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1.
Cell ; 2021 Dec 24.
Article in English | MEDLINE | ID: covidwho-1588147

ABSTRACT

The rapid spread of the SARS-CoV-2 Omicron variant suggests that the virus might become globally dominant. Further, the high number of mutations in the viral spike protein raised concerns that the virus might evade antibodies induced by infection or vaccination. Here, we report that the Omicron spike was resistant against most therapeutic antibodies but remained susceptible to inhibition by sotrovimab. Similarly, the Omicron spike evaded neutralization by antibodies from convalescent patients or individuals vaccinated with the BioNTech-Pfizer vaccine (BNT162b2) with 12- to 44-fold higher efficiency than the spike of the Delta variant. Neutralization of the Omicron spike by antibodies induced upon heterologous ChAdOx1 (Astra Zeneca-Oxford)/BNT162b2 vaccination or vaccination with three doses of BNT162b2 was more efficient, but the Omicron spike still evaded neutralization more efficiently than the Delta spike. These findings indicate that most therapeutic antibodies will be ineffective against the Omicron variant and that double immunization with BNT162b2 might not adequately protect against severe disease induced by this variant.

2.
Frontiers in medicine ; 8, 2021.
Article in English | EuropePMC | ID: covidwho-1564209

ABSTRACT

Since its declaration as a pandemic in March 2020, SARS-CoV-2 has infected more than 217 million people worldwide and despite mild disease in the majority of the cases, more than 4.5 million cases of COVID-19-associated death have been reported as of September 2021. The question whether recovery from COVID-19 results in prevention of reinfection can be answered with a “no” since cases of reinfections have been reported. The more important question is whether during SARS-CoV-2 infection, a protective immunity is built and maintained afterwards in a way which protects from possibly severe courses of disease in case of a reinfection. A similar question arises with respect to vaccination: as of September 2021, globally, more than 5.2 billion doses of vaccines have been administered. Therefore, it is of utmost importance to study the cellular and humoral immunity toward SARS-CoV-2 in a longitudinal manner. In this study, reconvalescent COVID-19 patients have been followed up for more than 1 year after SARS-CoV-2 infection to characterize in detail the long-term humoral as well as cellular immunity. Both SARS-CoV-2-specific T cells and antibodies could be detected for a period of more than 1 year after infection, indicating that the immune protection established during initial infection is maintained and might possibly protect from severe disease in case of reinfection or infection with novel emerging variants. Moreover, these data demonstrate the opportunity for immunotherapy of hospitalized COVID-19 patients via adoptive transfer of functional antiviral T cells isolated from reconvalescent individuals.

3.
Clin Infect Dis ; 73(11): 2000-2008, 2021 12 06.
Article in English | MEDLINE | ID: covidwho-1559548

ABSTRACT

BACKGROUND: Vaccine-induced neutralizing antibodies are key in combating the coronavirus disease 2019 (COVID-19) pandemic. However, delays of boost immunization due to limited availability of vaccines may leave individuals vulnerable to infection and prolonged or severe disease courses. The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOC)-B.1.1.7 (United Kingdom), B.1.351 (South Africa), and P.1 (Brazil)-may exacerbate this issue, as the latter two are able to evade control by antibodies. METHODS: We assessed humoral and T-cell responses against SARS-CoV-2 wild-type (WT), VOC, and endemic human coronaviruses (hCoVs) that were induced after single and double vaccination with BNT162b2. RESULTS: Despite readily detectable immunoglobulin G (IgG) against the receptor-binding domain of the SARS-CoV-2 S protein at day 14 after a single vaccination, inhibition of SARS-CoV-2 S-driven host cell entry was weak and particularly low for the B.1.351 variant. Frequencies of SARS-CoV-2 WT and VOC-specific T cells were low in many vaccinees after application of a single dose and influenced by immunity against endemic hCoV. The second vaccination significantly boosted T-cell frequencies reactive for WT and B.1.1.7 and B.1.351 variants. CONCLUSIONS: These results call into question whether neutralizing antibodies significantly contribute to protection against COVID-19 upon single vaccination and suggest that cellular immunity is central for the early defenses against COVID-19.

4.
HIV Med ; 2021 Nov 02.
Article in English | MEDLINE | ID: covidwho-1494675

ABSTRACT

OBJECTIVES: People living with HIV (PLWH) with low CD4 T-cell counts may be at a higher risk for severe coronavirus disease 2019 (COVID-19) outcomes and in need of efficient vaccination. The World Health Organization (WHO) now recommends prioritizing PLHIV for COVID-19 vaccination. Data on immune responses after messenger RNA (mRNA) vaccination in PLHIV in relation to CD4 counts are scarce. We aimed at assessing the humoral immune response in PLHIV after mRNA vaccination against COVID-19. METHODS: We examined a cohort of PLHIV after prime (n = 88) and boost (n = 52) vaccination with BNT162b2. We assessed levels of anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein-specific immunoglobulin G (IgG)/IgA and circulating neutralizing antibodies in plasma and correlated results to the cellular immune status. BNT162b2-vaccinated health care workers served as controls. RESULTS: All PLWH had a viral load of ≤ 200 HIV-1 RNA copies/mL and 96.5% had a viral load of < 50 copies/mL. Anti-S IgG and neutralizing antibody responses after BNT162b2 priming were significantly lower in PLHIV having a CD4:CD8 T-cell ratio of < 0.5. However, we observed robust humoral immunity in the majority of PLWH receiving antiretroviral therapy (ART) irrespective of CD4 T-cell nadir, current CD4 count or CD4:CD8 ratio after full BNT162b2 vaccination. Nevertheless, HIV-negative controls produced significantly higher mean anti-S IgG concentrations with less variability. CONCLUSIONS: The majority of PLWH mounted robust responses after complete BNT162b2 vaccination but overall amounts of antibodies directed against the SARS-CoV-2 receptor-binding domain were variable. The impact on clinical efficacy remains unclear.

7.
Cell Rep ; 37(2): 109825, 2021 10 12.
Article in English | MEDLINE | ID: covidwho-1439920

ABSTRACT

The Delta variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), B.1.617.2, emerged in India and has spread to over 80 countries. B.1.617.2 replaced B.1.1.7 as the dominant virus in the United Kingdom, resulting in a steep increase in new infections, and a similar development is expected for other countries. Effective countermeasures require information on susceptibility of B.1.617.2 to control by antibodies elicited by vaccines and used for coronavirus disease 2019 (COVID-19) therapy. We show, using pseudotyping, that B.1.617.2 evades control by antibodies induced upon infection and BNT162b2 vaccination, although to a lesser extent as compared to B.1.351. We find that B.1.617.2 is resistant against bamlanivimab, a monoclonal antibody with emergency use authorization for COVID-19 therapy. Finally, we show increased Calu-3 lung cell entry and enhanced cell-to-cell fusion of B.1.617.2, which may contribute to augmented transmissibility and pathogenicity of this variant. These results identify B.1.617.2 as an immune evasion variant with increased capacity to enter and fuse lung cells.


Subject(s)
COVID-19/immunology , Immune Evasion/immunology , SARS-CoV-2/immunology , Adult , Antibodies, Monoclonal/immunology , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/metabolism , COVID-19/therapy , COVID-19 Vaccines/immunology , Cell Fusion , Cell Line , Female , HEK293 Cells , Humans , Immune Evasion/physiology , Immunization, Passive/methods , Lung/pathology , Lung/virology , Male , Middle Aged , Neutralization Tests , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/immunology , Vaccination/methods
9.
EBioMedicine ; 70: 103524, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1356202

ABSTRACT

BACKGROUND: Patients with chronic renal insufficiency on maintenance haemodialysis face an increased risk of COVID-19 induced mortality and impaired vaccine responses. To date, only a few studies have addressed SARS-CoV-2 vaccine elicited immunity in this immunocompromised population. METHODS: We assessed immunogenicity of the mRNA vaccine BNT162b2 in at-risk dialysis patients and characterised systemic cellular and humoral immune responses in serum and saliva using interferon γ release assay and multiplex-based cytokine and immunoglobulin measurements. We further compared binding capacity and neutralization efficacy of vaccination-induced immunoglobulins against emerging SARS-CoV-2 variants Alpha, Beta, Epsilon and Cluster 5 by ACE2-RBD competition assay. FINDINGS: Patients on maintenance haemodialysis exhibit detectable but variable cellular and humoral immune responses against SARS-CoV-2 and variants of concern after a two-dose regimen of BNT162b2. Although vaccination-induced immunoglobulins were detectable in saliva and plasma, both anti-SARS-CoV-2 IgG and neutralization efficacy was reduced compared to a vaccinated non-dialysed control population. Similarly, T-cell mediated interferon γ release after stimulation with SARS-CoV-2 spike peptides was significantly diminished. INTERPRETATION: Quantifiable humoral and cellular immune responses after BNT162b2 vaccination in individuals on maintenance haemodialysis are encouraging, but urge for longitudinal follow-up to assess longevity of immunity. Diminished virus neutralization and interferon γ responses in the face of emerging variants of concern may favour this at-risk population for re-vaccination using modified vaccines at the earliest opportunity. FUNDING: Initiative and Networking Fund of the Helmholtz Association of German Research Centres, EU Horizon 2020 research and innovation program, State Ministry of Baden-Württemberg for Economic Affairs, Labour and Tourism.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/immunology , Immunity, Cellular/immunology , Immunity, Humoral/immunology , Immunogenicity, Vaccine/immunology , SARS-CoV-2/immunology , Vaccines, Synthetic/immunology , Aged , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Female , Humans , Immunoglobulin G/immunology , Male , Middle Aged , Renal Dialysis/methods , Spike Glycoprotein, Coronavirus/immunology , T-Lymphocytes/immunology , Vaccination/methods
10.
Nat Med ; 27(9): 1525-1529, 2021 09.
Article in English | MEDLINE | ID: covidwho-1310811

ABSTRACT

Currently approved viral vector-based and mRNA-based vaccine approaches against coronavirus disease 2019 (COVID-19) consider only homologous prime-boost vaccination. After reports of thromboembolic events, several European governments recommended using AstraZeneca's ChAdOx1-nCov-19 (ChAd) only in individuals older than 60 years, leaving millions of already ChAd-primed individuals with the decision to receive either a second shot of ChAd or a heterologous boost with mRNA-based vaccines. However, such combinations have not been tested so far. We used Hannover Medical School's COVID-19 Contact Study cohort of healthcare professionals to monitor ChAd-primed immune responses before and 3 weeks after booster with ChAd (n = 32) or BioNTech/Pfizer's BNT162b2 (n = 55). Although both vaccines boosted prime-induced immunity, BNT162b2 induced significantly higher frequencies of spike-specific CD4+ and CD8+ T cells and, in particular, high titers of neutralizing antibodies against the B.1.1.7, B.1.351 and P.1 variants of concern of severe acute respiratory syndrome coronavirus 2.


Subject(s)
Antibodies, Neutralizing/blood , Antibodies, Viral/blood , COVID-19 Vaccines/adverse effects , COVID-19 Vaccines/immunology , SARS-CoV-2/immunology , CD4 Lymphocyte Count , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , Humans , Immunization, Secondary/methods , Immunogenicity, Vaccine/immunology , Spike Glycoprotein, Coronavirus/immunology , Vaccination
11.
Cell Rep ; 36(3): 109415, 2021 07 20.
Article in English | MEDLINE | ID: covidwho-1283976

ABSTRACT

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants threatens efforts to contain the coronavirus disease 2019 (COVID-19) pandemic. The number of COVID-19 cases and deaths in India has risen steeply, and a SARS-CoV-2 variant, B.1.617, is believed to be responsible for many of these cases. The spike protein of B.1.617 harbors two mutations in the receptor binding domain, which interacts with the angiotensin converting enzyme 2 (ACE2) receptor and constitutes the main target of neutralizing antibodies. Therefore, we analyze whether B.1.617 is more adept in entering cells and/or evades antibody responses. B.1.617 enters two of eight cell lines tested with roughly 50% increased efficiency and is equally inhibited by two entry inhibitors. In contrast, B.1.617 is resistant against bamlanivimab, an antibody used for COVID-19 treatment. B.1.617 evades antibodies induced by infection or vaccination, although less so than the B.1.351 variant. Collectively, our study reveals that antibody evasion of B.1.617 may contribute to the rapid spread of this variant.


Subject(s)
Angiotensin-Converting Enzyme 2/pharmacology , Antibodies, Monoclonal, Humanized/pharmacology , Antibodies, Viral/pharmacology , COVID-19/drug therapy , Esters/pharmacology , Guanidines/pharmacology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Antibodies, Monoclonal, Humanized/immunology , Antibodies, Viral/immunology , COVID-19/immunology , Cell Line , Humans , Protease Inhibitors/pharmacology , Protein Binding , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Vaccination
12.
Immunity ; 54(2): 340-354.e6, 2021 02 09.
Article in English | MEDLINE | ID: covidwho-1071479

ABSTRACT

Cellular and humoral immunity to SARS-CoV-2 is critical to control primary infection and correlates with severity of disease. The role of SARS-CoV-2-specific T cell immunity, its relationship to antibodies, and pre-existing immunity against endemic coronaviruses (huCoV), which has been hypothesized to be protective, were investigated in 82 healthy donors (HDs), 204 recovered (RCs), and 92 active COVID-19 patients (ACs). ACs had high amounts of anti-SARS-CoV-2 nucleocapsid and spike IgG but lymphopenia and overall reduced antiviral T cell responses due to the inflammatory milieu, expression of inhibitory molecules (PD-1, Tim-3) as well as effector caspase-3, -7, and -8 activity in T cells. SARS-CoV-2-specific T cell immunity conferred by polyfunctional, mainly interferon-γ-secreting CD4+ T cells remained stable throughout convalescence, whereas humoral responses declined. Immune responses toward huCoV in RCs with mild disease and strong cellular SARS-CoV-2 T cell reactivity imply a protective role of pre-existing immunity against huCoV.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , COVID-19/immunology , Immunity, Cellular/immunology , Adult , Aged , Aged, 80 and over , Antibodies, Viral/blood , Antibodies, Viral/immunology , Female , Humans , Immunity, Humoral/immunology , Male , Middle Aged , SARS-CoV-2/immunology , Young Adult
13.
Cell Mol Immunol ; 18(4): 936-944, 2021 04.
Article in English | MEDLINE | ID: covidwho-899921

ABSTRACT

Neutralizing antibodies targeting the receptor-binding domain (RBD) of the SARS-CoV-2 spike (S) block severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry into cells via surface-expressed angiotensin-converting enzyme 2 (ACE2). We used a surrogate virus neutralization test (sVNT) and SARS-CoV-2 S protein-pseudotyped vesicular stomatitis virus (VSV) vector-based neutralization assay (pVNT) to assess the degree to which serum antibodies from coronavirus disease 2019 (COVID-19) convalescent patients interfere with the binding of SARS-CoV-2 S to ACE2. Both tests revealed neutralizing anti-SARS-CoV-2 S antibodies in the sera of ~90% of mildly and 100% of severely affected COVID-19 convalescent patients. Importantly, sVNT and pVNT results correlated strongly with each other and to the levels of anti-SARS-CoV-2 S1 IgG and IgA antibodies. Moreover, levels of neutralizing antibodies correlated with the duration and severity of clinical symptoms but not with patient age. Compared to pVNT, sVNT is less sophisticated and does not require any biosafety labs. Since this assay is also much faster and cheaper, sVNT will not only be important for evaluating the prevalence of neutralizing antibodies in a population but also for identifying promising plasma donors for successful passive antibody therapy.


Subject(s)
Antibodies, Neutralizing/blood , Antibodies, Viral/blood , COVID-19/immunology , Spike Glycoprotein, Coronavirus/immunology , Adult , Aged , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/blood , Cell Line , Convalescence , Female , Humans , Immunoglobulin A/blood , Immunoglobulin G/blood , Male , Middle Aged , Neutralization Tests/methods
14.
Infect Dis Ther ; 9(4): 837-849, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-743789

ABSTRACT

BACKGROUND: Serology testing is explored for epidemiological research and to inform individuals after suspected infection. During the coronavirus disease 2019 (COVID-19) pandemic, frontline healthcare professionals (HCP) may be at particular risk for infection. No longitudinal data on functional seroconversion in HCP in regions with low COVID-19 prevalence and low pre-test probability exist. METHODS: In a large German university hospital, we performed weekly questionnaire assessments and anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunoglobulin G (IgG) measurements with various commercial tests, a novel surrogate virus neutralisation test, and a neutralisation assay using live SARS-CoV-2. RESULTS: From baseline to week 6, 1080 screening measurements for anti-SARS CoV-2 (S1) IgG from 217 frontline HCP (65% female) were performed. Overall, 75.6% of HCP reported at least one symptom of respiratory infection. Self-perceived infection probability declined over time (from mean 20.1% at baseline to 12.4% in week 6, p < 0.001). In sera of convalescent patients with PCR-confirmed COVID-19, we measured high anti-SARS-CoV-2 IgG levels, obtained highly concordant results from enzyme-linked immunosorbent assays (ELISA) using e.g. the spike 1 (S1) protein domain and the nucleocapsid protein (NCP) as targets, and confirmed antiviral neutralisation. However, in HCP the cumulative incidence for anti-SARS-CoV-2 (S1) IgG was 1.86% for positive and 0.93% for equivocal positive results over the study period of 6 weeks. Except for one HCP, none of the eight initial positive results were confirmed by alternative serology tests or showed in vitro neutralisation against live SARS-CoV-2. The only true seroconversion occurred without symptoms and mounted strong functional humoral immunity. Thus, the confirmed cumulative incidence for neutralizing anti-SARS-CoV-2 IgG was 0.47%. CONCLUSION: When assessing anti-SARS-CoV-2 immune status in individuals with low pre-test probability, we suggest confirming positive results from single measurements by alternative serology tests or functional assays. Our data highlight the need for a methodical serology screening approach in regions with low SARS-CoV-2 infection rates. TRIAL REGISTRATION: The study is registered at DRKS00021152.

15.
Infection ; 48(4): 631-634, 2020 Aug.
Article in English | MEDLINE | ID: covidwho-592158

ABSTRACT

There have been concerns about high rates of thus far undiagnosed SARS-CoV-2 infections in the health-care system. The COVID-19 Contact (CoCo) Study follows 217 frontline health-care professionals at a university hospital with weekly SARS-CoV-2-specific serology (IgA/IgG). Study participants estimated their personal likelihood of having had a SARS-CoV-2 infection with a mean of 21% [median 15%, interquartile range (IQR) 5-30%]. In contrast, anti-SARS-CoV-2 IgG prevalence was about 1-2% at baseline. Regular anti-SARS-CoV-2 IgG testing of health-care professionals may aid in directing resources for protective measures and care of COVID-19 patients in the long run.


Subject(s)
Antibodies, Viral/blood , Coronavirus Infections/immunology , Health Personnel , Pneumonia, Viral/immunology , Adolescent , Adult , Aged , Betacoronavirus , COVID-19 , Coronavirus Infections/diagnosis , Female , Germany , Hospitals, University , Humans , Immunoglobulin A/blood , Immunoglobulin G/blood , Male , Middle Aged , Pandemics , Pneumonia, Viral/diagnosis , Prevalence , SARS-CoV-2 , Seroepidemiologic Studies , Serologic Tests , Young Adult
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