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Article ; Online: GALT CD4

Onabajo, Olusegun O / Lewis, Mark G / Mattapallil, Joseph J

2021 Volume 366, Page(s) 104396

Abstract: Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infections are characterized by dramatic alterations in the mucosal CD4 T cell compartment. Though viremia is effectively suppressed, and peripheral CD4 T cell numbers recover to ... ...

Abstract	Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infections are characterized by dramatic alterations in the mucosal CD4 T cell compartment. Though viremia is effectively suppressed, and peripheral CD4 T cell numbers recover to near healthy levels after highly active anti-retroviral therapy (HAART), some of the dysfunctional consequences of HIV infection continue to persist during therapy. We hypothesized that CD4 T follicular helper (Tfh) cell deficiencies may play a role in this process. Using the macaque model we show that SIV infection was associated with a significant loss of Tfh cells in the GALT that drain the mesentery lining the gastrointestinal tract (GIT). Loss of Tfh cells significantly correlated with the depletion of the overall memory CD4 T cell compartment; most Tfh cells in the GALT expressed a CD95+CD28+ memory phenotype suggesting that infection of the memory compartment likely drives the loss of GALT Tfh cells during infection. Continuous anti-retroviral therapy (cART) was accompanied by a significant repopulation of Tfh cells in the GALT to levels similar to those of uninfected animals. Repopulating Tfh cells displayed significantly higher capacity to produce IL-21 as compared to SIV infected animals suggesting that cART fully restores Tfh cells that are functionally capable of supporting GC reactions in the GALT.
MeSH term(s)	Animals ; Antiretroviral Therapy, Highly Active/methods ; CD4-Positive T-Lymphocytes/drug effects ; CD4-Positive T-Lymphocytes/immunology ; Cell Movement ; Disease Models, Animal ; Germinal Center/immunology ; HIV Infections/drug therapy ; HIV Infections/immunology ; HIV-1/physiology ; Humans ; Immunologic Memory ; Interleukins/metabolism ; Intestines/immunology ; Lymphoid Tissue/immunology ; Lymphopenia ; Macaca ; Programmed Cell Death 1 Receptor/metabolism ; Simian Acquired Immunodeficiency Syndrome/drug therapy ; Simian Acquired Immunodeficiency Syndrome/immunology ; Simian Immunodeficiency Virus/physiology
Chemical Substances	Interleukins ; Programmed Cell Death 1 Receptor ; interleukin-21 (MKM3CA6LT1)
Language	English
Publishing date	2021-06-16
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	80094-6
ISSN	1090-2163 ; 0008-8749
ISSN (online)	1090-2163
ISSN	0008-8749
DOI	10.1016/j.cellimm.2021.104396
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Article ; Online: Synthetic multiantigen MVA vaccine COH04S1 and variant-specific derivatives protect Syrian hamsters from SARS-CoV-2 Omicron subvariants.

Wussow, Felix / Kha, Mindy / Kim, Taehyun / Ly, Minh / Yll-Pico, Marcal / Kar, Swagata / Lewis, Mark G / Chiuppesi, Flavia / Diamond, Don J

NPJ vaccines

2023 Volume 8, Issue 1, Page(s) 41

Abstract: Emerging SARS-CoV-2 Omicron subvariants continue to disrupt COVID-19 vaccine efficacy through multiple immune mechanisms including neutralizing antibody evasion. We developed COH04S1, a synthetic modified vaccinia Ankara vector that co-expresses Wuhan-Hu- ...

Abstract	Emerging SARS-CoV-2 Omicron subvariants continue to disrupt COVID-19 vaccine efficacy through multiple immune mechanisms including neutralizing antibody evasion. We developed COH04S1, a synthetic modified vaccinia Ankara vector that co-expresses Wuhan-Hu-1-based spike and nucleocapsid antigens. COH04S1 demonstrated efficacy against ancestral virus and Beta and Delta variants in animal models and was safe and immunogenic in a Phase 1 clinical trial. Here, we report efficacy of COH04S1 and analogous Omicron BA.1- and Beta-specific vaccines to protect Syrian hamsters from Omicron subvariants. Despite eliciting strain-specific antibody responses, all three vaccines protect hamsters from weight loss, lower respiratory tract infection, and lung pathology following challenge with Omicron BA.1 or BA.2.12.1. While the BA.1-specifc vaccine affords consistently improved efficacy compared to COH04S1 to protect against homologous challenge with BA.1, all three vaccines confer similar protection against heterologous challenge with BA.2.12.1. These results demonstrate efficacy of COH04S1 and variant-specific derivatives to confer cross-protective immunity against SARS-CoV-2 Omicron subvariants.
Language	English
Publishing date	2023-03-16
Publishing country	England
Document type	Journal Article
ISSN	2059-0105
ISSN (online)	2059-0105
DOI	10.1038/s41541-023-00640-y
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Article ; Online: Protection from COVID-19 disease in hamsters vaccinated with subunit SARS-CoV-2 S1 mucosal vaccines adjuvanted with different adjuvants.

Sui, Yongjun / Andersen, Hanne / Li, Jianping / Hoang, Tanya / Bekele, Yonas / Kar, Swagata / Lewis, Mark G / Berzofsky, Jay A

Frontiers in immunology

2023 Volume 14, Page(s) 1154496

Abstract: Introduction: Adjuvant plays an important role in directing the immune responses induced by vaccines. In previous studies, we have shown that a mucosal SARS-CoV-2 S1 subunit vaccine adjuvanted with a combination of CpG, Poly I:C and IL-15 (named CP15) ... ...

Abstract	Introduction: Adjuvant plays an important role in directing the immune responses induced by vaccines. In previous studies, we have shown that a mucosal SARS-CoV-2 S1 subunit vaccine adjuvanted with a combination of CpG, Poly I:C and IL-15 (named CP15) induced effective mucosal and systemic immunity and conferred nearly sterile protection against SARS-CoV-2 viral replication in macaque models. Methods: In this study, we used a hamster model, which mimics the human scenario and reliably exhibits severe SARS-CoV-2 disease similar to hospitalized patients, to investigate the protection efficacy of the vaccines against COVID-19 disease. We compared the weight loss, viral loads (VLs), and clinical observation scores of three different vaccine regimens. All three regimens consisted of priming/boosting with S1 subunit vaccines, but adjuvanted with alum and/or CP15 administrated by either intramuscular (IM) or intranasal (IN) routes: Group 1 was adjuvanted with alum/alum administrated IM/IM; Group 2 was alum-IM/CP15-IN; and Group 3 was CP15-IM/CP15-IN. Results: After challenge with SARS-CoV-2 WA strain, we found that the alum/CP15 group showed best protection against weight loss, while the CP15 group demonstrated best reduction of oral SARS-CoV-2 VLs, suggesting that the protection profiles were different. Sex differences for VL and clinical scores were observed. Humoral immunity was induced but not correlated with protection. Moreover, S1-specific binding antibody titers against beta, omicron BA.1, and BA.2 variants showed 2.6-, 4.9- and 2.8- fold reduction, respectively, compared to the Wuhan strain. Discussion: Overall, the data suggested that adjuvants in subunit vaccines determine the protection profiles after SARS-CoV-2 infection and that nasal/oral mucosal immunization can protect against systemic COVID-19 disease.
MeSH term(s)	Male ; Cricetinae ; Animals ; Humans ; Female ; COVID-19 Vaccines ; SARS-CoV-2 ; COVID-19 ; Adjuvants, Immunologic ; Adjuvants, Pharmaceutic ; Vaccines, Subunit
Chemical Substances	COVID-19 Vaccines ; aluminum sulfate (34S289N54E) ; Adjuvants, Immunologic ; Adjuvants, Pharmaceutic ; Vaccines, Subunit
Language	English
Publishing date	2023-03-20
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Intramural
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2023.1154496
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Article ; Online: Chronic simian immunodeficiency virus infection is associated with contrasting phenotypes of dysfunctional Bcl6

Onabajo, Olusegun O / Lewis, Mark G / Mattapallil, Joseph J

Journal of cellular and molecular medicine

2018 Volume 22, Issue 11, Page(s) 5682–5687

Abstract: Human immunodeficiency virus (HIV) infection is characterized by dysfunctional B cell responses. Here we show that chronic simian immunodeficiency virus (SIV) infection is characterized by an expansion of either lymph node germinal center (GC) B cells ... ...

Abstract	Human immunodeficiency virus (HIV) infection is characterized by dysfunctional B cell responses. Here we show that chronic simian immunodeficiency virus (SIV) infection is characterized by an expansion of either lymph node germinal center (GC) B cells that co-express Bcl6, Ki-67 and IL-21R and correlate with expanded T follicular helper (Tfh) cells or B cells that lack Bcl6, Ki-67 and IL-21R but express high levels of anti-apoptotic Bcl2 that negatively correlate with Tfh cells. The lack of Tfh cells likely contributes to persistence of dysfunctional non-proliferating B cells during chronic infection. These findings have implications for protective immunity in HIV-infected individuals who harbour low frequencies of Tfh cells.
MeSH term(s)	Animals ; B-Lymphocytes/immunology ; B-Lymphocytes/pathology ; Cell Differentiation/immunology ; Germinal Center/immunology ; Germinal Center/virology ; HIV Infections/genetics ; HIV Infections/immunology ; HIV Infections/pathology ; HIV Infections/virology ; Humans ; Lymph Nodes/immunology ; Lymph Nodes/pathology ; Macaca mulatta/immunology ; Phenotype ; Proto-Oncogene Proteins c-bcl-2/genetics ; Proto-Oncogene Proteins c-bcl-6/genetics ; Simian Acquired Immunodeficiency Syndrome/genetics ; Simian Acquired Immunodeficiency Syndrome/immunology ; Simian Acquired Immunodeficiency Syndrome/pathology ; Simian Acquired Immunodeficiency Syndrome/virology ; Simian Immunodeficiency Virus/genetics ; Simian Immunodeficiency Virus/immunology ; Simian Immunodeficiency Virus/pathogenicity ; T-Lymphocytes, Helper-Inducer/immunology ; T-Lymphocytes, Helper-Inducer/pathology
Chemical Substances	Proto-Oncogene Proteins c-bcl-2 ; Proto-Oncogene Proteins c-bcl-6
Language	English
Publishing date	2018-09-06
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2074559-X
ISSN	1582-4934 ; 1582-4934 ; 1582-1838
ISSN (online)	1582-4934
ISSN	1582-4934 ; 1582-1838
DOI	10.1111/jcmm.13844
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Zs.A 5752: Show issues

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Jg. 1995 - 2021: Lesesall (2.OG)
ab Jg. 2022: Lesesaal (EG)

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Article ; Online: SARS-CoV-2 mucosal vaccine protects against clinical disease with sex bias in efficacy.

Sui, Yongjun / Andersen, Hanne / Li, Jianping / Hoang, Tanya / Minai, Mahnaz / Nagata, Bianca M / Bock, Kevin W / Alves, Derron A / Lewis, Mark G / Berzofsky, Jay A

Vaccine

2023 Volume 42, Issue 2, Page(s) 339–351

Abstract: Intranasal mucosal vaccines can more effectively induce mucosal immune responses against SARS-CoV-2. Here, we show in hamsters that an intranasal subunit mucosal vaccine boost with the beta variant S1 can prevent weight loss, in addition to reducing ... ...

Abstract	Intranasal mucosal vaccines can more effectively induce mucosal immune responses against SARS-CoV-2. Here, we show in hamsters that an intranasal subunit mucosal vaccine boost with the beta variant S1 can prevent weight loss, in addition to reducing viral load, which cannot be studied in macaques that don't develop COVID-like disease. Protective efficacy against both viral load and weight loss correlated with serum antibody titers. A sex bias was detected in that immune responses and protection against viral load were greater in females than males. We also found that priming with S1 from the Wuhan strain elicited lower humoral immune responses against beta variant and led to less protection against beta viral challenge, suggesting the importance of matched antigens. The greater efficacy of mucosal vaccines in the upper respiratory tract and the need to consider sex differences in vaccine protection are important in the development of future improved COVID-19 vaccines.
MeSH term(s)	Female ; Male ; Animals ; Cricetinae ; Humans ; COVID-19 Vaccines ; Sexism ; SARS-CoV-2 ; COVID-19/prevention & control ; Macaca ; Weight Loss ; Antibodies, Viral ; Antibodies, Neutralizing ; Spike Glycoprotein, Coronavirus
Chemical Substances	COVID-19 Vaccines ; Antibodies, Viral ; Antibodies, Neutralizing ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2
Language	English
Publishing date	2023-12-08
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	605674-x
ISSN	1873-2518 ; 0264-410X
ISSN (online)	1873-2518
ISSN	0264-410X
DOI	10.1016/j.vaccine.2023.11.059
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Zs.A 1930: 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)
Zs.MO 458: Show issues

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Article ; Online: Correction: Preclinical safety and biodistribution of CRISPR targeting SIV in non-human primates.

Gene therapy

2024

Language	English
Publishing date	2024-01-12
Publishing country	England
Document type	Published Erratum
ZDB-ID	1191036-7
ISSN	1476-5462 ; 0969-7128
ISSN (online)	1476-5462
ISSN	0969-7128
DOI	10.1038/s41434-023-00438-6
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Zs.A 3991: Show issues

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Article ; Online: Comparison of the immunogenicity and protective efficacy of ACAM2000, MVA, and vectored subunit vaccines for Mpox in rhesus macaques.

Science translational medicine

2024 Volume 16, Issue 740, Page(s) eadl4317

Abstract: The 2022-2023 mpox outbreak triggered vaccination efforts using smallpox vaccines that were approved for mpox, including modified vaccinia Ankara (MVA; JYNNEOS), which is a safer alternative to live replicating vaccinia virus (ACAM2000). Here, we compare ...

Abstract	The 2022-2023 mpox outbreak triggered vaccination efforts using smallpox vaccines that were approved for mpox, including modified vaccinia Ankara (MVA; JYNNEOS), which is a safer alternative to live replicating vaccinia virus (ACAM2000). Here, we compare the immunogenicity and protective efficacy of JYNNEOS by the subcutaneous or intradermal routes, ACAM2000 by the percutaneous route, and subunit Ad35 vector-based L1R/B5R or L1R/B5R/A27L/A33R vaccines by the intramuscular route in rhesus macaques. All vaccines provided robust protection against high-dose intravenous mpox virus challenge with the current outbreak strain, with ACAM2000 providing near complete protection and JYNNEOS and Ad35 vaccines providing robust but incomplete protection. Protection correlated with neutralizing antibody responses as well as L1R/M1R- and B5R/B6R-specific binding antibody responses, although additional immune responses likely also contributed to protection. This study demonstrates the protective efficacy of multiple vaccine platforms against mpox virus challenge, including both current clinical vaccines and vectored subunit vaccines.
MeSH term(s)	Animals ; Vaccinia virus/genetics ; Macaca mulatta ; Mpox (monkeypox) ; Antibodies, Viral ; Smallpox Vaccine ; Vaccines, Subunit
Chemical Substances	ACAM2000 ; Antibodies, Viral ; Smallpox Vaccine ; Vaccines, Subunit
Language	English
Publishing date	2024-03-27
Publishing country	United States
Document type	Journal Article
ZDB-ID	2518854-9
ISSN	1946-6242 ; 1946-6234
ISSN (online)	1946-6242
ISSN	1946-6234
DOI	10.1126/scitranslmed.adl4317
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Article: Investigation of the impact of clonal hematopoiesis on severity and pathophysiology of COVID-19 in rhesus macaques.

Shin, Tae-Hoon / Zhou, Yifan / Lee, Byung-Chul / Hong, So Gun / Andrew, Shayne F / Flynn, Barbara J / Gagne, Matthew / Todd, John-Paul M / Moore, Ian N / Cook, Anthony / Lewis, Mark G / Foulds, Kathryn E / Seder, Robert A / Douek, Daniel C / Roederer, Mario / Dunbar, Cynthia E

Frontiers in veterinary science

2023 Volume 10, Page(s) 1182197

Abstract: Clinical manifestations of COVID-19 vary widely, ranging from asymptomatic to severe respiratory failure with profound inflammation. Although risk factors for severe illness have been identified, definitive determinants remain elusive. Clonal ... ...

Abstract	Clinical manifestations of COVID-19 vary widely, ranging from asymptomatic to severe respiratory failure with profound inflammation. Although risk factors for severe illness have been identified, definitive determinants remain elusive. Clonal hematopoiesis (CH), the expansion of hematopoietic stem and progenitor cells bearing acquired somatic mutations, is associated with advanced age and hyperinflammation. Given the similar age range and hyperinflammatory phenotype between frequent CH and severe COVID-19, CH could impact the risk of severe COVID-19. Human cohort studies have attempted to prove this relationship, but conclusions are conflicting. Rhesus macaques (RMs) are being utilized to test vaccines and therapeutics for COVID-19. However, RMs, even other species, have not yet been reported to develop late inflammatory COVID-19 disease. Here, RMs with either spontaneous DNMT3A or engineered TET2 CH along with similarly transplanted and conditioned controls were infected with SARS-CoV-2 and monitored until 12 days post-inoculation (dpi). Although no significant differences in clinical symptoms and blood counts were noted, an aged animal with natural DNMT3A CH died on 10 dpi. CH macaques showed evidence of sustained local inflammatory responses compared to controls. Interestingly, viral loads in respiratory tracts were higher at every timepoint in the CH group. Lung sections from euthanasia showed evidence of mild inflammation in all animals, while viral antigen was more frequently detected in the lung tissues of CH macaques even at the time of autopsy. Despite the lack of striking inflammation and serious illness, our findings suggest potential pathophysiological differences in RMs with or without CH upon SARS-CoV-2 infection.
Language	English
Publishing date	2023-07-06
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2834243-4
ISSN	2297-1769
ISSN	2297-1769
DOI	10.3389/fvets.2023.1182197
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Article: Investigation of the Impact of Clonal Hematopoiesis on Severity and Pathophysiology of COVID-19 in Rhesus Macaques.

bioRxiv : the preprint server for biology

2023

Abstract	Clinical manifestations of COVID-19 vary widely, ranging from asymptomatic to severe respiratory failure with profound inflammation. Although risk factors for severe illness have been identified, definitive determinants remain elusive. Clonal hematopoiesis (CH), the expansion of hematopoietic stem and progenitor cells bearing acquired somatic mutations, is associated with advanced age and hyperinflammation. Given the similar age range and hyperinflammatory phenotype between frequent CH and severe COVID-19, CH could impact the risk of severe COVID-19. Human cohort studies have attempted to prove this relationship, but conclusions are conflicting. Rhesus macaques (RMs) are being utilized to test vaccines and therapeutics for COVID-19. However, RMs, even other species, have not yet been reported to develop late inflammatory COVID-19 disease. Here, RMs with either spontaneous DNMT3A or engineered TET2 CH along with similarly transplanted and conditioned controls were infected with SARS-CoV-2 and monitored until 12 days post-inoculation (dpi). Although no significant differences in clinical symptoms and blood counts were noted, an aged animal with natural Highlights: No evidence of association between CH and COVID-19 clinical severity in macaques.The presence of CH is associated with prolonged local inflammatory responses in COVID-19.SARS-CoV-2 persists longer in respiratory tracts of macaques with CH following infection.
Language	English
Publishing date	2023-01-03
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.01.01.522064
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Article ; Online: COH04S1 and beta sequence-modified vaccine protect hamsters from SARS-CoV-2 variants.

Wussow, Felix / Kha, Mindy / Faircloth, Katelyn / Nguyen, Vu H / Iniguez, Angelina / Martinez, Joy / Park, Yoonsuh / Nguyen, Jenny / Kar, Swagata / Andersen, Hanne / Lewis, Mark G / Chiuppesi, Flavia / Diamond, Don J

iScience

2022 Volume 25, Issue 6, Page(s) 104457

Abstract: COVID-19 vaccine efficacy is threatened by emerging SARS-CoV-2 variants of concern (VOC) with the capacity to evade protective neutralizing antibody responses. We recently developed clinical vaccine candidate COH04S1, a synthetic modified vaccinia Ankara ...

Abstract	COVID-19 vaccine efficacy is threatened by emerging SARS-CoV-2 variants of concern (VOC) with the capacity to evade protective neutralizing antibody responses. We recently developed clinical vaccine candidate COH04S1, a synthetic modified vaccinia Ankara vector (sMVA) co-expressing spike and nucleocapsid antigens based on the Wuhan-Hu-1 reference strain that showed potent efficacy to protect against ancestral SARS-CoV-2 in Syrian hamsters and non-human primates and was safe and immunogenic in healthy volunteers. Here, we demonstrate that intramuscular immunization of Syrian hamsters with COH04S1 and an analogous Beta variant-adapted vaccine candidate (COH04S351) elicits potent cross-reactive antibody responses and protects against weight loss, lower respiratory tract infection, and lung pathology following challenge with major SARS-CoV-2 VOC, including Beta and the highly contagious Delta variant. These results demonstrate efficacy of COH04S1 and a variant-adapted vaccine analog to confer cross-protective immunity against SARS-CoV-2 and its emerging VOC, supporting clinical investigation of these sMVA-based COVID-19 vaccine candidates.
Language	English
Publishing date	2022-05-23
Publishing country	United States
Document type	Journal Article
ISSN	2589-0042
ISSN (online)	2589-0042
DOI	10.1016/j.isci.2022.104457
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