Research Article: Cross-Neutralizing Antibodies to Pandemic 2009 H1N1 and Recent Seasonal H1N1 Influenza A Strains Influenced by a Mutation in Hemagglutinin Subunit 2

Date Published: June 9, 2011

Publisher: Public Library of Science

Author(s): Wei Wang, Christine M. Anderson, Christopher J. De Feo, Min Zhuang, Hong Yang, Russell Vassell, Hang Xie, Zhiping Ye, Dorothy Scott, Carol D. Weiss, Andrew Pekosz.


Pandemic 2009 H1N1 influenza A virus (2009 H1N1) differs from H1N1 strains that circulated in the past 50 years, but resembles the A/New Jersey/1976 H1N1 strain used in the 1976 swine influenza vaccine. We investigated whether sera from persons immunized with the 1976 swine influenza or recent seasonal influenza vaccines, or both, neutralize 2009 H1N1. Using retroviral pseudovirions bearing hemagglutinins on their surface (HA-pseudotypes), we found that 77% of the sera collected in 1976 after immunization with the A/New Jersey/1976 H1N1 swine influenza vaccine neutralized 2009 H1N1. Forty five percent also neutralized A/New Caledonia/20/1999 H1N1, a strain used in seasonal influenza vaccines during the 2000/01–2006/07 seasons. Among adults aged 48–64 who received the swine influenza vaccine in 1976 and recent seasonal influenza vaccines during the 2004/05–2008/09 seasons, 83% had sera that neutralized 2009 H1N1. However, 68% of age-matched subjects who received the same seasonal influenza vaccines, but did not receive the 1976 swine influenza vaccine, also had sera that neutralized 2009 H1N1. Sera from both 1976 and contemporary cohorts frequently had cross-neutralizing antibodies to 2009 H1N1 and A/New Caledonia/20/1999 that mapped to hemagglutinin subunit 2 (HA2). A conservative mutation in HA2 corresponding to a residue in the A/Solomon Islands/3/2006 and A/Brisbane/59/2007 H1N1 strains that circulated in the 2006/07 and 2007/08 influenza seasons, respectively, abrogated this neutralization. These findings highlight a cross-neutralization determinant influenced by a point mutation in HA2 and suggest that HA2 may be evolving under direct or indirect immune pressure.

Partial Text

In June 2009 the World Health Organization declared a new influenza pandemic due to sustained human to human transmission in several geographic regions of the novel swine-origin influenza A H1N1 virus, which was first identified in April by the Centers for Disease Control and Prevention (CDC) of the United States of America [1]. This novel H1N1 virus, referred to as pandemic 2009 H1N1 virus (2009 H1N1), has a hemagglutinin (HA) of classical swine lineage viruses that have circulated in the swine population for decades with little change in HA antigenicity [2]. The 2009 H1N1 HA is antigenically different from those of recent human seasonal influenza H1N1 viruses, but is closely related to A/New Jersey/1976 (NJ/76) influenza virus (Figure 1), a strain used in 1976 to immunize approximately 45 million people in the US during the swine influenza vaccination campaign after a localized outbreak [3]. However, NJ/76 influenza virus did not circulate. Emergence of the novel pandemic 2009 H1N1 virus raised questions about whether immunization with the 1976 swine or recent seasonal influenza vaccines could confer any protection. Several groups have reported that older persons may have substantial cross-immunity to the 2009 H1N1, though the literature is mixed on the degree of cross-immunity induced by prior seasonal influenza vaccines [4]–[9].

The 2009 H1N1 HA diverges considerably from recent seasonal H1N1 HA and is more closely related to the NJ/76 HA (Figure 1), raising doubts about the extent of protection that could be afforded by vaccination with recent seasonal influenza vaccines. Our studies show that sera from the NJ/76 swine influenza vaccine trials and contemporary sera from subjects who received recent seasonal influenza vaccines, regardless of whether they had been immunized with the NJ/76 swine influenza vaccine, frequently have cross-neutralizing activity to the 2009 H1N1. Further, these sera revealed one or more cross-neutralization epitopes that were sensitive to a conservative amino acid change in position 89 in the HA2 subunit, corresponding to a naturally-occurring amino acid variant that emerged in seasonal H1N1 influenza viruses in recent years.