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Cross-neutralizing antibodies to pandemic 2009 H1N1 and recent seasonal H1N1 influenza A strains influenced by a mutation in hemagglutinin subunit 2.

Wang W, Anderson CM, De Feo CJ, Zhuang M, Yang H, Vassell R, Xie H, Ye Z, Scott D, Weiss CD - PLoS Pathog. (2011)

Bottom Line: 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).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.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Immunoregulation, Division of Viral Products, Center for Biologics Evaluation and Research, US Food and Drug Administration, Bethesda, Maryland, United States of America.

ABSTRACT
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.

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HA2 influences cross-neutralization between Mex/4108/09 and recent seasonal H1N1 influenza A strains.(A) Bris.HA1-Mex.HA2 pseudotypes were used to map the target of cross-neutralizing antibodies in the samples with cross-neutralization titers to Mex/4108/09, but not to Bris/59/07, in sera from the contemporary cohort of subjects who received seasonal influenza vaccines. (B) Neutralization to NCD/20/99, but not to Mex/4108/09, was mapped to NCD/20/99 HA1 using NCD.HA1-Mex.HA2 pseudotypes and sera from the contemporary cohort of subjects who received seasonal influenza vaccines. The dotted lines in both panels A and B represent the neutralization titer of 160, which has been proposed as a correlate of seroprotection in microneutralization assays involving replicating influenza virus [4]. Protective titers for neutralization of HA-pseudotypes have not been determined. Data are shown as means +/− SD and reflect two or more independent experiments with each sample run in duplicate. Bris: Bris/59/07; Mex: Mex/4108/09; NCD: NCD/20/99.
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ppat-1002081-g005: HA2 influences cross-neutralization between Mex/4108/09 and recent seasonal H1N1 influenza A strains.(A) Bris.HA1-Mex.HA2 pseudotypes were used to map the target of cross-neutralizing antibodies in the samples with cross-neutralization titers to Mex/4108/09, but not to Bris/59/07, in sera from the contemporary cohort of subjects who received seasonal influenza vaccines. (B) Neutralization to NCD/20/99, but not to Mex/4108/09, was mapped to NCD/20/99 HA1 using NCD.HA1-Mex.HA2 pseudotypes and sera from the contemporary cohort of subjects who received seasonal influenza vaccines. The dotted lines in both panels A and B represent the neutralization titer of 160, which has been proposed as a correlate of seroprotection in microneutralization assays involving replicating influenza virus [4]. Protective titers for neutralization of HA-pseudotypes have not been determined. Data are shown as means +/− SD and reflect two or more independent experiments with each sample run in duplicate. Bris: Bris/59/07; Mex: Mex/4108/09; NCD: NCD/20/99.

Mentions: Next we analyzed the sera from the contemporary cohort. Sera with cross-neutralization titers (>160) to Mex/4108/09, but without neutralization titers (<160) to Bris/59/07 were identified (Table S3) and used for evaluating neutralizing antibodies that may be directed to Mex/4108/09 HA1 and/or HA2 subunits. HA-pseudotypes carrying the chimeric HA consisting of Bris/59/07 HA1 and Mex/4108/09 HA2 (Bris.HA1-Mex.HA2) showed that neutralization titers to Mex/4108/09 HA and Bris.HA1-Mex.HA2 were similar in all comparisons (samples S1, S7, S24, S31, S42, S44, S45, S58 and S59) (Figure 5A), suggesting that cross-neutralization to Mex/4108/09 involves the Mex/4108/09 HA2 subunit. Curiously, the chimeric Mex.HA1-Bris.HA2 HA-pseudotypes did not have high enough infectivity for neutralization studies, despite good HA incorporation and cleavage of HA0 in the HA-pseudotypes (Figure S1). Therefore, we could not directly assess the contributions of the Mex/4108/09 HA1 subunit to cross-neutralization.


Cross-neutralizing antibodies to pandemic 2009 H1N1 and recent seasonal H1N1 influenza A strains influenced by a mutation in hemagglutinin subunit 2.

Wang W, Anderson CM, De Feo CJ, Zhuang M, Yang H, Vassell R, Xie H, Ye Z, Scott D, Weiss CD - PLoS Pathog. (2011)

HA2 influences cross-neutralization between Mex/4108/09 and recent seasonal H1N1 influenza A strains.(A) Bris.HA1-Mex.HA2 pseudotypes were used to map the target of cross-neutralizing antibodies in the samples with cross-neutralization titers to Mex/4108/09, but not to Bris/59/07, in sera from the contemporary cohort of subjects who received seasonal influenza vaccines. (B) Neutralization to NCD/20/99, but not to Mex/4108/09, was mapped to NCD/20/99 HA1 using NCD.HA1-Mex.HA2 pseudotypes and sera from the contemporary cohort of subjects who received seasonal influenza vaccines. The dotted lines in both panels A and B represent the neutralization titer of 160, which has been proposed as a correlate of seroprotection in microneutralization assays involving replicating influenza virus [4]. Protective titers for neutralization of HA-pseudotypes have not been determined. Data are shown as means +/− SD and reflect two or more independent experiments with each sample run in duplicate. Bris: Bris/59/07; Mex: Mex/4108/09; NCD: NCD/20/99.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3111540&req=5

ppat-1002081-g005: HA2 influences cross-neutralization between Mex/4108/09 and recent seasonal H1N1 influenza A strains.(A) Bris.HA1-Mex.HA2 pseudotypes were used to map the target of cross-neutralizing antibodies in the samples with cross-neutralization titers to Mex/4108/09, but not to Bris/59/07, in sera from the contemporary cohort of subjects who received seasonal influenza vaccines. (B) Neutralization to NCD/20/99, but not to Mex/4108/09, was mapped to NCD/20/99 HA1 using NCD.HA1-Mex.HA2 pseudotypes and sera from the contemporary cohort of subjects who received seasonal influenza vaccines. The dotted lines in both panels A and B represent the neutralization titer of 160, which has been proposed as a correlate of seroprotection in microneutralization assays involving replicating influenza virus [4]. Protective titers for neutralization of HA-pseudotypes have not been determined. Data are shown as means +/− SD and reflect two or more independent experiments with each sample run in duplicate. Bris: Bris/59/07; Mex: Mex/4108/09; NCD: NCD/20/99.
Mentions: Next we analyzed the sera from the contemporary cohort. Sera with cross-neutralization titers (>160) to Mex/4108/09, but without neutralization titers (<160) to Bris/59/07 were identified (Table S3) and used for evaluating neutralizing antibodies that may be directed to Mex/4108/09 HA1 and/or HA2 subunits. HA-pseudotypes carrying the chimeric HA consisting of Bris/59/07 HA1 and Mex/4108/09 HA2 (Bris.HA1-Mex.HA2) showed that neutralization titers to Mex/4108/09 HA and Bris.HA1-Mex.HA2 were similar in all comparisons (samples S1, S7, S24, S31, S42, S44, S45, S58 and S59) (Figure 5A), suggesting that cross-neutralization to Mex/4108/09 involves the Mex/4108/09 HA2 subunit. Curiously, the chimeric Mex.HA1-Bris.HA2 HA-pseudotypes did not have high enough infectivity for neutralization studies, despite good HA incorporation and cleavage of HA0 in the HA-pseudotypes (Figure S1). Therefore, we could not directly assess the contributions of the Mex/4108/09 HA1 subunit to cross-neutralization.

Bottom Line: 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).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.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Immunoregulation, Division of Viral Products, Center for Biologics Evaluation and Research, US Food and Drug Administration, Bethesda, Maryland, United States of America.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus