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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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Cross-neutralization to NCD/20/99 from NJ/76 vaccination frequently maps to HA2.Bris.HA1-NCD.HA2 and NCD.HA1-Bris.HA2 pseudotypes were used to map the target of cross-neutralizing antibodies in the sera from the NJ/76 vaccine trials with neutralization titers to NCD/20/99, but not to Bris/59/07. The dotted line represents a 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; NCD: NCD/20/99.
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ppat-1002081-g004: Cross-neutralization to NCD/20/99 from NJ/76 vaccination frequently maps to HA2.Bris.HA1-NCD.HA2 and NCD.HA1-Bris.HA2 pseudotypes were used to map the target of cross-neutralizing antibodies in the sera from the NJ/76 vaccine trials with neutralization titers to NCD/20/99, but not to Bris/59/07. The dotted line represents a 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; NCD: NCD/20/99.

Mentions: First we analyzed the sera from the NJ/76 vaccination trials. The sera with neutralization titers <160 to Bris/59/07 HA-pseudotypes were considered negative for neutralization to either HA1 or HA2 of Bris/59/07 HA. Twenty-one out of 65 post NJ/76 vaccination sera without neutralization activity to Bris/59/07, but with neutralization titers >160 and a 4-fold increase over pre-immunization titers to NCD/20/99 (neutralization titers <160 before vaccination), were identified (Table S2) and used for mapping. Chimeric HA involving the NCD/20/99 HA1 and Bris/59/07 HA2 subunits (NCD.HA1-Bris.HA2), as well the Bris/59/07 HA1 and NCD/20/99 HA2 subunits (Bris.HA1-NCD HA2) were constructed and used for making HA-pseudotypes. The infectivity and amount of HA in these chimeric HA-pseudotypes were comparable to the wild-type HA-pseudotypes (Figure S1). The chimeric HA-pseudotypes showed that: HA1 was responsible for most of the NCD/20/99 cross-neutralization in 2 out of 21 sera (e.g. 2S5H and 2S5A); HA2 was responsible for most of the NCD/20/99 cross-neutralization in 9 out of 21 sera (e.g. 2S5G, 2S5F, 2S5B, 2S4H, 2S3D, 2S2E, 2S1A, 1S2B and 1S1B); and both HA1 and HA2 were responsible for much of the NCD/20/99 cross-neutralization in 10 out of 21 sera (e.g. 2S6E, 2S6B, 2S5C, 2S4G, 2S4F, 2S4B, 2S3E, 2S3C, 2S3B and 1S2A) (Figure 4). In many cases, cross-neutralization titers to NCD/20/99 did not simply reflect the sum of the individual neutralization titers to each of the chimeras containing either NCD HA1 or HA2 subunits (e.g. 2S6B, 2S4G, 2S4F, 2S4B, 2S3E, 2S3D and 2S3C), indicating that HA1-HA2 interactions affected neutralization. These data suggested that there may be several targets for cross-neutralization. Nonetheless, the neutralization activity frequently mapped to the HA2 subunit, and in many cases, HA2 appeared to be the major determinant for 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)

Cross-neutralization to NCD/20/99 from NJ/76 vaccination frequently maps to HA2.Bris.HA1-NCD.HA2 and NCD.HA1-Bris.HA2 pseudotypes were used to map the target of cross-neutralizing antibodies in the sera from the NJ/76 vaccine trials with neutralization titers to NCD/20/99, but not to Bris/59/07. The dotted line represents a 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; NCD: NCD/20/99.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3111540&req=5

ppat-1002081-g004: Cross-neutralization to NCD/20/99 from NJ/76 vaccination frequently maps to HA2.Bris.HA1-NCD.HA2 and NCD.HA1-Bris.HA2 pseudotypes were used to map the target of cross-neutralizing antibodies in the sera from the NJ/76 vaccine trials with neutralization titers to NCD/20/99, but not to Bris/59/07. The dotted line represents a 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; NCD: NCD/20/99.
Mentions: First we analyzed the sera from the NJ/76 vaccination trials. The sera with neutralization titers <160 to Bris/59/07 HA-pseudotypes were considered negative for neutralization to either HA1 or HA2 of Bris/59/07 HA. Twenty-one out of 65 post NJ/76 vaccination sera without neutralization activity to Bris/59/07, but with neutralization titers >160 and a 4-fold increase over pre-immunization titers to NCD/20/99 (neutralization titers <160 before vaccination), were identified (Table S2) and used for mapping. Chimeric HA involving the NCD/20/99 HA1 and Bris/59/07 HA2 subunits (NCD.HA1-Bris.HA2), as well the Bris/59/07 HA1 and NCD/20/99 HA2 subunits (Bris.HA1-NCD HA2) were constructed and used for making HA-pseudotypes. The infectivity and amount of HA in these chimeric HA-pseudotypes were comparable to the wild-type HA-pseudotypes (Figure S1). The chimeric HA-pseudotypes showed that: HA1 was responsible for most of the NCD/20/99 cross-neutralization in 2 out of 21 sera (e.g. 2S5H and 2S5A); HA2 was responsible for most of the NCD/20/99 cross-neutralization in 9 out of 21 sera (e.g. 2S5G, 2S5F, 2S5B, 2S4H, 2S3D, 2S2E, 2S1A, 1S2B and 1S1B); and both HA1 and HA2 were responsible for much of the NCD/20/99 cross-neutralization in 10 out of 21 sera (e.g. 2S6E, 2S6B, 2S5C, 2S4G, 2S4F, 2S4B, 2S3E, 2S3C, 2S3B and 1S2A) (Figure 4). In many cases, cross-neutralization titers to NCD/20/99 did not simply reflect the sum of the individual neutralization titers to each of the chimeras containing either NCD HA1 or HA2 subunits (e.g. 2S6B, 2S4G, 2S4F, 2S4B, 2S3E, 2S3D and 2S3C), indicating that HA1-HA2 interactions affected neutralization. These data suggested that there may be several targets for cross-neutralization. Nonetheless, the neutralization activity frequently mapped to the HA2 subunit, and in many cases, HA2 appeared to be the major determinant for 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