Vaccine manufacturers seek to broaden influenza B protection coverage

Block SL. Pediatr Infect Dis J. 2012;doi:10.1097/INF.0b013e31825687b0.

  • April 19, 2012

A quadrivalent influenza vaccine could offer some important advantages over other influenza vaccines, and in clinical trials, was nearly equal to that of two trivalent vaccines for children aged 2 to 17 years, according to results in a recently published study.

“Influenza B strains account for an average of 25% of overall influenza infections in the last decade. The previously available trivalent influenza vaccines have only targeted one B subtype, either Yamagata or Victoria. And as would be expected, for the past 10 years (2001 to 2011), we have been correct only 50% of the time,” said Infectious Diseases in Children Editorial Board member Stan L. Block, MD. “So why not target both influenza B subtypes and make a quadrivalent influenza vaccine by including both B Yagamata and B Victoria strains, along with the customary two A subtypes?”

Block and colleagues compared post-dose geometric mean titers of hemagglutination inhibition antibodies from a group of 2,312 children who received the quadrivalent vaccine or one of two trivalent vaccines.

Children randomly received on a 3:1:1 basis either the quadrivalent vaccine, which contained the Ann Arbor strain live-attenuated influenza (Q/LAIV) or one of two trivalent vaccines that each had a B strain from a different lineage (T/LAIV). Block and colleagues said the overall results of the various study groups were comparable when it came to immunogenicity and safety, with one exception: Children aged 2 to 8 years were more prone to fever after the first dose of Q/LAIV (5.1% vs. the T/LAIV group’s 3.1%).

“Q/LAIV induced robust antibody titers to influenza B strains from both lineages, but the trivalent vaccines each induced robust antibody titers only to B strains from the homologous lineage,” the study researchers wrote.

They said the use of Q/LAIV has the potential to provide additional protection when trivalent vaccines contain a mismatched B virus that is responsible for most of the influenza B disease. This has occurred in five of the most recent 10 influenza seasons (2001-2002 to 2010-2011), according to the study findings.

“The influenza virus is a crafty organism. Although two influenza types infect humans (A and B), both types have two distinct subtypes — A has H1N1 and H3N2 subtypes, and B has Yamagata and Victoria subtypes. Even within the A and B subtypes, vaccine-type drifted antigenic variants are commonly encountered every year or two. This can render the annual flu vaccine less effective,” Block told Infectious Diseases in Children.

He said the Q/LAIV should have some important pediatric advantages over the influenza vaccine, including:

  • LAIV has shown longer durability during the same season and even the second season (55%) without a booster.
  • A single dose of LAIV is highly protective in vaccine-naive children (65% to 87% vs. 0% to 20%).
  • LAIV has demonstrated better efficacy against antigenic drift among A subtypes.
  • Most children prefer not to receive a shot.
  • The vaccine has both B subtypes covered.

The downside, Block said, is that LAIV is not approved for children aged 6 to 24 months. Fluzone (Sanofi-Pasteur) is the only influenza formulation approved for use in children in that age group. In addition, LAIV use in children with recent asthma/wheezing or chronic illnesses is still controversial and a precaution.

Block said there is more good news on the horizon for pediatrics: “We have completed testing on a quadrivalent formulation of Fluzone and a totally different cell-culture (not-egg containing) formulation of flu shot (Optaflu, Novartis).”

Disclosure: Dr. Block reports receiving vaccine research grants from MedImmune, Novartis and Sanofi.

Perspective

  • Until recently, the inactivated and the live-attenuated influenza vaccines (LAIV) were formulated annually with three different influenza viruses based on the recommendation by the World Health Organization and FDA’s Vaccines and Related Biological Products Advisory Committee. The trivalent formulation provides coverage against influenza A (2009 H1N1), influenza A (H3N2) and influenza B.

    For a number of years, however, two different influenza B lineages have been in circulation worldwide: influenza B/Yamagata and Influenza B/Victoria. These two influenza B lineages are significantly different so that an influenza vaccine formulated with the B/Yamagata lineage will not provide protection against infection with an influenza B virus from the B/Victoria lineage and vice versa. This is particularly relevant in pediatrics because children have the highest influenza attack rates, and the spectrum of disease caused by influenza B viruses is similar to that caused by influenza A viruses. The limitation of a trivalent influenza vaccine was observed in the United States this year. Influenza B has accounted for approximately 10% of the influenza isolates reported to the CDC for the 2011-12 influenza season (week ending April 7, 2012; CDC. 2012; www.cdc.gov/flu/weekly/weeklyarchives2011-2012/weekly 14.htm). Of the influenza B isolates that have been characterized, approximately 60% belong to B/Yamagata lineage which is not similar to the influenza B component (B/Victoria lineage) in the 2011-12 influenza vaccine. If this had been a major influenza B epidemic, the pediatric population would not have been protected against influenza.

    Stan Block and colleagues conducted a large randomized, double-blind study designed to show the immunologic noninferiority of the quadrivalent LAIV (Q/LAIV) compared to two different trivalent LAIV (T/LAIV), each formulated with the same influenza A components but with the different B lineages. The study was conducted in 2,479 children aged 2 through 17 years. The immunogenicity of the Q/LAIV was shown to be noninferior to that of T/LAIV and the overall safety was comparable to T/LAIV. Thus, the Q/LAIV should provide a more robust protection against all circulating seasonal influenza viruses, including those in the different B lineages. In February 2012, the FDA approved Q/LAIV for use in patients aged 2 through 49 years (Feb. 29, 2012, Approval letter – FluMist Quadrivalent; www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm294293.htm). Other influenza vaccine manufacturers are also developing Q/LAIV vaccines for improved coverage.

    • Pedro A. Piedra, MD
    • Infectious Diseases in Children Editorial Board
  • Disclosures: Dr. Piedra reports no relevant financial disclosures.

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