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1.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-336791

ABSTRACT

As SARS-CoV-2 continues to evolve, several variants of concern (VOCs) have arisen which are defined by multiple mutations in their spike proteins. These VOCs have shown variable escape from antibody responses, and have been shown to trigger qualitatively different antibody responses during infection. By studying plasma from individuals infected with either the original D614G, Beta or Delta variants, we show that the Beta and Delta variants elicit antibody responses that are overall more cross-reactive than those triggered by D614G. Patterns of cross-reactivity varied, and the Beta and Delta variants did not elicit cross-reactive responses to each other. However, Beta-elicited plasma was highly cross-reactive against Delta plus (Delta+) which differs from Delta by a single K417N mutation in the receptor binding domain, suggesting the plasma response targets the N417 residue. To probe this further, we isolated monoclonal antibodies from a Beta-infected individual with plasma responses against Beta, Delta+ and Omicron, which all possess the N417 residue. We isolated a N417-dependent antibody, 084-7D, which showed similar neutralization breadth to the plasma. The 084-7D mAb utilized the IGHV3-23*01 germline gene and had similar somatic hypermutations compared to previously described public antibodies which target the 417 residue. Thus, we have identified a novel antibody which targets a shared epitope found on three distinct VOCs, enabling their cross-neutralization. Understanding antibodies targetting escape mutations such as K417N, which repeatedly emerge through convergent evolution in SARS-CoV-2 variants, may aid in the development of next-generation antibody therapeutics and vaccines. Importance The evolution of SARS-CoV-2 has resulted in variants of concern (VOCs) with distinct spike mutations conferring varying immune escape profiles. These variable mutations also influence the cross-reactivity of the antibody response mounted by individuals infected with each of these variants. This study sought to understand the antibody responses elicited by different SARS-CoV-2 variants, and to define shared epitopes. We show that Beta and Delta infection resulted in antibody responses that were more cross-reactive compared to the original D614G variant, but each with differing patterns of cross-reactivity. We further isolated an antibody from Beta infection, which targeted the N417 site, enabling cross-neutralization of Beta, Delta+ and Omicron, all of which possess this residue. The discovery of antibodies which target escape mutations common to multiple variants highlights conserved epitopes to target in future vaccines and therapeutics.

2.
Cell Rep Med ; 3(3): 100535, 2022 Mar 15.
Article in English | MEDLINE | ID: covidwho-1815266

ABSTRACT

The Janssen (Johnson & Johnson) Ad26.COV2.S non-replicating viral vector vaccine has been widely deployed for COVID-19 vaccination programs in resource-limited settings. Here we confirm that neutralizing and binding antibody responses to Ad26.COV2.S vaccination are stable for 6 months post-vaccination, when tested against multiple SARS-CoV-2 variants. Secondly, using longitudinal samples from individuals who experienced clinically mild breakthrough infections 4 to 5 months after vaccination, we show dramatically boosted binding antibodies, Fc effector function, and neutralization. These high titer responses are of similar magnitude to humoral immune responses measured in convalescent donors who had been hospitalized with severe illness, and are cross-reactive against diverse SARS-CoV-2 variants, including the neutralization-resistant Omicron (B.1.1.529) variant that currently dominates global infections, as well as SARS-CoV-1. These data have implications for population immunity in areas where the Ad26.COV2.S vaccine has been widely deployed, but where ongoing infections continue to occur at high levels.


Subject(s)
COVID-19 , Viral Vaccines , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/prevention & control , COVID-19 Vaccines/therapeutic use , Humans , SARS-CoV-2/genetics
4.
Cell Host Microbe ; 30(6): 880-886.e4, 2022 06 08.
Article in English | MEDLINE | ID: covidwho-1757202

ABSTRACT

The SARS-CoV-2 Omicron variant escapes neutralizing antibodies elicited by vaccines or infection. However, whether Omicron triggers cross-reactive humoral responses to other variants of concern (VOCs) remains unknown. We used plasma from 20 unvaccinated and 7 vaccinated individuals infected by Omicron BA.1 to test binding, Fc effector function, and neutralization against VOCs. In unvaccinated individuals, Fc effector function and binding antibodies targeted Omicron and other VOCs at comparable levels. However, Omicron BA.1-triggered neutralization was not extensively cross-reactive for VOCs (14- to 31-fold titer reduction), and we observed 4-fold decreased titers against Omicron BA.2. In contrast, vaccination followed by breakthrough Omicron infection associated with improved cross-neutralization of VOCs with titers exceeding 1:2,100. This has important implications for the vulnerability of unvaccinated Omicron-infected individuals to reinfection by circulating and emerging VOCs. Although Omicron-based immunogens might be adequate boosters, they are unlikely to be superior to existing vaccines for priming in SARS-CoV-2-naive individuals.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/prevention & control , Humans , Neutralization Tests
5.
EuropePMC;
Preprint in English | EuropePMC | ID: ppcovidwho-327610

ABSTRACT

The SARS-CoV-2 Omicron variant largely escapes neutralizing antibodies elicited by vaccines or infection. However, whether Omicron triggers humoral responses that are cross-reactive to other variants of concern (VOCs) remains largely unknown. We use plasma from 20 unvaccinated and seven vaccinated individuals infected during the Omicron wave in South Africa to test binding, antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) and neutralization against VOCs. In unvaccinated individuals, Fc effector function and binding antibodies target Omicron and other VOCs at comparable levels. However, Omicron-triggered neutralization is not extensively cross-reactive to VOCs, with 20 to 43-fold reductions in titer. In contrast, vaccination followed by breakthrough Omicron infection improved cross-neutralization of VOCs, with titers exceeding 1:2,900. This has important implications for the vulnerability of unvaccinated Omicron-infected individuals to reinfection by circulating and emerging VOCs. Further, while Omicron-based immunogens may be adequate boosters, they are unlikely to be superior to existing vaccines for priming in SARS-CoV-2 naive individuals.

6.
Nature ; 603(7901): 488-492, 2022 03.
Article in English | MEDLINE | ID: covidwho-1661968

ABSTRACT

The SARS-CoV-2 Omicron variant (B.1.1.529) has multiple spike protein mutations1,2 that contribute to viral escape from antibody neutralization3-6 and reduce vaccine protection from infection7,8. The extent to which other components of the adaptive response such as T cells may still target Omicron and contribute to protection from severe outcomes is unknown. Here we assessed the ability of T cells to react to Omicron spike protein in participants who were vaccinated with Ad26.CoV2.S or BNT162b2, or unvaccinated convalescent COVID-19 patients (n = 70). Between 70% and 80% of the CD4+ and CD8+ T cell response to spike was maintained across study groups. Moreover, the magnitude of Omicron cross-reactive T cells was similar for Beta (B.1.351) and Delta (B.1.617.2) variants, despite Omicron harbouring considerably more mutations. In patients who were hospitalized with Omicron infections (n = 19), there were comparable T cell responses to ancestral spike, nucleocapsid and membrane proteins to those in patients hospitalized in previous waves dominated by the ancestral, Beta or Delta variants (n = 49). Thus, despite extensive mutations and reduced susceptibility to neutralizing antibodies of Omicron, the majority of T cell responses induced by vaccination or infection cross-recognize the variant. It remains to be determined whether well-preserved T cell immunity to Omicron contributes to protection from severe COVID-19 and is linked to early clinical observations from South Africa and elsewhere9-12.


Subject(s)
COVID-19/immunology , COVID-19/virology , Cross Reactions/immunology , Immunity, Cellular , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , T-Lymphocytes/immunology , Adult , Aged , COVID-19 Vaccines/immunology , Convalescence , Hospitalization , Humans , Middle Aged , SARS-CoV-2/chemistry , SARS-CoV-2/classification
7.
Cell Rep Med ; 3(2): 100510, 2022 02 15.
Article in English | MEDLINE | ID: covidwho-1636907

ABSTRACT

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants of concern (VOCs) exhibit escape from neutralizing antibodies, causing concern about vaccine effectiveness. However, while non-neutralizing cytotoxic functions of antibodies are associated with improved disease outcome and vaccine protection, Fc effector function escape from VOCs is poorly defined. Furthermore, whether VOCs trigger Fc functions with altered specificity, as has been reported for neutralization, is unknown. Here, we demonstrate that the Beta VOC partially evades Fc effector activity in individuals infected with the original (D614G) variant. However, not all functions are equivalently affected, suggesting differential targeting by antibodies mediating distinct Fc functions. Furthermore, Beta and Delta infection trigger responses with significantly improved Fc cross-reactivity against global VOCs compared with D614G-infected or Ad26.COV2.S-vaccinated individuals. This suggests that, as for neutralization, the infecting spike sequence affects Fc effector function. These data have important implications for vaccine strategies that incorporate VOCs, suggesting these may induce broader Fc effector responses.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/immunology , Immunoglobulin Fc Fragments/immunology , SARS-CoV-2/immunology , /immunology , Adult , Aged , COVID-19/blood , COVID-19/prevention & control , COVID-19/virology , Cohort Studies , Cross Reactions , Female , HEK293 Cells , Humans , Jurkat Cells , Male , Middle Aged , Neutralization Tests , Protein Binding , Spike Glycoprotein, Coronavirus/immunology , THP-1 Cells , Treatment Outcome , Vaccination/methods
8.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-296563

ABSTRACT

Background: HIV is moderate risk factor for developing severe COVID-19 and is associated with increased risk of COVID-19 mortality. HIV infection causes immune dysregulation characterised by progressive lymphopenia, chronic immune activation, immunological senescence, and T cell exhaustion. These changes are partly reversed by effective antiretroviral therapy (ART), which reduces morbidity and mortality in people living with HIV (PWH). We investigated the associations among clinical phenotypes, laboratory biomarkers, and hospitalisation outcomes in a cohort of people hospitalised with COVID-19 in a high HIV prevalence area. Methods: : We conducted a prospective observational cohort study in the Tshwane District Hospital complex in Pretoria, South Africa. We analysed data for patients admitted from April to November 2020, before the SARS-CoV-2 Beta variant-driven second wave. Respiratory disease severity was quantified using the respiratory oxygenation (ROX) score. Analysed biomarkers included full blood counts, differential white cell counts, C-reactive protein (CRP), ferritin, procalcitonin (PCT), D-dimer (DDIM), creatinine, alanine aminotransferase (ALT), CD4 T cell counts, and HIV-1 viral loads (HIVVL). Results: : The analysis included 558 patients, of whom 112 (21.7%) died during admission. The mean age of the cohort was 54 (SD ±16) years, and numbers of males (50.5%) and females (49.5%) were equivalent. A total of 82 (15%) were HIV-positive. PWH were younger (mean age 46 years) than HIV-negative people;most were on ART with a suppressed HIVVL (72%) and the median CD4 count was 159 (IQR 66-397) cells/µL at the time of admission. After adjusting for age, HIV was not associated with significantly increased risk of mortality during hospitalisation (aHR=1.1, 95% CI: 0.6-2.0). Levels of supportive care were similar in HIV-negative patients and PWH. Inflammatory biomarker levels were equivalent in PWH and HIV-negative patients. A total of 15 PWH had detectable HIVVLs (>1000 copies/mL). Detectable HIVVL was associated with higher ROX scores - indicating less severe respiratory disease. In PWH, mortality was associated with higher levels of CRP, ferritin, PCT and DDIM. When compared to HIV-negative patients who died, PWH who died were younger, had higher DDIM levels, and were more likely to have tuberculosis. Conclusions: : HIV per se was not associated with substantively increased risk of severe disease, or in-hospital mortality from COVID-19. Respiratory disease was less severe in PWH with detectable HIVVL. Inflammatory biomarker levels were equivalent in PWH and HIV-negative people, regardless of HIVVL. Increased levels of inflammatory biomarkers and DDIM were associated with in-hospital mortality irrespective of HIV status.

9.
Afr J Emerg Med ; 11(4): 436-441, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1401137

ABSTRACT

INTRODUCTION: SARS-CoV-2 has resulted in increased worldwide demand for personal protective equipment (PPE). With pressure from ongoing epidemic and endemic episodes, we assessed an adapted snorkel mask that provides full-face protection for healthcare workers (HCWs), particularly during aerosol-generating procedures. These masks have a custom-made adaptor which allows the fitment of standard medical respiratory filters. The aim of this study was to evaluate the fit, seal and clinical usability of these masks. METHODS: This multicentre, non-blinded in-situ simulation study recruited fifty-two HCWs to don and doff the adapted snorkel mask. Negative pressure seal checks and a qualitative fit test were performed. The HCWs completed intubation and extubation of a manikin in a university skills training laboratory, followed by a web-based questionnaire on the clinical usability of the masks. RESULTS: Whilst fit and usability data were generally satisfactory, two of the 52 participants (3.8%) felt that the mask did not span the correct distance from the nose to the chin, and 3 of 34 participants (8.8%) who underwent qualitative testing with a Bitrex test failed. The majority of users reported no fogging, humidity or irritation. It was reportedly easy to speak while wearing the mask, although some participants perceived that they were not always understood. Twenty-one participants (40%) experienced a subjective physiological effect from wearing the mask; most commonly a sensation of shortness of breath. DISCUSSION: A fit-tested modified full-face snorkel mask may offer benefit as a substitute for N95 respirators and face shields. It is, however, important to properly select the correct mask based on size, fit testing, quality of the three-dimensional (3D) printed parts and respiratory filter to be used. Additionally, HCWs should be trained in the use of the mask, and each mask should be used by a single HCW and not shared.

11.
J Clin Med ; 10(7)2021 Apr 01.
Article in English | MEDLINE | ID: covidwho-1167622

ABSTRACT

The interaction between obesity, cardiometabolic disorders and COVID-19 represents a syndemic that requires both social intervention and a multipharmacological approach [...].

12.
Nat Med ; 27(4): 622-625, 2021 04.
Article in English | MEDLINE | ID: covidwho-1114719

ABSTRACT

SARS-CoV-2 501Y.V2 (B.1.351), a novel lineage of coronavirus causing COVID-19, contains substitutions in two immunodominant domains of the spike protein. Here, we show that pseudovirus expressing 501Y.V2 spike protein completely escapes three classes of therapeutically relevant antibodies. This pseudovirus also exhibits substantial to complete escape from neutralization, but not binding, by convalescent plasma. These data highlight the prospect of reinfection with antigenically distinct variants and foreshadows reduced efficacy of spike-based vaccines.


Subject(s)
COVID-19/immunology , Immune Evasion , Neutralization Tests , SARS-CoV-2/immunology , Antibodies, Viral/chemistry , Antibodies, Viral/immunology , Blood Donors , COVID-19 Vaccines/immunology , Humans , Spike Glycoprotein, Coronavirus/immunology
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