Current Status of Live Attenuated Influenza Vaccine in the United States for Seasonal and Pandemic Influenza

Christopher S. Ambrose; Catherine Luke; Kathleen Coelingh

Disclosures

Influenza Resp Viruses. 2008;2(6):193-202. 

In This Article

Abstract and Seasonal Live Attenuated Influenza Vaccine

Abstract

A live attenuated influenza vaccine (LAIV) is currently approved in the United States for the prevention of influenza in individuals 2–49 years of age. This article summarizes the available data describing the safety and efficacy of LAIV for the prevention of influenza in both children and adults. LAIV is administered as an intranasal spray and has been shown to provide high levels of efficacy against influenza illness caused by both matched and mismatched strains in children and adults. In studies comparing LAIV and inactivated influenza vaccine in children, LAIV recipients experienced 35–53% fewer cases of culture-confirmed influenza illness caused by antigenically matched strains. Protection through a second influenza season against antigenically matched strains has also been seen in children. In adults, definitive comparative studies of LAIV and inactivated vaccine have not been conducted and no statistically significant differences in efficacy have been demonstrated. The most common adverse reactions with LAIV include runny nose/nasal congestion in all age groups, fever > 100ºF in children, and sore throat in adults. Formulations of LAIV against pandemic influenza strains, including H5N1, H9N2, and H7N3, are currently being tested in preclinical and phase I clinical studies.

Seasonal Live Attenuated Influenza Vaccine

Live attenuated influenza vaccine (LAIV; marketed in the United States as FluMist® [Influenza Virus Vaccine Live, Intranasal]) was approved for use in the United States in 2003, becoming the first nasally administered vaccine for human use in the United States. The approval of LAIV was the culmination of more than 30 years of collaborative research and development by scientists from academia, the National Institutes of Health (NIH), and the biopharmaceutical industry (MedImmune and Wyeth Vaccines). LAIV is currently approved in the United States for use in individuals 2–49 years of age.

Live attenuated influenza vaccine was originally derived by cold adaptation of an influenza type A strain (A/Ann Arbor/6/60 H2N2) and a type B strain (B/Ann Arbor/1/66) by serial passage at sequentially lower temperatures in specific pathogen-free primary chick kidney cells.[1] During this process, the viruses acquired multiple mutations in internal protein gene segments (i.e., genes encoding "internal" nonglycosylated proteins) that produced the cold-adapted (ca), temperature-sensitive (ts), and attenuated (att) phenotype of the master donor viruses (MDVs). The MDVs represent the LAIV genetic backbone that is updated annually with hemagglutinin (HA) and neuraminidase (NA) genes from contemporary influenza viruses to produce the annual trivalent formulation.

The individual contributions of the genetic sequences of the six internal gene segments to the ca, ts, and att phenotype of the MDVs are not completely understood, but many of the mutations associated with the phenotypes have been identified ( Table 1 ). For the type A MDV, at least five genetic loci in three different internal protein gene segments contribute to the ts and att phenotypes.[2,3] For the type B MDV, at least three genetic loci in two different gene segments contribute to both the ts and att properties; two additional loci in a third gene segment also contribute to the att property; five loci in three segments control the ca property.[4,5]

Because multiple loci in several genes control the ca, ts, and att phenotypes of LAIV vaccine viruses, it is highly improbable that LAIV would lose these phenotypes as a result of reversion.[6,7] Given the error rate of 10-4 to 10-5 misincorporations per nucleotide position during influenza virus replication and the fact that at least five point mutations are responsible for the attenuated properties of each MDV,[7,8] the probability of a LAIV vaccine virus reverting to wild-type influenza, with mutations in the five attenuating loci, would be one in at least 1020 replication cycles. In one study of 135 vaccine strains recovered from young vaccinated children, no evidence of reversion was observed.[9]

Each of the three influenza virus strains contained in LAIV is a 6:2 genetic reassortant virus, containing six internal gene segments from ca, ts, and att MDVs and two gene segments (encoding the HA and NA proteins) from a wild-type influenza virus that is selected annually by the World Health Organization and the US Public Health Service. Genetic reassortant viruses are prepared using reverse genetics technology in cell culture, a technique whereby influenza viruses can be generated from DNA plasmids containing influenza genes (Figure 1). LAIV vaccine viruses were originally generated using classical reassortment, but in 2008 the process transitioned to reverse genetics technology.

Figure 1.

Schematic diagram of LAIV vaccine seed strain preparation using reverse genetics. Plasmids containing the MDV genes that control ca, ts, and att phenotypes and wild-type virus HA and NA genes are electroporated into Vero cells to generate the appropriate 6:2 vaccine strain. The 6:2 seed strain is used to manufacture LAIV. att = attenuated; ca = cold-adapted; HA = hemagglutinin; LAIV = live attenuated influenza vaccine; MDV = master donor virus; NA = neuraminidase; ts = temperature sensitive.

Three vaccine strains are formulated together to produce a trivalent LAIV vaccine in single-dose sprayers. Bulk vaccine is currently produced in specific pathogen-free embryonated hens' eggs, and plans are ongoing to assess future manufacture in cell culture. No preservatives are used in the manufacture of LAIV.

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