H1N1 Vaccine
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The 2009 swine flu pandemic vaccines were
influenza vaccine Influenza vaccines, also known as flu shots, are vaccines that protect against infection by influenza viruses. New versions of the vaccines are developed twice a year, as the influenza virus rapidly changes. While their effectiveness varies fr ...
s developed to protect against the
pandemic H1N1/09 virus The pandemic H1N1/09 virus is a swine origin influenza A virus subtype H1N1 strain that was responsible for the 2009 swine flu pandemic. This strain is often called swine flu by the public media. For other names, see the Nomenclature section ...
. These vaccines either contained inactivated (killed) influenza virus, or weakened live virus that could not cause influenza. The killed virus was injected, while the live virus was given as a nasal spray. Both these types of vaccine were produced by growing the virus in chicken eggs. Around three billion doses were produced, with delivery in November 2009. In studies, the vaccine appeared both effective and safe, providing a strong protective immune response and having a similar safety profile to the usual seasonal influenza vaccine. However, about 30% of people already had some immunity to the virus, with the vaccine conferring greatest benefit on young people, since many older people are already immune through exposure to similar viruses in the past. The vaccine also provided some cross-protection against the
1918 flu pandemic The 1918–1920 influenza pandemic, commonly known by the misnomer Spanish flu or as the Great Influenza epidemic, was an exceptionally deadly global influenza pandemic caused by the H1N1 influenza A virus. The earliest documented case was ...
strain. Early results (pre-25 December 2009) from an observational cohort of 248,000 individuals in Scotland showed the vaccine to be effective at preventing H1N1 influenza (95.0% effectiveness 5% confidence intervals 76.0–100.0% and influenza-related hospital admissions (64.7% 5% confidence intervals 12.0–85.8%. Developing, testing, and manufacturing sufficient quantities of a vaccine is a process that takes many months. According to Keiji Fukuda of the
World Health Organization The World Health Organization (WHO) is a specialized agency of the United Nations responsible for international public health. The WHO Constitution states its main objective as "the attainment by all peoples of the highest possible level of h ...
, "There's much greater vaccine capacity than there was a few years ago, but there is not enough vaccine capacity to instantly make vaccines for the entire world's population for influenza." The nasal mist version of the vaccine started shipping on 1 October 2009.


Types of vaccine

Two types of influenza vaccines were available: * TIV (flu shot (
injection Injection or injected may refer to: Science and technology * Injective function, a mathematical function mapping distinct arguments to distinct values * Injection (medicine), insertion of liquid into the body with a syringe * Injection, in broadca ...
) of trivalent (three strains; usually A/H1N1, A/
H3N2 Influenza A virus subtype H3N2 (A/H3N2) is a subtype of viruses that causes influenza (flu). H3N2 viruses can infect birds and mammals. In birds, humans, and pigs, the virus has mutated into many strains. In years in which H3N2 is the predomina ...
, 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 the body with those same three strains, but in a modified form that cannot cause illness. LAIV is not recommended for individuals under age 2 or over age 49, but might be comparatively more effective among children over age two.


Manufacturing methods

For the inactivated vaccines, the virus is grown by injecting it, along with some
antibiotic An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention of ...
s, into fertilized chicken eggs. About one to two eggs are needed to make each dose of vaccine.Egg-based vs. cell-based influenza vaccine production
GlaxoSmithKline GSK plc, formerly GlaxoSmithKline plc, is a British multinational pharmaceutical and biotechnology company with global headquarters in London, England. Established in 2000 by a merger of Glaxo Wellcome and SmithKline Beecham. GSK is the ten ...
. 2005
The virus replicates within the
allantois The allantois (plural ''allantoides'' or ''allantoises'') is a hollow sac-like structure filled with clear fluid that forms part of a developing amniote's conceptus (which consists of all embryonic and extraembryonic tissues). It helps the embryo ...
of the embryo, which is the equivalent of the
placenta The placenta is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas and waste exchange between the physically separate mater ...
in mammals. The fluid in this structure is removed and the virus purified from this fluid by methods such as
filtration Filtration is a physical separation process that separates solid matter and fluid from a mixture using a ''filter medium'' that has a complex structure through which only the fluid can pass. Solid particles that cannot pass through the filter ...
or
centrifugation Centrifugation is a mechanical process which involves the use of the centrifugal force to separate particles from a solution according to their size, shape, density, medium viscosity and rotor speed. The denser components of the mixture migrate ...
. The purified viruses are then inactivated ("killed") with a small amount of a disinfectant. The inactivated virus is treated with detergent to break up the virus into particles, and the broken capsule segments and released proteins are concentrated by centrifugation. The final preparation is suspended in sterile
phosphate buffered saline Phosphate-buffered saline (PBS) is a buffer solution (pH ~ 7.4) commonly used in biological research. It is a water-based salt solution containing disodium hydrogen phosphate, sodium chloride and, in some formulations, potassium chloride and potass ...
ready for injection. This vaccine mainly contains the killed virus but might also contain tiny amounts of egg protein and the antibiotics, disinfectant and detergent used in the manufacturing process. In multi-dose versions of the vaccine, the preservative
thimerosal Thiomersal (INN), or thimerosal (USAN, JAN), is an organomercury compound. It is a well-established antiseptic and antifungal agent. The pharmaceutical corporation Eli Lilly and Company gave thiomersal the trade name Merthiolate. It has been u ...
is added to prevent growth of bacteria. In some versions of the vaccine used in Europe and Canada, such as ''Arepanrix'' and ''Fluad'', an
adjuvant In pharmacology, an adjuvant is a drug or other substance, or a combination of substances, that is used to increase the efficacy or potency of certain drugs. Specifically, the term can refer to: * Adjuvant therapy in cancer management * Analgesic ...
is also added, this contains
squalene Squalene is an organic compound. It is a triterpenoid with the formula C30H50. It is a colourless oil, although impure samples appear yellow. It was originally obtained from shark liver oil (hence its name, as ''Squalus'' is a genus of sharks). A ...
,
vitamin E Vitamin E is a group of eight fat soluble compounds that include four tocopherols and four tocotrienols. Vitamin E deficiency, which is rare and usually due to an underlying problem with digesting dietary fat rather than from a diet low in vitami ...
and an
emulsifier An emulsion is a mixture of two or more liquids that are normally immiscible (unmixable or unblendable) owing to liquid-liquid phase separation. Emulsions are part of a more general class of two-phase systems of matter called colloids. Altho ...
called
polysorbate 80 Polysorbate 80 is a nonionic surfactant and emulsifier often used in pharmaceuticals, foods, and cosmetics. This synthetic compound is a viscous, water-soluble yellow liquid. Chemistry Polysorbate 80 is derived from polyethoxylated sorbitan and ...
.Pandemic H1N1 (pH1N1) Influenza Vaccine Quick Reference Guide
Winnipeg Regional Health Authority. 2009.
To make the live vaccine, the virus is first adapted to grow at and then grown at this temperature until it loses the ability to cause illness in humans, which requires the virus to grow at normal human body temperature of . Multiple mutations are needed for the virus to grow at cold temperatures, so this process is effectively irreversible and once the virus has lost
virulence Virulence is a pathogen's or microorganism's ability to cause damage to a host. In most, especially in animal systems, virulence refers to the degree of damage caused by a microbe to its host. The pathogenicity of an organism—its ability to ca ...
(become "attenuated"), it will not regain the ability to infect people. The attenuated virus is then grown in chicken eggs as before. The virus-containing fluid is harvested and the virus purified by filtration; this step also removes any contaminating bacteria. The filtered preparation is then diluted into a solution that stabilizes the virus. This solution contains
monosodium glutamate Monosodium glutamate (MSG), also known as sodium glutamate, is the sodium salt of glutamic acid. MSG is found naturally in some foods including tomatoes and cheese in this glutamic acid form. MSG is used in cooking as a flavor enhancer wit ...
,
potassium phosphate Potassium phosphate is a generic term for the salt (chemistry), salts of potassium and phosphate ions including: * Monopotassium phosphate (KH2PO4) (Molar mass approx: 136 g/mol) * Dipotassium phosphate (K2HPO4) (Molar mass approx: 174 g/mol) * ...
,
gelatin Gelatin or gelatine (from la, gelatus meaning "stiff" or "frozen") is a translucent, colorless, flavorless food ingredient, commonly derived from collagen taken from animal body parts. It is brittle when dry and rubbery when moist. It may also ...
, the antibiotic
gentamicin Gentamicin is an antibiotic used to treat several types of bacterial infections. This may include bone infections, endocarditis, pelvic inflammatory disease, meningitis, pneumonia, urinary tract infections, and sepsis among others. It is not e ...
, and sugar. A different method of producing influenza virus was used to produce the
Novartis Novartis AG is a Swiss-American multinational pharmaceutical corporation based in Basel, Switzerland and Cambridge, Massachusetts, United States (global research).name="novartis.com">https://www.novartis.com/research-development/research-loc ...
vaccine Optaflu. In this vaccine the virus is grown in
cell culture Cell culture or tissue culture is the process by which cells are grown under controlled conditions, generally outside of their natural environment. The term "tissue culture" was coined by American pathologist Montrose Thomas Burrows. This te ...
instead of in eggs. This method is faster than the classic egg-based system and produces a purer final product. There are no traces of egg proteins in the final product, so it is safe for people with egg allergies.


Previous seasonal vaccine production

Prior to the H1N1/09 outbreak, WHO recommended that vaccines for the Northern Hemisphere's 2009–2010 flu season contain an A(H1N1)-like virus, and stocks were made available. However, the strain of H1N1 in the
seasonal flu Flu season is an annually recurring time period characterized by the prevalence of an outbreak of influenza (flu). The season occurs during the cold half of the year in each hemisphere. It takes approximately two days to show symptoms. Influen ...
vaccine was different from the pandemic strain H1N1/09 and offered no immunity against it. The US
Centers for Disease Control and Prevention The Centers for Disease Control and Prevention (CDC) is the national public health agency of the United States. It is a United States federal agency, under the Department of Health and Human Services, and is headquartered in Atlanta, Georgi ...
(CDC) characterized over 80 new H1N1 viruses that may be used in a vaccine.


Production questions and decisions


Questions

There was concern in mid-2009 that, should a second, deadlier wave of this new H1N1 strain appear during the northern autumn of 2009, producing pandemic vaccines ahead of time could turn out to be a serious waste of resources as the vaccine might not be effective against it, and there would also be a shortage of seasonal flu vaccine available if production facilities were switched to the new vaccine. Seasonal flu vaccine was being made as of May 2009. Although vaccine makers would be ready to switch to making a swine flu vaccine, many questions remained unanswered, including: "Should we really make a swine flu vaccine? Should we base a vaccine on the current virus, since flu viruses change rapidly? Vaccine against the current virus might be far less effective against a changed virus – should we wait to see if the virus changes? If vaccine production doesn't start soon, swine flu vaccine won't be ready when it's needed." The costs of producing a vaccine also became an issue, with some U.S. lawmakers questioning whether a new vaccine was worth the unknown benefits. Representatives
Phil Gingrey John Phillip Gingrey (born July 10, 1942) is an American physician and former politician who served as a U.S. Representative for from 2003 to 2015. He is a member of the Republican Party (GOP). His district comprised the northwestern suburbs o ...
and
Paul Broun Paul Collins Broun Jr. (born May 14, 1946) is an American physician and politician who served as the U.S. representative for from 2007 to 2015. He is a member of the Republican Party and was a member of the Tea Party Caucus. Broun unsuccessf ...
, for instance, were not convinced that the U.S. should spend up to US$2 billion to produce one, with Gingrey stating "We can't let all of our spending and our reaction be media-driven in responding to a panic so that we don't get Katrina-ed. ... It's important because what we are talking about as we discuss the appropriateness of spending $2 billion to produce a vaccine that may never be used – that is a very important decision that our country has to make." In fact, a
Fairleigh Dickinson University Fairleigh Dickinson University is a private university with its main campuses in the U.S. state of New Jersey. Founded in 1942, Fairleigh Dickinson University currently offers more than 100 degree programs to its students. In addition to its tw ...
PublicMind poll found in October 2009 that a majority (62%) of New Jerseyans were not planning on getting the vaccine at all. Before the pandemic was declared, the WHO said that if a pandemic was declared it would attempt to make sure that a substantial amount of vaccine was available for the benefit of developing countries. Vaccine makers and countries with standing orders, such as the U.S. and a number of European countries, would be asked, according to WHO officials, "to share with developing countries from the moment the first batches are ready if an H1N1 vaccine is made" for a pandemic strain. The global body stated that it wanted companies to donate at least 10% of their production or offer reduced prices for poor countries that could otherwise be left without vaccines if there is a sudden surge in demand.
Gennady Onishchenko Gennadiy Grigoryevich Onishchenko (russian: Геннадий Григорьевич Онищенко, born 20 November 1950) is a Russian government official who was the Chief Sanitary Inspector of Russia from 1996 to 2013. Early life Gennad ...
, Russia's chief doctor, said on 2 June 2009 that swine flu was not aggressive enough to cause a worldwide pandemic, noting that the current mortality rate of confirmed cases was 1.6% in Mexico and only 0.1% in the United States. He stated at a press conference, "So far it is unclear if we need to use vaccines against the flu because the virus that is now circulating throughout Europe and North America does not have a pandemic nature." In his opinion, a vaccine could be produced, but said that preparing a vaccine now would be considered "practice," since the world would soon need a new vaccine against a new virus. "What's 16,000 sick people? During any flu season, some 10,000 a day become ill in Moscow alone," he said.


Production timelines

After a meeting with the WHO on 14 May 2009, pharmaceutical companies said they were ready to begin making a swine flu vaccine. According to news reports, the WHO's experts would present recommendations to WHO Director-General Margaret Chan, who was expected to issue advice to vaccine manufacturers and the Sixty-second World Health Assembly. WHO's
Keiji Fukuda is a Japanese-American physician and epidemiologist, specializing in influenza epidemiology. He was an Assistant Director-General of the World Health Organization (WHO) from 2009 to 2016, and the Director of the School of Public Health at th ...
told reporters "These are enormously complicated questions, and they are not something that anyone can make in a single meeting." Most flu vaccine companies can not make both seasonal flu vaccine and pandemic flu vaccine at the same time. Production takes months and it is impossible to switch halfway through if health officials make a mistake. If the swine flu mutates, scientists aren't sure how effective a vaccine made now from the current strain will remain. Rather than wait on the WHO decision, however, some countries in Europe have decided to go ahead with early vaccine orders. On 20 May 2009, AP reported: "Manufacturers won't be able to start making the wine fluvaccine until mid-July at the earliest, weeks later than previous predictions, according to an expert panel convened by WHO. It will then take months to produce the vaccine in large quantities. The swine flu virus is not growing very fast in laboratories, making it difficult for scientists to get the key ingredient they need for a vaccine, the 'seed stock' from the virus ..In any case, mass producing a pandemic vaccine would be a gamble, as it would take away manufacturing capacity for the seasonal flu vaccine for the flu that kills up to 500,000 people each year. Some experts have wondered whether the world really needs a vaccine for an illness that so far appears mild." Another option proposed by the CDC was an "earlier rollout of seasonal vaccine," according to the CDC's Daniel Jernigan. He said the CDC would work with vaccine manufacturers and experts to see if that would be possible and desirable. Flu vaccination usually starts in September in the United States and peaks in November. Some vaccine experts agree it would be better to launch a second round of vaccinations against the new H1N1 strain instead of trying to add it to the seasonal flu vaccine or replacing one of its three components with the new H1N1 virus. The Australian company
CSL CSL as an abbreviation may stand for: Places * Coordinated Science Laboratory, at the University of Illinois * Liège Space Center (Centre spatial de Liège), at the University of Liege in Belgium * Central Science Laboratory, a former UK DEFRA ...
said that they were developing a vaccine for the swine flu and predicted that a suitable vaccine would be ready by August. However, John Sterling, Editor in Chief of ''Genetic Engineering & Biotechnology News'', said on 2 June, "It can take five or six months to come up with an entirely novel influenza vaccine. There is a great deal of hope that biotech and pharma companies might be able to have something ready sooner." a vaccine for
H1N1/09 The pandemic H1N1/09 virus is a swine origin influenza A virus subtype H1N1 strain that was responsible for the 2009 swine flu pandemic. This strain is often called swine flu by the public media. For other names, see the Nomenclature section ...
was expected to be available starting in November 2009, with production of three billion doses per year. It was expected that two doses would be needed to provide sufficient protection, but tests indicated that one dose would be sufficient for adults.
GlaxoSmithKline GSK plc, formerly GlaxoSmithKline plc, is a British multinational pharmaceutical and biotechnology company with global headquarters in London, England. Established in 2000 by a merger of Glaxo Wellcome and SmithKline Beecham. GSK is the ten ...
produced a vaccine made by growing the virus in hens' eggs, then breaking and deactivating the virus, and
Baxter International Baxter International Inc. is an American multinational healthcare company with headquarters in Deerfield, Illinois. The company primarily focuses on products to treat kidney disease, and other chronic and acute medical conditions. The company ...
produced a vaccine made in cell culture, suitable for those who have an egg allergy. The vaccines have been approved for use in the
European Union The European Union (EU) is a supranational political and economic union of member states that are located primarily in Europe. The union has a total area of and an estimated total population of about 447million. The EU has often been des ...
.


Testing

Initial Phase I human testing began with
Novartis Novartis AG is a Swiss-American multinational pharmaceutical corporation based in Basel, Switzerland and Cambridge, Massachusetts, United States (global research).name="novartis.com">https://www.novartis.com/research-development/research-loc ...
'
MF59 MF59 is an immunologic adjuvant that uses squalene. It is Novartis' proprietary adjuvant that is added to influenza vaccines to help stimulate the human body's immune response through production of CD4 memory cells. MF59 is the first oil-in-water ...
candidate in July 2009, at which time phase II trials of CSL's candidate CSL425 vaccine were planned to start in August 2009, but had not begun recruiting.
Sanofi Pasteur Sanofi Pasteur is the vaccines division of the French multinational pharmaceutical company Sanofi. Sanofi Pasteur is the largest company in the world devoted entirely to vaccines. It is one of four global producers of the yellow fever vaccine. ...
's candidate inactivated H1N1 had several phase II trials planned , but had not begun recruiting. News coverage conflicted with this information, as Australian trials of the CSL candidate were announced as having started on 21 July, and the Chinese government announced the start of trials of the Hualan Biological Engineering candidate.
Pandemrix Pandemrix is an influenza vaccine for influenza pandemics, such as the 2009 flu pandemic. The vaccine was developed by GlaxoSmithKline (GSK) and patented in September 2006. The vaccine was one of the H1N1 vaccines approved for use by the Europea ...
, made by
GlaxoSmithKline GSK plc, formerly GlaxoSmithKline plc, is a British multinational pharmaceutical and biotechnology company with global headquarters in London, England. Established in 2000 by a merger of Glaxo Wellcome and SmithKline Beecham. GSK is the ten ...
(GSK), and Focetria, made by
Novartis Novartis AG is a Swiss-American multinational pharmaceutical corporation based in Basel, Switzerland and Cambridge, Massachusetts, United States (global research).name="novartis.com">https://www.novartis.com/research-development/research-loc ...
were approved by the
European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of medicinal products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products or Euro ...
on 25 September 2009, and Celvapan, made by Baxter was approved the following week.Swine flu vaccines get first UK trial, 28 September 2009
. BBC News. 28 September 2009.
The first comparative clinical study of both vaccines started on children in the United Kingdom on 25 September 2009. GSK announced results from clinical trials assessing the use of Pandemrix in children, adults, and the elderly. A 2009 trial examined the safety and efficacy of two different doses of the split-virus vaccine, and was published in ''
The New England Journal of Medicine ''The New England Journal of Medicine'' (''NEJM'') is a weekly medical journal published by the Massachusetts Medical Society. It is among the most prestigious peer-reviewed medical journals as well as the oldest continuously published one. His ...
''. The vaccine used in the trial was prepared by CSL Biotherapies in chicken eggs, in the same way as the seasonal vaccine. A robust immune response was produced in over 90% of patients after a single dose of either 15 or 30 μg of antigen. This study suggested that the current recommendation for two doses of vaccine are overkill and that a single dose is quite sufficient. Arepanrix, an
AS03 AS03 (for "Adjuvant System 03") is the trade name for a squalene-based immunologic adjuvant used in various vaccine products by GlaxoSmithKline (GSK). It is used, for example, in GSK's A/H1N1 pandemic flu vaccine Pandemrix. It is also in Arepanrix a ...
- Adjuvanted H1N1 Pandemic Influenza Vaccine similar to Pandemrix and also made by GSK, was authorized by Canada's Minister of Health on 21 October 2009.


Adverse events

A review by the
U.S. National Institutes of Health The National Institutes of Health, commonly referred to as NIH (with each letter pronounced individually), is the primary agency of the United States government responsible for biomedical and public health research. It was founded in the late 1 ...
(NIH) concluded that the 2009 H1N1 ("swine flu") vaccine has a safety profile similar to that of seasonal vaccine. In an initial clinical trial in Australia, non-serious adverse events were reported by about half of the 240 people vaccinated, with these events including tenderness and pain at the site of injection, headache, malaise, and muscle pain. Two people had more severe events, with a much longer spell of nausea, muscle pain and malaise that lasted several days. The authors stated that the frequency and severity of these adverse events were similar to those normally seen with seasonal influenza vaccines. A second trial involved 2,200 people ranging from 3 to 77 years of age. In this study no patients reported serious adverse events, with the most commonly observed events being pain at the injection site and fever, which occurred in 10–25% of people. Although this trial followed up patients individually, the Government has been criticized for relying on voluntary reporting for post-vaccination evaluation in other circumstances, since this is "unlikely to accurately measure the percentage of people who get adverse effect". , the World Health Organization (WHO) said that 65 million doses of vaccine had been administered and that it had a similar safety profile to the seasonal flu vaccine, with no significant differences in the adverse events produced by the different types of vaccine.Transcript of virtual press conference with Dr Marie-Paule Kieny, Director, Initiative for Vaccine Research
World Health Organization The World Health Organization (WHO) is a specialized agency of the United Nations responsible for international public health. The WHO Constitution states its main objective as "the attainment by all peoples of the highest possible level of h ...
. 19 November 2009.
There has been one report of an adverse event per 10,000 doses of vaccine, with only five percent of these adverse events being serious, an overall rate of serious events of one in 200,000 doses. In Canada, after 6.6 million doses of vaccine had been distributed between 21 October and 7 November, there were reports of mild adverse events in 598 people vaccinated including: nausea, dizziness, headache, fever, vomiting, and swelling or soreness at the injection site. There were reports of tingling lips or tongue, difficulty breathing, hives, and skin rashes. Thirty six people had serious adverse events, including
anaphylaxis Anaphylaxis is a serious, potentially fatal allergic reaction and medical emergency that is rapid in onset and requires immediate medical attention regardless of use of emergency medication on site. It typically causes more than one of the follow ...
and febrile convulsions. The rate of serious adverse events is one in 200,000 doses distributed, which according to Canada's chief public health officer, is less than expected for the seasonal flu vaccine. GlaxoSmithKline recalled a batch of vaccine in Canada after it appeared to cause higher rates of adverse events than other batches. In the USA 46 million doses had been distributed and 3182 adverse events were reported. The CDC stated that the "vast majority" were mild, with about one serious adverse event in 260,000 doses. In Japan around 15 million people had been vaccinated by 31 December 2009. 1,900 cases of side effects and 104 cases of death were reported from medical institutions. The health ministry announced that it will conduct epidemiologic investigation. In France, around five million people had been vaccinated by 30 December 2009. 2,657 cases of side effects, eight cases of intrauterine death and five cases of miscarriages were reported after vaccination by afssaps. Rare potential adverse events are temporary bleeding disorders and
Guillain–Barré syndrome Guillain–Barré syndrome (GBS) is a rapid-onset muscle weakness caused by the immune system damaging the peripheral nervous system. Typically, both sides of the body are involved, and the initial symptoms are changes in sensation or pain often ...
(GBS), a serious condition involving the
peripheral nervous system The peripheral nervous system (PNS) is one of two components that make up the nervous system of bilateral animals, with the other part being the central nervous system (CNS). The PNS consists of nerves and ganglia, which lie outside the brain ...
, from which most patients recover fully within a few months to a year. Some studies have indicated that influenza-like illness is itself associated with an increased risk of GBS, suggesting that vaccination might indirectly protect against the disorder by protecting against flu. According to Marie-Paule Kieny of WHO assessing the side-effects of large-scale influenza vaccination is complicated by the fact that in any large population a few people will become ill and die at any time. For example, in any six-week period in the UK six sudden deaths from unknown causes and 22 cases of Guillain–Barré syndrome would be expected, so if everyone in the UK were vaccinated, this background rate of illness and death would continue as normal and some people would die simply by chance soon after the vaccination. Some scientists have reported concerns about the longer-term effects of the vaccine. For instance,
Sucharit Bhakdi Sucharit Bhakdi is a retired Thai-German microbiologist. In 2020 and 2021 Bhakdi became a prominent source of misinformation about the COVID-19 pandemic, claiming that the pandemic was "fake" and that COVID-19 vaccines were going to decimate ...
, professor of medical microbiology at the Johannes Gutenberg University of Mainz in Germany, wrote in the journal, ''Medical Microbiology and Immunology'', of the possibility that immune stimulation by vaccines or any other cause might worsen pre-existing heart disease. Chris Shaw, a neuroscientist at the University of British Columbia, expressed concern that serious side-effects may not appear immediately; he said it took five to ten years to see most of the
Gulf War syndrome Gulf War syndrome or Gulf War illness is a chronic and multi-symptomatic disorder affecting military veterans of both sides of the 1990–1991 Persian Gulf War. A wide range of acute and chronic symptoms have been linked to it, including fatigue ...
outcomes. The CDC states that most studies on modern influenza vaccines have seen no link with GBS, Although one review gives an incidence of about one case per million vaccinations, a large study in China, reported in ''
The New England Journal of Medicine ''The New England Journal of Medicine'' (''NEJM'') is a weekly medical journal published by the Massachusetts Medical Society. It is among the most prestigious peer-reviewed medical journals as well as the oldest continuously published one. His ...
'' covering close to 100 million doses of H1N1 flu vaccine found only eleven cases of
Guillain–Barré syndrome Guillain–Barré syndrome (GBS) is a rapid-onset muscle weakness caused by the immune system damaging the peripheral nervous system. Typically, both sides of the body are involved, and the initial symptoms are changes in sensation or pain often ...
, actually lower than the normal rate of the disease in China, and no other notable side effects.


Pregnant women and children

A 2009 review of the use of influenza vaccines in pregnant women stated that influenza infections posed a major risk during pregnancy and that multiple studies had shown that the inactivated vaccine was safe in pregnant women, concluding that this vaccine "can be safely and effectively administered during any trimester of pregnancy" and that high levels of immunization would avert "a significant number of deaths". A 2004 review of the safety of influenza vaccines in children stated that the live vaccine had been shown to be safe but that it might trigger wheezing in some children with asthma; less data for the trivalent inactivated vaccine was available, but no serious symptoms had been seen in clinical trials.


Squalene

''Newsweek'' states that "wild rumours" about the swine flu vaccine are being spread through e-mails, it writes that "The claims are nearly pure bunk, with only trace amounts of fact." These rumours generally make unfounded claims that the vaccine is dangerous and they may also promote
conspiracy theories A conspiracy theory is an explanation for an event or situation that invokes a conspiracy by sinister and powerful groups, often political in motivation, when other explanations are more probable.Additional sources: * * * * The term has a nega ...
. For example, ''Newsweek'' states that some chain e-mails make false claims about
squalene Squalene is an organic compound. It is a triterpenoid with the formula C30H50. It is a colourless oil, although impure samples appear yellow. It was originally obtained from shark liver oil (hence its name, as ''Squalus'' is a genus of sharks). A ...
(shark liver oil) in vaccines. ''The New York Times'' also notes that anti-vaccine groups have spread "dire warnings" about formulations of the vaccine that contain squalene as an
adjuvant In pharmacology, an adjuvant is a drug or other substance, or a combination of substances, that is used to increase the efficacy or potency of certain drugs. Specifically, the term can refer to: * Adjuvant therapy in cancer management * Analgesic ...
. An adjuvant is a substance that boosts the body's immune response, thereby stretching the supply of the vaccine and helping immunize elderly people with a weak immune system.Smith, Joanna
Batch of H1N1 vaccine recalled for severe reactions
''Toronto Star'', 20 November 2009.
Squalene is a normal part of the human body, made in the liver and circulating in the blood, and is also found in many foods, such as
egg An egg is an organic vessel grown by an animal to carry a possibly fertilized egg cell (a zygote) and to incubate from it an embryo within the egg until the embryo has become an animal fetus that can survive on its own, at which point the a ...
s and
olive oil Olive oil is a liquid fat obtained from olives (the fruit of ''Olea europaea''; family Oleaceae), a traditional tree crop of the Mediterranean Basin, produced by pressing whole olives and extracting the oil. It is commonly used in cooking: f ...
.The Facts on Squalene
U.S. Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...
(FDA).
None of the formulations of vaccine used in the US contain squalene, or any other adjuvant.Misconceptions about Seasonal Influenza and Influenza Vaccines
United States Department of Health and Human Services The United States Department of Health and Human Services (HHS) is a cabinet-level executive branch department of the U.S. federal government created to protect the health of all Americans and providing essential human services. Its motto is ...
.
However, some European and Canadian formulations do contain 25 μg of squalene per dose, which is roughly the amount found in a drop of olive oil. Some animal experiments have suggested that squalene might be linked to autoimmune disorders.Roslin, Alex
What's in your H1N1 flu vaccine?
Straight.com. Vancouver. 19 November 2009.
although others suggest squalene might protect people against cancer. Squalene-based adjuvants have been used in European influenza vaccines since 1997, with about 22 million doses administered over the past twelve years. The WHO states that no severe side effects have been associated with these vaccines, although they can produce mild inflammation at the site of injection. The safety of squalene-containing influenza vaccines have also been tested in two separate clinical trials, one with healthy non-elderly people, and one with elderly people, in both trials the vaccine was safe and well tolerated, with only weak side-effects, such as mild pain at the injection site. A 2009
meta-analysis A meta-analysis is a statistical analysis that combines the results of multiple scientific studies. Meta-analyses can be performed when there are multiple scientific studies addressing the same question, with each individual study reporting me ...
brought together data from 64 clinical trials of influenza vaccines with the squalene-containing adjuvant MF59 and compared them to the effects of vaccines with no adjuvant. The analysis reported that the adjuvanted vaccines were associated with slightly lower risks of chronic diseases, but that neither type of vaccines altered the normal rate of autoimmune diseases; the authors concluded that their data "supports the good safety profile associated with MF59-adjuvanted influenza vaccines and suggests there may be a clinical benefit over non-MF59-containing vaccines". A 2004 review of the effects of adjuvants on mice and humans concluded that "despite numerous case reports on vaccination induced autoimmunity, most epidemiological studies failed to confirm the association and the risk appears to be extremely low or non-existent", although the authors noted that the possibility that adjuvants might cause damaging immune reactions in a few susceptible people has not been completely ruled out. A 2009 review of oil-based adjuvants in influenza vaccines stated that this type of adjuvant "neither stimulates antibodies against squalene oil naturally produced by the humans body nor enhances titers of preexisting antibodies to squalene" and that these formulations did not raise any safety concerns. A paper published in 2000 suggested that squalene might have caused of
Gulf War syndrome Gulf War syndrome or Gulf War illness is a chronic and multi-symptomatic disorder affecting military veterans of both sides of the 1990–1991 Persian Gulf War. A wide range of acute and chronic symptoms have been linked to it, including fatigue ...
by producing anti-squalene antibodies, although other scientists stated that it was uncertain if the methods used were actually capable of detecting these antibodies. A 2009 U.S. Department of Defense study comparing healthy Navy personnel to those suffering from Gulf War syndrome was published in the journal ''Vaccine'', this used a validated test for these antibodies and found no link between the presence of the antibodies and illness, with about half of both groups having these antibodies and no correlation between symptoms and antibodies. Furthermore, none of the vaccines given to US troops during the Gulf war actually contained any squalene adjuvants.Safety of squalene
World Health Organization The World Health Organization (WHO) is a specialized agency of the United Nations responsible for international public health. The WHO Constitution states its main objective as "the attainment by all peoples of the highest possible level of h ...
''WHO Weekly Epidemiological Record'', 14 July 2006


Thiomersal

Multi-dose versions of the vaccine contain the preservative
thiomersal Thiomersal (INN), or thimerosal (USAN, JAN), is an organomercury compound. It is a well-established antiseptic and antifungal agent. The pharmaceutical corporation Eli Lilly and Company gave thiomersal the trade name Merthiolate. It has been u ...
(also known as thimerosal), a
mercury Mercury commonly refers to: * Mercury (planet), the nearest planet to the Sun * Mercury (element), a metallic chemical element with the symbol Hg * Mercury (mythology), a Roman god Mercury or The Mercury may also refer to: Companies * Merc ...
compound that prevents contamination when the vial is used repeatedly. Single-dose versions and the live vaccine do not contain this preservative. In the U.S., one dose from a multi-dose vial contains approximately 25 micrograms of mercury, a bit less than a typical
tuna fish sandwich A tuna fish sandwich, also known as a tuna salad sandwich or a tuna sandwich, is a sandwich made from canned tuna—usually made into a tuna salad by adding mayonnaise, and sometimes other ingredients such as celery or onion—as well as other c ...
. (The comparison of the injected and ingested quantities is for reference only, since the rate of absorption of ingested elemental mercury into the bloodstream is less than 0.01%.) In Canada, different variants contain five and 50 micrograms of thimerosal per dose. The use of thiomersal has been
controversial Controversy is a state of prolonged public dispute or debate, usually concerning a matter of conflicting opinion or point of view. The word was coined from the Latin ''controversia'', as a composite of ''controversus'' – "turned in an opposite ...
, with claims that it can cause
autism The autism spectrum, often referred to as just autism or in the context of a professional diagnosis autism spectrum disorder (ASD) or autism spectrum condition (ASC), is a neurodevelopmental condition (or conditions) characterized by difficulti ...
and other
developmental disorder Developmental disorders comprise a group of psychiatric conditions originating in childhood that involve serious impairment in different areas. There are several ways of using this term. The most narrow concept is used in the category "Specific Di ...
s. The U.S.
Institute of Medicine The National Academy of Medicine (NAM), formerly called the Institute of Medicine (IoM) until 2015, is an American nonprofit, non-governmental organization. The National Academy of Medicine is a part of the National Academies of Sciences, E ...
examined these claims and concluded in 2004 that the evidence did not support any link between vaccines and autism. Other reviews came to similar conclusions, with a 2006 review in the ''
Canadian Journal of Neurological Sciences The ''Canadian Journal of Neurological Sciences'' is a bimonthly peer-reviewed medical journal and the official journal of the Canadian Neurological Society, Canadian Neurosurgical Society, Canadian Society of Clinical Neurophysiologists, Canadian ...
'' stating that there is no convincing evidence to support the claim that thimerosal has a causal role in autism, and a 2009 review in the journal ''
Clinical Infectious Diseases ''Clinical Infectious Diseases'' is a peer-reviewed medical journal published by Oxford University Press covering research on the pathogenesis, clinical investigation, medical microbiology, diagnosis, immune mechanisms, and treatment of diseases ...
'' stating that claims that mercury can cause autism are "biologically implausible". The U.K.
National Health Service The National Health Service (NHS) is the umbrella term for the publicly funded healthcare systems of the United Kingdom (UK). Since 1948, they have been funded out of general taxation. There are three systems which are referred to using the " ...
stated in 2003 that "There is no evidence of long-term adverse effects due to the exposure levels of thiomersal in vaccines." The
World Health Organization The World Health Organization (WHO) is a specialized agency of the United Nations responsible for international public health. The WHO Constitution states its main objective as "the attainment by all peoples of the highest possible level of h ...
concluded that there is "no evidence of toxicity in infants, children or adults exposed to thiomersal in vaccines". In 2008 a review noted that even though thiomersal was removed from all US childhood vaccines in 2001, this has not changed the number of autism diagnoses, which are still increasing.


Dystonia

According to the CDC, there is no evidence either for or against
dystonia Dystonia is a neurological hyperkinetic movement disorder in which sustained or repetitive muscle contractions result in twisting and repetitive movements or abnormal fixed postures. The movements may resemble a tremor. Dystonia is often inten ...
being caused by the vaccinations. Dystonia is extremely rare. Due to the very low numbers of cases, dystonia is poorly understood. There were only five cases noted that might have been associated with influenza vaccinations over a span of eighteen years."Doctors Back Woman's Claim Of Adverse Reaction To Seasonal Flu Vaccine"
Surae Chinn. 9NEWS NOW. 15 October 2009.
In one discredited case, a woman wrongly blamed difficulties with movement and speech on a seasonal influenza vaccination. The Dystonia Medical Research Foundation stated that it is unlikely that the symptoms in this case were actually dystonia and stated that there has "never been a validated case of dystonia resulting from a flu shot". A
vaccine court The Office of Special Masters of the U.S. Court of Federal Claims, popularly known as "vaccine court", administers a no-fault system for litigating vaccine injury claims. These claims against vaccine manufacturers cannot normally be filed in s ...
special master concluded that the woman's symptoms weren't from the vaccine. Additionally, the woman later said that Jenny McCarthy's anti-vaccine group
Generation Rescue Generation Rescue is a nonprofit organization that advocates the scientifically disproven view that autism and related disorders are primarily caused by environmental factors, particularly vaccines. The organization was established in 2005 by ...
had "commandeered my injury to turn it into a poster story for their cause against vaccines."


Children vaccine recall

On 15 December 2009, one of the five manufacturers supplying the H1N1 vaccine to the United States recalled thousands of doses because they were not as potent as expected. The French manufacturer
Sanofi Pasteur Sanofi Pasteur is the vaccines division of the French multinational pharmaceutical company Sanofi. Sanofi Pasteur is the largest company in the world devoted entirely to vaccines. It is one of four global producers of the yellow fever vaccine. ...
voluntarily recalled about 800,000 doses of vaccine meant for children between the ages of six months and 35 months. The company and the
Centers for Disease Control and Prevention The Centers for Disease Control and Prevention (CDC) is the national public health agency of the United States. It is a United States federal agency, under the Department of Health and Human Services, and is headquartered in Atlanta, Georgi ...
(CDC) emphasized that the recall was not prompted by safety concerns, and that even though the vaccine is not quite as potent as it is supposed to be, children who received it do not need to be immunized again. The CDC emphasized that there is no danger for any child who received the recalled vaccine. When asked what parents should do, CDC spokesman Tom Skinner said, "absolutely nothing." He said if children receive this vaccine, they will be fine.


Pandemrix-related increase of narcolepsy in Finland and Sweden

In 2010, The Swedish Medical Products Agency (MPA) and The Finnish National Institute for Health and Welfare (THL) received reports from Swedish and Finnish health care professionals regarding
narcolepsy Narcolepsy is a long-term neurological disorder that involves a decreased ability to regulate sleep–wake cycles. Symptoms often include periods of excessive daytime sleepiness and brief involuntary sleep episodes. About 70% of those affec ...
as suspected adverse reaction following
Pandemrix Pandemrix is an influenza vaccine for influenza pandemics, such as the 2009 flu pandemic. The vaccine was developed by GlaxoSmithKline (GSK) and patented in September 2006. The vaccine was one of the H1N1 vaccines approved for use by the Europea ...
flu vaccination. The reports concern children aged 12–16 years where symptoms compatible with
narcolepsy Narcolepsy is a long-term neurological disorder that involves a decreased ability to regulate sleep–wake cycles. Symptoms often include periods of excessive daytime sleepiness and brief involuntary sleep episodes. About 70% of those affec ...
, diagnosed after thorough medical investigation, have occurred one to two months after vaccination. THL concluded in February 2011 that there is a clear connection between the Pandemrix vaccination campaign of 2009 and 2010 and narcolepsy epidemic in Finland: there was a nine times higher probability to get narcolepsy with vaccination than without it. At the end of March 2011, an MPA press release stated: "Results from a Swedish registry based cohort study indicate a 4-fold increased risk of narcolepsy in children and adolescents below the age of 20 vaccinated with Pandemrix, compared to children of the same age that were not vaccinated." The same study found no increased risk in adults who were vaccinated with Pandemrix.


Availability


Centers for Disease Control and Prevention

The American
Centers for Disease Control and Prevention The Centers for Disease Control and Prevention (CDC) is the national public health agency of the United States. It is a United States federal agency, under the Department of Health and Human Services, and is headquartered in Atlanta, Georgi ...
issued the following recommendations on who should be vaccinated (order is not in priority): In addition, the CDC recommend


National Health Service

The UK's
National Health Service The National Health Service (NHS) is the umbrella term for the publicly funded healthcare systems of the United Kingdom (UK). Since 1948, they have been funded out of general taxation. There are three systems which are referred to using the " ...
policy is to provide vaccine in this order of priority: This excludes the large majority of individuals aged six months to 24 years, a group for which the CDC recommends vaccination. The NHS notes that: * Healthy people over 65 years of age seem to have some natural immunity. * Children, while disproportionately affected, tend to make full recoveries. * The vaccine is ineffective in young infants. The United Kingdom began its administration program 21 October 2009. UK Soldiers serving in Afghanistan will also be offered vaccination. By April 2010, it was apparent that most of the vaccine was not needed. The US government had bought 229 million doses of H1N1 vaccines of which 91 million doses were used; of the surplus, 5 million doses were stored in bulk, 15 million doses were sent to developing countries and 71 million doses were destroyed. The
World Health Organization The World Health Organization (WHO) is a specialized agency of the United Nations responsible for international public health. The WHO Constitution states its main objective as "the attainment by all peoples of the highest possible level of h ...
is planning to examine if it overreacted to the H1N1 outbreak.


Political issues

General political issues, not restricted to the 2009 outbreak, arose regarding the distribution of vaccine. In many countries supplies are controlled by national or local governments, and the question of how the vaccine will be allocated should there be an insufficient supply for everyone is critical, and will likely depend on the patterns of any pandemic, and the age groups most at risk for serious complications, including death. In the case of a lethal pandemic people will be demanding access to the vaccine and the major problem will be making it available to those who need it. While it has been suggested that
compulsory vaccination A vaccination policy is a health policy adopted in order to prevent the spread of infectious disease. These policies are generally put into place by State or local governments, but may also be set by private facilities, such as workplaces or sc ...
may be needed to control a pandemic, many countries do not have a legal framework that would allow this. The only populations easily compelled to accept vaccination are military personnel (who can be given routine vaccinations as part of their service obligations), health care personnel (who can be required to be vaccinated to protect patients), and school children, who (under United States constitutional law) could be required to be vaccinated as a condition of attending school.


See also

*
2009 swine flu pandemic The 2009 swine flu pandemic, caused by the H1N1 influenza virus and declared by the World Health Organization (WHO) from June 2009 to August 2010, is the third recent flu pandemic involving the H1N1 virus (the first being the 1918–1920 Span ...
*
COVID-19 vaccine A COVID19 vaccine is a vaccine intended to provide acquired immunity against severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2), the virus that causes coronavirus disease 2019 ( COVID19). Prior to the COVID19 pandemic, an e ...
*
Immunologic adjuvant In immunology, an adjuvant is a substance that increases or modulates the immune response to a vaccine. The word "adjuvant" comes from the Latin word ''adiuvare'', meaning to help or aid. "An immunologic adjuvant is defined as any substance that ...


References


External links


"2009 H1N1 Vaccine Doses Allocated, Ordered, and Shipped by Project Area"
(CDC) *
Vaccines for pandemic (H1N1) 2009
World Health Organization The World Health Organization (WHO) is a specialized agency of the United Nations responsible for international public health. The WHO Constitution states its main objective as "the attainment by all peoples of the highest possible level of h ...
(WHO).
Vaccine against 2009 H1N1 Influenza Virus
Centers for Disease Control and Prevention The Centers for Disease Control and Prevention (CDC) is the national public health agency of the United States. It is a United States federal agency, under the Department of Health and Human Services, and is headquartered in Atlanta, Georgi ...
(CDC).
2009 influenza A (H1N1) pandemic
European Centre for Disease Prevention and Control The European Centre for Disease Prevention and Control (ECDC) is an agency of the European Union (EU) whose mission is to strengthen Europe's defences against infectious diseases. It covers a wide spectrum of activities, such as: surveillance, e ...
(ECDC).
Summaries of the pandemic
European Centre for Disease Prevention and Control The European Centre for Disease Prevention and Control (ECDC) is an agency of the European Union (EU) whose mission is to strengthen Europe's defences against infectious diseases. It covers a wide spectrum of activities, such as: surveillance, e ...
(ECDC). {{DEFAULTSORT:2009 Flu Pandemic Vaccine
vaccine A vaccine is a biological Dosage form, preparation that provides active acquired immunity to a particular infectious disease, infectious or cancer, malignant disease. The safety and effectiveness of vaccines has been widely studied and verifie ...
Influenza vaccines