In this issue of Pediatrics, Essink et al report data from a large phase 3, randomized, observer-blind, comparator-controlled trial in which children were randomized to receive either a cell-based quadrivalent influenza vaccine (QIVc; Flucelvax, CSL Seqirus) or a traditional, egg-based quadrivalent influenza vaccine (QIV, Afluria, CSL Seqirus).1  This study enrolled an impressive 2414 healthy children in the United States between 6 and 47 months of age during the 2019–2020 influenza season and randomized them 2:1 to receive either QIVc or QIV. Serologic responses were evaluated at baseline and 28 days after last vaccination, with safety followed for 180 days. The authors found that QIVc was safe and well tolerated, with seroresponse and seroconversion noninferior to traditional egg-based vaccines.1  These data have now led to an expanded indication for Flucelvax in the 6 to 47-month-old population,2  providing a nonegg-based influenza vaccine for infants and toddlers.

Influenza virus is unique in that ongoing viral evolution presents challenges for the rational development of broadly protective influenza vaccines. Although influenza vaccination remains the best method to prevent influenza-associated morbidity and mortality, vaccine effectiveness (VE) remains lower than ideal, especially against the H3N2 subtype. In a systematic review and meta-analysis conducted between 2004 and 2015, the point estimate for pooled VE in pediatric studies (defined as aged <20 years) was 43% for H3N2 strains, compared with 56% for influenza B and 69% for H1N1pdm09.3  Although many factors may contribute to this low VE, one factor is likely poor growth of H3N2 candidate vaccine viruses in eggs containing avian instead of mammalian cell surface receptors.4 

For >70 years, influenza vaccines have been manufactured in an egg-dependent process where seed viruses are passaged in fertilized chicken eggs either directly or after reassortment with a donor strain adapted for egg growth. However, growth in eggs can introduce mutations in the hemagglutinin (HA) protein because of egg adaptation, with a resulting increase in antigenic distance between the vaccine and circulating viruses. Cell-based influenza vaccines are unique because candidate strains are derived from and produced using a mammalian cell-based platform rather than eggs. This platform is not dependent upon the supply of fertilized eggs and is less likely to introduce HA mutations because of the presence of mammalian cell surface receptors.5  Cell-based influenza vaccines have been shown to be efficacious, with a phase 3–4 randomized trial evaluating QIVc compared with a noninfluenza vaccine (meningococcal ACWY vaccine) in healthy children and adolescents demonstrating 54.6% overall efficacy against laboratory-confirmed influenza in 2017 to 2019.6 

The clearest example of egg adaptation of influenza vaccine strains occurred in 2017 to 2018, when H3N2 subtype VE was lower than expected despite little meaningful antigenic drift between circulating viruses and the cell-propagated reference strain. Although viruses in circulation were well inhibited by ferret antiserum raised against the cell-propagated vaccine virus, this inhibition declined when tested against ferret antiserum raised against the egg-propagated virus.7  The egg-derived virus was ultimately found to have a T160K HA mutation that resulted in the loss of a glycosylation site,8  as well as an L194P mutation that disrupted a large region in the HA receptor-binding region.9  QIVc lacks these egg adaptations and increased effectiveness has been demonstrated in several studies, including 1 with a pediatric subgroup analysis showing increased protection against hospitalizations/emergency department visits related to asthma and pneumonia in children aged 4 to 17 years.10 

QIVc will provide an additional influenza vaccine platform for the pediatric population and, importantly, a nonegg-based vaccine that might result in improved antigenic match in some influenza seasons. This could have important implications with regard to imprinting, or the establishment of lasting anti-influenza protective immunity in childhood1114  In adults, egg-adapted vaccines can preferentially boost antibodies specific for epitopes (antigenic determinants recognized by the immune system) on historically, but not currently, circulating viral strains because of changes introduced during egg adaptation.9  In immunologically naive children, vaccination with egg-adapted influenza strains could potentially prime and establish lasting immune memory to egg-adapted epitopes not present in currently circulating viral strains. This was demonstrated by Liu et al, where the majority of the postvaccination antibody response in previously unprimed children targeted egg-adapted epitopes absent on circulating wild type viruses.15  The long-term impact of this type of immune memory is unknown.

Although QIVc will still focus the immune response on single antigenic variants and require accurate prediction of circulating strains for effectiveness, this vaccine utilizes a widely available, egg-sparing platform that minimizes adaptation of candidate vaccine strains. The availability of QIVc for the youngest of children thus has potential to direct early life influenza immunity toward clinically relevant epitopes, avoiding development of anti-influenza immune memory against undesirable epitopes only present in egg-adapted viruses. By demonstrating the safety and immunogenicity of cell-based vaccines in young children, the manuscript by Essink et al thus represents an important advancement for pediatric influenza vaccines.

Dr Nayak conceptualized the commentary and prepared the original draft; Dr Caserta participated in review and editing of the manuscript; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

COMPANION PAPER: A companion to this article can be found online at www.pediatrics.org/cgi/doi/10.1542/peds.2022-057509.

FUNDING: No external funding.

CONFLICT OF INTEREST DISCLAIMER: Drs Nayak and Caserta receive research support from Pfizer Inc, Moderna Inc, Merck & Co, Inc, and the National Institutes of Health.

     
  • HA

    hemagglutinin

  •  
  • QIV

    egg-based quadrivalent influenza vaccine (Afluria)

  •  
  • QIVc

    cell-based quadrivalent influenza vaccine (Flucelvax)

  •  
  • VE

    vaccine effectiveness

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