki, TM; Mootrey, G; Bresee, JS; Cox, NJ; Centers for Disease Control and Prevention (2009). "Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2009" (PDF). MMWR Recomm Rep 58 (RR–8): 1–52. PMID 19644442. Annual vaccination of all children aged 6 months – 18 years should begin as soon as the 2009–10 influenza vaccine is available. Annual vaccination of all children aged 6 months – 4 years (59 months) and older children with conditions that place them at increased risk for complications from influenza should continue to be a primary focus of vaccination efforts as providers and programs transition to routinely vaccinating all children.
  69. ↑ 69.0 69.1 Altman, Lawrence K. (February 28, 2008). "Panel Advises Flu Shots for Children Up to Age 18". The New York Times.
  70. ↑ Plotkin & Mortimer (1988). Vaccines. Philadelphia: W.B. Saunders Company. ISBN 0-7216-1946-0.
  71. ↑ Product Monograph: Flumist, Astrazeneca Canada Inc., 2011
  72. ↑ immunize.org article Summary of Recommendations for Adult Immunization, which is linked from CDC website CDC
  73. ↑ "The Nasal-Spray Flu Vaccine (Live Attenuated Influenza Vaccine [LAIV])" Centers for Disease Control and Prevention (CDC)
  74. ↑ "Immunization Schedules". CDC. Center for Disease Control and Prevention. Retrieved 4 November 2014.
  75. ↑ Coverage in healthcare workers
  76. ↑ "Influenza Vaccination Coverage Among Health-Care Personnel – United States, 2010–11 Influenza Season". Morbidity and Mortality Weekly Report (MMWR)
  77. ↑ "Influenza vaccination coverage among health-care personnel: 2011–12 influenza season, United States" (PDF). MMWR Morb. Mortal. Wkly. Rep. 61 (38): 753–7. September 2012. ISSN 0149-2195. PMID 23013720.
  78. ↑ 78.0 78.1 how it's made
  79. ↑ 79.0 79.1 79.2 79.3 79.4 New and Old Ways to Make Flu Vaccines, November 8, 2007, National Public Radio.
  80. ↑ WHO:Influenza vaccine viruses and reagents
  81. ↑ "Recommendations for the production and control of influenza vaccine (inactivated)" (PDF). World Health Organization. Retrieved 27 May 2013.
  82. ↑ "Priming with DNA vaccine makes avian flu vaccine work better (NIH News)". October 3, 2011.
  83. ↑ "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.
  84. ↑ "FDA approves first seasonal influenza vaccine manufactured using cell culture technology"
  85. ↑ "November 20, 2012 Approval Letter- Flucelvax"
  86. ↑ PATH, Oliver Wyman. Influenza Vaccine Strategies for Broad Global Access. 2007. http://www.path.org/files/VAC_infl_publ_rpt_10-07.pdf
  87. ↑ Bright, R. A.; Carter, D. M.; Daniluk, S.; Toapanta, F. R.; Ahmad, A.; Gavrilov, V.; Massare, M.; Pushko, P. et al. (May 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.
  88. ↑ 88.0 88.1 Racaniello, Vincent (Dec 2009). "Influenza virus growth in eggs". Virology Blog.
  89. ↑ Izzat, Fakhrul (Apr 2012). "Viral Cultivation in Chicken Embryo". Youtube.
  90. ↑ 90.0 90.1 "How Influenza (Flu) Vaccines Are Made". Centers for Disease Control and Prevention. May 2014.
  91. ↑ WHO article Global influenza surveillance
  92. ↑ Keeping ahead of flu comes down to guessing game : Health and Fitness : Knoxville News Sentinel
  93. ↑ WHO Report on Global Surveillance of Epidemic-prone Infectious Diseases (pdf)
  94. ↑ WHO | Recommended composition of influenza virus vaccines for use in the 2015–2016 northern hemisphere influenza season
  95. ↑ WHO | Recommended composition of influenza virus vaccines for use in the 2015 southern hemisphere influenza season.
  96. ↑ Update on Influenza A (H1N1) 2009 Monovalent Vaccines, 9 October 2009 Accessed 9 February 2015
  97. ↑ Webster, Robert; Walker, Elizabeth (2003). "Influenza". American Scientist 91 (2): 122. doi:10.1511/2003.2.122.
  98. ↑ Blakemore, C. (2006-04-09). "Battle of time, luck and science". The Sunday Times (London). Retrieved 2006-06-22.
  99. ↑ Hilleman, M (19 August 2002). "Realities and enigmas of human viral influenza: pathogenesis, epidemiology and control". Vaccine 20 (25–26): 3068–87. doi:10.1016/S0264-410X(02)00254-2. PMID 12163258.
  100. ↑ "Ten things you need to know about pandemic influenza". World Health Organization. 14 October 2005. Archived from the original on 23 September 2009. Retrieved 26 September 2009.
  101. ↑ Valleron AJ, Cori A, Valtat S, Meurisse S, Carrat F, Boëlle PY (May 2010). "Transmissibility and geographic spread of the 1889 influenza pandemic". Proc. Natl. Acad. Sci. U.S.A. 107 (19): 8778–81. Bibcode:2010PNAS..107.8778V. doi:10.1073/pnas.1000886107. PMC 2889325. PMID 20421481.
  102. ↑ Mills CE, Robins JM, Lipsitch M (December 2004). "Transmissibility of 1918 pandemic influenza". Nature 432 (7019): 904–6. Bibcode:2004Natur.432..904M. doi:10.1038/nature03063. PMID 15602562.
  103. ↑ Donaldson LJ; Rutter PD; Ellis BM et al. (2009). "Mortality from pandemic A/H1N1 2009 influenza in England: public health surveillance study". BMJ 339: b5213. doi:10.1136/bmj.b5213. PMC 2791802. PMID 20007665.
  104. ↑ 104.0 104.1 "ECDC Daily Update – Pandemic (H1N1) 2009 – January 18, 2010" (PDF). European Centre for Disease Prevention and Control. 2010-01-18. Retrieved 2015-02-08.
  105. ↑ Simonsen, L.; Spreeuwenberg, P.; Lustig, R.; Taylor, R. J.; Fleming, D. M.; Kroneman, M.; Van Kerkhove, M. D.; Mounts, A. W.; Paget, W. J. (2013). "Global Mortality Estimates for the 2009 Influenza Pandemic from the GLaMOR Project: A Modeling Study". PLoS Medicine 10 (11): e1001558. doi:10.1371/journal.pmed.1001558. (>40 citations. By the WHO-supported Global Pandemic Mortality (GLaMOR) project)
  106. ↑ Widdowson, M. A.; Iuliano, A. D.; Dawood, F. S. (2014). "Challenges to global pandemic mortality estimation". The Lancet Infectious Diseases 14 (8): 670. doi:10.1016/S1473-3099(14)70835-7.]
  107. ↑ The Threat of Pandemic Influenza: Are We Ready? Workshop Summary (2005) (free online book) page 62
  108. ↑ 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.
  109. ↑ Artenstein, A.W. "Influenza" In: Vaccines: A Biography Andrew W. Artenstein, ed. pp. 191–205.
  110. ↑ Hampson, AW. Vaccines for Pandemic Influenza. The History of our Current Vaccines, their Limitations and the Requirements to Deal with a Pandemic Threat. Ann Acad Med Singapore 2008;37:510-7.
  111. ↑ USFDA FDA approves first seasonal influenza vaccine manufactured using cell culture technology. November 20, 2012.
  112. ↑ USFDA FDA approves new seasonal influenza vaccine made using novel technology. Jan. 16, 2013.
  113. ↑ Landry, Nathalie; Brian J. Ward, Sonia Trépanier, Emanuele Montomoli, Michèle Dargis, Giulia Lapini, Louis-P. Vézina (2010-12-22). "Preclinical and Clinical Development of Plant-Made Virus-Like Particle Vaccine against Avian H5N1 Influenza". PLOS One 5 (12). Bibcode:2010PLoSO...515559L. doi:10.1371/journal.pone.0015559. PMC 3008737. PMID 21203523. Retrieved 14 May 2013.
  114. ↑ CDC report Prevention and Control of Influenza published April 12, 2002.
  115. ↑ Osterholm, Michael T. (2005). "Preparing for the Next Pandemic". New England Journal of Medicine 352 (18): 1839–42. doi:10.1056/NEJMp058068. PMID 15872196.
  116. ↑ The Sky is Falling: An Analysis of the Swine Flu Affair of 1976
  117. ↑ McCullers JA, Van De Velde LA, Allison KJ, Branum KC, Webby RJ, Flynn PM (June 2010). "Vaccinees against the 1976 "swine flu" have enhanced neutralization responses to the 2009 novel H1N1 influenza virus". Clin. Infect. Dis. 50 (11): 1487–92. doi:10.1086/652441. PMC 2946351. PMID 20415539.
  118. ↑ Jit, Mark; Newall, Anthony T.; Beutels, Philippe (1 April 2013). "Key issues for estimating the impact and cost-effectiveness of seasonal influenza vaccination strategies". Human vaccines & immunotherapeutics 9 (4): 834–840. doi:10.4161/hv.23637.
  119. ↑ Postma, M.J; Baltussen, R.P.M.; Palache, A.M; Wilschut, J.C. (2006). "Further evidence for favorable cost-effectiveness of elderly influenza vaccination". Expert Review of Pharmacoeconomics and Outcomes Research 6 (2): 215–27. doi:10.1586/14737167.6.2.215. PMID 20528557.
  120. ↑ Newall, AT; Kelly, H; Harsley, S; Scuffham, PA (2009). "Cost Effectiveness of Influenza Vaccination in Older Adults". PharmacoEconomics 27 (6): 439–50. doi:10.2165/00019053-200927060-00001. PMID 19640008.
  121. ↑ Newall, AT; Viboud, C; Wood, JG (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.
  122. ↑ Newall, Anthony T.; Dehollain, Juan Pablo; Creighton, Prudence; Beutels, Philippe; Wood, James G. (4 May 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.
  123. ↑ Newall, A.T.; Scuffham, P.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.
  124. ↑ Gatwood, J; Meltzer, MI; Messonnier, M; Ortega-Sanchez, IR; Balkrishnan, R; Prosser, LA (2012). "Seasonal Influenza Vaccination of Healthy Working-Age Adults". Drugs 72 (1): 35–48. doi:10.2165/11597310-000000000-00000. PMID 22191794.
  125. ↑ Newall, Anthony T.; Jit, Mark; Beutels, Philippe (August 1, 2012). "Economic Evaluations of Childhood Influenza Vaccination". PharmacoEconomics 30 (8): 647–660. doi:10.2165/11599130-000000000-00000.
  126. ↑ Newall, A.T.; Wood, J.G.; Oudin, N.; MacIntyre, C.R. (2010). "Cost-effectiveness of pharmaceutical-based pandemic influenza mitigation strategies". Emerging Infectious Diseases 16 (2). doi:10.3201/eid1602.090571.
  127. ↑ "Influenza Genome Sequencing Project – Overview". National Institutes of Health – National Institute of Allergy and Infectious Diseases. Retrieved 27 May 2013.
  128. ↑ World Health Organization. Acyte Respiratory Infections: Influenza. 2009. http://www.who.int/vaccine_research/diseases/ari/en/index1.html
  129. ↑ 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
  130. ↑ 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
  131. ↑ "First Quadrivalent Vaccine Against Seasonal Flu Wins FDA Approval"
  132. ↑ "FDA approves first quadrivalent vaccine to prevent seasonal influenza"
  133. ↑ "December 14, 2012 Approval Letter- Fluarix Quadrivalent"
  134. ↑ Du, Lanying; Zhou, Yusen; Jiang, Shibo (2010). "Research and development of universal influenza vaccines". Microbes and Infection 12 (4): 280–6. doi:10.1016/j.micinf.2010.01.001. PMID 20079871.
  135. ↑ <http://www.fiercebiotech.com/press-releases/biondvax-begins-phase-iia-study-universal-flu-vaccine-0>
  136. ↑ Seattle's Theraclone makes a 'first step' on long road to universal flu vaccine. The Seattle Times.
  137. ↑ Dynavax Reports Positive Data on Universal Flu Vaccine Candidate. Rita Biotech.
  138. ↑ VaxInnate's Universal Flu Vaccine Candidate Shown Safe and Immunogenic in Phase I Clinical Study. Fierce Biotech.
  139. ↑ Johnson & Johnson pursues vaccine firm. Charleston Gazette.
  140. ↑ 140.0 140.1 "Inovio Pharmaceuticals, Inc. Immunizes First Subject In U.S. Influenza DNA Vaccine Clinical Trial". Reuters.
  141. ↑ Immune Targeting Systems – About Us
  142. ↑ "Universal Influenza Vaccine Tested Successfully In Humans".
  143. ↑ The Wistar Institute obtains patent for universal flu vaccine technology. Wistar Institute.
  144. ↑ NIH Scientists Advance Universal Flu Vaccine. NIH.
  145. ↑ Inovio Biomedical's SynCon preventive DNA vaccine receives approval in Korea for Phase I clinical trial
  146. ↑ "Scientific Paper on Inovio Pharmaceuticals SynCon(TM) DNA Vaccines and Intradermal DNA Delivery Technology One of Most Cited Articles in the Journal Vaccine". October 14, 2010.
  147. ↑ 147.0 147.1 BBC: 'Super antibody' fights off flu
  148. ↑ 148.0 148.1 Independent: Scientists hail the prospect of a universal vaccine for flu
  149. ↑ 149.0 149.1 "Universal Flu Vaccine On The Horizon: Researchers Find 'Super Antibody'" The Huffington Post. July 28, 2011
  150. ↑ Influenza Virus Vaccine Based on the Conserved Hemagglutinin Stalk Domain
  151. ↑ Wang TT, Tan GS, Hai R, Pica N, Ngai L, Ekiert DC, Wilson IA, García-Sastre A, Moran TM (November 2010). "Vaccination with a synthetic peptide from the influenza virus hemagglutinin provides protection against distinct viral subtypes.". Proc Natl Acad Sci U S A 107 (44): 18979–84. Bibcode:2010PNAS..10718979W. doi:10.1073/pnas.1013387107. PMC 2973924. PMID 20956293.
  152. ↑ Hidden weakness could yield universal flu vaccine – health – February 24, 2009 – New Scientist
  153. ↑ http://biopharminternational.findpharma.com/biopharm/News/Phase-1-2-Completed-for-Universal-Influenza-Vaccin/ArticleStandard/Article/detail/651691, 2010
  154. ↑ "BiondVax Begins Phase IIa Study for Universal Flu Vaccine". October 14, 2010.
  155. ↑ "Dynavax Presents Data From Novel Universal Flu Vaccine Candidate". 2009.
  156. ↑ MarketWatch.com
  157. ↑ Immune Targeting Systems – FP01 Influenza, undated page
  158. ↑ Lambert and Fauci; Fauci, Anthony S. (2010). "Influenza Vaccines for the Future". NEJM 363 (21): 2036–44. doi:10.1056/NEJMra1002842. PMID 21083388.
  159. ↑ "H1N1 Gives Clues to Universal Flu Vaccine". January 18, 2011.
  160. ↑ Wrammert; Koutsonanos, D.; Li, G.-M. et al. (January 2011). "Broadly cross-reactive antibodies dominate the human B cell response against 2009 pandemic H1N1 influenza virus infection" (PDF). JEM 208: 181–193. doi:10.1084/jem.20101352.
  161. ↑ "A vaccine for all flu seasons". Spring 2011.
  162. ↑ Roos, Robert. "FDA expert: Universal flu vaccine still 5–10 years off". Center for Infectious Disease Research and Policy (CIDRAP). Retrieved Feb 13, 2013.
  163. ↑ Influenza Report (online book) chapter Avian Influenza by Timm C. Harder and Ortrud Werner
  164. ↑ equiflunet_vaccines
  165. ↑ UAE Equestrian & Racing Federation
  166. ↑ FEI guidelines
  167. ↑ McNeil, Donald G. Jr. (May 2, 2006). "Turning to Chickens in Fight With Bird Flu". The New York Times.
  168. ↑ SciDev.Net article Bird flu warning over partial protection of flocks published August 16, 2006
  169. ↑ 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
  170. ↑ Yen, Hui-Ling; Joseph Sriyal Malik Peiris (21 June 2012). "Virology: Bird flu in mammals". Nature 486 (7403): 332–333. Bibcode:2012Natur.486..332Y. doi:10.1038/nature11192. PMID 22722190. Retrieved 27 May 2013.
  171. ↑ National Hog Farmer article Swine Flu Virus Turns Endemic published September 15, 2007
  172. ↑ livestock.novartis.com Custom Vaccines: Swine
  173. ↑ Karaca K, Dubovi E, Siger L, Robles A, Audonnet J, Jiansheng Y, Nordgren R, Minke J; Dubovi; Siger; Robles; Audonnet; Jiansheng; Nordgren; Minke (2007). "Evaluation of the ability of canarypox-vectored equine influenza virus vaccines to induce humoral immune responses against canine influenza viruses in dogs". Am. J. Vet. Res. 68 (2): 208–12. doi:10.2460/ajvr.68.2.208. PMID 17269888.

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