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1.
Nat Microbiol ; 7(6): 896-908, 2022 06.
Article in English | MEDLINE | ID: covidwho-1873507

ABSTRACT

Genetically distinct variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have emerged since the start of the COVID-19 pandemic. Over this period, we developed a rapid platform (R-20) for viral isolation and characterization using primary remnant diagnostic swabs. This, combined with quarantine testing and genomics surveillance, enabled the rapid isolation and characterization of all major SARS-CoV-2 variants circulating in Australia in 2021. Our platform facilitated viral variant isolation, rapid resolution of variant fitness using nasopharyngeal swabs and ranking of evasion of neutralizing antibodies. In late 2021, variant of concern Omicron (B1.1.529) emerged. Using our platform, we detected and characterized SARS-CoV-2 VOC Omicron. We show that Omicron effectively evades neutralization antibodies and has a different entry route that is TMPRSS2-independent. Our low-cost platform is available to all and can detect all variants of SARS-CoV-2 studied so far, with the main limitation being that our platform still requires appropriate biocontainment.


Subject(s)
COVID-19 , SARS-CoV-2 , Australia , COVID-19/diagnosis , Humans , Pandemics , SARS-CoV-2/genetics
2.
Cell ; 185(6): 945-948, 2022 03 17.
Article in English | MEDLINE | ID: covidwho-1748152

ABSTRACT

Long-term protection against SARS-CoV-2 requires effective and durable immunity. In this issue of Cell, two papers closely examine germinal centers, the physiological birthplace of adaptive immunity, to quantify the specificity, breadth, magnitude, and persistence of systemic and local humoral immune responses following natural infection with, or vaccination against, SARS-CoV-2.


Subject(s)
COVID-19 , Immunity, Humoral , Antibodies, Neutralizing , Antibodies, Viral , COVID-19 Vaccines , Germinal Center , Humans , SARS-CoV-2
3.
Eur J Immunol ; 52(6): 970-977, 2022 Jun.
Article in English | MEDLINE | ID: covidwho-1729126

ABSTRACT

Effective vaccines and monoclonal antibodies have been developed against coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the appearance of virus variants with higher transmissibility and pathogenicity is a major concern because of their potential to escape vaccines and clinically approved SARS-CoV-2- antibodies. Here, we use flow cytometry-based binding and pseudotyped SARS-CoV-2 neutralization assays to determine the efficacy of boost immunization and therapeutic antibodies to neutralize the dominant Omicron variant. We provide compelling evidence that the third vaccination with BNT162b2 increases the amount of neutralizing serum antibodies against Delta and Omicron variants, albeit to a lower degree when compared to the parental Wuhan strain. Therefore, a third vaccination is warranted to increase titers of protective serum antibodies, especially in the case of the Omicron variant. We also found that most clinically approved and otherwise potent therapeutic antibodies against the Delta variant failed to recognize and neutralize the Omicron variant. In contrast, some antibodies under preclinical development potentially neutralized the Omicron variant. Our studies also support using a flow cytometry-based antibody binding assay to rapidly monitor therapeutic candidates and serum titers against emerging SARS-CoV-2 variants.


Subject(s)
Antineoplastic Agents, Immunological , COVID-19 , Antibodies, Monoclonal , Antibodies, Neutralizing , Antibodies, Viral , BNT162 Vaccine , COVID-19 Vaccines , Humans , SARS-CoV-2 , Vaccination
4.
Immunity ; 54(12): 2908-2921.e6, 2021 12 14.
Article in English | MEDLINE | ID: covidwho-1521063

ABSTRACT

Viral mutations are an emerging concern in reducing SARS-CoV-2 vaccination efficacy. Second-generation vaccines will need to elicit neutralizing antibodies against sites that are evolutionarily conserved across the sarbecovirus subgenus. Here, we immunized mice containing a human antibody repertoire with diverse sarbecovirus receptor-binding domains (RBDs) to identify antibodies targeting conserved sites of vulnerability. Antibodies with broad reactivity against diverse clade B RBDs targeting the conserved class 4 epitope, with recurring IGHV/IGKV pairs, were readily elicited but were non-neutralizing. However, rare class 4 antibodies binding this conserved RBD supersite showed potent neutralization of SARS-CoV-2 and all variants of concern. Structural analysis revealed that the neutralizing ability of cross-reactive antibodies was reserved only for those with an elongated CDRH3 that extends the antiparallel beta-sheet RBD core and orients the antibody light chain to obstruct ACE2-RBD interactions. These results identify a structurally defined pathway for vaccine strategies eliciting escape-resistant SARS-CoV-2 neutralizing antibodies.


Subject(s)
Betacoronavirus/physiology , COVID-19 Vaccines/immunology , Coronavirus Infections/immunology , SARS Virus/physiology , Spike Glycoprotein, Coronavirus/metabolism , Animals , Antibodies, Neutralizing/metabolism , Antibodies, Viral/metabolism , Conserved Sequence/genetics , Evolution, Molecular , Humans , Immunization , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Protein Binding , Protein Domains/genetics , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Vaccine Development
5.
Immunity ; 2021.
Article in English | EuropePMC | ID: covidwho-1489418

ABSTRACT

Viral mutations are an emerging concern in reducing SARS-CoV-2 vaccination efficacy. Burnett et al. immunized humanized mice with different diverse sarbecovirus RBDs to elicit antibodies targeting conserved sites. Non-neutralizing cross-reactive antibodies targeting the conserved class 4 epitope were readily elicited. Neutralizing ability was reserved only for antibodies binding this conserved supersite through an elongated CDRH3 that obstructed ACE2-RBD interactions.

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