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Introduction: The ongoing COVID-19 pandemic situation caused by SARSCoV-2 and variants of concern such as B.1.617.2 (Delta) and recently, B.1.1.529 (Omicron) is posing multiple challenges to humanity. The rapid evolution of the virus requires adaptation of diagnostic and therapeutic applications. Objectives: In this study, we describe camelid heavy-chain-only antibodies (hcAb) as useful tools for novel in vitro diagnostic assays and for therapeutic applications due to their neutralizing capacity. Methods: Five antibody candidates were selected out of a naïve camelid library by phage display and expressed as full length IgG2 antibodies. The antibodies were characterized by Western blot, enzyme-linked immunosorbent assays, surface plasmon resonance with regard to their specificity to the recombinant SARS-CoV-2 Spike protein and to SARS-CoV-2 virus-like particles. Neutralization assays were performed with authentic SARS-CoV-2 and pseudotyped viruses (wildtype and Omicron). Results: All antibodies efficiently detect recombinant SARS-CoV-2 Spike protein and SARS-CoV-2 virus-like particles in different ELISA setups. The best combination was shown with hcAb B10 as catcher antibody and HRPconjugated hcAb A7.2 as the detection antibody. Further, four out of five antibodies potently neutralized authentic wildtype SARS-CoV-2 and particles pseudotyped with the SARS-CoV-2 Spike proteins of the wildtype and Omicron variant, sublineage BA.1 at concentrations between 0.1 and 0.35 ng/mL (ND50). Conclusion: Collectively, we report novel camelid hcAbs suitable for diagnostics and potential therapy. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

WHICH ANTIVIRAL TREATMENT OPTIONS ARE SUITABLE FOR THERAPY OF PATIENTS INFECTED WITH THE OMIC... Treatment with recombinant monoclonal antibodies (mAbs) that neutralize SARS-CoV-2 can reduce the risk for severe disease. In contrast, neutralization of the Omicron variant is dramatically reduced,1 indicating that immunity following infection by previously circulating SARS-CoV-2 variants provides little to no protection against the Omicron variant. Keywords: antibody; omicron; SARS-CoV-2; spike EN antibody omicron SARS-CoV-2 spike 1 3 3 05/31/22 20220501 NES 220501 The severe acute respiratory syndrome coronavirus 2 Omicron variant (B.1.1.529) swept the globe with breathtaking speed, rapidly displacing the Delta variant and causing record numbers of new infections. [Extracted from the article]

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. [Display omitted] • Omicron uses human and animal ACE2 for host cell entry • Omicron is resistant against neutralization by several therapeutic antibodies • Omicron efficiently evades antibodies from infected or 2 × BNT-vaccinated patients • Omicron moderately evades antibodies induced by 3 × BNT or heterologous vaccination The SARS-CoV-2 Omicron variant is rapidly spreading worldwide and a public health concern. Experiments show that this variant is resistant against several therapeutic antibodies for COVID-19 and efficiently evades antibodies induced upon infection or double BNT162b2 vaccination, but not triple BNT162b2 or ChAdOx1/BNT162b2 vaccination. [ABSTRACT FROM AUTHOR]

The devastating impact of COVID-19 on global health shows the need to increase our pandemic preparedness. Recombinant therapeutic antibodies were successfully used to treat and protect at-risk patients from COVID-19. However, the currently circulating Omicron subvariants of SARS-CoV-2 are largely resistant to therapeutic antibodies, and novel approaches to generate broadly neutralizing antibodies are urgently needed. Here, we describe a tetravalent bispecific antibody, A7A9 TVB, which actively neutralized many SARS-CoV-2 variants of concern, including early Omicron subvariants. Interestingly, A7A9 TVB neutralized more variants at lower concentration as compared to the combination of its parental monoclonal antibodies, A7K and A9L. A7A9 also reduced the viral load of authentic Omicron BA.1 virus in infected pseudostratified primary human nasal epithelial cells. Overall, A7A9 displayed the characteristics of a potent broadly neutralizing antibody, which may be suitable for prophylactic and therapeutic applications in the clinics, thus highlighting the usefulness of an effective antibody-designing approach. • Efficient modular antibody-designing and delivery with gene therapy tools. • Retrovirus-based pseudoparticles of 12 SAR-CoV-2 variants of concern tested. • Tetravalent bispecific neutralizing antibody overcomes viral evasion. • Tetravalent design outperforms the combination of monoclonal antibodies. • Early neutralizing antibody clones benefit with new design. [ABSTRACT FROM AUTHOR]

BA.2.86, a recently identified descendant of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron BA.2 sublineage, contains ∼35 mutations in the spike (S) protein and spreads in multiple countries. Here, we investigated whether the virus exhibits altered biological traits, focusing on S protein-driven viral entry. Employing pseudotyped particles, we show that BA.2.86, unlike other Omicron sublineages, enters Calu-3 lung cells with high efficiency and in a serine- but not cysteine-protease-dependent manner. Robust lung cell infection was confirmed with authentic BA.2.86, but the virus exhibited low specific infectivity. Further, BA.2.86 was highly resistant against all therapeutic antibodies tested, efficiently evading neutralization by antibodies induced by non-adapted vaccines. In contrast, BA.2.86 and the currently circulating EG.5.1 sublineage were appreciably neutralized by antibodies induced by the XBB.1.5-adapted vaccine. Collectively, BA.2.86 has regained a trait characteristic of early SARS-CoV-2 lineages, robust lung cell entry, and evades neutralizing antibodies. However, BA.2.86 exhibits low specific infectivity, which might limit transmissibility. [Display omitted] • BA.2.86 efficiently enters lung cells and uses TMPRSS2 for lung cell entry • Mutations S50L and K356T are responsible for efficient lung cell entry of BA.2.86 • BA.2.86 is highly resistant against therapeutic antibodies • BA.2.86 evades antibodies induced upon infection and vaccination BA.2.86 is a recently emerged, highly mutated SARS-CoV-2 variant that spreads in many countries and threatens human health. This study shows that BA.2.86, unlike closely related variants, can enter lung cells with high efficiency and in a TMPRSS2-dependent fashion and is resistant against therapeutic antibodies. [ABSTRACT FROM AUTHOR]