The influenza vaccine, also known as flu shot, is an annual vaccine to protect against the highly variable influenza virus. Each injected seasonal influenza vaccine contains three influenza viruses: one A (H3N2) virus, one regular seasonal A (H1N1) virus (in 2010 this was replaced by the 2009 pandemic H1N1 virus), and one B virus.
Vaccines are used in both humans and nonhumans. Human vaccine is meant unless specifically identified as a veterinary, poultry or livestock vaccine.
In the world wide Spanish flu pandemic of 1918, "Physicians tried everything they knew, everything they had ever heard of, from the ancient art of bleeding patients, to administering oxygen, to developing new vaccines and sera (chiefly against what we now call Hemophilus influenzae—a name derived from the fact that it was originally considered the etiological agent—and several types of pneumococci). Only one therapeutic measure, transfusing blood from recovered patients to new victims, showed any hint of success."
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 Frances, 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. Greater advances were made in vaccinology and immunology, and vaccines became safer and mass-produced. Today, thanks to the advances of molecular technology, we are on the verge of making influenza vaccines through the genetic manipulation of influenza genes.
According to the CDC: "Influenza vaccination is the primary method for preventing influenza and its severe complications. Vaccination is associated with reductions in influenza-related respiratory illness and physician visits among all age groups, hospitalization and death among persons at high risk, otitis media among children, and work absenteeism among adults. Although influenza vaccination levels increased substantially during the 1990s, further improvements in vaccine coverage levels are needed".
The current egg-based technology for producing influenza vaccine was created in the 1950s. In the U.S. swine flu scare of 1976, President Gerald Ford was confronted with a potential swine flu pandemic. The vaccination program was rushed, yet plagued by delays and public relations problems. Meanwhile, maximum military containment efforts succeeded unexpectedly in confining the new strain to the single army base where it had originated. On that base a number of soldiers fell severely ill, but only one died. The program was canceled, after about 24% of the population had received vaccinations. An excess in deaths of twenty-five over normal annual levels as well as 400 excess hospitalizations, both from Guillain-Barré syndrome, were estimated to have occurred from the vaccination program itself, illustrating that vaccine itself is not free of risks. The result has been cited to stoke lingering doubts about vaccination. In the end, however, even the maligned 1976 vaccine may have saved lives. A 2010 study found a significantly enhanced immune response against the 2009 pandemic H1N1 in study participants who had received vaccination against the swine flu in 1976.
Influenza research includes molecular virology, molecular evolution, pathogenesis, host immune responses, genomics, and epidemiology. These help in developing influenza countermeasures such as vaccines, therapies and diagnostic tools. Improved influenza countermeasures require basic research on how viruses enter cells, replicate, mutate, evolve into new strains and induce an immune response. The Influenza Genome Sequencing Project is creating a library of influenza sequences that will help us understand what makes one strain more lethal than another, what genetic determinants most affect immunogenicity, and how the virus evolves over time. Solutions to limitations in current vaccine methods are being researched.
The rapid development, production, and distribution of pandemic influenza vaccines could potentially save millions of lives during an influenza pandemic. Due to the short time frame between identification of a pandemic strain and need for vaccination, researchers are looking at novel technologies for vaccine production that could provide better "real-time" access and be produced more affordably, thereby increasing access for people living in low- and moderate-income countries, where an influenza pandemic may likely originate, such as live attenuated (egg-based or cell-based) technology and recombinant technologies (proteins and virus-like particles). As of July 2009, more than 70 known clinical trials have been completed or are ongoing for pandemic influenza vaccines. In September 2009, the US Food and Drug Administration approved four vaccines against the 2009 H1N1 influenza virus (the current pandemic strain), and expected the initial vaccine lots to be available within the following month.
Clinical trials of vaccines
A vaccine is assessed by the reduction of the risk of disease that is produced by vaccination, the vaccine's efficacy. In contrast, in the field, the effectiveness of a vaccine is the practical reduction in risk for an individual when they are vaccinated under real-world conditions. Measuring efficacy of influenza vaccines is relatively simple, as the immune response produced by the vaccine can be assessed in animal models, or the amount of antibody produced in vaccinated people can be measured, or most rigorously, by immunising adult volunteers and then challenging with virulent influenza virus. In studies such as these, influenza vaccines showed high efficacy and produced a protective immune response. For ethical reasons, such challenge studies cannot be performed in the population most at risk from influenza – the elderly and young children. However, studies on the effectiveness of flu vaccines in the real world are uniquely difficult. The vaccine may not be matched to the viruses in circulation that year; virus prevalence varies widely between years, and influenza is often confused with other influenza-like illnesses.
Nevertheless, multiple clinical trials of both live and inactivated influenza vaccines against seasonal influenza have been performed and their results pooled and analyzed in several recent meta-analyses. Studies on live vaccines have very limited data, but these preparations may be more effective than inactivated vaccines. The meta-analyses examined the efficacy and effectiveness of inactivated vaccines against seasonal influenza in adults, children, and the elderly. In adults, vaccines show high efficacy against the targeted strains, but low effectiveness overall, so the benefits of vaccination are small, with a one-quarter reduction in risk of contracting influenza but no significant effect on the rate of hospitalization. However, the risk of serious complications from influenza is small in adults, so unless the effect from vaccination is large it might not have been detected. In children, vaccines again showed high efficacy, but low effectiveness in preventing "flu-like illness". In children under two the data are extremely limited, but vaccination appeared to confer no measurable benefit. In the elderly, vaccination does not reduce the frequency of influenza, but seems to reduce pneumonia, hospital admission and deaths from influenza or pneumonia. However, the current data on the effectiveness of influenza vaccines in the elderly may be unreliable, due to high levels of selection bias.
Overall, the benefit of influenza vaccination is clear in the elderly and vaccination of children may be beneficial. Routine vaccination of adults is not predicted to produce significant improvements in public health. The apparent contradiction between vaccines with high efficacy, but low effectiveness, may reflect the difficulty in diagnosing influenza under clinical conditions and the large number of strains circulating in the population. In contrast, during an influenza pandemic, where a single strain of virus is responsible for illnesses, an effective vaccine could produce a large decrease in the number of cases and be highly effective in controlling an epidemic. However, such a vaccine would have to be produced and distributed rapidly to have maximum effect.
Effectiveness of vaccine
The CDC reports that studies demonstrate that vaccination is a cost-effective counter-measure to seasonal outbreaks of influenza]. However it is not perfect. A study led by Dr. David K. Shay in February, 2008 reported that
"full immunization against flu provided about a 75 percent effectiveness rate in preventing hospitalizations from influenza complications in the 2005-6 and 2006-7 influenza seasons."
Influenza vaccine has been demonstrated to prevent disease and death, both in numerous controlled studies and in painstaking scientific reviews of these studies. However the rigor of the science of these studies has also been criticized. A 2006 Cochrane review of influenza vaccination in the elderly stated "The apparent high effectiveness of the vaccines in preventing death from all causes may reflect a baseline imbalance in health status and other systematic differences in the two groups of participants. In one observational study, a sharply lower risk of death or hospitalization for pneumonia was seen in vaccinated persons:
Results: The relative risk of death for vaccinated persons compared with unvaccinated persons was 0.39 [95% confidence interval (95% CI), 0.33-0.47] before influenza season, 0.56 (0.52-0.61) during influenza season, and 0.74 (0.67-0.80) after influenza season. The relative risk of pneumonia hospitalization was 0.72 (0.59-0.89) before, 0.82 (0.75-0.89) during, and 0.95 (0.85-1.07) after influenza season. Adjustment for diagnosis code variables resulted in estimates that were further from the null, in all time periods.
A better vitality and lower pneumonia hospitalization was thus observed in the vaccinated group in this non-randomized population study before, during, and after influenza season. This could, however, have been ascribed in whole or in part to self-selection bias, since vaccinated persons were already healthier before flu season. Some sub-populations have been assumed to benefit from vaccination in the absence of directly specific studies. For example, a 2008 Cochrane review of healthy children found "Influenza vaccines are efficacious in children older than two but little evidence is available for children under two.". The CDC in 2010, after a review of extant studies, extended its guidelines to recommend that every child over 6 months be given the influenza vaccine. Vaccines were shown effective against the influenza strains they are designed to protect against, but this translated to only a modest impact on working days lost due to influenza-like infections in a 2007 Cochrane review on influenza vaccines in healthy adults. While a 2010 Cochrane review noted that "Influenza vaccines have a modest effect in reducing influenza symptoms and working days lost" it stated found no evidence of prevention of complications, such as pneumonia, or transmission.
The group most vulnerable to non-pandemic flu, the elderly, is also the least benefitted by the vaccine, with an average efficacy rate ranging from 40-50% at age 65, and only 15-30% past age 70. 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. An influenza vaccine with four times the usual amount of antigen (Fluzone High Dose) has shown increased immune response in the elderly and has now been approved by the U.S. Food and Drug Administration (FDA).
In a non-pandemic year, a person in the United States aged 50–64 is nearly ten times more likely to die an influenza-associated death than a younger person, and a person over age 65 is over ten times more likely to die an influenza-associated death than the 50–64 age group. Vaccination of those over age 65 reduces influenza-associated death by about 50%. However, it is unlikely that the vaccine completely explains the results since elderly people who get vaccinated are probably more healthy and health-conscious than those who do not. Elderly participants randomized to a high-dose group (60 micrograms) had antibody levels 44 to 79 percent higher than did those who received the normal dose of vaccine. Elderly volunteers receiving the higher dose were more likely to achieve protective levels of antibody.
As mortality is also high among infants who contract influenza, the household contacts and caregivers of infants should be vaccinated to reduce the risk of passing an influenza infection to the infant. Data from the years when Japan required annual flu vaccinations for school-aged children indicate that vaccinating children—the group most likely to catch and spread the disease—has a strikingly positive effect on reducing mortality among older people: one life saved for every 420 children who received the flu vaccine. This may be due to herd immunity or to direct causes, such as individual older people not being exposed to influenza. For example, retired grandparents often risk infection by caring for their sick grandchildren in households where the parents can't take time off work or are sick themselves.
In most years (16 of the 19 years before 2007), the flu vaccine strains have been a good match for the circulating strains. In other flu seasons like that of 2007/2008, the match was less useful. But even a mis-matched vaccine can often provide some protection:
...ntibodies made in response to vaccination with one strain of influenza viruses can provide protection against different, but related strains. A less than ideal match may result in reduced vaccine effectiveness against the variant viruses, but it still can provide enough protection to prevent or lessen illness severity and prevent flu-related complications. In addition, it's important to remember that the influenza vaccine contains three virus strains so the vaccine can also protect against the other two viruses. For these reasons, even during seasons when there is a less than ideal match, CDC continues to recommend influenza vaccination. This is particularly important for people at high risk for serious flu complications and their close contacts.
Vaccination recommendations
Various public health organizations, including the World Health Organization, have recommended that yearly influenza vaccination be routinely offered to patients at risk of complications of influenza and those individuals who live with or care for high-risk individuals, including:
* the elderly (UK recommendation is those aged 65 or above)
* patients with chronic lung diseases (asthma, COPD, etc.)
* patients with chronic heart diseases (congenital heart disease, chronic heart failure, ischaemic heart disease)
* patients with chronic liver diseases (including cirrhosis)
* patients with chronic renal diseases (such as the nephrotic syndrome)
* patients who are immunosuppressed (those with HIV or who are receiving drugs to suppress the immune system such as chemotherapy and long-term steroids) and their household contacts
* people who live together in large numbers in an environment where influenza can spread rapidly, such as prisons, nursing homes, schools, and dormitories
* healthcare workers (both to prevent sickness and to prevent spread to patients)
* pregnant women. However, a 2009 review concluded that there was insufficient evidence to recommend routine use of trivalent influenza vaccine during the first trimester of pregnancy.
* children from ages six months to two years
Both types of flu vaccines are contraindicated for those with severe allergies to egg proteins and people with a history of Guillain-Barré syndrome.
Flu vaccine manufacturing
Flu vaccine is usually grown in fertilized chicken eggs. In February preceding each fall's flu season (in the Northern hemisphere), three strains of flu are selected and chicken eggs inoculated.
As of November 2007, both the conventional injection and the nasal spray are manufactured using chicken eggs. The European Union has also approved Optaflu, a vaccine produced by Novartis using vats of animal cells. This technique is expected to be more scalable and avoid problems with eggs, such as allergic reactions and incompatibility with strains that affect avians like chickens. A DNA-based vaccination, which is hoped to be even faster to manufacture, is currently in clinical trials, but has not yet been proven safe and effective. Research continues into the idea of a "universal" influenza vaccine (but no vaccine candidates have been announced) which would not need to be tailored to work on particular strains, but would be effective against a broad variety of influenza viruses.
In a 2007 report, the current global capacity of approximately 826 million seasonal influenza vaccine doses (inactivated and live) was double the current production of 413 million doses. In an aggressive scenario of producing pandemic influenza vaccines by 2013, only 2.8 billion courses could be produced in a six-month time frame. If all high- and upper-middle-income countries sought vaccines for their entire populations in a pandemic, nearly 2 billion courses would be required. If China pursued this goal as well, more than 3 billion courses would be required to serve these populations. Vaccine research and development is ongoing to identify novel vaccine approaches that could produce much greater quantities of vaccine at a price that is affordable to the global population.
An effective method of vaccine generation that bypasses the need for eggs is the construction of "influenza virus-like particle (VLP)". VLP is a non-egg, non-mammalian cell culture-based vaccine, purified from the supernatants of Spodoptera frugiperda Sf9 insect cells following infection of baculovirus vectors encoding an expression cassette made up of only three influenza virus structural proteins, hemagglutinin (HA), neuraminidase (NA), and matrix (M1) VLPs elicit antibodies that recognize a broader panel of antigenically distinct viral isolates compared to other vaccines in the hemagglutination-inhibition (HAI) assay.
Flu vaccine for nonhumans
"Vaccination in the veterinary world pursues four goals: (i) protection from clinical disease, (ii) protection from infection with virulent virus, (iii) protection from virus excretion, and (iv) serological differentiation of infected from vaccinated animals (so-called DIVA principle). In the field of influenza vaccination, neither commercially available nor experimentally tested vaccines have been shown so far to fulfil all of these requirements."
Horses with horse flu can run a fever, have a dry hacking cough, have a runny nose, and become depressed and reluctant to eat or drink for several days but usually recover in two to three weeks. "Vaccination schedules generally require a primary course of 2 doses, 3–6 weeks apart, followed by boosters at 6–12 month intervals. It is generally recognised that in many cases such schedules may not maintain protective levels of antibody and more frequent administration is advised in high-risk situations."
Poultry
Poultry vaccines for bird flu are made on the cheap and are not filtered and purified like human vaccines to remove bits of bacteria or other viruses. They usually contain whole virus, not just hemagglutinin as in most human flu vaccines. Purification to standards needed for humans is far more expensive than the original creation of the unpurified vaccine from eggs. There is no market for veterinary vaccines that are that expensive. Another difference between human and poultry vaccines is that poultry vaccines are adjuvated with mineral oil, which induces a strong immune reaction but can cause inflammation and abscesses. "Chicken vaccinators who have accidentally jabbed themselves have developed painful swollen fingers or even lost thumbs, doctors said. Effectiveness may also be limited. Chicken vaccines are often only vaguely similar to circulating flu strains — some contain an H5N2 strain isolated in Mexico years ago. 'With a chicken, if you use a vaccine that's only 85 percent related, you'll get protection,' Dr. Cardona said. 'In humans, you can get a single point mutation, and a vaccine that's 99.99 percent related won't protect you.' And they are weaker [than human vaccines]. 'Chickens are smaller and you only need to protect them for six weeks, because that's how long they live till you eat them,' said Dr. John J. Treanor, a vaccine expert at the University of Rochester. Human seasonal flu vaccines contain about 45 micrograms of antigen, while an experimental A(H5N1) vaccine contains 180. Chicken vaccines may contain less than 1 microgram. 'You have to be careful about extrapolating data from poultry to humans,' warned Dr. David E. Swayne, director of the agriculture department's Southeast Poultry Research Laboratory. 'Birds are more closely related to dinosaurs.'"
Pigs
Swine origin influenza virus (SoIV) vaccines are extensively used in the swine industry in Europe and North America. Most swine flu vaccine manufacturers include an H1N1 and an H3N2 SoIV strains.
Swine influenza has become a greater problem in recent decades. Evolution of the virus has resulted in inconsistent responses to traditional vaccines. Standard commercial swine origin flu vaccines are effective in controlling the problem when the virus strains match enough to have significant cross-protection and custom (autogenous) vaccines made from the specific viruses isolated are created and used in the more difficult cases. SoIV vaccine manufacture Novartis paints this picture: "A strain of swine origin influenza virus (SoIV) called H3N2, first identified in the US in 1998, has brought exasperating production losses to swine producers. Abortion storms are a common sign. Sows go off feed for two or three days and run a fever up to 106°F. Mortality in a naïve herd can run as high as 15%."
Dogs
In 2004, Influenza A virus subtype H3N8 was discovered to cause canine influenza. Because of the lack of previous exposure to this virus, dogs have no natural immunity to this virus. However a vaccine is now available.
Purpose and benefits of annual flu vaccination
An influenza epidemic emerges during each winter's flu season. Each year there are two flu seasons due to the occurrence of influenza at different times in the Northern and Southern Hemispheres. Tens of thousands of Americans die in a typical year, but there are notable variations from year to year. In 2010 the Centers for Disease Control and Prevention (CDC) in the United States changed the way it reports the 30-year estimates for deaths from influenza. Now they are reported as a range from a low of about 3,300 deaths to a high of 49,000 per year over the past 30 years.
Worldwide, seasonal influenza kills an estimated 250,000 to 500,000 people each year.
The majority of deaths in the industrialized world occur in adults age of 65 and over. A review at the NIAID division of the NIH in 2008 concluded that "Seasonal influenza causes more than 200,000 hospitalizations and 41,000 deaths in the U.S. every year, and is the seventh leading cause of death in the U.S." The economic costs in the U.S. have been estimated at over $80 billion. The number of annual influenza-related hospitalizations is many times the number of deaths. "The high costs of hospitalizing young children for influenza creates a significant economic burden in the United States, underscoring the importance of preventive flu shots for children and the people with whom they have regular contact..."
In Canada, the National Advisory Committee on Immunization, the group that advises the Public Health Agency of Canada, currently recommends that everyone aged 2 to 64 years be encouraged to receive annual influenza vaccination, and that children between the age of six and 24 months, and their household contacts, should be considered a high priority for the flu vaccine. Vaccination of children aged 6 months through 5 years was found to prevent illness in more than half in an six-year observational study.
In the United States, "Routine influenza vaccination is recommended for all persons aged ≥6 months." The sole group for whom routine influenza vaccination is is still not recommended is infants less than six months of age.
Within its blanket recommendation for general vaccination, the United States, the CDC emphasizes to clinicians the special urgency of vaccination for members of certain vulnerable groups, and of those who care for them:
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.
Vaccination against influenza is also, according to research published in July 2010, thought to be important for members of high-risk groups who would be likely to suffer complications from influenza, for example pregnant women and children and teenagers from six months to 18 years of age;
In expanding the new 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 expected benefit would be indirect — to reduce the number of influenza cases among parents and other household members, and possibly spread to the general community.
Vaccination of school-age children has a strong protective effect on the adults and elderly with whom the children are in contact. Children born to mothers who received flu vaccination while pregnant are strongly protected from having to be hospitalized with the flu. "The effectiveness of influenza vaccine given to mothers during pregnancy in preventing hospitalization among their infants, adjusted for potential confounders, was 91.5%"
Healthy, working adults who received influenza vaccine reported 25 percent fewer episodes of upper respiratory illness than those who received the placebo (105 vs. 140 episodes per 100 subjects, P < 0.001), 43 percent fewer days of sick leave from work due to upper respiratory illness (70 vs. 122 days per 100 subjects, P = 0.001), and 44 percent fewer visits to physicians' offices for upper respiratory illnesses (31 vs. 55 visits per 100 subjects, P = 0.004). The study, reported in the NEJM, estimated cost savings at $46.85 per person vaccinated, and concluded that "Vaccination against influenza has substantial health-related and economic benefits for healthy, working adults." PMID 7666874
Influenza vaccination has been shown highly effective in health care workers, with minimal adverse effects. In a study of forty matched nursing homes, staff influenza vaccination rates were 69.9% in the vaccination arm versus 31.8% in the control arm. The vaccinated staff experienced a 42% reduction in sick leave from work (P=.03). A review of eighteen studies likewise found a strong net benefit to health care workers. Only two of these eighteen studies also included an assessment of patient mortality relative to staff influenza vaccine. Both studies including this assessment found that higher rates of health care worker vaccination correlated with reduced patient deaths.
Annual seasonal flu vaccination may provide some level of protection against novel flu viruses. A number of studies suggest that seasonal flu vaccine may offer cross-protection, both against the H5N1-type (avian influenza) H5N1 infection and the 2009 flu pandemic (the H1N1 "swine flu.") A significantly enhanced immune response against the 2009 pandemic H1N1 was also found in study participants who had received vaccination against the swine flu in 1976.
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