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1.
Topics in Antiviral Medicine ; 30(1 SUPPL):101, 2022.
Article in English | EMBASE | ID: covidwho-1880973

ABSTRACT

Background: The emergence of new SARS-CoV-2 variants raises concerns whether preexisting artificial (vaccine-induced) and natural immunity from prior COVID-19 prevents re-infections. Here, we investigated the differences in primary humoral immune response following SARS-CoV-2 variants of concern (VOCs) infection and aimed to identify the key mutations involved in these differences. Methods: Patients with primary PCR-proven SARS-CoV-2 infection with no history of previous COVID-19 vaccination were included between October 2020 and May 2021 at Amsterdam UMC and via the Dutch SARS-CoV-2 sequence surveillance program. Serum was collected 4-8 weeks after symptom onset and tested for IgG binding and pseudovirus neutralization of the wild-type (WT, Wuhan/D614G), Alpha, Beta and Delta variants. Results: We included 51 COVID-19 patients, who were infected with the WT (n=20), Alpha (n=10), Beta (n=9) or Delta variant (n=12). Generally, the highest neutralization titers were against the autologous virus. After stratifying for hospitalization status, non-hospitalized patients infected with the WT (ID50 817) or Alpha (ID50 2524) variant showed the strongest geometric mean autologous neutralization, followed by the Delta variant (ID50 704) infected participants. By contrast, only one participant infected with the Beta variant showed strong autologous neutralization (median ID50 171). The VOCs also differed in their ability to induce cross-neutralizing responses, with WT-infected patients showing the broadest immune response, followed by Alpha, Delta and Beta infected participants. Additionally, participants infected with the WT, Alpha or Delta variant showed the lowest cross-neutralization against the Beta variant, with a median 5.0-fold (2 to 16-fold), 7.7-fold (2 to 32-fold), and 5.3-fold (1 to 19-fold) reduction compared to the autologous neutralization, respectively. We identified the E484K mutation as the key mutation responsible for this low cross-neutralization. Conclusion: We demonstrated that even small differences in the S protein influences the polyclonal antibody response following infection. The low level of (cross-)neutralization induced by the Beta variant may implicate a higher re-infection risk, but further research of the memory B cell compartment and clinical studies are needed. The broadest cross-neutralizing response observed for WT-infected patients suggests that artificial immunity induced by the current approved COVID-19 vaccines already protects against many re-infections.

2.
Embase; 2021.
Preprint in English | EMBASE | ID: ppcovidwho-336180

ABSTRACT

Background Emerging and future SARS-CoV-2 variants may jeopardize the effectiveness of vaccination campaigns. Therefore, it is important to know how the different vaccines perform against diverse SARS-CoV-2 variants. Methods In a prospective cohort of 165 SARS-CoV-2 naive health care workers, vaccinated with either one of four vaccines (BNT162b2, mRNA-1273, AZD1222 or Ad26.COV2.S), we performed a head-to-head comparison of the ability of sera to recognize and neutralize SARS-CoV-2 variants of concern (VOCs;Alpha, Beta, Gamma, Delta and Omicron). Repeated serum sampling was performed 5 times during a year (from January 2021 till January 2022), including before and after booster vaccination with BNT162b2. Findings Four weeks after completing the initial vaccination series, SARS-CoV-2 wild-type neutralizing antibody titers were highest in recipients of BNT162b2 and mRNA-1273 (geometric mean titers (GMT) of 197 [95% CI 149-260] and 313 [95% CI 218-448], respectively), and substantially lower in those vaccinated with the adenovirus vector-based vaccines AZD1222 and Ad26.COV2.S (GMT of 26 [95% CI 18-37] and 14 [95% CI 8-25] IU/ml, respectively). These findings were robust for adjustment to age and sex. VOCs neutralization was reduced in all vaccine groups, with the largest (9- to 80-fold) reduction in neutralization observed against the Omicron variant. The booster BNT162b2 vaccination increased neutralizing antibody titers for all groups with substantial improvement against the VOCs including the Omicron variant. Study limitations include the lack of cellular immunity data. Conclusions Overall, this study shows that the mRNA vaccines appear superior to adenovirus vector-based vaccines in inducing neutralizing antibodies against VOCs four weeks after initial vaccination and after booster vaccination.

4.
Blood ; 138(SUPPL 1):754, 2021.
Article in English | EMBASE | ID: covidwho-1770336

ABSTRACT

Background: Patients with hematologic conditions have a high mortality rate when infected with SARS-CoV-2 (Williamson, Nature 2020). Protection of this group from severe COVID-19 is therefore important. However, according to available vaccination guidelines, one should consider to postpone vaccination of patients on or early after chemotherapy, hematopoietic progenitor cell transplantation (HCT) or with graft versus host disease, because of anticipated poor efficacy. Based on previous (non-COVID-19) vaccination studies among hematology patients, we hypothesized that a significant group of patients may acquire sufficient protection following COVID-19 vaccination, despite disease and therapy related immunodeficiencies. Methods: We conducted a prospective cohort study with 17 cohorts of hematology patients of particular risk for severe COVID-19 who are considered to have no or limited benefit from vaccination. We evaluated humoral immune responses following 2 doses (28 days apart) of the mRNA-1273 vaccine (Moderna/Spikevax) in 722 patients, at baseline and 28 days after each vaccination as SARS-COV-2 S1- (spike)-specific serum IgG antibody concentrations by bead-based multiplex immune assay. The threshold for adequate antibody response is set at ≥300 binding antibody units (BAU)/ml according to the international WHO standard, and is associated with virus plaque reducing neutralization test titers of ≥40 PRNT 50. This study is registered as EudraCT 2021-001072-41, NL76768.029.21. Results: Patient cohorts and corresponding vaccine responses are depicted in Table 1. Vaccine efficacy, as measured by antibody concentration, 4 weeks after the 2nd mRNA-1273 vaccination was available for 691 out of 722 participants. The majority of patients (389/691;56%) obtained an S1 antibody titer that is considered adequate (≥300 BAU/ml). Twenty-nine percent of patients (198/691) did not seroconvert (S1 antibody titer <10 BAU/ml), while the remaining 15% (104/691) did seroconvert but not to sufficient levels (10-300 BAU/ml). Adequate responses were observed in the majority of patients with sickle cell disease using hydroxyurea, chronic myeloid leukemia (CML) receiving tyrosine kinase inhibitor therapy, acute myeloid leukemia (AML) on or early after high dose chemotherapy, patients with myeloproliferative disorders on ruxolitinib, patients with multiple myeloma (MM), including those on daratumumab and those early after high-dose melphalan and autologous HCT, patients with untreated chronic lymphocytic leukemia (CLL), and patients with chronic GvHD. Insufficient or absent antibody responses were observed in the majority of AML patients receiving hypomethylating agents, CLL patients on ibrutinib, patients with B-cell non-Hodgkin's Lymphoma (NHL) during or shortly after rituximab-chemotherapy or following BEAM chemotherapy and autologous HCT, allogeneic HCT recipients <6 months after transplantation, and CAR-T cell therapy recipients. However, even in these low-responder groups considerable numbers of patients did mount sufficient antibody titers. In others, titers increased after each of both vaccinations, suggesting that booster vaccination may enhance antibody titers to sufficient levels (Figure 1). Conclusion: Vaccination with mRNA-1273 had significant efficacy in severely immunocompromised hematology patients. Adequate humoral immune responses after two dose vaccination were reached in the majority of patients receiving therapy for sickle cell disease, MPD, MM, CML and AML, in patients early after HCT and in patients with GvHD. We are currently evaluating clinical and immunologic parameters that correlate with sufficient antibody responses, pseudovirus neutralization and SARS-COV-2-specific B and T cell numbers, phenotype and function. Per study design, all participants with absent or insufficient antibody responses (<300 BAU/ml) will receive a booster vaccination 5 months after initial vaccination, and antibody responses to booster vaccinations will be presented as well. Unlike currently available guidelines, COVID-19 vaccination should not be postponed. Moreover, as antibody titers increased after each of both vaccinations, booster vaccination of patients with absent or insufficient antibody responses seems warranted. (Figure Presented) .

5.
Embase; 2021.
Preprint in English | EMBASE | ID: ppcovidwho-330436

ABSTRACT

Emerging and future SARS-CoV-2 variants may jeopardize the effectiveness of vaccination campaigns. We performed a head-to-head comparison of the ability of sera from individuals vaccinated with either one of four vaccines (BNT162b2, mRNA-1273, AZD1222 or Ad26.COV2.S) to recognize and neutralize SARS-CoV-2 variants of concern (VOCs;Alpha, Beta, Gamma, Delta and Omicron). Four weeks after completing the vaccination series, SARSCoV-2 wild-type neutralizing antibody titers were highest in recipients of BNT162b2 and mRNA-1273 (median titers of 1891 and 3061, respectively), and substantially lower in those vaccinated with the adenovirus vector-based vaccines AZD1222 and Ad26.COV2.S (median titers of 241 and 119, respectively). VOCs neutralization was reduced in all vaccine groups, with the largest (9 to 80-fold) reduction in neutralization being observed against the Omicron variant. Overall, the mRNA vaccines appear superior to adenovirus vector-based vaccines in inducing neutralizing antibodies against VOCs four weeks after the second vaccination.

12.
Topics in Antiviral Medicine ; 29(1):32, 2021.
Article in English | EMBASE | ID: covidwho-1250654

ABSTRACT

Background: Understanding antibody immunity to SARS-CoV-2 and how the virus evades it is of critical importance in the fight against COVID-19. Our best hope of ending the pandemic is antibody-inducing vaccination, yet the precise targets and indeed protective capacity of antibodies remain incompletely defined. The coronaviral spike is the dominant viral antigen and the target of neutralizing antibodies. We discovered neutralizing epitopes located on the distal face of the SARS-CoV-2 spike N-terminal domain (NTD). Remarkably, instead of glycosylation, the virus uses a surface-exposed loop to restrict the access to this patch, and the gate is controlled through recruitment and dissociation of a metabolite. Methods: Using cryo-electron microscopy and X-ray crystallography we mapped a tetrapyrrole binding site to a deep cleft on the spike N-terminal domain (NTD, Fig. 1) and characterized structural features of a neutralizing epitope controlled by metabolite dissociation. Results: We show that SARS-CoV-2 spike binds biliverdin and bilirubin, the tetrapyrrole products of haem metabolism, with nanomolar affinity in a pH-sensitive manner. At physiological concentrations, biliverdin significantly dampened the reactivity of SARS-CoV-2 spike with immune sera and inhibited a subset of neutralizing antibodies. Access to the tetrapyrrole-sensitive epitope is gated by a flexible loop on the distal face of the NTD. Accompanied by profound conformational changes in the NTD, antibody binding requires relocation of the gating loop, which folds into the cleft vacated by the metabolite. Conclusion: It is well-established that viruses employ extensive glycosylation of their envelopes to shield antibody epitopes. Compared to glycosylation, epitope masking via metabolite recruitment has the advantage of reversibility. For instance, pH-dependence of the spike-tetrapyrrole interaction potentially allows dissociation within the late endosomal compartment. In summary, our results indicate that the virus co-opts the haem metabolite for the evasion of humoral immunity via allosteric shielding of a sensitive epitope and demonstrate the remarkable structural plasticity of the NTD.

13.
PubMed; 2021.
Preprint in English | PubMed | ID: ppcovidwho-8066

ABSTRACT

One year into the Coronavirus Disease 2019 (COVID-19) pandemic caused by Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), effective treatments are still needed <sup>1-3</sup> . Monoclonal antibodies, given alone or as part of a therapeutic cocktail, have shown promising results in patients, raising the hope that they could play an important role in preventing clinical deterioration in severely ill or in exposed, high risk individuals <sup>4-6</sup> . Here, we evaluated the prophylactic and therapeutic effect of COVA1-18 in vivo , a neutralizing antibody isolated from a convalescent patient <sup>7</sup> and highly potent against the B.1.1.7. isolate <sup>8,9</sup> . In both prophylactic and therapeutic settings, SARS-CoV-2 remained undetectable in the lungs of COVA1-18 treated hACE2 mice. Therapeutic treatment also caused a dramatic reduction in viral loads in the lungs of Syrian hamsters. When administered at 10 mg kg <sup>- 1</sup> one day prior to a high dose SARS-CoV-2 challenge in cynomolgus macaques, COVA1-18 had a very strong antiviral activity in the upper respiratory compartments with an estimated reduction in viral infectivity of more than 95%, and prevented lymphopenia and extensive lung lesions. Modelling and experimental findings demonstrate that COVA1-18 has a strong antiviral activity in three different preclinical models and could be a valuable candidate for further clinical evaluation.

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