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The flu vaccine is a vaccine to protect against the highly variable influenza virus.
The annual flu kills an estimated 36,000 people in the United States each year. The annually updated trivalent flu vaccine for the 2005-2006 season consists of hemagglutinin (HA) surface glycoprotein components from influenza H3N2, H1N1, and B influenza viruses. CDC
Each year the influenza virus changes and different strains become dominant. Due to the high mutability of the virus a particular vaccine formulation usually only works for about a year. The World Health Organization co-ordinates the contents of the vaccine each year to contain the most likely strains of the virus to attack the next year. The flu vaccine is usually recommended for anyone in a high-risk group who would be likely to suffer complications from influenza.
Who should get it
Yearly influenza vaccination should be routinely offered to patients at risk of complications of influenza:
- 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 liver cirrhosis)
- 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
- healthcare workers (both to prevent sickness and to prevent spread to patients)
The only contraindication is known anaphylaxis to the vaccine or its component.
Effectiveness in the Elderly
In the United States a person aged 50-64 is nearly ten times more likely to die an influenza-associated death as a person over age 65 and a person over age 65 is over ten times more likely to die an influenza-associated death as a person in the 50-64 age group. Vaccination of those over age 65 reduces influenza-associated death by about 50% .Flu vaccine virus selection
Selecting viruses for the vaccine manufacturing process is very difficult.
At the U.S.'s Food and Drug Administration's (FDA) Center for Biologics Evaluation and Research's Vaccines and Related Biological Products Advisory Committee's 101st meeting of February 16 2005, an extensive discussion and vote was held concerning next year's flu vaccine virus selection; but began with a summary of the previous year:
- Influenza B
- "For Influenza B, the question was asked: are there new strains present? And the answer was yes, and in 2004, the majority of the viruses were similar to a strain called B/Shanghai/361/2002, which is from the so-called B/Yamagata/1688 hemagglutinin lineage. That lineage was not the one that was being used in the vaccine that was current last year. In a minority of the strains that were found during the epidemiologic studies were similar to the strain that was in the vaccine for last year, which was B/Hong Kong/330/2001, which belongs to the HA lineage that we represent with the strain B/Victoria/287. In answer to the question were these new viruses spreading, the answer, of course, is definitely yes. The Fujian-like viruses had become widespread around the world and were predominant everywhere, and these B/Shanghai-like strains at the time we were holding this meeting in February were predominant not only in North America and the United States, but also in Asia and Europe."
- New viruses
- "Were the new viruses that were identified and spreading, were those inhibited by the current vaccines? And this question, as it sometimes is, was not a very definite no or yes. It was a little bit difficult to interpret, but it seemed like man of the A/Fujian-like viruses were not well inhibited by the current vaccines, although some of them were. For the B/Shanghai-like strains, of course, we've known for a long time that these two divergent hemagglutinin lineages are not that well inhibited one by the other, and as time has gone on and antigenic drift has occurred in these strains, that has become truer. Generally we also know that for the B/Yamagata-like strains and the B/Victoria-like strains, that very young children and people who haven't been immunologically primed, exposure to one of these does not seem to immediately give antibodies that cross-react with the other HA lineage."
- Manufacturing issues
- "So were there strains that were suitable for manufacturing? And the answer was yes. Of course, we all know that for inactivated vaccines and for live attenuated vaccines manufacturing depends on having egg adapted strains, either the wild-type or reassortant, and in the case of the live vaccine, of course, it has to be a reassortant for the attenuation phenotype. But there were A/Fujian-like strains that were available, and there was a high growth reassortant that was being used in manufacturing for the Southern Hemisphere already, the A/Wyoming/3/2003 X 147 reassortant. For the B strain, there were a number of wild-type isolates that seemed to be suitable for manufacturing, including B/Jilin/20/2003 and B/Jiangsu/10/2003, in addition to the B/Shanghai/361 strain itself.
- Strains selected
- "So based on that, the strains that were selected for this year include A/New Caledonia/20/99-like strain, which in this case really is A/New Caledonia/20/99. For the B/Shanghai/361/2002-like recommendation that was made, there were all three of these strains, B/Shanghai, B/Jilin, and B/Jiangsu. And for the A/Fujian/411/2002-like recommendation that was made and the A/Wyoming/3/2003 strain was chosen or is the one that has become widely used for vaccine preparation. Now, the implications of the strain selection were that preparation of the vaccines was on schedule throughout the year. All of the strains seemed to be typical and easy to adapt for manufacturing purposes, and going into the summer, the supply of vaccine was expected to match the demand predicted by previous years' experiences."
- Unexpected difficulties
- "But what happened was that we ended up with a vaccine shortage at the end of the summer, and just to try to put that into a little perspective, from January until August, manufacturing had been progressing on schedule even including these two new strains that were recommended for use in vaccines, and it was anticipated there were going to be about 100 million doses of vaccine from all of the manufacturers combined for this year. In August of 2004, Chiron notified regulatory authorities about a sterility issue and indicated that investigation to identify the cause and the implementation of corrections was underway, and at that time Chiron made a public announcement indicating that there would be a possible delay in distribution and possibly a reduction in the amount of vaccine that would be available. You also probably all know that in early October of 2004, the MHRA, the UK regulatory authority, announced that they were suspending Chiron's license to manufacture inactivated influenza vaccine for three months, and that was based on the issues that have previously been identified and were in investigation and correction by Chiron. Subsequently, over the next few weeks and certainly by November of 2004, it became clear after consultation between FDA and MHRA that the vaccine that Chiron had planned to make was not going to be available for us in the United States."
- Response to unexpected difficulties
- "In response to that, there were a number of things that happened within the Public Health Service, and I'll just very briefly indicate some of those. At FDA there was a lot of work done to evaluate manufacturers who were not licensed in the United States to identify whether their vaccines could be used under IND. There was consultation with manufacturers to discuss regulatory mechanisms going forward from this time for getting approval of new products in the United States. That includes accelerated approval, fast track and priority reviews to facilitate those new licenses, and all of these things actually have been continuing." (transcript of U.S. FDA Center for Biologics Evaluation and Research Vaccines and Related Biological Products Advisory Committee's 101st meeting of February 16, 2005 is here: origin.www.fda.gov in .DOC format in Google provided HTML format)
Flu vaccine manufacturing
Flu vaccines are available both as an injection of killed virus and as nasal spray of live attenuated influenza virus (LAIV) (sold as FluMist). Clinical trials suggest that the live virus may be more effective at preventing infection, but FluMist has not been approved in the United States for use in children younger than 5. Yahoo News
Flu vaccine is usually grown in fertilized chicken eggs. Both types of flu vaccines are contraindicated for those with severe allergies to egg proteins and people with a history of Guillain-Barré syndrome. CDC
On October 5 2004, Chiron Corporation, a corporation contracted to deliver half of the expected flu vaccine for the United States and a significant portion to the UK, issued a press release Chiron that stated it was unable to dispense its stock for the 2004-2005 season, due to suspension of the corporation's license to produce the vaccine by the Medicines and Healthcare Products Regulatory Agency. However, the Centers for Disease Control and Prevention took action to enlist the help of other companies such as MedImmune and Aventis Pasteur to supply vaccine in high-risk populations in the United States.
H5N1
There are several H5N1 vaccines for several of the avian H5N1 varieties. H5N1 continually mutates, meaning vaccines based on current samples of avian H5N1 cannot be depended upon to work in the case of a future human 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. 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. Wired News JVI
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. Department of Health & Human Services
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. NAID - 2004 News NAID - 2005 News 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. NPR
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. New England Journal of MedicineVolume 354:1411-1413 - March 30, 2006 - Number 13 - Vaccines against Avian Influenza — A Race against Time
2003-2004 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." Nature
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. CDC article Update: Influenza Activity --- United States and Worldwide, 2003--04 Season, and Composition of the 2004--05 Influenza Vaccine published July 2, 2004
Viral Surveillance
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.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.
- Human Infections with Avian Influenza Viruses
- H9N2
- H5N1
- H7N3
- H7N2
2004-2005 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.
2005-2006 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 US, 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. Yahoo News Associated Press article CDC: Milder Than Normal Flu Season Ending published April 27, 2006
2006-2007 Season
The 2006-07 influenza vaccine composition recommended by the World Health Organization on February 15, 2006 and the US 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. CDC fluwatch B/Victoria/2/87 lineage
Flu vaccine for nonhumans
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 2 to 3 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." equiflunet_vaccines
"vaccines, made on the cheap, are not filtered and purified [like human vaccines to remove bits of bacteria or other viruses. They usually contain whole virus, not just the hemagglutin spike that attaches to cells. Purification is far more expensive than the work in eggs, Dr. Stöhr said; a modest factory for human vaccine costs $100 million, and no veterinary manufacturer is ready to build one. Also, poultry vaccines are "adjuvated" — boosted — 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 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.'" New York Times article Turning to Chickens in Fight With Bird Flu published May 2, 2006
See also
- Vaccine for information valid about all vaccines, not just flu vaccines.
- Vaccine controversy for the pros and cons of being vaccinated.
- Thimerosal is a controversial mercury-containing organic compound used as an antiseptic and antifungal agent in vaccines.
Sources and notes
Further reading
"Flu vaccine"