Live attenuated influenza vaccine

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
Legal status
  • AU: S4 (Prescription only)
  • US: ℞-only
  • EU: Rx-only
  • In general: ℞ (Prescription only)
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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.[1] In June 2016, the Centers for Disease Control and Prevention (CDC) stopped recommending the use of LAIV as its effectiveness had appeared to have decreased between 2013 and 2016,[2][3] but this recommendation was reversed in February 2018, for the 2018-2019 influenza season.[4]

It is an attenuated vaccine, unlike most influenza vaccines, which are inactivated vaccines. LAIV is administered intranasally,[5] while inactivated vaccines are administered by intramuscular injection. LAIV is sold under the brand name FluMist Quadrivalent in the United States and the brand name Fluenz Tetra in the European Union.[6][7] FluMist was first introduced in 2003 by MedImmune.[3][8][9]

Medication uses

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.[2] This was due to the poor effectiveness of this type of vaccine between 2013, and 2016, with it being ineffective during the 2015–2016 season.[2] A 2018 review found that LAIV prevents influenza in about one out of six children under six that it is given to.[10] It was believed to prevent about 50% more cases of flu than the flu shot in younger children.[11] In those less than two years old the evidence was however unclear.[10] Why there appears to be a decrease in effectiveness is unknown.[2]

However, in February 2018, the CDC Advisory Committee on Immunization Practices (ACIP) reinstated the use of LAIV for the 2018-2019 flu season.[4] The inactivated and recombinant influenza vaccines are no longer preferred by ACIP over LAIV.[4]

Contraindications

The use of LAIV is contraindicated, and should therefore not be used, in the following populations:

  • children <24 months of age, due to increased risk of wheezing[12]
  • individuals with a history of hypersensitivity to previous influenza vaccination.[12]
  • 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 [12]
  • 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[13]
  • 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[13]
  • Children less than 5 years old with a history of recurrent wheezing[13]
  • Children or adolescents receiving aspirin[13]
  • People with a history of Guillain–Barré syndrome, a rare disorder of the nervous system[13]
  • Pregnant women[13]
  • People who have a severe allergy to chicken eggs or who are allergic to any of the nasal spray vaccine components[13]

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.[14]

Risks

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. LAIV 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 LAIV.[15] 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) and possible recombination with other (wild or live vaccine) flu strains.[1]

History

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 the National Institutes of Health (NIH) in the mid-1990s. MedImmune, Inc. purchased Aviron in 2002, and the US Food and Drug Administration (FDA) approved FluMist in June 2003.[16][9] FluMist was first made available in September 2003.

The FDA initially approved FluMist only for healthy people aged 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 III clinical trials.[17]

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,[9] 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.[18] The price was sharply lowered the next year, and the company reported distributing 1.6 million doses in 2005.[19] 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.[20] 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.

The FDA's regulatory pathway for FluMist has been suggested as a possible precedent for phage therapy.[21]

Society and culture

MedImmune is one company that manufactures LAIV, which it sells under the trade name "FluMist" in the United States and "Fluenz Tetra"[7] in Europe. For the 2010–2011 flu season, FluMist was the only LAIV approved by the FDA for use in the US.[22][23] All other FDA-approved lots were inactivated virus vaccines. In September 2009 a LAIV intranasal vaccine for the novel H1N1 influenza virus was approved[24] and the seasonal intranasal vaccine was approved by the European Medicines Agency (EMA) for use in the European Union in 2011.[25] The quadrivalent version was approved for use in the European Union in 2013.[7]

As of 2007, the only other company holding LAIV vaccine rights was 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] BCHT plans to market a trivalent LAIV vaccine for H1N1 flu by the end of 2016.[28] The BCHT flu vaccine is one of several candidates for WHO prequalification in the near future,[29] reflecting a shift of Chinese market priorities from a large domestic market toward export.[30] 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 Organization of Thailand. It was the first and (as of 2007) the only live attenuated vaccine for influenza available outside of Europe.[31] In September 2009, a LAIV intranasal vaccine for the novel H1N1 influenza virus was approved.[24] In 2011, the vaccine was approved by the European Medicines Agency (EMA) for use in the European Union under the name Fluenz.[32]

AstraZeneca acquired MedImmune and subsequently retired the MedImmune name.[33][34]

Research

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.[35]

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.[36]

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.[37] Attenuated live viruses were found protective against H5N1 in mice and chickens in a 2009 study.[38]

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)[39] "[V]accine formulas inducing heterosubtypic T cell–mediated immunity may confer broad protection against avian and human influenza A viruses."[39]

In September 2009, a LAIV intranasal vaccine for the novel H1N1 influenza virus was approved.[24]

References

  1. 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): 4940–6. doi:10.1016/j.vaccine.2008.07.013. PMID 18662737.
  2. 1 2 3 4 "ACIP votes down use of LAIV for 2016-2017 flu season". 22 June 2016. Retrieved 14 July 2016.
  3. 1 2 "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.
  4. 1 2 3 "ACIP Reinstates FluMist for 2018-2019 Flu Season". medpagetoday.com. MedPage Today, LLC. 21 February 2018. Retrieved 23 February 2018.
  5. ↑ 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. doi:10.1056/NEJMoa065368. PMID 17301299.
  6. ↑ "FluMist Quadrivalent". U.S. Food and Drug Administration (FDA). 15 November 2019. STN 125020.
  7. 1 2 3 "Fluenz Tetra EPAR". European Medicines Agency (EMA). Archived from the original on 28 November 2019. Retrieved 27 November 2019.
  8. ↑ Midthun, Karen; Steven Masiello (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.
  9. 1 2 3 "FluMist". U.S. Food and Drug Administration (FDA). Archived from the original on 22 July 2017. Retrieved 10 April 2020.
  10. 1 2 Jefferson, Tom; Rivetti, Alessandro; Di Pietrantonj, Carlo; Demicheli, Vittorio (1 February 2018). "Vaccines for preventing influenza in healthy children". The Cochrane Database of Systematic Reviews. 2: CD004879. doi:10.1002/14651858.CD004879.pub5. ISSN 1469-493X. PMC 6491174. PMID 29388195.
  11. ↑ "Nasal Spray Flu Vaccine in Children 2 through 8 Years Old". Centers for Disease Control and Prevention (CDC). Archived from the original on 28 October 2014. Retrieved 4 November 2014.
  12. 1 2 3 AstraZeneca Inc. (2013). Product Monograph: FluMist. AstraZeneca Inc. Archived from the original on 23 July 2014. Retrieved 27 August 2013.
  13. 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.
  14. ↑ FDA Vaccines and Related Biological Products Advisory Committee (April 2007). "FluMist Live, Attenuated Influenza Vaccine Briefing Document" (PDF). Archived from the original (PDF) on 26 January 2018.
  15. ↑ "Facts and Myths about FluMist | FluMist® Quadrivalent (Influenza Vaccine Live, Intranasal)". www.flumistquadrivalent.com. AstraZeneca. September 2020. Retrieved 10 November 2020.
  16. ↑ Appleby, Julie (7 January 2004). "Nasal FluMist overcomes obstacles to reach public". USA Today. Retrieved 6 July 2008.
  17. ↑ "MedImmune begins shipping live intranasal flu vaccine for 2006-2007 after U.S. FDA release". Lab Law Weekly. 25 August 2006. Retrieved 6 July 2008.
  18. ↑ Rosenwald, Michael (6 January 2005). "FluMist Sales Falling Short, Survey Finds". The Washington Post. p. E05. Retrieved 6 July 2008.
  19. ↑ "MedImmune reports revenues of $1.2 billion". Pharma Business Week. 27 February 2006. Retrieved 6 July 2008.
  20. ↑ Rosenwald, Michael (3 February 2006). "Sales of MedImmune's Flu Vaccine Drop Sharply". The Washington Post. p. D04. Retrieved 6 July 2008.
  21. ↑ Keen, E. C. (2012). "Phage Therapy: Concept to Cure". Frontiers in Microbiology. 3: 238. doi:10.3389/fmicb.2012.00238. PMC 3400130. PMID 22833738.
  22. ↑ "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.{{cite web}}: CS1 maint: unfit URL (link)
  23. ↑ "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.{{cite web}}: CS1 maint: unfit URL (link)
  24. 1 2 3 "Update on Influenza A (H1N1) 2009 Monovalent Vaccines". 9 October 2009. Retrieved 23 October 2009.
  25. ↑ "Fluenz EPAR". European Medicines Agency (EMA). Retrieved 9 April 2020.
  26. ↑ "MedImmune takeover holds promise for BioDiem". BioTechnologyNews. 26 April 2007.
  27. ↑ "BioDiem licenses LAIV technology to Changchun BCHT". ResearchInChina. 10 February 2012.
  28. ↑ Jinchang Wu (March 2013). "Overview of BCHT and Update to LAIV Project" (PDF). Changchun BCHT.
  29. ↑ "Progress under GAP Pillar 2 "Increase Production Capacity" Contribution of the WHO Technology Transfer Programme" (PDF). World Health Organization. 18 March 2013.
  30. ↑ Jiao Li (18 October 2013). "China enters global vaccine marketplace". Nature. doi:10.1038/nature.2013.13975. S2CID 168137737.
  31. ↑ Harper, Scott A; Fukuda, Keiji; Cox, Nancy J; Bridges, Carolyn B (26 September 2003). "Using Live, Attenuated Influenza Vaccine for Prevention and Control of Influenza: Supplemental Recommendations of the Advisory Committee on Immunization Practices (ACIP)". MMWR Recomm Rep. 52 (RR-13): 1–8. PMID 14557799.
  32. ↑ AstraZeneca's Nasal Flu Vaccine Approved In Europe
  33. ↑ "AstraZeneca Ships FLUMIST QUADRIVALENT Vaccine in the US for 2020-2021 Flu Season" (Press release). AstraZeneca. 13 August 2020. Retrieved 8 July 2021 – via Business Wire.
  34. ↑ "AstraZeneca retires Medimmune name amid sales turnaround". BioPharma Dive. 14 February 2019. Retrieved 8 July 2021.
  35. ↑ 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
  36. ↑ 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 15 June 2006
  37. ↑ 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. doi:10.1371/journal.pmed.0030360. PMC 1564176. PMID 16968127. open access
  38. ↑ 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. doi:10.1128/JVI.01920-08. PMC 2643794. PMID 19073731.
  39. 1 2 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. doi:10.1172/JCI32460. PMC 2542885. PMID 18802496.
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