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Article ; Online: A SARS-CoV-2 variant elicits an antibody response with a shifted immunodominance hierarchy.

Greaney, Allison J / Starr, Tyler N / Eguia, Rachel T / Loes, Andrea N / Khan, Khadija / Karim, Farina / Cele, Sandile / Bowen, John E / Logue, Jennifer K / Corti, Davide / Veesler, David / Chu, Helen Y / Sigal, Alex / Bloom, Jesse D

PLoS pathogens

2022 Volume 18, Issue 2, Page(s) e1010248

Abstract: Many SARS-CoV-2 variants have mutations at key sites targeted by antibodies. However, it is unknown if antibodies elicited by infection with these variants target the same or different regions of the viral spike as antibodies elicited by earlier viral ... ...

Abstract	Many SARS-CoV-2 variants have mutations at key sites targeted by antibodies. However, it is unknown if antibodies elicited by infection with these variants target the same or different regions of the viral spike as antibodies elicited by earlier viral isolates. Here we compare the specificities of polyclonal antibodies produced by humans infected with early 2020 isolates versus the B.1.351 variant of concern (also known as Beta or 20H/501Y.V2), which contains mutations in multiple key spike epitopes. The serum neutralizing activity of antibodies elicited by infection with both early 2020 viruses and B.1.351 is heavily focused on the spike receptor-binding domain (RBD). However, within the RBD, B.1.351-elicited antibodies are more focused on the "class 3" epitope spanning sites 443 to 452, and neutralization by these antibodies is notably less affected by mutations at residue 484. Our results show that SARS-CoV-2 variants can elicit polyclonal antibodies with different immunodominance hierarchies.
MeSH term(s)	Antibodies, Monoclonal/immunology ; Antibodies, Monoclonal/pharmacology ; Antibodies, Neutralizing/immunology ; Antibodies, Viral/immunology ; Antibody Formation/immunology ; COVID-19/immunology ; Epitopes/immunology ; Humans ; Immunization, Passive/methods ; Neutralization Tests ; SARS-CoV-2/genetics ; SARS-CoV-2/immunology ; SARS-CoV-2/pathogenicity ; Spike Glycoprotein, Coronavirus/immunology ; Spike Glycoprotein, Coronavirus/metabolism ; COVID-19 Drug Treatment
Chemical Substances	Antibodies, Monoclonal ; Antibodies, Neutralizing ; Antibodies, Viral ; Epitopes ; Spike Glycoprotein, Coronavirus
Language	English
Publishing date	2022-02-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7374
ISSN (online)	1553-7374
ISSN	1553-7374
DOI	10.1371/journal.ppat.1010248
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: SARS-CoV-2 infection in immunosuppression evolves sub-lineages which independently accumulate neutralization escape mutations.

Virus evolution

2023 Volume 10, Issue 1, Page(s) vead075

Abstract: One mechanism of variant formation may be evolution during long-term infection in immunosuppressed people. To understand the viral phenotypes evolved during such infection, we tested SARS-CoV-2 viruses evolved from an ancestral B.1 lineage infection ... ...

Abstract	One mechanism of variant formation may be evolution during long-term infection in immunosuppressed people. To understand the viral phenotypes evolved during such infection, we tested SARS-CoV-2 viruses evolved from an ancestral B.1 lineage infection lasting over 190 days post-diagnosis in an advanced HIV disease immunosuppressed individual. Sequence and phylogenetic analysis showed two evolving sub-lineages, with the second sub-lineage replacing the first sub-lineage in a seeming evolutionary sweep. Each sub-lineage independently evolved escape from neutralizing antibodies. The most evolved virus for the first sub-lineage (isolated day 34) and the second sub-lineage (isolated day 190) showed similar escape from ancestral SARS-CoV-2 and Delta-variant infection elicited neutralizing immunity despite having no spike mutations in common relative to the B.1 lineage. The day 190 isolate also evolved higher cell-cell fusion and faster viral replication and caused more cell death relative to virus isolated soon after diagnosis, though cell death was similar to day 34 first sub-lineage virus. These data show that SARS-CoV-2 strains in prolonged infection in a single individual can follow independent evolutionary trajectories which lead to neutralization escape and other changes in viral properties.
Language	English
Publishing date	2023-12-28
Publishing country	England
Document type	Journal Article
ZDB-ID	2818949-8
ISSN	2057-1577
ISSN	2057-1577
DOI	10.1093/ve/vead075
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Article: SARS-CoV-2 evolves increased infection elicited cell death and fusion in an immunosuppressed individual.

Lustig, Gila / Ganga, Yashica / Rodel, Hylton / Tegally, Houriiyah / Jackson, Laurelle / Cele, Sandile / Khan, Khadija / Jule, Zesuliwe / Reedoy, Kajal / Karim, Farina / Bernstein, Mallory / Moosa, Mahomed-Yunus S / Archary, Derseree / de Oliveira, Tulio / Lessells, Richard / Abdool Karim, Salim S / Sigal, Alex

medRxiv : the preprint server for health sciences

2022

Abstract: The milder clinical manifestations of Omicron infection relative to pre-Omicron SARS CoV-2 raises the possibility that extensive evolution results in reduced pathogenicity. To test this hypothesis, we quantified induction of cell fusion and cell death in ...

Abstract	The milder clinical manifestations of Omicron infection relative to pre-Omicron SARS CoV-2 raises the possibility that extensive evolution results in reduced pathogenicity. To test this hypothesis, we quantified induction of cell fusion and cell death in SARS CoV-2 evolved from ancestral virus during long-term infection. Both cell fusion and death were reduced in Omicron BA.1 infection relative to ancestral virus. Evolved virus was isolated at different times during a 6-month infection in an immunosuppressed individual with advanced HIV disease. The virus isolated 16 days post-reported symptom onset induced fusogenicity and cell death at levels similar to BA.1. However, fusogenicity was increased in virus isolated at 6 months post-symptoms to levels intermediate between BA.1 and ancestral SARS-CoV-2. Similarly, infected cell death showed a graded increase from earlier to later isolates. These results may indicate that, at least by the cellular measures used here, evolution in long-term infection does not necessarily attenuate the virus.
Language	English
Publishing date	2022-11-30
Publishing country	United States
Document type	Preprint
DOI	10.1101/2022.11.23.22282673
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Article: A SARS-CoV-2 variant elicits an antibody response with a shifted immunodominance hierarchy.

bioRxiv : the preprint server for biology

2021

Abstract	Many SARS-CoV-2 variants have mutations at key sites targeted by antibodies. However, it is unknown if antibodies elicited by infection with these variants target the same or different regions of the viral spike as antibodies elicited by earlier viral isolates. Here we compare the specificities of polyclonal antibodies produced by humans infected with early 2020 isolates versus the B.1.351 variant of concern (also known as Beta or 20H/501Y.V2), which contains mutations in multiple key spike epitopes. The serum neutralizing activity of antibodies elicited by infection with both early 2020 viruses and B.1.351 is heavily focused on the spike receptor-binding domain (RBD). However, within the RBD, B.1.351-elicited antibodies are more focused on the "class 3" epitope spanning sites 443 to 452, and neutralization by these antibodies is notably less affected by mutations at residue 484. Our results show that SARS-CoV-2 variants can elicit polyclonal antibodies with different immunodominance hierarchies.
Language	English
Publishing date	2021-10-13
Publishing country	United States
Document type	Preprint
DOI	10.1101/2021.10.12.464114
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Article ; Online: Association Between Human Immunodeficiency Virus Viremia and Compromised Neutralization of Severe Acute Respiratory Syndrome Coronavirus 2 Beta Variant.

Hwa, Shi-Hsia / Snyman, Jumari / Bernstein, Mallory / Ganga, Yashica / Cele, Sandile / Muema, Daniel / Tan, Chee Wah / Khan, Khadija / Karim, Farina / Hanekom, Willem / Bernstein, Leslie / Kaufmann, Stefan H E / Wang, Lin-Fa / Ndung'u, Thumbi / Sigal, Alex

The Journal of infectious diseases

2022 Volume 227, Issue 2, Page(s) 211–220

Abstract: Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may be associated with worse clinical outcomes in people with human immunodeficiency virus (HIV) (PWH). We report anti-SARS-CoV-2 antibody responses in patients ... ...

Abstract	Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may be associated with worse clinical outcomes in people with human immunodeficiency virus (HIV) (PWH). We report anti-SARS-CoV-2 antibody responses in patients hospitalized with coronavirus disease 2019 in Durban, South Africa, during the second SARS-CoV-2 infection wave dominated by the Beta (B.1.351) variant. Methods: Thirty-four participants with confirmed SARS-CoV-2 infection were followed up with weekly blood sampling to examine antibody levels and neutralization potency against SARS-CoV-2 variants. Participants included 18 PWH, of whom 11 were HIV viremic. Results: SARS-CoV-2-specific antibody concentrations were generally lower in viremic PWH than in virologically suppressed PWH and HIV-negative participants, and neutralization of the Beta variant was 4.9-fold lower in viremic PWH. Most HIV-negative participants and antiretroviral therapy-suppressed PWH also neutralized the Delta (B.1.617.2) variant, whereas the majority of viremic PWH did not. CD4 cell counts <500/μL were associated with lower frequencies of immunoglobulin G and A seroconversion. In addition, there was a high correlation between a surrogate virus neutralization test and live virus neutralization against ancestral SARS-CoV-2 virus in both PWH and HIV-negative individuals, but correlation decreased for the Beta variant neutralization in PWH. Conclusions: HIV viremia was associated with reduced Beta variant neutralization. This highlights the importance of HIV suppression in maintaining an effective SARS-CoV-2 neutralization response.
MeSH term(s)	Humans ; SARS-CoV-2 ; HIV ; COVID-19 ; Viremia ; South Africa/epidemiology ; Antibodies, Viral ; HIV Infections/drug therapy ; Spike Glycoprotein, Coronavirus ; Antibodies, Neutralizing ; Neutralization Tests
Chemical Substances	Antibodies, Viral ; Spike Glycoprotein, Coronavirus ; Antibodies, Neutralizing ; spike protein, SARS-CoV-2
Language	English
Publishing date	2022-08-14
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3019-3
ISSN	1537-6613 ; 0022-1899
ISSN (online)	1537-6613
ISSN	0022-1899
DOI	10.1093/infdis/jiac343
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Uh II Zs.50: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
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Article ; Online: A SARS-CoV-2 variant elicits an antibody response with a shifted immunodominance hierarchy.

Allison J Greaney / Tyler N Starr / Rachel T Eguia / Andrea N Loes / Khadija Khan / Farina Karim / Sandile Cele / John E Bowen / Jennifer K Logue / Davide Corti / David Veesler / Helen Y Chu / Alex Sigal / Jesse D Bloom

PLoS Pathogens, Vol 18, Iss 2, p e

2022 Volume 1010248

Abstract	Many SARS-CoV-2 variants have mutations at key sites targeted by antibodies. However, it is unknown if antibodies elicited by infection with these variants target the same or different regions of the viral spike as antibodies elicited by earlier viral isolates. Here we compare the specificities of polyclonal antibodies produced by humans infected with early 2020 isolates versus the B.1.351 variant of concern (also known as Beta or 20H/501Y.V2), which contains mutations in multiple key spike epitopes. The serum neutralizing activity of antibodies elicited by infection with both early 2020 viruses and B.1.351 is heavily focused on the spike receptor-binding domain (RBD). However, within the RBD, B.1.351-elicited antibodies are more focused on the "class 3" epitope spanning sites 443 to 452, and neutralization by these antibodies is notably less affected by mutations at residue 484. Our results show that SARS-CoV-2 variants can elicit polyclonal antibodies with different immunodominance hierarchies.
Keywords	Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2022-02-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: T cell derived HIV-1 is present in the CSF in the face of suppressive antiretroviral therapy.

Lustig, Gila / Cele, Sandile / Karim, Farina / Derache, Anne / Ngoepe, Abigail / Khan, Khadija / Gosnell, Bernadett I / Moosa, Mahomed-Yunus S / Ntshuba, Ntombi / Marais, Suzaan / Jeena, Prakash M / Govender, Katya / Adamson, John / Kløverpris, Henrik / Gupta, Ravindra K / Harrichandparsad, Rohen / Patel, Vinod B / Sigal, Alex

PLoS pathogens

2021 Volume 17, Issue 9, Page(s) e1009871

Abstract: HIV cerebrospinal fluid (CSF) escape, where HIV is suppressed in blood but detectable in CSF, occurs when HIV persists in the CNS despite antiretroviral therapy (ART). To determine the virus producing cell type and whether lowered CSF ART levels are ... ...

Abstract	HIV cerebrospinal fluid (CSF) escape, where HIV is suppressed in blood but detectable in CSF, occurs when HIV persists in the CNS despite antiretroviral therapy (ART). To determine the virus producing cell type and whether lowered CSF ART levels are responsible for CSF escape, we collected blood and CSF from 156 neurosymptomatic participants from Durban, South Africa. We observed that 28% of participants with an undetectable HIV blood viral load showed CSF escape. We detected host cell surface markers on the HIV envelope to determine the cellular source of HIV in participants on the first line regimen of efavirenz, emtricitabine, and tenofovir. We confirmed CD26 as a marker which could differentiate between T cells and macrophages and microglia, and quantified CD26 levels on the virion surface, comparing the result to virus from in vitro infected T cells or macrophages. The measured CD26 level was consistent with the presence of T cell produced virus. We found no significant differences in ART concentrations between CSF escape and fully suppressed individuals in CSF or blood, and did not observe a clear association with drug resistance mutations in CSF virus which would allow HIV to replicate. Hence, CSF HIV in the face of ART may at least partly originate in CD4+ T cell populations.
MeSH term(s)	Adult ; Alkynes/therapeutic use ; Anti-HIV Agents/therapeutic use ; Benzoxazines/therapeutic use ; Cyclopropanes/therapeutic use ; Emtricitabine/therapeutic use ; Female ; HIV Infections/cerebrospinal fluid ; HIV Infections/drug therapy ; HIV Infections/virology ; HIV-1 ; Humans ; Male ; Middle Aged ; T-Lymphocytes/virology ; Tenofovir/therapeutic use
Chemical Substances	Alkynes ; Anti-HIV Agents ; Benzoxazines ; Cyclopropanes ; Tenofovir (99YXE507IL) ; Emtricitabine (G70B4ETF4S) ; efavirenz (JE6H2O27P8)
Language	English
Publishing date	2021-09-23
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7366
ISSN (online)	1553-7374
ISSN	1553-7366
DOI	10.1371/journal.ppat.1009871
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Article ; Online: Author Correction: Omicron BA.4/BA.5 escape neutralizing immunity elicited by BA.1 infection.

Khan, Khadija / Karim, Farina / Ganga, Yashica / Bernstein, Mallory / Jule, Zesuliwe / Reedoy, Kajal / Cele, Sandile / Lustig, Gila / Amoako, Daniel / Wolter, Nicole / Samsunder, Natasha / Sivro, Aida / San, James Emmanuel / Giandhari, Jennifer / Tegally, Houriiyah / Pillay, Sureshnee / Naidoo, Yeshnee / Mazibuko, Matilda / Miya, Yoliswa /

Ngcobo, Nokuthula / Manickchund, Nithendra / Magula, Nombulelo / Karim, Quarraisha Abdool / von Gottberg, Anne / Abdool Karim, Salim S / Hanekom, Willem / Gosnell, Bernadett I / Lessells, Richard J / de Oliveira, Tulio / Moosa, Mahomed-Yunus S / Sigal, Alex

Nature communications

2022 Volume 13, Issue 1, Page(s) 6057

Language	English
Publishing date	2022-10-13
Publishing country	England
Document type	Published Erratum
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-022-33371-0
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Article ; Online: Safety and immunogenicity of booster vaccination and fractional dosing with Ad26.COV2.S or BNT162b2 in Ad26.COV2.S-vaccinated participants.

Riou, Catherine / Bhiman, Jinal N / Ganga, Yashica / Sawry, Shobna / Ayres, Frances / Baguma, Richard / Balla, Sashkia R / Benede, Ntombi / Bernstein, Mallory / Besethi, Asiphe S / Cele, Sandile / Crowther, Carol / Dhar, Mrinmayee / Geyer, Sohair / Gill, Katherine / Grifoni, Alba / Hermanus, Tandile / Kaldine, Haajira / Keeton, Roanne S /

Kgagudi, Prudence / Khan, Khadija / Lazarus, Erica / Le Roux, Jean / Lustig, Gila / Madzivhandila, Mashudu / Magugu, Siyabulela F J / Makhado, Zanele / Manamela, Nelia P / Mkhize, Qiniso / Mosala, Paballo / Motlou, Thopisang P / Mutavhatsindi, Hygon / Mzindle, Nonkululeko B / Nana, Anusha / Nesamari, Rofhiwa / Ngomti, Amkele / Nkayi, Anathi A / Nkosi, Thandeka P / Omondi, Millicent A / Panchia, Ravindre / Patel, Faeezah / Sette, Alessandro / Singh, Upasna / van Graan, Strauss / Venter, Elizabeth M / Walters, Avril / Moyo-Gwete, Thandeka / Richardson, Simone I / Garrett, Nigel / Rees, Helen / Bekker, Linda-Gail / Gray, Glenda / Burgers, Wendy A / Sigal, Alex / Moore, Penny L / Fairlie, Lee

PLOS global public health

2024 Volume 4, Issue 4, Page(s) e0002703

Abstract: We report the safety and immunogenicity of fractional and full dose Ad26.COV2.S and BNT162b2 in an open label phase 2 trial of participants previously vaccinated with a single dose of Ad26.COV2.S, with 91.4% showing evidence of previous SARS-CoV-2 ... ...

Abstract	We report the safety and immunogenicity of fractional and full dose Ad26.COV2.S and BNT162b2 in an open label phase 2 trial of participants previously vaccinated with a single dose of Ad26.COV2.S, with 91.4% showing evidence of previous SARS-CoV-2 infection. A total of 286 adults (with or without HIV) were enrolled >4 months after an Ad26.COV2.S prime and randomized 1:1:1:1 to receive either a full or half-dose booster of Ad26.COV2.S or BNT162b2 vaccine. B cell responses (binding, neutralization and antibody dependent cellular cytotoxicity-ADCC), and spike-specific T-cell responses were evaluated at baseline, 2, 12 and 24 weeks post-boost. Antibody and T-cell immunity targeting the Ad26 vector was also evaluated. No vaccine-associated serious adverse events were recorded. The full- and half-dose BNT162b2 boosted anti-SARS-CoV-2 binding antibody levels (3.9- and 4.5-fold, respectively) and neutralizing antibody levels (4.4- and 10-fold). Binding and neutralizing antibodies following half-dose Ad26.COV2.S were not significantly boosted. Full-dose Ad26.COV2.S did not boost binding antibodies but slightly enhanced neutralizing antibodies (2.1-fold). ADCC was marginally increased only after a full-dose BNT162b2. T-cell responses followed a similar pattern to neutralizing antibodies. Six months post-boost, antibody and T-cell responses had waned to baseline levels. While we detected strong anti-vector immunity, there was no correlation between anti-vector immunity in Ad26.COV2.S recipients and spike-specific neutralizing antibody or T-cell responses post-Ad26.COV2.S boosting. Overall, in the context of hybrid immunity, boosting with heterologous full- or half-dose BNT162b2 mRNA vaccine demonstrated superior immunogenicity 2 weeks post-vaccination compared to homologous Ad26.COV2.S, though rapid waning occurred by 12 weeks post-boost. Trial Registration: The study has been registered to the South African National Clinical Trial Registry (SANCTR): DOH-27-012022-7841. The approval letter from SANCTR has been provided in the up-loaded documents.
Language	English
Publishing date	2024-04-11
Publishing country	United States
Document type	Journal Article
ISSN	2767-3375
ISSN (online)	2767-3375
DOI	10.1371/journal.pgph.0002703
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Article ; Online: Escape of SARS-CoV-2 501Y.V2 from neutralization by convalescent plasma.

Nature

2021 Volume 593, Issue 7857, Page(s) 142–146

Abstract: SARS-CoV-2 variants of concern (VOC) have arisen independently at multiple ... ...

Abstract	SARS-CoV-2 variants of concern (VOC) have arisen independently at multiple locations
MeSH term(s)	Animals ; Antibodies, Neutralizing/biosynthesis ; Antibodies, Neutralizing/immunology ; Antibodies, Viral/biosynthesis ; Antibodies, Viral/immunology ; COVID-19/epidemiology ; COVID-19/immunology ; COVID-19/therapy ; COVID-19/virology ; Cell Line ; Chlorocebus aethiops ; Humans ; Immune Evasion/genetics ; Immune Evasion/immunology ; Immunization, Passive ; Mutation ; Neutralization Tests ; SARS-CoV-2/genetics ; SARS-CoV-2/immunology ; South Africa/epidemiology ; Time Factors ; Vero Cells ; COVID-19 Serotherapy
Chemical Substances	Antibodies, Neutralizing ; Antibodies, Viral
Language	English
Publishing date	2021-03-29
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	120714-3
ISSN	1476-4687 ; 0028-0836
ISSN (online)	1476-4687
ISSN	0028-0836
DOI	10.1038/s41586-021-03471-w
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