Slow Delivery Immunization Enhances HIV Neutralizing Antibody and Germinal Center Responses via Modulation of Immunodominance

Cirelli, Kimberly M.; Carnathan, Diane G.; Nogal, Bartek; Martin, Jacob T.; Rodriguez, Oscar L.; Upadhyay, Amit A.; Enemuo, Chiamaka A.; Gebru, Etse H.; Choe, Yury; Viviano, Federico; Nakao, Catherine; Pauthner, Matthias G.; Reiss, Samantha; Cottrell, Christopher A.; Smith, Melissa L.; Bastidas, Raiza; Gibson, William; Wolabaugh, Amber N.; Melo, Mariane B.; Cossette, Benjamin; Kumar, Venkatesh; Patel, Nirav B.; Tokatlian, Talar; Menis, Sergey; Kulp, Daniel W.; Burton, Dennis R.; Murrell, Ben; Schief, William R.; Bosinger, Steven E.; Ward, Andrew B.; Watson, Corey T.; Silvestri, Guido; Irvine, Darrell J.; Crotty, Shane

doi:10.1016/j.cell.2019.04.012

Cited by 433HIV Research and TreatmentSARS-CoV-2 and COVID-19 ResearchMonoclonal and Polyclonal Antibodies Research

Slow Delivery Immunization Enhances HIV Neutralizing Antibody and Germinal Center Responses via Modulation of Immunodominance

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Cirelli, Kimberly M., Carnathan, Diane G., Nogal, Bartek, Martin, Jacob T., Rodriguez, Oscar L., Upadhyay, Amit A., Enemuo, Chiamaka A., Gebru, Etse H. +26 more·2019·Cell

DOI 10.1016/j.cell.2019.04.012PMC PMC6619430

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Abstract

Conventional immunization strategies will likely be insufficient for the development of a broadly neutralizing antibody (bnAb) vaccine for HIV or other difficult pathogens because of the immunological hurdles posed, including B cell immunodominance and germinal center (GC) quantity and quality. We found that two independent methods of slow delivery immunization of rhesus monkeys (RMs) resulted in more robust T follicular helper (T FH) cell responses and GC B cells with improved Env-binding, tracked by longitudinal fine needle aspirates. Improved GCs correlated with the development of >20-fold higher titers of autologous nAbs. Using a new RM genomic immunoglobulin locus reference, we identified differential IgV gene use between immunization modalities. Ab mapping demonstrated targeting of immunodominant non-neutralizing epitopes by conventional bolus-immunized animals, whereas slow delivery-immunized animals targeted a more diverse set of epitopes. Thus, alternative immunization strategies can enhance nAb development by altering GCs and modulating the immunodominance of non-neutralizing epitopes.

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Germinal centre responses induced by more robust adjuvants such as sheep red blood cells, complete Freund's adjuvant or saponin-based adjuvants tend to peak at 2-4 weeks after vaccination and can persist at low frequencies for several months.
“Germinal centre responses induced by immunization with more robust adjuvants such as sheep red blood cells, complete Freund’s adjuvant or saponin-based adjuvants tend to peak slightly later, at 2–4 weeks after vaccination, and can persist at low frequencies for several months27–33.”
From SARS-CoV-2 mRNA vaccines induce persistent human germinal centre responses (2021) · cites this paper as [33]

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Authors: Cirelli, K. M., Carnathan, D. G., Nogal, B., Martin, J. T., Rodriguez, O. L., Upadhyay, A. A., Enemuo, C. A., Gebru, E. H., Choe, Y., Viviano, F., Nakao, C., Pauthner, M. G., Reiss, S., Cottrell, C. A., Smith, M. L., Bastidas, R., Gibson, W., Wolabaugh, A. N., Melo, M. B., Cossette, B., Kumar, V., Patel, N. B., Tokatlian, T., Menis, S., Kulp, D. W., Burton, D. R., Murrell, B., Schief, W. R., Bosinger, S. E., Ward, A. B., Watson, C. T., Silvestri, G., Irvine, D. J., & Crotty, S.
Affiliations: Scripps Research Institute (US)
Icahn School of Medicine at Mount Sinai (US)
Emory University (US)
La Jolla Institute for Immunology (US)
University of Louisville (US)
Koch Institute for Integrative Cancer Research At MIT (US)
University of California San Diego (US)
Emory National Primate Research Center (US)
The Wistar Institute (US)
Karolinska Institutet (SE)
Corresponding author: Crotty, Shane
ORCID: Cirelli, Kimberly M.
Carnathan, Diane G.
Nogal, Bartek
Martin, Jacob T.
Rodriguez, Oscar L.
Upadhyay, Amit A.
Nakao, Catherine
Pauthner, Matthias G.
Reiss, Samantha
Cottrell, Christopher A.
Smith, Melissa L.
Gibson, William
Melo, Mariane B.
Patel, Nirav B.
Tokatlian, Talar
Menis, Sergey
Kulp, Daniel W.
Burton, Dennis R.
Murrell, Ben
Schief, William R.
Bosinger, Steven E.
Ward, Andrew B.
Watson, Corey T.
Silvestri, Guido
Irvine, Darrell J.
Crotty, Shane
Venue: Cell
Publisher: Elsevier BV
Published: 2019-05
Volume: 177
Issue: 5
Pages: 1153-1171.e28
ISSN: 0092-8674 (ISSN-L)
DOI: 10.1016/j.cell.2019.04.012
PMC: PMC6619430
OpenAlex: W2894112953
Cited by: 433
References: 102
Citations by year: 2026: 54 · 2025: 57 · 2024: 58 · 2023: 56 · 2022: 65 · 2021: 70 · 2020: 50 · 2019: 22 · 2017: 1
FWCI: 29.02
Type: journal article
Language: en
Update notices: erratum (2020-01-09)
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 381 d)
Locations: Cell (publishedVersion)
bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-nd)
Funders: Ragon Institute of MGH, MIT and Harvard
Howard Hughes Medical Institute
National Institutes of Health (AI124436, AI136621, AI125068, RR00165/OD011132, Al100663, F31Al131873)
Topics: Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
Keywords: HIV neutralizing antibodies, germinal center reaction, immunodominance, HIV Env, vaccination strategies
MeSH terms: Animals, B-Lymphocytes, Female, T-Lymphocytes, Helper-Inducer, Immunization, Passive, Macaca mulatta, Male, HIV Antibodies, HIV-1, Germinal Center, env Gene Products, Human Immunodeficiency Virus, Antibodies, Neutralizing

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Slow Delivery Immunization Enhances HIV Neutralizing Antibody and Germinal Center Responses via Modulation of Immunodominance

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