Influenza vaccine

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Model of Influenza Virus from U.S. National Institutes of Health

The influenza vaccination is an annual vaccination using a vaccine 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, also known as a flu shot, 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]

Overall most seasonal influenza vaccines showed efficacy or effectiveness, which was acceptable or high for laboratory-confirmed cases and of modest magnitude for clinically-confirmed cases.[5] Influenza vaccine effectiveness can vary from year to year and among different age and risk groups.[6] Despite somewhat limited research, the safety of flu vaccines is reassuring; there is no evidence that they can cause serious harm, and no reason for serious side effects to be a concern.[5] The flu vaccine is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.[7]

Medical uses[edit]

The WHO recommends annual vaccination for (in order of priority): nursing-home residents (the elderly or disabled), people with chronic medical conditions, elderly individuals and other groups such as pregnant women, health care workers, those with essential functions in society, as well as children from ages six months to two years.[8]

According to the US CDC everyone who is at least 6 months of age should get a flu vaccine in 2013-2014. This recommendation has been in place since February 24, 2010 when CDC’s Advisory Committee on Immunization Practices (ACIP) voted for “universal” flu vaccination in the United States to expand protection against the flu to more people. Vaccination is especially important for some people:

People who are at high risk of developing serious complications (like pneumonia) if they get sick with the flu like people who have certain medical conditions including asthma, diabetes, and chronic lung disease, pregnant women, people younger than 5 years (and especially those younger than 2), and people 65 years and older. Also people with heart disease, diabetes mellitus, kidney disease, weakened immune system and morbidly obese people.

People who live with or care for others who are at high risk of developing serious complications as household contacts and caregivers of people with certain medical conditions including asthma, diabetes, and chronic lung disease, household contacts and caregivers of infants less than 6 months old, health care personnel.[9]

Seasonal flu[edit]

An influenza epidemic emerges during flu season each winter. There are two flu seasons annually, corresponding to the occurrence of winter in the Northern and Southern Hemispheres (winter in one hemisphere is at the same time as summer in the other).

Although difficult to assess, these annual epidemics are thought to result in between three and five million cases of severe illness and between 250,000 and 500,000 deaths every year around the world.[10] Tens of thousands of Americans die in a typical flu season, but there are notable variations from year to year. In 2010 the Centers for Disease Control and Prevention (CDC) in the United States changed the way it reports the 30-year estimates for deaths from influenza. They are reported as a range from a low of about 3,300 deaths to a high of 49,000 per year over the past 30 years.[11][12]

The majority of influenza-caused deaths in the industrialized world occur in adults aged 65 and over.[4] 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.[13]

A review at the National Institute of Allergy and Infectious Diseases (NIAID) division of the National Institutes of Health (NIH) in 2008 concluded that "Seasonal influenza causes more than 200,000 hospitalizations and 41,000 deaths in the U.S. each year, and is the seventh leading cause of death in the U.S."[14] The average total economic costs caused by the annual influenza outbreak in the U.S. have been estimated at over $80 billion.[15][16]

The number of annual influenza-related hospitalizations is many times the number of deaths.[17] "The high costs of hospitalizing young children for influenza creates a significant economic burden in the United States"[18] The CDC has projected that a total of 38 million days of school were missed by American students due to the flu.[19]

Efficacy and effectiveness[edit]

A vaccine is assessed by its efficacy; the extent to which it reduces risk of disease under controlled conditions (clinical trial), and its effectiveness, the observed reduction in risk after the vaccine is put into use (observational study).[20] 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.[21]

Overall most seasonal influenza vaccines showed statistically significant efficacy/effectiveness, which was acceptable or high for laboratory-confirmed cases and of modest magnitude for clinically-confirmed cases.[22] Studies on the effectiveness of flu vaccines in the real world are uniquely difficult; vaccines may be imperfectly matched, virus prevalence varies widely between years, and influenza is often confused with other influenza-like illnesses.[23] However, in most years (16 of the 19 years before 2007), the flu vaccine strains have been a good match for the circulating strains,[24] and even a mis-matched vaccine can often provide cross-protection.[25]

Nevertheless, multiple clinical trials and observational studies of both live and inactivated influenza vaccines against seasonal influenza have been performed and their results pooled and analyzed in several systematic reviews on different groups. Those examined the efficacy and effectiveness of vaccines against seasonal influenza in adults,[26] children,[27] the elderly[28][29] and people at risk of complications.

In healthy adults a meta-analysis of cohort studies and clinical trials on the effectiveness of influenza vaccination trials conducted between 1967 and 2011, found the pooled efficacy of flu shots was 59%. So for healthy, working adults, influenza vaccines could provide moderate protection against virologically confirmed influenza, but such protection was greatly reduced or absent in some seasons.[30] In adults the overall effectiveness of parenteral inactivated vaccine against influenza-like illness is limited, corresponding to a number needed to vaccinate (NNV) of 40. So 40 persons have to get a flu shot for one to avoid the "flu". The overall efficacy of inactivated vaccines in preventing confirmed influenza has a number needed to vaccinate (NNV) of 71. So 71 people have to get a flu shot to prevent one confirmed seasonal influenza. The difference between these two values depends on the different incidence of influenza-like illness and confirmed influenza among the study populations: 15.6% of unvaccinated participants versus 9.9% of vaccinated participants developed influenza-like illness symptoms, whilst only 2.4% and 1.1%, respectively, developed laboratory-confirmed influenza. There were no RCTs assessing vaccination in pregnant women found and the only evidence available came from observational studies with modest methodological quality. Vaccination had a modest effect on time off work and had no effect on hospital admissions or complication rates.[26]

In adults live aerosol vaccines had an overall effectiveness corresponding to a number needed to vaccinate (NNV) of 46. The performance of one-dose or two-dose whole virion pandemic vaccines was higher, showing a number needed to vaccinate (NNV) of 16 against influenza-like illness and a NNV of 35 against influenza, while a limited impact on hospitalisation was found NNV 94.[26]

In children older than two years influenza vaccines are efficacious in preventing influenza. In children under the age of two the data for live attenuated vaccine are extremely limited and vaccination with inactivated vaccines appeared to have no measurable benefit. In children under the age of six, 6 need to be vaccinated with live attenuated vaccine to prevent one case of influenza (efficacy). In children over the age of six, 28 need to be vaccinated with inactivated vaccine to prevent one case of influenza (efficacy) and 8 to prevent one case of influenza-like-illness (effectiveness). There was no proof of effect on secondary cases, lower respiratory tract disease, drug prescriptions, otitis media and socio-economic impact.[27] Pooled efficacy of living attenuated vaccine was 83% in children aged 6 months to 7 years. No such trials met inclusion criteria for children aged 8–17 years.[30] In an overarching meta-analysis for laboratory confirmed cases vaccine efficacy was around 60% for parenteral inactivated vaccines and around 68% for living attenuated vaccines, and for clinically confirmed cases respectively 38% and 33%.[5]

In the elderly earlier individual cohort studies and a 2002 meta analyses from observational studies showed effectiveness. The meta analysis found reduced mortality from all causes by 50%.[31][32][33] Several research groups have shown that some previous observational studies overestimated the mortality benefits of flu vaccination in the elderly. The studies were shown to be unreliable because of the "healthy user effect". Reasonably healthy elderly people were more likely to be vaccinated, and those in poorer health were less likely to be vaccinated and more likely to die for any reason.[34] So systematic reviews found that there is still insufficient overall evidence to draw clear conclusions on the effectiveness of vaccination in the elderly,[28][29][30][35] including a new high-dose flu vaccine for which available evidence indicates that the it produces a stronger immune response.[36] One systematic review found that evidence for protection in adults aged 65 years or older was lacking,[30] another found the available evidence was of poor quality and provided no guidance regarding the safety, efficacy or effectiveness of influenza vaccines for people aged 65 years or older.[29] Moreover, it is well known that people over 65 years mount a weaker immune response to flu vaccines than younger adults do, as measured by antibody titers.[37] 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.[38]

Research is still lacking on the issues of the efficacy or effectiveness of influenza vaccination in people with serious medical conditions which place them at higher risk of complications. Data were insufficient for the effect from vaccination on prevention of coronary heart disease.[39] A later meta analysis based on 6 clinical trials found, within one year in those at high risk of cardiovascular events, immunization might reduce the risk of major adverse cardiovascular events with a number needed to treat of 58 to prevent 1 major adverse cardiovascular event, with most effect in people with a recent acute coronary syndrome. A Dare critical appraisal found uncertainties surrounding the generally small and heterogeneous evidence base, and that the reliability of the findings remained uncertain and that they should be considered preliminary.[40] In people with chronic obstructive pulmonary disease there was a decrease of exacerbations against placebo. There was not enough data to find an effect on mortality.[41] In people with asthma (18 trials),[42] or with bronchiectasis[43] or cystic fibrosis disease[44] effects are uncertain. In children with asthma in one trial there were no differences in the number of people experiencing an asthma attack (worsening of symptoms); however, people reported fewer asthma symptoms in weeks in which children had a positive test for influenza.[45]

Vaccination is widely recommended for immunocompromised people as because they are vulnerable to severe or complicated influenza infection. A systematic review (209 studies, only 23 RCTs) about people with immunodepression as cancer, HIV and transplant patients found a high risk of bias in many studies. It showed a lower chance of preventing influenza-like illness and laboratory confirmed influenza by vaccinating immunocompromised patients compared to placebo or unvaccinated controls. It concluded that potential for bias and confounding and the presence of heterogeneity showed the evidence reviewed was generally weak, although the directions of effects were consistent.[46] In people with haematological malignancies there was a lower risk of lower respiratory infections and hospitalisations, but the quality of evidence was low.[47] In children treated with chemotherapy for cancer,[48] in immunosuppressed adults with cancer[49] and in people with HIV infections[50] effects are uncertain.

Influenza vaccination has been shown highly effective in health care workers, with minimal adverse effects. In a study of forty matched nursing homes, staff influenza vaccination rates were 69.9% in the vaccination arm versus 31.8% in the control arm. The vaccinated staff experienced a 42% reduction in sick leave from work (P=.03).[51] A review of eighteen studies likewise found a strong net benefit to health care workers.[52] Of these eighteen health care worker 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.[52] Even though a 2010 Cochrane found no effect on laboratory-proven influenza, nor in pneumonia or deaths from pneumonia in people over 60 years old in long-term care facilities who were cared for by vaccinated health care workers from, vaccination of health care providers was nonetheless found to reduce patient influenza like infections and all-cause patient mortality .[53]

Duration of protection[edit]

According to work published in 1973, 1983, and 2004, after vaccination against seasonal flu, antibody titres peak after typically two to four weeks. They decrease by about 50% over the next six months (the decrease is less for older adults), then remain stable for two to three years; protection without revaccination persists for at least three years for children and young adults.[54]

The limited studies available do provide some evidence of a long-term immune effect. Immunity apparently does last a lifetime where it results from an actual flu infection, (as distinct from simply a vaccination). A 2008 study, published in Nature, found that 90 years after the 1918 pandemic, survivors had antibody-producing cells that produced antibodies with "remarkable power to block 1918 flu virus infection in mice, proving that, even nine decades after infection with this virus, survivors retain protection from it".[55] As to long-term immunity from vaccination, a 2010 study found a significantly enhanced immune response against the 2009 pandemic H1N1 in study participants who had received vaccination against a different swine flu outbreak in 1976, over 30 years before.[56]

Injection versus nasal spray [edit]

Flu vaccines are available either as

TIV (trivalent inactivated influenza vaccine) induces protection after injection (typically intramuscular, though subcutaneous and intradermal routes can also be protective)[57] 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.[58]

LAIV (live attenuated influenza vaccine) is not recommended for individuals under age 2 or over age 50,[59] but might be comparatively more effective among children over age 2.[60]

Cross-protection[edit]

Annual seasonal flu vaccination provides some protection against flu viruses that the vaccine was not designed for, including novel viruses.[61] The CDC made the following statement in relation to the 2007-2008 vaccine:

...[A]ntibodies made in response to vaccination with one strain of influenza viruses can provide protection against different, but related strains. A less than ideal match may result in reduced vaccine effectiveness against the variant viruses, but it still can provide enough protection to prevent or lessen illness severity and prevent flu-related complications. In addition, it is important to remember that the influenza vaccine contains three virus strains so the vaccine can also protect against the other two viruses. For these reasons, even during seasons when there is a less than ideal match, CDC continues to recommend influenza vaccination. This is particularly important for people at high risk for serious flu complications and their close contacts.[25]

Side effects[edit]

Overall data on vaccine harms are reassuring, but their value is diminished by inconsistent reporting.[5] The side effects of vaccine are almost always minor, and are far less costly overall than the public and personal effects of unprotected exposure to the influenza virus, with its attendant risks of hospitalization or death.

Flu vaccination may lead to side effects such as runny nose and sore throat, which can last for up to several days.[citation needed] Egg allergy may also be a concern, since flu vaccines are typically made using eggs,[62][63] however research into egg-allergy and influenza vaccination [64] has led some advisory groups to recommend vaccine delivery protocols for egg allergic persons.[65]

The evidence for a causal association of influenza vaccine and Guillain-Barré is strongest for the swine influenza vaccine that was used in 1976-77. There was an estimated relative risk of Guillain-Barré of 7 - 8 after vaccination.[citation needed] Studies of influenza vaccines used in subsequent years, however, have found small or no increased risk of Guillain-Barré. [66] A US review found an incidence of about one case of Guillain-Barré per million influenza vaccinations.[67] Getting infected by influenza itself 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).[68][69]

Several studies in Finland, Sweden, Ireland, France, UK and Norway have identified an increased incidence of narcolepsy among recipients of the pandemic H1N1 influenza ASO3-adjuvanted vaccine in children and adolescents.[70] Efforts to identify a mechanism for this suggest that narcolepsy is autoimmune, and that the H1N1 vaccine may mimic hypocretin, serving as a trigger.[71]

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,[72] 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.[73]

Cost-effectiveness[edit]

The cost-effectiveness of seasonal influenza vaccination has been widely evaluated for different groups and in different settings.[74] 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.[75] 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.[76] The uncertainty in influenza cost-effectiveness models can partially be explained by the complexities involved in estimating the disease burden,[77] as well as the seasonal variability in the circulating strains and the match of the vaccine.[78][79] 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.[80] 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.[81] 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.[82]

Vaccination recommendations[edit]

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 patients 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.[87]

As of 2013, the UN World Health Organization recommends vaccination for, in order of priority:[88]

  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:

  • Children younger than 2 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[89]

National advice on flu vaccination[edit]

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.[90] The NACI also recommends the flu vaccine for:[91]

  • People at high risk of influenza-related complications or hospitalization, including the morbidly obese, healthy pregnant women, children 6 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

In the United States, "Routine influenza vaccination is recommended for all persons aged ≥ 6 months" since 2010.[92][93][94]

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.[95] 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.[96]

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.[97]

Manufacturing[edit]

Schematic of influenza vaccine creation

Flu vaccine is usually grown by vaccine manufacturers in fertilized chicken eggs.[98][99] In the Northern hemisphere, the manufacturing process begins following the announcement (typically in February) of the WHO recommended strains for the winter flu season.[98][100] 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.[101]

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.[99] The European Union has also approved Optaflu, a vaccine produced by Novartis using vats of animal cells.[99] 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.[99] 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.[99]

A DNA-based vaccination, which is hoped to be even faster to manufacture, is as of 2011 in clinical trials, determining safety and efficacy.[102]

On November 20, 2012, Novartis received FDA approval for the first cell-culture vaccine.[103][104][105]

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.[106] 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).[107]

Annual reformulation[edit]

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."[108]

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.[109]

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).[110]

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

2014-2015 Northern Hemisphere influenza season[edit]

The composition of trivalent virus vaccines for use in the 2014-2015 Northern Hemisphere influenza season recommended by the World Health Organization on February 20, 2014 was:

  • an A/California/7/2009 (H1N1)pdm09-like virus;
  • an A/Texas/50/2012 (H3N2)-like virus
  • B/Massachusetts/2/2012-like virus.

The WHO recommends that quadrivalent vaccines containing two influenza B viruses contain the above three viruses and a B/Brisbane/60/2008-like virus.[111]

2014 Southern Hemisphere influenza season[edit]

The composition of virus vaccines for use in the 2014 Southern Hemisphere influenza season recommended by the World Health Organization September 26, 2013 was:

  • an A/California/7/2009 (H1N1)pdm09-like virus;
  • an A/Texas/50/2012 (H3N2)-like virus;
  • a B/Massachusetts/2/2012-like virus.

It is recommended that quadrivalent vaccines containing two influenza B viruses contain the above three viruses and a B/Brisbane/60/2008-like virus.[112]

The H1N1 strain used in these compositions is the same strain used in the 2009 flu pandemic vaccine, now known as A(H1N1)pdm09.[113] As of December 2013, vaccine manufacturers estimate that 138-145 million doses of flu vaccine to be produced during the 2013-2014 Northern Hemisphere influenza season.[114]

2014 Vaccine Products[edit]

Every year, multiple manufacturers produce and market the influenza vaccination. Below is a list of the common vaccinations available:[115]

•Flulaval - Distributed by GlaxoSmithKline and manufactured in Quebec City, QC, Canada.[116]
•Afluria - Distributed by Merck and manufactured in Parkville, Victoria Australia.[117]
•Fluarix - Distributed by GlaxoSmithKline and manufactured in Dresden, Germany.[118]
•Fluvirin -Distributed by Novartis and manufactured in Liverpool, UK[119]
•Fluzone - Distributed by Sanofi Pasteur and manufactured in Swiftwater, PA 18370 USA.[120]

History[edit]

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.[121] However, the etiological cause of influenza, the orthomyxoviridae was discovered by the Medical Research Council (MRC) of the United Kingdom in 1933.[122]

Known flu pandemics[123][124]
Name of pandemic Date Deaths Case fatality rate Subtype involved Pandemic severity index
1889–1890 flu pandemic
(Asiatic or Russian Flu)[125]
1889–1890 1 million 0.15% possibly H3N8
or H2N2
NA
1918 flu pandemic
(Spanish flu)[126]
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[127][128] 2009–2010 18,000 0.03% H1N1 NA

Origins and development[edit]

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."[129]

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.[130] In the 1940s, the US military developed the first approved inactivated vaccines for influenza, which were used in the Second World War.[131] 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.[132] Recently, the US FDA has approved influenza vaccines made by growing virus in cell cultures[133] and influenza vaccines made from recombinant proteins[134] have been approved, with plant-based influenza vaccines being tested in clinical trials.[135]

Acceptance[edit]

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".[136]

The egg-based technology (still in use as of 2005) for producing influenza vaccine was created in the 1950s.[137] 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.[138] 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.[56]

Research[edit]

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[139] 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.

According to VaccineNewsDaily, a recent study published in Vaccines found that by providing a school-located vaccination clinic, flu vaccination rates among children increased 13.2 percent when compared to children in schools without vaccination clinics. The vaccine can be lifesaving for children and less costly than a doctor's office visit.[140]

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).[141] As of July 2009, more than 70 known clinical trials have been completed or are ongoing for pandemic influenza vaccines.[142] 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.[143] A quadrivalent flu vaccine administered by nasal mist was approved by the U.S. Food and Drug Administration (FDA) in March 2012.[144][145] Fluarix Quadrivalent was approved by the FDA in December 2012.[146]

Prospects for universal flu vaccines[edit]

Many groups worldwide are pursuing development of a universal flu vaccine that does not require modification each year.[147] Companies pursuing the vaccine as of 2009 and 2010 include BiondVax,[148] Theraclone,[149] Dynavax Technologies Corporation,[150] VaxInnate,[151] Crucell NV,[152] Inovio Pharmaceuticals,[153] and Immune Targeting Systems (ITS)[154]

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.[155] The vaccine was tested in a human trial in the United States, where it was reported in 2008 to have developed antibodies against flu virus in 90% of individuals; further human trials were planned.[156] 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.[157]

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.[158]

DNA vaccines, such as VGX-3400X (aimed at multiple H5N1 strains), contain DNA fragments (plasmids).[153][159] Inovio's SynCon DNA vaccines include H5N1 and H1N1 subtypes.[160]

In July 2011, researchers created an antibody, which targets a protein found on the surface of all influenza A viruses called haemagglutinin.[161][162][163] 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.[161][162][163] 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.[164]

Chimeric hemagglutinin constructs that contain exotic head domains with conserved stalk regions have also been proposed and created to elicit the generation of stalk-specific antibodies. Studies in mice that have been repeatedly immunized with such constructs showed robust protection and broad-based immunity against several strains of viruses. A proposed universal flu vaccination strategy includes a priming vaccine followed by two booster vaccines.[165][166]

Other vaccines are polypeptide based.[167]

Some universal flu vaccines have started early stage clinical trials.

  • BiondVax are targeting the less variable stalk of the haemagglutinin molecule[168] with Multimeric-001.[169] This is aimed at type A (inc H1N1) and Type B influenza and has started a phase IIa study.[170]
  • Dynavax have developed a vaccine N8295 based on two highly conserved antigens NP and M2e[171] and their TLR9 agonist, and started clinical trials in June 2010.[172]
  • ITS's fp01[173] includes 6 peptide antigens to highly conserved segments of the PA, PB1, PB2, NP & M1 proteins, and has started phase I 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.[174]

Some people given a 2009 H1N1 flu vaccine have developed broadly protective antibodies, raises hopes for a universal flu vaccine.[175][176][177]

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."[178]

Veterinary use[edit]

"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."[179]

Horses[edit]

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."[180]

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.[181][182]

Poultry[edit]

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.'"[183]

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."[184] 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.[185]

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.[186]

Pigs[edit]

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.[187] 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%."[188]

Dogs[edit]

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.[189]

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