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Article ; Online: Immunogenicity and efficacy of DNA/MVA HIV vaccines in rhesus macaque models.

Chea, Lynette Siv / Amara, Rama Rao

2017 Volume 16, Issue 10, Page(s) 973–985

Abstract: Introduction: Despite 30 years of research on HIV, a vaccine to prevent infection and limit disease progression remains elusive. The RV144 trial showed moderate, but significant protection in humans and highlighted the contribution of antibody responses ...

Abstract	Introduction: Despite 30 years of research on HIV, a vaccine to prevent infection and limit disease progression remains elusive. The RV144 trial showed moderate, but significant protection in humans and highlighted the contribution of antibody responses directed against HIV envelope as an important immune correlate for protection. Efforts to further build upon the progress include the use of a heterologous prime-boost regimen using DNA as the priming agent and the attenuated vaccinia virus, Modified Vaccinia Ankara (MVA), as a boosting vector for generating protective HIV-specific immunity. Areas covered: In this review, we summarize the immunogenicity of DNA/MVA vaccines in non-human primate models and describe the efficacy seen in SIV infection models. We discuss immunological correlates of protection determined by these studies and potential approaches for improving the protective immunity. Additionally, we describe the current progress of DNA/MVA vaccines in human trials. Expert commentary: Efforts over the past decade have provided the opportunity to better understand the dynamics of vaccine-induced immune responses and immune correlates of protection against HIV. Based on what we have learned, we outline multiple areas where the field will likely focus on in the next five years.
MeSH term(s)	AIDS Vaccines/administration & dosage ; AIDS Vaccines/biosynthesis ; AIDS Vaccines/genetics ; Animals ; Antibodies, Viral/biosynthesis ; HIV Infections/immunology ; HIV Infections/prevention & control ; HIV Infections/virology ; HIV-1/immunology ; Humans ; Immunity, Cellular/drug effects ; Immunity, Humoral/drug effects ; Immunization, Secondary ; Immunogenicity, Vaccine ; Macaca mulatta ; Simian Acquired Immunodeficiency Syndrome/immunology ; Simian Acquired Immunodeficiency Syndrome/prevention & control ; Simian Acquired Immunodeficiency Syndrome/virology ; Simian Immunodeficiency Virus/immunology ; Vaccination/methods ; Vaccines, DNA/administration & dosage ; Vaccines, DNA/biosynthesis ; Vaccines, DNA/genetics ; Vaccines, Subunit ; Vaccinia virus/genetics ; Vaccinia virus/immunology
Chemical Substances	AIDS Vaccines ; Antibodies, Viral ; Vaccines, DNA ; Vaccines, Subunit
Language	English
Publishing date	2017-09-04
Publishing country	England
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural
ZDB-ID	2181284-6
ISSN	1744-8395 ; 1476-0584
ISSN (online)	1744-8395
ISSN	1476-0584
DOI	10.1080/14760584.2017.1371594
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Article ; Online: PD-1 blockade following ART interruption enhances control of pathogenic SIV in rhesus macaques.

Velu, Vijayakumar / Titanji, Kehmia / Ahmed, Hasan / Shetty, Ravi Dyavar / Chennareddi, Lakshmi S / Freeman, Gordon J / Ahmed, Rafi / Amara, Rama Rao

Proceedings of the National Academy of Sciences of the United States of America

2022 Volume 119, Issue 33, Page(s) e2202148119

Abstract: Programmed death-1 (PD-1) blockade during chronic Simian immunodeficiency virus (SIV) infection results in restoration of CD8 T-cell function and enhances viral control. Here, we tested the therapeutic benefits of PD-1 blockade administered soon after ... ...

Abstract	Programmed death-1 (PD-1) blockade during chronic Simian immunodeficiency virus (SIV) infection results in restoration of CD8 T-cell function and enhances viral control. Here, we tested the therapeutic benefits of PD-1 blockade administered soon after anti-retrovial therapy (ART) interruption (ATI) by treating SIV-infected and ART-suppressed macaques with either an anti-PD-1 antibody (
MeSH term(s)	Animals ; Anti-Retroviral Agents/therapeutic use ; CD4-Positive T-Lymphocytes/virology ; CD8-Positive T-Lymphocytes/virology ; Immune Checkpoint Inhibitors/pharmacology ; Immune Checkpoint Inhibitors/therapeutic use ; Immunologic Memory ; Macaca mulatta ; Programmed Cell Death 1 Receptor/antagonists & inhibitors ; Simian Acquired Immunodeficiency Syndrome/drug therapy ; Simian Acquired Immunodeficiency Syndrome/immunology ; Simian Immunodeficiency Virus/drug effects ; Viral Load/drug effects ; Viremia/drug therapy
Chemical Substances	Anti-Retroviral Agents ; Immune Checkpoint Inhibitors ; Programmed Cell Death 1 Receptor
Language	English
Publishing date	2022-08-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2202148119
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Article: Methods for quantitating antigen-specific T cell responses using functional assays in rhesus macaques.

Amara, Rama Rao

Methods in molecular biology (Clifton, N.J.)

2009 Volume 485, Page(s) 417–424

Abstract: Ex vivo enumeration of the absolute frequencies of antigen-specific T cells is key for evaluating the immunogenicity of T cell-based vaccines. Currently there are three methods that are widely used to quantify cellular immune responses: Enzyme-Linked ... ...

Abstract	Ex vivo enumeration of the absolute frequencies of antigen-specific T cells is key for evaluating the immunogenicity of T cell-based vaccines. Currently there are three methods that are widely used to quantify cellular immune responses: Enzyme-Linked Immuno Spot assay (ELISpot), Intracellular Cytokine Staining assay (ICS) and Tetramer assay. These three different assays offer different information. In this chapter, I discuss the two functional assays, ELISpot and ICS. The ELISpot and ICS assays use short term in vitro stimulation to assay the frequency and cytokine expression profiles of responding cells. The ELISpot assay scores spots of captured cytokine produced by individual cells whereas, ICS uses flow cytometry to profile individual cells for surface markers and the production of cytokines.
MeSH term(s)	AIDS Vaccines/immunology ; Animals ; Cytokines/biosynthesis ; Cytokines/immunology ; Flow Cytometry/methods ; Immunoassay/methods ; Macaca mulatta ; T-Lymphocytes/immunology
Chemical Substances	AIDS Vaccines ; Cytokines
Language	English
Publishing date	2009
Publishing country	United States
Document type	Journal Article
ISSN	1064-3745
ISSN	1064-3745
DOI	10.1007/978-1-59745-170-3_28
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Article: Tailoring Tfh Profiles Enhances Antibody Persistence to a Clade C HIV-1 Vaccine in Rhesus Macaques.

Verma, Anil / Hawes, Chase E / Elizaldi, Sonny R / Smith, Justin C / Rajasundaram, Dhivyaa / Pedersen, Gabriel Kristian / Shen, Xiaoying / Williams, LaTonya D / Tomaras, Georgia D / Kozlowski, Pamela A / Amara, Rama Rao / Iyer, Smita S

bioRxiv : the preprint server for biology

2023

Abstract: CD4 T follicular helper cells (Tfh) are essential for establishing serological memory and have distinct helper attributes that impact both the quantity and quality of the antibody response. Insights into Tfh subsets that promote antibody persistence and ... ...

Abstract	CD4 T follicular helper cells (Tfh) are essential for establishing serological memory and have distinct helper attributes that impact both the quantity and quality of the antibody response. Insights into Tfh subsets that promote antibody persistence and functional capacity can critically inform vaccine design. Based on the Tfh profiles evoked by the live attenuated measles virus vaccine, renowned for its ability to establish durable humoral immunity, we investigated the potential of a Tfh1/17 recall response during the boost phase to enhance persistence of HIV-1 Envelope (Env) antibodies in rhesus macaques. Using a DNA-prime encoding gp160 antigen and Tfh polarizing cytokines (interferon protein-10 (IP-10) and interleukin-6 (IL-6)), followed by a gp140 protein boost formulated in a cationic liposome-based adjuvant (CAF01), we successfully generated germinal center (GC) Tfh1/17 cells. In contrast, a similar DNA-prime (including IP-10) followed by gp140 formulated with monophosphoryl lipid A (MPLA)+QS-21 adjuvant predominantly induced GC Tfh1 cells. While the generation of GC Tfh1/17 cells with CAF01 and GC Tfh1 cells with MPLA+QS-21 induced comparable peak Env antibodies, the latter group demonstrated significantly greater antibody concentrations at week 8 after final immunization which persisted up to 30 weeks (gp140 IgG ng/ml- MPLA; 5500; CAF01, 2155; p <0.05). Notably, interferon γ+ Env-specific Tfh responses were consistently higher with gp140 in MPLA+QS-21 and positively correlated with Env antibody persistence. These findings suggest that vaccine platforms maximizing GC Tfh1 induction promote persistent Env antibodies, important for protective immunity against HIV.
Language	English
Publishing date	2023-11-02
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.07.18.549515
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Article: Tfh1 Cells in Germinal Centers During Chronic HIV/SIV Infection.

Velu, Vijayakumar / Mylvaganam, Geetha / Ibegbu, Chris / Amara, Rama Rao

Frontiers in immunology

2018 Volume 9, Page(s) 1272

Abstract: T follicular helper CD4 cells (Tfh) are essential for the development and maintenance of germinal center (GC) reactions, a critical process that promotes the generation of long-lived high affinity humoral immunity. It is becoming increasingly evident ... ...

Abstract	T follicular helper CD4 cells (Tfh) are essential for the development and maintenance of germinal center (GC) reactions, a critical process that promotes the generation of long-lived high affinity humoral immunity. It is becoming increasingly evident that GC-Tfh cells are heterogeneous in nature with some cellular characteristics associated with a Th1, Th2, and Th17 phenotype. Emerging studies suggest that GC-Tfh cells are directed to differentiate into distinct phenotypes during chronic HIV/SIV infection and these changes in GC-Tfh cells can greatly impact the B cell response and subclass of antibodies generated. Studies in HIV-infected humans have shown that certain Tfh phenotypes are associated with the generation of broadly neutralizing antibody responses. Moreover, the susceptibility of particular GC-Tfh subsets to HIV infection within the secondary lymphoid sites can also impact GC-Tfh/B cell interactions. In this review, we discuss the recent advances that show Tfh heterogeneity during chronic HIV/SIV infection. In particular, we will discuss the dynamics of GC-Tfh cells, their altered differentiation state and function, and their impact on B cell responses during HIV/SIV infection. In addition, we will also discuss the potential role of a recently described novel subset of follicular homing CXCR5
MeSH term(s)	Animals ; Biomarkers ; CD8-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/metabolism ; Cell Differentiation/immunology ; Cell Movement/immunology ; Chronic Disease ; Germinal Center/cytology ; Germinal Center/immunology ; Germinal Center/metabolism ; HIV/immunology ; HIV Infections/immunology ; HIV Infections/virology ; Host-Pathogen Interactions/immunology ; Humans ; Phenotype ; Simian Acquired Immunodeficiency Syndrome/immunology ; Simian Acquired Immunodeficiency Syndrome/virology ; Simian Immunodeficiency Virus/immunology ; Th1 Cells/cytology ; Th1 Cells/immunology ; Th1 Cells/metabolism ; Viral Load
Chemical Substances	Biomarkers
Language	English
Publishing date	2018-06-06
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2606827-8
ISSN	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2018.01272
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Article ; Online: Protective immunity from a germinal center sanctuary.

Robinson, Harriet L / Amara, Rama Rao

Nature medicine

2012 Volume 18, Issue 11, Page(s) 1614–1616

Abstract: A new study provides mechanistic insights into how live attenuated simian immunodeficiency virus (SIV) vaccines (LAVs) can protect monkeys from infection with pathogenic SIV. The authors show that replicating LAVs stimulate a protective immune response ... ...

Abstract	A new study provides mechanistic insights into how live attenuated simian immunodeficiency virus (SIV) vaccines (LAVs) can protect monkeys from infection with pathogenic SIV. The authors show that replicating LAVs stimulate a protective immune response from a safe haven in the germinal centers of lymph nodes (pages 1673-1681).
MeSH term(s)	Animals ; CD8-Positive T-Lymphocytes/immunology ; Humans ; Male ; SAIDS Vaccines ; Simian Acquired Immunodeficiency Syndrome ; Simian Immunodeficiency Virus ; Vaccines, Attenuated
Chemical Substances	SAIDS Vaccines ; Vaccines, Attenuated
Language	English
Publishing date	2012-11-06
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	1220066-9
ISSN	1546-170X ; 1078-8956
ISSN (online)	1546-170X
ISSN	1078-8956
DOI	10.1038/nm.2986
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Zs.A 4212: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Antibody response, neutralizing potency, and transplacental antibody transfer following SARS-CoV-2 infection versus mRNA-1273, BNT162b2 COVID-19 vaccination in pregnancy.

Dude, Carolynn M / Joseph, Naima T / Forrest, Alexandra D / Verkerke, Hans P / Cheedarla, Narayanaiah / Govindaraj, Sakthivel / Irby, Les'Shon S / Easley, Kirk A / Smith, Alicia K / Stowell, Sean R / Neish, Andrew / Amara, Rama Rao / Jamieson, Denise J / Dunlop, Anne L / Badell, Martina L / Velu, Vijayakumar

International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics

2023 Volume 162, Issue 1, Page(s) 154–162

Abstract: Objective: To improve our understanding of the immune response, including the neutralization antibody response, following COVID-19 vaccination in pregnancy.: Methods: This was a prospective cohort study comprising patients with PCR-confirmed SARS-CoV- ...

Abstract	Objective: To improve our understanding of the immune response, including the neutralization antibody response, following COVID-19 vaccination in pregnancy. Methods: This was a prospective cohort study comprising patients with PCR-confirmed SARS-CoV-2 infection and patients who received both doses of mRNA COVID-19 vaccine (mRNA-1273, BNT162b2) in pregnancy recruited from two hospitals in Atlanta, GA, USA. Maternal blood and cord blood at delivery were assayed for anti-receptor binding domain (RBD) IgG, IgA and IgM, and neutralizing antibody. The detection of antibodies, titers, and maternal to fetal transfer ratios were compared. Results: Nearly all patients had detectable RBD-binding IgG in maternal and cord samples. The vaccinated versus infected cohort had a significantly greater proportion of cord samples with detectable neutralizing antibody (94% vs. 28%, P < 0.001) and significantly higher transfer ratios for RBD-specific IgG and neutralizing antibodies with a transfer efficiency of 105% (vs. 80%, P < 0.001) and 110% (vs. 90%, P < 0.001), respectively. There was a significant linear decline in maternal and cord blood RBD-specific IgG and neutralizing antibody titers as time from vaccination to delivery increased. Conclusions: Those who receive the mRNA COVID-19 vaccine mount an immune response that is equivalent to-if not greater than-those naturally infected by SARS-CoV-2 during pregnancy.
MeSH term(s)	Female ; Pregnancy ; Humans ; 2019-nCoV Vaccine mRNA-1273 ; BNT162 Vaccine ; COVID-19 Vaccines ; Antibody Formation ; Prospective Studies ; COVID-19/prevention & control ; SARS-CoV-2 ; Antibodies, Neutralizing ; RNA, Messenger ; Immunoglobulin G ; Antibodies, Viral ; Vaccination
Chemical Substances	2019-nCoV Vaccine mRNA-1273 (EPK39PL4R4) ; BNT162 Vaccine ; COVID-19 Vaccines ; Antibodies, Neutralizing ; RNA, Messenger ; Immunoglobulin G ; Antibodies, Viral
Language	English
Publishing date	2023-01-19
Publishing country	United States
Document type	Journal Article
ZDB-ID	80149-5
ISSN	1879-3479 ; 0020-7292
ISSN (online)	1879-3479
ISSN	0020-7292
DOI	10.1002/ijgo.14648
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Zs.A 355: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: V2 hotspot optimized MVA vaccine expressing stabilized HIV-1 Clade C envelope Gp140 delays acquisition of heterologous Clade C Tier 2 challenges in Mamu-A*01 negative Rhesus Macaques.

Styles, Tiffany M / Gangadhara, Sailaja / Reddy, Pradeep B J / Sahoo, Anusmita / Shiferaw, Ayalensh / Welbourn, Sarah / Kozlowski, Pamela A / Derdeyn, Cynthia A / Velu, Vijayakumar / Amara, Rama Rao

Frontiers in immunology

2022 Volume 13, Page(s) 914969

Abstract: Stabilized HIV envelope (Env) trimeric protein immunogens have been shown to induce strong autologous neutralizing antibody response. However, there is limited data on the immunogenicity and efficacy of stabilized Env expressed by a viral vector-based ... ...

Abstract	Stabilized HIV envelope (Env) trimeric protein immunogens have been shown to induce strong autologous neutralizing antibody response. However, there is limited data on the immunogenicity and efficacy of stabilized Env expressed by a viral vector-based immunogen. Here, we compared the immunogenicity and efficacy of two modified vaccinia Ankara (MVA) vaccines based on variable loop 2 hotspot (V2 HS) optimized C.1086 envelope (Env) sequences, one expressing the membrane anchored gp150 (MVA-150) and the other expressing soluble uncleaved pre-fusion optimized (UFO) gp140 trimer (MVA-UFO) in a DNA prime/MVA boost approach against heterologous tier 2 SHIV1157ipd3N4 intrarectal challenges in rhesus macaques (RMs). Both MVA vaccines also expressed SIVmac239 Gag and form virus-like particles. The DNA vaccine expressed SIVmac239 Gag, C.1086 gp160 Env and rhesus CD40L as a built-in adjuvant. Additionally, all immunizations were administered intradermally (ID) to reduce induction of vaccine-specific IFNγ+ CD4 T cell responses. Our results showed that both MVA-150 and MVA-UFO vaccines induce comparable Env specific IgG responses in serum and rectal secretions. The vaccine-induced serum antibody showed ADCC and ADCVI activities against the challenge virus. Comparison with a previous study that used similar immunogens
MeSH term(s)	Animals ; Antibodies, Viral ; DNA ; HIV-1/genetics ; Macaca mulatta ; Vaccines, DNA ; Vaccinia ; Vaccinia virus/genetics ; Viral Vaccines
Chemical Substances	Antibodies, Viral ; MVA vaccine ; Vaccines, DNA ; Viral Vaccines ; DNA (9007-49-2)
Language	English
Publishing date	2022-07-22
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2022.914969
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Article ; Online: HIV therapeutic vaccines: moving towards a functional cure.

Mylvaganam, Geetha H / Silvestri, Guido / Amara, Rama Rao

Current opinion in immunology

2015 Volume 35, Page(s) 1–8

Abstract: Anti-viral T-cell and B-cell responses play a crucial role in suppressing HIV and SIV replication during chronic infection. However, these infections are rarely controlled by the host immune response, and most infected individuals need lifelong ... ...

Abstract	Anti-viral T-cell and B-cell responses play a crucial role in suppressing HIV and SIV replication during chronic infection. However, these infections are rarely controlled by the host immune response, and most infected individuals need lifelong antiretroviral therapy (ART). Recent advances in our understanding of how anti-HIV immune responses are elicited and regulated prompted a surge of interest in harnessing these responses to reduce the HIV 'residual disease' that is present in ART-treated HIV-infected individuals. Novel approaches that are currently explored include both conventional therapeutic vaccines (i.e., active immunization strategies using HIV-derived immunogens) as well as the use of checkpoint blockers such as anti-PD-1 antibodies. These approaches appear promising as key components of complex therapeutic strategies aimed at curing HIV infection.
MeSH term(s)	AIDS Vaccines/immunology ; Adoptive Transfer ; Animals ; Antibodies, Monoclonal/therapeutic use ; B-Lymphocytes/immunology ; B-Lymphocytes/transplantation ; HIV/immunology ; HIV Antigens/immunology ; HIV Infections/immunology ; HIV Infections/therapy ; Humans ; Immunotherapy ; Lymphocyte Activation ; Programmed Cell Death 1 Receptor/immunology ; T-Lymphocytes/immunology ; T-Lymphocytes/transplantation
Chemical Substances	AIDS Vaccines ; Antibodies, Monoclonal ; HIV Antigens ; PDCD1 protein, human ; Programmed Cell Death 1 Receptor
Language	English
Publishing date	2015-08
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1035767-1
ISSN	1879-0372 ; 0952-7915
ISSN (online)	1879-0372
ISSN	0952-7915
DOI	10.1016/j.coi.2015.05.001
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Article ; Online: Structure-guided changes at the V2 apex of HIV-1 clade C trimer enhance elicitation of autologous neutralizing and broad V1V2-scaffold antibodies.

Sahoo, Anusmita / Hodge, Edgar A / LaBranche, Celia C / Styles, Tiffany M / Shen, Xiaoying / Cheedarla, Narayanaiah / Shiferaw, Ayalnesh / Ozorowski, Gabriel / Lee, Wen-Hsin / Ward, Andrew B / Tomaras, Georgia D / Montefiori, David C / Irvine, Darrell J / Lee, Kelly K / Amara, Rama Rao

Cell reports

2022 Volume 38, Issue 9, Page(s) 110436

Abstract: HIV-1 clade C envelope immunogens that elicit both neutralizing and non-neutralizing V1V2-scaffold-specific antibodies (protective correlates from RV144 human trial) are urgently needed due to the prevalence of this clade in the most impacted regions ... ...

Abstract	HIV-1 clade C envelope immunogens that elicit both neutralizing and non-neutralizing V1V2-scaffold-specific antibodies (protective correlates from RV144 human trial) are urgently needed due to the prevalence of this clade in the most impacted regions worldwide. To achieve this, we introduce structure-guided changes followed by consensus-C-sequence-guided optimizations at the V2 region to generate UFO-v2-RQH
MeSH term(s)	AIDS Vaccines ; Animals ; Antibodies, Neutralizing ; HIV Antibodies ; HIV Antigens ; HIV Infections ; HIV Seropositivity ; HIV-1 ; Rabbits ; env Gene Products, Human Immunodeficiency Virus
Chemical Substances	AIDS Vaccines ; Antibodies, Neutralizing ; HIV Antibodies ; HIV Antigens ; env Gene Products, Human Immunodeficiency Virus
Language	English
Publishing date	2022-03-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2022.110436
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