Extremely potent monoclonal antibodies neutralize Omicron and other SARS-CoV-2 variants

The ongoing coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has triggered a devastating global health, social and economic crisis. The RNA nature and broad circulation of this virus facilitate the accumulation of mutations, leading to the continuous emergence of variants of concern with increased transmissibility or pathogenicity1. This poses a major challenge to the effectiveness of current vaccines and therapeutic antibodies1,2. Thus, there is an urgent need for effective therapeutic and preventive measures with a broad spectrum of action, especially against variants with an unparalleled number of mutations such as the recently emerged Omicron variant, which is rapidly spreading across the globe3. Here, we used combinatorial antibody phage-display libraries from convalescent COVID-19 patients to generate monoclonal antibodies against the receptor-binding domain of the SARS-CoV-2 spike protein with ultrapotent neutralizing activity. One such antibody, NE12, neutralizes an early isolate, the WA-1 strain, as well as the Alpha and Delta variants with half-maximal inhibitory concentrations at picomolar level. A second antibody, NA8, has an unusual breadth of neutralization, with picomolar activity against both the Beta and Omicron variants. The prophylactic and therapeutic efficacy of NE12 and NA8 was confirmed in preclinical studies in the golden Syrian hamster model. Analysis by cryo-EM illustrated the structural basis for the neutralization properties of NE12 and NA8. Potent and broadly neutralizing antibodies against conserved regions of the SARS-CoV-2 spike protein may play a key role against future variants of concern that evade immune control.

Circulating SARS-CoV-2 variants B.1.1.7, 501Y.V2, and P.1 have gained ability to utilize rat and mouse Ace2 and altered in vitro sensitivity to neutralizing antibodies and ACE2-Ig

Spontaneous and selection-pressure-driven evolution of SARS-CoV-2 has started to pose more challenges to controlling the pandemic. Here, we first investigated cross-species receptor usage of multiple SARS-CoV-2 variants that emerged during the pandemic. We found that, in contrast to an early isolate WHU01, the circulating variants B.1.1.7/501Y.V1, B.1.351/501Y.V2, and P.1/501Y.V3 were able to use rat and mouse Ace2 orthologs as entry receptors, suggesting that rats and mice might be able to harbor and spread these variants. We then evaluated in vitro sensitivity of these variants to three therapeutic antibodies in clinics (etesevimab/LY-CoV016, casirivimab/REGN10933, and imdevimab/REGN10987) and an ACE2-Ig variant we developed recently. We found that all the tested SARS-CoV-2 variants showed reduced sensitivity to at least one of the tested antibodies but slightly increased sensitivity to the ACE2-Ig protein. These data demonstrate that the ACE2-Ig is a good drug candidate against SARS-CoV-2 variants that emerge over the course of the pandemic.

Complete Genome Sequence of Pseudomonas aeruginosa Strain AA2 (LMG 27630), an Early Isolate Recovered from the Airway of a German Cystic Fibrosis Patient

ABSTRACT Pseudomonas aeruginosa is an opportunistic pathogen that is able to cause various infections, including airway infections in cystic fibrosis patients. Here, we present the complete closed and annotated genome sequence of P. aeruginosa AA2, an isolate obtained early during infection of the respiratory tract of a German cystic fibrosis patient.

Phenotypic Analysis Reveals that the 2010 Haiti Cholera Epidemic Is Linked to a Hypervirulent Strain

Vibrio choleraeO1 El Tor strains have been responsible for pandemic cholera since 1961. These strains have evolved over time, spreading globally in three separate waves. Wave 3 is caused by altered El Tor (AET) variant strains, which include the strain with the signaturectxB7allele that was introduced in 2010 into Haiti, where it caused a devastating epidemic. In this study, we used phenotypic analysis to compare an early isolate from the Haiti epidemic to wave 1 El Tor isolates commonly used for research. It is demonstrated that the Haiti isolate has increased production of cholera toxin (CT) and hemolysin, increased motility, and a reduced ability to form biofilms. This strain also outcompetes common wave 1 El Tor isolates for colonization of infant mice, indicating that it has increased virulence. Monitoring of CT production and motility in additional wave 3 isolates revealed that this phenotypic variation likely evolved over time rather than in a single genetic event. Analysis of available whole-genome sequences and phylogenetic analyses suggested that increased virulence arose from positive selection for mutations found in known and putative regulatory genes, includinghnsandvieA, diguanylate cyclase genes, and genes belonging to thelysRandgntRregulatory families. Overall, the studies presented here revealed thatV. choleraevirulence potential can evolve and that the currently prevalent wave 3 AET strains are both phenotypically distinct from and more virulent than many El Tor isolates.

Early HIV-1 Envelope-specific Cytotoxic T Lymphocyte Responses in Vertically Infected Infants

High frequencies of cytotoxic T lymphocyte precursors (CTLp) recognizing HIV-1 laboratory strain gene products have been detected in adults within weeks of primary infection. In contrast, HIV-1–specific CTLp are uncommonly detected in infants younger than 6 mo. To address the hypothesis that the use of target cells expressing laboratory strain env gene products might limit the detection of HIV-1 env-specific CTLp in early infancy, recombinant vaccinia vectors (vv) expressing HIV-1 env genes from early isolates of four vertically infected infants were generated. The frequencies of CTLp recognizing target cells infected with vv-expressing env gene products from early isolates and HIV-1 IIIB were serially measured using limiting dilution followed by in vitro stimulation with mAb to CD3. In one infant, the detection of early isolate env-specific CTLp preceded the detection of IIIB-specific CTLp. CTLp recognizing HIV-1 IIIB and infant isolate env were detected by 6 mo of age in two infants. In a fourth infant, HIV-1 IIIB env and early isolate env-specific CTLp were simultaneously detected at 12 mo of age. These results provide evidence that young infants can generate HIV-1–specific CTL responses and provide support for the concept of neonatal vaccination to prevent HIV-1 transmission. However, the early predominance of type-specific CTL detected in some young infants suggests that the use of vaccines based on laboratory strains of HIV-1 may not protect against vertical infection.

Quantitation and analysis of the specificity of post-immunization antibodies to influenza B viruses using single radial haemolysis

SummaryThe single radial haemolysis (SRH) technique detected anti-B/HK/8/73 HA antibody rises in 59–85 % of paired sera from persons immunized with different influenza vaccines. In contrast, analysis of the same sera by the haemagglutination inhibition (HI) test indicated significant antibody rises in only 27–54% of paired sera. High levels of antibody were detected to influenza B/HK/8/73 and B/Singapore/222/79 viruses in post-immunization sera analysed by SRH, whereas the HI test indicated comparatively low geometric mean antibody titres. Most adults responded to immunization with influenza B virus by producing cross-reactive (CR) antibody which reacted with different influenza B viruses including the early isolate B/Lee/40.