Giuseppe
Emeritus
[Source: PLoS Pathogens, full text: (LINK). Abstract, edited.]
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AID Activity in B Cells Strongly Correlates with Polyclonal Antibody Affinity Maturation in-vivo Following Pandemic 2009-H1N1 Vaccination in Humans
Surender Khurana<SUP>1</SUP><SUP>*</SUP>, Daniela Frasca<SUP>2</SUP>, Bonnie Blomberg<SUP>2</SUP>, Hana Golding<SUP>1</SUP><SUP>*</SUP>
<SUP></SUP>
1 Division of Viral Products, Center for Biologics Evaluation and Research (CBER), Food and Drug Administration (FDA), Bethesda, Maryland, United States of America, 2 Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, Florida, United States of America
Abstract
The role of Activation-Induced Cytidine Deaminase (AID) in somatic hypermutation and polyclonal antibody affinity maturation has not been shown for polyclonal responses in humans. We investigated whether AID induction in human B cells following H1N1pdm09 vaccination correlated with in-vivo antibody affinity maturation against hemagglutinin domains in plasma of young and elderly individuals. AID was measured by qPCR in B cells from individuals of different ages immunized with the H1N1pdm09 influenza vaccine. Polyclonal antibody affinity in human plasma for the HA1 and HA2 domains of the H1N1pdm09 hemagglutinin was measured by antibody-antigen complex dissociation rates using real time kinetics in Surface Plasmon Resonance. Results show an age-related decrease in AID induction in B cells following H1N1pdm09 vaccination. Levels of AID mRNA before vaccination and fold-increase of AID mRNA expression after H1N1pdm09 vaccination directly correlated with increase in polyclonal antibody affinity to the HA1 globular domain (but not to the conserved HA2 stalk). In the younger population, significant affinity maturation to the HA1 globular domain was observed, which associated with initial levels of AID and fold-increase in AID after vaccination. In some older individuals (>65 yr), higher affinity to the HA1 domain was observed before vaccination and H1N1pdm09 vaccination resulted in minimal change in antibody affinity, which correlated with low AID induction in this age group. These findings demonstrate for the first time a strong correlation between AID induction and in-vivo antibody affinity maturation in humans. The ability to generate high affinity antibodies could have significant impact on the elucidation of age-specific antibody responses following vaccination and eventual clinical efficacy and disease outcome.
Author Summary
Antibody affinity maturation is a key aspect of an effective immune response to vaccines, likely to have an impact on clinical outcome following exposure to pathogens. Activation-Induced Cytidine Deaminase (AID) in B cells is a key enzyme involved in antibody class switching and somatic hypermutation, required for antibody affinity maturation. This human study demonstrated for the first time that induction of AID following H1N1pdm09 influenza vaccination directly correlated with in-vivo antibody affinity maturation against the hemagglutinin globular domain (HA1), containing most of the protective targets. Importantly, age differences were found. In younger adults, significant affinity maturation to the HA1 globular domain was observed, which associated with higher initial levels of AID and >2-fold-increase in AID after vaccination. With increased age, a drop in AID activity post-vaccination correlated with lower affinity maturation of the polyclonal antibody responses against the pandemic influenza HA1. However, in a subset of elderly (>65 yr), high affinity antibodies against the HA1 were present prior to vaccination but, in the absence of AID, did not undergo further maturation. Therefore, vaccination of divergent human populations, especially older individuals, should take into consideration their individual AID status and the history of exposure and vaccination against the specific pathogen.
Citation: Khurana S, Frasca D, Blomberg B, Golding H (2012) AID Activity in B Cells Strongly Correlates with Polyclonal Antibody Affinity Maturation in-vivo Following Pandemic 2009-H1N1 Vaccination in Humans. PLoS Pathog 8(9): e1002920. doi:10.1371/journal.ppat.1002920
Editor: Patrick Wilson, University of Chicago, United States of America
Received: April 18, 2012; Accepted: August 7, 2012; Published: September 13, 2012
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
Funding: This work was supported by NIH AG023717 and AG032576 (BB). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
* E-mail: surender.khurana@fda.hhs.gov (SK); hana.golding@fda.hhs.gov (HG)
-Surender Khurana<SUP>1</SUP><SUP>*</SUP>, Daniela Frasca<SUP>2</SUP>, Bonnie Blomberg<SUP>2</SUP>, Hana Golding<SUP>1</SUP><SUP>*</SUP>
<SUP></SUP>
1 Division of Viral Products, Center for Biologics Evaluation and Research (CBER), Food and Drug Administration (FDA), Bethesda, Maryland, United States of America, 2 Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, Florida, United States of America
Abstract
The role of Activation-Induced Cytidine Deaminase (AID) in somatic hypermutation and polyclonal antibody affinity maturation has not been shown for polyclonal responses in humans. We investigated whether AID induction in human B cells following H1N1pdm09 vaccination correlated with in-vivo antibody affinity maturation against hemagglutinin domains in plasma of young and elderly individuals. AID was measured by qPCR in B cells from individuals of different ages immunized with the H1N1pdm09 influenza vaccine. Polyclonal antibody affinity in human plasma for the HA1 and HA2 domains of the H1N1pdm09 hemagglutinin was measured by antibody-antigen complex dissociation rates using real time kinetics in Surface Plasmon Resonance. Results show an age-related decrease in AID induction in B cells following H1N1pdm09 vaccination. Levels of AID mRNA before vaccination and fold-increase of AID mRNA expression after H1N1pdm09 vaccination directly correlated with increase in polyclonal antibody affinity to the HA1 globular domain (but not to the conserved HA2 stalk). In the younger population, significant affinity maturation to the HA1 globular domain was observed, which associated with initial levels of AID and fold-increase in AID after vaccination. In some older individuals (>65 yr), higher affinity to the HA1 domain was observed before vaccination and H1N1pdm09 vaccination resulted in minimal change in antibody affinity, which correlated with low AID induction in this age group. These findings demonstrate for the first time a strong correlation between AID induction and in-vivo antibody affinity maturation in humans. The ability to generate high affinity antibodies could have significant impact on the elucidation of age-specific antibody responses following vaccination and eventual clinical efficacy and disease outcome.
Author Summary
Antibody affinity maturation is a key aspect of an effective immune response to vaccines, likely to have an impact on clinical outcome following exposure to pathogens. Activation-Induced Cytidine Deaminase (AID) in B cells is a key enzyme involved in antibody class switching and somatic hypermutation, required for antibody affinity maturation. This human study demonstrated for the first time that induction of AID following H1N1pdm09 influenza vaccination directly correlated with in-vivo antibody affinity maturation against the hemagglutinin globular domain (HA1), containing most of the protective targets. Importantly, age differences were found. In younger adults, significant affinity maturation to the HA1 globular domain was observed, which associated with higher initial levels of AID and >2-fold-increase in AID after vaccination. With increased age, a drop in AID activity post-vaccination correlated with lower affinity maturation of the polyclonal antibody responses against the pandemic influenza HA1. However, in a subset of elderly (>65 yr), high affinity antibodies against the HA1 were present prior to vaccination but, in the absence of AID, did not undergo further maturation. Therefore, vaccination of divergent human populations, especially older individuals, should take into consideration their individual AID status and the history of exposure and vaccination against the specific pathogen.
Citation: Khurana S, Frasca D, Blomberg B, Golding H (2012) AID Activity in B Cells Strongly Correlates with Polyclonal Antibody Affinity Maturation in-vivo Following Pandemic 2009-H1N1 Vaccination in Humans. PLoS Pathog 8(9): e1002920. doi:10.1371/journal.ppat.1002920
Editor: Patrick Wilson, University of Chicago, United States of America
Received: April 18, 2012; Accepted: August 7, 2012; Published: September 13, 2012
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
Funding: This work was supported by NIH AG023717 and AG032576 (BB). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
* E-mail: surender.khurana@fda.hhs.gov (SK); hana.golding@fda.hhs.gov (HG)
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