Live attenuated influenza vaccine
Nurse administering the FluMist product
|Trade names||FluMist, Fluenz|
|(what is this?)|
Live attenuated influenza vaccine (LAIV) is a type of influenza vaccine in the form of a nasal spray that used to be recommended to prevent influenza. In June 2016 the CDC stopped recommending the use of LAIV as its effectiveness has appeared to have decreased between 2013 and 2016.
It is an attenuated vaccine, unlike most influenza vaccines, which are inactivated vaccines. LAIV is administered intranasally, while inactivated vaccines are administered by intramuscular injection. Both live attenuated and inactivated vaccines are typically trivalent. That is, they contain material from three different influenza virus strains recommended by national and international public health agencies as most likely to be protective against seasonal influenza in any given year. LAIV is sold under the trade name FluMist in the United States and Canada, and Fluenz in Europe. FluMist is manufactured by MedImmune and was first introduced in 2003.
In 2016 the CDC recommended that LAIV not be used for the 2016-2017 flu season and instead another type of influenza vaccine be used. This is due to the poor effectiveness of this type of vaccine between 2013 and 2016 with it being non effective during the 2015-2016 season. A 2012 review found that LAIV prevents influenza in about one out of six children under six it is given to. It was believed to prevent about 50% more cases of flu than the flu shot in younger children. In those less than 2 years old evidence the evidence was however unclear. Why there appears to be a decrease in effectiveness is unknown.
- children <24 months of age, due to increased risk of wheezing 
- individuals with a history of hypersensitivity to previous influenza vaccination.
- individuals with a history of hypersensitivity, especially anaphylactic reactions, to eggs, egg proteins, gentamicin, gelatin, or arginine or to any other ingredient in the formulation 
- People with a medical condition that places them at high risk for complications from influenza, including those with chronic heart or lung disease, such as asthma or reactive airways disease
- People with medical conditions such as diabetes or kidney failure or people with illnesses that weaken the immune system, or who take medications that can weaken the immune system
- Children less than 5 years old with a history of recurrent wheezing
- Children or adolescents receiving aspirin
- People with a history of Guillain–Barré syndrome, a rare disorder of the nervous system
- Pregnant women
- People who have a severe allergy to chicken eggs or who are allergic to any of the nasal spray vaccine components
It is possible for individuals vaccinated with FluMist to spread the virus to others for up to 21 days after vaccination. For this reason it is recommended that those vaccinated with FluMist avoid close contact with individuals with weak immune systems during that time.
Even though the virus in LAIV is attenuated (low in virulence), it is still a living virus, and may cause an infection with complications in people with weakened immune systems or other underlying medical conditions. As of 2010, LAIV is recommended only for people 2–49 years of age, and is not recommended for people who have a weakened immune system, for pregnant women, or for people with certain chronic diseases. In contrast, inactivated virus vaccines contain no living virus, and cannot cause a live infection. Persons receiving LAIV may shed small amounts of the vaccine virus during the first week. People coming in contact with the vaccinated person are not considered to be at risk, unless their immune systems are severely weakened (for example, bone marrow transplant recipients).
FluMist was originally developed by Hunein "John" Maassab, Professor of Epidemiology at the University of Michigan School of Public Health in Ann Arbor, Michigan and later by Aviron, in Mountain View, California, under the sponsorship of NIH in the mid-1990s. MedImmune, Inc. purchased Aviron in 2002, and the FDA approved FluMist in June 2003. FluMist was first made available in September 2003.
The U.S. FDA initially approved FluMist only for healthy people ages 5 to 49 because of concerns over possible side effects. Now FluMist is approved and recommended for healthy children 24 months of age and older. The FDA approved the current unfrozen refrigerated version for the same age group (ages 5–49) in August 2006 following completion of phase 3 clinical trials. CAIV-T has been approved by the FDA and is the version offered on the market beginning in fall of 2007.
The current version of the vaccine is called CAIV-T, and is stable for storage in a refrigerator, rather than requiring freezer storage as did the originally-approved formulation. Approved for the 2007-2008 flu season, the refrigerated formulation can be distributed more economically, so that the price differential with shots (which had hampered sales of the original frozen version of FluMist) is now largely eliminated. FluMist was initially priced higher than the injectable vaccines, but sold only 500,000 of the 4 million doses it produced its first year on the market, despite a comparative shortage of flu vaccine in fall 2004. The price was sharply lowered the next year, and the company reports distributing 1.6 million doses in 2005. Because of the price drop, despite selling almost three times as many doses in 2005, the company reported $21 million in FluMist sales, compared to $48 million the previous year. Further cuts in pricing had to await FDA approval of a refrigerator-cooled FluMist formulation, as the initial formulation required freezer storage and thawing on demand before administration. Although it is positioned as a premium product, the remaining price premium for FluMist over the cost of needle-injected vaccine is small.
Society and culture
MedImmune is one company that manufactures LAIV, which it sells under the trade name "FluMist" in the United States and "Fluenz" in Europe. For the 2010–2011 flu season, FluMist was the only LAIV approved by the FDA for use in the USA. All other FDA-approved lots were inactivated virus vaccines. In September 2009 a LAIV intranasal vaccine for the novel H1N1 influenza virus was approved and the seasonal intranasal vaccine was approved by the European Medicines Agency for use in the European Union in 2011, though distribution would not likely begin until 2012.
As of 2007, the only other company holding LAIV vaccine rights was BioDiem of Australia. BioDiem licensed rights to private production of the vaccine in China to Changchun BCHT Biotechnology, which also holds public rights for production in China sublicensed from the World Health Organization. BCHT plans to market a trivalent LAIV vaccine for H1N1 flu by the end of 2016. The BCHT flu vaccine is one of several candidates for WHO prequalification in the near future, reflecting a shift of Chinese market priorities from a large domestic market toward export. BioDiem has also licensed production to the Serum Institute of India, which holds exclusive licenses for production in Mexico, Argentina, Peru, South Africa, Bangladesh, Bhutan, Nepal, Pakistan and Sri Lanka, and the Government Pharmaceutical Office of Thailand. It was the first and (as of 2007) the only live attenuated vaccine for influenza available outside of Europe. In September 2009 a LAIV intranasal vaccine for the novel H1N1 influenza virus was approved. In 2011, the vaccine was approved by the European Medicines Agency for use in the European Union under the name Fluenz.
FluMist is designed to be quickly modifiable to present the surface antigens of seasonal flu. The modifiability could also allow it to be quickly customized as a vaccine against a pandemic influenza if one were to emerge. In light of the Global spread of H5N1 advance preparation to reduce human mortality in the event of an H5N1 pandemic has begun. Modifying FluMist to serve as a specific human H5N1 vaccine is among the measures studied.
In June 2006, the National Institutes of Health (NIH) began enrolling participants in a Phase 1 H5N1 study of an intranasal influenza vaccine candidate based on MedImmune's live, attenuated vaccine technology.
In September 2006 the NIH NIAID reported that inoculation with a FluMist vaccine modified to present the surface antigens of certain H5N1 variants provided broad protection against other H5N1 variants in the mouse and ferret models. Attenuated live viruses were found protective against H5N1 in mice and chickens in a 2009 study.
Although early work is focusing on the looming H5N1 threat, the CDC team led by Kanta Subbarao and others intends to eventually prepare and store surface antigens for all known strains of influenza, ready to be grafted onto the base attenuated FluMist core virus whenever a pandemic threat might emerge.
"Several trials have reported that LAIVs can boost virus-specific CTLs as well as mucosal and serum antibodies and provide broad cross-protection against heterologous human influenza A viruses." (58, 59) "[V]accine formulas inducing heterosubtypic T cell–mediated immunity may confer broad protection against avian and human influenza A viruses." 
In September 2009 a LAIV intranasal vaccine for the novel H1N1 influenza virus was approved.
- Fluenz: EPAR - Summary for the public
- Block, S. L.; Yogev, R.; Hayden, F. G.; Ambrose, C. S.; Zeng, W.; Walker, R. E. (2008). "Shedding and immunogenicity of live attenuated influenza vaccine virus in subjects 5–49 years of age". Vaccine. 26 (38): 4940–4946. PMID 18662737. doi:10.1016/j.vaccine.2008.07.013.
- "ACIP votes down use of LAIV for 2016-2017 flu season". June 22, 2016. Retrieved 14 July 2016.
- Belshe, R. B.; Edwards, K. M.; Vesikari, T.; Black, S. V.; Walker, R. E.; Hultquist, M.; Kemble, G.; Connor, E. M.; CAIV-T Comparative Efficacy Study Group (2007). "Live Attenuated versus Inactivated Influenza Vaccine in Infants and Young Children". New England Journal of Medicine. 356 (7): 685–696. PMID 17301299. doi:10.1056/NEJMoa065368.
- Influenza vaccine: annual reformulation of flu vaccine.
- Influenza Virus Vaccine Composition and Lot Release, US Food and Drug Administration
- Midthun, Karen; Steven Masiello (2003-07-17). "CBER Approval Letter, Influenza Virus Vaccine, Live, Intranasal (FluMist)". U.S. Food and Drug Administration. Archived from the original on September 29, 2007. Retrieved 2008-07-06.
- Jefferson, T.; Rivetti, A.; Di Pietrantonj, C.; Demicheli, V.; Ferroni, E. (2012). Jefferson, Tom, ed. "Vaccines for preventing influenza in healthy children". The Cochrane Library. 8: CD004879. PMID 22895945. doi:10.1002/14651858.CD004879.pub4.
- "Nasal Spray Flu Vaccine in Children 2 through 8 Years Old". CDC. Center for Disease Control and Prevention. Retrieved 4 November 2014.
- AstraZeneca Inc. (2013). Product Monograph: FluMist. AstraZeneca Inc.
- "The Nasal-Spray Flu Vaccine (Live Attenuated Influenza Vaccine [LAIV])". National Center for Immunization and Respiratory Diseases. 2008-01-22. Archived from the original on 2009-11-26. Retrieved 2008-07-06.
- "Risks of FluMist Vaccine".
- FluMist Safety and Eligibility Information
- Appleby, Julie (2004-01-07). "Nasal FluMist overcomes obstacles to reach public". USA Today. Retrieved 2008-07-06.
- "MedImmune begins shipping live intranasal flu vaccine for 2006-2007 after U.S. FDA release". Lab Law Weekly. 2006-08-25. Retrieved 2008-07-06.
- Rosenwald, Michael (2005-01-06). "FluMist Sales Falling Short, Survey Finds". The Washington Post. p. E05. Retrieved 2008-07-06.
- "MedImmune reports revenues of $1.2 billion". Pharma Business Week. 2006-02-27. Retrieved 2008-07-06.
- Rosenwald, Michael (2006-02-03). "Sales of MedImmune's Flu Vaccine Drop Sharply". The Washington Post. p. D04. Retrieved 2008-07-06.
- Keen, E. C. (2012). "Phage Therapy: Concept to Cure". Frontiers in Microbiology. 3. PMC . PMID 22833738. doi:10.3389/fmicb.2012.00238.
- "Update on Influenza A (H1N1) 2009 Monovalent Vaccines". October 9, 2009. Retrieved October 23, 2009.
- AstraZeneca's Nasal Flu Vaccine Approved In Europe[permanent dead link]
- "MedImmune takeover holds promise for BioDiem". BioTechnologyNews. 2007-04-26.
- "BioDiem licenses LAIV technology to Changchun BCHT". ResearchInChina. 2012-02-10.
- Jinchang Wu (March 2013). "Overview of BCHT and Update to LAIV Project" (PDF). Changchun BCHT.
- "Progress under GAP Pillar 2 "Increase Production Capacity" Contribution of the WHO Technology Transfer Programme" (PDF). World Health Organization. 2013-03-18.
- Jiao Li (2013-10-18). "China enters global vaccine marketplace".
- https://www.cdc.gov/mmwr/preview/mmwrhtml/rr5213a1.htm Recommendations and Reports September 26, 2003 / 52(RR13);1-8 Using Live, Attenuated Influenza Vaccine for Prevention and Control of Influenza Supplemental Recommendations of the Advisory Committee on Immunization Practices (ACIP) Prepared by Scott A. Harper, M.D.1 Keiji Fukuda, M.D.1 Nancy J. Cox, Ph.D.1 Carolyn B. Bridges, M.D.2 1Division of Viral and Rickettsial Diseases National Center for Infectious Diseases 2Epidemiology and Surveillance Division National Immunization Program
- See, e.g., https://www.cdc.gov/ncidod/EID/vol12no01/05-1147-G.htm | Volume 12, Number 1, January 2006 Vaccines for Pandemic Influenza Catherine J. Luke* and Kanta Subbarao*
- National Institutes of Health, Bethesda, Maryland, USA
- MedImmune Press release MedImmune and National Institutes of Health Begin Clinical Testing of a Live, Attenuated Intranasal Vaccine Against an H5N1 Avian Influenza Virus published June 15, 2006
- Suguitan AL, McAuliffe J, Mills KL, et al. (September 2006). "Live, attenuated influenza A H5N1 candidate vaccines provide broad cross-protection in mice and ferrets". PLoS Med. 3 (9): e360. PMC . PMID 16968127. doi:10.1371/journal.pmed.0030360.
- Steel J, Lowen AC, Pena L, et al. (February 2009). "Live attenuated influenza viruses containing NS1 truncations as vaccine candidates against H5N1 highly pathogenic avian influenza". J. Virol. 83 (4): 1742–53. PMC . PMID 19073731. doi:10.1128/JVI.01920-08.
- Lee LY, Ha do LA, Simmons C, et al. (October 2008). "Memory T cells established by seasonal human influenza A infection cross-react with avian influenza A (H5N1) in healthy individuals". J. Clin. Invest. 118 (10): 3478–90. PMC . PMID 18802496. doi:10.1172/JCI32460.
- FluMist nasal flu vaccine - Official website
- FluMist information on University of Michigan, School of Public Health website
- Live Attenuated Vaccine in Russia presentation on Russian live influenza vaccines since 1961
- CDC Vaccine Information Statement Live, Attenuated Inﬂuenza Vaccine
- CDC Vaccine Information Statement 2009 H1N1 LAIV
- Summary of the European public assessment report (EPAR) for Fluenz
- FDA prescribing information