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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

Clonal lineage 641 from TIV01.During screening, 15/18 rmAbs (83%) bound one influenza antigen (blue dots), 1/18 (6%) bound two antigens (yellow dot), 2/18 (11%) bound no antigen tested (crossed dots). Antibody 1270 bound rHA H1 SI with high affinity and H1 Bris with weak affinity. Two branches of the tree derived from IgA1-expressing plasma cells. Inferred intermediates (int) of one of these branches were consistent with affinity maturation (arrows pointing to circles on the tree indicate the position produced int rmAbs); int #15 bound with lower affinity to H1 SI than later int #3 or int #5. Branches of the tree near the bottom showed breadth. Int #10 bound only H1 SI; int #9 had higher affinity for H1 SI, bound H1 Bris and H1 Cal with moderate affinity, and weakly bound H3 Wisc. Int #11 bound H1 Cal more weakly and recovered rmAbs 676 and 1261 bound with a similar pattern. Recovered rmAb 2258 had the highest H1 SI affinity in this part of the lineage but lost cross-reactivity, retaining only weak reactivity to H1 Cal. Embedded tables show affinity measurements in nM for each rmAb; NB = no binding observed. H1 SI = H1N1 A/Solomon Islands/03/2006; H1 Bris = H1N1 A/Brisbane/59/2007; H1 Cal = H1N1 A/California/04/2009; H3 Wisc = H3N2 A/Wisconsin/67/2005; H3 Bris = H3N2 A/Brisbane/10/2007; H3 Jobg = H3N2 A/Johannesburg/33/1994.
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pone-0025797-g004: Clonal lineage 641 from TIV01.During screening, 15/18 rmAbs (83%) bound one influenza antigen (blue dots), 1/18 (6%) bound two antigens (yellow dot), 2/18 (11%) bound no antigen tested (crossed dots). Antibody 1270 bound rHA H1 SI with high affinity and H1 Bris with weak affinity. Two branches of the tree derived from IgA1-expressing plasma cells. Inferred intermediates (int) of one of these branches were consistent with affinity maturation (arrows pointing to circles on the tree indicate the position produced int rmAbs); int #15 bound with lower affinity to H1 SI than later int #3 or int #5. Branches of the tree near the bottom showed breadth. Int #10 bound only H1 SI; int #9 had higher affinity for H1 SI, bound H1 Bris and H1 Cal with moderate affinity, and weakly bound H3 Wisc. Int #11 bound H1 Cal more weakly and recovered rmAbs 676 and 1261 bound with a similar pattern. Recovered rmAb 2258 had the highest H1 SI affinity in this part of the lineage but lost cross-reactivity, retaining only weak reactivity to H1 Cal. Embedded tables show affinity measurements in nM for each rmAb; NB = no binding observed. H1 SI = H1N1 A/Solomon Islands/03/2006; H1 Bris = H1N1 A/Brisbane/59/2007; H1 Cal = H1N1 A/California/04/2009; H3 Wisc = H3N2 A/Wisconsin/67/2005; H3 Bris = H3N2 A/Brisbane/10/2007; H3 Jobg = H3N2 A/Johannesburg/33/1994.

Mentions: Clonal lineages from TIV subjects were commonly recovered and largely influenza strain-specific (Table S1 online). Analysis of lineage 641 recovered from TIV01 showed remarkable divergence in rHA reactivity within the clonal lineage (Fig. 4). This lineage is composed of IgG1 and IgA1 members (10/18 and 8/18, respectively), and rmAbs in the upper portion of the lineage reacted primarily with rHA H1 A/Solomon Islands/03/2006 (15/18, 83%). For example, rmAb 1270 displayed high affinity for H1 A/Solomon Islands/03/2006 and much lower affinity for H1 A/Brisbane/59/2007 (Fig. 4). These data were consistent with the neutralization pattern of rmAb 1270 that inhibited H1N1 A/Solomon Islands/03/2006 at 0.02 µg/mL but did not inhibit H3N2 A/Wisconsin/67/2005.


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)

Clonal lineage 641 from TIV01.During screening, 15/18 rmAbs (83%) bound one influenza antigen (blue dots), 1/18 (6%) bound two antigens (yellow dot), 2/18 (11%) bound no antigen tested (crossed dots). Antibody 1270 bound rHA H1 SI with high affinity and H1 Bris with weak affinity. Two branches of the tree derived from IgA1-expressing plasma cells. Inferred intermediates (int) of one of these branches were consistent with affinity maturation (arrows pointing to circles on the tree indicate the position produced int rmAbs); int #15 bound with lower affinity to H1 SI than later int #3 or int #5. Branches of the tree near the bottom showed breadth. Int #10 bound only H1 SI; int #9 had higher affinity for H1 SI, bound H1 Bris and H1 Cal with moderate affinity, and weakly bound H3 Wisc. Int #11 bound H1 Cal more weakly and recovered rmAbs 676 and 1261 bound with a similar pattern. Recovered rmAb 2258 had the highest H1 SI affinity in this part of the lineage but lost cross-reactivity, retaining only weak reactivity to H1 Cal. Embedded tables show affinity measurements in nM for each rmAb; NB = no binding observed. H1 SI = H1N1 A/Solomon Islands/03/2006; H1 Bris = H1N1 A/Brisbane/59/2007; H1 Cal = H1N1 A/California/04/2009; H3 Wisc = H3N2 A/Wisconsin/67/2005; H3 Bris = H3N2 A/Brisbane/10/2007; H3 Jobg = H3N2 A/Johannesburg/33/1994.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3198447&req=5

pone-0025797-g004: Clonal lineage 641 from TIV01.During screening, 15/18 rmAbs (83%) bound one influenza antigen (blue dots), 1/18 (6%) bound two antigens (yellow dot), 2/18 (11%) bound no antigen tested (crossed dots). Antibody 1270 bound rHA H1 SI with high affinity and H1 Bris with weak affinity. Two branches of the tree derived from IgA1-expressing plasma cells. Inferred intermediates (int) of one of these branches were consistent with affinity maturation (arrows pointing to circles on the tree indicate the position produced int rmAbs); int #15 bound with lower affinity to H1 SI than later int #3 or int #5. Branches of the tree near the bottom showed breadth. Int #10 bound only H1 SI; int #9 had higher affinity for H1 SI, bound H1 Bris and H1 Cal with moderate affinity, and weakly bound H3 Wisc. Int #11 bound H1 Cal more weakly and recovered rmAbs 676 and 1261 bound with a similar pattern. Recovered rmAb 2258 had the highest H1 SI affinity in this part of the lineage but lost cross-reactivity, retaining only weak reactivity to H1 Cal. Embedded tables show affinity measurements in nM for each rmAb; NB = no binding observed. H1 SI = H1N1 A/Solomon Islands/03/2006; H1 Bris = H1N1 A/Brisbane/59/2007; H1 Cal = H1N1 A/California/04/2009; H3 Wisc = H3N2 A/Wisconsin/67/2005; H3 Bris = H3N2 A/Brisbane/10/2007; H3 Jobg = H3N2 A/Johannesburg/33/1994.
Mentions: Clonal lineages from TIV subjects were commonly recovered and largely influenza strain-specific (Table S1 online). Analysis of lineage 641 recovered from TIV01 showed remarkable divergence in rHA reactivity within the clonal lineage (Fig. 4). This lineage is composed of IgG1 and IgA1 members (10/18 and 8/18, respectively), and rmAbs in the upper portion of the lineage reacted primarily with rHA H1 A/Solomon Islands/03/2006 (15/18, 83%). For example, rmAb 1270 displayed high affinity for H1 A/Solomon Islands/03/2006 and much lower affinity for H1 A/Brisbane/59/2007 (Fig. 4). These data were consistent with the neutralization pattern of rmAb 1270 that inhibited H1N1 A/Solomon Islands/03/2006 at 0.02 µg/mL but did not inhibit H3N2 A/Wisconsin/67/2005.

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