Potent neutralizing anti-SARS-CoV-2 human antibodies cure infection with SARS-CoV-2 variants in hamster model

Imbrechts, Maya; Maes, Wim; Ampofo, Louanne; Berghe, Nathalie Van den; Calcoen, Bas; Looveren, Dominique Van; Noppen, Sam; Hollevoet, Kevin; Vercruysse, Thomas; Zhang, Xin; Abdelnabi, Rana; Foo, Caroline Shi-Yan; Thibaut, Hendrik Jan; Jochmans, Dirk; Ven, Karen; Lammertyn, Jeroen; Vanhoorelbeke, Karen; Callewaert, Nico; Munter, Paul De; Schols, Dominique; Neyts, Johan; Declerck, Paul

doi:10.1101/2021.11.25.470011

Cited by 3 publications

(3 citation statements)

References 55 publications

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“…These findings are of diagnostic value as automated binding inhibition assay could be used in routine laboratories as a substitute for the more complex VSV pseudovirus neutralization assays. Furthermore, by implementing an approach designed in-house to retrieve RBD-specific B cell clones in SARS-CoV-2 convalescent patients [36], we were able to look beyond antibody secretion and enumerate circulating RBD-specific B cells. The latter can considered to be a surrogate marker for the resident clones present within the secondary lymphoid organs and thus a reflection of ongoing B cell activity [17,[66][67][68].…”

Section: Discussionmentioning

confidence: 99%

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High Incidence of SARS-CoV-2 Variant of Concern Breakthrough Infections Despite Residual Humoral and Cellular Immunity Induced by BNT162b2 Vaccination in Healthcare Workers: A Long-Term Follow-Up Study in Belgium

Calcoen

Callewaert

Vandenbulcke

et al. 2022

Viruses

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To mitigate the massive COVID-19 burden caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), several vaccination campaigns were initiated. We performed a single-center observational trial to monitor the mid- (3 months) and long-term (10 months) adaptive immune response and to document breakthrough infections (BTI) in healthcare workers (n = 84) upon BNT162b2 vaccination in a real-world setting. Firstly, serology was determined through immunoassays. Secondly, antibody functionality was analyzed via in vitro binding inhibition and pseudovirus neutralization and circulating receptor-binding domain (RBD)-specific B cells were assessed. Moreover, the induction of SARS-CoV-2-specific T cells was investigated by an interferon-γ release assay combined with flowcytometric profiling of activated CD4+ and CD8+ T cells. Within individuals that did not experience BTI (n = 62), vaccine-induced humoral and cellular immune responses were not correlated. Interestingly, waning over time was more pronounced within humoral compared to cellular immunity. In particular, 45 of these 62 subjects no longer displayed functional neutralization against the delta variant of concern (VoC) at long-term follow-up. Noteworthily, we reported a high incidence of symptomatic BTI cases (17.11%) caused by alpha and delta VoCs, although vaccine-induced immunity was only slightly reduced compared to subjects without BTI at mid-term follow-up.

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Section: Discussionmentioning

confidence: 99%

“…Nr. 40952-V27H-B) and PE-streptavidin as described by Imbrechts et al [36]. For each sample, a negative control tube (without RBDbiotin) was included to correct for sample-specific background.…”

Section: Quantification Of Circulating Rbd-specific B Cellsmentioning

confidence: 99%

High Incidence of SARS-CoV-2 Variant of Concern Breakthrough Infections Despite Residual Humoral and Cellular Immunity Induced by BNT162b2 Vaccination in Healthcare Workers: A Long-Term Follow-Up Study in Belgium

Calcoen

Callewaert

Vandenbulcke

et al. 2022

Viruses

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“…Intramuscular (IM), intratumoral (IT) and intradermal EP all have been evaluated in clinical trials (7). We and others previously demonstrated preclinical proof of concept for antibody gene transfer in a variety of indications, including infectious diseases, auto-immune diseases, and cancer (1,2,9). For the latter, this includes IM and IT EP of DNA-based antibody therapeutics targeted against cancer cells or immunomodulatory checkpoints, as single agents and in DNA cocktails encoding for mAbs or cytokines (10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

Clinically relevant dosing and pharmacokinetics of DNA-encoded antibody therapeutics in a sheep model

et al. 2022

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DNA-encoded delivery and in vivo expression of antibody therapeutics presents an innovative alternative to conventional protein production and administration, including for cancer treatment. To support clinical translation, we evaluated this approach in 18 40-45 kg sheep, using a clinical-matched intramuscular electroporation (IM EP) and hyaluronidase-plasmid DNA (pDNA) coformulation setup. Two cohorts of eight sheep received either 1 or 4 mg pDNA encoding an ovine anti-cancer embryonic antigen (CEA) monoclonal antibody (mAb; OVAC). Results showed a dose-response with average maximum serum concentrations of respectively 0.3 and 0.7 µg/ml OVAC, 4-6 weeks after IM EP. OVAC was detected in all 16 sheep throughout the 6-week follow-up, and no anti-OVAC antibodies were observed. Another, more exploratory, cohort of two sheep received a 12 mg pOVAC dose. Both animals displayed a similar dose-dependent mAb increase and expression profile in the first two weeks. However, in one animal, an anti-OVAC antibody response led to loss of mAb detection four weeks after IM EP. In the other animal, no anti-drug antibodies were observed. Serum OVAC concentrations peaked at 4.9 µg/ml 6 weeks after IM EP, after which levels gradually decreased but remained detectable around 0.2 to 0.3 µg/ml throughout a 13-month follow-up. In conclusion, using a delivery protocol that is currently employed in clinical Phase 1 studies of DNA-based antibodies, we achieved robust and prolonged in vivo production of anti-cancer DNA-encoded antibody therapeutics in sheep. The learnings from this large-animal model regarding the impact of pDNA dose and host immune response on the expressed mAb pharmacokinetics can contribute to advancing clinical translation.

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Anti-SARS-CoV-2 human antibodies retaining neutralizing activity against SARS-CoV-2 B.1.1.529 (omicron)

Imbrechts

Kerstens

Rasulova

et al. 2021

Preprint

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SARS-CoV-2 B.1.1.529, designated omicron, was recently identified as a new variant of concern by WHO and is rapidly replacing SARS-CoV-2 delta as the most dominant variant in many countries. Unfortunately, because of the high number of mutations present in the spike of SARS-CoV-2 omicron, most monoclonal antibodies (mAbs) currently approved for treatment of COVID-19 lose their in vitro neutralizing activity against this variant. We recently described a panel of human anti-SARS-CoV-2 mAbs that potently neutralize SARS-CoV-2 Wuhan, D614G and variants alpha, beta, gamma and delta. In this work, we evaluated our mAb panel for potential in vitro activity against SARS-CoV-2 delta and omicron. Three mAbs from our panel retain neutralizing activity against both delta and omicron, with mAb 3B8 still resulting in complete neutralization at a concentration as low as 0.02 ug/ml for both variants. Overall, our data indicate that mAb 3B8 may have the potential to become a game-changer in the fight against the continuously evolving SARS-CoV-2.

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Potent neutralizing anti-SARS-CoV-2 human antibodies cure infection with SARS-CoV-2 variants in hamster model

Cited by 3 publications

References 55 publications

High Incidence of SARS-CoV-2 Variant of Concern Breakthrough Infections Despite Residual Humoral and Cellular Immunity Induced by BNT162b2 Vaccination in Healthcare Workers: A Long-Term Follow-Up Study in Belgium

High Incidence of SARS-CoV-2 Variant of Concern Breakthrough Infections Despite Residual Humoral and Cellular Immunity Induced by BNT162b2 Vaccination in Healthcare Workers: A Long-Term Follow-Up Study in Belgium

Clinically relevant dosing and pharmacokinetics of DNA-encoded antibody therapeutics in a sheep model

Anti-SARS-CoV-2 human antibodies retaining neutralizing activity against SARS-CoV-2 B.1.1.529 (omicron)

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