<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Influenza vaccine and can you explain it in depth? [/INST] Influenza vaccines, also known as flu shots, are vaccines that protect against infection by influenza viruses. New versions of the vaccines are developed twice a year, as the influenza virus rapidly changes. While their effectiveness varies from year to year, most provide modest to high protection against influenza. The United States Centers for Disease Control and Prevention (CDC) estimates that vaccination against influenza reduces sickness, medical visits, hospitalizations, and deaths. Immunized workers who do catch the flu return to work half a day sooner on average. Vaccine effectiveness in those over 65 years old remains uncertain due to a lack of high-quality research. Vaccinating children may protect those around them.Vaccination against influenza began in the 1930s, with large-scale availability in the United States beginning in 1945. It is on the World Health Organizations List of Essential Medicines.The World Health Organization (WHO) and the CDC recommend yearly vaccination for nearly all people over the age of six months, especially those at high risk. The European Centre for Disease Prevention and Control (ECDC) also recommends yearly vaccination of high risk groups. These groups include pregnant women, the elderly, children between six months and five years of age, and those with certain health problems.The vaccines are generally safe; fever occurs in five to ten percent of children vaccinated, and temporary muscle pains or feelings of tiredness may occur. In certain years, the vaccine was linked to an increase in Guillain–Barré syndrome among older people at a rate of about one case per million doses. Although most influenza vaccines are produced using egg proteins, they are still recommended as safe for people who have severe egg allergies, as no increased risk of allergic reaction to the egg-based vaccines has been shown for people with egg allergies. Vaccines produced using other technologies, notably recombinant vaccines and those based on cell culture rather than egg protein, started to become available from 2012 in the US, and later in Europe and Australia. Influenza vaccines are not recommended in those who have had a severe allergy to previous versions of the vaccine itself. The vaccine comes in inactive and weakened viral forms. The live, weakened vaccine is generally not recommended in pregnant women, children less than two years old, adults older than 50, or people with a weakened immune system. Depending on the type they can be injected into a muscle, sprayed into the nose, or injected into the middle layer of the skin (intradermal). The intradermal vaccine was not available during the 2018–2019 and 2019–2020 influenza seasons.

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

Origins and development
In the worldwide Spanish flu pandemic of 1918, "Pharmacists 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 serums (chiefly against what we now call Hemophilus influenzae – a name derived from the fact that it was originally considered the etiological agent – and several types of pneumococci). Only one therapeutic measure, transfusing blood from recovered patients to new victims, showed any hint of success."In 1931, viral growth in embryonated hens eggs was reported by Ernest William Goodpasture and colleagues at Vanderbilt University. The work was extended to growth of influenza virus by several workers, including Thomas Francis, Jonas Salk, Wilson Smith and Macfarlane Burnet, leading to the first experimental influenza vaccines. In the 1940s, the US military developed the first approved inactivated vaccines for influenza, which were used in the Second World War. Hens 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. In 2012, the US Food and Drug Administration (FDA) approved influenza vaccines made by growing virus in cell cultures and influenza vaccines made from recombinant proteins have been approved, with plant-based influenza vaccines being tested in clinical trials.

Acceptance
The egg-based technology for producing influenza vaccine was created in the 1950s. In the US 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 25 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, demonstrating that the vaccine itself is not free of risks. The result can be cited to support lingering doubts about vaccination as well as to counter ungrounded claims about the safety of vaccination. In the end, however, even the maligned 1976 vaccine may have saved lives. A 2010 study found a significantly enhanced immune response against the 2009 pandemic H1N1 in study participants who had received vaccination against the swine flu in 1976.

Quadrivalent vaccines for seasonal flu
A quadrivalent flu vaccine administered by nasal mist was approved by the FDA in March 2012. Fluarix Quadrivalent was approved by the FDA in December 2012.In 2014, the Canadian National Advisory Committee on Immunization (NACI) published a review of quadrivalent influenza vaccines.Starting with the 2018–2019 influenza season most of the regular-dose egg-based flu shots and all the recombinant and cell-grown flu vaccines in the United States are quadrivalent. In the 2019–2020 influenza season all regular-dose flu shots and all recombinant influenza vaccine in the United States are quadrivalent.In November 2019, the FDA approved Fluzone High-Dose Quadrivalent for use in the United States starting with the 2020–2021 influenza season.In February 2020, the FDA approved Fluad Quadrivalent for use in the United States. In July 2020, the FDA approved both Fluad and Fluad Quadrivalent for use in the United States for the 2020–2021 influenza season.

Medical uses
The U.S Centers for Disease Control and Prevention (CDC) recommends the flu vaccine as the best way to protect people against the flu and prevent its spread. The flu vaccine can also reduce the severity of the flu if a person contracts a strain that the vaccine did not contain. It takes about two weeks following vaccination for protective antibodies to form.A 2012 meta-analysis found that flu vaccination was effective 67 percent of the time; the populations that benefited the most were HIV-positive adults aged 18 to 55 (76 percent), healthy adults aged 18 to 46 (approximately 70 percent), and healthy children aged six months to 24 months (66 percent). The influenza vaccine also appears to protect against myocardial infarction with a benefit of 15–45%.

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. 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. Studies on the effectiveness of flu vaccines in the real world are difficult; vaccines may be imperfectly matched, virus prevalence varies widely between years, and influenza is often confused with other influenza-like illnesses. However, in most years (16 of the 19 years before 2007), the flu vaccine strains have been a good match for the circulating strains, and even a mismatched vaccine can often provide cross-protection. The virus rapidly changes due to antigenic drift, a slight mutation in the virus that causes a new strain to arise.The effectiveness of seasonal flu vaccines varies significantly, with an estimated average efficacy of 50–60% against symptomatic disease, depending on vaccine strain, age, prior immunity, and immune function, so vaccinated people can still contract influenza. The effectiveness of flu vaccines is considered to be suboptimal, particularly among the elderly, but vaccination is still beneficial in reducing the mortality rate and hospitalization rate due to influenza as well as duration of hospitalization. Vaccination of school-age children has shown to provide indirect protection for other age groups. LAIVs are recommended for children based on superior efficacy, especially for children under 6, and greater immunity against non-vaccine strains when compared to inactivated vaccines.From 2012 to 2015 in New Zealand, vaccine effectiveness against admission to an intensive care unit was 82%. Effectiveness against hospitalized influenza illness in the 2019–2020 United States flu season was 41% overall and 54% in people aged 65 years or older. One review found 31% effectiveness against death among adults.Repeated annual influenza vaccination generally offer consistent year-on-year protection against influenza. There is, however, suggestive evidence that repeated vaccinations may cause a reduction in vaccine effectiveness for certain influenza subtypes; this has no relevance to current recommendations for yearly vaccinations but might influence future vaccination policy. As of 2019, the CDC recommends a yearly vaccine as most studies demonstrate overall effectiveness of annual influenza vaccination.There is not enough evidence to establish significant differences in the effectiveness of different influenza vaccine types, but there are high-dose or adjuvanted products that induce a stronger immune response in the elderly.

Children
In April 2002, the Advisory Committee on Immunization Practices (ACIP) encouraged that children 6 to 23 months of age be vaccinated annually against influenza. In 2010, ACIP recommended annual influenza vaccination for those 6 months of age and older. Currently the CDC recommends that everyone except infants under the age of six months should receive the seasonal influenza vaccine. Vaccination campaigns usually focus special attention on people who are at high risk of serious complications if they catch the flu, such as pregnant women, children under 59 months, the elderly, and people with chronic illnesses or weakened immune systems, as well as those to whom they are exposed, such as health care workers.As the death rate is also high among infants who catch influenza, the CDC and the WHO recommend that household contacts and caregivers of infants be vaccinated to reduce the risk of passing an influenza infection to the infant.In children, the vaccine appears to decrease the risk of influenza and possibly influenza-like illness. In children under the age of two data are limited. During the 2017–18 flu season, the CDC director indicated that 85 percent of the children who died "likely will not have been vaccinated".In the United States, as of January 2019, the CDC recommend that children aged six through 35 months may receive either 0.25 milliliters or 0.5 milliliters per dose of Fluzone Quadrivalent. There is no preference for one or the other dose volume of Fluzone Quadrivalent for that age group. All persons 36 months of age and older should receive 0.5 milliliters per dose of Fluzone Quadrivalent. As of October 2018, Afluria Quadrivalent is licensed for children six months of age and older in the United States. Children six months through 35 months of age should receive 0.25 milliliters for each dose of Afluria Quadrivalent. All persons 36 months of age and older should receive 0.5 milliliters per dose of Afluria Quadrivalent. As of February 2018, Afluria Tetra is licensed for adults and children five years of age and older in Canada.In 2014, the Canadian National Advisory Committee on Immunization (NACI) published a review of influenza vaccination in healthy 5–18-year-olds, and in 2015, published a review of the use of pediatric Fluad in children 6–72 months of age. In one study, conducted in a tertiary referral center, the rate of influenza vaccination in children was only 31%. Higher rates were found among immuno-suppressed pediatric patients (46%), and in patients with inflammatory bowel disease (50%).

Adults
In unvaccinated adults, 16% get symptoms similar to the flu, while about 10% of vaccinated adults do. Vaccination decreased confirmed cases of influenza from about 2.4% to 1.1%. No effect on hospitalization was found.In working adults, a review by the Cochrane Collaboration found that vaccination resulted in a modest decrease in both influenza symptoms and working days lost, without affecting transmission or influenza-related complications. In healthy working adults, influenza vaccines can provide moderate protection against virologically confirmed influenza, though such protection is greatly reduced or absent in some seasons.In health care workers, a 2006 review found a net benefit. Of the eighteen studies in this review, only two also assessed the relationship of patient mortality relative to staff influenza vaccine uptake; both found that higher rates of health care worker vaccination correlated with reduced patient deaths. A 2014 review found benefits to patients when health care workers were immunized, as supported by moderate evidence based in part on the observed reduction in all-cause deaths in patients whose health care workers were given immunization compared with comparison patients where the workers were not offered vaccine.

Elderly
Evidence for an effect in adults over 65 is unclear. Systematic reviews examining both randomized controlled and case–control studies found a lack of high-quality evidence. Reviews of case–control studies found effects against laboratory-confirmed influenza, pneumonia, and death among the community-dwelling elderly.The group most vulnerable to non-pandemic flu, the elderly, benefits least from the vaccine. There are multiple reasons behind this steep decline in vaccine efficacy, the most common of which are the declining immunological function and frailty associated with advanced age. In a non-pandemic year, a person in the United States aged 50–64 is nearly ten times more likely to die an influenza-associated death than a younger person, and a person over 65 is more than ten times more likely to die an influenza-associated death than the 50–64 age group.There is a high-dose flu vaccine specifically formulated to provide a stronger immune response. Available evidence indicates that vaccinating the elderly with the high-dose vaccine leads to a stronger immune response against influenza than the regular-dose vaccine.A flu vaccine containing an adjuvant was approved by the US Food and Drug Administration (FDA) in November 2015, for use by adults aged 65 years of age and older. The vaccine is marketed as Fluad in the US and was first available in the 2016–2017 flu season. The vaccine contains the MF59C.1 adjuvant which is an oil-in-water emulsion of squalene oil. It is the first adjuvanted seasonal flu vaccine marketed in the United States. It is not clear if there is a significant benefit for the elderly to use a flu vaccine containing the MF59C.1 adjuvant. Per Advisory Committee on Immunization Practices guidelines, Fluad can be used as an alternative to other influenza vaccines approved for people 65 years and older.Vaccinating health care workers who work with elderly people is recommended in many countries, with the goal of reducing influenza outbreaks in this vulnerable population. While there is no conclusive evidence from randomized clinical trials that vaccinating health care workers helps protect elderly people from influenza, there is tentative evidence of benefit.Fluad Quad was approved for use in Australia in September 2019, Fluad Quadrivalent was approved for use in the United States in February 2020, and Fluad Tetra was approved for use in the European Union in May 2020.

Pregnancy
As well as protecting mother and child from the effects of an influenza infection, the immunization of pregnant women tends to increase their chances of experiencing a successful full-term pregnancy.The trivalent inactivated influenza vaccine is protective in pregnant women infected with HIV.

Safety
Side effects
Common side effects of vaccination include local injection-site reactions and cold-like symptoms. Fever, malaise, and myalgia are less common. Flu vaccines are contraindicated for people who have experienced a severe allergic reaction in response to a flu vaccine or to any component of the vaccine. LAIVs are not given to children or adolescents with severe immunodeficiency or to those who are using salicylate treatments because of the risk of developing Reye syndrome. LAIVs are also not recommended for children under the age of 2, pregnant women, and adults with immunosuppression. Inactivated flu vaccines cannot cause influenza and are regarded as safe during pregnancy.While side effects of the flu vaccine may occur, they are usually minor, including soreness, redness, and swelling around the point of injection, headache, fever, nausea or fatigue. Side effects of a nasal spray vaccine may include runny nose, wheezing, sore throat, cough, or vomiting.In some people, a flu vaccine may cause serious side effects, including an allergic reaction, but this is rare. Furthermore, the common side effects and risks are mild and temporary when compared to the risks and severe health effects of the annual influenza epidemic.

Guillain–Barré syndrome
Although Guillain–Barré syndrome had been feared as a complication of vaccination, the CDC states that most studies on modern influenza vaccines have seen no link with Guillain–Barré. Infection with influenza virus itself increases both the risk of death (up to one in ten thousand) and the risk of developing Guillain–Barré syndrome to a far higher level than the highest level of suspected vaccine involvement (approximately ten times higher by 2009 estimates).Although one review gives an incidence of about one case of Guillain–Barré per million vaccinations, a large study in China, covering close to a hundred million doses of vaccine against the 2009 H1N1 "swine" flu found only eleven cases of Guillain–Barré syndrome, (0.1 per million doses) total incidence in persons vaccinated, actually lower than the normal rate of the disease in China, and no other notable side effects.

Egg allergy
Although most influenza vaccines are produced using egg-based techniques, influenza vaccines are nonetheless still recommended for people with egg allergies, even if severe. Studies examining the safety of influenza vaccines in people with severe egg allergies found that anaphylaxis was very rare, occurring in 1.3 cases per million doses given.Monitoring for symptoms from vaccination is recommended in those with more severe symptoms. A study of nearly 800 children with egg allergy, including over 250 with previous anaphylactic reactions, had zero systemic allergic reactions when given the live attenuated flu vaccine.

Other
Several studies have identified an increased incidence of narcolepsy among recipients of the pandemic H1N1 influenza AS03-adjuvanted vaccine; efforts to identify a mechanism for this suggest that narcolepsy is autoimmune, and that the AS03-adjuvanted H1N1 vaccine may mimic hypocretin, serving as a trigger.Some injection-based flu vaccines intended for adults in the United States contain thiomersal (also known as thimerosal), a mercury-based preservative. Despite some controversy in the media, the World Health Organizations 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.

Types
Flu vaccines are available either as:
a trivalent or quadrivalent intramuscular injection (IIV3, IIV4, or RIV4, that is, TIV or QIV), which contains the inactivated form of the virus
a nasal spray of live attenuated influenza vaccine (LAIV, Q/LAIV), which contains the live but attenuated (weakened) form of the virus.TIV or QIV induce protection after injection (typically intramuscular, though subcutaneous and intradermal routes can also be protective) based on an immune response to the antigens present on the inactivated virus, while cold-adapted LAIV works by establishing infection in the nasal passages.

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

people aged 50 years of age or older
people with chronic lung diseases, including asthma
people with chronic heart diseases
people with chronic liver diseases
people with chronic kidney diseases
people who have had their spleen removed or whose spleen is not working properly
people who are immunocompromised
residents of nursing homes and other long-term care facilities
health care workers (both to prevent sickness and to prevent spread to their patients)
women who are or will be pregnant during the influenza season
children and adolescents (aged 6 months through 18 years) who are receiving aspirin- or salicylate-containing medications and who might be at risk for experiencing Reye syndrome after influenza virus infection
American Indians/Alaska Natives
people who are extremely obese (body mass index ≥40 for adults)The flu vaccine is contraindicated for those under six months of age and those with severe, life-threatening allergies to flu vaccine or any ingredient in the vaccine.

World Health Organization
As of 2016, the World Health Organization (WHO) recommends seasonal influenza vaccination for:First priority:

Pregnant womenSecond priority (in no particular order):

Children aged 6–59 months
Elderly
Individuals with specific chronic medical conditions
Health-care workers

Canada
The National Advisory Committee on Immunization (NACI), the group that advises the Public Health Agency of Canada, recommends that everyone over six months of age be encouraged to receive annual influenza vaccination, and that children between the age of six months and 24 months, and their household contacts, should be considered a high priority for the flu vaccine.
Particularly:

People at high risk of influenza-related complications or hospitalization, including people who are morbidly obese, healthy pregnant women, children aged 6–59 months, the elderly, aboriginals, and people with one of an itemized list of chronic health conditions
People capable of transmitting influenza to those at high risk, including household contacts and health care workers
People who provide essential community services
Certain poultry workersLive attenuated influenza vaccine (LAIV) was not available in Canada for the 2019–2020 season.

European Union
The European Centre for Disease Prevention and Control (ECDC) recommends vaccinating the elderly as a priority, with a secondary priority people with chronic medical conditions and health care workers.The influenza vaccination strategy is generally that of protecting vulnerable people, rather than limiting influenza circulation or eliminating human influenza sickness. This is in contrast with the high herd immunity strategies for other infectious diseases such as polio and measles. This is also due in part to the financial and logistics burden associated with the need of an annual injection.

United States
In the United States routine influenza vaccination is recommended for all persons aged six months and over. It takes up to two weeks after vaccination for sufficient antibodies to develop in the body. The CDC recommends vaccination before the end of October, although it considers getting a vaccine in December or even later to be still beneficial.According to the CDC, the live attenuated virus (LAIV4) (which comes in the form of the nasal spray in the US) should be avoided by some groups.Within its blanket recommendation for general vaccination in the United States, the CDC, which began recommending the influenza vaccine to health care workers in 1981, emphasizes to clinicians the special urgency of vaccination for members of certain vulnerable groups, and their caregivers:

Vaccination is especially important for people at higher risk of serious influenza complications or people who live with or care for people at higher risk for serious complications. In 2009, a new high-dose formulation of the standard influenza vaccine was approved. The Fluzone High Dose is specifically for people 65 and older; the difference is that it has four times the antigen dose of the standard Fluzone.The US government requires hospitals to report worker vaccination rates. Some US states and hundreds of US hospitals require health care workers to either get vaccinations or wear masks during flu season. These requirements occasionally engender union lawsuits on narrow collective bargaining grounds, but proponents note that courts have generally endorsed forced vaccination laws affecting the general population during disease outbreaks.Vaccination against influenza is especially considered important for members of high-risk groups who would be likely to have complications from influenza, for example pregnant women and children and teenagers from six months to 18 years of age who are receiving aspirin- or salicylate-containing medications and who might be at risk for experiencing Reye syndrome after influenza virus infection;
In raising the upper age limit to 18 years, the aim is to reduce both the time children and parents lose from visits to pediatricians and missing school and the need for antibiotics for complications
An added benefit expected from the vaccination of children is a reduction in the number of influenza cases among parents and other household members, and of possible spread to the general community.The CDC indicated that live attenuated influenza vaccine (LAIV), also called the nasal spray vaccine, was not recommended for the 2016–2017 flu season in the United States.Furthermore, the CDC recommends that health care personnel who care for severely immunocompromised persons receive injections (TIV or QIV) rather than LAIV.

United Kingdom
Dr Jenny Harries maintained winter 2021–2022 in the UK will be "uncertain" since flu and COVID-19 will be circulating together for the first time. She urged eligible people to get COVID-19 and flu vaccines. She maintains flu vaccination is important every year. People need to know that flu can be fatal as many people do not know this.

Australia
The Australian Government recommends seasonal flu vaccination for everyone over the age of six months. Australia uses inactivated vaccines. Until 2021, the egg-based vaccine has been the only one available (and continues to be the only free one), but from March 2021 a new cell-based vaccine is available for those who wish to pay for it, and it is expected that this one will become the standard by 2026.
The standard flu vaccine is free for the following people:
children aged six months to five years;
people aged 65 years and over;
Aboriginal and Torres Strait Islander people aged six months and over;
pregnant women; and
anyone over six months of age with medical conditions such as severe asthma, lung disease or heart disease, low immunity or diabetes that can lead to complications from influenza.

Uptake
At risk groups
Uptake of flu vaccination, both seasonally and during pandemics, is often low. Systematic reviews of pandemic flu vaccination uptake have identified several personal factors that may influence uptake, including gender (higher uptake in men), ethnicity (higher in people from ethnic minorities) and having a chronic illness. Beliefs in the safety and effectiveness of the vaccine are also important.A number of measures have been found to be useful to increase rates of vaccination in those over sixty including: patient reminders using leaflets and letters, postcard reminders, client outreach programs, vaccine home visits, group vaccinations, free vaccinations, physician payment, physician reminders and encouraging physician competition.

Health care workers
Frontline health care workers are often recommended to get seasonal and any pandemic flu vaccination. For example, in the UK all health care workers involved in patient care are recommended to receive the seasonal flu vaccine, and were also recommended to be vaccinated against the H1N1/09 (later renamed A(H1N1)pdm09) swine flu virus during the 2009 pandemic. However, uptake is often low. During the 2009 pandemic, low uptake by healthcare workers was seen in countries including the UK, Italy, Greece, and Hong Kong.In a 2010 survey of United States health care workers, 63.5% reported that they received the flu vaccine during the 2010–11 season, an increase from 61.9% reported the previous season. US Health professionals with direct patient contact had higher vaccination uptake, such as physicians and dentists (84.2%) and nurse practitioners (82.6%).The main reason to vaccinate health care workers is to prevent staff from spreading flu to their patients and to reduce staff absence at a time of high service demand, but the reasons health care workers state for their decisions to accept or decline vaccination may more often be to do with perceived personal benefits.In Victoria (Australia) public hospitals, rates of health care worker vaccination in 2005 ranged from 34% for non-clinical staff to 42% for laboratory staff. One of the reasons for rejecting vaccines was concern over adverse reactions; in one study, 31% of resident physicians at a teaching hospital incorrectly believed Australian vaccines could cause influenza.

Manufacturing
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. No vaccine candidates had been announced by November 2007, but as of 2021, there are several universal vaccines candidates, in pre-clinical development and in clinical trials.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 two billion courses would be required. If China pursued this goal as well, more than three billion courses would be required to serve these populations. Vaccine research and development is ongoing to identify novel vaccine approaches that could produce much greater quantities of vaccine at a price that is affordable to the global population.

Egg-based
Most flu vaccines are grown by vaccine manufacturers in fertilized chicken eggs. In the Northern hemisphere, the manufacturing process begins following the announcement (typically in February) of the WHO recommended strains for the winter flu season. Three strains (representing an H1N1, an H3N2, and a B strain) of flu are selected and chicken eggs are inoculated separately. These monovalent harvests are then combined to make the trivalent vaccine.

As of November 2007, both the conventional injection and the nasal spray are manufactured using chicken eggs. The European Union also approved Optaflu, a vaccine produced by Novartis using vats of animal cells. This technique is expected to be more scalable and avoid problems with eggs, such as allergic reactions and incompatibility with strains that affect avians like chickens.Influenza vaccines are produced in pathogen-free eggs that are eleven or twelve days old. The top of the egg is disinfected by wiping it with alcohol and then the egg is candled to identify a non-veinous area in the allantoic cavity where a small hole is poked to serve as a pressure release. A second hole is made at the top of the egg, where the influenza virus is injected in the allantoic cavity, past the chorioallantoic membrane. The two holes are then sealed with melted paraffin and the inoculated eggs are incubated for 48 hours at 37 degrees Celsius. During incubation time, the virus replicates and newly replicated viruses are released into the allantoic fluidAfter the 48-hour incubation period, the top of the egg is cracked and the ten milliliters of allantoic fluid is removed, from which about fifteen micrograms of the flu vaccine can be obtained. At this point, the viruses have been weakened or killed and the viral antigen is purified and placed inside vials, syringes, or nasal sprayers. Done on a large-scale, this method is used to produce the flu vaccine for the human population.

Other methods of manufacture
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).A gene-based DNA vaccine, used to prime the immune system after boosting with an inactivated H5N1 vaccine, underwent clinical trials in 2011.On November 20, 2012, Novartis received FDA approval for the first cell-culture vaccine. In 2013, the recombinant influenza vaccine, Flublok, was approved for use in the United States.On September 17, 2020, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for Supemtek, a quadrivalent influenza vaccine (recombinant, prepared in cell culture). The applicant for this medicinal product is Sanofi Pasteur. Supemtek was approved for medical use in the European Union in November 2020.Australia authorised its first and cell-based vaccine in March 2021, based on an "eternal cell line" of a dog kidney. Because of the way it is produced, it produces better-matched vaccine (to the flu strains).

Vaccine manufacturing countries
According to the WHO, as of 2019, countries where influenza vaccine is produced include:

In addition, Kazakhstan, Serbia and Thailand had facilities in final stages of establishing production.

Cost-effectiveness
The cost-effectiveness of seasonal influenza vaccination has been widely evaluated for different groups and in different settings. In the elderly (over 65), the majority of published studies have found that vaccination is cost saving, with the cost savings associated with influenza vaccination (e.g. prevented health care visits) outweighing the cost of vaccination. In older adults (aged 50–64 years), several published studies have found that influenza vaccination is likely to be cost-effective, however the results of these studies were often found to be dependent on key assumptions used in the economic evaluations. The uncertainty in influenza cost-effectiveness models can partially be explained by the complexities involved in estimating the disease burden, as well as the seasonal variability in the circulating strains and the match of the vaccine. In healthy working adults (aged 18–49 years), a 2012 review found that vaccination was generally not cost-saving, with the suitability for funding being dependent on the willingness to pay to obtain the associated health benefits. In children, the majority of studies have found that influenza vaccination was cost-effective, however many of the studies included (indirect) productivity gains, which may not be given the same weight in all settings. Several studies have attempted to predict the cost-effectiveness of interventions (including prepandemic vaccination) to help protect against a future pandemic, however estimating the cost-effectiveness has been complicated by uncertainty as to the severity of a potential future pandemic and the efficacy of measures against it.

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 that will help researchers understanding of 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.
A different approach uses Internet content to estimate the impact of an influenza vaccination campaign. More specifically, researchers have used data from Twitter and Microsofts Bing search engine, and proposed a statistical framework which, after a series of operations, maps this information to estimates of the influenza-like illness reduction percentage in areas where vaccinations have been performed. The method has been used to quantify the impact of two flu vaccination programmes in England (2013/14 and 2014/15), where school-age children were administered a live attenuated influenza vaccine (LAIV). Notably, the impact estimates were in accordance with estimations from Public Health England based on traditional syndromic surveillance endpoints.

Rapid response to pandemic flu
The rapid development, production, and distribution of pandemic influenza vaccines could potentially save millions of lives during an influenza pandemic. Due to the short time frame between identification of a pandemic strain and need for vaccination, researchers are looking at novel technologies for vaccine production that could provide better "real-time" access and be produced more affordably, thereby increasing access for people living in low- and moderate-income countries, where an influenza pandemic may likely originate, such as live attenuated (egg-based or cell-based) technology and recombinant technologies (proteins and virus-like particles). As of July 2009, more than seventy known clinical trials have been completed or are ongoing for pandemic influenza vaccines. In September 2009, the FDA 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.In January 2020, the US Food and Drug Administration (FDA) approved Audenz as a vaccine for the H5N1 flu virus. Audenz is a vaccine indicated for active immunization for the prevention of disease caused by the influenza A virus H5N1 subtype contained in the vaccine. Audenz is approved for use in persons six months of age and older at increased risk of exposure to the influenza A virus H5N1 subtype contained in the vaccine.

Universal flu vaccines
A "universal vaccine" that would not have to be designed and made for each flu season in each hemisphere would stabilize the supply, avoid error in predicting the seasons variants, and protect against escape of the circulating strains by mutation. Such a vaccine has been the subject of research for decades.One approach is to use broadly neutralizing antibodies that, unlike the annual seasonal vaccines used over the first decades of the 21st century that provoke the body to generate an immune response, instead provide a component of the immune response itself. The first neutralizing antibodies were identified in 1993, via experimentation. It was found that the flu neutralizing antibodies bound to the stalk of the Hemagglutinin protein. Antibodies that could bind to the head of those proteins were identified. The highly conserved M2 proton channel was proposed as a potential target for broadly neutralizing antibodies.The challenges for researchers are to identify single antibodies that could neutralize many subtypes of the virus, so that they could be useful in any season, and that target conserved domains that are resistant to antigenic drift.Another approach is to take the conserved domains identified from these projects, and to deliver groups of these antigens to provoke an immune response; various approaches with different antigens, presented different ways (as fusion proteins, mounted on virus-like particles, on non-pathogenic viruses, as DNA, and others), are under development.Efforts have also been undertaken to develop universal vaccines that specifically activate a T-cell response, based on clinical data showing that people with a strong, early T-cell response have better outcomes when infected with influenza and because T-cells respond to conserved epitopes. The challenge for developers is that these epitopes are on internal protein domains that are only mildly immunogenic.Along with the rest of the vaccine field, people working on universal vaccines have experimented with vaccine adjuvants to improve the ability of their vaccines to create a sufficiently powerful and enduring immune response.

Oral influenza vaccine
As of 2019, an oral flu vaccine was in clinical research. The oral vaccine candidate is based on an adenovirus type 5 vector modified to remove genes needed for replication, with an added gene that expresses a small double-stranded RNA hairpin molecule as an adjuvant. In 2020, a Phase II human trial of the pill form of the vaccine showed that it was well tolerated and provided similar immunity to a licensed injectable vaccine.

COVID-19
An influenza vaccine and a COVID-19 vaccine may be given safely at the same time. Preliminary research indicates that influenza vaccination does not prevent COVID-19, but may reduce the incidence and severity of COVID-19 infection.

Criticism
Tom Jefferson, who has led Cochrane Collaboration reviews of flu vaccines, has called clinical evidence concerning flu vaccines "rubbish" and has therefore declared them to be ineffective; he has called for placebo-controlled randomized clinical trials, which most in the field hold as unethical. His views on the efficacy of flu vaccines are rejected by medical institutions including the CDC and the National Institutes of Health, and by key figures in the field like Anthony Fauci.Michael Osterholm, who led the Center for Infectious Disease Research and Policy 2012 review on flu vaccines, recommended getting the vaccine but criticized its promotion, saying, "We have overpromoted and overhyped this vaccine ... it does not protect as promoted. Its all a sales job: its all public relations."

Veterinary use
Veterinary influenza vaccination aims to achieve the following four objectives:
Protection from clinical disease
Protection from infection with virulent virus
Protection from virus excretion
Serological differentiation of infected from vaccinated animals (so-called DIVA principle).

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 two doses, 3–6 weeks apart, followed by boosters at 6–12 month intervals. It is generally recognized that in many cases such schedules may not maintain protective levels of antibody and more frequent administration is advised in high-risk situations."It is a common requirement at shows in the United Kingdom that horses be vaccinated against equine flu and a vaccination card must be produced; the International Federation for Equestrian Sports (FEI) requires vaccination every six months.

Poultry
Poultry vaccines for bird flu are made inexpensively and are not filtered and purified like human vaccines to remove bits of bacteria or other viruses. They usually contain whole virus, not just hemagglutinin as in most human flu vaccines. 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 thats only 85 percent related, youll get protection, Dr. Cardona said. In humans, you can get a single point mutation, and a vaccine thats 99.99 percent related wont protect you. And they are weaker [than human vaccines]. Chickens are smaller and you only need to protect them for six weeks, because thats how long they live till you eat them, said Dr. John J. Treanor, a vaccine expert at the University of Rochester. Human seasonal flu vaccines contain about 45 micrograms of antigen, while an experimental A(H5N1) vaccine contains 180. Chicken vaccines may contain less than one microgram. You have to be careful about extrapolating data from poultry to humans, warned Dr. David E. Swayne, director of the agriculture departments Southeast Poultry Research Laboratory. Birds are more closely related to dinosaurs."Researchers, led by Nicholas Savill of the University of Edinburgh in Scotland, used mathematical models to simulate the spread of H5N1 and concluded that "at least 95 percent of birds need to be protected to prevent the virus spreading silently. In practice, it is difficult to protect more than 90 percent of a flock; protection levels achieved by a vaccine are usually much lower than this." The Food and Agriculture Organization of the United Nations has issued recommendations on the prevention and control of avian influenza in poultry, including the use of vaccination.A filtered and purified Influenza A vaccine for humans is being developed 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.

Pigs
Swine influenza vaccines are extensively used in pig farming in Europe and North America. Most swine flu vaccines include an H1N1 and an H3N2 strain.
Swine influenza has been recognized as a major problem since the outbreak in 1976. Evolution of the virus has resulted in inconsistent responses to traditional vaccines. Standard commercial swine flu vaccines are effective in controlling the problem when the virus strains match enough to have significant cross-protection. Customised (autogenous) vaccines made from the specific viruses isolated, are made and used in the more difficult cases. The vaccine manufacturer Novartis claims that the H3N2 strain (first identified in 1998) has brought major losses to pig farmers. Abortion storms are a common sign and sows stop eating for a few days and run a high fever. The mortality rate can be as high as fifteen percent.

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 was found in 2004.

Annual reformulation
Each year, three strains are chosen for selection in that years flu vaccination by the WHO Global Influenza Surveillance and Response System. 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 (WHO) 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 [renamed "Global Influenza Surveillance and Response System" in 2011]. The network comprises four WHO Collaborating Centres (WHO CCs) and 112 institutions in 83 countries, which are recognized by WHO as WHO National Influenza Centres (NICs). These NICs collect specimens in their country, perform primary virus isolation and preliminary antigenic characterization. They ship newly isolated strains to WHO CCs for high level antigenic and genetic analysis, the result of which forms the basis for WHO recommendations on the composition of influenza vaccine for the Northern and Southern Hemisphere each year."The Global Influenza Surveillance and Response Systems selection of viruses for the vaccine manufacturing process is based on its best estimate of which strains will predominate the next year, amounting in the end to well-informed but fallible guesswork.Formal WHO recommendations were first issued in 1973. Beginning in 1999 there have been two recommendations per year: one for the northern hemisphere and the other for the southern hemisphere.Historical annual reformulations of the influenza vaccine are listed in a separate article. Recent WHO seasonal influenza vaccine composition recommendations:

2020–2021 northern hemisphere
The composition of virus vaccines for use in the 2020–2021 Northern Hemisphere influenza season recommended by the World Health Organization on February 28, 2020, is:for egg-based:

an A/Guangdong-Maonan/SWL1536/2019 (H1N1)pdm09-like virus
an A/Hong Kong/2671/2019 (H3N2)-like virus
a B/Washington/02/2019 (B/Victoria lineage)-like virus
a B/Phuket/3073/2013 (B/Yamagata lineage)-like virusfor cell- or recombinant-based:
an A/Hawaii/70/2019 (H1N1)pdm09-like virus
an A/Hong Kong/45/2019 (H3N2)-like virus
a B/Washington/02/2019 (B/Victoria lineage)-like virus
a B/Phuket/3073/2013 (B/Yamagata lineage)-like virusThe WHO recommends that trivalent vaccines use as their influenza B virus a B/Washington/02/2019 (B/Victoria lineage)-like virus.
United StatesThe Vaccines and Related Biological Products Advisory Committee (VRBPAC) of the Food and Drug Administration (FDA) recommended that the quadrivalent formulation of egg-based influenza vaccines for the US 2020–2021 influenza season contain the following:
an A/Guangdong-Maonan/SWL1536/2019 (H1N1)pdm09-like virus;
an A/HongKong/2671/2019 (H3N2)-like virus;
a B/Washington/02/2019-like virus (B/Victoria lineage);
a B/Phuket/3073/2013-like virus (B/Yamagata lineage).The committee recommended that the quadrivalent formulation of cell- or recombinant-based influenza vaccines for the US 2020–2021 influenza season contain the following:
an A/Hawaii/70/2019 (H1N1)pdm09-like virus;
an A/HongKong/45/2019 (H3N2)-like virus;
a B/Washington/02/2019-like virus (B/Victoria lineage);
a B/Phuket/3073/2013-like virus (B/Yamagata lineage)For trivalent influenza vaccines for use in the US for the 2020–2021 influenza season, depending on the manufacturing method of the vaccine, the committee recommended that the A(H1N1)pdm09, A(H3N2) and B/Victoria lineage viruses recommended above for the quadrivalent vaccines be used.
European UnionThe composition of virus vaccines for use in the European Union for the 2020–2021 Northern Hemisphere influenza season recommended by the European Medicines Agency on April 1, 2020, was:Egg-based or live attenuated trivalent vaccines should contain:
an A/Guangdong-Maonan/SWL1536/2019 (H1N1)pdm09-like virus;
an A/Hong Kong/2671/2019 (H3N2)-like virus;
a B/Washington/02/2019 (B/Victoria lineage)-like virus.Cell-based trivalent vaccines should contain:
an A/Hawaii/70/2019 (H1N1)pdm09-like virus;
an A/Hong Kong/45/2019 (H3N2)-like virus;
a B/Washington/02/2019 (B/Victoria lineage)-like virus.A B/Phuket/3073/2013-like virus is recommended in addition to the strains mentioned above for the quadrivalent vaccines.

2021 southern hemisphere
The composition of vaccines for use in the 2021 Southern Hemisphere influenza season influenza season recommended by the World Health Organization in September 2020:For egg-based (trivalent):

an A/Victoria/2570/2019 (H1N1)pdm09-like virus;
an A/Hong Kong/2671/2019 (H3N2)-like virus; and
a B/Washington/02/2019 (B/Victoria lineage)-like virus.For cell- or recombinant-based (trivalent):

an A/Wisconsin/588/2019 (H1N1)pdm09-like virus;
an A/Hong Kong/45/2019 (H3N2)-like virus; and
a B/Washington/02/2019 (B/Victoria lineage)-like virus.The quadrivalent version should contain, in addition to the above:

a B/Phuket/3073/2013 (B/Yamagata lineage)-like virus.In Australia, the standard vaccine under the National Immunisation Program for 2021 is the quadrivalent one.

2021–2022 northern hemisphere
The composition of virus vaccines for use in the 2021–2022 Northern Hemisphere influenza season is

European UnionThe composition of virus vaccines for use in the European Union for the 2021–2022 Northern Hemisphere influenza season recommended by the European Medicines Agency on March 30, 2021, is:Egg-based or live attenuated trivalent vaccines should contain:
an A/Victoria/2570/2019 (H1N1)pdm09-like virus;
an A/Cambodia/e0826360/2020 (H3N2)-like virus;
a B/Washington/02/2019 (B/Victoria lineage)-like virus.Cell-based trivalent vaccines should contain:
an A/Wisconsin/588/2019 (H1N1)pdm09-like virus;
an A/Cambodia/e0826360/2020 (H3N2)-like virus;
a B/Washington/02/2019 (B/Victoria lineage)-like virus.A B/Phuket/3073/2013-like virus is recommended in addition to the strains mentioned above for the quadrivalent vaccines.
United StatesThe FDA Vaccines and Related Biological Products Advisory Committee (VRBPAC) recommended that the quadrivalent formulation of egg-based influenza vaccines for the US 2021-2022 influenza season contain the following:
an A/Victoria/2570/2019 (H1N1) pdm09-like virus;
an A/Cambodia/e0826360/2020 (H3N2)-like virus;
a B/Washington/02/2019- like virus (B/Victoria lineage);
a B/Phuket/3073/2013-like virus (B/Yamagata lineage).The committee recommended that the quadrivalent formulation of cell- or recombinant based influenza vaccines for the US 2021-2022 influenza season contain the following:
an A/Wisconsin/588/2019 (H1N1) pdm09-like virus;
an A/Cambodia/e0826360/2020 (H3N2)-like virus;
a B/Washington/02/2019- like virus (B/Victoria lineage);
a B/Phuket/3073/2013-like virus (B/Yamagata lineage).For trivalent influenza vaccines for use in the US for the 2021-2022 influenza season, depending on the manufacturing method of the vaccine, the committee recommended that the A(H1N1) pdm09, A(H3N2) and B/Washington/02/2019-like virus (B/Victoria lineage) viruses recommended above for the quadrivalent vaccines be used.

2022 southern hemisphere
The composition of vaccines for use in the 2022 Southern Hemisphere influenza season influenza season recommended by the World Health Organization in September 2021:Egg-based vaccines:

A/Victoria/2570/2019 (H1N1)pdm09-like virus;
A/Darwin/9/2021 (H3N2)-like virus;
B/Austria/1359417/2021 (B/Victoria lineage)-like virus; and
B/Phuket/3073/2013 (B/Yamagata lineage)-like virus.Cell- or recombinant-based vaccines:

A/Wisconsin/588/2019 (H1N1)pdm09-like virus;
A/Darwin/6/2021 (H3N2)-like virus;
B/Austria/1359417/2021 (B/Victoria lineage)-like virus; and
B/Phuket/3073/2013 (B/Yamagata lineage)-like virus.It is recommended that trivalent influenza vaccines for use in the 2022 southern hemisphere influenza season contain the following:
Egg-based vaccines:

A/Victoria/2570/2019 (H1N1)pdm09-like virus;
A/Darwin/9/2021 (H3N2)-like virus; and
B/Austria/1359417/2021 (B/Victoria lineage)-like virus.Cell- or Recombinant-based vaccines:

A/Wisconsin/588/2019 (H1N1)pdm09-like virus;
A/Darwin/6/2021 (H3N2)-like virus; and
B/Austria/1359417/2021 (B/Victoria lineage)-like virus

2022–2023 northern hemisphere
The composition of virus vaccines for use in the 2022–2023 Northern Hemisphere influenza season is
European UnionThe composition of virus vaccines for use in the European Union for the 2022–2023 Northern Hemisphere influenza season recommended by the European Medicines Agency on March 29, 2022, is:Quadrivalent egg-based or live attenuated vaccines should contain:
an A/Victoria/2570/2019 (H1N1)pdm09-like virus;
an A/Darwin/9/2021 (H3N2)-like virus;
a B/Austria/1359417/2021 (B/Victoria lineage)-like virus; and
a B/Phuket/3073/2013 (B/Yamagata lineage)-like virus.Quadrivalent cell-culture or recombinant-based vaccines should contain:
an A/Wisconsin/588/2019 (H1N1)pdm09-like virus;
an A/Darwin/6/2021 (H3N2)-like virus;
a B/Austria/1359417/2021 (B/Victoria lineage)-like virus; and
a B/Phuket/3073/2013 (B/Yamagata lineage)-like virus.United StatesThe FDA Vaccines and Related Biological Products Advisory Committee (VRBPAC) recommended that the quadrivalent formulation of egg-based influenza vaccines for the U.S. 2022-2023 influenza season contain the following:
an A/Victoria/2570/2019 (H1N1)pdm09-like virus;
an A/Darwin/9/2021 (H3N2)-like virus;
a B/Austria/1359417/2021-like virus (B/Victoria lineage); and
a B/Phuket/3073/2013-like virus (B/Yamagata lineage).The committee recommended that the quadrivalent formulation of cell- or recombinant-based influenza vaccines for the US 2022–2023 influenza season contain the following:
an A/Wisconsin/588/2019 (H1N1)pdm09-like virus;
an A/Darwin/6/2021 (H3N2)-like virus;
a B/Austria/1359417/2021-like virus (B/Victoria lineage); and
a B/Phuket/3073/2013-like virus (B/Yamagata lineage).For trivalent influenza vaccines for use in the US for the 2022–2023 influenza season, depending on the manufacturing method of the vaccine, the committee recommended that the A(H1N1)pdm09, A(H3N2) and B/Austria/1359417/2021-like virus (B/Victoria lineage) viruses recommended above for the quadrivalent vaccines be used.

Notes
See also
H5N1 vaccine
Seasonal influenza vaccine brands
Universal influenza vaccine

References
Further reading
World Health Organization (October 2017). The immunological basis for immunization series: module 23: influenza vaccines. World Health Organization (WHO). hdl:10665/259211. ISBN 978-9241513050.
Ramsay M (ed.). "Chapter 19: Influenza". Immunisation against infectious disease. Public Health England.
Hamborsky J, Kroger A, Wolfe S, eds. (2015). "Chapter 12: Influenza". Epidemiology and Prevention of Vaccine-Preventable Diseases (13th ed.). Washington D.C.: U.S. Centers for Disease Control and Prevention (CDC). ISBN 978-0990449119.
Budd A, Blanton L, Grohskopf L, Campbell A, Dugan V, Wentworth DE,  et al. (March 29, 2019). "Chapter 6: Influenza".  In Roush SW, Baldy LM, Hall MA (eds.). Manual for the surveillance of vaccine-preventable diseases. Atlanta GA: U.S. Centers for Disease Control and Prevention (CDC).
National Advisory Committee on Immunization (May 2020). "Canadian Immunization Guide Chapter on Influenza and Statement on Seasonal Influenza Vaccine for 2020–2021" (PDF). Public Health Agency of Canada. Cat.: HP37-25F-PDF; Pub.: 200003. Lay summary. {{cite web}}: Cite uses deprecated parameter |lay-url= (help)
National Advisory Committee on Immunization (NACI) (May 2018). NACI literature review on the comparative effectiveness and immunogenicity of subunit and split virus inactivated influenza vaccines in adults 65 years of age and older (PDF). Government of Canada. ISBN 9780660264387. Cat.: HP40-213/2018E-PDF; Pub.: 180039. Lay summary </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Aminophylline and can you explain it in depth? [/INST] Aminophylline is a compound of the bronchodilator theophylline with ethylenediamine in 2:1 ratio. The ethylenediamine improves solubility, and the aminophylline is usually found as a dihydrate.Aminophylline is less potent and shorter-acting than theophylline. Its most common use is in the treatment of airway obstruction from asthma or COPD. Aminophylline is a nonselective adenosine receptor antagonist and phosphodiesterase inhibitor.

Medical uses
Intravenous aminophylline can be used for acute exacerbation of symptoms and reversible airway obstruction in asthma and other chronic lung disease such as COPD, emphysema and chronic bronchitis. It is used as an adjunct to inhaled beta-2 selective agonists and systemically administered corticosteroids.Aminophylline is used to reverse regadenoson, dipyridamole or adenosine based infusions during nuclear cardiology stress testing. Aminophylline has also been reported to be effective in preventing slow heart rates during complex cardiovascular interventions [Atherectomy of the right coronary artery]. It is also used in the treatment of heart block due to acute inferior myocardial infarction. It can also cause cardiac arrest.
Aminophylline has shown some promise as a bodyfat reducer when used as a topical cream. Aminophylline is also a treatment option for anaphylactic shock.While it has been suggested for use in cardiac arrest evidence does not support a benefit.

Side effects
Aminophylline can lead to theophylline toxicity. Aminophylline has been found to decrease the sedative effects of propofol  and decrease topiramate antiseizure action.

Properties
It is more soluble in water than theophylline. White or slightly yellowish granules or powder, having a slight ammoniacal odor and a bitter taste. Upon exposure to air, it gradually loses ethylenediamine and absorbs carbon dioxide with the liberation of free theophylline. Its solutions are alkaline. 1 g dissolves in 25 mL of water to give a clear solution; 1 g dissolved in 5 mL of water crystallizes upon standing, but redissolves when a small amount of ethylenediamine is added. Insoluble in alcohol and in ether.

Pharmacology
Like other methylated xanthine derivatives, aminophylline is both a

competitive nonselective phosphodiesterase inhibitor which raises intracellular cAMP, activates PKA, inhibits TNF-alpha and leukotriene synthesis, and reduces inflammation and innate immunity and
nonselective adenosine receptor antagonist.Aminophylline causes bronchodilation, diuresis†, central nervous system and cardiac stimulation, and gastric acid secretion by blocking phosphodiesterase which increases tissue concentrations of cyclic adenosine monophosphate (cAMP) which in turn promotes catecholamine stimulation of lipolysis, glycogenolysis, and gluconeogenesis, and induces release of epinephrine from adrenal medulla cells.†Note that diuresis is caused by an increase in cAMP which acts in the CNS to inhibit the release of antidiuretic hormone (arginine-vasopressin).
Adenosine is an endogenous extracellular messenger that can regulate myocardial oxygen needs. It acts through cellular surface receptors which effect intracellular signalling pathways to increase coronary artery blood flow, slow heart rate, block atrioventricular node conduction, suppress cardiac automaticity, and decrease β-adrenergic effects on contractility </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Cladribine and can you explain it in depth? [/INST] Cladribine, sold under the brand name Leustatin, among others, is a medication used to treat hairy cell leukemia (leukemic reticuloendotheliosis) and B-cell chronic lymphocytic leukemia.Cladribine, sold under the brand name Mavenclad, is indicated for the treatment of adult patients with highly active forms of relapsing-remitting multiple sclerosis.Cladribine (2-chloro-2-deoxyadenosine [2-CdA]) is a purine analogue that selectively targets and suppresses lymphocytes implicated in the underlying pathogenesis of multiple sclerosis and B-cell leukaemia. Chemically, it mimics the nucleoside adenosine. However, unlike adenosine, it is relatively resistant to breakdown by the enzyme adenosine deaminase, which causes it to accumulate in targeted cells and interfere with the cells ability to process DNA.Cladribine is taken up by cells via transporter proteins. Once inside a cell, cladribine undergoes phosphorylation by the enzyme deoxycytidine kinase (DCK) to produce mononucleotide 2-chlorodeoxyadenosine 5’monophosphate (2-CdAMP), which is subsequently phosphorylated to the triphosphorylated active compound 2-chlorodeoxyadenosine 5’triphosphate (2-CdATP).  Activated cladribine is incorporated into cellular DNA, which triggers apoptosis.  Accumulation of cladribine into cells is dependent on the ratio of 2-CdATP and 5-nucleotidase (5’-NT), which breaks down and inactivates the compound. This ratio differs between cell types, with high levels in T and B lymphocytes, resulting in selective targeting of these cells. In contrast, CdATP:5NT is relatively low in other cell types, thus sparing numerous non-haematological cells.

Medical uses
Cladribine is used as a first- and second-line treatment for symptomatic hairy cell leukemia and for B-cell chronic lymphocytic leukaemia, and is administered by intravenous or subcutaneous infusion. Some investigators have used the parenteral formulation orally to treat patients with hairy cell leukemia.  About 37–51% of oral cladribine is bioavailable orally. It is used, often in combination with other cytotoxic agents, to treat various kinds of histiocytosis, including Erdheim–Chester disease and Langerhans cell histiocytosis.Following EMA approval of cladribine tablets for the treatment of adult patients with highly active relapsing-remitting multiple sclerosis in 2017, as of July 2020, cladribine tablets have gained marketing authorisation in over 75 countries. In 2019, cladribine tablets were approved by the FDA for the treatment of relapsing forms of multiple sclerosis, to include relapsing-remitting disease and active secondary progressive disease, in adult patients who have had an inadequate response to, or are unable to tolerate, an alternate drug indicated for the treatment of multiple sclerosis.Cladribine may cause foetal harm when administered to a pregnant woman and is listed by the FDA as pregnancy category D; safety and efficacy in children has not been established.

Mechanism of action
As a purine analogue, cladribine (2-chloro-2-deoxyadenosine [2-CdA]) is taken up into rapidly proliferating cells, including B and T lymphocytes, to be incorporated into DNA synthesis. Chemically, it mimics nucleoside adenosine; however, unlike adenosine, cladribine has a chlorine molecule at position 2, which renders it partially resistant to breakdown by adenosine deaminase. This causes it to accumulate in cells and interfere with the targeted cells ability to process DNA.Cladribine is taken up by specific nucleoside transporter proteins. Once inside a cell, cladribine undergoes phosphorylation by the enzyme deoxycytidine kinase (DCK) to produce mononucleotide 2-chlorodeoxyadenosine 5’monophosphate (2-CdAMP), which is subsequently phosphorylated to the triphosphorylated active compound, 2-chlorodeoxyadenosine 5’triphosphate (2-CdATP).Activated cladribine is incorporated into the DNA synthesis pathway, where it disrupts DNA repair and synthesis, resulting in an accumulation of DNA strand breaks This is followed by the activation of transcription factor p53, the release of cytochrome c from mitochondria and eventual programmed cell death (apoptosis). This process occurs over approximately 2 months, with a peak level of cell depletion 4–8 weeks after treatment.Another family of enzymes, the 5-nucleotidase (5-NT) family, is also capable of dephosphorylating cladribine, making it inactive. The most important subtypes of this group appear to be cytosolic 5-NT, c-5NCT1A and c-NT1B, which are cytosolically active and specific for purine analogues.Accumulation of cladribine into cells is dependent on the ratio of 2-CdATP and 5-NT. This ratio differs between cell types, with high levels in T and B lymphocytes, making them particularly susceptible to cell death. The cells with the highest ratios are B cells, especially germinal centre and naïve B cells. This helps to explain which B cells are more vulnerable to cladribine-mediated apoptosis. DCK is the rate-limiting enzyme for conversion of the cladribine prodrug into its active triphosphate form, leading to the selective depletion of dividing and non-dividing T and B lymphocytes. In contrast, the CdATP:5-NT ratio is relatively low in other cell types, thus sparing numerous non-hematologic cells.In multiple sclerosis, cladribines effectiveness may be due to depletion of B cells, in particular memory B cells.  In the pivotal phase 3 clinical trial of oral cladribine in multiple sclerosis, CLARITY, cladribine selectively depleted 80% of peripheral B cells, compared to only 40–45% of CD4+ T cells and 15‒30% CD8+ T cells.  More recently, cladribine has been shown to induce long term, selective suppression of certain subtypes of B cells, especially memory B cells.Although cladribine is selective for B cells, the long-term suppression of memory B cells, which may contribute to its effect in multiple sclerosis, is not explained by gene or protein expression. Instead, cladribine appears to deplete the entire B cell department, but while naïve B cells rapidly move from lymphoid organs, the memory B cell pool repopulates slowly from the bone marrow.  Both hairy cell leukemia and B-cell chronic lymphocytic leukaemia are types of B cell blood cancers.

History in hairy cell leukemia
Ernest Beutler and Dennis A. Carson had studied adenosine deaminase deficiency and recognised that because the lack of adenosine deaminase led to the destruction of B cell lymphocytes, a drug designed to inhibit adenosine deaminase might be useful in lymphomas.  Carson then synthesised cladribine, and through clinical research at Scripps starting in the 1980s, Beutler tested it as intravenous infusion and found it was especially useful to treat hairy cell leukemia.  No pharmaceutical companies were interested in selling the drug because hairy cell leukemia was an orphan disease, so Beutlers lab synthesised and packaged it and supplied it to the hospital pharmacy; the laboratory also developed a test to monitor blood levels.  This was the first treatment that led to prolonged remission of hairy cell leukemia, which was previously untreatable.: 14–15 In February 1991, Scripps began a collaboration with Johnson & Johnson to bring intravenous cladribine to market, and by December of that year, Johnson & Johnson had filed a new drug application; cladribine was approved by the FDA in 1993 for hairy cell leukemia as an orphan drug, and was approved in Europe later that year.: 2 The subcutaneous formulation was developed in Switzerland in the early 1990s and it was commercialised by Lipomed GmbH in the 2000s.: 2

Safety profile of cladribine in hairy cell leukemia
Injectable cladribine suppresses the bodys ability to make new lymphocytes, natural killer cells, and neutrophils (called myelosuppression); data from hairy cell leukemia studies showed that about 70% of people taking the drug developed dangerously  low levels of white blood cells and about 30% developed infections and some of those progressed to septic shock; about 40% of people taking the drug had fewer red blood cells and became severely anaemic; and about 10% of people had too few platelets.  At the dosage used to treat hairy cell leukemia in two clinical trials, 16% of people had rashes and 22% had nausea, the nausea generally did not lead to vomiting.

History in multiple sclerosis
In the mid-1990s, Beutler, in collaboration with Jack Sipe, a neurologist at Scripps Institute, ran several clinical trials exploring the utility of cladribine in multiple sclerosis, based on the drugs immunosuppressive effects. Sipes insight into multiple sclerosis, and Beutlers interest in multiple sclerosis due to his sister having the disease, initiated a very productive collaboration. Ortho-Clinical, a subsidiary of Johnson & Johnson, filed a new drug application for cladribine for multiple sclerosis in 1997 but withdrew it in the late 1990s after discussion with the FDA proved that more clinical data would be needed.Ivax acquired the rights for oral administration of cladribine to treat multiple sclerosis from Scripps in 2000, and partnered with Serono in 2002. Ivax was acquired by Teva in 2006, and Merck KGaA acquired control of Seronos drug business in 2006.An oral formulation of the drug with cyclodextrin was developed: 16  by Ivax and Serono, and then Merck KGaA conducted clinical trials.  Merck KGaA submitted an application to the European Medicines Agency in 2009, which was rejected in 2010, and an appeal was denied in 2011.: 4–5   Likewise Merck KGaAs new drug application with the FDA rejected in 2011.The ratio of benefit to harm was not clear to regulators, and further studies were requested to address concerns related to severe lymphopenia and cancer cases observed during pivotal trials.: 54–55  Clinical studies of multiple sclerosis were still ongoing at the time of the rejections, and Merck KGaA committed to completing them.  A meta-analysis of data from clinical trials comparing the risk of cancer and other disease-modifying therapies showed that cladribine tablets did not increase the risk of cancer at the doses used in the initial clinical trials.Based on the supporting data from the completed clinical trials that confirmed no increased risk of cancer, Merck announced it would again seek regulatory approval. In 2016, the EMA accepted its application for review. On June 22, 2017, the EMAs Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the granting of a marketing authorisation for the treatment of relapsing forms of multiple sclerosis.Cladribine tablets were later approved in Europe, in August 2017, for highly active relapsing-remitting multiple sclerosis, and has since been approved by the FDA for the treatment of relapsing-remitting and secondary progressive multiple sclerosis in the US.

Use in multiple sclerosis
As per the EU label, cladribine tablets are indicated for the treatment of adult patients with highly active relapsing multiple sclerosis as defined by clinical or imaging features: (i) patients with a relapse in the previous year and at least one T1 Gd+ lesion or 9 or more T2 lesions, while on another disease-modifying therapies or (ii) patients with two or more relapses in the previous year, whether on disease-modifying treatment or not.Two main approaches to multiple sclerosis treatment maintenance therapy are used – immunomodulation and immunosuppression and alternatively, immune reconstitution therapy. Classified as the latter, cladribine tablets are administered intermittently as a short treatment course without continuous immunosuppression. In contrast to maintenance therapies, clinical efficacy extends beyond the dosing period.Cladribine tablets are administered as 2 courses separated by 1 year (a maximum of 20 days of treatment). The recommended cumulative dose is 3.5 mg/kg weight over 2 years, administered as 1 treatment course of 1.75 mg/kg per year. Each treatment course consists of 2 treatment weeks, one at the beginning of the first month and one at the beginning of the second month of the respective treatment year. Each treatment week consists of 4 or 5 days on which a patient receives 10 mg or 20 mg (1 or 2 tablets) as a single daily dose based on body weight.Before initiating treatment with cladribine tablets, blood tests, MRI and infection screening must be performed. Due to an increased risk of herpes zoster with cladribine tablets, patients who are antibody-negative for varicella zoster virus are recommended to be vaccinated before starting treatment. Treatment should not be initiated within 4 to 6 weeks of receiving a live or attenuated live vaccine because of a risk of active infection. Vaccination with live or attenuated live vaccines should also be avoided during and after treatment, but can be considered when lymphocyte counts have recovered to ≥1000 cells/mm3.Following completion of the two treatment courses, no further treatment or additional monitoring is required.The use of cladribine tablets is contraindicated in pregnant women, and women of childbearing potential must use effective contraception to prevent pregnancy during treatment and 6 months after receiving the last dose.

Efficacy of cladribine tablets in multiple sclerosis
Clinical trial results have shown that cladribine tablets can be an effective treatment for highly active, relapsing forms of multiple sclerosis, with significant clinical benefits in relapse rate, disability progression, and radiological measures. Compared with placebo, patients who received cladribine tablets (3.5 mg/kg) in the CLARITY study had a 58% reduction in annualized relapse rate and 47% of patients showed no evidence of disease activity at 2 years.  Clinical improvements can be observed at Week 24 of treatment, and benefits may be sustained up to 4 years, beyond the 2-year dosing period and recovery of total lymphocytes. Post-hoc analyses of clinical trial data showed that 89% of patients remained free from disability progression two years after treatment.Further analyses of a subgroup of patients in the CLARITY study who had very active multiple sclerosis showed a 67% reduction in relapse rates and an 82% reduction in disability progression in those treated with cladribine tablets. Similarly, clinical improvements were seen in lesion burden on MRI scans in this population.Studies evaluating the treatment effects of cladribine tablets across a spectrum of baseline demographics and disease characteristics showed that the relative risk of relapse was significantly reduced compared with placebo, irrespective of previous treatment experience.Furthermore, treatment with cladribine tablets has been shown to significantly reduce the rate of brain atrophy in patients with highly active relapsing-remitting multiple sclerosis. This reduction correlated with a reduced risk in disability progression in a retrospective analysis.In clinical trials, higher cumulative doses of cladribine tablets did not result in further improvement in efficacy nor did additional courses after the 2-year treatment period, but was associated with a higher incidence of Grade 3 and Grade 4 lymphopenia.

Safety profile of cladribine tablets in multiple sclerosis
Cladribine tablets target the cells of the adaptive immune system with minimal impact on innate immune cells. Although the exact mechanism by which cladribine exerts its therapeutic effect is not fully elucidated, it is proposed to have a transient effect on B and T lymphocyte depletion, interrupting the cascade of immune events central to multiple sclerosis. As a result, a reduction in lymphocyte count (lymphopenia) may be reported following treatment </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Imipenem/cilastatin and can you explain it in depth? [/INST] Imipenem/cilastatin, sold under the brand name Primaxin among others, is an antibiotic useful for the treatment of a number of bacterial infections. It is made from a combination of imipenem and cilastatin. Specifically it is used for pneumonia, sepsis, endocarditis, joint infections, intra-abdominal infections, and urinary tract infections. It is given by injection into a vein or muscle.Common side effects include nausea, diarrhea, and pain at the site of injection. Other side effects may include Clostridium difficile diarrhea and allergic reactions including anaphylaxis. It is unclear if use during pregnancy is safe for the baby. Imipenem is in the carbapenem family of medications and works by interfering with the bacterias cell wall. Cilastatin blocks the activity of dehydropeptidase I which prevents the breakdown of imipenem.Imipenem/cilastatin was first sold in 1987. It is on the World Health Organizations List of Essential Medicines.

Medical uses
Imipenem/cilastatin is used for lower respiratory tract infections, urinary tract infections, intra-abdominal infections, gynecologic infections, bacterial sepsis, bone and joint infections, skin and skin structure infections, endocarditis and polymicrobic infections.It is a broad-spectrum beta-lactam containing equal quantities of imipenem and cilastatin.

Side effects
Common side effects for both forms are:
Upset stomach
Vomiting
Stomach painMajor side effects requiring medical attention:
Diarrhea
Rash
Fever
Facial swelling
Difficulty breathing
Unusual bleeding
SeizuresThis medicine is passed through breast milk, so its use during pregnancy or breastfeeding should only be done when clearly needed. Primaxin is cleared from the body by the kidneys, so it is important to tell ones doctor about any other drugs being taken that are also cleared through the kidneys (such as other antibiotics), especially for older patients, as kidney function declines with age.Patients who are allergic to penicillin, cephalosporins, and related drugs may react to imipenem.
It is important tell ones doctor or pharmacist ones medical history, especially of brain disorders (e.g., seizures, head injury, tumor), kidney disease, liver disease, and stomach/intestinal diseases (e.g., colitis).

Hepatotoxicity
In large clinical trials, imipenem was associated with transient and asymptomatic elevations in serum aminotransferase levels in about 6% of patients given the drug for five to 14 days. More serious hepatic injury from imipenem/cilastatin is rare, but jaundice and liver test abnormalities have been reported in 0.1% of patients in prospective trials of the agent. Several instances of cholestatic jaundice arising during or shortly after therapy have been reported with imipenem-cilastatin and other carbapenems. The latency to onset has been within one to three weeks, and the pattern of enzyme elevations is usually cholestatic. Immunoallergic features can occur, but autoantibodies are rare. The course is usually self-limiting, but at least one case of vanishing bile duct syndrome related to the carbapenems has been reported. Imipenem and other carbapenems have not been linked to cases of acute liver failure.

Mechanism of liver injury
The cause of the mild, transient serum enzyme elevations during imipenem-cilastatin therapy is not known. The cholestatic hepatitis attributed to imipenem-cilastatin and the carbapenems is probably immunoallergic and resembles the rare, clinically apparent liver injury that has been linked to penicillins and cephalosporins.

Outcome and management
The liver injury due to the carbapenems is usually mild and self-limited. Rarely, the carbapenems can cause a clinically apparent acute cholestatic hepatitis that is usually self-limiting and not requiring therapy or intervention. In patients with vanishing bile duct syndrome, corticosteroids are often used but have not been shown to be beneficial and are best avoided. Some patients may benefit from symptomatic therapy of the pruritus associated with cholestasis using antihistamines, ursodiol, or cholestyramine. Little information is available on possible cross-sensitivity to liver injury among the different betalactam antibiotics, but patients with clinically apparent liver injury due to imipenem should probably avoid the other carbapenems.

Interactions
valproic acid (Depakene, Stavzor)
ganciclovir (Cytovene)
probenecid (Benemid)
penicillin antibiotics such as amoxicillin (Amoxil, Augmentin), ampicillin (Omnipen, Principen), dicloxacillin (Dycill, Dynapen), oxacillin (Bactocill), or penicillin (Beepen-VK, Ledercillin VK, Pen-V, Pen-Vee K, Pfizerpen, V-Cillin K, Veetids, and others); or
cephalosporin antibiotics such as cefaclor (Ceclor), cefuroxime (Ceftin), cefadroxil (Duricef), cephalexin (Keflex), and others.

Mechanism of action
Imipenem/cilastatin has the ability to kill a wide variety of bacteria. Imipenem is the active antibiotic agent and works by interfering with their ability to form cell walls, so the bacteria break up and die.
Imipenem is rapidly degraded by the renal enzyme dehydropeptidase if administered alone (making it less effective); the metabolites can cause kidney damage.
Imipenem is a broad-spectrum betalactam antibiotic used for severe bacterial infections caused by susceptible organisms. Because imipenem is rapidly inactivated by renal dehydropeptidase I, it is given in combination with cilastatin, a DHP-I inhibitor which increases half-life and tissue penetration of imipenem. Imipenem/cilastatin, like other carbapenems, binds to bacterial penicillin-binding proteins and interferes with bacterial cell wall integrity and synthesis. It has activity against many aerobic and anaerobic Gram-positive and Gram-negative organisms, including Staphylococcus aureus, Streptococcus pyogenes, S. agalactiae, S </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Alpha-1 antitrypsin and can you explain it in depth? [/INST] Alpha-1 antitrypsin or α1-antitrypsin (A1AT, α1AT, A1A, or AAT) is a protein belonging to the serpin superfamily. It is encoded in humans by the SERPINA1 gene. A protease inhibitor, it is also known as alpha1–proteinase inhibitor (A1PI) or alpha1-antiproteinase (A1AP) because it inhibits various proteases (not just trypsin). In older biomedical literature it was sometimes called serum trypsin inhibitor (STI, dated terminology), because its capability as a trypsin inhibitor was a salient feature of its early study. As a type of enzyme inhibitor, it protects tissues from enzymes of inflammatory cells, especially neutrophil elastase, and has a reference range in blood of 0.9–2.3 g/L (in the US the reference range is expressed as mg/dL or micromoles), but the concentration can rise manyfold upon acute inflammation.When the blood contains inadequate amounts of A1AT or functionally defective A1AT (such as in alpha-1 antitrypsin deficiency), neutrophil elastase is excessively free to break down elastin, degrading the elasticity of the lungs, which results in respiratory complications, such as chronic obstructive pulmonary disease, in adults. Normally, A1AT leaves its site of origin, the liver, and joins the systemic circulation; defective A1AT can fail to do so, building up in the liver, which results in cirrhosis in either adults or children.
In addition to binding to neutrophil elastase released by inflammatory cells, A1AT also binds to elastase localized on the cell surface in which case elastase does not act as an enzyme, but instead acts to signal cells to undergo locomotion. Besides liver cells, A1PI is produced in bone marrow, by lymphocytic and monocytic cells in lymphoid tissue, and by the Paneth cells of the gut.Inactivation of A1AT by enzymes other than elastase due to inflammation/infection causes the migration of T cells to halt precisely at the site where the pathologic insult exists. This suggests a role for α1PI not only in locomotion of lymphocytes through tissue, but as a consequence of infection, a primary role as a sentinel in immune vigilance.A1AT is both an endogenous protease inhibitor and an exogenous one used as medication. The pharmaceutical form is purified from human donor blood and is sold under the nonproprietary name alpha1–proteinase inhibitor (human) and under various trade names (including  Aralast NP, Glassia, Prolastin, Prolastin-C, and Zemaira). Recombinant versions are also available but are currently used in medical research more than as medication.

Function
A1AT is a 52-kDa serpin and, in medicine, it is considered the most prominent serpin; the terms α1-antitrypsin and protease inhibitor (Pi) are often used interchangeably.
Most serpins inactivate enzymes by binding to them covalently. These enzymes are released locally in relatively low concentrations where they are immediately cleared by proteins such as A1AT. In the acute phase reaction, a further elevation is required to "limit" the damage caused by activated neutrophil granulocytes and their enzyme elastase, which breaks down the connective tissue fiber elastin.
Besides limiting elastase activity to limit tissue degradation, A1PI also acts to induce locomotion of lymphocytes through tissue including immature T cells through the thymus where immature T cells mature to become immunocompetent T cells that are released into tissue to elevate immune responsiveness.Like all serine protease inhibitors, A1AT has a characteristic secondary structure of beta sheets and alpha helices. Mutations in these areas can lead to non-functional proteins that can polymerise and accumulate in the liver (infantile hepatic cirrhosis).

Role in disease
Disorders of this protein include alpha-1 antitrypsin deficiency, an autosomal co-dominant hereditary disorder in which a deficiency of alpha-1 antitrypsin leads to a chronic uninhibited tissue breakdown. This causes the degradation especially of lung tissue and eventually leads to characteristic manifestations of pulmonary emphysema. Evidence has shown that cigarette smoke can result in oxidation of methionine 358 of α1-antitrypsin (382 in the pre-processed form containing the 24 amino acid signal peptide), a residue essential for binding elastase; this is thought to be one of the primary mechanisms by which cigarette smoking (or second-hand smoke) can lead to emphysema. Because A1AT is expressed in the liver, certain mutations in the gene encoding the protein can cause misfolding and impaired secretion, which can lead to liver cirrhosis.
An extremely rare form of Pi, termed PiPittsburgh, functions as an antithrombin (a related serpin), due to a mutation (Met358Arg). One person with this mutation has been reported to have died of a bleeding diathesis.A liver biopsy will show abundant PAS-positive globules within periportal hepatocytes.
Patients with rheumatoid arthritis (RA) have been found to make autoantibodies toward the carbamylated form of A1AT in the synovial fluid. This suggests that A1AT may play an anti-inflammatory or tissue-protecting role outside the lungs. These antibodies are associated with a more severe disease course, can be observed years before disease onset, and may predict the development of RA in arthralgia patients. Consequently, carbamylated A1AT is currently being developed as an antigenic biomarker for RA.

Nomenclature
The protein was initially named "antitrypsin" because of its ability to bind and irreversibly inactivate the enzyme trypsin in vitro covalently. Trypsin, a type of peptidase, is a digestive enzyme active in the duodenum and elsewhere.
The term alpha-1 refers to the proteins behavior on protein electrophoresis. On electrophoresis, the protein component of the blood is separated by electric current. There are several clusters, the first being albumin, the second being the alpha, the third beta and the fourth gamma (immunoglobulins). The non-albumin proteins are referred to as globulins.
The alpha region can be further divided into two sub-regions, termed "1" and "2". Alpha-1 antitrypsin is the main protein of the alpha-globulin 1 region.
Another name used is alpha-1 proteinase inhibitor (α1-PI).

Genetics
The gene is located on the long arm of chromosome 14 (14q32.1).
Over 100 different variants of α1-antitrypsin have been described in various populations. North-Western Europeans are most at risk for carrying one of the most common mutant forms of A1AT, the Z mutation (Glu342Lys on M1A, rs28929474).

Biochemical properties
A1AT is a single-chain glycoprotein consisting of 394 amino acids in the mature form and exhibits many glycoforms. The three N-linked glycosylations sites are mainly equipped with so-called diantennary N-glycans. However, one particular site shows a considerable amount of heterogeneity since tri- and even tetraantennary N-glycans can be attached to the Asparagine 107 (UniProtKB amino acid nomenclature). These glycans carry different amounts of negatively charged sialic acids; this causes the heterogeneity observed on normal A1AT when analysed by isoelectric focusing. Also, the fucosylated triantennary N-glycans were shown to have the fucose as part of a so-called Sialyl Lewis x epitope, which could confer this protein particular protein-cell recognition properties. The single cysteine residue of A1AT in position 256 (UniProtKB nomenclature) is found to be covalently linked to a free single cysteine by a disulfide bridge.

Analysis
The level of A1AT in serum is most often determined by adding an antibody that binds to A1AT, then using turbidimetry to measure how much A1AT is present. Other detection methods include the use of enzyme-linked-immuno-sorbent-assays and radial immunodiffusion.
Different analytical methods are used to determine A1AT phenotype. As protein electrophoresis is imprecise, the A1AT phenotype is analysed by isoelectric focusing (IEF) in the pH range 4.5-5.5, where the protein migrates in a gel according to its isoelectric point or charge in a pH gradient.
Normal A1AT is termed M, as it migrates toward the center of such an IEF gel. Other variants are less functional and are termed A-L and N-Z, dependent on whether they run proximal or distal to the M band. The presence of deviant bands on IEF can signify the presence of alpha-1 antitrypsin deficiency. Since the number of identified mutations has exceeded the number of letters in the alphabet, subscripts have been added to most recent discoveries in this area, as in the Pittsburgh mutation described above.
As every person has two copies of the A1AT gene, a heterozygote with two different copies of the gene may have two different bands showing on electrofocusing, although heterozygote with one null mutant that abolishes expression of the gene will only show one band.
In blood test results, the IEF results are notated as in PiMM, where Pi stands for protease inhibitor and "MM" is the banding pattern of that patient.
Alpha-1 antitrypsin levels in the blood depend on the genotype. Some mutant forms fail to fold properly and are, thus, targeted for destruction in the proteasome, whereas others have a tendency to polymerise, being retained in the endoplasmic reticulum. The serum levels of some of the common genotypes are:

PiMM: 100% (normal)
PiMS: 80% of normal serum level of A1AT
PiSS: 60% of normal serum level of A1AT
PiMZ: 60% of normal serum level of A1AT
PiSZ: 40% of normal serum level of A1AT
PiZZ: 10-15% (severe alpha-1 antitrypsin deficiency)
PiZ is caused by a glutamate to lysine mutation at position 342 (366 in pre-processed form)
PiS is caused by a glutamate to valine mutation at position 264 (288 in pre-processed form)Other rarer forms have been described; in all, there are over 80 variants.

Medical uses
Alpha-1 antitrypsin concentrates are prepared from the blood plasma of blood donors. The US Food and Drug Administration (FDA) has approved the use of four alpha-1 antitrypsin products derived from a human plasma: Prolastin, Zemaira, Glassia, and Aralast. These products for intravenous augmentation A1AT therapy can cost up to $100,000 per year per patient. They are administered intravenously at a dose of 60 mg/kg once a week; higher doses do not provided additional benefit although they can be used in anticipation of an interruption of weekly administration, such as for a vacation.Alpha1-proteinase inhibitor (Respreeza) was approved for medical use in the European Union in August 2015. It is indicated for maintenance treatment, to slow the progression of emphysema in adults with documented severe alpha1-proteinase inhibitor deficiency (e.g., genotypes PiZZ, PiZ (null), Pi (null, null), PiSZ) </s>