Influenza vaccination in the elderly boosts antibodies against conserved viral proteins and egg-produced glycans

Jiwon Jung, Sophia T. Mundle, Irina V. Ustyugova, Andrew P. Horton, Daniel R. Boutz, Svetlana Pougatcheva, Ponraj Prabakaran, Jonathan R. McDaniel, Gregory R. King, Daechan Park, Maria D. Person, Congxi Ye, Bing Tan, Yuri Tanno, Jin Eyun Kim, Nicholas C. Curtis, Joshua DiNapoli, Simon Delagrave, Ted M. Ross, Gregory C. IppolitoHarry Kleanthous, Jiwon Lee, George Georgiou

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


Seasonal influenza vaccination elicits a diminished adaptive immune response in the elderly, and the mechanisms of immunosenescence are not fully understood. Using Ig-Seq, we found a marked increase with age in the prevalence of crossreactive (CR) serum antibodies that recognize both the H1N1 (vaccine-H1) and H3N2 (vaccine-H3) components of an eggproduced split influenza vaccine. CR antibodies accounted for 73% ± 18% of the serum vaccine responses in a cohort of elderly donors, 65% ± 15% in late middle-aged donors, and only 13% ± 5% in persons under 35 years of age. The antibody response to non-HA antigens was boosted by vaccination. Recombinant expression of 19 vaccine-H1+H3 CR serum monoclonal antibodies (s-mAbs) revealed that they predominantly bound to non-HA influenza proteins. A sizable fraction of vaccine- H1+H3 CR s-mAbs recognized with high affinity the sulfated glycans, in particular sulfated type 2 N-acetyllactosamine (Galβ1-4GalNAcβ), which is found on egg-produced proteins and thus unlikely to contribute to protection against influenza infection in humans. Antibodies against sulfated glycans in egg-produced vaccine had been identified in animals but were not previously characterized in humans. Collectively, our results provide a quantitative basis for how repeated exposure to split influenza vaccine correlates with unintended focusing of serum antibody responses to non-HA antigens that may result in suboptimal immunity against influenza.

Original languageEnglish (US)
Article numbere148763
JournalJournal of Clinical Investigation
Issue number13
StatePublished - Jul 1 2021


  • Adult
  • Age Factors
  • Aged
  • Animals
  • Antibodies, Monoclonal/immunology
  • Antibodies, Viral/biosynthesis
  • Cohort Studies
  • Cross Reactions
  • Eggs/analysis
  • Humans
  • Immunoglobulin G/biosynthesis
  • Influenza A Virus, H1N1 Subtype/immunology
  • Influenza A Virus, H3N2 Subtype/immunology
  • Influenza Vaccines/immunology
  • Influenza, Human/immunology
  • Middle Aged
  • Polysaccharides/immunology
  • Vaccination
  • Viral Proteins/immunology

ASJC Scopus subject areas

  • Medicine(all)


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