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1.
medrxiv; 2023.
Preprint in English | medRxiv | ID: ppzbmed-10.1101.2023.01.09.23284335

ABSTRACT

Introduction - Monitoring of COVID-19 vaccine effectiveness (VE) is needed to inform vaccine policy. We estimated VE of primary vaccination, and first and second booster vaccination, against SARS-CoV-2 infection overall, and in four risk groups defined by age and medical risk condition, in the Delta and Omicron BA.1/BA.2 periods. Methods - VASCO is an ongoing prospective cohort study among vaccinated and unvaccinated Dutch adults. The primary endpoint was a self-reported positive SARS-CoV-2 test during 12 July 2021-6 June 2022. Participants with a prior SARS-CoV-2 infection, based on a positive test or serology, were excluded. We used Cox proportional hazard models with vaccination status as time-varying exposure and adjustment for age, sex, educational level, and medical risk condition. We stratified by Delta and Omicron BA.1/BA.2 periods, risk group, and time since vaccination. Results - 37,170 participants (mean age 57 years) were included. In the Delta period, VE <6 weeks after primary vaccination was 80% (95%CI 69-87) and decreased to 71% (65-77) after 6 months. VE increased to 96% (86-99) shortly after the first booster vaccination. In the Omicron period these estimates were 46% (22-63), 25% (8-39) and 57% (52-62), respectively. VE was 50% (34-62) <6 weeks after a second booster vaccination in participants aged [≥]60 years. For the Omicron period, an interaction term between vaccination status and risk group significantly improved the model (p<0.001), with generally lower VEs for those with a medical risk condition. Conclusions - Our results show the benefit of booster vaccinations against infection, also in risk groups, although the additional protection wanes quite rapidly.


Subject(s)
COVID-19
2.
medrxiv; 2023.
Preprint in English | medRxiv | ID: ppzbmed-10.1101.2023.01.09.23284334

ABSTRACT

Objectives: To estimate the protective effect of previous infections and vaccinations on SARS-CoV-2 Omicron infection. Design: Prospective cohort study Setting: Community-based cohort, the Netherlands Participants: 43,257 Community-dwelling adults aged 18-85 years contributed 8,291,966 person-days between 10 January 2022 and 1 September 2022. Main outcome measures: SARS-CoV-2 infection, defined as either a reported positive (self-administered) antigen or PCR test, or seroconversion or 4-fold increase in Nucleoprotein-antibodies, based on 6-monthly serum samples. Cox proportional hazard models were used with SARS-CoV-2 infection and any COVID-19 vaccination as time-varying exposures, calendar time as underlying time scale and adjustment for age, sex, medical risk and educational level. Results: In participants with 2, 3 or 4 prior immunizing events (vaccination or previous infection), we found a relative reduction of 71-85% in Omicron infection in weeks 4-10 post-last event with hybrid immunity compared to vaccine-induced immunity. Differences in risk of infection were partly explained by differences in anti-Spike RBD (S) antibody concentration, which showed a similar pattern but with smaller differences between vaccine-induced and hybrid immunity. Compared to the lowest quartile, participants in subsequent quartiles of S-antibody concentrations had 19%, 35% and 71% reduced risk of infection, respectively. Among participants with hybrid immunity, with one previous pre-Omicron infection, there was no relevant difference in risk of Omicron infection by sequence of vaccination(s) and infection). Regardless of the type of previous immunizing events, additional events increased the protection against infection, but not above the level of the first weeks after the previous event. Conclusions: Our results showed that hybrid immunity is more protective against infection with SARS-CoV-2 Omicron than vaccine-induced immunity, up to at least 30 weeks after the last immunizing event. Among those with hybrid immunity, the sequence and number of immunizing events was not found to be of importance, and its protective effect was partly explained by circulating S-antibodies. In our population with a high level of immunity, additional immunizing events reduced risk of infection with Omicron variants only temporarily. Trial registration: Dutch Trial Register (NTR), registration number NL9279 (available via ICTRP Search Portal (who.int))


Subject(s)
COVID-19 , Severe Acute Respiratory Syndrome
3.
medrxiv; 2022.
Preprint in English | medRxiv | ID: ppzbmed-10.1101.2022.05.18.22275209

ABSTRACT

Vaccine-induced protection of the population against severe COVID-19, hospitalization and death is of utmost importance, especially in the elderly. However, limited data are available on humoral immune responses following COVID-19 vaccination in the general population across a broad age range. We performed an integrated analysis of the effect of age, sex and prior SARS-CoV-2 infection on Spike S1-specific (S1) IgG concentrations up to three months post BNT162b2 vaccination. 1,735 persons, eligible for COVID-19 vaccination through the national program, were recruited from the general population (12 to 92 years old). Sixty percent were female and the median vaccination interval was 35 days (interquartile range, IQR: 35-35). All participants had seroconverted to S1 one month after two doses of vaccine. S1 IgG was higher in participants with a history of SARS-CoV-2 infection (median: 4,535 BAU/ml, IQR: 2,341-7,205) compared to infection-naive persons (1,842 BAU/ml, 1,019-3,116) after two doses, p<0.001. In infection-naive persons, linear mixed effects regression showed a strong negative association between age and S1 IgG one month after the first vaccination (p<0.001) across the entire age range. The association was still present after the second vaccination, but less pronounced. Females had higher S1 IgG than males after both the first and second vaccination (p<0.001); although this difference was lower after the second dose. In persons with an infection history, age nor sex was associated with peak S1 IgG. As IgG decreased with age and time since vaccination, older persons may become at risk of infection, especially with escape variants such as Omicron.


Subject(s)
COVID-19
4.
researchsquare; 2022.
Preprint in English | PREPRINT-RESEARCHSQUARE | ID: ppzbmed-10.21203.rs.3.rs-1645696.v1

ABSTRACT

VAccine Study COvid-19 (VASCO) is a cohort study with 5-year follow-up to assess the real-world vaccine effectiveness (VE) of COVID-19 vaccines in the Netherlands. VASCO was initiated when COVID-19 vaccination was introduced in the Netherlands. The primary objective is to estimate vaccine-specific VE against symptomatic SARS-CoV-2 infection, overall and in four subpopulations defined by age and medical risk, at 9 months after study start when most participants would have accumulated at least 6 months of follow-up. Secondary objectives are to estimate VE by time since vaccination and by severity of SARS-CoV-2 infection. Between May and December 2021, 45,271 participants aged 18–85 years have been enrolled in VASCO. Participants were included irrespective of their COVID-19 vaccination status or intention to get vaccinated. At inclusion, at 6, 12, 24, 36, 48 and 60 months after inclusion, and at one month after primary vaccination, participants are asked to take a self-collected fingerprick blood sample at home. In the serum samples, nucleoprotein (N) and spike protein receptor binding domain (RBD)-specific antibody titers are assessed to determine vaccine response and prior SARS-CoV-2 infection(s), including prior asymptomatic infections. Participants are also asked to complete monthly digital questionnaires in the first year, and 3-monthly in years 2–5, including questions on sociodemographic factors, health status, COVID-19 vaccination, SARS-CoV-2 related symptoms and testing results, and behavioral responses to COVID-19 measures. The main aim of VASCO is to contribute to policy decision-making regarding future COVID-19 vaccination. Furthermore, VASCO provides an infrastructure to conduct substudies in response to unforeseen developments within the COVID-19 pandemic.


Subject(s)
COVID-19
5.
medrxiv; 2022.
Preprint in English | medRxiv | ID: ppzbmed-10.1101.2022.04.08.22273602

ABSTRACT

ImportanceIn patients with hematologic malignancies, the immunogenicity of the standard 2-dose mRNA-1273 coronavirus disease 19 (COVID-19) vaccination schedule is often insufficient due to underlying disease and current or recent therapy. ObjectiveTo determine whether a 3rd mRNA-1273 vaccination raises antibody concentrations in immunocompromised hematology patients to levels obtained in healthy individuals after the standard 2-dose mRNA-1273 vaccination schedule. DesignProspective observational cohort study. SettingFour academic hospitals in the Netherlands. Participants584 evaluable immunocompromised hematology patients, all grouped in predefined cohorts spanning the spectrum of hematologic malignancies. ExposureOne additional vaccination with mRNA-1273 5 months after completion of the standard 2-dose mRNA-1273 vaccination schedule. Main Outcomes and MeasuresSerum IgG antibodies to spike subunit 1 (S1) antigens prior to and 4 weeks after each vaccination, and pseudovirus neutralization of wildtype, delta and omicron variants in a subgroup of patients. ResultsIn immunocompromised hematology patients, a 3rd mRNA-1273 vaccination led to median S1 IgG concentrations comparable to concentrations obtained by healthy individuals after the 2-dose mRNA-1273 schedule. The rise in S1 IgG concentration after the 3rd vaccination was most pronounced in patients with a recovering immune system, but potent responses were also observed in patients with persistent immunodeficiencies. Specifically, patients with myeloid malignancies or multiple myeloma, and recipients of autologous or allogeneic hematopoietic cell transplantation (HCT) reached median S1 IgG concentrations similar to those obtained by healthy individuals after a 2-dose schedule. Patients on or shortly after rituximab therapy, CD19-directed chimeric antigen receptor T cell therapy recipients, and chronic lymphocytic leukemia patients on ibrutinib were less or unresponsive to the 3rd vaccination. In the 27 patients who received cell therapy between the 2nd and 3rd vaccination, S1 antibodies were preserved, but a 3rd mRNA-1273 vaccination did not significantly enhance S1 IgG concentrations except for multiple myeloma patients receiving autologous HCT. A 3rd vaccination significantly improved neutralization capacity per antibody. Conclusions and RelevanceThe primary schedule for immunocompromised patients with hematologic malignancies should be supplemented with a delayed 3rd vaccination. B cell lymphoma patients and allogeneic HCT recipients need to be revaccinated after treatment or transplantation. Trial RegistrationEudraCT 2021-001072-41 Key pointsO_ST_ABSQuestionC_ST_ABSCan a 3rd mRNA-1273 vaccination improve COVID-19 antibody concentrations in immunocompromised hematology patients to levels similar to healthy adults after the standard 2-dose mRNA-1273 schedule? FindingsIn this prospective observational cohort study that included 584 immunocompromised hematology patients, a 3rd mRNA-1273 vaccination significantly improved SARS-CoV-2 antibody concentrations to levels not significantly different from those obtained by healthy individuals after the standard 2-dose mRNA-1273 vaccination schedule. Pseudovirus neutralization capacity per antibody of wild type virus and variants of concern also significantly improved. MeaningThe primary COVID-19 vaccination schedule for immunocompromised patients with hematologic malignancies should be supplemented with a delayed 3rd vaccination.


Subject(s)
Lymphoma, B-Cell , Hematologic Neoplasms , Immunologic Deficiency Syndromes , Coronavirus Infections , COVID-19 , Leukemia, Lymphocytic, Chronic, B-Cell , Multiple Myeloma
7.
researchsquare; 2021.
Preprint in English | PREPRINT-RESEARCHSQUARE | ID: ppzbmed-10.21203.rs.3.rs-1026794.v2

ABSTRACT

Background. The impact of COVID-19 on population health is recognised as being substantial, yet few studies have attempted to quantify to what extent infection causes mild or moderate symptoms only, requires hospital and/or ICU admission, results in prolonged and chronic illness, or leads to premature death. We aimed to quantify the total disease burden of acute COVID-19 in the Netherlands in 2020 using the disability-adjusted life-years (DALY) measure, and to investigate how burden varies between age-groups and occupations.Methods. Using standard methods and diverse data sources (mandatory notifications, population-level seroprevalence, hospital and ICU admissions, registered COVID-19 deaths, and the literature), we estimated years of life lost (YLL), years lived with disability, DALY and DALY per 100,000 population due to COVID-19, excluding post-acute sequelae, stratified by 5-year age-group and occupation category.Results. The total disease burden due to acute COVID-19 was 286,100 (95% CI:281,700–290,500) DALY, and the per-capita burden was 1640 (95% CI:1620–1670) DALY/100,000, of which 99.4% consisted of YLL. The per-capita burden increased steeply with age, starting from 60–64 years, with relatively little burden estimated for persons under 50 years old.Conclusions. SARS-CoV-2 infection and associated premature mortality was responsible for a considerable direct health burden in the Netherlands, despite extensive public health measures. DALY were much higher than for other high-burden infectious diseases, but lower than estimated for coronary heart disease. These findings are valuable for informing public health decision-makers regarding the expected COVID-19 health burden among population subgroups, and the possible gains from targeted preventative interventions.


Subject(s)
COVID-19
8.
medrxiv; 2021.
Preprint in English | medRxiv | ID: ppzbmed-10.1101.2021.10.25.21265467

ABSTRACT

mRNA- and vector-based vaccines are used at a large scale to prevent COVID-19. We compared Spike S1-specific (S1) IgG antibodies after vaccination with mRNA-based (Comirnaty, Spikevax) or vector-based (Janssen, Vaxzevria) vaccines, using samples from a Dutch nationwide cohort. mRNA vaccines induced faster inclines and higher S1 antibodies compared to vector-based vaccines in adults 18-64 years old (n=2,412). For all vaccines, one dose resulted in boosting of S1 antibodies in adults with a history of SARS-CoV-2 infection. For Comirnaty, two to four months following the second dose (n=196), S1 antibodies in adults aged 18-64 years old (436 BAU/mL, interquartile range: 328-891) were less variable and median concentrations higher compared to those in persons [≥]80 years old (366, 177-743), but differences were not statistically significant (p>0.100). Nearly all participants seroconverted following COVID-19 vaccination, including the aging population. These data confirm results from controlled vaccine trials in a general population, including vulnerable groups.


Subject(s)
COVID-19
9.
medrxiv; 2021.
Preprint in English | medRxiv | ID: ppzbmed-10.1101.2021.10.05.21264555

ABSTRACT

BackgroundWith COVID-19 vaccine roll-out ongoing in many countries globally, monitoring of breakthrough infections is of great importance. Antibodies persist in the blood after a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Since COVID-19 vaccines induce immune response to the Spike protein of the virus, which is the main serosurveillance target to date, alternative targets should be explored to distinguish infection from vaccination. MethodsMultiplex immunoassay data from 1,513 SARS-CoV-2 RT-qPCR-tested individuals (352 positive and 1,161 negative) with a primary infection and no vaccination history were used to determine the accuracy of Nucleoprotein-specific immunoglobulin G (IgG) in detecting past SARS-CoV-2 infection. We also described Spike S1 and Nucleoprotein-specific IgG responses in 230 COVID-19 vaccinated individuals (Pfizer/BioNTech). ResultsThe sensitivity of Nucleoprotein seropositivity was 85% (95% confidence interval: 80-90%) for mild COVID-19 in the first two months following symptom onset. Sensitivity was lower in asymptomatic individuals (67%, 50-81%). Participants who had experienced a SARS-CoV-2 infection up to 11 months preceding vaccination, as assessed by Spike S1 seropositivity or RT-qPCR, produced 2.7-fold higher median levels of IgG to Spike S1 [≥]14 days after the first dose as compared to those unexposed to SARS-CoV-2 at [≥]7 days after the second dose (p=0.011). Nucleoprotein-specific IgG concentrations were not affected by vaccination in naive participants. ConclusionsSerological responses to Nucleoprotein may prove helpful in identifying SARS-CoV-2 infections after vaccination. Furthermore, it can help interpret IgG to Spike S1 after COVID-19 vaccination as particularly high responses shortly after vaccination could be explained by prior exposure history.


Subject(s)
Breakthrough Pain , Coronavirus Infections , COVID-19 , Severe Acute Respiratory Syndrome
10.
medrxiv; 2021.
Preprint in English | medRxiv | ID: ppzbmed-10.1101.2021.09.10.21263333

ABSTRACT

BackgroundSevere acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has led to considerable morbidity/mortality worldwide, but most infections, especially among children, have a mild course. However, it remains largely unknown whether infected children develop cellular immune memory. MethodsTo determine whether a memory T cell response is being developed as an indicator for long-term immune protection, we performed a longitudinal assessment of the SARS-CoV-2-specific T cell response by IFN-{gamma} ELISPOT and activation marker expression analyses of peripheral blood samples from children and adults with mild-to-moderate COVID-19. ResultsUpon stimulation of PBMCs with heat-inactivated SARS-CoV-2 or overlapping peptides of spike (S-SARS-CoV-2) and nucleocapsid proteins, we found S-SARS-CoV-2-specific IFN-{gamma} T cell responses in most infected children (83%) and all adults (100%) that were absent in unexposed controls. Frequencies of SARS-CoV-2-specific T cells were higher in infected adults, especially in those with moderate symptoms, compared to infected children. The S-SARS-CoV-2 IFN-{gamma} T cell response correlated with S1-SARS-CoV-2-specific serum IgM, IgG, and IgA antibody concentrations. Predominantly, effector memory CD4+ T cells of a Th1 phenotype were activated upon exposure to SARS-CoV-2 antigens, which persisted for 4-8 weeks after symptom onset. We detected very low frequencies of SARS-CoV-2-reactive CD8+ T cells in these individuals. ConclusionsOur data indicate that an antigen-specific memory CD4+ T cell response is induced in children and adults with mild SARS-CoV-2 infection. T cell immunity induced after mild COVID-19 could contribute to protection against re-infection.


Subject(s)
COVID-19 , Memory Disorders , Severe Acute Respiratory Syndrome
11.
ssrn; 2021.
Preprint in English | PREPRINT-SSRN | ID: ppzbmed-10.2139.ssrn.3892129

ABSTRACT

Background: There is an urgent need for fair and equitable access to safe and effective vaccines to end the COVID-19 pandemic. Shortages in reagents and vaccines are a major challenge, as well as limited knowledge on dose response relationship with mRNA COVID-19 vaccines. We explored intradermal fractional dose administration of a mRNA SARS-CoV-2/COVID-19 vaccine as a potential dose-sparing strategy. Methods: We conducted a proof-of-concept, dose-escalation, open-label, randomised-controlled vaccine trial (IDSCOVA) in healthy adults aged 18-30 years. To test initial safety, ten participants received 10 µg mRNA-1273 vaccine through intradermal injection at day 1 and 29. Following a favourable safety review, thirty participants were 1:1 randomised to receive 20 µg mRNA-1273 either intradermally or intramuscularly. The primary endpoint was tolerability and safety. The secondary endpoint was seroconversion and specific IgG concentration against SARS-CoV-2 spike S1 and Receptor Binding Domain (RBD) after the second dose at day 43. We compared results to two historical cohorts of non-hospitalised COVID-19 patients and vaccinated individuals. Findings: Thirty-eight of forty included participants (median age 25 years) completed the study. There were no serious adverse events. Self-reported local adverse reactions after intradermal delivery were mild, both in the 10 µg and the 20 µg group. In the higher dose group, systemic adverse reactions were more common , but still well tolerated. All 38 participants mounted substantially higher IgG-anti-S1 and IgG-anti-RBD concentrations at day 43 than COVID-19 controls. At day 43, anti-S1 (95% CI) was 1,696 (1,309-2,198) BAU/mL for the 10 µg intradermal group, 1,406 (953·5-2,074) BAU/mL for the 20 µg intramuscular group and 2,057 (1,421-2,975) BAU/mL for the 20 µg intradermal group. Anti-S1 was 107·2 (63-182·2) BAU/mL for the convalescent plasma control group and 1,558 (547·8-4,433) BAU/mL for the individuals vaccinated with 100 µg mRNA-1273.Interpretation: Intradermal administration of 10 µg and 20 µg mRNA-1273 vaccine was well tolerated and safe, and resulted in a robust antibody response. Intradermal vaccination has the potential to be deployed for vaccine dose-sparing.Clinical Trial Registration Details: registered in the Netherlands Trial Register (NTR) (https://www.trialregister.nl/trial/9275).Funding Information: The trial was supported by crowdfunding (Wake Up to Corona).Declaration of Interests: All authors declare no competing interests. Ethics Approval Statement: The trial was performed in accordance with the ethical principles of the Declaration of Helsinki and Good Clinical Practice guidelines developed by the International Harmonisation Task Force. The protocol was approved by the Medical Ethical Committee Leiden, Den Haag, Delft (NL 76702.058.21). All participants provided written informed consent. The vaccine manufacturer was not involved in this trial.


Subject(s)
COVID-19
12.
medrxiv; 2021.
Preprint in English | medRxiv | ID: ppzbmed-10.1101.2021.03.29.21254334

ABSTRACT

BackgroundThe proportion of SARS-CoV-2 positive persons who are asymptomatic - and whether this proportion is age-dependent - are still open research questions. Because an unknown proportion of reported symptoms among SARS-CoV-2 positives will be attributable to another infection or affliction, the observed, or crude proportion without symptoms may underestimate the proportion of persons without symptoms that are caused by SARS-CoV-2 infection. MethodsBased on a large population-based serological study comprising test results on seropositivity and self-reported symptom history conducted in April/May 2020 in the Netherlands (n=3147), we estimated the proportion of reported symptoms among those persons infected with SARS-CoV-2 that is attributable to this infection, where the set of relevant symptoms fulfills the ECDC case definition of COVID-19, using inferential methods for the attributable risk (AR). Generalised additive regression modelling was used to estimate the age-dependent relative risk (RR) of reported symptoms, and the AR and asymptomatic proportion (AP) were calculated from the fitted RR. ResultsUsing age-aggregated data, the estimated AP was 70% (95% CI: 65-77%). The estimated AP decreased with age, from 80% (95% CI: 67-100%) for the <20 years age-group, to 55% (95% CI: 48-68%) for the 70+ years age-group. ConclusionWhereas the crude AP represents a lower bound for the proportion of persons infected with SARS-CoV-2 without COVID-19 symptoms, the AP as estimated via an attributable risk approach represents an upper bound. Age-specific AP estimates can inform the implementation of public health actions such as targetted virological testing and therefore enhance containment strategies.


Subject(s)
COVID-19
13.
ssrn; 2021.
Preprint in English | PREPRINT-SSRN | ID: ppzbmed-10.2139.ssrn.3800076

ABSTRACT

Background: Cases of reinfection with SARS-CoV-2 are reported in increasing numbers. Since the required molecular proof of reinfection is challenging to obtain, we aimed to provide serological evidence of reinfection in a cohort of potential reinfection cases.Methods: The study comprises 38 RT-PCR confirmed reinfection cases, with a COVID-19 symptom-free interval of at least 8 weeks (range 57-133 days) since their first RT-PCR confirmed episode. Specific disease symptoms were retrieved from 22 cases by contact tracing and compared between the two disease episodes. The oropharyngeal specimens from 13 cases enabled adequate genomic sequence comparisons. Seventeen cases provided a serum specimen, of which 12 within 7 days after onset of symptoms. Antibody determinations included SARS-CoV-2-specific total Ig, IgM, IgG, avidity, and virus neutralization. Antibody data were compared to that of a control group of primary cases (n=86) in relation to time since onset of disease symptoms.Findings: Reinfection cases generally experienced fewer or milder symptoms. Five of 8 cases which passed genomic comparison between both disease episodes showed reinfection with a different lineage. From 12 reinfection cases that provided a serum sample within 7 days after onset of symptoms, 11/12 (92%) and 12/12 (100%) showed high levels of specific total Ig and IgG antibodies, respectively, compared to 1/23 (4%) and 2/23 (9%) within the control group. Virus neutralizing antibodies were detected in 9/12 (75%) reinfection cases, 5 of which were above a titer of 30. Serological discrimination diminished after 7 days, except for IgG avidity; all 17 reinfection cases had antibodies of higher avidity when compared to control cases.Interpretation: IgG concentration and avidity can be used as an additional diagnostic marker to confirm reinfection with SARS-Cov-2. Reinfection cases that show a rapid and effective secondary immune response are expected to clear the infection more effectively, thereby reducing contagiousness and clinical severity. Understanding this reinfection response is also important for breakthrough infections following vaccination.Funding Statement: This work was supported by the National Institute for Public Health and the Environment, The Netherlands.Declaration of Interests: None of the authors have an association that poses a conflict of interest.Ethics Approval Statement: Approved by the Medical-Ethical Review Committee of the University Medical Center Utrecht.


Subject(s)
COVID-19
14.
medrxiv; 2021.
Preprint in English | medRxiv | ID: ppzbmed-10.1101.2021.02.10.21251477

ABSTRACT

ABSTRACT This large nationwide population-based seroepidemiological study provides evidence on the effectiveness of physical distancing (>1.5m) and indoor group size reductions on SARS-CoV-2 infection. Additionally, young adults seem to play a significant role in viral spread, opposed to children up until the primary school age with whom close contact is permitted.


Subject(s)
COVID-19 , HIV Seropositivity
15.
biorxiv; 2020.
Preprint in English | bioRxiv | ID: ppzbmed-10.1101.2020.12.23.424199

ABSTRACT

Since the beginning of the COVID19 pandemics, an unprecedented research effort has been conducted to analyze the antibody responses in patients, and many trials based on passive immunotherapy -notably monoclonal antibodies - are ongoing. Twenty-one antibodies have entered clinical trials, 6 having reached phase 2/3, phase 3 or having received emergency authorization. These represent only the tip of the iceberg, since many more antibodies have been discovered and represent opportunities either for diagnosis purposes or as drug candidates. The main problem facing laboratories willing to develop such antibodies is the huge task of analyzing them and choosing the best candidate for exhaustive experimental validation. In this work we show how artificial intelligence-based methods can help in analyzing large sets of antibodies in order to determine in a few hours the best candidates in few hours. The MAbCluster method, which only requires knowledge of the amino acid sequences of the antibodies, allows to group the antibodies having the same epitope, considering only their amino acid sequences and their 3D structures (actual or predicted), and to infer some of their functional properties. We then use MAbTope to predict the epitopes for all antibodies for which they are not already known. This allows an exhaustive comparison of the available epitopes, but also gives a synthetic view of the possible combinations. Finally, we show how these results can be used to predict which antibodies might be affected by the different mutations arising in the circulating strains of the virus, such as the N501Y mutation that has started to spread in Great-Britain.


Subject(s)
COVID-19
16.
biorxiv; 2020.
Preprint in English | bioRxiv | ID: ppzbmed-10.1101.2020.12.23.424189

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged as a new human pathogen in late 2019 and has infected an estimated 10% of the global population in less than a year. There is a clear need for effective antiviral drugs to complement current preventive measures including vaccines. In this study, we demonstrate that berberine and obatoclax, two broad-spectrum antiviral compounds, are effective against multiple isolates of SARS-CoV-2. Berberine, a plant-derived alkaloid, inhibited SARS-CoV-2 at low micromolar concentrations and obatoclax, originally developed as an anti-apoptotic protein antagonist, was effective at sub-micromolar concentrations. Time-of-addition studies indicated that berberine acts on the late stage of the viral life cycle. In agreement, berberine mildly affected viral RNA synthesis, but strongly reduced infectious viral titers, leading to an increase in the particle-to-pfu ratio. In contrast, obatoclax acted at the early stage of the infection, in line with its activity to neutralize the acidic environment in endosomes. We assessed infection of primary human nasal epithelial cells cultured on an air-liquid interface and found that SARS-CoV-2 infection induced and repressed expression of a specific set of cytokines and chemokines. Moreover, both obatoclax and berberine inhibited SARS-CoV-2 replication in these primary target cells. We propose berberine and obatoclax as potential antiviral drugs against SARS-CoV-2 that could be considered for further efficacy testing.


Subject(s)
Coronavirus Infections , COVID-19
17.
biorxiv; 2020.
Preprint in English | bioRxiv | ID: ppzbmed-10.1101.2020.11.15.382044

ABSTRACT

The Spike protein of SARS-CoV-2 is essential for virus entry into human cells. In fact, most neutralizing antibodies against SARS-CoV-2 are directed against the Spike, making it the antigen of choice for use in vaccines and diagnostic tests. In the current pandemic context, global demand for Spike proteins has rapidly increased and could exceed hundreds of grams to kilograms annually. Coronavirus Spikes are large, heavily glycosylated, homotrimeric complexes, with inherent instability. Their poor manufacturability now threatens availability of these proteins for vaccines and diagnostic tests. Here, we outline a scalable, GMP-compliant, chemically defined process for production of a cell secreted, stabilized form of the trimeric Spike protein. The process is chemically defined and based on clonal, suspension-CHO cell populations and on protein purification via a two-step, scalable downstream process. The trimeric conformation was confirmed using electron microscopy and HPLC analysis. Binding to susceptible cells was shown using a virus-inhibition assay. The diagnostic sensitivity and specificity for detection of serum SARS-CoV-2 specific IgG1 was investigated and found to exceed that of Spike fragments (S1 and RBD). The process described here will enable production of sufficient high-quality trimeric Spike protein to meet the global demand for SARS-CoV-2 vaccines and diagnostic tests.

18.
medrxiv; 2020.
Preprint in English | medRxiv | ID: ppzbmed-10.1101.2020.06.18.20133660

ABSTRACT

Background The COVID-19 pandemic demands detailed understanding of the kinetics of antibody production induced by infection with SARS-CoV-2. We aimed to develop a high throughput multiplex assay to detect antibodies to SARS-CoV-2 to assess immunity to the virus in the general population. Methods Spike protein subunits S1 and RBD, and Nucleoprotein were coupled to distinct microspheres. Sera collected before the emergence of SARS-CoV-2 (N=224), and of non-SARS-CoV-2 influenza-like illness (N=184), and laboratory-confirmed cases of SARS-CoV-2 infection (N=115) with various severity of COVID-19 were tested for SARS-CoV-2-specific concentrations of IgG. Results Our assay discriminated SARS-CoV-2-induced antibodies and those induced by other viruses. The assay obtained a specificity between 95.1 and 99.0% with a sensitivity ranging from 83.6-95.7%. By merging the test results for all 3 antigens a specificity of 100% was achieved with a sensitivity of at least 90%. Hospitalized COVID-19 patients developed higher IgG concentrations and the rate of IgG production increased faster compared to non-hospitalized cases. Conclusions The bead-based serological assay for quantitation of SARS-CoV-2-specific antibodies proved to be robust and can be conducted in many laboratories. Finally, we demonstrated that testing of antibodies against different antigens increases sensitivity and specificity compared to single antigen-specific IgG determination.


Subject(s)
COVID-19
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