Live attenuated influenza vaccine
Nurse administering the FluMist product
Vaccine description
TargetInfluenza
Vaccine typeAttenuated
Clinical data
Trade namesFlumist Quadrivalent, Fluenz Tetra
AHFS/Drugs.comMonograph
License data
Routes of
administration		Intranasal
ATC code
Legal status
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ChemSpider
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Live attenuated influenza vaccine (LAIV) is a type of influenza vaccine in the form of a nasal spray that is recommended for the prevention of influenza.[5]

It is an attenuated live vaccine, unlike other influenza vaccines, which are inactivated vaccines. Live attenuated influenza vaccine is administered intranasally,[6] while inactivated vaccines are administered by intramuscular injection. Live attenuated influenza vaccine is sold under the brand name FluMist Quadrivalent in the United States and the brand name Fluenz Tetra in the European Union.[7][4] FluMist was first introduced in 2003 by MedImmune.[8][9][10]

Medical uses

The live attenuated influenza vaccine is used to provide protection against the flu caused by infection with influenza viruses.[11][12][13]

Contraindications

The use of the live attenuated influenza vaccine is contraindicated, and should therefore not be used, in the following populations:

  • children <24 months of age, due to increased risk of wheezing[14]
  • individuals with a history of hypersensitivity to previous influenza vaccination.[14]
  • 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 [14]
  • 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[15]
  • 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[15]
  • Children less than 5 years old with a history of recurrent wheezing[15]
  • Children or adolescents receiving aspirin[15]
  • People with a history of Guillain–Barré syndrome, a rare disorder of the nervous system[15]
  • Pregnant women[15]
  • People who have a severe allergy to chicken eggs or who are allergic to any of the nasal spray vaccine components[15]

Production

The live attenuated vaccine is based on a flu strain that does not cause disease, that replicates well at relatively cold temperatures (about 25 °C, for incubation purposes), and replicates poorly at body temperature (which minimizes risk to humans). Genes that code for surface proteins (targeted antigens) are combined with this host using genetic reassortment from strains that are projected to be circulating widely in the coming months. The resulting viruses are then incubated in chicken eggs and chick kidney cells. To make the refrigerated version, the virus is purified in centrifuges through a sucrose gradient, then packaged with sucrose, phosphate, glutamate, arginine, and gelatin made from pigs that has been hydrolyzed with acid.[16]

Risks

Even though the virus in the live attenuated influenza vaccine 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. The live attenuated influenza vaccine is recommended only for people 2–49 years of age, and people who have a weakened immune system, pregnant women, and people with certain chronic diseases may not be eligible to receive live attenuated influenza vaccine.[17] In contrast, inactivated virus vaccines contain no living virus, and cannot cause a live infection. Persons receiving the live attenuated influenza vaccine 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) and possible recombination with other (wild or live vaccine) flu strains.[5]

History

The live attenuated influenza vaccine was developed by the University of Michigan School of Public Health in Ann Arbor, Michigan and later by Aviron, in Mountain View, California, under the sponsorship of the National Institutes of Health (NIH) in the 1990s. MedImmune, Inc. purchased Aviron in 2002, and the US Food and Drug Administration (FDA) approved the live attenuated influenza vaccine in June 2003.[18][10]

The FDA initially approved the live attenuated influenza vaccine only for healthy people aged 5 to 49 because of concerns over possible side effects. The live attenuated influenza vaccine is approved and recommended for healthy children 24 months of age and older. The FDA approved the unfrozen refrigerated version for the same age group (ages 5–49) in August 2006, following completion of phase III clinical trials.[19]

The cold-adapted influenza vaccine 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,[10] 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 four million doses it produced its first year on the market, despite a comparative shortage of flu vaccine in fall 2004.[20] The price was sharply lowered the next year, and the company reported distributing 1.6 million doses in 2005.[21] 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.[22]

Society and culture

MedImmune is one company that manufactures the live attenuated influenza vaccine, which it sells under the brand name FluMist in the United States and the brand name Fluenz Tetra[4] in the European Union. For the 2010–2011 flu season, FluMist was the only live attenuated influenza vaccine approved by the FDA for use in the US.[23][24] All other FDA-approved lots were inactivated virus vaccines. In September 2009, a live attenuated influenza vaccine for the novel H1N1 influenza virus was approved[25] and the seasonal intranasal vaccine was approved by the European Medicines Agency (EMA) for use in the European Union in 2011.[3] The quadrivalent version was approved for use in the European Union in 2013.[4]

As of 2007, the only other company holding live attenuated influenza vaccine rights is BioDiem of Australia.[26] 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.[27]

It was the first and, as of 2007, the only live attenuated vaccine for influenza available outside of Europe.[28] In September 2009, a live attenuated influenza vaccine for the novel H1N1 influenza virus was approved.[25] In 2011, the vaccine was approved by the European Medicines Agency (EMA) for use in the European Union under the brand name Fluenz.[3][29]

AstraZeneca acquired MedImmune and retired the MedImmune name.[30][31]

Research

The live attenuated influenza vaccine 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, ways of reducing human mortality in the event of an H5N1 pandemic have been investigated. Modifying FluMist to serve as a specific human H5N1 vaccine is among the measures studied.[32]

In June 2006, the National Institutes of Health (NIH) began enrolling participants in a Phase I H5N1 study of an intranasal influenza vaccine candidate based on MedImmune's live, attenuated vaccine technology.[33]

In September 2006, the National Institute of Allergy and Infectious Diseases (NIAID) reported that inoculation with a live attenuated influenza vaccine modified to present the surface antigens of certain H5N1 variants provided broad protection against other H5N1 variants in the mouse and ferret models.[34] Attenuated live viruses were found protective against H5N1 in mice and chickens in a 2009 study.[35]

"Several trials have reported that live attenuated influenza vaccines 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)[36] "[V]accine formulas inducing heterosubtypic T cell–mediated immunity may confer broad protection against avian and human influenza A viruses."[36]

References

  1. ↑ "Prescription medicines: registration of new chemical entities in Australia, 2016". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 10 April 2023.
  2. ↑ "FluMist Quadrivalent (Influenza Vaccine Live, Intranasal) Intranasal Spray 2021-2022 Formula Initial U.S. Approval: 2003". DailyMed. 2 August 2021. Archived from the original on 23 June 2022. Retrieved 22 June 2022.
  3. 1 2 3 "Fluenz EPAR". European Medicines Agency (EMA). 17 September 2018. Archived from the original on 31 July 2020. Retrieved 9 April 2020.
  4. 1 2 3 4 "Fluenz Tetra EPAR". European Medicines Agency (EMA). 17 September 2018. Archived from the original on 28 November 2019. Retrieved 27 November 2019.
  5. 1 2 Block SL, Yogev R, Hayden FG, Ambrose CS, Zeng W, Walker RE (September 2008). "Shedding and immunogenicity of live attenuated influenza vaccine virus in subjects 5-49 years of age". Vaccine. 26 (38): 4940–4946. doi:10.1016/j.vaccine.2008.07.013. PMID 18662737.
  6. ↑ Belshe RB, Edwards KM, Vesikari T, Black SV, Walker RE, Hultquist M, et al. (CAIV-T Comparative Efficacy Study Group) (February 2007). "Live attenuated versus inactivated influenza vaccine in infants and young children". The New England Journal of Medicine. 356 (7): 685–696. doi:10.1056/NEJMoa065368. PMID 17301299.{{cite journal}}: CS1 maint: overridden setting (link)
  7. ↑ "FluMist Quadrivalent". U.S. Food and Drug Administration (FDA). 15 November 2019. STN 125020. Archived from the original on 28 November 2019. Retrieved 28 November 2019.
  8. ↑ "FDA Information Regarding FluMist Quadrivalent Vaccine". U.S. Food and Drug Administration (FDA). 16 January 2018. Archived from the original on 28 November 2019. Retrieved 27 November 2019.
  9. ↑ Midthun K, Masiello S (17 July 2003). "CBER Approval Letter, Influenza Virus Vaccine, Live, Intranasal (FluMist)". U.S. Food and Drug Administration (FDA). Archived from the original on 29 September 2007. Retrieved 6 July 2008.
  10. 1 2 3 "FluMist". U.S. Food and Drug Administration (FDA). Archived from the original on 22 July 2017. Retrieved 10 April 2020.
  11. ↑ "Live Intranasal Influenza Vaccine Information Statement". Centers for Disease Control and Prevention (CDC). August 2021. Archived from the original on 31 July 2020. Retrieved 22 June 2022.
  12. ↑ "Live Attenuated Influenza Vaccine. The Nasal Spray Flu Vaccine". Centers for Disease Control and Prevention (CDC). 15 October 2021. Archived from the original on 14 October 2019. Retrieved 22 June 2022.
  13. ↑ "FluMist". U.S. Food and Drug Administration (FDA). 17 April 2019. STN: 125020. Archived from the original on 23 June 2022. Retrieved 22 June 2022.
  14. 1 2 3 AstraZeneca Inc. (2013). Product Monograph: FluMist. AstraZeneca Inc. Archived from the original on 23 July 2014. Retrieved 27 August 2013.
  15. 1 2 3 4 5 6 7 "The Nasal-Spray Flu Vaccine (Live Attenuated Influenza Vaccine [LAIV])". National Center for Immunization and Respiratory Diseases. 22 January 2008. Archived from the original on 26 November 2009. Retrieved 6 July 2008.
  16. ↑ FDA Vaccines and Related Biological Products Advisory Committee (April 2007). "FluMist Live, Attenuated Influenza Vaccine Briefing Document" (PDF). Food and Drug Administration. Archived from the original (PDF) on 26 January 2018.
  17. ↑ "Facts and Myths about FluMist". AstraZeneca. September 2020. Archived from the original on 11 November 2020. Retrieved 10 November 2020.
  18. ↑ Appleby J (7 January 2004). "Nasal FluMist overcomes obstacles to reach public". USA Today. Archived from the original on 22 May 2006. Retrieved 6 July 2008.
  19. ↑ "MedImmune begins shipping live intranasal flu vaccine for 2006-2007 after U.S. FDA release". Lab Law Weekly. 25 August 2006. Archived from the original on 14 July 2011. Retrieved 6 July 2008.
  20. ↑ Rosenwald M (6 January 2005). "FluMist Sales Falling Short, Survey Finds". The Washington Post. p. E05. Retrieved 6 July 2008.
  21. ↑ "MedImmune reports revenues of $1.2 billion". Pharma Business Week. 27 February 2006. Archived from the original on 5 January 2009. Retrieved 6 July 2008.
  22. ↑ Rosenwald M (3 February 2006). "Sales of MedImmune's Flu Vaccine Drop Sharply". The Washington Post. p. D04. Archived from the original on 23 October 2016. Retrieved 6 July 2008.
  23. ↑ "2010-2011 Influenza Season Vaccine Questions and Answers". U.S. Food and Drug Administration (FDA). Archived from the original on 4 April 2017. Retrieved 9 April 2020.
  24. ↑ "Influenza Virus Vaccine for the 2010-2011 Season". U.S. Food and Drug Administration (FDA). Archived from the original on 6 April 2017. Retrieved 9 April 2020.
  25. 1 2 "Update on Influenza A (H1N1) 2009 Monovalent Vaccines" (PDF). 9 October 2009. Archived from the original on 6 April 2020. Retrieved 23 October 2009.
  26. ↑ "MedImmune takeover holds promise for BioDiem". BioTechnologyNews. 26 April 2007. Archived from the original on 21 October 2013. Retrieved 21 October 2013.
  27. ↑ "BioDiem licenses LAIV technology to Changchun BCHT". ResearchInChina. 10 February 2012. Archived from the original on 21 October 2013. Retrieved 21 October 2013.
  28. ↑ Harper SA, Fukuda K, Cox NJ, Bridges CB (September 2003). "Using live, attenuated influenza vaccine for prevention and control of influenza: supplemental recommendations of the Advisory Committee on Immunization Practices (ACIP)". MMWR. Recommendations and Reports. 52 (RR-13): 1–8. PMID 14557799. Archived from the original on 23 November 2017. Retrieved 9 September 2017.
  29. ↑ "European Commission approves nasal spray vaccine Fluenz for the prevention of seasonal influenza in children". AstraZeneca (Press release). 1 February 2011. Archived from the original on 13 June 2022. Retrieved 29 August 2022.
  30. ↑ "AstraZeneca Ships FluMist Quadrivalent Vaccine in the US for 2020-2021 Flu Season" (Press release). AstraZeneca. 13 August 2020. Archived from the original on 9 July 2021. Retrieved 8 July 2021 – via Business Wire.
  31. ↑ "AstraZeneca retires Medimmune name amid sales turnaround". BioPharma Dive. 14 February 2019. Archived from the original on 9 July 2021. Retrieved 8 July 2021.
  32. ↑ Luke CJ, Subbarao K (January 2006). "Vaccines for pandemic influenza" (PDF). Emerging Infectious Diseases. 12 (1): 66–72. doi:10.3201/eid1201.051147. PMC 3291408. PMID 16494720. Archived (PDF) from the original on 4 February 2022. Retrieved 23 June 2022.
  33. ↑ "MedImmune and National Institutes of Health Begin Clinical Testing of a Live, Attenuated Intranasal Vaccine Against an H5N1 Avian Influenza Virus". phx.corporate-ir.net (Press release). 15 June 2006. Archived from the original on 9 January 2016. Retrieved 22 June 2022.
  34. ↑ Suguitan AL, McAuliffe J, Mills KL, Jin H, Duke G, Lu B, et al. (September 2006). "Live, attenuated influenza A H5N1 candidate vaccines provide broad cross-protection in mice and ferrets". PLOS Medicine. 3 (9): e360. doi:10.1371/journal.pmed.0030360. PMC 1564176. PMID 16968127.{{cite journal}}: CS1 maint: overridden setting (link) Open access icon
  35. ↑ Steel J, Lowen AC, Pena L, Angel M, Solórzano A, Albrecht R, et al. (February 2009). "Live attenuated influenza viruses containing NS1 truncations as vaccine candidates against H5N1 highly pathogenic avian influenza". Journal of Virology. 83 (4): 1742–1753. doi:10.1128/JVI.01920-08. PMC 2643794. PMID 19073731.{{cite journal}}: CS1 maint: overridden setting (link)
  36. 1 2 Lee LY, Ha D, Simmons C, de Jong MD, Chau NV, Schumacher R, et al. (October 2008). "Memory T cells established by seasonal human influenza A infection cross-react with avian influenza A (H5N1) in healthy individuals". The Journal of Clinical Investigation. 118 (10): 3478–3490. doi:10.1172/JCI32460. PMC 2542885. PMID 18802496.{{cite journal}}: CS1 maint: overridden setting (link)
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