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1.
Sci Transl Med ; 14(655): eabn3715, 2022 Jul 27.
Article in English | MEDLINE | ID: covidwho-1962064

ABSTRACT

Several variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have emerged during the current coronavirus disease 2019 (COVID-19) pandemic. Although antibody cross-reactivity with the spike glycoproteins (S) of diverse coronaviruses, including endemic common cold coronaviruses (HCoVs), has been documented, it remains unclear whether such antibody responses, typically targeting the conserved S2 subunit, contribute to protection when induced by infection or through vaccination. Using a mouse model, we found that prior HCoV-OC43 S-targeted immunity primes neutralizing antibody responses to otherwise subimmunogenic SARS-CoV-2 S exposure and promotes S2-targeting antibody responses. Moreover, vaccination with SARS-CoV-2 S2 elicited antibodies in mice that neutralized diverse animal and human alphacoronaviruses and betacoronaviruses in vitro and provided a degree of protection against SARS-CoV-2 challenge in vivo. Last, in mice with a history of SARS-CoV-2 Wuhan-based S vaccination, further S2 vaccination induced broader neutralizing antibody response than booster Wuhan S vaccination, suggesting that it may prevent repertoire focusing caused by repeated homologous vaccination. These data establish the protective value of an S2-targeting vaccine and support the notion that S2 vaccination may better prepare the immune system to respond to the changing nature of the S1 subunit in SARS-CoV-2 variants of concern, as well as to future coronavirus zoonoses.


Subject(s)
COVID-19 Vaccines , COVID-19 , Coronavirus OC43, Human , Spike Glycoprotein, Coronavirus , Animals , Antibodies, Neutralizing , Antibodies, Viral , Broadly Neutralizing Antibodies , COVID-19/prevention & control , COVID-19 Vaccines/immunology , Coronavirus OC43, Human/immunology , Humans , Mice , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/immunology , Vaccination
2.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-335169

ABSTRACT

Two mutations occurred in SARS-CoV-2 early during the COVID-19 pandemic that have come to define circulating virus lineages 1 first a change in the spike protein (D614G) that defines the B.1 lineage and second, a double substitution in the nucleocapsid protein (R203K, G204R) that defines the B.1.1 lineage, which has subsequently given rise to three Variants of Concern: Alpha, Gamma and Omicron. While the latter mutations appear unremarkable at the protein level, there are dramatic implications at the nucleotide level: the GGG→AAC substitution generates a new Transcription Regulatory Sequence (TRS) motif, driving SARS-CoV-2 to express a novel subgenomic mRNA (sgmRNA) encoding a truncated C-terminal portion of nucleocapsid (N.iORF3), which is an inhibitor of type I interferon production. We find that N.iORF3 also emerged independently within the Iota variant, and further show that additional TRS motifs have convergently evolved to express novel sgmRNAs;notably upstream of Spike within the nsp16 coding region of ORF1b, which is expressed during human infection. Our findings demonstrate that SARS-CoV-2 is undergoing evolutionary changes at the functional RNA level in addition to the amino acid level, reminiscent of eukaryotic evolution. Greater attention to this aspect in the assessment of emerging strains of SARS-CoV-2 is warranted.

3.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-334389

ABSTRACT

Third dose COVID-19 vaccines are being deployed widely but their efficacy has not been assessed adequately in vulnerable elderly people who exhibit suboptimal responses after primary series vaccination. We studied spike-specific immune responses in 341 staff and residents in long-term care facilities (LTCF) who received an mRNA vaccine following dual primary series vaccination with BNT162b2 or ChAdOx1. Third dose vaccination strongly increased antibody responses with preferential enhancement in older people and was required to elicit neutralisation of Omicron. Cellular immune responses were also enhanced with strong cross-reactive recognition of Omicron. However, antibody titres fell 21-78% within 100 days post vaccine and 27% of participants developed a breakthrough Omicron infection. These findings reveal strong immunogenicity of a 3rd vaccine in one of the most vulnerable population groups and endorse an approach for widespread delivery across this population. Ongoing assessment will be required to determine the stability of immune protection.

5.
Fendler, Annika, Shepherd, Scott, Au, Lewis, Wilkinson, Katalin, Wu, Mary, Byrne, Fiona, Cerrone, Maddalena, Schmitt, Andreas, Joharatnam-Hogan, Nalinie, Shum, Ben, Tippu, Zayd, Rzeniewicz, Karolina, Boos, Laura, Harvey, Ruth, Carlyle, Eleanor, Edmonds, Kim, Rosario, Lyra Del, Sarker, Sarah, Lingard, Karla, Mangwende, Mary, Holt, Lucy, Ahmod, Hamid, Koreweg, Justine, Foley, Tara, Bazin, Jessica, Gordon, William, Barber, Taja, Emslie-Henry, Andrea, Xie, Wenyi, Gerard, Camille, Deng, Daqi, Wall, Emma, Agua-Doce, Ana, Namjou, Sina, Caidan, Simon, Gavrielides, Mike, MacRae, James, Kelly, Gavin, Peat, Kema, Kelly, Denise, Murra, Aida, Kelly, Kayleigh, O'Flaherty, Molly, Dowdie, Lauren, Ash, Natalie, Grounthoud, Firza, Shea, Robyn, Gardner, Gail, Murray, Darren, Kinnaird, Fiona, Cui, Wanyuan, Pascual, Javier, Rodney, Simon, Mencel, Justin, Curtis, Olivia, Stephenson, Clemency, Robinson, Anna, Oza, Bhavna, Farag, Sheima, Leslie, Isla, Rogiers, Aljosja, Lyengar, Sunil, Ethell, Mark, Messiou, Christina, Cunningham, David, Chau, Ian, Starling, Naureen, Turner, Nicholas, Welsh, Liam, As, Nicholas van, Jones, Robin, Droney, Joanne, Banerjee, Susana, Tatham, Kate, O'Brien, Mary, Harrington, Kevin, Bhide, Shreerang, Okines, Alicia, Reid, Alison, Young, Kate, Furness, Andrew, Pickering, Lisa, Swanton, Charles, Gandhi, Sonia, Gamblin, Steve, Bauer, David, Kassiotis, George, Kumar, Sacheen, Yousaf, Nadia, Jhanji, Shaman, Nicholson, Emma, Howell, Michael, Walker, Susanna, Wilkinson, Robert, Larkin, James, Turajlic, Samra.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-310349

ABSTRACT

CAPTURE (NCT03226886) is a prospective cohort study of COVID-19 immunity in patients with cancer. Here we evaluated 585 patients following administration of two doses of BNT162b2 or AZD1222 vaccines, administered 12 weeks apart. Seroconversion rates after two doses were 85% and 59% in patients with solid and hematological malignancies, respectively. A lower proportion of patients had detectable neutralizing antibody titers (NAbT) against SARS-CoV-2 variants of concern (VOCs) vs wild-type (WT). Patients with hematological malignancies were more likely to have undetectable NAbT and had lower median NAbT vs solid cancers against both WT and VOCs. In comparison with individuals without cancer, patients with haematological, but not solid, malignancies had reduced NAb responses. Seroconversion showed poor concordance with NAbT against VOCs. Prior SARS-CoV-2 infection boosted NAb response including against VOCs, and anti-CD20 treatment was associated with undetectable NAbT. Vaccine-induced T-cell responses were detected in 80% of patients, and were comparable between vaccines or cancer types. Our results have implications for the management of cancer patients during the ongoing COVID-19 pandemic.

6.
EuropePMC;
Preprint in English | EuropePMC | ID: ppcovidwho-327543

ABSTRACT

SARS-CoV-2 is a betacoronavirus and the etiological agent of COVID-19, a devastating infectious disease. Due to its far-reaching effect on human health, there is an urgent and growing need to understand the viral molecular biology of SARS-CoV-2 and its interaction with the host cell. SARS-CoV-2 encodes 9 predicted accessory proteins, which are presumed to be dispensable for in vitro replication, most likely having a role in modulating the host cell environment to aid viral replication. Here we show that the ORF6 accessory protein interacts with cellular Rae1 to inhibit cellular protein production by blocking mRNA export. We utilised cell fractionation coupled with mRNAseq to explore which cellular mRNA species are affected by ORF6 expression and show that ORF6 can inhibit the export of many mRNA including those encoding antiviral factors such as IRF1 and RIG-I. We also show that export of these mRNA is blocked in the context of SARS-CoV-2 infection. Together, our studies identify a novel mechanism by which SARS-CoV-2 can manipulate the host cell environment to supress antiviral responses, providing further understanding to the replication strategies of a virus that has caused an unprecedented global health crisis. Author Summary SARS-CoV-2 is the virus responsible for the current COVID-19 pandemic. Coronaviruses, like SARS-CoV-2, replicate their genome in the cytoplasm of the host cell by hijacking the cellular machinery. In addition to structural proteins and viral enzymes, SARS-CoV-2 encodes 9 accessory proteins. Although these are not required for in vitro replication, they are thought to modulate the host cell environment to favour viral replication. In this work, we show that the ORF6 accessory protein can supress cellular protein production by blocking mRNA nuclear export through interacting with the cellular protein Rae1, a known mRNA export factor. We also investigated which cellular mRNAs were retained in the nucleus when ORF6 was overexpressed. Interestingly, we found that ORF6 inhibited the export of many different mRNAs, including those encoding antiviral factors, like IRF1 and RIG-I, even in the absence of stimulation by interferon. Importantly, we found that the export of these mRNAs was similarly affected in the context of SARS-CoV-2 infection. Therefore, we believe we have identified a novel mechanism that SARS-CoV-2 uses to suppress antiviral responses in order to make the cell more permissive to infection.

7.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-324106

ABSTRACT

The CR3022 antibody, selected from a group of SARS-CoV-1 monoclonal antibodies for its ability to cross-react with SARS-CoV-2, has been examined for its ability to bind to the ectodomain of the SARS-CoV-2 spike glycoprotein. Using electron cryo-microscopy we show that antibody binding requires rearrangements in the S1 domain that result in dissociation of the spike.

8.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-323010

ABSTRACT

We present a case of cytokine release syndrome (CRS) that occurred five days after vaccination with BTN162b2 (tozinameran), an mRNA COVID-19 vaccine, in a patient with colorectal cancer on long-standing anti-PD-1 monotherapy. The CRS was evidenced by raised inflammatory markers, thrombocytopenia, elevated cytokine levels (IFN-y/IL-2R/IL-18/IL-16/IL-10), and steroid responsiveness.

9.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-322593

ABSTRACT

Background: Accurate and sensitive detection of antibody to SARS-CoV-2 remains an essential component of the pandemic response. Measuring antibody that predicts neutralising activity and the vaccine response is an absolute requirement for laboratory-based confirmatory and reference activity.Methods: The viral receptor binding domain (RBD) constitutes the prime target antigen for neutralising antibody. A double antigen binding assay (DABA) provides the most sensitive format. It has been exploited in a novel hybrid manner employing an S1 solid-phase preferentially presenting RBD once solid-phase bound, coupled with a labelled RBD conjugate, used in a two-step sequential assay.Findings: This assay showed a specificity of 100% on 825 pre COVID-19 samples and a potential sensitivity of 99.6% on 276 recovery samples, predicting quantitatively the presence of neutralising antibody determined by pseudo-type neutralisation and by plaque reduction. Anti-RBD is also measurable in ferrets immunised with ChadOx1 nCoV-19 vaccine. The early response at presentation with illness, elevated responsiveness with disease severity, detection of asymptomatic seroconversion and persistence after the loss of antibody to the nucleoprotein (anti-NP) are all documented.Trial Registration: The ISARIC WHO CCP-UK study was registered at https://www.isrctn.com/ISRCTN66726260 and designated an Urgent Public Health Research Study by NIHR.Interpretation: The hybrid DABA displays the attributes necessary for an antibody test to be used in both clinical and reference serology. It allows the neutralising antibody response to be inferred early in infection and potentially in vaccine recipients. It is also of sufficient sensitivity to be used to provide serological confirmation of prior infection and provides a more secure measure for seroprevalence studies in the population generally than does anti-NP based on the Architect platform.Funding: This work is variously supported by grants from: the National Institute for Health Research (NIHR;award CO-CIN-01), the Medical Research Council (MRC;grant MC_PC_19059 and MC_PC_19078), MRC NIHR (grant CV220-111) and by the NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections at University of Liverpool in partnership with Public Health England (PHE), in collaboration with Liverpool School of Tropical Medicine and the University of Oxford (award 200907), NIHR HPRU in Respiratory Infections at Imperial College London with PHE (award 200927), Wellcome Trust and Department for International Development (DID;215091/Z/18/Z), the Bill and Melinda Gates Foundation (OPP1209135), Liverpool Experimental Cancer Medicine Centre (grant reference C18616/A25153), NIHR Biomedical Research Centre at Imperial College London (IS-BRC-1215-20013), EU Platform for European Preparedness Against (Re-)emerging Epidemics (PREPARE;FP7 project 602525), and NIHR Clinical Research Network for providing infrastructure support for this research.Declaration of Interests: RST, MOM and PC report patent pending (Patent Application No. 2011047.4 for “SARS-CoV-2 antibody detection assay). All other authors declare no competing interests.Ethics Approval Statement: The use of tissues was approved by the CDRTB Steering Committee in accordance with the responsibility delegated by the National Research Ethics Service (South Central Ethics Committee – C, NRES reference 15/SC/0089).Written informed consent was obtained from all patients. Ethical approval was given by the South Central–Oxford C Research Ethics Committee in England (reference: 13/SC/0149), Scotland A Research Ethics Committee (reference: 20/SS/0028) and World Health Organization Ethics Review Committee (RPC571 and RPC572l;25 April 2013)

10.
J Virol Methods ; 302: 114475, 2022 04.
Article in English | MEDLINE | ID: covidwho-1652648

ABSTRACT

Accurate and sensitive detection of antibody to SARS-CoV-2 remains an essential component of the pandemic response. Measuring antibody that predicts neutralising activity and the vaccine response is an absolute requirement for laboratory-based confirmatory and reference activity. The viral receptor binding domain (RBD) constitutes the prime target antigen for neutralising antibody. A double antigen binding assay (DABA), providing the most sensitive format has been exploited in a novel hybrid manner employing a solid-phase S1 preferentially presenting RBD, coupled with a labelled RBD conjugate, used in a two-step sequential assay for detection and measurement of antibody to RBD (anti-RBD). This class and species neutral assay showed a specificity of 100 % on 825 pre COVID-19 samples and a potential sensitivity of 99.6 % on 276 recovery samples, predicting quantitatively the presence of neutralising antibody determined by pseudo-type neutralization and by plaque reduction. Anti-RBD is also measurable in ferrets immunised with ChadOx1 nCoV-19 vaccine and in humans immunised with both AstraZeneca and Pfizer vaccines. This assay detects anti-RBD at presentation with illness, demonstrates its elevation with disease severity, its sequel to asymptomatic infection and its persistence after the loss of antibody to the nucleoprotein (anti-NP). It also provides serological confirmation of prior infection and offers a secure measure for seroprevalence and studies of vaccine immunisation in human and animal populations. The hybrid DABA also displays the attributes necessary for the detection and quantification of anti-RBD to be used in clinical practice. An absence of detectable anti-RBD by this assay predicates the need for passive immune prophylaxis in at-risk patients.


Subject(s)
Antibodies, Viral/isolation & purification , COVID-19 , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/immunology , Animals , Antibodies, Neutralizing/isolation & purification , COVID-19/diagnosis , Ferrets , Humans , RNA, Viral , Seroepidemiologic Studies
16.
Cancer Cell ; 40(2): 114-116, 2022 02 14.
Article in English | MEDLINE | ID: covidwho-1588171
17.
2021.
Preprint in English | Other preprints | ID: ppcovidwho-296138

ABSTRACT

Mauritius, a small island in the Indian Ocean, has had a unique experience of the SARS-CoV-2 pandemic. In March 2020, Mauritius endured a small first wave and quickly implemented control measures which allowed elimination of local transmission of SARS-CoV-2. When borders to the island reopened, it was accompanied by mandatory quarantine and testing of incoming passengers to avoid reintroduction of the virus into the community. As variants of concern (VOCs) emerged elsewhere in the world, Mauritius began using genomic surveillance to keep track of quarantined cases of these variants. In March 2021, another local outbreak occurred, and sequencing was used to investigate this new wave of local infections. Here, we analyze 154 SARS-CoV-2 viral genomes from Mauritius, which represent 12% of all the infections seem in Mauritius, these were both from specimens of incoming passengers before March 2021 and those of cases during the second wave. Our findings indicate that despite the presence of known VOCs Beta (B.1.351) and Alpha (B.1.1.7) among quarantined passengers, the second wave of local SARS-CoV-2 infections in Mauritius was caused by a single introduction and dominant circulation of the B.1.1.318 virus. The B.1.1.318 variant is characterized by fourteen non-synonymous mutations in the S-gene, with five encoded amino acid substitutions (T95I, E484K, D614G, P681H, D796H) and one deletion (Y144del) in the Spike glycoprotein. This variant seems to be increasing in prevalence and it is now present in 34 countries. This study highlights that despite having stopped the introduction of more transmissible VOCs by travel quarantines, a single undetected introduction of a B.1.1.318 lineage virus was enough to initiate a large local outbreak in Mauritius and demonstrated the need for continuous genomic surveillance to fully inform public health decisions.

18.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-293390

ABSTRACT

Several common-cold coronaviruses (HCoVs) are endemic in humans and several variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have emerged during the current Coronavirus disease 2019 (COVID-19) pandemic. Whilst antibody cross-reactivity with the Spike glycoproteins (S) of diverse coronaviruses has been documented, it remains unclear whether such antibody responses, typically targeting the conserved S2 subunit, contribute to or mediate protection, when induced naturally or through vaccination. Using a mouse model, we show that prior HCoV-OC43 S immunity primes neutralising antibody responses to otherwise subimmunogenic SARS-CoV-2 S exposure and promotes S2-targeting antibody responses. Moreover, mouse vaccination with SARS-CoV-2 S2 elicits antibodies that neutralise diverse animal and human alphacoronaviruses and betacoronaviruses in vitro, and protects against SARS-CoV-2 challenge in vivo. Lastly, in mice with a history of SARS-CoV-2 Wuhan-based S vaccination, further S2 vaccination induces stronger and broader neutralising antibody response than booster Wuhan S vaccination, suggesting it may prevent repertoire focusing caused by repeated homologous vaccination. The data presented here establish the protective value of an S2-targeting vaccine and support the notion that S2 vaccination may better prepare the immune system to respond to the changing nature of the S1 subunit in SARS-CoV-2 variants of concern (VOCs), as well as to unpredictable, yet inevitable future coronavirus zoonoses.

19.
Nat Cancer ; 2(12): 1305-1320, 2021 12.
Article in English | MEDLINE | ID: covidwho-1510627

ABSTRACT

Coronavirus disease 2019 (COVID-19) antiviral response in a pan-tumor immune monitoring (CAPTURE) ( NCT03226886 ) is a prospective cohort study of COVID-19 immunity in patients with cancer. Here we evaluated 585 patients following administration of two doses of BNT162b2 or AZD1222 vaccines, administered 12 weeks apart. Seroconversion rates after two doses were 85% and 59% in patients with solid and hematological malignancies, respectively. A lower proportion of patients had detectable titers of neutralizing antibodies (NAbT) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOC) versus wild-type (WT) SARS-CoV-2. Patients with hematological malignancies were more likely to have undetectable NAbT and had lower median NAbT than those with solid cancers against both SARS-CoV-2 WT and VOC. By comparison with individuals without cancer, patients with hematological, but not solid, malignancies had reduced neutralizing antibody (NAb) responses. Seroconversion showed poor concordance with NAbT against VOC. Previous SARS-CoV-2 infection boosted the NAb response including against VOC, and anti-CD20 treatment was associated with undetectable NAbT. Vaccine-induced T cell responses were detected in 80% of patients and were comparable between vaccines or cancer types. Our results have implications for the management of patients with cancer during the ongoing COVID-19 pandemic.


Subject(s)
/immunology , COVID-19/prevention & control , Neoplasms/immunology , SARS-CoV-2/immunology , Aged , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/immunology , Antibodies, Viral/blood , Antibodies, Viral/immunology , COVID-19/blood , COVID-19/immunology , Female , Humans , Immunity, Cellular , Immunogenicity, Vaccine , Male , Middle Aged , Neoplasms/blood , Neoplasms/complications , Prospective Studies , T-Lymphocytes/immunology
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