Influenza vaccine
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Influenza (flu) |
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The influenza vaccine, also known as flu shot, 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 (in 2010 this was replaced by the 2009 pandemic H1N1 virus), and one B virus.[2]
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 flu season each winter. There are two flu seasons annually, corresponding to the occurrence of winter in opposite months in the Northern and Southern Hemispheres.
Worldwide, seasonal influenza kills an estimated 250,000 to 500,000 people each year.[6] Tens of thousands of Americans die in a typical flu season, but there are notable variations from year to year. In 2010 the Centers for Disease Control and Prevention (CDC) in the United States changed the way it reports the 30-year estimates for deaths from influenza. 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.[7][8]
The majority of deaths in the industrialized world occur in adults aged 65 and over.[9] 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."[10] The average total economic costs caused by the annual influenza outbreak in the U.S. have been estimated at over $80 billion.[11][12] The number of annual influenza-related hospitalizations is many times the number of deaths.[13] "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..."[14]
In 2006 the United States began recommending influenza vaccinations for preschoolers but Canada did not follow suit until 2010, "thereby creating a natural experiment to evaluate the effect of the policy in the United States."[15] A Canadian study found emergency room visits significantly lower for 2- to 4-year-olds in Boston than in Montreal through the period (34% fewer ER trips). Vaccination of preschoolers may have reduced their likelihood of transmission of flu to older siblings and raised the chances that their parents would vaccinate older children as well, since there were also 18 percent fewer emergency room visits by 5- to 18-year-olds in Boston than Montreal during the study period.[16] In another six-year observational study, vaccination of children aged 6 months through 5 years was found to prevent illness in more than half.[17]
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.[18]
In the United States, "Routine influenza vaccination is recommended for all persons aged ≥6 months."[19] The sole group for whom routine influenza vaccination is still not recommended is infants less than six months of age.
Within its blanket recommendation for general vaccination, the United States, the Centers for Disease Control and Prevention (CDC) 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.[20]
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[19][21] and children and teenagers from six months to 18 years of age;[22]
- 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[23]
- 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.[23]
Vaccination of school-age children has a strong protective effect on the adults and elderly with whom the children are in contact.[24] 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%."[25]
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).[26] A review of eighteen studies likewise found a strong net benefit to health care workers.[27] The two of these eighteen studies that assessed the relationship of patient mortality relative to staff influenza vaccine uptake found that higher rates of health care worker vaccination correlated with reduced patient deaths.[27] An analysis of data and patient population health in New Mexico's 75 long-term care facilities nursing homes found that as vaccination rates of health care personnel with direct patient contact rose from 51 to 75 percent, the chances of a flu outbreak among patients in that facility went down by 87 percent. The study showed that vaccinating health care personnel provided more protection to residents than vaccinating residents themselves.[28]
In a 2010 survey of healthcare workers, 63.5% reported that they received the flu vaccine during the 2010-11 season, an increase from 61.9% reported the previous season. Health professionals with direct patient contact had higher vaccination uptake, such as physicians and dentists (84.2%) and nurse practitioners (82.6%).[29][30]
Annual seasonal flu vaccination may provide some level of protection against novel flu viruses.[31] A number of studies suggest that seasonal flu vaccine may offer cross-protection, both against the H5N1-type (avian influenza) H5N1 infection[32][33][34][35] and the 2009 flu pandemic (the H1N1 "swine flu.")[36][37][38][38][39][40] 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.[41]
History of the flu vaccine
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.[42] The etiological cause of influenza, the orthomyxoviridae was finally discovered by the Medical Research Council (MRC) of the United Kingdom in 1933.[43]
Known flu pandemics:[44]
- 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
- 2009 - Swine Flu, caused by H1N1/09, Template:Swine-flu-deaths died[45]
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."[46]
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.[47] In the 1940s, the US military developed the first approved inactivated vaccines for influenza, which were used in the Second World War.[48] 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.[49]
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".[50]
The current egg-based technology for producing influenza vaccine was created in the 1950s.[51] 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.[52] 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.[41]
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[citation needed] 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).[53] As of July 2009, more than 70 known clinical trials have been completed or are ongoing for pandemic influenza vaccines.[54] 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.[55]
Prospects for universal flu vaccines
Many groups world wide are working on a universal flu vaccine that will not need changing each year,[56] as the sector has been viewed as "increasingly hot".[57] Companies pursuing the vaccine as of 2009 and 2010 include BiondVax,[58] Theraclone,[59] Dynavax Technologies Corporation,[60] VaxInnate,[61] Crucell NV,[57] Inovio Pharmaceuticals,[62] and Immune Targeting Systems (ITS)[63]
In 2008 Acambis announced work on a universal flu vaccine (ACAM-FLU-ATM) based on the less variable M2 protein component of the flu virus shell.[64] See also H5N1 vaccines.
In 2009, the Wistar Institute received a patent for using "a variety of peptides" in a flu vaccine, and announced it was seeking a corporate partner.[65]
In 2010, the National Institute of Allergy and Infectious Diseases (NIAID) of the U.S. NIH announced a breakthrough; the effort targets the stem, which mutates less often than the head of the virus.[66]
DNA vaccines such as VGX-3400X (aimed at multiple H5N1 strains) contain DNA fragments (plasmids)[62] .[67] Inovios SynCon DNA vaccines include H5N1 and H1N1 subtypes.[68]
In July 2011, F16 researchers created an antibody, which targets a protein found on the surface of all influenza A viruses called haemagglutinin.[69][70][71] F16 is the only known antibody that treats all 16 subtypes of the influenza A virus and might be the lynchpin for a universal influenza vaccine.[69][70][71]
Other vaccines are polypeptide based.
Some universal flu vaccines have started early stage clinical trials.
- BiondVax are targeting the less variable stalk of the haemagglutinin molecule[72] with Multimeric-001.[73] This is aimed at type A (inc H1N1) and Type B influenza and has started a phase IIa study.[74]
- Dynavax have developed a vaccine N8295 based on two highly conserved antigens NP and M2e[75] and their TLR9 agonist, and started clinical trials in June 2010.[76]
- ITS's fp01[77] includes 6 peptide antigens to highly conserved segments of the PA, PB1, PB2, NP & M1 proteins, and has started phase I trials.
Based on the results of animal studies, a universal flu vaccine may use a two-step vaccination strategy — priming with a DNA-based HA vaccine followed by a second dose with an inactivated, attenuated, or adenovirus-vector–based vaccine.[78]
Some people given a 2009 H1N1 flu vaccine have developed broadly protective antibodies which has raised hopes for a universal flu vaccine.[79][80][81]
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.[82] 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,[83] or most rigorously, by immunising adult volunteers and then challenging with virulent influenza virus.[84] 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.[85]
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.[84] The meta-analyses examined the efficacy and effectiveness of inactivated vaccines against seasonal influenza in adults,[86] children,[87] and the elderly.[88][89] 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.[86] 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.[87] In the elderly, vaccination does not reduce the frequency of influenza, but seems to reduce pneumonia, hospital admission and deaths from influenza or pneumonia.[88][89] However, the current data on the effectiveness of influenza vaccines in the elderly may be unreliable, due to high levels of selection bias.[90]
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.[85] 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.[91] However, such a vaccine would have to be produced and distributed rapidly to have maximum effect.[92]
Effectiveness of vaccine
The CDC reports that studies demonstrate that vaccination is a cost-effective counter-measure to seasonal outbreaks of influenza.[93] 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."[23]
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.[94] 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.[95] 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.".[96] 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.[97] 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.[98] 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.[99]
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.[100][101][102] 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.[103] 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).[104]
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.[105] Vaccination of those over age 65 reduces influenza-associated death by about 50%.[106][107] 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.[108][109][110] 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.[111]
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.[112] 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.[113] 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.[114] 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.[115]
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 vaccine.)
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 inoculating against those same three strains that have been genetically modified to minimize symptoms of illness.[citation needed]
LAIV is not recommended for individuals under age 2 or over age 50,[116] but might be comparatively more effective among children over age 2.[117]
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 may be more protective than inactivated vaccines, because the population will probably lack preexisting immunity."[118]
High-dose vaccine
A high-dose vaccine (Fluzone High-Dose) 4x the strength of standard flu vaccine was approved by the FDA in late 2009.[119][120] This vaccine is intended for people 65 and over, who typically have weakened immune response due to normal aging. The vaccine produces a greater immune response than standard vaccine, but it is not yet known whether it provides greater protection against flu. Study results are expected in 2012. CDC recommends the high-dose vaccine for people 65 and over but expresses no preference between it and standard vaccine.[121]
Vaccination recommendations
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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)[122]
- 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.[123]
- 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.[124]
Public Health Law Research,[125] an independent organization, published in 2009 several evidence briefs summarizing the research assessing the effect of specific laws and policy on public health.
There is sufficient evidence supporting the effectiveness of requiring vaccinations as a condition for attending child care facilities and schools.[126]
There is insufficient evidence to assess the effectiveness of requiring vaccinations as a condition for specified jobs as a means of reducing incidence of specific diseases among particularly vulnerable populations.[127]
There is strong evidence supporting the effectiveness of standing orders which allow healthcare workers without prescription authority to administer vaccines under defined circumstances as a public health intervention aimed at increasing vaccination rates.[128]
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.[129]
Side effects of the activated/live/LAIV flu nasal spray vaccine:
Some children and adolescents 2–17 years of age have reported:[130]
- 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:[130]
- runny nose or nasal congestion
- sore throat
- cough, chills, tiredness/weakness
- headache
More severe, but very rare side effects include:[130]
- life-threatening allergic reaction
Some injection-based flu vaccines intended for adults in the United States contain thiomersal (also known as thimerosal). Despite some controversy in the media,[131] the World Health Organization 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.[132]
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.[133][134]
A review has concluded that the 2009 H1N1 ("swine flu") vaccine has a safety profile similar to that of seasonal vaccine.[135] Although one review gives an incidence of about one case per million vaccinations,[136] a large study in China, reported in the NEJM covering close to 100 million doses of vaccine against the 2009 H1N1 "swine" flu found only eleven cases of Guillain-Barre syndrome, (0.1%) total incidence in persons vaccinated, actually lower than the normal rate of the disease in China, and no other notable side effects; "The risk-benefit ratio, which is what vaccines and everything in medicine is about, is overwhelmingly in favor of vaccination."[137] Getting infected by influenza itself increases both the risk of death (up to 1 in 10,000) and increases the risk of developing Guillain-Barré syndrome to a much higher level than the highest level of suspected vaccine involvement (approx. 10 times higher by recent estimates).[138][139]
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.[140]
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.[141] 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)[142] VLPs elicit antibodies that recognize a broader panel of antigenically distinct viral isolates compared to other vaccines in the hemagglutination-inhibition (HAI) assay.
H5N1
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Vaccines have been formulated against several of the avian H5N1 influenza varieties. Vaccination of poultry against the ongoing H5N1 epizootic is widespread in certain countries. Some vaccines also exist for use in humans, and others are in testing, but none have been made available to civilian populations, nor produced in quantities sufficient to protect more than a tiny fraction of the Earth's population in the event of an H5N1 pandemic.
Three H5N1 vaccines for humans have been licensed as of June 2008:[143]
- Sanofi Pasteur's vaccine approved by the United States in April 2007,
- GlaxoSmithKline's vaccine Pandemrix approved by the European Union in May 2008, and
- CSL Limited's vaccine approved by Australia in June 2008.
All are produced in eggs and would require many months to be altered to a pandemic version.
H5N1 continually mutates, meaning vaccines based on current samples of avian H5N1 cannot be depended upon to work in the case of a future pandemic of H5N1. While there can be some cross-protection against related flu strains, the best protection would be from a vaccine specifically produced for any future pandemic flu virus strain. Dr. Daniel Lucey, co-director of the Biohazardous Threats and Emerging Diseases graduate program at Georgetown University, has made this point, "There is no H5N1 pandemic so there can be no pandemic vaccine." However, "pre-pandemic vaccines" have been created; are being refined and tested; and do have some promise both in furthering research and preparedness for the next pandemic. Vaccine manufacturing companies are being encouraged to increase capacity so that if a pandemic vaccine is needed, facilities will be available for rapid production of large amounts of a vaccine specific to a new pandemic strain.
Problems with H5N1 vaccine production include:
- lack of overall production capacity
- lack of surge production capacity (it is impractical to develop a system that depends on hundreds of millions of 11-day old specialized eggs on a standby basis)
- the pandemic H5N1 might be lethal to chickens
Cell culture (cell-based) manufacturing technology can be applied to influenza vaccines as they are with most viral vaccines and thereby solve the problems associated with creating flu vaccines using chicken eggs as is currently done.[144]:
- Currently, influenza vaccine for the annual, seasonal influenza program comes from four manufacturers. However, only a single manufacturer produces the annual vaccine entirely within the U.S. Thus, if a pandemic occurred and existing U.S.-based influenza vaccine manufacturing capacity was completely diverted to producing a pandemic vaccine, supply would be severely limited. Moreover, because the annual influenza manufacturing process takes place during most of the year, the time and capacity to produce vaccine against potential pandemic viruses for a stockpile, while continuing annual influenza vaccine production, is limited. Since supply will be limited, it is critical for HHS to be able to direct vaccine distribution in accordance with predefined groups (see Appendix D); HHS will ensure the building of capacity and will engage states in a discussion about the purchase and distribution of pandemic influenza vaccine.
- Vaccine production capacity: The protective immune response generated by current influenza vaccines is largely based on viral hemagglutinin (HA) and neuraminidase (NA) antigens in the vaccine. As a consequence, the basis of influenza vaccine manufacturing is growing massive quantities of virus in order to have sufficient amounts of these protein antigens to stimulate immune responses. Influenza vaccines used in the United States and around world are manufactured by growing virus in fertilized hens' eggs, a commercial process that has been in place for decades. To achieve current vaccine production targets millions of 11-day old fertilized eggs must be available every day of production.
- In the near term, further expansion of these systems will provide additional capacity for the U.S.-based production of both seasonal and pandemic vaccines, however, the surge capacity that will be needed for a pandemic response cannot be met by egg-based vaccine production alone, as it is impractical to develop a system that depends on hundreds of millions of 11-day old specialized eggs on a standby basis. In addition, because a pandemic could result from an avian influenza strain that is lethal to chickens, it is impossible to ensure that eggs will be available to produce vaccine when needed.
- In contrast, cell culture manufacturing technology can be applied to influenza vaccines as they are with most viral vaccines (e.g., polio vaccine, measles-mumps-rubella vaccine, chickenpox vaccine). In this system, viruses are grown in closed systems such as bioreactors containing large numbers of cells in growth media rather than eggs. The surge capacity afforded by cell-based technology is insensitive to seasons and can be adjusted to vaccine demand, as capacity can be increased or decreased by the number of bioreactors or the volume used within a bioreactor. In addition to supporting basic research on cell-based influenza vaccine development, HHS is currently supporting a number of vaccine manufacturers in the advanced development of cell-based influenza vaccines with the goal of developing U.S.-licensed cell-based influenza vaccines produced in the United States.</ref>[145] The US government has purchased from Sanofi Pasteur and Chiron Corporation several million doses of vaccine meant to be used in case of an influenza pandemic of H5N1 avian influenza and is conducting clinical trials with these vaccines.[146] Researchers at the University of Pittsburgh have had success with a genetically engineered vaccine that took only a month to make and completely protected chickens from the highly pathogenic H5N1 virus.[147][148]
According to the United States Department of Health & Human Services:
- In addition to supporting basic research on cell-based influenza vaccine development, HHS is currently supporting a number of vaccine manufacturers in the advanced development of cell-based influenza vaccines with the goal of developing U.S.-licensed cell-based influenza vaccines produced in the United States. Dose-sparing technologies. Current U.S.-licensed vaccines stimulate an immune response based on the quantity of HA (hemagglutinin) antigen included in the dose. Methods to stimulate a strong immune response using less HA antigen are being studied in H5N1 and H9N2 vaccine trials. These include changing the mode of delivery from intramuscular to intradermal and the addition of immune-enhancing adjuvant to the vaccine formulation. Additionally, HHS is soliciting contract proposals from manufacturers of vaccines, adjuvants, and medical devices for the development and licensure of influenza vaccines that will provide dose-sparing alternative strategies.[149]
Chiron Corporation is now recertified and under contract with the National Institutes of Health to produce 8,000–10,000 investigational doses of Avian Flu (H5N1) vaccine. MedImmune and Aventis Pasteur are under similar contracts.[150] The United States government hopes to obtain enough vaccine in 2006 to treat 4 million people. However, it is unclear whether this vaccine would be effective against a hypothetical mutated strain that would be easily transmitted through human populations, and the shelflife of stockpiled doses has yet to be determined.[151]
The New England Journal of Medicine reported on March 30, 2006 on one of dozens of vaccine studies currently being conducted. The Treanor et al. study was on vaccine produced from the human isolate (A/Vietnam/1203/2004 H5N1) of a virulent clade 1 influenza A (H5N1) virus with the use of a plasmid rescue system, with only the hemagglutinin and neuraminidase genes expressed and administered without adjuvant. "The rest of the genes were derived from an avirulent egg-adapted influenza A/PR/8/34 strain. The hemagglutinin gene was further modified to replace six basic amino acids associated with high pathogenicity in birds at the cleavage site between hemagglutinin 1 and hemagglutinin 2. Immunogenicity was assessed by microneutralization and hemagglutination-inhibition assays with the use of the vaccine virus, although a subgroup of samples were tested with the use of the wild-type influenza A/Vietnam/1203/2004 (H5N1) virus." The results of this study combined with others scheduled to be completed by spring 2007 is hoped will provide a highly immunogenic vaccine that is cross-protective against heterologous influenza strains.[152]
On August 18, 2006. the World Health Organization changed the H5N1 strains recommended for candidate vaccines for the first time since 2004. "The WHO's new prototype strains, prepared by reverse genetics, include three new H5N1 subclades. The hemagglutinin sequences of most of the H5N1 avian influenza viruses circulating in the past few years fall into two genetic groups, or clades. Clade 1 includes human and bird isolates from Vietnam, Thailand, and Cambodia and bird isolates from Laos and Malaysia. Clade 2 viruses were first identified in bird isolates from China, Indonesia, Japan, and South Korea before spreading westward to the Middle East, Europe, and Africa. The clade 2 viruses have been primarily responsible for human H5N1 infections that have occurred during late 2005 and 2006, according to WHO. Genetic analysis has identified six subclades of clade 2, three of which have a distinct geographic distribution and have been implicated in human infections:
- Subclade 1, Indonesia
- Subclade 2, Middle East, Europe, and Africa
- Subclade 3, China
On the basis of the three subclades, the WHO is offering companies and other groups that are interested in pandemic vaccine development these three new prototype strains:
- An A/Indonesia/2/2005-like virus
- An A/Bar headed goose/Quinghai/1A/2005-like virus
- An A/Anhui/1/2005-like virus
[...] Until now, researchers have been working on prepandemic vaccines for H5N1 viruses in clade 1. In March, the first clinical trial of a U.S. vaccine for H5N1 showed modest results. In May, French researchers showed somewhat better results in a clinical trial of an H5N1 vaccine that included an adjuvant. Vaccine experts aren't sure if a vaccine effective against known H5N1 viral strains would be effective against future strains. Although the new viruses will now be available for vaccine research, WHO said clinical trials using the clade 1 viruses should continue as an essential step in pandemic preparedness, because the trials yield useful information on priming, cross-reactivity, and cross-protection by vaccine viruses from different clades and subclades."[153][154]
As of November 2006, the United States Department of Health and Human Services still had enough H5N1 pre-pandemic vaccine to treat about 3 million people (5.9 million full-potency doses) in spite of 0.2 million doses used for research and 1.4 million doses that have begun to lose potency (from the original 7.5 million full-potency doses purchased from Sanofi Pasteur and Chiron Corp.). The expected shelf life of seasonal flu vaccine is about a year so the fact that most of the H5N1 pre-pandemic stockpile is still good after about 2 years is considered encouraging.[155]
Annual reformulation of flu vaccine
Each year, three strains are chosen for selection in that year's flu vaccination by the WHO Global Influenza Surveillance Network. The chosen strains are the H1N1, H3N2, and Type-B strains thought most likely to cause significant human suffering in the coming season. Due to the high mutation rate of the virus a particular vaccine formulation is effective for at most about a year. The World Health Organization coordinates the contents of the vaccine each year to contain the most likely strains of the virus to attack the next year.
- "The WHO Global Influenza Surveillance Network was established in 1952. The network comprises 4 WHO Collaborating Centres (WHO CCs) and 112 institutions in 83 countries, which are recognized by WHO as WHO National Influenza Centres (NICs). These NICs collect specimens in their country, perform primary virus isolation and preliminary antigenic characterization. They ship newly isolated strains to WHO CCs for high level antigenic and genetic analysis, the result of which forms the basis for WHO recommendations on the composition of influenza vaccine for the Northern and Southern Hemisphere each year."[156]
The Global Influenza Surveillance Network's selection of viruses for the vaccine manufacturing process is based on its best estimate of which strains will be predominant the next year, amounting in the end to well-informed but fallible guesswork.[157]
Formal WHO recommendations first issued in 1973; beginning 1999 there have been two recommendations per year, one for the northern hemisphere (N) and the other for the southern hemisphere (S).[158]
History of past WHO seasonal influenza vaccine composition recommendations[159]:
2002–2003 Northern Hemisphere winter season
The vaccines produced for the 2002–2003 season use[160]:
- an A/New Caledonia/20/1999-like(H1N1);
- an A/Moscow/10/1999-like(H3N2);
- a B/Hong Kong/330/2001-like viruses.
2003 Southern Hemisphere winter season
The composition of influenza virus vaccines for use in the 2003 Southern Hemisphere influenza season recommended by the World Health Organization was[161]:
- an A/New Caledonia/20/99(H1N1)-like virus
- an A/Moscow/10/99(H3N2)-like virus (The widely used vaccine strain is A/Panama/2007/99)
- a B/Hong Kong/330/2001-like virus (Some vaccine strains used were B/Shandong/7/97, B/Hong Kong/330/2001, B/Hong Kong/1434/2002)
2003–2004 Northern Hemisphere winter season
The production of flu vaccine requires a lead time of about six months before the season. It is possible that by flu season a strain becomes common for which the vaccine does not provide protection. In the 2003–2004 season the vaccine was produced to protect against A/Panama, A/New Caledonia, and B/Hong Kong. A new strain, A/Fujian, was discovered after production of the vaccine started and vaccination gave only partial protection against this strain.
Nature magazine reported that the Influenza Genome Sequencing Project, using phylogenetic analysis of 156 H3N2 genomes, "explains the appearance, during the 2003–2004 season, of the 'Fujian/411/2002'-like strain, for which the existing vaccine had limited effectiveness" as due to an epidemiologically significant reassortment. "Through a reassortment event, a minor clade provided the haemagglutinin gene that later became part of the dominant strain after the 2002–2003 season. Two of our samples, A/New York/269/2003 (H3N2) and A/New York/32/2003 (H3N2), show that this minor clade continued to circulate in the 2003–2004 season, when most other isolates were reassortants."[162]
According to the CDC:
- During the 2003–2004 influenza season, influenza A (H1), A (H3N2), and B viruses co-circulated worldwide, and influenza A (H3N2) viruses predominated. Several Asian countries reported widespread outbreaks of avian influenza A (H5N1) among poultry. In Vietnam and Thailand, these outbreaks were associated with severe illnesses and deaths among humans. In the United States, the 2003–2004 influenza season began earlier than most seasons, peaked in December, was moderately severe in terms of its impact on mortality, and was associated predominantly with influenza A (H3N2) viruses.[163]
During September 28, 2003 – May 22, 2004, WHO and NREVSS collaborating laboratories in the United States tested 130,577 respiratory specimens for influenza viruses; 24,649 (18.9%) were positive. Of these, 24,393 (99.0%) were influenza A viruses, and 249 (1.0%) were influenza B viruses. Among the influenza A viruses, 7,191 (29.5%) were subtyped; 7,189 (99.9%) were influenza A (H3N2) viruses, and two (0.1%) were influenza A (H1) viruses. The proportion of specimens testing positive for influenza first increased to >10% during the week ending October 25, 2003 (week 43), peaked at 35.2% during the week ending November 29 (week 48), and declined to <10% during the week ending January 17, 2004 (week 2). The peak percentage of specimens testing positive for influenza during the previous four seasons had ranged from 23% to 31% and peaked during late December to late February.[163]
As of June 15, 2004, CDC had antigenically characterized 1,024 influenza viruses collected by U.S. laboratories since October 1, 2003: 949 influenza A (H3N2) viruses, three influenza A (H1) viruses, one influenza A (H7N2) virus, and 71 influenza B viruses. Of the 949 influenza A (H3N2) isolates characterized, 106 (11.2%) were similar antigenically to the vaccine strain A/Panama/2007/99 (H3N2), and 843 (88.8%) were similar to the drift variant, A/Fujian/411/2002 (H3N2). Of the three A (H1) isolates that were characterized, two were H1N1 viruses, and one was an H1N2 virus. The hemagglutinin proteins of the influenza A (H1) viruses were similar antigenically to the hemagglutinin of the vaccine strain A/New Caledonia/20/99. Of the 71 influenza B isolates that were characterized, 66 (93%) belonged to the B/Yamagata/16/88 lineage and were similar antigenically to B/Sichuan/379/99, and five (7%) belonged to the B/Victoria/2/87 lineage and were similar antigenically to the corresponding vaccine strain B/Hong Kong/330/2001.[163]
- H9N2
In December 2003, one confirmed case of avian influenza A (H9N2) virus infection was reported in a child aged five years in Hong Kong. The child had fever, cough, and nasal discharge in late November, was hospitalized for two days, and fully recovered. The source of this child's H9N2 infection is unknown.[163]
- H5N1
During January–March 2004, a total of 34 confirmed human cases of avian influenza A (H5N1) virus infection were reported in Vietnam and Thailand. The cases were associated with severe respiratory illness requiring hospitalization and a case-fatality proportion of 68% (Vietnam: 22 cases, 15 deaths; Thailand: 12 cases, eight deaths). A substantial proportion of the cases were among children and young adults (i.e., persons aged 5–24 years). These cases were associated with widespread outbreaks of highly pathogenic H5N1 influenza among domestic poultry.[163]
- H7N3
During March 2004, health authorities in Canada reported two confirmed cases of avian influenza A (H7N3) virus infection in poultry workers who were involved in culling of poultry during outbreaks of highly pathogenic H7N3 on farms in the Fraser River Valley, British Columbia. One patient had unilateral conjunctivitis and nasal discharge, and the other had unilateral conjunctivitis and headache. Both illnesses resolved without hospitalization.[163]
- H7N2
During the 2003–2004 influenza season, a case of avian influenza A (H7N2) virus infection was detected in an adult male from New York, who was hospitalized for upper and lower respiratory tract illness in November 2003. Influenza A (H7N2) virus was isolated from a respiratory specimen from the patient, whose acute symptoms resolved. The source of this person's infection is unknown.[163]
2004 Southern Hemisphere winter season
The composition of influenza virus vaccines for use in the 2004 Southern Hemisphere influenza season recommended by the World Health Organization was:
- an A/New Caledonia/20/99(H1N1)-like virus
- an A/Fujian/411/2002(H3N2)-like virus (A/Kumamoto/102/2002 and A/Wyoming/3/2003 were egg-grown A/Fujian/411/2002-like viruses)
- a B/Hong Kong/330/2001-like virus (B/Shandong/7/97, B/Hong Kong/330/2001 and B/Hong Kong/1434/2002 were among those used at the time. B/Brisbane/32/2002 was also available.)[164][165]
2004–2005 Northern Hemisphere winter season
According to the CDC:
- On the basis of antigenic analyses of recently isolated influenza viruses, epidemiologic data, and postvaccination serologic studies in humans, the Food and Drug Administration's Vaccines and Related Biological Products Advisory Committee (VRBPAC) recommended that the 2004–05 trivalent influenza vaccine for the United States contain A/New Caledonia/20/99-like (H1N1), A/Fujian/411/2002-like (H3N2), and B/Shanghai/361/2002-like viruses. Because of the growth properties of the A/Wyoming/3/2003 and B/Jiangsu/10/2003 viruses, U.S. vaccine manufacturers are using these antigenically equivalent strains in the vaccine as the H3N2 and B components, respectively. The A/New Caledonia/20/99 virus will be retained as the H1N1 component of the vaccine.[163]
2005 Southern Hemisphere winter season
The composition of influenza virus vaccines for use in the 2005 Southern Hemisphere influenza season recommended by the World Health Organization was:
- an A/New Caledonia/20/99(H1N1)-like virus;
- an A/Wellington/1/2004(H3N2)-like virus;
- a B/Shanghai/361/2002-like virus (B/Shanghai/361/2002, B/Jilin/20/2003 and B/Jiangsu/10/2003 were used at the time)[166][167]
2005–2006 Northern Hemisphere winter season
The vaccines produced for the 2005–2006 season use:
- an A/New Caledonia/20/1999-like(H1N1);
- an A/California/7/2004-like(H3N2) (or the antigenically equivalent strain A/New York/55/2004);
- a B/Jiangsu/10/2003-like viruses.
In people in the United States, overall flu and pneumonia deaths were below those of a typical flu season with 84% Influenzavirus A and the rest Influenzavirus B. Of the patients who had Type A viruses, 80% had viruses identical or similar to the A bugs in the vaccine. 70% of the people testing positive for a B virus had Type B Victoria, a version not found in the vaccine.[168]
"During the 2005–06 season, influenza A (H3N2) viruses predominated overall, but late in the season influenza B viruses were more frequently isolated than influenza A viruses. Influenza A (H1N1) viruses circulated at low levels throughout the season. Nationally, activity was low from October through early January, increased during February, and peaked in early March. Peak activity was less intense, but activity remained elevated for a longer period of time this season compared to the previous three seasons. The longer period of elevated activity may be due in part to regional differences in the timing of peak activity and intensity of influenza B activity later in the season."[169]
2006 Southern Hemisphere winter season
The composition of influenza virus vaccines for use in the 2006 Southern Hemisphere influenza season recommended by the World Health Organization was:
- an A/New Caledonia/20/99(H1N1)-like virus;
- an A/California/7/2004(H3N2)-like virus (A/New York/55/2004 was used at the time);
- a B/Malaysia/2506/2004-like virus[170][171]
2006–2007 Northern Hemisphere winter season
The 2006–2007 influenza vaccine composition recommended by the World Health Organization on February 15, 2006 and the U.S. FDA's Vaccines and Related Biological Products Advisory Committee (VRBPAC) on February 17, 2006 use:
- an A/New Caledonia/20/99 (H1N1)-like virus;
- an A/Wisconsin/67/2005 (H3N2)-like virus (A/Wisconsin/67/2005 and A/Hiroshima/52/2005 strains);
- a B/Malaysia/2506/2004-like virus from B/Malaysia/2506/2004 and B/Ohio/1/2005 strains which are of B/Victoria/2/87 lineage.[172]
2007 Southern Hemisphere winter season
The composition of influenza virus vaccines for use in the 2007 Southern Hemisphere influenza season recommended by the World Health Organization on September 20, 2006[173] was:
- an A/New Caledonia/20/99(H1N1)-like virus,
- an A/Wisconsin/67/2005(H3N2)-like virus (A/Wisconsin/67/2005 and A/Hiroshima/52/2005 were used at the time),
- a B/Malaysia/2506/2004-like virus[174][175]
2007–2008 Northern Hemisphere winter season
The composition of influenza virus vaccines for use in the 2007–2008 Northern Hemisphere influenza season recommended by the World Health Organization on February 14, 2007[176] was:
- an A/Solomon Islands/3/2006 (H1N1)-like virus;
- an A/Wisconsin/67/2005 (H3N2)-like virus (A/Wisconsin/67/2005 (H3N2) and A/Hiroshima/52/2005 were used at the time);
- a B/Malaysia/2506/2004-like virus[177][178]
In the US, the CDC reported in Feb 2008 that the H1N1 component was a good match (96%) to the infections occurring. But 87% of the H3N2 are A/Brisbane/10/2007-like viruses, which are a recent antigenic variant of the vaccine strain, A/Wisconsin. And 93% of the B viruses are in a B/Yamagata lineage that is relatively distinct from the vaccine strain B/Victoria lineage. Only one of the three components was a good match; A/Wisconsin is moderately protective against the drifted A/Brisbane strain. 4.5% of those viruses tested are resistant to Oseltamivir, or Tamiflu—a significant increase over previous years.[179]
This vaccine has been described as 40% effective compared to other years that have been 85–95% effective.[179][180]
2008 Southern Hemisphere winter season
The composition of virus vaccines for use in the 2008 Southern Hemisphere influenza season recommended by the World Health Organization on September 17–19, 2007 was:
- an A/Solomon Islands/3/2006 (H1N1)-like virus;
- an A/Brisbane/10/2007 (H3N2)-like virus;
- a B/Florida/4/2006-like virus[181][182]
2008-2009 Northern Hemisphere winter season
The composition of virus vaccines for use in the 2008-2009 Northern Hemisphere influenza season recommended by the World Health Organization on February 14, 2008[183] was:
- an A/Brisbane/59/2007 (H1N1)-like virus;
- an A/Brisbane/10/2007 (H3N2)-like virus;
- a B/Florida/4/2006-like virus (B/Florida/4/2006 and B/Brisbane/3/2007 (a B/Florida/4/2006-like virus) were used at the time).[184][185]
As of May 30, 2009: "CDC has antigenically characterized 1,567 seasonal human influenza viruses [947 influenza A (H1), 162 influenza A (H3) and 458 influenza B viruses] collected by U.S. laboratories since October 1, 2008, and 84 novel influenza A (H1N1) viruses. All 947 influenza seasonal A (H1) viruses are related to the influenza A (H1N1) component of the 2008-09 influenza vaccine (A/Brisbane/59/2007). All 162 influenza A (H3N2) viruses are related to the A (H3N2) vaccine component (A/Brisbane/10/2007). All 84 novel influenza A (H1N1) viruses are related to the A/California/07/2009 (H1N1) reference virus selected by WHO as a potential candidate for novel influenza A (H1N1) vaccine. Influenza B viruses currently circulating can be divided into two distinct lineages represented by the B/Yamagata/16/88 and B/Victoria/02/87 viruses. Sixty-one influenza B viruses tested belong to the B/Yamagata lineage and are related to the vaccine strain (B/Florida/04/2006). The remaining 397 viruses belong to the B/Victoria lineage and are not related to the vaccine strain."[186]
2009 Southern Hemisphere winter season
The composition of virus vaccines for use in the 2009 Southern Hemisphere influenza season recommended by the World Health Organization on September 17–19, 2008[187] was:
- an A/Brisbane/59/2007 (H1N1)-like virus;
- an A/Brisbane/10/2007 (H3N2)-like virus;
- a B/Florida/4/2006-like virus[188]
2009-2010 Northern Hemisphere winter season
The composition of virus vaccines for use in the 2009-2010 Northern Hemisphere influenza season recommended by the World Health Organization on February 12, 2009[189] was:
- an A/Brisbane/59/2007 (H1N1)-like virus;
- an A/Brisbane/10/2007 (H3N2)-like virus;
- a B/Brisbane/60/2008-like virus.[190][191]
Since the A/Brisbane/59/2007 (H1N1)-like virus used in the vaccine is an unrelated seasonal strain of influenza, it probably cannot create immunity to the new, non-seasonal strain of influenza A virus subtype H1N1 responsible for the 2009 swine flu outbreak.[186]
2010 Southern Hemisphere winter season
- an A/California/7/2009 (H1N1)-like virus;
- an A/Perth/16/2009 (H3N2)-like virus;
- a B/Brisbane/60/2008-like virus.[192][dead link]
The H1N1 strain used in this composition is the same strain used in the 2009 flu pandemic vaccine.[193]
2010-2011 Northern Hemisphere winter season
The composition of virus vaccines for use in the 2010-2011 Northern Hemisphere influenza season recommended by the World Health Organization on February 18, 2010 was:
- an A/California/7/2009 (H1N1)-like virus;
- an A/Perth/16/2009 (H3N2)-like virus;
- a B/Brisbane/60/2008-like virus.[194][dead link][195]
The H1N1 strain used in this composition is the same strain used in the 2009 flu pandemic vaccine.[193]
2011 Southern Hemisphere winter season
The composition of virus vaccines for use in the 2011 Southern Hemisphere influenza season recommended by the World Health Organization on September 29, 2010 was:
- an A/California/7/2009 (H1N1)-like virus;
- an A/Perth/16/2009 (H3N2)-like virus;
- a B/Brisbane/60/2008-like virus.[196]
The H1N1 strain used in this composition is the same strain used in the 2009 flu pandemic vaccine.[193]
2011-2012 Northern Hemisphere winter season
The composition of virus vaccines for use in the 2011-2012 Northern Hemisphere influenza season recommended by the World Health Organization on February 17, 2011 was:
- an A/California/7/2009 (H1N1)-like virus;
- an A/Perth/16/2009 (H3N2)-like virus;
- a B/Brisbane/60/2008-like virus.[197][198]
The H1N1 strain used in this composition is the same strain used in the 2009 flu pandemic vaccine.[193]
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."[199]
Horses
Horses with horse flu can run a fever, have a dry hacking cough, have a runny nose, and become depressed and reluctant to eat or drink for several days but usually recover in two to three weeks. "Vaccination schedules generally require a primary course of 2 doses, 3–6 weeks apart, followed by boosters at 6–12 month intervals. It is generally recognised that in many cases such schedules may not maintain protective levels of antibody and more frequent administration is advised in high-risk situations."[200]
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 FEI requires vaccination every six months.[201][202]
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.'"[203]
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 per cent of birds need to be protected to prevent the virus spreading silently. In practice, it is difficult to protect more than 90 per cent of a flock; protection levels achieved by a vaccine are usually much lower than this."[204] 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.[205]
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 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.[206] 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%."[207]
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.[208]
Computer-assisted vaccine design
A new parameter[clarification needed] has been defined to quantify the antigenic distance between two H3N2 influenza strains. This parameter was used to measure antigenic distance between circulating H3N2 strains and the closest vaccine component of the influenza vaccine. For the data between 1971 and 2004, the measure of antigenic distance correlated better with efficacy in humans of the H3N2 influenza A annual vaccine than did current measures of antigenic distance such as phylogenetic sequence analysis or ferret antisera inhibition assays. This measure of antigenic distance could be used to guide the design of the annual flu vaccine. The antigenic distance combined with a multiple-strain avian influenza transmission model was used to study the threat of simultaneous introduction of multiple avian influenza strains. Population at Risk (PaR) can be used to quantify the risk of a flu pandemic and to calculate the improvement that a multiple vaccine offers.[209]
See also
- Influenza
- 2009 flu pandemic vaccine
- H5N1
- Influenza research
- Influenza pandemic
- Vaccine shortage of 2004
References
- ^ Couch, RB (2008). "Seasonal Inactivated Influenza Virus Vaccines". Vaccine. 26 Suppl 4 (Suppl 4): D5–9. doi:10.1016/j.vaccine.2008.05.076. PMC 2643340. PMID 18602728.
- ^ CDC - Seasonal Influenza (Flu) - Key Facts About Seasonal Flu Vaccine
- ^ Influenza Vaccination: A Summary for Clinicians x-summary.htm
- ^ Flu Shots Halve Risk of Death, Cut Illness in Elderly (Update1)
- Influenza vaccines ... cut the risk that elderly people will die of the virus in half and reduced the chance of hospitalization by more than a quarter, according to a study released today by the New England Journal of Medicine. pid=20601081&sid=aoDQn_PvtPGw&refer=Australia
- ^ McNeil, Donald G. Jr. (March 28, 2008). "A Multitude of Vaccine Benefits, Yet Controversy Persists". The New York Times.
Public health experts generally agree that after clean water and flush toilets, the most important health advances in history have been vaccinations
- ^ [http://www.who.int/mediacentre/factsheets/2003/fs211/en/ WHO Influenza Overview]
- ^ Centers for Disease Control and Prevention (CDC) (2010). "Estimates of deaths associated with seasonal influenza --- United States, 1976-2007" (PDF). MMWR. Morbidity and mortality weekly report. 59 (33): 1057–62. PMID 20798667.
{{cite journal}}
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ignored (help) - ^ Julie Steenhuysen (August 26, 2010). "CDC backs away from decades-old flu death estimate". Reuters. Retrieved 2010-09-13.
Instead of the estimated 36,000 annual flu deaths in the United States ... the actual number in the past 30 years has ranged from a low of about 3,300 deaths to a high of nearly 49,000, the CDC said on Thursday.
- ^ World Health Organization. Seasonal Influenza
- ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 18679129, please use {{cite journal}} with
|pmid=18679129
instead. - ^ WHO
Influenza Overview
http://www.who.int/mediacentre/factsheets/2003/fs211/en/
- "In the United States of America, for example, recent estimates put the cost of influenza epidemics to the economy at US$ 71-167 billion per year."
- ^ Molinari, Ortega-Sanchez, Messonnier, Thompson, Wortley, Weintraub, Bridges The annual impact of seasonal influenza in the US: Measuring disease burden and costs PMID 17544181 doi:10.1016/j.vaccine.2007.03.046 (Estimates that in the United States, annual influenza epidemics result in approximately 600,000 life-years lost, 3 million hospitalized days, and 30 million outpatient visits, resulting in direct medical costs of $10 billion annually. Lost earnings due to illness and loss of life added over $15 billion in direct costs annually and the average of all direct and indirect economic burdens of annual influenza epidemics (funeral expenses, lost productivity, etc.) amounts to over $80 billion.
- ^ Huge flu vaccine trial to be held. March 31, 2008 :"Professor Robert Booy, of the National Centre for Immunisation Research and Surveillance at Westmead in Sydney, said influenza put 15,000 Australians in hospital each year."
- ...
- "About 1,500 deaths annually are attributed to the virus and it costs our country millions of dollars annually in lost productivity, Professor Robert Booy said.
- ^ "Young Children Hospitalized for Flu Associated With Higher Costs and Higher Risk Illness" (Press release). Cincinnati Children's Hospital Medical Center. May 4, 2008.
After analyzing data in three U.S. cities over the course of three flu seasons (2003-2006), the researchers found that 90 percent of the highest-cost hospitalizations for children were linked to influenza, or flu with a co-infection of the respiratory tract
- ^ Anne Gatewood Hoen, PhD, David L. Buckeridge, MD PhD, Katia M.L. Charland, PhD, Kenneth D. Mandl, MD MPH, Caroline Quach, MD MSc, John S. Brownstein, PhD Effect of expanded US recommendations for seasonal influenza vaccination: comparison of two pediatric emergency departments in the United States and Canada http://www.cmaj.ca/content/183/13/E1025
- ^ Prevention: Flu Shots’ Benefits Seen in Hospital Study http://www.nytimes.com/2011/09/20/health/research/20prevention.html?_r=1 Vital Signs By NICHOLAS BAKALAR New York Times September 19, 2011
- ^ http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6TD4-51V45S2-4&_user=10&_coverDate=02%2F17%2F2011&_rdoc=1&_fmt=high&_orig=search&_origin=search&_sort=d&_docanchor=&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=8ba69fb523e7227fa294019f21653bab&searchtype=a Masahiko Katayosea, Mitsuaki Hosoyab, Takashi Hanedac, Hideo Yamaguchid, Yukihiko Kawasakib, Masatoki Satob, Peter F. Wright The effectiveness of trivalent inactivated influenza vaccine in children over six consecutive influenza seasons Vaccine Volume 29, Issue 9, 17 February 2011, Pages 1844-1849
- ^ U.S. panel recommends all kids get the flu shot Updated Wed. Feb. 27 2008 1:56 PM ET CTV.ca News Staff http://www.ctv.ca/servlet/ArticleNews/story/CTVNews/20080227/flu_shot_080226/20080227?hub=TopStories
- ^ a b Fiore, AE; Uyeki, TM; Broder, K; Finelli, L; Euler, GL; Singleton, JA; Iskander, JK; Wortley, PM; Shay, DK (2010). "Prevention and control of influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2010". MMWR Recomm Rep. 59 (RR–8): 1–62. PMID 20689501.
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ignored (help) - ^ CDC - Influenza (Flu) | Vaccination: Summary for Clinicians
- ^ Centers for Disease Control and Prevention (CDC) (2010). "Seasonal influenza and 2009 H1N1 influenza vaccination coverage among pregnant women--10 states, 2009-10 influenza season" (PDF). MMWR Morb Mortal Wkly Rep. 59 (47): 1541–5. PMID 21124293.
Because pregnant women are at increased risk for severe disease associated with influenza infection, the American College of Obstetricians and Gynecologists and the Advisory Committee on Immunization Practices have recommended seasonal influenza vaccination for women while pregnant, regardless of trimester (1,2). In 2009, a novel strain of influenza A (H1N1) virus was identified (3), and pregnant women also were found to be at greater risk for influenza-related complications from this new virus (4). As a result, during the 2009--10 influenza season, two separate influenza vaccines were recommended to pregnant women: inactivated trivalent 2009--10 seasonal vaccine and influenza A (H1N1) 2009 monovalent vaccine (2,5)
{{cite journal}}
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ignored (help) - ^ Fiore, AE; Shay, DK; Broder, K; Iskander, JK; Uyeki, TM; Mootrey, G; Bresee, JS; Cox, NJ; Centers for Disease Control and Prevention (2009). "Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2009" (PDF). MMWR Recomm Rep. 58 (RR–8): 1–52. PMID 19644442.
Annual vaccination of all children aged 6 months--18 years should begin as soon as the 2009--10 influenza vaccine is available. Annual vaccination of all children aged 6 months--4 years (59 months) and older children with conditions that place them at increased risk for complications from influenza should continue to be a primary focus of vaccination efforts as providers and programs transition to routinely vaccinating all children.
- ^ a b c Altman, Lawrence K. (February 28, 2008). "Panel Advises Flu Shots for Children Up to Age 18". The New York Times.
- ^ McNeil, Donald G. Jr. (March 9, 2010). "Flu Shots in Children Can Help Community". The New York Times.
- ^ Benowitz, I.; Esposito, D. B.; Gracey, K. D.; Shapiro, E. D.; Vázquez, M. (2010). "Influenza Vaccine Given to Pregnant Women Reduces Hospitalization Due to Influenza in Their Infants". Clin Infect Dis. 51 (12): 1355–61. doi:10.1086/657309. PMC 3106242. PMID 21058908.
{{cite journal}}
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ignored (help) - ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 19682118, please use {{cite journal}} with
|pmid=19682118
instead. - ^ a b Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 16546308, please use {{cite journal}} with
|pmid=16546308
instead. - ^ Wendelboe, Aaron M., et al. Importance of Employee Vaccination against Influenza in Preventing Cases in Long-Term Care Facilities. Infection Control and Hospital Epidemiology, October 2011. Vol. 32, No. 10. Society for Healthcare Epidemiology of America (SHEA). DOI: 10.1086/661916 PMID 21931249
- ^ http://www.cidrap.umn.edu/cidrap/content/influenza/general/news/aug1811vaccine-br.html Coverage in healthcare workers
- ^ http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6032a1.htm Influenza Vaccination Coverage Among Health-Care Personnel --- United States, 2010--11 Influenza Season Morbidity and Mortality Weekly Report (MMWR)
- ^ Xie H, Jing X, Li X, Lin Z, Plant E, et al. 2011 Immunogenicity and Cross-Reactivity of 2009–2010 Inactivated Seasonal Influenza Vaccine in US Adults and Elderly. PLoS ONE 6(1): e16650. http://www.plosone.org/article/info:doi/10.1371/journal.pone.0016650 doi:10.1371/journal.pone.0016650
- ^ JR Minkel Can Seasonal Flu Shots Help Fight a Pandemic? http://www.scientificamerican.com/article.cfm?doi=can-seasonal-flu-shots-help
- ^ Seasonal Flu Vaccination May Offer Partial Immunity to H5N1 http://www.upmc-cbn.org/report_archive/2007/02_February_2007/cbnreport_02212007.html
- ^ Sandbulte, Matthew R.; Jimenez, Gretchen S.; Boon, Adrianus C. M.; Smith, Larry R.; Treanor, John J.; Webby, Richard J. (2007). "Cross-Reactive Neuraminidase Antibodies Afford Partial Protection against H5N1 in Mice and Are Present in Unexposed Humans". PLoS Medicine. 4 (2): e59. doi:10.1371/journal.pmed.0040059. PMC 1796909. PMID 17298168.
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: CS1 maint: unflagged free DOI (link) - ^ 1918 Spanish flu records could hold the key to solving future pandemics November 2008. Australian study suggesting city dwellers, who were more likely to have been exposed to common flu may have benefited from some protection from the 1918 pandemic influenza (the "Spanish Flu"). http://www.physorg.com/news145530214.html
- ^ Garcia-Garcia, L.; Valdespino-Gomez, J. L.; Lazcano-Ponce, E.; Jimenez-Corona, A.; Higuera-Iglesias, A.; Cruz-Hervert, P.; Cano-Arellano, B.; Garcia-Anaya, A.; Ferreira-Guerrero, E. (2009). "Partial protection of seasonal trivalent inactivated vaccine against novel pandemic influenza A/H1N1 2009: case-control study in Mexico City". BMJ. 339: b3928. doi:10.1136/bmj.b3928. PMC 2758337. PMID 19808768.
- ^ Chen, Honglin; Wang, Y; Liu, W; Zhang, J; Dong, B; Fan, X; De Jong, MD; Farrar, J; Riley, S (2009). "Serologic Survey of Pandemic (H1N1) 2009 Virus, Guangxi Province, China". Emerging Infectious Diseases. 15 (11): 1849–50. doi:10.3201/eid1511.090868. PMC 2857250. PMID 19891883.
- ^ a b Xing, Zheng (2009). "Preexisting Immunity to Pandemic (H1N1) 2009". Emerging Infectious Diseases. doi:10.3201/eid1511.090685.
- ^ Seasonal flu vaccine protects against H1N1: Study Article by Neka Sehgal - November 21, 2009 http://www.themoneytimes.com/featured/20091121/seasonal-flu-vaccine-protects-against-h1n1-study-id-1091674.html
- ^ Johns, Matthew C.; Eick, Angelia A.; Blazes, David L.; Lee, Seung-eun; Perdue, Christopher L.; Lipnick, Robert; Vest, Kelly G.; Russell, Kevin L.; Defraites, Robert F. (2010). Fouchier, Ron A. M. (ed.). "Seasonal Influenza Vaccine and Protection against Pandemic (H1N1) 2009-Associated Illness among US Military Personnel". PLoS ONE. 5 (5): e10722. Bibcode:2010PLoSO...510722J. doi:10.1371/journal.pone.0010722. PMC 2873284. PMID 20502705.
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: CS1 maint: unflagged free DOI (link) - ^ a b McCullers JA, Van De Velde LA, Allison KJ, Branum KC, Webby RJ, Flynn PM (2010). "Vaccinees against the 1976 "swine flu" have enhanced neutralization responses to the 2009 novel H1N1 influenza virus". Clin. Infect. Dis. 50 (11): 1487–92. doi:10.1086/652441. PMC 2946351. PMID 20415539.
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ignored (help)CS1 maint: multiple names: authors list (link) - ^ Webster, Robert; Walker, Elizabeth (2003). "Influenza". American Scientist. 91 (2): 122. doi:10.1511/2003.2.122.
- ^ Blakemore, C. (2006-04-09). "Battle of time, luck and science". The Sunday Times. London. Retrieved 2006-06-22.
- ^ Influenza PDF.
- ^ "ECDC Daily Update – Pandemic (H1N1) 2009 – 18 January 2010" (PDF). European Centre for Disease Prevention and Control. 2010-01-18. Retrieved 2010-01-18.
- ^ The Threat of Pandemic Influenza: Are We Ready? Workshop Summary (2005) (free online book) page 62
- ^ Plotkin, S.L. and Plotkin, S.A. "A short history of vaccination." In: Vaccines, Stanley A. Plotkin, Walter A. Orenstein, Paul A. Offit, eds. Elsevier Health Sciences, 2008, pp. 6-7.
- ^ Artenstein, A.W. "Influenza" In: Vaccines: A Biography Andrew W. Artenstein, ed. pp. 191-205.
- ^ Influenza Report article Vaccines by Stephen Korsman
- ^ CDC report Prevention and Control of Influenza published April 12, 2002
- ^ Osterholm, Michael T. (2005). "Preparing for the Next Pandemic". New England Journal of Medicine. 352 (18): 1839–42. doi:10.1056/NEJMp058068. PMID 15872196.
- ^ The Sky is Falling: An Analysis of the Swine Flu Affair of 1976
- ^ World Health Organization. Acyte Respiratory Infections: Influenza. 2009. http://www.who.int/vaccine_research/diseases/ari/en/index1.html
- ^ World Health Organization. Tables on the Clinical trials of pandemic influenza prototype vaccines. July 2009. http://www.who.int/vaccine_research/immunogenicity/immunogenicity_table.xls
- ^ US Food & Drug Administration. FDA Approves Vaccines for 2009 H1N1 Influenza Virus Approval Provides Important Tool to Fight Pandemic. September 15, 2009. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm182399.htm
- ^ Du, Lanying; Zhou, Yusen; Jiang, Shibo (2010). "Research and development of universal influenza vaccines". Microbes and Infection. 12 (4): 280–6. doi:10.1016/j.micinf.2010.01.001. PMID 20079871.
- ^ a b Johnson & Johnson pursues vaccine firm. Charleston Gazette.
- ^ (http://www.fiercebiotech.com/press-releases/biondvax-begins-phase-iia-study-universal-flu-vaccine-0)
- ^ Seattle's Theraclone makes a 'first step' on long road to universal flu vaccine. The Seattle Times.
- ^ Dynavax Reports Positive Data on Universal Flu Vaccine Candidate. Rita Biotech.
- ^ VaxInnate's Universal Flu Vaccine Candidate Shown Safe and Immunogenic in Phase I Clinical Study. Fierce Biotech.
- ^ a b "Inovio Pharmaceuticals, Inc. Immunizes First Subject In U.S. Influenza DNA Vaccine Clinical Trial". Reuters.
- ^ http://www.its-innovation.com/about-us/
- ^ "Universal Influenza Vaccine Tested Successfully In Humans".
- ^ The Wistar Institute obtains patent for universal flu vaccine technology. Wistar Institute.
- ^ NIH Scientists Advance Universal Flu Vaccine. NIH.
- ^ Inovio Biomedical's SynCon preventive DNA vaccine receives approval in Korea for Phase I clinical trial
- ^ "Scientific Paper on Inovio Pharmaceuticals SynCon(TM) DNA Vaccines and Intradermal DNA Delivery Technology One of Most Cited Articles in the Journal Vaccine". 14 Oct 2010.
- ^ a b BBC: 'Super antibody' fights off flu
- ^ a b Independent: Scientists hail the prospect of a universal vaccine for flu
- ^ a b Huffington Post: Universal Flu Vaccine On The Horizon: Researchers Find 'Super Antibody'
- ^ Hidden weakness could yield universal flu vaccine - health - 24 February 2009 - New Scientist
- ^ http://biopharminternational.findpharma.com/biopharm/News/Phase-1-2-Completed-for-Universal-Influenza-Vaccin/ArticleStandard/Article/detail/651691
- ^ "BiondVax Begins Phase IIa Study for Universal Flu Vaccine". 14 Oct 2010.
- ^ "Dynavax Presents Data From Novel Universal Flu Vaccine Candidate".
- ^ MarketWatch.com
- ^ http://www.its-innovation.com/pipeline/fp01-influenza/
- ^ Lambert and Fauci; Fauci, Anthony S. (2010). "Influenza Vaccines for the Future". NEJM. 363 (21): 2036–44. doi:10.1056/NEJMra1002842. PMID 21083388.
- ^ "H1N1 Gives Clues to Universal Flu Vaccine". 18 Jan 2011.
- ^ Wrammert Date=Jan 2011; et al. (2011). "Broadly cross-reactive antibodies dominate the human B cell response against 2009 pandemic H1N1 influenza virus infection". JEM. 208: 181–193. doi:10.1084/jem.20101352.
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ignored (help)CS1 maint: numeric names: authors list (link) - ^ "A vaccine for all flu seasons". Spring 2011.
- ^ Fedson DS (1998). "Measuring protection: efficacy versus effectiveness". Dev Biol Stand. 95: 195–201. PMID 9855432.
- ^ Stephenson, I.; Zambon, M. C.; Rudin, A.; Colegate, A.; Podda, A.; Bugarini, R.; Del Giudice, G.; Minutello, A.; Bonnington, S. (2006). "Phase I Evaluation of Intranasal Trivalent Inactivated Influenza Vaccine with Nontoxigenic Escherichia coli Enterotoxin and Novel Biovector as Mucosal Adjuvants, Using Adult Volunteers". J Virol. 80 (10): 4962–70. doi:10.1128/JVI.80.10.4962-4970.2006. PMC 1472052. PMID 16641287.
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ignored (help) - ^ a b Treanor, J.; Kotloff, K.; Betts, R.; Belshe, R.; Newman, F.; Iacuzio, D.; Wittes, J.; Bryant, M. (1999). "Evaluation of trivalent, live, cold-adapted (CAIV-T) and inactivated (TIV) influenza vaccines in prevention of virus infection and illness following challenge of adults with wild-type influenza A (H1N1), A (H3N2), and B viruses". Vaccine. 18 (9–10): 899–906. doi:10.1016/S0264-410X(99)00334-5. PMID 10580204.
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ignored (help) - ^ a b Jefferson, T. (2006). "Influenza vaccination: policy versus evidence". BMJ. 333 (7574): 912–5. doi:10.1136/bmj.38995.531701.80. PMC 1626345. PMID 17068038.
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ignored (help) - ^ a b Demicheli, V.; Rivetti, D.; Deeks, J. J.; Jefferson, T. O. (2004). Demicheli, Vittorio (ed.). "Vaccines for preventing influenza in healthy adults". Cochrane Database Syst Rev (3): CD001269. doi:10.1002/14651858.CD001269.pub2. PMID 15266445. CD001269.
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ignored (help) - ^ a b Smith S, Demicheli V, Di Pietrantonj C, Harnden A, Jefferson T, Matheson N, Rivetti A (2006). Smith, Sue (ed.). "Vaccines for preventing influenza in healthy children". Cochrane Database Syst Rev (1): CD004879. doi:10.1002/14651858.CD004879.pub2. PMID 16437500.
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: CS1 maint: multiple names: authors list (link) - ^ a b Rivetti D, Jefferson T, Thomas R, Rudin M, Rivetti A, Di Pietrantonj C, Demicheli V (2006). Rivetti, Daniela (ed.). "Vaccines for preventing influenza in the elderly". Cochrane Database Syst Rev. 3: CD004876. doi:10.1002/14651858.CD004876.pub2. PMID 16856068.
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: CS1 maint: multiple names: authors list (link) - ^ a b Jefferson T, Rivetti D, Rivetti A, Rudin M, Di Pietrantonj C, Demicheli V (2005). "Efficacy and effectiveness of influenza vaccines in elderly people: a systematic review". Lancet. 366 (9492): 1165–74. doi:10.1016/S0140-6736(05)67339-4. PMID 16198765.
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: CS1 maint: multiple names: authors list (link) - ^ Simonsen L, Viboud C, Taylor RJ, Miller MA, Jackson L (2009). "Influenza vaccination and mortality benefits: new insights, new opportunities". Vaccine. 27 (45): 6300–4. doi:10.1016/j.vaccine.2009.07.008. PMID 19840664.
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ignored (help)CS1 maint: multiple names: authors list (link) - ^ Nuño, M.; Chowell, G.; Gumel, A. B. (2007). "Assessing the role of basic control measures, antivirals and vaccine in curtailing pandemic influenza: scenarios for the US, UK and the Netherlands". Journal of the Royal Society Interface. 4 (14): 505–521. doi:10.1098/rsif.2006.0186. PMC 2373400. PMID 17251132.
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ignored (help) - ^ Ferguson, N. M.; Cummings, D. A.; Fraser, C.; Cajka, J. C.; Cooley, P. C.; Burke, D. S. (2006). "Strategies for mitigating an influenza pandemic". Nature. 442 (7101): 448–452. Bibcode:2006Natur.442..448F. doi:10.1038/nature04795. PMID 16642006.
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ignored (help) - ^ Comparisons of LAIV and TAIV Efficacy Centers for Disease Control and Prevention (CDC)
- ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1002/14651858.CD004876.pub2, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with
|doi=10.1002/14651858.CD004876.pub2
instead. - ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1093/ije/dyi274, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with
|doi=10.1093/ije/dyi274
instead. - ^ Jefferson T, Rivetti A, Harnden A, Di Pietrantonj C, Demicheli V (2008). Jefferson, Tom (ed.). "Vaccines for preventing influenza in healthy children". Cochrane Database Syst Rev (2): CD004879. doi:10.1002/14651858.CD004879.pub3. PMID 18425905.
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: CS1 maint: multiple names: authors list (link) - ^ Children, the Flu, and the Flu Vaccine http://www.cdc.gov/flu/protect/children.htm
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|doi=10.1002/14651858.CD001269.pub3
instead. - ^ Jefferson, T.; Di Pietrantonj, C.; Rivetti, A.; Bawazeer, G. A.; Al-Ansary, L. A.; Ferroni, E. (2010). Jefferson, Tom (ed.). "Vaccines for preventing influenza in healthy adults". Cochrane Database Syst Rev (7): CD001269. doi:10.1002/14651858.CD001269.pub4. PMID 20614424.
Studies funded from public sources were significantly less likely to report conclusions favorable to the vaccines. The review showed that reliable evidence on influenza vaccines is thin but there is evidence of widespread manipulation of conclusions and spurious notoriety of the studies
- ^ Nichol, K.L.; Nordin, J.D.; Nelson, D.B.; Mullooly, J.D.; Hak, E. (2007). "Effectiveness of Influenza Vaccine in the community-dwelling elderly". The New England Journal of Medicine. 357 (14): 1373–1381. doi:10.1056/NEJMoa070844. PMID 17914038.
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- ^ Nordin, J.; Mullooly, J.; Poblete, S.; Strikas, R.; Petrucci, R.; Wei, F.; Rush, B; Safirstein, B; Wheeler, D (2001). "Influenza vaccine effectiveness in preventing hospitalizations and deaths in persons 65 years or older in Minnesota, New York, and Oregon: Data from 3 health plans". The Journal of Infectious Diseases. 184 (6): 665–670. doi:10.1086/323085. PMID 11517426.
- ^ Simonsen, L.; Taylor, R.J.; Viboud, C.; Miller, M.A.; Jackson, L.A. (2007). "Mortality benefits of influenza vaccination in elderly people: An ongoing controversy". The Lancet Infectious Diseases. 7 (10): 658–666. doi:10.1016/S1473-3099(07)70236-0. PMID 17897608.
- ^ CDC | Fluzone High–Dose Seasonal Influenza Vaccine
- ^ Thompson WW, Shay DK, Weintraub E, Brammer L, Cox N, Anderson LJ, Fukuda K (2003). "Mortality associated with influenza and respiratory syncytial virus in the United States". The Journal of the American Medical Association. 289 (2): 179–186. doi:10.1001/jama.289.2.179. PMID 12517228.
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: CS1 maint: multiple names: authors list (link) - ^ Nichol KL, Nordin J, Mullooly J, Lask R, Fillbrandt K, Iwane M (2003). "Influenza vaccination and reduction in hospitalizations for cardiac disease and stroke among the elderly". The New England Journal of Medicine. 348 (14): 1322–1332. doi:10.1056/NEJMoa025028. PMID 12672859.
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: CS1 maint: multiple names: authors list (link) - ^ Woloshin S, Schwartz LM, Welch HG (2005-10-25). "A shot of fear". The Washington Post. Retrieved 2006-11-09.
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: CS1 maint: multiple names: authors list (link) - ^ Jackson LA, Jackson ML, Nelson JC, Neuzil KM, Weiss NS (2006). "Evidence of bias in estimates of influenza vaccine effectiveness in seniors". Int J Epidemiol. 35 (2): 337–44. doi:10.1093/ije/dyi274. PMID 16368725.
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ignored (help)CS1 maint: multiple names: authors list (link) - ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1093/ije/dyi275, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with
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instead. - ^ Keitel, W. A.; Atmar, R. L.; Cate, T. R.; Petersen, N. J.; Greenberg, S. B.; Ruben, F.; Couch, R. B. (2006). "Safety of high doses of influenza vaccine and effect on antibody responses in elderly persons". Arch Intern Med. 166 (10): 1121–7. doi:10.1001/archinte.166.10.1121. PMID 16717175.
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ignored (help) - ^ World Health Organization Seasonal Influenza fact sheet. http://www.who.int/mediacentre/factsheets/fs211/en/index.html
- ^ NEJM - The Japanese Experience with Vaccinating Schoolchildren against Influenza
- ^ CDC - Influenza (Flu) | Q & A: 2007-08 Flu Season
- ^ CDC - seasonal flu
- ^ immunize.org article Summary of Recommendations for Adult Immunization which is linked from CDC website CDC
- ^ "The Nasal-Spray Flu Vaccine (Live Attenuated Influenza Vaccine [LAIV])" Centers for Disease Control and Prevention (CDC)
- ^ Wang, Z.; Tobler, S.; Roayaei, J.; Eick, A. (2009). "Live attenuated or inactivated influenza vaccines and medical encounters for respiratory illnesses among US military personnel". JAMA: the Journal of the American Medical Association. 301 (9): 945–53. doi:10.1001/jama.2009.265. PMID 19255113.
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ignored (help) - ^ "FDA Approves A High Dose Seasonal Influenza Vaccine Specifically Intended for People Ages 65 and Older" (Press release). U.S. Food and Drug Administration (FDA). December 23, 2009.
- ^ Centers for Disease Control and Prevention (CDC) (2010). "Licensure of a high-dose inactivated influenza vaccine for persons aged >or=65 years (Fluzone High-Dose) and guidance for use - United States, 2010" (PDF). MMWR. Morbidity and mortality weekly report. 59 (16): 485–6. PMID 20431524.
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ignored (help) - ^ "Fluzone High–Dose Seasonal Influenza Vaccine" Centers for Disease Control and Prevention (CDC)
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- ^ CDC
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- ^ CDC - Inactivated Influenza Vaccine 2007-2008 - What You Need To Know
- ^ a b c Flu - LAIV
- ^ Offit PA (2007). "Thimerosal and vaccines—a cautionary tale". N Engl J Med. 357 (13): 1278–9. doi:10.1056/NEJMp078187. PMID 17898096.
- ^ Global Advisory Committee on Vaccine Safety (2006-07-14). "Thiomersal and vaccines". World Health Organization. Retrieved 2007-11-20.
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ignored (help)CS1 maint: multiple names: authors list (link) - ^ Denise Grady (December 4, 2009). "Review Shows Safety of H1N1 Vaccine, Officials Say". The New York Times.
No substantial differences between H1N1 and seasonal influenza vaccines were noted in the proportion or types of serious adverse events reported
- ^ Vellozzi C, Burwen DR, Dobardzic A, Ball R, Walton K, Haber P (2009). "Safety of trivalent inactivated influenza vaccines in adults: Background for pandemic influenza vaccine safety monitoring". Vaccine. 27 (15): 2114–2120. doi:10.1016/j.vaccine.2009.01.125. PMID 19356614.
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ignored (help)CS1 maint: multiple names: authors list (link) - ^ Last Year's [2009's] H1N1 Flu Vaccine Was Safe, Study Finds Wednesday, February 2, 2011 http://www.nlm.nih.gov/medlineplus/news/fullstory_108398.html (*available only until 05/03/2011) [later access: http://www.wunderground.com/DisplayHealthDay.asp?id=649531 ]
- ^ Stowe J, Andrews N, Wise L, Miller E (2009). "Investigation of the temporal association of Guillain-Barre syndrome with influenza vaccine and influenzalike illness using the United Kingdom General Practice Research Database". Am. J. Epidemiol. 169 (3): 382–8. doi:10.1093/aje/kwn310. PMID 19033158.
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ignored (help)CS1 maint: multiple names: authors list (link) - ^ Sivadon-Tardy V; Orlikowski D; Porcher R; et al. (2009). "Guillain-Barré syndrome and influenza virus infection". Clin. Infect. Dis. 48 (1): 48–56. doi:10.1086/594124. PMID 19025491.
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ignored (help) - ^ New and Old Ways to Make Flu Vaccines, 8 November 2007, National Public Radio.
- ^ PATH, Oliver Wyman. Influenza Vaccine Strategies for Broad Global Access. 2007. http://www.path.org/files/VAC_infl_publ_rpt_10-07.pdf
- ^ Bright, R. A.; Carter, D. M.; Daniluk, S.; Toapanta, F. R.; Ahmad, A.; Gavrilov, V.; Massare, M.; Pushko, P.; Mytle, N. (2007). "Influenza virus-like particles elicit broader immune responses than whole virion inactivated influenza virus or recombinant hemagglutinin". Vaccine. 25 (19): 3871–8. doi:10.1016/j.vaccine.2007.01.106. PMID 17337102.
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ignored (help) - ^ CIDRAP article Australia approves CSL's H5N1 vaccine published June 17, 2008
- ^ According to the U.S. HHS (United States Department of Health & Human Services) Pandemic Influenza Plan Appendix F: Current HHS Activities last revised on November 8, 2005 at http://www.hhs.gov/pandemicflu/plan/appendixf.html
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- ^ Denise Grady (March 30, 2006). "Doubt Cast on Stockpile of a Vaccine for Bird Flu". The New York Times. Retrieved 19 October 2006.
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- ^ CIDRAP News article WHO changes H5N1 strains for pandemic vaccines, raising concern over virus evolution published August 18, 2006
- ^ WHO (PDF) article Antigenic and genetic characteristics of H5N1 viruses and candidate H5N1 vaccine viruses developed for potential use as pre-pandemic vaccines published August 18, 2006
- ^ CIDRAP article HHS: Most H5N1 vaccine on hand is still potent published November 17, 2006
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- ^ WHO website recommendation for the 2006 season
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- ^ Flu Outbreak Widespread.
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- ^ a b CDC article "2008-2009 Influenza Season Week 21 ending May 30, 2009" published May 30, 2009
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: CS1 maint: multiple names: authors list (link) - ^ Zhou (2010). "Computer-assisted Vaccine Design". Influenza: Molecular Virology. Caister Academic Press. ISBN 978-1-904455-57-8.
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External links
- Vaccine Strains vs. Circulating Strains
- NHS seasonal flu vaccination campaign NHS flu fighter
- History of past WHO seasonal influenza vaccine composition recommendations
- Vaccine Research Center Information from NIAID regarding preventative vaccine research studies
- About the flu jab (NHS Direct)
- World Health Organization's Initiative for Vaccine Research Influenza web page
- PandemicFlu.gov
- Influenza Strategies for Broad Global Access
- PATH's Vaccine Resource Library influenza resources
- Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 8985189, please use {{cite journal}} with
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instead. - Orr, Pamela (2000). "Influenza vaccination for health care workers: A duty of care". Canadian Journal of Infectious Diseases. 11 (5): 225–6. PMC 2094777. PMID 18159292.
- CDC 2009 H1N1 Influenza Vaccine Supply Status
- CDC Vaccine Information Statement Inactivated Influenza Vaccine
- 2009-10 Swine Flu Vaccination Clinic Locations in Canada
- Read Congressional Research Service (CRS) Reports regarding Influenza and vaccines
- Influenza Research Database – Database of influenza genomic sequences and related information.
- Health-EU portal EU response to influenza
- European Commission - Public Health EU coordination on Pandemic (H1N1) 2009
- Centers for Disease Control and Prevention - Vaccines and Preventable Diseases - Seasonal Influenza (Flu) Vaccination
- Centers for Disease Control and Prevention - Misconceptions about Seasonal Influenza and Influenza Vaccines
- Influenza Vaccine (NYTimes / Adam)