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H3N2 influenza infection elicits more cross-reactive and less clonally expanded anti-hemagglutinin antibodies than influenza vaccination.

Moody MA, Zhang R, Walter EB, Woods CW, Ginsburg GS, McClain MT, Denny TN, Chen X, Munshaw S, Marshall DJ, Whitesides JF, Drinker MS, Amos JD, Gurley TC, Eudailey JA, Foulger A, DeRosa KR, Parks R, Meyerhoff RR, Yu JS, Kozink DM, Barefoot BE, Ramsburg EA, Khurana S, Golding H, Vandergrift NA, Alam SM, Tomaras GD, Kepler TB, Kelsoe G, Liao HX, Haynes BF - PLoS ONE (2011)

Bottom Line: In contrast, a history of recent seasonal trivalent vaccine in younger adults was not associated with protection.Plasma cell-derived anti-HA antibodies from TIV subjects showed more evidence of clonal expansion compared with antibodies from EI subjects.This broad reactivity was not detected in post-infection plasma suggesting this broadly reactive clonal lineage was not immunodominant in this subject.

View Article: PubMed Central - PubMed

Affiliation: Duke Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, United States of America. moody007@mc.duke.edu

ABSTRACT

Background: During the recent H1N1 influenza pandemic, excess morbidity and mortality was seen in young but not older adults suggesting that prior infection with influenza strains may have protected older subjects. In contrast, a history of recent seasonal trivalent vaccine in younger adults was not associated with protection.

Methods and findings: To study hemagglutinin (HA) antibody responses in influenza immunization and infection, we have studied the day 7 plasma cell repertoires of subjects immunized with seasonal trivalent inactivated influenza vaccine (TIV) and compared them to the plasma cell repertoires of subjects experimentally infected (EI) with influenza H3N2 A/Wisconsin/67/2005. The majority of circulating plasma cells after TIV produced influenza-specific antibodies, while most plasma cells after EI produced antibodies that did not react with influenza HA. While anti-HA antibodies from TIV subjects were primarily reactive with single or few HA strains, anti-HA antibodies from EI subjects were isolated that reacted with multiple HA strains. Plasma cell-derived anti-HA antibodies from TIV subjects showed more evidence of clonal expansion compared with antibodies from EI subjects. From an H3N2-infected subject, we isolated a 4-member clonal lineage of broadly cross-reactive antibodies that bound to multiple HA subtypes and neutralized both H1N1 and H3N2 viruses. This broad reactivity was not detected in post-infection plasma suggesting this broadly reactive clonal lineage was not immunodominant in this subject.

Conclusion: The presence of broadly reactive subdominant antibody responses in some EI subjects suggests that improved vaccine designs that make broadly reactive antibody responses immunodominant could protect against novel influenza strains.

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Related in: MedlinePlus

Characterization of influenza-specific mAbs from TIV or EI subjects.A. Clonal lineages. From TIV subjects, 159/252 (63.1%) of influenza-specific rmAbs were members of 44 clonal lineages (purple wedge); from EI subjects, 6/37 (16.2%) were members of 2 clonal lineages (χ2 = 28.9, p<0.0001). B, Multiple reactivity to influenza antigens. From TIV subjects, 159/252 (63%) of rmAbs were strain-specific (blue wedge); multiply reactive rmAbs were less common [two antigens 79/252 (31.4%) (yellow wedge); three antigens 11/252 (4.4%) (orange wedge); four antigens 2/252 (0.8%) (red wedge); five antigens 1/252 (0.4%) (black wedge)]. From EI subjects, 16/37 (43.2%) were strain-specific (χ2 = 7.74, p = 0.0054); multiply reactive mAbs were more common [two antigens 8/37 (21.6%); three antigens 8/37 (21.6%); four antigens 3/37 (8.1%); five antigens 1/37 (2.7%); six antigens 1/37 (2.7%) (white wedge)]. C. Original antigenic sin rmAbs. From TIV subjects, 5/252 (2%) of influenza-specific rmAbs did not react with strains contained in the administered vaccine but only with previously circulating influenza antigens (striped wedge). From EI subjects, 7/37 (19%) of influenza-specific rmAbs did not react with the infecting strain but only with previously circulating antigens (χ2 = 19.2, p<0.0001).
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pone-0025797-g002: Characterization of influenza-specific mAbs from TIV or EI subjects.A. Clonal lineages. From TIV subjects, 159/252 (63.1%) of influenza-specific rmAbs were members of 44 clonal lineages (purple wedge); from EI subjects, 6/37 (16.2%) were members of 2 clonal lineages (χ2 = 28.9, p<0.0001). B, Multiple reactivity to influenza antigens. From TIV subjects, 159/252 (63%) of rmAbs were strain-specific (blue wedge); multiply reactive rmAbs were less common [two antigens 79/252 (31.4%) (yellow wedge); three antigens 11/252 (4.4%) (orange wedge); four antigens 2/252 (0.8%) (red wedge); five antigens 1/252 (0.4%) (black wedge)]. From EI subjects, 16/37 (43.2%) were strain-specific (χ2 = 7.74, p = 0.0054); multiply reactive mAbs were more common [two antigens 8/37 (21.6%); three antigens 8/37 (21.6%); four antigens 3/37 (8.1%); five antigens 1/37 (2.7%); six antigens 1/37 (2.7%) (white wedge)]. C. Original antigenic sin rmAbs. From TIV subjects, 5/252 (2%) of influenza-specific rmAbs did not react with strains contained in the administered vaccine but only with previously circulating influenza antigens (striped wedge). From EI subjects, 7/37 (19%) of influenza-specific rmAbs did not react with the infecting strain but only with previously circulating antigens (χ2 = 19.2, p<0.0001).

Mentions: Of the 46 clonal lineages identified from TIV subjects, 44 (96%) had at least one rmAb that reacted with influenza antigens; clonal lineages containing rmAbs reactive with influenza antigens were found in all four TIV subjects with identified clonal lineages (Table S1 online). In contrast, of the 12 clonal lineages recovered from EI subjects, only 2 (17%) contained members reactive with rHAs and split-virus vaccine preparations (Table S2 online). Both influenza-reactive lineages were from one subject (EI13) and all rmAbs from these two lineages reacted with rHA. Ninety-one percent (159/175) of rmAbs in TIV clonal lineages were reactive with influenza antigens (Table S1 online) while only 21% (6/28) of clonal members from EI subjects were reactive with influenza antigens (Table S2 online) (χ2 = 76.5, p<0.0001). When viewed as a proportion of all rHA-specific mAbs, antibodies from TIV were more likely to be in a clonal lineage (159/252; 63.1%) compared to mAbs from EI (6/37; 16.2%) (Fig. 2A; Fig. S4 online) (χ2 = 28.9, p<0.0001). Thus, while EI and TIV were associated with a similar degree of plasmacytosis, TIV was associated with more clonal expansion of plasma cells making anti-HA antibodies.


H3N2 influenza infection elicits more cross-reactive and less clonally expanded anti-hemagglutinin antibodies than influenza vaccination.

Moody MA, Zhang R, Walter EB, Woods CW, Ginsburg GS, McClain MT, Denny TN, Chen X, Munshaw S, Marshall DJ, Whitesides JF, Drinker MS, Amos JD, Gurley TC, Eudailey JA, Foulger A, DeRosa KR, Parks R, Meyerhoff RR, Yu JS, Kozink DM, Barefoot BE, Ramsburg EA, Khurana S, Golding H, Vandergrift NA, Alam SM, Tomaras GD, Kepler TB, Kelsoe G, Liao HX, Haynes BF - PLoS ONE (2011)

Characterization of influenza-specific mAbs from TIV or EI subjects.A. Clonal lineages. From TIV subjects, 159/252 (63.1%) of influenza-specific rmAbs were members of 44 clonal lineages (purple wedge); from EI subjects, 6/37 (16.2%) were members of 2 clonal lineages (χ2 = 28.9, p<0.0001). B, Multiple reactivity to influenza antigens. From TIV subjects, 159/252 (63%) of rmAbs were strain-specific (blue wedge); multiply reactive rmAbs were less common [two antigens 79/252 (31.4%) (yellow wedge); three antigens 11/252 (4.4%) (orange wedge); four antigens 2/252 (0.8%) (red wedge); five antigens 1/252 (0.4%) (black wedge)]. From EI subjects, 16/37 (43.2%) were strain-specific (χ2 = 7.74, p = 0.0054); multiply reactive mAbs were more common [two antigens 8/37 (21.6%); three antigens 8/37 (21.6%); four antigens 3/37 (8.1%); five antigens 1/37 (2.7%); six antigens 1/37 (2.7%) (white wedge)]. C. Original antigenic sin rmAbs. From TIV subjects, 5/252 (2%) of influenza-specific rmAbs did not react with strains contained in the administered vaccine but only with previously circulating influenza antigens (striped wedge). From EI subjects, 7/37 (19%) of influenza-specific rmAbs did not react with the infecting strain but only with previously circulating antigens (χ2 = 19.2, p<0.0001).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3198447&req=5

pone-0025797-g002: Characterization of influenza-specific mAbs from TIV or EI subjects.A. Clonal lineages. From TIV subjects, 159/252 (63.1%) of influenza-specific rmAbs were members of 44 clonal lineages (purple wedge); from EI subjects, 6/37 (16.2%) were members of 2 clonal lineages (χ2 = 28.9, p<0.0001). B, Multiple reactivity to influenza antigens. From TIV subjects, 159/252 (63%) of rmAbs were strain-specific (blue wedge); multiply reactive rmAbs were less common [two antigens 79/252 (31.4%) (yellow wedge); three antigens 11/252 (4.4%) (orange wedge); four antigens 2/252 (0.8%) (red wedge); five antigens 1/252 (0.4%) (black wedge)]. From EI subjects, 16/37 (43.2%) were strain-specific (χ2 = 7.74, p = 0.0054); multiply reactive mAbs were more common [two antigens 8/37 (21.6%); three antigens 8/37 (21.6%); four antigens 3/37 (8.1%); five antigens 1/37 (2.7%); six antigens 1/37 (2.7%) (white wedge)]. C. Original antigenic sin rmAbs. From TIV subjects, 5/252 (2%) of influenza-specific rmAbs did not react with strains contained in the administered vaccine but only with previously circulating influenza antigens (striped wedge). From EI subjects, 7/37 (19%) of influenza-specific rmAbs did not react with the infecting strain but only with previously circulating antigens (χ2 = 19.2, p<0.0001).
Mentions: Of the 46 clonal lineages identified from TIV subjects, 44 (96%) had at least one rmAb that reacted with influenza antigens; clonal lineages containing rmAbs reactive with influenza antigens were found in all four TIV subjects with identified clonal lineages (Table S1 online). In contrast, of the 12 clonal lineages recovered from EI subjects, only 2 (17%) contained members reactive with rHAs and split-virus vaccine preparations (Table S2 online). Both influenza-reactive lineages were from one subject (EI13) and all rmAbs from these two lineages reacted with rHA. Ninety-one percent (159/175) of rmAbs in TIV clonal lineages were reactive with influenza antigens (Table S1 online) while only 21% (6/28) of clonal members from EI subjects were reactive with influenza antigens (Table S2 online) (χ2 = 76.5, p<0.0001). When viewed as a proportion of all rHA-specific mAbs, antibodies from TIV were more likely to be in a clonal lineage (159/252; 63.1%) compared to mAbs from EI (6/37; 16.2%) (Fig. 2A; Fig. S4 online) (χ2 = 28.9, p<0.0001). Thus, while EI and TIV were associated with a similar degree of plasmacytosis, TIV was associated with more clonal expansion of plasma cells making anti-HA antibodies.

Bottom Line: In contrast, a history of recent seasonal trivalent vaccine in younger adults was not associated with protection.Plasma cell-derived anti-HA antibodies from TIV subjects showed more evidence of clonal expansion compared with antibodies from EI subjects.This broad reactivity was not detected in post-infection plasma suggesting this broadly reactive clonal lineage was not immunodominant in this subject.

View Article: PubMed Central - PubMed

Affiliation: Duke Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, United States of America. moody007@mc.duke.edu

ABSTRACT

Background: During the recent H1N1 influenza pandemic, excess morbidity and mortality was seen in young but not older adults suggesting that prior infection with influenza strains may have protected older subjects. In contrast, a history of recent seasonal trivalent vaccine in younger adults was not associated with protection.

Methods and findings: To study hemagglutinin (HA) antibody responses in influenza immunization and infection, we have studied the day 7 plasma cell repertoires of subjects immunized with seasonal trivalent inactivated influenza vaccine (TIV) and compared them to the plasma cell repertoires of subjects experimentally infected (EI) with influenza H3N2 A/Wisconsin/67/2005. The majority of circulating plasma cells after TIV produced influenza-specific antibodies, while most plasma cells after EI produced antibodies that did not react with influenza HA. While anti-HA antibodies from TIV subjects were primarily reactive with single or few HA strains, anti-HA antibodies from EI subjects were isolated that reacted with multiple HA strains. Plasma cell-derived anti-HA antibodies from TIV subjects showed more evidence of clonal expansion compared with antibodies from EI subjects. From an H3N2-infected subject, we isolated a 4-member clonal lineage of broadly cross-reactive antibodies that bound to multiple HA subtypes and neutralized both H1N1 and H3N2 viruses. This broad reactivity was not detected in post-infection plasma suggesting this broadly reactive clonal lineage was not immunodominant in this subject.

Conclusion: The presence of broadly reactive subdominant antibody responses in some EI subjects suggests that improved vaccine designs that make broadly reactive antibody responses immunodominant could protect against novel influenza strains.

Show MeSH
Related in: MedlinePlus