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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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Clonal lineage 2569 from EI13.Three of 4 members (75%) derived from IgM-expressing plasma cells, 1/4 (25%) derived from an IgA1 plasma cell. The highest affinity binding for all members was to H3 Jobg; high affinity binding to other H3 rHAs and H1 Bris was also observed. Three members were tested for HAI and neutralization and displayed similar breadth (Table 3). 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; H5 Indo = H5N1 A/Indonesia/05/2005; H5 Viet = H5N1 A/Vietnam/1203/2004.
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pone-0025797-g003: Clonal lineage 2569 from EI13.Three of 4 members (75%) derived from IgM-expressing plasma cells, 1/4 (25%) derived from an IgA1 plasma cell. The highest affinity binding for all members was to H3 Jobg; high affinity binding to other H3 rHAs and H1 Bris was also observed. Three members were tested for HAI and neutralization and displayed similar breadth (Table 3). 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; H5 Indo = H5N1 A/Indonesia/05/2005; H5 Viet = H5N1 A/Vietnam/1203/2004.

Mentions: The antibody response in TIV subjects was largely restricted to the subtypes present in the administered vaccine and for most subjects was strain-specific (Text S1, Figs. S1, S8 online). The strain specificity of the response was most striking in the rmAb-binding pattern against rHAs (Text S1, Figs. S1, S8 online). In EI subjects plasma antibody rose more modestly (Fig. S1 online) and recovered rmAbs were less strain specific (Fig. S8 online). The most broadly cross-reactive anti-HA rmAbs were recovered from subject EI13 (Fig. 3; Fig. S8, Table S11 online); comparison of plasma antibody at time zero and 28 days after infection demonstrated a 13-fold increase in rHA H3 A/Wisconsin/67/2005 binding (Fig. S1 online) but only a 2-fold rise in virus neutralization titer to that strain (Table 1). Thus, the broad neutralizing rmAbs isolated from EI13 (Fig. 3) did not contribute significantly to plasma antibody 28 days following EI.


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 2569 from EI13.Three of 4 members (75%) derived from IgM-expressing plasma cells, 1/4 (25%) derived from an IgA1 plasma cell. The highest affinity binding for all members was to H3 Jobg; high affinity binding to other H3 rHAs and H1 Bris was also observed. Three members were tested for HAI and neutralization and displayed similar breadth (Table 3). 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; H5 Indo = H5N1 A/Indonesia/05/2005; H5 Viet = H5N1 A/Vietnam/1203/2004.
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Related In: Results  -  Collection

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pone-0025797-g003: Clonal lineage 2569 from EI13.Three of 4 members (75%) derived from IgM-expressing plasma cells, 1/4 (25%) derived from an IgA1 plasma cell. The highest affinity binding for all members was to H3 Jobg; high affinity binding to other H3 rHAs and H1 Bris was also observed. Three members were tested for HAI and neutralization and displayed similar breadth (Table 3). 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; H5 Indo = H5N1 A/Indonesia/05/2005; H5 Viet = H5N1 A/Vietnam/1203/2004.
Mentions: The antibody response in TIV subjects was largely restricted to the subtypes present in the administered vaccine and for most subjects was strain-specific (Text S1, Figs. S1, S8 online). The strain specificity of the response was most striking in the rmAb-binding pattern against rHAs (Text S1, Figs. S1, S8 online). In EI subjects plasma antibody rose more modestly (Fig. S1 online) and recovered rmAbs were less strain specific (Fig. S8 online). The most broadly cross-reactive anti-HA rmAbs were recovered from subject EI13 (Fig. 3; Fig. S8, Table S11 online); comparison of plasma antibody at time zero and 28 days after infection demonstrated a 13-fold increase in rHA H3 A/Wisconsin/67/2005 binding (Fig. S1 online) but only a 2-fold rise in virus neutralization titer to that strain (Table 1). Thus, the broad neutralizing rmAbs isolated from EI13 (Fig. 3) did not contribute significantly to plasma antibody 28 days following EI.

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