Induction of broadly cross-reactive antibody responses to the influenza HA stem region following H5N1 vaccination in humans

Ali H. Ellebedy, Florian Krammer, Gui Mei Li, Matthew S. Miller, Christopher Chiu, Jens Wrammert, Cathy Y. Chang, Carl W. Davis, Megan McCausland, Rivka Elbein, Srilatha Edupuganti, Paul Spearman, Sarah F. Andrews, Patrick C. Wilson, Adolfo Garciá-Sastre, Mark J. Mulligan, Aneesh K. Mehta, Peter Palese, Rafi Ahmed

Research output: Contribution to journalArticlepeer-review

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The emergence of pandemic influenza viruses poses a major public health threat. Therefore, there is a need for a vaccine that can induce broadly cross-reactive antibodies that protect against seasonal as well as pandemic influenza strains. Human broadly neutralizing antibodies directed against highly conserved epitopes in the stem region of influenza virus HA have been recently characterized. However, it remains unknown what the baseline levels are of antibodies and memory B cells that are directed against these conserved epitopes. More importantly, it is also not known to what extent anti-HA stem B-cell responses get boosted in humans after seasonal influenza vaccination. In this study, we have addressed these two outstanding questions. Our data show that: (i) antibodies and memory B cells directed against the conserved HA stem region are prevalent in humans, but their levels are much lower than B-cell responses directed to variable epitopes in the HA head; (ii) current seasonal influenza vaccines are efficient in inducing B-cell responses to the variable HA head region but they fail to boost responses to the conserved HA stem region; and (iii) in striking contrast, immunization of humans with the avian influenza virus H5N1 induced broadly cross-reactive HA stem-specific antibodies. Taken together, our findings provide a potential vaccination strategy where heterologous influenza immunization could be used for increasing the levels of broadly neutralizing antibodies and for priming the human population to respond quickly to emerging pandemic influenza threats.

Original languageEnglish
Pages (from-to)13133-13138
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number36
StatePublished - 2014


  • Breadth
  • Immunoglobulin
  • Neutralization
  • Stalk


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