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1.
Preprint in English | bioRxiv | ID: ppbiorxiv-515748

ABSTRACT

The impact of variants of concern (VoC) on SARS-CoV-2 viral dynamics remains poorly understood and essentially relies on observational studies subject to various sorts of biases. In contrast, experimental models of infection constitute a powerful model to perform controlled comparisons of the viral dynamics observed with VoC and better quantify how VoC escape from the immune response. Here we used molecular and infectious viral load of 78 cynomolgus macaques to characterize in detail the effects of VoC on viral dynamics. We first developed a mathematical model that recapitulate the observed dynamics, and we found that the best model describing the data assumed a rapid antigen-dependent stimulation of the immune response leading to a rapid reduction of viral infectivity. When compared with the historical variant, all VoC except beta were associated with an escape from this immune response, and this effect was particularly sensitive for delta and omicron variant (p<10-6 for both). Interestingly, delta variant was associated with a 1.8-fold increased viral production rate (p=0.046), while conversely omicron variant was associated with a 14-fold reduction in viral production rate (p<10-6). During a natural infection, our models predict that delta variant is associated with a higher peak viral RNA than omicron variant (7.6 log10 copies/mL 95% CI 6.8 - 8 for delta; 5.6 log10 copies/mL 95% CI 4.8 - 6.3 for omicron) while having similar peak infectious titers (3.7 log10 PFU/mL 95% CI 2.4 - 4.6 for delta; 2.8 log10 PFU/mL 95% CI 1.9 - 3.8 for omicron). These results provide a detailed picture of the effects of VoC on total and infectious viral load and may help understand some differences observed in the patterns of viral transmission of these viruses.

2.
Houriiyah Tegally; James E. San; Matthew Cotten; Bryan Tegomoh; Gerald Mboowa; Darren P. Martin; Cheryl Baxter; Monika Moir; Arnold Lambisia; Amadou Diallo; Daniel G. Amoako; Moussa M. Diagne; Abay Sisay; Abdel-Rahman N. Zekri; Abdelhamid Barakat; Abdou Salam Gueye; Abdoul K. Sangare; Abdoul-Salam Ouedraogo; Abdourahmane SOW; Abdualmoniem O. Musa; Abdul K. Sesay; Adamou LAGARE; Adedotun-Sulaiman Kemi; Aden Elmi Abar; Adeniji A. Johnson; Adeola Fowotade; Adewumi M. Olubusuyi; Adeyemi O. Oluwapelumi; Adrienne A. Amuri; Agnes Juru; Ahmad Mabrouk Ramadan; Ahmed Kandeil; Ahmed Mostafa; Ahmed Rebai; Ahmed Sayed; Akano Kazeem; Aladje Balde; Alan Christoffels; Alexander J. Trotter; Allan Campbell; Alpha Kabinet KEITA; Amadou Kone; Amal Bouzid; Amal Souissi; Ambrose Agweyu; Ana V. Gutierrez; Andrew J. Page; Anges Yadouleton; Anika Vinze; Anise N. Happi; Anissa Chouikha; Arash Iranzadeh; Arisha Maharaj; Armel Landry Batchi-Bouyou; Arshad Ismail; Augustina Sylverken; Augustine Goba; Ayoade Femi; Ayotunde Elijah Sijuwola; Azeddine Ibrahimi; Baba Marycelin; Babatunde Lawal Salako; Bamidele S. Oderinde; Bankole Bolajoko; Beatrice Dhaala; Belinda L. Herring; Benjamin Tsofa; Bernard Mvula; Berthe-Marie Njanpop-Lafourcade; Blessing T. Marondera; Bouh Abdi KHAIREH; Bourema Kouriba; Bright Adu; Brigitte Pool; Bronwyn McInnis; Cara Brook; Carolyn Williamson; Catherine Anscombe; Catherine B. Pratt; Cathrine Scheepers; Chantal G. Akoua-Koffi; Charles N. Agoti; Cheikh Loucoubar; Chika Kingsley Onwuamah; Chikwe Ihekweazu; Christian Noel MALAKA; Christophe Peyrefitte; Chukwuma Ewean Omoruyi; Clotaire Donatien Rafai; Collins M. Morang'a; D. James Nokes; Daniel Bugembe Lule; Daniel J. Bridges; Daniel Mukadi-Bamuleka; Danny Park; David Baker; Deelan Doolabh; Deogratius Ssemwanga; Derek Tshiabuila; Diarra Bassirou; Dominic S.Y. Amuzu; Dominique Goedhals; Donald S. Grant; Donwilliams O. Omuoyo; Dorcas Maruapula; Dorcas Waruguru Wanjohi; Ebenezer Foster-Nyarko; Eddy K. Lusamaki; Edgar Simulundu; Edidah M. Ong'era; Edith N. Ngabana; Edward O. Abworo; Edward Otieno; Edwin Shumba; Edwine Barasa; EL BARA AHMED; Elmostafa EL FAHIME; Emmanuel Lokilo; Enatha Mukantwari; Erameh Cyril; Eromon Philomena; Essia Belarbi; Etienne Simon-Loriere; Etile A. Anoh; Fabian Leendertz; Fahn M. Taweh; Fares Wasfi; Fatma Abdelmoula; Faustinos T. Takawira; Fawzi Derrar; Fehintola V Ajogbasile; Florette Treurnicht; Folarin Onikepe; Francine Ntoumi; Francisca M. Muyembe; FRANCISCO NGIAMBUDULU; Frank Edgard ZONGO Ragomzingba; Fred Athanasius DRATIBI; Fred-Akintunwa Iyanu; Gabriel K. Mbunsu; Gaetan Thilliez; Gemma L. Kay; George O. Akpede; George E Uwem; Gert van Zyl; Gordon A. Awandare; Grit Schubert; Gugu P. Maphalala; Hafaliana C. Ranaivoson; Hajar Lemriss; Hannah E Omunakwe; Harris Onywera; Haruka Abe; HELA KARRAY; Hellen Nansumba; Henda Triki; Herve Alberic ADJE KADJO; Hesham Elgahzaly; Hlanai Gumbo; HOTA mathieu; Hugo Kavunga-Membo; Ibtihel Smeti; Idowu B. Olawoye; Ifedayo Adetifa; Ikponmwosa Odia; Ilhem Boutiba-Ben Boubaker; Isaac Ssewanyana; Isatta Wurie; Iyaloo S Konstantinus; Jacqueline Wemboo Afiwa Halatoko; James Ayei; Janaki Sonoo; Jean Bernard LEKANA-DOUKI; Jean-Claude C. Makangara; Jean-Jacques M. Tamfum; Jean-Michel Heraud; Jeffrey G. Shaffer; Jennifer Giandhari; Jennifer Musyoki; Jessica N. Uwanibe; Jinal N. Bhiman; Jiro Yasuda; Joana Morais; Joana Q. Mends; Jocelyn Kiconco; John Demby Sandi; John Huddleston; John Kofi Odoom; John M. Morobe; John O. Gyapong; John T. Kayiwa; Johnson C. Okolie; Joicymara Santos Xavier; Jones Gyamfi; Joseph Humphrey Kofi Bonney; Joseph Nyandwi; Josie Everatt; Jouali Farah; Joweria Nakaseegu; Joyce M. Ngoi; Joyce Namulondo; Judith U. Oguzie; Julia C. Andeko; Julius J. Lutwama; Justin O'Grady; Katherine J Siddle; Kathleen Victoir; Kayode T. Adeyemi; Kefentse A. Tumedi; Kevin Sanders Carvalho; Khadija Said Mohammed; Kunda G. Musonda; Kwabena O. Duedu; Lahcen Belyamani; Lamia Fki-Berrajah; Lavanya Singh; Leon Biscornet; Leonardo de Oliveira Martins; Lucious Chabuka; Luicer Olubayo; Lul Lojok Deng; Lynette Isabella Ochola-Oyier; Madisa Mine; Magalutcheemee Ramuth; Maha Mastouri; Mahmoud ElHefnawi; Maimouna Mbanne; Maitshwarelo I. Matsheka; Malebogo Kebabonye; Mamadou Diop; Mambu Momoh; Maria da Luz Lima Mendonca; Marietjie Venter; Marietou F Paye; Martin Faye; Martin M. Nyaga; Mathabo Mareka; Matoke-Muhia Damaris; Maureen W. Mburu; Maximillian Mpina; Claujens Chastel MFOUTOU MAPANGUY; Michael Owusu; Michael R. Wiley; Mirabeau Youtchou Tatfeng; Mitoha Ondo'o Ayekaba; Mohamed Abouelhoda; Mohamed Amine Beloufa; Mohamed G Seadawy; Mohamed K. Khalifa; Mohammed Koussai DELLAGI; Mooko Marethabile Matobo; Mouhamed Kane; Mouna Ouadghiri; Mounerou Salou; Mphaphi B. Mbulawa; Mudashiru Femi Saibu; Mulenga Mwenda; My V.T. Phan; Nabil Abid; Nadia Touil; Nadine Rujeni; Nalia Ismael; Ndeye Marieme Top; Ndongo Dia; Nedio Mabunda; Nei-yuan Hsiao; Nelson Borico Silochi; Ngonda Saasa; Nicholas Bbosa; Nickson Murunga; Nicksy Gumede; Nicole Wolter; Nikita Sitharam; Nnaemeka Ndodo; Nnennaya A. Ajayi; Noel Tordo; Nokuzola Mbhele; Norosoa H Razanajatovo; Nosamiefan Iguosadolo; Nwando Mba; Ojide C. Kingsley; Okogbenin Sylvanus; Okokhere Peter; Oladiji Femi; Olumade Testimony; Olusola Akinola Ogunsanya; Oluwatosin Fakayode; Onwe E. Ogah; Ousmane Faye; Pamela Smith-Lawrence; Pascale Ondoa; Patrice Combe; Patricia Nabisubi; Patrick Semanda; Paul E. Oluniyi; Paulo Arnaldo; Peter Kojo Quashie; Philip Bejon; Philippe Dussart; Phillip A. Bester; Placide K. Mbala; Pontiano Kaleebu; Priscilla Abechi; Rabeh El-Shesheny; Rageema Joseph; Ramy Karam Aziz; Rene Ghislain Essomba; Reuben Ayivor-Djanie; Richard Njouom; Richard O. Phillips; Richmond Gorman; Robert A. Kingsley; Rosemary Audu; Rosina A.A. Carr; Saad El Kabbaj; Saba Gargouri; Saber Masmoudi; Safietou Sankhe; Sahra Isse Mohamed; Salma MHALLA; Salome Hosch; Samar Kamal Kassim; Samar Metha; Sameh Trabelsi; Sanaa Lemriss; Sara Hassan Agwa; Sarah Wambui Mwangi; Seydou Doumbia; Sheila Makiala-Mandanda; Sherihane Aryeetey; Shymaa S. Ahmed; SIDI MOHAMED AHMED; Siham Elhamoumi; Sikhulile Moyo; Silvia Lutucuta; Simani Gaseitsiwe; Simbirie Jalloh; Soafy Andriamandimby; Sobajo Oguntope; Solene Grayo; Sonia Lekana-Douki; Sophie Prosolek; Soumeya Ouangraoua; Stephanie van Wyk; Stephen F. Schaffner; Stephen Kanyerezi; Steve AHUKA-MUNDEKE; Steven Rudder; Sureshnee Pillay; Susan Nabadda; Sylvie Behillil; Sylvie L. Budiaki; Sylvie van der Werf; Tapfumanei Mashe; Tarik Aanniz; Thabo Mohale; Thanh Le-Viet; Thirumalaisamy P. Velavan; Tobias Schindler; Tongai Maponga; Trevor Bedford; Ugochukwu J. Anyaneji; Ugwu Chinedu; Upasana Ramphal; Vincent Enouf; Vishvanath Nene; Vivianne Gorova; Wael H. Roshdy; Wasim Abdul Karim; William K. Ampofo; Wolfgang Preiser; Wonderful T. Choga; Yahaya ALI ALI AHMED; Yajna Ramphal; Yaw Bediako; Yeshnee Naidoo; Yvan Butera; Zaydah R. de Laurent; Ahmed E.O. Ouma; Anne von Gottberg; George Githinji; Matshidiso Moeti; Oyewale Tomori; Pardis C. Sabeti; Amadou A. Sall; Samuel O. Oyola; Yenew K. Tebeje; Sofonias K. Tessema; Tulio de Oliveira; Christian Happi; Richard Lessells; John Nkengasong; Eduan Wilkinson.
Preprint in English | medRxiv | ID: ppmedrxiv-22273906

ABSTRACT

Investment in Africa over the past year with regards to SARS-CoV-2 genotyping has led to a massive increase in the number of sequences, exceeding 100,000 genomes generated to track the pandemic on the continent. Our results show an increase in the number of African countries able to sequence within their own borders, coupled with a decrease in sequencing turnaround time. Findings from this genomic surveillance underscores the heterogeneous nature of the pandemic but we observe repeated dissemination of SARS-CoV-2 variants within the continent. Sustained investment for genomic surveillance in Africa is needed as the virus continues to evolve, particularly in the low vaccination landscape. These investments are very crucial for preparedness and response for future pathogen outbreaks. One-Sentence SummaryExpanding Africa SARS-CoV-2 sequencing capacity in a fast evolving pandemic.

3.
Preprint in English | bioRxiv | ID: ppbiorxiv-486719

ABSTRACT

Memory B-cell and antibody responses to the SARS-CoV-2 spike protein contribute to long-term immune protection against severe COVID-19, which can also be prevented by antibody-based interventions. Here, wide SARS-CoV-2 immunoprofiling in COVID-19 convalescents combining serological, cellular and monoclonal antibody explorations, revealed humoral immunity coordination. Detailed characterization of a hundred SARS-CoV-2 spike memory B-cell monoclonal antibodies uncovered diversity in their repertoire and antiviral functions. The latter were influenced by the targeted spike region with strong Fc-dependent effectors to the S2 subunit and potent neutralizers to the receptor binding domain. Amongst those, Cv2.1169 and Cv2.3194 antibodies cross-neutralized SARS-CoV-2 variants of concern including Omicron BA.1 and BA.2. Cv2.1169, isolated from a mucosa-derived IgA memory B cell, demonstrated potency boost as IgA dimers and therapeutic efficacy as IgG antibodies in animal models. Structural data provided mechanistic clues to Cv2.1169 potency and breadth. Thus, potent broadly neutralizing IgA antibodies elicited in mucosal tissues can stem SARS-CoV-2 infection, and Cv2.1169 and Cv2.3194 are prime candidates for COVID-19 prevention and treatment.

4.
Preprint in English | medRxiv | ID: ppmedrxiv-22273175

ABSTRACT

BackgroundThe protective immunity against Omicron following a BNT162b2 Pfizer booster dose among elderly is not well characterized. MethodsThirty-eight residents from three nursing homes were recruited for the study. Antibodies targeting the Spike protein of SARS-CoV-2 were measured with the S-Flow assay. Neutralizing activities in sera were measured as effective dilution 50% (ED50) with the S-Fuse assay using authentic isolates of Delta and Omicron. ResultsAmong the 38 elderly included in the study, with median (inter-quartile range, IQR) age of 88 (81-92) years, 30 (78.9%) had been previously infected. The ED50 of neutralization were lower against Omicron than Delta, and higher among convalescent compared to naive residents. During an Omicron epidemic affecting two of the three nursing homes in December 2021-January 2022, 75% (6/8) of naive residents got infected, compared to 25% (6/24) of convalescents (P=0.03). Antibody levels to Spike and ED50 of neutralization against Omicron after the BNT162b2 booster dose were lower in those with breakthrough infection (n=12) compared to those without (n=20): median of 1256 vs 2523 BAU/mL (P=0.02) and median ED50 of 234 vs 1298 (P=0.0004), respectively. ConclusionThis study confirmed the importance of receiving at least three antigenic exposures to the SARS-CoV-2 Spike protein for achieving satisfactory neutralizing antibody levels. In this population, protection against Omicron infection was increased in individuals who had been previously infected in addition to the three vaccine doses. Thus, a fourth antigenic exposure may be useful in the elderly population to prevent infection with Omicron, a variant known for its high escape immunity properties.

5.
Preprint in English | bioRxiv | ID: ppbiorxiv-470527

ABSTRACT

Coronavirus RNA-dependent RNA polymerases produce subgenomic RNAs (sgRNAs) that encode viral structural and accessory proteins. User-friendly bioinformatic tools to detect and quantify sgRNA production are urgently needed to study the growing number of next-generation sequencing (NGS) data of SARS-CoV-2. We introduced sgDI-tector to identify and quantify sgRNA in SARS-CoV-2 NGS data. sgDI-tector allowed detection of sgRNA without initial knowledge of the transcription-regulatory sequences. We produced NGS data and successfully detected the nested set of sgRNAs with the ranking M>ORF3a>N>ORF6>ORF7a>ORF8>S>E>ORF7b. We also compared the level of sgRNA production with other types of viral RNA products such as defective interfering viral genomes.

6.
Preprint in English | bioRxiv | ID: ppbiorxiv-459577

ABSTRACT

SARS-CoV-2 infection results in impaired interferon response in severe COVID-19 patients. However, how SARS-CoV-2 interferes with host immune response is incompletely understood. Here, we sequenced small RNAs from SARS-CoV-2-infected human cells and identified a micro-RNA (miRNA) encoded in a recently evolved region of the viral genome. We show that the virus-encoded miRNA produces two miRNA isoforms in infected cells by the enzyme Dicer and they are loaded into Argonaute proteins. Moreover, the predominant miRNA isoform targets the 3UTR of interferon-stimulated genes and represses their expression in a miRNA-like fashion. Finally, the two viral miRNA isoforms were detected in nasopharyngeal swabs from COVID-19 patients. We propose that SARS-CoV-2 employs a virus-encoded miRNA to hijack the host miRNA machinery and evade the interferon-mediated immune response.

7.
Preprint in English | bioRxiv | ID: ppbiorxiv-454991

ABSTRACT

A challenge for the development of host-targeted anti-infectives against a large spectrum of AB-like toxin-producing bacteria encompasses the identification of chemical compounds corrupting toxin transport through both endolysosomal and retrograde pathways. Here, we performed a high-throughput screening of small chemical compounds blocking active Rac1 proteasomal degradation triggered by the Cytotoxic Necrotizing Factor-1 (CNF1) toxin, followed by orthogonal screens against two AB toxins hijacking defined endolysosomal (Diphtheria toxin) or retrograde (Shiga-like toxin 1) pathways to intoxicate cells. This led to the identification of the molecule N-(3,3-diphenylpropyl)-1-propyl-4-piperidinamine, referred to as C910. This compound induces the swelling of EEA1-positive early endosomes, in absence of PIKfyve kinase inhibition, and disturbs the trafficking of CNF1 and the B-subunit of Shiga toxin along the endolysosomal or retrograde pathways, respectively. Together, we show that C910 protects cells against 8 bacterial AB toxins including large clostridial glucosylating toxins from Clostridium difficile. Of interest, C910 also reduced viral infection in vitro including influenza A virus subtype H1N1 and SARS-CoV-2. Moreover, parenteral administration of C910 to the mice resulted in its accumulation in lung tissues and reduced lethal influenza infection.

8.
Preprint in English | medRxiv | ID: ppmedrxiv-21261285

ABSTRACT

BackgroundWe aimed to assess the effectiveness of the BNT162b2 mRNA vaccine against B.1.351 (beta) variant among residents of long-term care facilities (LCTFs) in eastern France. MethodsWe used routinely collected surveillance and COVID-19 vaccination data to conduct a retrospective cohort study of SARS-CoV-2 B.1.351 infection incidence and vaccine effectiveness among LCTFs residents in eastern France between 15 January and 19 May 2021. Data from secondary RT-PCR screening were used to identify B.1.351 variants. FindingsIncluded in our analysis were 378 residents from five LCTFs: 287 (76%) females, with median (IQR) age of 89 (83-92) years. Two B.1.351 outbreaks took place in LTCFs in which more than 70% of residents had received two doses of BNT162b2 mRNA vaccine, which included 11 cases of severe disease and six deaths among those who had received two doses. Vaccine effectiveness (95% CI) seven days after the second dose of vaccine was 49% (14-69) against any infection with B.1.351 and 86% (67-94) against severe forms of COVID-19. In multivariable analysis, females were less likely to develop severe forms of disease (IRR = 0.35, 95% CI = 0.20-0.63). InterpretationWe observed reduced vaccine effectiveness associated with B.1.351, as well as B.1.351 outbreaks in two LTCFs among individuals who had received two doses of vaccine. Our findings highlight the need to maintain SARS-CoV-2 surveillance in these high-risk settings beyond the current COVID-19 mass vaccination campaign, and advocate for a booster vaccine dose prior to the next winter season.

9.
Preprint in English | bioRxiv | ID: ppbiorxiv-453755

ABSTRACT

The SARS-CoV-2 pandemic causes an ongoing global health crisis, which requires efficient and safe vaccination programs. Here, we present synthetic SARS-CoV2 S glycoprotein-coated liposomes that resemble in size and surface structure virus-like particles. Soluble S glycoprotein trimers were stabilized by formaldehyde cross-linking and coated onto lipid vesicles (S-VLP). Immunization of cynomolgus macaques with S-VLPs induced high antibody titers and TH1 CD4+ biased T cell responses. Although antibody responses were initially dominated by RBD specificity, the third immunization boosted non-RBD antibody titers. Antibodies showed potent neutralization against the vaccine strain and the Alpha variant after two immunizations and robust neutralization of Beta and Gamma strains. Challenge of animals with SARS-CoV-2 protected all vaccinated animals by sterilizing immunity. Thus, the S-VLP approach is an efficient and safe vaccine candidate based on a proven classical approach for further development and clinical testing.

10.
Preprint in English | bioRxiv | ID: ppbiorxiv-451880

ABSTRACT

SARS-CoV-2 has infected almost 200 million humans and caused over 4 million deaths worldwide. Evaluating countermeasures and improving our understanding of COVID-19 pathophysiology require access to animal models that replicate the hallmarks of human disease. Mouse infection with SARS-CoV-2 is limited by poor affinity between the virus spike protein and its cellular receptor ACE2. We have developed by serial passages the MACo3 virus strain which efficiently replicates in the lungs of standard mouse strains and induces age-dependent lung lesions. Compared to other mouse-adapted strains and severe mouse models, infection with MACo3 results in mild to moderate disease and will be useful to investigate the role of host genetics and other factors modulating COVID-19 severity.

11.
Eduan Wilkinson; Marta Giovanetti; Houriiyah Tegally; James E San; Richard Lessels; Diego Cuadros; Darren P Martin; Abdel-Rahman N Zekri; Abdoul Sangare; Abdoul Salam Ouedraogo; Abdul K Sesay; Adnene Hammami; Adrienne A Amuri; Ahmad Sayed; Ahmed Rebai; Aida Elargoubi; Alpha K Keita; Amadou A Sall; Amadou Kone; Amal Souissi; Ana V Gutierrez; Andrew Page; Arnold Lambisia; Arash Iranzadeh; Augustina Sylverken; Azeddine Ibrahimi; Bourema Kouriba; Bronwyn Kleinhans; Beatrice Dhaala; Cara Brook; Carolyn Williamson; Catherine B Pratt; Chantal G Akoua-Koffi; Charles Agoti; Collins M Moranga; James D Nokes; Daniel J Bridges; Daniel L Bugembe; Deelan Doolabh; Deogratius Ssemwanga; Derek Tshabuila; Diarra Bassirou; Dominic S.Y. Amuzu; Dominique Goedhals; Dorcas Maruapula; Edith N Ngabana; Eddy Lusamaki; Edidah Moraa; Elmostafa El Fahime; Emerald Jacob; Emmanuel Lokilo; Enatha Mukantwari; Essia Belarbi; Etienne Simon-Loriere; Etile A Anoh; Fabian Leendertz; Faida Ajili; Fares Wasfi; Faustinos T Takawira; Fawzi Derrar; Feriel Bouzid; Francisca M Muyembe; Frank Tanser; Gabriel Mbunsu; Gaetan Thilliez; Gert van Zyl; Grit Schubert; George Githinji; Gordon A Awandare; Haruka Abe; Hela H Karray; Hellen Nansumba; Hesham A Elgahzaly; Hlanai Gumbo; Ibtihel Smeti; Ikhlass B Ayed; Imed Gaaloul; Ilhem B.B. Boubaker; Inbal Gazy; Isaac Ssewanyana; Jean B Lekana-Douk; Jean-Claude C Makangara; Jean-Jacques M Tamfum; Jean M Heraud; Jeffrey G Shaffer; Jennifer Giandhari; Jingjing Li; Jiro Yasuda; Joana Q Mends; Jocelyn Kiconco; Jonathan A Edwards; John Morobe; John N Nkengasong; John Gyapong; John T Kayiwa; Jones Gyamfi; Jouali Farah; Joyce M Ngoi; Joyce Namulondo; Julia C Andeko; Julius J Lutwama; Justin O Grady; Kefenstse A Tumedi; Khadija Said; Kim Hae-Young; Kwabena O Duedu; Lahcen Belyamani; Lavanya Singh; Leonardo de O. Martins; Madisa Mine; Mahmoud el Hefnawi; Mahjoub Aouni; Maha Mastouri; Maitshwarelo I Matsheka; Malebogo Kebabonye; Manel Turki; Martin Nyaga; Matoke Damaris; Matthew Cotten; Maureen W Mburu; Maximillian Mpina; Michael R Wiley; Mohamed A Ali; Mohamed K Khalifa; Mohamed G Seadawy; Mouna Ouadghiri; Mulenga Mwenda; Mushal Allam; My V.T. Phan; Nabil Abid; Nadia Touil; Najla Kharrat; Nalia Ismael; Nedio Mabunda; Nei-yuan Hsiao; Nelson Silochi; Ngonda Saasa; Nicola Mulder; Patrice Combe; Patrick Semanda; Paul E Oluniyi; Paulo Arnaldo; Peter K Quashie; Reuben Ayivor-Djanie; Philip A Bester; Philippe Dussart; Placide K Mbala; Pontiano Kaleebu; Richard Njouom; Richmond Gorman; Robert A Kingsley; Rosina A.A. Carr; Saba Gargouri; Saber Masmoudi; Samar Kassim; Sameh Trabelsi; Sami Kammoun; Sanaa Lemriss; Sara H Agwa; Sebastien Calvignac-Spencer; Seydou Doumbia; Sheila M Madinda; Sherihane Aryeetey; Shymaa S Ahmed; Sikhulile Moyo; Simani Gaseitsiwe; Edgar Simulundu; Sonia Lekana-Douki; Soumeya Ouangraoua; Steve A Mundeke; Sumir Panji; Sureshnee Pillay; Susan Engelbrecht; Susan Nabadda; Sylvie Behillil; Sylvie van der Werf; Tarik Aanniz; Tapfumanei Mashe; Thabo Mohale; Thanh Le-Viet; Tobias Schindler; Upasana Ramphal; Magalutcheemee Ramuth; Vagner Fonseca; Vincent Enouf; Wael H Roshdy; William Ampofo; Wolfgang Preiser; Wonderful T Choga; Yaw Bediako; Yenew K. Tebeje; Yeshnee Naidoo; Zaydah de Laurent; Sofonias K Tessema; Tulio de Oliveira.
Preprint in English | medRxiv | ID: ppmedrxiv-21257080

ABSTRACT

The progression of the SARS-CoV-2 pandemic in Africa has so far been heterogeneous and the full impact is not yet well understood. Here, we describe the genomic epidemiology using a dataset of 8746 genomes from 33 African countries and two overseas territories. We show that the epidemics in most countries were initiated by importations, predominantly from Europe, which diminished following the early introduction of international travel restrictions. As the pandemic progressed, ongoing transmission in many countries and increasing mobility led to the emergence and spread within the continent of many variants of concern and interest, such as B.1.351, B.1.525, A.23.1 and C.1.1. Although distorted by low sampling numbers and blind-spots, the findings highlight that Africa must not be left behind in the global pandemic response, otherwise it could become a breeding ground for new variants.

12.
Preprint in English | medRxiv | ID: ppmedrxiv-21256690

ABSTRACT

BackgroundIn early January 2021, an outbreak of nosocomial cases of COVID-19 emerged in Western France, with RT-PCR tests repeatedly negative on nasopharyngeal samples but positive on lower respiratory tract samples. Whole genome sequencing (WGS) revealed a new variant, currently defining a novel SARS-CoV-2 lineage: B.1.616. In March, WHO classified this variant as under investigation (VUI). We analyzed the characteristics and outcomes of COVID-19 cases related to this new variant. MethodsClinical, virological, and radiological data were retrospectively collected from medical charts in the two hospitals involved. We enrolled patients with at least one of the following: i) positive SARS-CoV-2 RT-PCR on a respiratory sample; ii) seroconversion with anti-SARS-CoV-2 IgG/IgM; iii) suggestive symptoms and typical features of COVID-19 on chest CT scan. Cases were categorized as either: i) B.1.616; ii) variant of concern (VOC); iii) unknown. FindingsFrom January 1st to March 24th, 2021, 114 patients fulfilled the inclusion criteria: B.1.616 (n=34), VOC (n=32), and unknown (n=48). B.1.616-related cases were older than VOC-related cases (81 years [73-88], vs 73 years [67-82], P<0.05) and their first RT-PCR tests were less often positive (5/34, 15% vs 31/32, 97%, P<0.05). The B.1.616 variant was independently associated with severe disease (multivariable Cox model HR 4.2 [1.3- 13.5], P=0.018), and increased lethality (logrank test P=0.01): 28-day mortality 15/34 (44%) with B.1.616, vs. 5/32 (16%) for VOC, P=0.036. InterpretationWe report a nosocomial outbreak of COVID-19 cases related to a new variant, B.1.616, poorly detected by RT-PCR on nasopharyngeal samples, with high lethality. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSAmong the numerous SARS-CoV-2 variants described worldwide, only 3 are currently classified as Variant of Concern (VOC) by the WHO, since they are associated with either an increased risk in transmissibility, severity, or significant reduction in neutralization by antibodies: B.1.1.7, B.1.351 and P.1 (Pango lineage nomenclature). With the ongoing circulation of SARS-CoV-2 in many places worldwide, the emergence of new variants may reduce the efficacy of vaccines and jeopardize our prospects to control the pandemic. In early January 2021, an outbreak of cases highly suggestive of COVID-19 despite negative RT-PCR tests on repeated nasopharyngeal (NP) samples was reported in Western France, leading to several nosocomial clusters. Whole-genome sequencing (WGS) from lower respiratory tract samples identified a new lineage of SARS-CoV-2 virus, classified as B1.616. Consequently, the French public health agency (Sante publique France) and the WHO classified B.1.616 as variant under investigation (VUI). Added value of this studyOur observational study, conducted from January 1st to March 24th 2021 in the B.1.616 identified area, provides the first clinical and virological description of B.1.616-associated COVID-19. The 34 cases had clinical, biological and radiological findings in line with classical features of COVID-19, while RT-PCR tests on nasopharyngeal (NP) samples failed to detect SARS-CoV-2 in most patients. Indeed, this gold-standard test was positive in only 15% of the first tests in B.1.616-related COVID-19 patients. Of note, the diagnostic performance of RT-PCR tests was satisfactory on lower respiratory tract samples, suggesting that failure to detect B.1.616 on NP samples would be due to a viral load below the limit of detection in the upper respiratory tract, rather than to genomic mismatches between routine RT-PCR targets and this variant. In our cohort, B.1.616 was independently associated with worse clinical outcome, with high 28-day mortality (44%). Implications of all the available evidenceDiagnosis of B.1.616-related COVID-19 cases should not rely on RT-PCR tests on NP samples. In the epidemic area, strict infection control measures must be maintained as long as COVID-19 diagnosis is not ruled out, in order to limit nosocomial clusters and case fatality. Further studies are needed to confirm and investigate the association between genomic characteristics of B.1.616, and i) poor detection by RT-PCR tests on NP samples; ii) prognosis.

13.
Preprint in English | bioRxiv | ID: ppbiorxiv-442916

ABSTRACT

Interferon restricts SARS-CoV-2 replication in cell culture, but only a handful of Interferon Stimulated Genes with antiviral activity against SARS-CoV-2 have been identified. Here, we describe a functional CRISPR/Cas9 screen aiming at identifying SARS-CoV-2 restriction factors. We identified DAXX, a scaffold protein residing in PML nuclear bodies known to limit the replication of DNA viruses and retroviruses, as a potent inhibitor of SARS-CoV-2 and SARS-CoV replication in human cells. Basal expression of DAXX was sufficient to limit the replication of SARS-CoV-2, and DAXX over-expression further restricted infection. In contrast with most of its previously described antiviral activities, DAXX-mediated restriction of SARS-CoV-2 was independent of the SUMOylation pathway. SARS-CoV-2 infection triggered the re-localization of DAXX to cytoplasmic sites and promoted its degradation. Mechanistically, this process was mediated by the viral papain-like protease (PLpro) and the proteasome. Together, these results demonstrate that DAXX restricts SARS-CoV-2, which in turn has evolved a mechanism to counteract its action.

14.
Preprint in English | bioRxiv | ID: ppbiorxiv-436013

ABSTRACT

Receptor recognition is a major determinant of viral host range, infectivity and pathogenesis. Emergences have been associated with serendipitous events of adaptation upon encounters with novel hosts, and the high mutation rate of RNA viruses may explain their frequent host shifts. SARS-CoV-2 extensive circulation in humans results in the emergence of variants, including variants of concern (VOCs) with diverse mutations notably in the spike, and increased transmissibility or immune escape. Here we show that, unlike the initial and Delta variants, the three VOCs bearing the N501Y mutation can infect common laboratory mice. Contact transmission occurred from infected to naive mice through two passages. This host range expansion likely results from an increased binding of the spike to the mouse ACE2. Together with the observed contact transmission, it raises the possibility of wild rodent secondary reservoirs enabling the emergence of new variants.

15.
Preprint in English | bioRxiv | ID: ppbiorxiv-430472

ABSTRACT

SARS-CoV-2 B.1.1.7 and B.1.351 variants emerged respectively in United Kingdom and South Africa and spread in many countries. Here, we isolated infectious B.1.1.7 and B.1.351 strains and examined their sensitivity to anti-SARS-CoV-2 antibodies present in sera and nasal swabs, in comparison with a D614G reference virus. We established a novel rapid neutralization assay, based on reporter cells that become GFP+ after overnight infection. B.1.1.7 was neutralized by 79/83 sera from convalescent patients collected up to 9 months post symptoms, almost similar to D614G. There was a mean 6-fold reduction in titers and even loss of activity against B.1.351 in 40% of convalescent sera after 9 months. Early sera from 19 vaccinated individuals were almost as potent against B.1.1.7 but less efficacious against B.1.351, when compared to D614G. Nasal swabs from vaccine recipients were not neutralizing, except in individuals who were diagnosed COVID-19+ before vaccination. Thus, faster-spreading variants acquired a partial resistance to humoral immunity generated by natural infection or vaccination, mostly visible in individuals with low antibody levels.

16.
Preprint in English | medRxiv | ID: ppmedrxiv-20249038

ABSTRACT

BackgroundThe systemic antibody responses to SARS-CoV-2 in COVID-19 patients has been extensively studied. However, much less is known about the mucosal responses in the upper airways at the site of initial SARS-CoV-2 replication. Local antibody responses in the nasopharyngeal epithelium, that are likely to determine the course of infection, have not been analysed so far nor their correlation with antibody responses in serum. MethodsThe IgG and IgA antibody responses were analysed in the plasma as well as in nasopharyngeal swabs (NPS) from the first four COVID-19 patients confirmed by RT-qPCR in France. Two were pauci-symptomatic while two developed severe disease. Taking advantage of a comprehensive series of plasma and nasopharyngeal samples, we characterized their antibody profiles from the second week post symptoms onset, by using an in-house ELISA to detect anti-SARS-CoV-2 Nucleoprotein (N) IgG and IgA. ResultsAnti-N IgG and IgA antibodies were detected in the NPS of severe patients. Overall, the levels of IgA and IgG antibodies in plasma and NPS appeared specific to each patient. ConclusionsAnti-N IgG and IgA antibodies are detected in NPS, and their levels are related to antibody levels in plasma. The two patients with severe disease exhibited different antibody profiles that may reflect different disease outcome. For the pauci-symptomatic patients, one showed a low anti-N IgG and IgA response in the plasma only, while the other one did not exhibit overt serological response.

17.
Preprint in English | bioRxiv | ID: ppbiorxiv-365726

ABSTRACT

The SARS-CoV-2 pandemic is continuing to disrupt personal lives, global healthcare systems and economies. Hence, there is an urgent need for a vaccine that prevents viral infection, transmission and disease. Here, we present a two-component protein-based nanoparticle vaccine that displays multiple copies of the SARS-CoV-2 spike protein. Immunization studies show that this vaccine induces potent neutralizing antibody responses in mice, rabbits and cynomolgus macaques. The vaccine-induced immunity protected macaques against a high dose challenge, resulting in strongly reduced viral infection and replication in upper and lower airways. These nanoparticles are a promising vaccine candidate to curtail the SARS-CoV-2 pandemic.

18.
Preprint in English | medRxiv | ID: ppmedrxiv-20213116

ABSTRACT

BackgroundAssessment of cumulative incidence of SARS-CoV-2 infections is critical for monitoring the course and the extent of the epidemic. As asymptomatic or mild cases were typically not captured by surveillance data in France, we implemented nationwide serological surveillance. We present estimates for prevalence of anti-SARS-CoV-2 antibodies in the French population and the proportion of infected individuals who developed potentially protective neutralizing antibodies throughout the first epidemic wave. MethodsWe performed serial cross-sectional sampling of residual sera over three periods: prior to (9-15 March), during (6-12 April) and following (11-17 May) a nationwide lockdown. Each sample was tested for anti-SARS-CoV-2 IgG antibodies targeting the Nucleoprotein and Spike using two Luciferase-Linked ImmunoSorbent Assays, and for neutralising antibodies using a pseudo-neutralisation assay. We fitted a general linear mixed model of seropositivity in a Bayesian framework to derive prevalence estimates stratified by age, sex and region. FindingsIn total, sera from 11 021 individuals were analysed. Nationwide seroprevalence of SARS-CoV-2 antibodies was estimated at 0.41% [0.05-0.88] mid-March, 4.14% [3.31-4.99] mid-April and 4.93% [4.02-5.89] mid-May. Approximately 70% of seropositive individuals had detectable neutralising antibodies. Seroprevalence was higher in regions where circulation occurred earlier and was more intense. Seroprevalence was lowest in children under 10 years of age (2.72% [1.10-4.87]). InterpretationSeroprevalence estimates confirm that the nationwide lockdown substantially curbed transmission and that the vast majority of the French population remains susceptible to SARS-CoV-2. Low seroprevalence in school age children suggests limited susceptibility and/or transmissibility in this age group. Our results show a clear picture of the progression of the first epidemic wave and provide a framework to inform the ongoing public health response as viral transmission is picking up again in France and globally. FundingSante publique France.

19.
Preprint in English | medRxiv | ID: ppmedrxiv-20194860

ABSTRACT

Objective: We aimed to estimate the risk of infection in Healthcare workers (HCWs) following a high-risk exposure without personal protective equipment (PPE). Methods: We conducted a prospective cohort in HCWs who had a high-risk exposure to SARS-CoV-2-infected subject without PPE. Daily symptoms were self-reported for 30 days, nasopharyngeal swabs for SARS-CoV-2 RT-PCR were performed at inclusion and at days 3, 5, 7 and 12, SARS-CoV-2 serology was assessed at inclusion and at day 30. Confirmed infection was defined by positive RT-PCR or seroconversion, and possible infection by one general and one specific symptom for two consecutive days. Results: Between February 5th and May 30th, 2020, 154 HCWs were enrolled within 14 days following one high-risk exposure to either a hospital patient (70/154; 46.1%) and/or a colleague (95/154; 62.5%). At day 30, 25.0% had a confirmed infection (37/148; 95%CI, 18.4%; 32.9%), and 43.9% (65/148; 95%CI, 35.9%; 52.3%) had a confirmed or possible infection. Factors independently associated with confirmed or possible SARS-CoV-2 infection were being a pharmacist or administrative assistant rather than being from medical staff (adjusted OR (aOR)=3.8, CI95%=1.3;11.2, p=0.01), and exposure to a SARS-CoV-2-infected patient rather than exposure to a SARS-CoV-2-infected colleague (aOR=2.6, CI95%=1.2;5.9, p=0.02). Among the 26 HCWs with a SARS-CoV-2-positive nasopharyngeal swab, 7 (26.9%) had no symptom at the time of the RT-PCR positivity. Conclusions: The proportion of HCWs with confirmed or possible SARS-CoV-2 infection was high. There were less occurrences of high-risk exposure with patients than with colleagues, but those were associated with an increased risk of infection.

20.
Preprint in English | bioRxiv | ID: ppbiorxiv-272955

ABSTRACT

The worldwide SARS-CoV-2 outbreak poses a serious challenge to human societies and economies. SARS-CoV-2 proteins orchestrate complex pathogenic mechanisms that underlie COVID-19 disease. Thus, understanding how viral polypeptides rewire host protein networks enables better-founded therapeutic research. In complement to existing proteomic studies, in this study we define the first proximal interaction network of SARS-CoV-2 proteins, at the whole proteome level in human cells. Applying a proximity-dependent biotinylation (BioID)-based approach greatly expanded the current knowledge by detecting interactions within poorly soluble compartments, transient, and/or of weak affinity in living cells. Our BioID study was complemented by a stringent filtering and uncovered 2,128 unique cellular targets (1,717 not previously associated with SARS-CoV-1 or 2 proteins) connected to the N- and C-ter BioID-tagged 28 SARS-CoV-2 proteins by a total of 5,415 (5,236 new) proximal interactions. In order to facilitate data exploitation, an innovative interactive 3D web interface was developed to allow customized analysis and exploration of the landscape of interactions (accessible at http://www.sars-cov-2-interactome.org/). Interestingly, 342 membrane proteins including interferon and interleukin pathways factors, were associated with specific viral proteins. We uncovered ORF7a and ORF7b protein proximal partners that could be related to anosmia and ageusia symptoms. Moreover, comparing proximal interactomes in basal and infection-mimicking conditions (poly(I:C) treatment) allowed us to detect novel links with major antiviral response pathway components, such as ORF9b with MAVS and ISG20; N with PKR and TARB2; NSP2 with RIG-I and STAT1; NSP16 with PARP9-DTX3L. Altogether, our study provides an unprecedented comprehensive resource for understanding how SARS-CoV-2 proteins orchestrate host proteome remodeling and innate immune response evasion, which can inform development of targeted therapeutic strategies.

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