The Nasal Flu Vaccine Returns: ACIP's 2018–19 Recommendation on LAIV4

Background

The nasal spray live attenuated influenza vaccine (LAIV) — FluMist, made by MedImmune — was first licensed in the United States in 2003 as a trivalent vaccine. Its quadrivalent version (LAIV4) was licensed in 2012 and replaced it from the 2013–14 season.

For the 2016–17 and 2017–18 seasons, CDC's Advisory Committee on Immunization Practices (ACIP) advised against using LAIV4, because it had shown low effectiveness against influenza A(H1N1)pdm09-like viruses in 2013–14 and 2015–16. On February 21, 2018, ACIP made it an option again for the 2018–19 season for people for whom it is appropriate. This report summarizes the evidence behind that decision.

What went wrong

Before the 2009 H1N1 pandemic, three randomized trials had found the trivalent nasal vaccine worked better than the trivalent inactivated (injected) vaccine in children. But in U.S. studies in 2013–14 and 2015–16, when H1N1 dominated, LAIV4 showed no significant effectiveness against A(H1N1)pdm09-like viruses in children aged 2 through 17.

The likely cause: the H1N1 strains in the vaccine those years — A/California/7/2009 and A/Bolivia/559/2013 — had poor replicative fitness, growing less well in human nasal lining cells than the pre-pandemic H1N1 strains used before. For 2017–18, a new strain, A/Slovenia/2903/2015, replaced A/Bolivia — but LAIV4 wasn't recommended that season, so there were no U.S. effectiveness data for it.

Evidence ACIP reviewed

1. Pooled data from five U.S. observational studies on LAIV4 and inactivated vaccine effectiveness in children aged 2 through 17, 2013–14 through 2015–16.
2. A systematic review of published studies of both nasal vaccines in children, 2010–11 through 2016–17.
3. A manufacturer's study of viral shedding and immune response to LAIV4 with the new A/Slovenia strain in U.S. children aged 24 months to under 4 years.

Findings:

• LAIV had low to no significant effectiveness against A(H1N1)pdm09, but was generally effective against influenza B, and about as effective as inactivated vaccine against H3N2.
• The new A/Slovenia strain was shed by more children on days 4 through 7 after the first of 2 doses, produced significantly higher antibody responses than A/Bolivia, and gave seroconversion rates comparable to pre-pandemic H1N1 strains from seasons when the vaccine did work against H1N1.
• The manufacturer will add two tests when choosing vaccine strains, sharing the results with the Food and Drug Administration each year: growth in human nasal cell culture — the older egg and canine kidney cell tests had failed to predict how A(H1N1)pdm09 vaccine strains grew in human cells — and measuring infectivity with a 50% tissue culture infective dose test alongside the fluorescent focus assay. The first tracks the virus spreading from cell to cell over repeated replication; the second does not. For the failed strains, the first gave much lower results than the second; for A/Slovenia, the two matched, as they had for effective pre-pandemic strains.

The decision

Flu vaccine effectiveness always varies — with the recipient's age and health, the virus type and subtype, past vaccination, and how well the vaccine matches circulating viruses — and may differ between products, though comparative data are scarce. Children's vaccination rates didn't drop much in 2016–17, the first season without LAIV, but they remain too low; a needle-free option might help, especially in school-based programs. No effectiveness data were yet available for the new strain against H1N1, because H3N2 and influenza B had dominated 2017–18.

ACIP's recommendation for 2018–19: providers may give any licensed, age-appropriate flu vaccine — inactivated, recombinant or LAIV4. LAIV4 is an option for anyone for whom it is otherwise appropriate, and no product is preferred over another. ACIP will keep reviewing LAIV4 data, and providers should know that the updated vaccine's effectiveness against current A(H1N1)pdm09 viruses is not yet known.

Sources

Based on Lisa A. Grohskopf, Leslie Z. Sokolow, Alicia M. Fry, Emmanuel B. Walter and Daniel B. Jernigan, "Update: ACIP Recommendations for the Use of Quadrivalent Live Attenuated Influenza Vaccine (LAIV4) — United States, 2018–19 Influenza Season," MMWR, Centers for Disease Control and Prevention; a work of the United States government in the public domain.