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Article ; Online: Guiding HIV-1 vaccine development with preclinical nonhuman primate research.

Counts, James A / Saunders, Kevin O

2023 Volume 18, Issue 6, Page(s) 315–322

Abstract: Purpose of the review: Nonhuman primates (NHPs) are seen as the closest animal model to humans in terms of anatomy and immune system makeup. Here, we review how preclinical studies in this model system are teaching the field of HIV vaccinology the basic ...

Abstract	Purpose of the review: Nonhuman primates (NHPs) are seen as the closest animal model to humans in terms of anatomy and immune system makeup. Here, we review how preclinical studies in this model system are teaching the field of HIV vaccinology the basic immunology that is needed to induce broadly neutralizing antibodies (bnAbs) with vaccination and elicit protective T cell responses. These lessons are being translated into clinical trials to advance towards protective active vaccination against HIV-1 infection. Recent findings: Preclinical vaccination studies in NHPs have shown that highly engineered HIV-1 immunogens can initiate bnAb precursors providing proof of concept for Phase I clinical trials. Additionally, NHP models of HIV-1 infection are elucidating the pathways for bnAb development while serving as systems to evaluate vaccine protection. Innovative immunization strategies have increased affinity maturation of HIV-1 antibodies in long-lived germinal centers. Preclinical studies in macaques have defined the protective level of neutralizing antibodies and have shown that T cell responses can synergize with antibody-mediated immunity to provide protection in the presence of lower neutralizing antibody titers. Summary: The NHP model provides vaccine regimens and desired antibody and T cell responses that serve as benchmarks for clinical trials, accelerating HIV vaccine design.
MeSH term(s)	Animals ; Humans ; HIV Infections/prevention & control ; HIV-1 ; Broadly Neutralizing Antibodies ; HIV Antibodies ; Antibodies, Neutralizing ; Primates ; Vaccines ; AIDS Vaccines
Chemical Substances	Broadly Neutralizing Antibodies ; HIV Antibodies ; Antibodies, Neutralizing ; Vaccines ; AIDS Vaccines
Language	English
Publishing date	2023-09-11
Publishing country	United States
Document type	Review ; Journal Article
ZDB-ID	2502511-9
ISSN	1746-6318 ; 1746-630X
ISSN (online)	1746-6318
ISSN	1746-630X
DOI	10.1097/COH.0000000000000819
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Article ; Online: Conceptual Approaches to Modulating Antibody Effector Functions and Circulation Half-Life.

Saunders, Kevin O

Frontiers in immunology

2019 Volume 10, Page(s) 1296

Abstract: Antibodies and Fc-fusion antibody-like proteins have become successful biologics developed for cancer treatment, passive immunity against infection, addiction, and autoimmune diseases. In general these biopharmaceuticals can be used for blocking protein: ... ...

Abstract	Antibodies and Fc-fusion antibody-like proteins have become successful biologics developed for cancer treatment, passive immunity against infection, addiction, and autoimmune diseases. In general these biopharmaceuticals can be used for blocking protein:protein interactions, crosslinking host receptors to induce signaling, recruiting effector cells to targets, and fixing complement. With the vast capability of antibodies to affect infectious and genetic diseases much effort has been placed on improving and tailoring antibodies for specific functions. While antibody:antigen engagement is critical for an efficacious antibody biologic, equally as important are the hinge and constant domains of the heavy chain. It is the hinge and constant domains of the antibody that engage host receptors or complement protein to mediate a myriad of effector functions and regulate antibody circulation. Molecular and structural studies have provided insight into how the hinge and constant domains from antibodies across different species, isotypes, subclasses, and alleles are recognized by host cell receptors and complement protein C1q. The molecular details of these interactions have led to manipulation of the sequences and glycosylation of hinge and constant domains to enhance or reduce antibody effector functions and circulating half-life. This review will describe the concepts being applied to optimize the hinge and crystallizable fragment of antibodies, and it will detail how these interactions can be tuned up or down to mediate a biological function that confers a desired disease outcome.
MeSH term(s)	Animals ; Antibodies, Monoclonal/chemistry ; Half-Life ; Humans ; Immunoglobulin Heavy Chains/blood ; Immunoglobulin Heavy Chains/chemistry ; Immunotherapy/methods ; Protein Engineering/methods ; Protein Stability
Chemical Substances	Antibodies, Monoclonal ; Immunoglobulin Heavy Chains
Language	English
Publishing date	2019-06-07
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2019.01296
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Article ; Online: Progress with induction of HIV broadly neutralizing antibodies in the Duke Consortia for HIV/AIDS Vaccine Development.

Haynes, Barton F / Wiehe, Kevin / Alam, S Munir / Weissman, Drew / Saunders, Kevin O

Current opinion in HIV and AIDS

2023 Volume 18, Issue 6, Page(s) 300–308

Abstract: Purpose of review: Design of an HIV vaccine that can induce broadly neutralizing antibodies (bnAbs) is a major goal. However, HIV bnAbs are not readily made by the immune system. Rather HIV bnAbs are disfavored by a number of virus and host factors. The ...

Abstract	Purpose of review: Design of an HIV vaccine that can induce broadly neutralizing antibodies (bnAbs) is a major goal. However, HIV bnAbs are not readily made by the immune system. Rather HIV bnAbs are disfavored by a number of virus and host factors. The purpose of the review is to discuss recent progress made in the design and use of immunogens capable of inducing HIV bnAbs in the Duke Consortia for HIV/AIDS Vaccine Development. Recent findings: New immunogens capable of binding with high affinity to unmutated common ancestors (UCAs) of bnAb B cell lineages have been designed and strategies for stabilization of HIV Env in its prefusion state are being developed. Success is starting to be translated from preclinical studies of UCA-targeting immunogens in animals, to success of initiating bnAb lineages in humans. Summary: Recent progress has been made in both immunogen design and in achieving bnAb B cell lineage induction in animal models and now in human clinical trials. With continued progress, a practical HIV/AIDS vaccine may be possible. However, host constraints on full bnAb maturation remain as potential roadblocks for full maturation of some types of bnAbs.
Language	English
Publishing date	2023-09-25
Publishing country	United States
Document type	Journal Article
ZDB-ID	2502511-9
ISSN	1746-6318 ; 1746-630X
ISSN (online)	1746-6318
ISSN	1746-630X
DOI	10.1097/COH.0000000000000820
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Article ; Online: Antibody responses to the HIV-1 envelope high mannose patch.

Daniels, Christine N / Saunders, Kevin O

Advances in immunology

2019 Volume 143, Page(s) 11–73

Abstract: Neutralizing antibodies against human immunodeficiency virus subtype 1 (HIV-1) bind to its envelope glycoprotein (Env). Half of the molecular mass of Env is carbohydrate making it one of the most heavily glycosylated proteins known in nature. HIV-1 Env ... ...

Abstract	Neutralizing antibodies against human immunodeficiency virus subtype 1 (HIV-1) bind to its envelope glycoprotein (Env). Half of the molecular mass of Env is carbohydrate making it one of the most heavily glycosylated proteins known in nature. HIV-1 Env glycans are derived from the host and present a formidable challenge for host anti-glycan antibody induction. Anti-glycan antibody induction is challenging because anti-HIV-1 glycan antibodies should recognize Env antigen while not acquiring autoreactivity. Thus, the glycan network on HIV-1 Env is referred to as the glycan shield. Despite the challenges presented by immune recognition of host-derived glycans, neutralizing antibodies capable of binding the glycans on HIV-1 Env can be generated by the host immune system in the setting of HIV-1 infection. In particular, a cluster of high mannose glycans, including an N-linked glycan at position 332, form the high mannose patch and are targeted by a variety of broadly neutralizing antibodies. These high mannose patch-directed HIV-1 antibodies can be categorized into distinct categories based on their antibody paratope structure, neutralization activity, and glycan and peptide reactivity. Below we will compare and contrast each of these classes of HIV-1 glycan-dependent antibodies and describe vaccine design efforts to elicit each of these antibody types.
MeSH term(s)	Animals ; Antibodies, Monoclonal/chemistry ; Antibodies, Monoclonal/metabolism ; Antibodies, Monoclonal/therapeutic use ; Antibodies, Neutralizing/chemistry ; Antibodies, Neutralizing/genetics ; Antibodies, Neutralizing/metabolism ; Antibodies, Neutralizing/therapeutic use ; Antibody Formation ; Broadly Neutralizing Antibodies/chemistry ; Broadly Neutralizing Antibodies/metabolism ; Broadly Neutralizing Antibodies/therapeutic use ; Epitopes/metabolism ; Glycosylation ; HIV Antibodies/chemistry ; HIV Antibodies/metabolism ; HIV Antibodies/therapeutic use ; HIV Envelope Protein gp120/immunology ; HIV Infections/immunology ; HIV Infections/metabolism ; HIV-1/immunology ; Humans ; Immunogenicity, Vaccine ; Mannose/immunology ; Peptide Fragments/immunology ; Polysaccharides/chemistry ; Polysaccharides/immunology
Chemical Substances	2G12 monoclonal antibody ; Antibodies, Monoclonal ; Antibodies, Neutralizing ; Broadly Neutralizing Antibodies ; Epitopes ; HIV Antibodies ; HIV Envelope Protein gp120 ; HIV envelope protein gp120 (305-321) ; Peptide Fragments ; Polysaccharides ; Mannose (PHA4727WTP)
Language	English
Publishing date	2019-09-11
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	80226-8
ISSN	1557-8445 ; 0065-2776
ISSN (online)	1557-8445
ISSN	0065-2776
DOI	10.1016/bs.ai.2019.08.002
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Article ; Online: Strategies for induction of HIV-1 envelope-reactive broadly neutralizing antibodies.

Williams, Wilton B / Wiehe, Kevin / Saunders, Kevin O / Haynes, Barton F

Journal of the International AIDS Society

2021 Volume 24 Suppl 7, Page(s) e25831

Abstract: Introduction: A primary focus of HIV-1 vaccine development is the activation of B cell receptors for naïve or precursor broadly neutralizing antibodies (bnAbs), followed by expansion and maturation of bnAb B cell lineage intermediates leading to highly ... ...

Abstract	Introduction: A primary focus of HIV-1 vaccine development is the activation of B cell receptors for naïve or precursor broadly neutralizing antibodies (bnAbs), followed by expansion and maturation of bnAb B cell lineage intermediates leading to highly affinity-matured bnAbs. HIV-1 envelope (Env) encodes epitopes for bnAbs of different specificities. Design of immunogens to induce bnAb precursors of different specificities and mature them into bnAb status is a goal for HIV-1 vaccine development. We review vaccine strategies for bnAb lineages development and highlight the immunological barriers that these strategies must overcome to generate bnAbs. Methods: We provide perspectives based on published research articles and reviews. Discussion: The recent Antibody Mediated Protection (AMP) trial that tested the protective efficacy of one HIV-1 Env bnAb specificity demonstrated that relatively high levels of long-lasting serum titers of multiple specificities of bnAbs will be required for protection from HIV-1 transmission. Current vaccine efforts for induction of bnAb lineages are focused on immunogens designed to expand naïve HIV-1 bnAb precursor B cells following the recent success of vaccine-induction of bnAb precursor B cells in macaques and humans. BnAb precursor B cells serve as templates for priming-immunogen design. However, design of boosting immunogens for bnAb maturation requires knowledge of the optimal immunogen design and immunological environment for bnAb B cell lineage affinity maturation. BnAb lineages acquire rare genetic changes as mutations during B cell maturation. Moreover, the immunological environment that supports bnAb development during HIV-1 infection is perturbed with an altered B cell repertoire and dysfunctional immunoregulatory controls, suggesting that in normal settings, bnAb development will be disfavoured. Thus, strategies for vaccine induction of bnAbs must circumvent immunological barriers for bnAb development that normally constrain bnAb B cell affinity maturation. Conclusions: A fully protective HIV-1 vaccine needs to induce durable high titers of bnAbs that can be generated by a sequential set of Env immunogens for expansion and maturation of bnAb B cell lineages in a permitted immunological environment. Moreover, multiple specificities of bnAbs will be required to be sufficiently broad to prevent the escape of HIV-1 strains during transmission.
MeSH term(s)	AIDS Vaccines ; Antibodies, Neutralizing ; Broadly Neutralizing Antibodies ; HIV Antibodies ; HIV Infections/prevention & control ; HIV-1 ; Humans ; env Gene Products, Human Immunodeficiency Virus/immunology
Chemical Substances	AIDS Vaccines ; Antibodies, Neutralizing ; Broadly Neutralizing Antibodies ; HIV Antibodies ; env Gene Products, Human Immunodeficiency Virus
Language	English
Publishing date	2021-11-22
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2467110-1
ISSN	1758-2652 ; 1758-2652
ISSN (online)	1758-2652
ISSN	1758-2652
DOI	10.1002/jia2.25831
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Article ; Online: Microsecond dynamics control the HIV-1 Envelope conformation.

Bennett, Ashley L / Edwards, Robert / Kosheleva, Irina / Saunders, Carrie / Bililign, Yishak / Williams, Ashliegh / Bubphamala, Pimthada / Manosouri, Katayoun / Anasti, Kara / Saunders, Kevin O / Alam, S Munir / Haynes, Barton F / Acharya, Priyamvada / Henderson, Rory

Science advances

2024 Volume 10, Issue 5, Page(s) eadj0396

Abstract: The HIV-1 Envelope (Env) glycoprotein facilitates host cell fusion through a complex series of receptor-induced structural changes. Although remarkable progress has been made in understanding the structures of various Env conformations, microsecond ... ...

Abstract	The HIV-1 Envelope (Env) glycoprotein facilitates host cell fusion through a complex series of receptor-induced structural changes. Although remarkable progress has been made in understanding the structures of various Env conformations, microsecond timescale dynamics have not been studied experimentally. Here, we used time-resolved, temperature-jump small-angle x-ray scattering to monitor structural rearrangements in an HIV-1 Env SOSIP ectodomain construct with microsecond precision. In two distinct Env variants, we detected a transition that correlated with known Env structure rearrangements with a time constant in the hundreds of microseconds range. A previously unknown structural transition was also observed, which occurred with a time constant below 10 μs, and involved an order-to-disorder transition in the trimer apex. Using this information, we engineered an Env SOSIP construct that locks the trimer in the prefusion closed state by connecting adjacent protomers via disulfides. Our findings show that the microsecond timescale structural dynamics play an essential role in controlling the Env conformation with impacts on vaccine design.
MeSH term(s)	env Gene Products, Human Immunodeficiency Virus/chemistry ; HIV-1 ; HIV Antibodies ; Molecular Conformation ; Protein Multimerization ; Protein Conformation
Chemical Substances	env Gene Products, Human Immunodeficiency Virus ; HIV Antibodies
Language	English
Publishing date	2024-02-02
Publishing country	United States
Document type	Journal Article
ZDB-ID	2810933-8
ISSN	2375-2548 ; 2375-2548
ISSN (online)	2375-2548
ISSN	2375-2548
DOI	10.1126/sciadv.adj0396
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Article ; Online: Value in Scoliosis Surgery: Coordinated Surgical and Anesthetic Techniques Avoid Blood Transfusion without Fibrinolytic Medications or Red Blood Cell Salvage.

Stanton, Robert P / Grauer, Jordan / Le, Robert V / Reutebuch, Kirsten / Saunders, Kevin J / Kiebzak, Gary M

Spine

2021 Volume 46, Issue 17, Page(s) 1160–1164

Abstract: Study design: Retrospective chart review.: Objective: The aim of this study was to document the impact of coordinated surgical and anesthetic techniques on estimated blood loss (EBL) and subsequent need for transfusion.: Summary of background data!# ...

Abstract	Study design: Retrospective chart review. Objective: The aim of this study was to document the impact of coordinated surgical and anesthetic techniques on estimated blood loss (EBL) and subsequent need for transfusion. Summary of background data: Scoliosis surgery is typically associated with large quantities of blood loss, and consequently blood transfusion may be necessary. Many strategies have been employed to minimize blood loss, including blood collection with reinfusion ("cell-saver") and the use of antifibrinolytic drugs. We reviewed our experience with methods to minimize blood loss to show that transfusion should be a rare event. Methods: One hundred and thirty consecutive cases of spine fusion for adolescent idiopathic scoliosis utilizing pedicle screw fixation were reviewed from March 2013 to October 2019. The senior author was the primary surgeon for all cases. Data were collected from the electronic medical record, including age, sex, weight, number of instrumented levels, EBL, total fluids administered during surgery, pre- and postoperative hemoglobin, and procedure duration. Results: The average EBL was 232 ± 152 mL (range 37-740 mL). The average preoperative hemoglobin was 13.4 ± 1.2 g/dL and the average postoperative hemoglobin (last measured before discharge) was 9.0 ± 1.2 g/dL. One patient received a transfusion of 270 mL homologous blood. Blood salvage and reinfusion ("cell-saver") was not used. No patient was managed with antifibrinolytic drugs. Conclusion: Minimizing blood loss using a combination of surgical and anesthesia techniques can effectively eliminate the need for blood transfusion. The elimination of costly adjuncts increases the value of a complex orthopedic procedure.Level of Evidence: 5.
MeSH term(s)	Adolescent ; Anesthetics ; Blood Loss, Surgical/prevention & control ; Blood Transfusion ; Erythrocytes ; Humans ; Retrospective Studies ; Scoliosis/surgery ; Spinal Fusion
Chemical Substances	Anesthetics
Language	English
Publishing date	2021-03-12
Publishing country	United States
Document type	Journal Article
ZDB-ID	752024-4
ISSN	1528-1159 ; 0362-2436
ISSN (online)	1528-1159
ISSN	0362-2436
DOI	10.1097/BRS.0000000000004026
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Article ; Online: SARS-CoV-2 Neutralizing Antibodies for COVID-19 Prevention and Treatment.

Li, Dapeng / Sempowski, Gregory D / Saunders, Kevin O / Acharya, Priyamvada / Haynes, Barton F

Annual review of medicine

2021 Volume 73, Page(s) 1–16

Abstract: Prophylactic and therapeutic drugs are urgently needed to combat coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Over the past year, SARS-CoV-2 neutralizing antibodies have been developed for ... ...

Abstract	Prophylactic and therapeutic drugs are urgently needed to combat coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Over the past year, SARS-CoV-2 neutralizing antibodies have been developed for preventive or therapeutic uses. While neutralizing antibodies target the spike protein, their neutralization potency and breadth vary according to recognition epitopes. Several potent SARS-CoV-2 antibodies have shown degrees of success in preclinical or clinical trials, and the US Food and Drug Administration has issued emergency use authorization for two neutralizing antibody cocktails.Nevertheless, antibody therapy for SARS-CoV-2 still faces potential challenges, including emerging viral variants of concern that have antibody-escape mutations and the potential for antibody-mediated enhancement of infection or inflammation. This review summarizes representative SARS-CoV-2 neutralizing antibodies that have been reported and discusses prospects and challenges for the development of the next generation of COVID-19 preventive or therapeutic antibodies.
MeSH term(s)	Antibodies, Monoclonal/therapeutic use ; Antibodies, Neutralizing ; COVID-19 ; Humans ; SARS-CoV-2 ; Spike Glycoprotein, Coronavirus
Chemical Substances	Antibodies, Monoclonal ; Antibodies, Neutralizing ; Spike Glycoprotein, Coronavirus
Language	English
Publishing date	2021-08-24
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	207930-6
ISSN	1545-326X ; 0066-4219
ISSN (online)	1545-326X
ISSN	0066-4219
DOI	10.1146/annurev-med-042420-113838
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Article: Pandemic Preparedness: Developing Vaccines and Therapeutic Antibodies For COVID-19

Sempowski, Gregory D / Saunders, Kevin O / Acharya, Priyamvada / Wiehe, Kevin J / Haynes, Barton F

Cell. 2020 June 25, v. 181, no. 7

2020

Abstract: The SARS-CoV-2 pandemic that causes COVID-19 respiratory syndrome has caused global public health and economic crises, necessitating rapid development of vaccines and therapeutic countermeasures. The world-wide response to the COVID-19 pandemic has been ... ...

Abstract	The SARS-CoV-2 pandemic that causes COVID-19 respiratory syndrome has caused global public health and economic crises, necessitating rapid development of vaccines and therapeutic countermeasures. The world-wide response to the COVID-19 pandemic has been unprecedented with government, academic, and private partnerships working together to rapidly develop vaccine and antibody countermeasures. Many of the technologies being used are derived from prior government-academic partnerships for response to other emerging infections.
Keywords	COVID-19 infection ; Severe acute respiratory syndrome coronavirus 2 ; antibodies ; economic crises ; emerging diseases ; pandemic ; public health ; therapeutics ; vaccine development
Language	English
Dates of publication	2020-0625
Size	p. 1458-1463.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	187009-9
ISSN	1097-4172 ; 0092-8674
ISSN (online)	1097-4172
ISSN	0092-8674
DOI	10.1016/j.cell.2020.05.041
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Article ; Online: Structure-Based Stabilization of SOSIP Env Enhances Recombinant Ectodomain Durability and Yield.

Wrapp, Daniel / Mu, Zekun / Thakur, Bhishem / Janowska, Katarzyna / Ajayi, Oluwatobi / Barr, Maggie / Parks, Robert / Mansouri, Katayoun / Edwards, Robert J / Hahn, Beatrice H / Acharya, Priyamvada / Saunders, Kevin O / Haynes, Barton F

Journal of virology

2023 Volume 97, Issue 1, Page(s) e0167322

Abstract: The envelope glycoprotein (Env) is the main focus of human immunodeficiency virus type 1 (HIV-1) vaccine development due to its critical role in viral entry. Despite advances in protein engineering, many Env proteins remain recalcitrant to recombinant ... ...

Abstract	The envelope glycoprotein (Env) is the main focus of human immunodeficiency virus type 1 (HIV-1) vaccine development due to its critical role in viral entry. Despite advances in protein engineering, many Env proteins remain recalcitrant to recombinant expression due to their inherent metastability, making biochemical and immunological experiments impractical or impossible. Here, we report a novel proline stabilization strategy to facilitate the production of prefusion Env trimers. This approach, termed "2P," works synergistically with previously described SOSIP mutations and dramatically increases the yield of recombinantly expressed Env ectodomains without altering the antigenic or conformational properties of near-native Env. We determined that the 2P mutations function by enhancing the durability of the prefusion conformation and that this stabilization strategy is broadly applicable to evolutionarily and antigenically diverse Env constructs. These findings provide a new Env stabilization platform to facilitate biochemical research and expand the number of Env variants that can be developed as future HIV-1 vaccine candidates.
MeSH term(s)	Humans ; env Gene Products, Human Immunodeficiency Virus/genetics ; Glycoproteins/genetics ; HIV Infections ; Molecular Conformation ; Protein Engineering ; Protein Multimerization ; Recombinant Proteins/genetics ; HIV-1/genetics
Chemical Substances	env Gene Products, Human Immunodeficiency Virus ; Glycoproteins ; Recombinant Proteins
Language	English
Publishing date	2023-01-12
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/jvi.01673-22
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