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Intranasal FluMISSED its target :

July 12, 2016

The Academy supports the Centers for Disease Control and Prevention’s (CDC’s) interim recommendation that quadrivalent live attenuated influenza vaccine (LAIV4) not be used in any setting during the 2016-’17 season.

Vaccination remains the best preventive measure against influenza, so everyone 6 months and older should receive any age-appropriate trivalent or quadrivalent (no preference) inactivated influenza vaccine (IIV) as soon as available.

Why no intranasal LAIV4 this season?

This approach was taken in light of new observational data from the U.S. Flu Vaccine Effectiveness Network that documented poor vaccine effectiveness (VE) of LAIV4 during each of the past three influenza seasons (see table), especially against 2009 influenza A (H1N1) and pandemic (H1N1pdm09) viruses. During the most recent season, LAIV4 had an overall adjusted VE of 3% against any influenza, while IIV had an adjusted VE of 63% in children 2 through 17 years of age.

In all pediatric age groups for all three seasons, LAIV did not have any statistically significant benefit in preventing influenza (all 95% CI cross zero), while IIV provided statistically significant protection, albeit to differing degrees by season. Children who received LAIV had more than 2.5 times higher odds of developing influenza due to any virus type compared with IIV vaccinated children. For H1N1pdm09 in particular, LAIV4 had an adjusted vaccine effectiveness of -21% (95% CI, -108% to 30%) compared with IIV of 65% (95% CI, 49% to 76%). The adjusted odds ratio was 3.67, indicating that children who received LAIV4 were almost four times more likely to get influenza than those who received IIV.

Although reported point estimates of vaccine effectiveness differed in two other U.S. studies of LAIV4 (one by the U.S. Department of Defense and the other by the manufacturer of LAIV4), all studies found that IIV always outperformed LAIV4. In contrast, LAIV4 was reported to be effective in a small number of international studies performed in countries that do not have a universal influenza immunization program like the U.S. Children in these countries are more likely to be vaccine naïve, perhaps resulting in a stronger immune response to LAIV.

How did we get to this new recommendation? 

LAIV was introduced in its trivalent form (LAIV3) in the 2003-’04 season. An international, randomized study with over 8,000 children documented significantly better efficacy for LAIV3 compared with IIV (Belshe RB, et al. N Engl J Med. 2007;356:685-696).

However, the same results have not been observed for LAIV4, which was introduced in the 2013-’14 season. At this point, there is no clear explanation. Hypotheses include problems with the H1N1pdm09 strain in LAIV4, interference when the fourth strain was added to LAIV3 beginning in 2013, or the larger proportion of children who have been vaccinated in their past, which may blunt the immune response generated by a live attenuated vaccine that requires replication intranasally.

Following is a summary of problems experienced during the last three influenza seasons:

  • During the 2013-’14 season, the U.S. Flu Vaccine Effectiveness Network observed that LAIV4 performance was inferior to that of IIV against more than 90% of circulating strains in that H1N1pdm2009-dominant season. It was suggested that this performance was particularly inferior in children 2 through 8 years of age. Although the addition of the fourth strain may have caused some interference, the manufacturer also suggested that the H1N1 strain used in its intranasal quadrivalent vaccine may have been unstable upon exposure to heat. In response, a different H1N1 strain was incorporated, although not in time for the 2014-’15 season.
  • For the 2014-’15 season, the CDC made a preferential recommendation for using LAIV4 in healthy children ages 2 through 8, after a thorough GRADE (Grading of Recommendations, Assessment, Development and Evaluations) analysis of pre-licensure data. The Academy did not make a preferential recommendation. As the anticipated predominant strain for the 2014-’15 season was influenza A (H3N2) virus, LAIV4 was expected to provide better protection than IIV since the Belshe study had reported superior efficacy for LAIV3 compared with IIV against both well-matched and mismatched influenza A (H3N2) viruses. However, vaccine effectiveness for both IIV and LAIV4 was reduced for all ages during the 2014-’15 season due to antigenic drift, highlighting that LAIV4 did not result in the same robust protection against mismatched influenza A (H3N2) viruses as LAIV3 had years back. The CDC rescinded its preference for LAIV as the 2014-’15 data became available.
  • For the 2015-’16 season, despite a change in influenza A (H1N1) strain within the intranasal vaccine, recent evidence has shown that LAIV4 continues to perform poorly against H1N1pdm09 compared with IIV. Although LAIV4 vaccine effectiveness against influenza A (H3N2) could not be evaluated, this uncertainty is outweighed by strong evidence indicating poor effectiveness against influenza A (H1N1) and inconsistent effectiveness against influenza B when compared with IIV in the U.S. It is important to keep in mind that influenza A (H1N1) is one of the circulating strains during every influenza season, even when it is not the predominant strain.

What’s next?

While the Academy anticipates the use of only IIV during the 2016-’17 season will protect children better and benefit public health, pediatricians face new challenges. To address pre-booked LAIV doses, the Academy is working with the CDC and IIV manufacturers to ensure pediatricians and families have access to appropriate inactivated vaccines and with the LAIV manufacturer to provide equitable solutions for pre-purchased LAIV doses.

The Food and Drug Administration also is exploring the poor vaccine effectiveness of LAIV4, although its timeline has not been defined and regulatory action is felt not to be warranted at this time.

Despite the absence of a non-injectable vaccine, the goal continues to be to immunize as many children 6 months of age and older as possible to protect against influenza. The Academy and CDC also are developing communication resources to convey these important messages and to help the public understand this influenza recommendation.

Dr. Bernstein is associate editor of Red Book Online and an ex officio member of the AAP Committee on Infectious Diseases (COID). Dr. Kimberlin is editor of the AAP Red Book and ex officio member of COID.

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