Live attenuated influenza vaccine
Nurse administering the FluMist product
|Trade names||FluMist Quadrivalent, Fluenz Tetra|
|(what is this?)|
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. 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, but this recommendation was reversed in February 2018, for the 2018-2019 influenza season.
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. LAIV is sold under the brand name FluMist Quadrivalent in the United States and the brand name Fluenz Tetra in Europe. FluMist was originally manufactured by MedImmune but is now manufactured by AstraZeneca 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 was due to the poor effectiveness of this type of vaccine between 2013, and 2016, with it being ineffective during the 2015–2016 season. A 2018 review found that LAIV prevents influenza in about one out of six children under six that 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 two years old the evidence was however unclear. Why there appears to be a decrease in effectiveness is unknown.
However, in February 2018, the CDC Advisory Committee on Immunization Practices (ACIP) reinstated the use of LAIV for the 2018-2019 flu season. The inactivated and recombinant influenza vaccines are no longer preferred by ACIP over LAIV.
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
- 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
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.
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. 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.
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. 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[when?] FluMist is approved and recommended for healthy children 24 months of age and older. The FDA approved the current[when?] unfrozen refrigerated version for the same age group (ages 5–49) in August 2006, following completion of phase III clinical trials.
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, 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. The price was sharply lowered the next year, and the company reported 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 Tetra" in Europe. For the 2010–2011 flu season, FluMist was the only LAIV approved by the FDA for use in the US. 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 (EMA) for use in the European Union in 2011. The quadrivalent version was approved for use in the European Union in 2013.
As of 2007[update], 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 Organization of Thailand. It was the first and (as of 2007[update]) 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 (EMA) 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[when?] 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.
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Vaccines for Pandemic Influenza
Catherine J. Luke* and Kanta Subbarao*
- National Institutes of Health, Bethesda, Maryland, USA
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