INTRODUCTION
The influenza vaccine is an annual vaccine to protect against the highly variable influenza virus[1]. Each injected seasonal influenza vaccine contains three influenza viruses-one A (H3N2) virus, one regular seasonal A (H1N1) virus (not the 2009 H1N1 virus), and one B virus.[2]
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Purpose and benefits of annual flu vaccination
"Influenza vaccination is the most effective method for preventing influenza virus infection and its potentially severe complications."[3][4][5]
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. It is frequently estimated that 36,000 people die each year from influenza and accompanying opportunistic infections and complications in the United States alone.[6] 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.[7] 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."[8] The economic costsin the U.S. have been estimated at over $80 billion.
The number of annual influenza-related hospitalizations is many times the number of deaths.[9] "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..."[10]
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.[11]
In the United States, the CDC recommends to clinicians that
In general, anyone who wants to reduce their chances of getting influenza can get vaccinated. 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.[12]
Vaccination against influenza is recommended for most members of high-risk groups who would be likely to suffer complications from influenza. Specific recommendations include all children and teenagers, from six months to 18 years of age;[11] [13]
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.[14]
In the event of exposure to H5N1-type (avian influenza), seasonal flu vaccine may also offer some protection against H5N1 infection.[15][16][17]
History of the flu vaccine
See also: Timeline of vaccines
Vaccines are used in both humans and nonhumans. Human vaccine is meant unless specifically identified as a veterinary, poultry or livestock vaccine.
Influenza
The first influenza pandemic was recorded in 1580; since this time, various methods have been employed to eradicate its cause.[18] The etiological cause of influenza, the orthomyxoviridae was finally discovered by the Medical Research Council (MRC) of the United Kingdom in 1933.[19]
Known flu pandemics:[20]
• 1889–90 — Asiatic (Russian) Flu, mortality rate said to be 0.75–1 death per 1000 possibly H2N2
• 1900 — Possibly H3N8
• 1918–20 – Spanish Flu, 500 million ill, at least 20–40 million died of H1N1
• 1957–58 – Asian Flu, 1 to 1.5 million died of H2N2
• 1968–69 – Hong Kong Flu, 3/4 to 1 million died of H3N2
•
Flu vaccine origins and development
In the world wide Spanish flu pandemic of 1918, "Physicians tried everything they knew, everything they had ever heard of, from the ancient art of bleeding patients, to administering oxygen, to developing new vaccines and sera (chiefly against what we now call Hemophilus influenzae—a name derived from the fact that it was originally considered the etiological agent—and several types of pneumococci). Only one therapeutic measure, transfusing blood from recovered patients to new victims, showed any hint of success."[21]
In 1931, viral growth in embryonated hens' eggs was discovered, and in the 1940s, the US military developed the first approved inactivated vaccines for influenza, which were used in the Second World War (Baker 2002, Hilleman 2000). 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 (Couch 1997, Hilleman 2002).[22]
Flu vaccine acceptance
According to the CDC: "Influenza vaccination is the primary method for preventing influenza and its severe complications. [...] Vaccination is associated with reductions in influenza-related respiratory illness and physician visits among all age groups, hospitalization and death among persons at high risk, otitis media among children, and work absenteeism among adults. Although influenza vaccination levels increased substantially during the 1990s, further improvements in vaccine coverage levels are needed".[23]
The current egg-based technology for producing influenza vaccine was created in the 1950s.[24] 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[25], even though the 24 excess deaths and 400 excess hospitalizations from the 1976 vaccine are dwarfed by the thousands of lives and tens or hundreds of thousands of hospitalizations saved annually by seasonal influenza vaccination.
Current status
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).[26] As of July 2009, more than 70 known clinical trials have been completed or are ongoing for pandemic influenza vaccines.[27] In September 2009, the US Food and Drug Administration approved four vaccines against the 2009 H1N1 influenza virus (the current pandemic strain), and expect the initial vaccine lots to be avaialable within the following month.[28]
Clinical trials of vaccines
A vaccine is assessed in terms of the reduction of the risk of disease produced by vaccination, its 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.[29] 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,[30] or most rigorously, by immunising adult volunteers and then challenging with virulent influenza virus.[31] 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 virus in circulation; virus prevalence varies widely between years, and influenza is often confused with other influenza-like illnesses.[32]
Nevertheless, multiple clinical trials of both live and inactivated influenza vaccines 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.[31] The meta-analyses examined the efficacy and effectiveness of inactivated vaccines in adults,[33] children,[34] and the elderly.[35][36] 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.[33] 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.[34] In the elderly, vaccination does not reduce the frequency of influenza, but seems to reduce pneumonia, hospital admission and deaths from influenza or pneumonia.[35][36] However, the measured effectiveness of the vaccine in the elderly varies depending on whether the population studied is in residential care homes, or in the community, with the vaccine appearing more effective in an institution. This apparent effect is unlikely to be real and may be due to selection bias affecting the analysis of the data, or differences in diagnosis and surveillance.
Overall, the benefit of influenza vaccination is clear in the elderly and vaccination of children may be beneficial. 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.[32] 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.[37] However, such a vaccine would have to be produced and distributed rapidly to have maximum effect.[38]
Effectiveness of vaccine
Studies demonstrate that vaccination can be a cost-effective counter-measure to seasonal outbreaks of influenza;[39] but 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."[40]
The group most vulnerable to flu, the elderly, is also the least affected by the vaccine, with an average efficacy rate ranging from 40-50% at age 65, and 15-30% past age 70.[41][42][43] 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.[44]
In the United States a person 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.[45] Vaccination of those over age 65 reduces influenza-associated death by about 50%.[46][47] 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.[48] 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.[49]
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.[50] 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.[51] 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.[52] 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:
...[A]ntibodies made in response to vaccination with one strain of influenza viruses can provide protection against different, but related strains. A less than ideal match may result in reduced vaccine effectiveness against the variant viruses, but it still can provide enough protection to prevent or lessen illness severity and prevent flu-related complications. In addition, it’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.[53]
Comparing flu shot to nasal spray
Flu vaccines are available either as
• TIV (flu shot (injection) of trivalent (three strains; usually A/H1N1, A/H3N2, and B) inactivated (killed) vaccine) or
• LAIV (nasal spray (mist) of live attenuated influenza virus).
TIV works by putting into the bloodstream those parts of three strains of flu virus that the body uses to create antibodies; while LAIV works by infecting a body with a single flu strain that has been genetically modified to minimize symptoms of illness.
LAIV is not recommended for individuals under age 2 or over age 50,[54] but might be comparatively more effective among children over age 2.[55]
A military study on military personnel showed that flu shots yielded less illness than nasal spray. Based on one of the largest head-to-head studies comparing LAIV and TIV (which was conducted by the U.S. Armed Forces Surveillance Center on military personnel who were stationed in the United States during three flu seasons from 2004 through 2007), investigators concluded that: "It may be prudent to use TIV in patients who were vaccinated at least once in the past 2 years [...] but LAIV against pandemic strains maybe be more protective than inactivated vaccines, because the population will probably lack preexisting immunity."[56]
Vaccination recommendations
U.S. Navy personnel receiving influenza vaccination
Various public health organizations, including the World Health Organization, have recommended that yearly influenza vaccination be routinely offered to 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)[57]
• pregnant women[58][59]
• 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.[60]
Side effects
Side effects of the inactivated/dead flu vaccine injection include:
• mild soreness, redness, and swelling where the shot was given
• fever
• aches
These problems usually begin soon after the injection, and last 1–2 days.[61]
Side effects of the activated/live/LAIV flu nasal spray vaccine:
Some children and adolescents 2–17 years of age have reported:[62]
• runny nose, nasal congestion or cough
• fever
• headache and muscle aches
• wheezing
• abdominal pain or occasional vomiting or diarrhea
Some adults 18–49 years of age have reported:[62]
• runny nose or nasal congestion
• sore throat
• cough, chills, tiredness/weakness
• headache
Some injection-based flu vaccines intended for adults in the United States contain thiomersal. Despite some controversy in the media,[63] the World Health Organization has concluded that there is no evidence of toxicity from thimerosal in vaccines and no reason on grounds of safety to change to more-expensive single-dose administration.[64]
