Michael Wu

Bioc 201
Literature Review Paper 1
10/21/2014
Discussion Group 3: Georgette Mills
Word Count: 556

Journal: Proceedings of the National Academy of Sciences of the United

States of America (PNAS)
Article: Potential antigenic explanation for atypical H1N1
infections among middle-aged adults during the 20132014
influenza season
Susanne L. Linderman, Benjamin S. Chambers, Seth J. Zost, Kaela Parkhouse, Yang Lia, Christin
Herrmann, Ali H. Ellebedy, Donald M. Carter, Sarah F. Andrews, Nai-Ying Zheng, Min Huang, Yunping
Huang, Donna Strauss, Beth H. Shaz, Richard L. Hodinka, Gustavo Reyes-Tern, Ted M. Ross, Patrick C.
Wilson, Rafi Ahmed, Jesse D. Bloom, and Scott E. Hensley
Edited by Peter Palese, Icahn School of Medicine at Mount Sinai, New York, NY, and approved
September 30, 2014 (received for review May 16, 2014). E-published before published in print. No
volume number available. 6 pages.

The authors intended to discover the reason for the unusually high levels of H1N1 influenza
infections among middle-aged adults in the 2013-2014 influenza season, caused by the pH1N1 virus that
first caused a pandemic in 2009. Usually, children and elderly are affected most due to their weaker
immune systems, but this time they fared better than the middle-aged adults. The team designed
experiments to figure out whether there were mutations on the new pH1N1 (pandemic H1N1) virus that
caused this, and how to use this information towards prevention.
After analysis of a series of blood serums through hemagglutinin-inhibition (HAI) assays, it was
determined that the recent pH1N1 strain possess a mutation on a hemagglutinin (HA) site, called the
K166Q HA mutation, that prevents antibodies from binding to the HA glycoprotein. Also, the K166
epitope is shielded by a glycosylation site (glycan shield) present in sH1N1 (seasonal H1N1) viruses
circulating after 1985. This explains why younger people were less affected. Before 1985, many of the
currently middle-aged adults had been exposed to sH1N1 without this glycan shield, so the antibodies
produced targeted the K166 HA glycoprotein. Thus, when the new strain appeared with K166 HA
mutation, the previous antibodies became a lot less functional, leading to a rise in infection rates among
middle-aged adults. Since the sH1N1 virus exposed to the younger generation likely had a glycan shield
covering K166, the antibodies targeted a different HA site to be effective; their Abs were not affected by
the mutated protein site and could function. The elderly people may have antibodies that were passed
down from the 1918 flu pandemic, which was similar to the new pH1N1.
The authors also discovered that a vaccination made with the current pH1N1 strain elicits K166
HA-specific antibodies. This finding suggested that K166 HA-specific Ab could be less efficient at
preventing disease (at least in a mouse model) following infection with a pH1N1 virus possessing K166Q
HA mutation. Thus the current vaccine from 2009 would elicit HA-specific Ab that would not be
functional against a mutated K166 pH1N1.

Lastly, the researchers wondered whether K166 HA-specific immunity could be recreated in
ferrets for surveillance. They infected various ferrets with strains of sH1N1 from different regions and
years (including USSR/1977, California/2009, Chile/1983, Singapore/1986), and found that 3/8 of the
ferrets infected with the Chile/1983 and California/2009 mounted enough K166 HA-specific Abs to be
detectable in HAI assays. The other combinations did not elicit this HA-specific Ab because, they
conjectured, that the epitope was glycan-shielded in one of them, and that in the other, there was variation
at a residue near the targeted residue 166.
It was concluded that recent pH1N1 viruses have acquired a significant antigenic mutation that
prevents binding of antibodies elicited in a large number of middle-aged adult humans. It attempts to
convince the scientific community that
1) The H1N1 vaccine needs to be updated to account for the K166Q HA mutation. However, the paper
acknowledges that even doing this may not stop the original antigenic sin in middle-aged humans
from acting up and preventing binding of antibodies.
2) The traditional practice of obtaining anti-sera for vaccines (from previously-infected ferrets who have
been sequentially infected or only infected once) may need to be revamped, as it does not accurately
reflect the immunity of humans who have had multiple exposure to sH1N1 or pH1N1.

Related References from PubMed

1. The hemagglutinin of the influenza A(H1N1)pdm09 is mutating towards stability. Casteln-Vega
JA, Magaa-Hernndez A, Jimnez-Alberto A, Ribas-Aparicio RM. Adv Appl Bioinform Chem.
2014 Oct 3;7:37-44. doi: 10.2147/AABC.S68934. eCollection 2014.
2. Minor changes in the hemagglutinin of influenza A(H1N1)2009 virus alter its antigenic
properties. Strengell M, Ikonen N, Ziegler T, Julkunen I. PLoS One. 2011;6(10):e25848. doi:
10.1371/journal.pone.0025848. Epub 2011 Oct 11. PMID: 22022458 [PubMed - indexed for
MEDLINE] Free PMC Article.