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1.
Clin Infect Dis ; 2022 Oct 05.
Article in English | MEDLINE | ID: covidwho-2188598

ABSTRACT

BACKGROUND: People with HIV on antiretroviral therapy with good CD4 T cell counts make effective immune responses following vaccination against SARS-CoV-2. There are few data on longer term responses and the impact of a booster dose. METHODS: Adults with HIV were enrolled into a single arm open label study. Two doses of ChAdOx1 nCoV-19 were followed twelve months later by a third heterologous vaccine dose. Participants had undetectable viraemia on ART and CD4 counts >350 cells/µl. Immune responses to the ancestral strain and variants of concern were measured by anti-spike IgG ELISA, MesoScale Discovery (MSD) anti-spike platform, ACE-2 inhibition, Activation Induced Marker (AIM) assay and T cell proliferation. FINDINGS: 54 participants received two doses of ChAdOx1 nCoV-19. 43 received a third dose (42 with BNT162b2; 1 with mRNA-1273) one year after the first dose. After the third dose, total anti-SARS-CoV-2 spike IgG titres (MSD), ACE-2 inhibition and IgG ELISA results were significantly higher compared to Day 182 titres (P < 0.0001 for all three). SARS-CoV-2 specific CD4+ T cell responses measured by AIM against SARS-CoV-2 S1 and S2 peptide pools were significantly increased after a third vaccine compared to 6 months after a first dose, with significant increases in proliferative CD4 + and CD8+ T cell responses to SARS-CoV-2 S1 and S2 after boosting. Responses to Alpha, Beta, Gamma, and Delta variants were boosted, although to a lesser extent for Omicron. CONCLUSIONS: In PWH receiving a third vaccine dose, there were significant increases in B and T cell immunity, including to known VOCs.

2.
Cell Reports ; : 111903, 2022.
Article in English | ScienceDirect | ID: covidwho-2158574

ABSTRACT

Summary Variants of SARS CoV-2 have caused successive global waves of infection. These variants, with multiple mutations in the spike protein are thought to facilitate escape from natural and vaccine-induced immunity and often increase in the affinity for ACE2. The latest variant to cause concern is BA.2.75, identified in India where it is now the dominant strain, with evidence of wider dissemination. BA.2.75 is derived from BA.2 and contains four additional mutations in the receptor binding domain (RBD). Here we perform an antigenic and biophysical characterization of BA.2.75, revealing an interesting balance between humoral evasion and ACE2 receptor affinity. ACE2 affinity for BA.2.75 is increased 9-fold compared to BA.2;there is also evidence of escape of BA.2.75 from immune serum, particularly that induced by Delta infection which may explain the rapid spread in India, where BA.2.75 is now the dominant variant. ACE2 affinity appears to be prioritised over greater escape.

3.
Eur J Immunol ; 2022 Nov 03.
Article in English | MEDLINE | ID: covidwho-2103546

ABSTRACT

Replication-incompetent adenovirus (Ad) vector and mRNA-lipid nanoparticle (LNP) constructs represent two modular vaccine platforms that have attracted substantial interest over the past two decades. Due to the COVID-19 pandemic and the rapid development of multiple successful vaccines based on these technologies, there is now clear real-world evidence of the utility and efficacy of these platforms. Considerable optimization and refinement efforts underpin the successful application of these technologies. Despite this, our understanding of the specific pathways and processes engaged by these vaccines to stimulate the immune response remains incomplete. This review will synthesize our current knowledge of the specific mechanisms by which CD8+ T cell and antibody responses are induced by each of these vaccine platforms, and how this can be impacted by specific vaccine construction techniques. Key gaps in our knowledge are also highlighted, which can hopefully focus future studies.

4.
Semin Immunol ; 61-64: 101661, 2022 Oct 28.
Article in English | MEDLINE | ID: covidwho-2086731

ABSTRACT

MAIT cells are one representative of a group of related unconventional or pre-set T cells, and are particularly abundant in humans. While these unconventional T cell types, which also include populations of Vδ2 cells and iNKT cells, recognise quite distinct ligands, they share functional features including the ability to sense "danger" by integration of cytokine signals. Since such signals are common to many human pathologies, activation of MAIT cells in particular has been widely observed. In this review we will discuss recent trends in these data, for example the findings from patients with Covid-19 and responses to novel vaccines. Covid-19 is an example where MAIT cell activation has been correlated with disease severity by several groups, and the pathways leading to activation are being clarified, but the overall role of the cells in vivo requires further exploration. Given the potential wide functional responsiveness of these cells, which ranges from tissue repair to cytotoxicity, and likely impacts on the activity of many other cell populations, defining the role of these cells - not only as sensitive biomarkers but also as mediators - across human disease remains an important task.

5.
Front Immunol ; 13: 984376, 2022.
Article in English | MEDLINE | ID: covidwho-2065516

ABSTRACT

Background: Individuals with primary and secondary immunodeficiency (PID/SID) were shown to be at risk of poor outcomes during the early stages of the SARS-CoV-2 pandemic. SARS-CoV-2 vaccines demonstrate reduced immunogenicity in these patients. Objectives: To understand whether the risk of severe COVID-19 in individuals with PID or SID has changed following the deployment of vaccination and therapeutics in the context of the emergence of novel viral variants of concern. Methods: The outcomes of two cohorts of patients with PID and SID were compared: the first, infected between March and July 2020, prior to vaccination and treatments, the second after these intervention became available between January 2021 and April 2022. Results: 22.7% of immunodeficient patients have been infected at least once with SARS-CoV-2 since the start of the pandemic, compared to over 70% of the general population. Immunodeficient patients were typically infected later in the pandemic when the B.1.1.529 (Omicron) variant was dominant. This delay was associated with receipt of more vaccine doses and higher pre-infection seroprevalence. Compared to March-July 2020, hospitalization rates (53.3% vs 17.9%, p<0.0001) and mortality (Infection fatality rate 20.0% vs 3.4%, p=0.0003) have significantly reduced for patients with PID but remain elevated compared to the general population. The presence of a serological response to vaccination was associated with a reduced duration of viral detection by PCR in the nasopharynx. Early outpatient treatment with antivirals or monoclonal antibodies reduced hospitalization during the Omicron wave. Conclusions: Most individuals with immunodeficiency in the United Kingdom remain SARS-CoV-2 infection naïve. Vaccination, widespread availability of outpatient treatments and, possibly, the emergence of the B.1.1.529 variant have led to significant improvements in morbidity and mortality followings SARS-CoV-2 infection since the start of the pandemic. However, individuals with PID and SID remain at significantly increased risk of poor outcomes compared to the general population; mitigation, vaccination and treatment strategies must be optimized to minimize the ongoing burden of the pandemic in these vulnerable cohorts.


Subject(s)
COVID-19 , Sudden Infant Death , Antibodies, Monoclonal , Antiviral Agents , COVID-19/epidemiology , COVID-19 Vaccines , Hospitalization , Humans , SARS-CoV-2/genetics , Seroepidemiologic Studies , Vaccination
7.
Hepatology ; 76(4): 1190-1202, 2022 10.
Article in English | MEDLINE | ID: covidwho-2059410

ABSTRACT

BACKGROUND AND AIMS: A prophylactic vaccine targeting multiple HCV genotypes (gt) is urgently required to meet World Health Organization elimination targets. Neutralizing antibodies (nAbs) and CD4+ and CD8+ T cells are associated with spontaneous clearance of HCV, and each may contribute to protective immunity. However, current vaccine candidates generate either nAbs or T cells targeting genetically variable epitopes and have failed to show efficacy in human trials. We have previously shown that a simian adenovirus vector (ChAdOx1) encoding conserved sequences across gt1-6 (ChAd-Gt1-6), and separately gt-1a E2 protein with variable regions deleted (E2Δ123HMW ), generates pan-genotypic T cells and nAbs, respectively. We now aim to develop a vaccine to generate both viral-specific B- and T-cell responses concurrently. APPROACH AND RESULTS: We show that vaccinating with ChAd-Gt1-6 and E2Δ123HMW sequentially in mice generates T-cell and antibody (Ab) responses comparable to either vaccine given alone. We encoded E2Δ123 in ChAdOx1 (ChAd-E2Δ123) and show that this, given with an E2Δ123HMW protein boost, induces greater CD81-E2 inhibitory and HCV-pseudoparticle nAb titers compared to the E2Δ123HMW prime boost. We developed bivalent viral vector vaccines (ChAdOx1 and modified vaccinia Ankara [MVA]) encoding both Gt1-6 and E2Δ123 immunogens (Gt1-6-E2Δ123) generating polyfunctional CD4+ and CD8+ T cells and nAb titers in prime/boost strategies. This approach generated nAb responses comparable to monovalent E2Δ123 ChAd/MVA vaccines and superior to three doses of recombinant E2Δ123HMW protein, while also generating high-magnitude T-cell responses. CONCLUSIONS: These data are an important step forward for the development of a pan-genotype HCV vaccine to elicit T cells and nAbs for future assessment in humans.


Subject(s)
Hepatitis C , Vaccines , Animals , Antibodies, Neutralizing , Antibodies, Viral , CD8-Positive T-Lymphocytes , Epitopes , Genotype , Hepacivirus/genetics , Hepatitis C/prevention & control , Hepatitis C Antibodies , Humans , Mice , Vaccinia virus/genetics
8.
Frontiers in immunology ; 13, 2022.
Article in English | EuropePMC | ID: covidwho-2046031

ABSTRACT

Two doses of BNT162b2 mRNA vaccine induces a strong systemic SARS-CoV-2 specific humoral response. However, SARS-CoV-2 airborne transmission makes mucosal immune response a crucial first line of defense. Therefore, we characterized SARS-CoV-2-specific IgG responses induced by BNT162b2 vaccine, as well as IgG responses to other pathogenic and seasonal human coronaviruses in oral fluid and plasma from 200 UK healthcare workers who were naïve (N=62) or previously infected with SARS-CoV-2 (N=138) using a pan-coronavirus multiplex binding immunoassay (Meso Scale Discovery®). Additionally, we investigated the impact of historical SARS-CoV-2 infection on vaccine-induced IgG, IgA and neutralizing responses in selected oral fluid samples before vaccination, after a first and second dose of BNT162b2, as well as following a third dose of mRNA vaccine or breakthrough infections using the same immunoassay and an ACE2 inhibition assay. Prior to vaccination, we found that spike-specific IgG levels in oral fluid positively correlated with IgG levels in plasma from previously-infected individuals (Spearman r=0.6858, p<0.0001) demonstrating that oral fluid could be used as a proxy for the presence of plasma SARS-CoV-2 IgG. However, the sensitivity was lower in oral fluid (0.85, 95% CI 0.77-0.91) than in plasma (0.94, 95% CI 0.88-0.97). Similar kinetics of mucosal and systemic spike-specific IgG levels were observed following vaccination in naïve and previously-infected individuals, respectively. In addition, a significant enhancement of OC43 and HKU1 spike-specific IgG levels was observed in previously-infected individuals following one vaccine dose in oral fluid (OC43 S: p<0.0001;HKU1 S: p=0.0423) suggesting cross-reactive IgG responses to seasonal beta coronaviruses. Mucosal spike-specific IgA responses were induced by mRNA vaccination particularly in previously-infected individuals (71%) but less frequently in naïve participants (23%). Neutralizing responses to SARS-CoV-2 ancestral and variants of concerns were detected following vaccination in naïve and previously-infected participants, with likely contribution from both IgG and IgA in previously-infected individuals (correlations between neutralizing responses and IgG: Spearman r=0.5642, p<0.0001;IgA: Spearman r=0.4545, p=0.0001). We also observed that breakthrough infections or a third vaccine dose enhanced mucosal antibody levels and neutralizing responses. These data contribute to show that a previous SARS-CoV-2 infection tailors the mucosal antibody profile induced by vaccination.

9.
Baruch, Joaquin, Rojek, Amanda, Kartsonaki, Christiana, Vijayaraghavan, Bharath K. T.; Gonçalves, Bronner P.; Pritchard, Mark G.; Merson, Laura, Dunning, Jake, Hall, Matthew, Sigfrid, Louise, Citarella, Barbara W.; Murthy, Srinivas, Yeabah, Trokon O.; Olliaro, Piero, Abbas, Ali, Abdukahil, Sheryl Ann, Abdulkadir, Nurul Najmee, Abe, Ryuzo, Abel, Laurent, Absil, Lara, Acharya, Subhash, Acker, Andrew, Adam, Elisabeth, Adrião, Diana, Al Ageel, Saleh, Ahmed, Shakeel, Ainscough, Kate, Airlangga, Eka, Aisa, Tharwat, Hssain, Ali Ait, Tamlihat, Younes Ait, Akimoto, Takako, Akmal, Ernita, Al Qasim, Eman, Alalqam, Razi, Alberti, Angela, Al‐dabbous, Tala, Alegesan, Senthilkumar, Alegre, Cynthia, Alessi, Marta, Alex, Beatrice, Alexandre, Kévin, Al‐Fares, Abdulrahman, Alfoudri, Huda, Ali, Imran, Ali, Adam, Shah, Naseem Ali, Alidjnou, Kazali Enagnon, Aliudin, Jeffrey, Alkhafajee, Qabas, Allavena, Clotilde, Allou, Nathalie, Altaf, Aneela, Alves, João, Alves, Rita, Alves, João Melo, Amaral, Maria, Amira, Nur, Ampaw, Phoebe, Andini, Roberto, Andréjak, Claire, Angheben, Andrea, Angoulvant, François, Ansart, Séverine, Anthonidass, Sivanesen, Antonelli, Massimo, de Brito, Carlos Alexandre Antunes, Apriyana, Ardiyan, Arabi, Yaseen, Aragao, Irene, Araujo, Carolline, Arcadipane, Antonio, Archambault, Patrick, Arenz, Lukas, Arlet, Jean‐Benoît, Arora, Lovkesh, Arora, Rakesh, Artaud‐Macari, Elise, Aryal, Diptesh, Asensio, Angel, Ashraf, Muhammad, Asif, Namra, Asim, Mohammad, Assie, Jean Baptiste, Asyraf, Amirul, Atique, Anika, Attanyake, A. M. Udara Lakshan, Auchabie, Johann, Aumaitre, Hugues, Auvet, Adrien, Axelsen, Eyvind W.; Azemar, Laurène, Azoulay, Cecile, Bach, Benjamin, Bachelet, Delphine, Badr, Claudine, Bævre‐Jensen, Roar, Baig, Nadia, Baillie, J. Kenneth, Baird, J. Kevin, Bak, Erica, Bakakos, Agamemnon, Bakar, Nazreen Abu, Bal, Andriy, Balakrishnan, Mohanaprasanth, Balan, Valeria, Bani‐Sadr, Firouzé, Barbalho, Renata, Barbosa, Nicholas Yuri, Barclay, Wendy S.; Barnett, Saef Umar, Barnikel, Michaela, Barrasa, Helena, Barrelet, Audrey, Barrigoto, Cleide, Bartoli, Marie, Baruch, Joaquín, Bashir, Mustehan, Basmaci, Romain, Basri, Muhammad Fadhli Hassin, Battaglini, Denise, Bauer, Jules, Rincon, Diego Fernando Bautista, Dow, Denisse Bazan, Beane, Abigail, Bedossa, Alexandra, Bee, Ker Hong, Begum, Husna, Behilill, Sylvie, Beishuizen, Albertus, Beljantsev, Aleksandr, Bellemare, David, Beltrame, Anna, Beltrão, Beatriz Amorim, Beluze, Marine, Benech, Nicolas, Benjiman, Lionel Eric, Benkerrou, Dehbia, Bennett, Suzanne, Bento, Luís, Berdal, Jan‐Erik, Bergeaud, Delphine, Bergin, Hazel, Sobrino, José Luis Bernal, Bertoli, Giulia, Bertolino, Lorenzo, Bessis, Simon, Bevilcaqua, Sybille, Bezulier, Karine, Bhatt, Amar, Bhavsar, Krishna, Bianco, Claudia, Bidin, Farah Nadiah, Singh, Moirangthem Bikram, Humaid, Felwa Bin, Kamarudin, Mohd Nazlin Bin, Bissuel, François, Bitker, Laurent, Bitton, Jonathan, Blanco‐Schweizer, Pablo, Blier, Catherine, Bloos, Frank, Blot, Mathieu, Boccia, Filomena, Bodenes, Laetitia, Bogaarts, Alice, Bogaert, Debby, Boivin, Anne‐Hélène, Bolze, Pierre‐Adrien, Bompart, François, Bonfasius, Aurelius, Borges, Diogo, Borie, Raphaël, Bosse, Hans Martin, Botelho‐Nevers, Elisabeth, Bouadma, Lila, Bouchaud, Olivier, Bouchez, Sabelline, Bouhmani, Dounia, Bouhour, Damien, Bouiller, Kévin, Bouillet, Laurence, Bouisse, Camile, Boureau, Anne‐Sophie, Bourke, John, Bouscambert, Maude, Bousquet, Aurore, Bouziotis, Jason, Boxma, Bianca, Boyer‐Besseyre, Marielle, Boylan, Maria, Bozza, Fernando Augusto, Braconnier, Axelle, Braga, Cynthia, Brandenburger, Timo, Monteiro, Filipa Brás, Brazzi, Luca, Breen, Patrick, Breen, Dorothy, Breen, Patrick, Brickell, Kathy, Browne, Shaunagh, Browne, Alex, Brozzi, Nicolas, Brunvoll, Sonja Hjellegjerde, Brusse‐Keizer, Marjolein, Buchtele, Nina, Buesaquillo, Christian, Bugaeva, Polina, Buisson, Marielle, Buonsenso, Danilo, Burhan, Erlina, Burrell, Aidan, Bustos, Ingrid G.; Butnaru, Denis, Cabie, André, Cabral, Susana, Caceres, Eder, Cadoz, Cyril, Calligy, Kate, Calvache, Jose Andres, Camões, João, Campana, Valentine, Campbell, Paul, Campisi, Josie, Canepa, Cecilia, Cantero, Mireia, Caraux‐Paz, Pauline, Cárcel, Sheila, Cardellino, Chiara Simona, Cardoso, Sofia, Cardoso, Filipe, Cardoso, Filipa, Cardoso, Nelson, Carelli, Simone, Carlier, Nicolas, Carmoi, Thierry, Carney, Gayle, Carqueja, Inês, Carret, Marie‐Christine, Carrier, François Martin, Carroll, Ida, Carson, Gail, Casanova, Maire‐Laure, Cascão, Mariana, Casey, Siobhan, Casimiro, José, Cassandra, Bailey, Castañeda, Silvia, Castanheira, Nidyanara, Castor‐Alexandre, Guylaine, Castrillón, Henry, Castro, Ivo, Catarino, Ana, Catherine, François‐Xavier, Cattaneo, Paolo, Cavalin, Roberta, Cavalli, Giulio Giovanni, Cavayas, Alexandros, Ceccato, Adrian, Cervantes‐Gonzalez, Minerva, Chair, Anissa, Chakveatze, Catherine, Chan, Adrienne, Chand, Meera, Auger, Christelle Chantalat, Chapplain, Jean‐Marc, Chas, Julie, Chatterjee, Allegra, Chaudry, Mobin, Iñiguez, Jonathan Samuel Chávez, Chen, Anjellica, Chen, Yih‐Sharng, Cheng, Matthew Pellan, Cheret, Antoine, Chiarabini, Thibault, Chica, Julian, Chidambaram, Suresh Kumar, Tho, Leong Chin, Chirouze, Catherine, Chiumello, Davide, Cho, Sung‐Min, Cholley, Bernard, Chopin, Marie‐Charlotte, Chow, Ting Soo, Chow, Yock Ping, Chua, Jonathan, Chua, Hiu Jian, Cidade, Jose Pedro, Herreros, José Miguel Cisneros, Citarella, Barbara Wanjiru, Ciullo, Anna, Clarke, Jennifer, Clarke, Emma, Granado, Rolando Claure‐Del, Clohisey, Sara, Cobb, Perren J.; Codan, Cassidy, Cody, Caitriona, Coelho, Alexandra, Coles, Megan, Colin, Gwenhaël, Collins, Michael, Colombo, Sebastiano Maria, Combs, Pamela, Connor, Marie, Conrad, Anne, Contreras, Sofía, Conway, Elaine, Cooke, Graham S.; Copland, Mary, Cordel, Hugues, Corley, Amanda, Cornelis, Sabine, Cornet, Alexander Daniel, Corpuz, Arianne Joy, Cortegiani, Andrea, Corvaisier, Grégory, Costigan, Emma, Couffignal, Camille, Couffin‐Cadiergues, Sandrine, Courtois, Roxane, Cousse, Stéphanie, Cregan, Rachel, Croonen, Sabine, Crowl, Gloria, Crump, Jonathan, Cruz, Claudina, Bermúdez, Juan Luis Cruz, Rojo, Jaime Cruz, Csete, Marc, Cullen, Ailbhe, Cummings, Matthew, Curley, Gerard, Curlier, Elodie, Curran, Colleen, Custodio, Paula, da Silva Filipe, Ana, Da Silveira, Charlene, Dabaliz, Al‐Awwab, Dagens, Andrew, Dahl, John Arne, Dahly, Darren, Dalton, Heidi, Dalton, Jo, Daly, Seamus, Daneman, Nick, Daniel, Corinne, Dankwa, Emmanuelle A.; Dantas, Jorge, D'Aragon, Frédérick, de Loughry, Gillian, de Mendoza, Diego, De Montmollin, Etienne, de Oliveira França, Rafael Freitas, de Pinho Oliveira, Ana Isabel, De Rosa, Rosanna, De Rose, Cristina, de Silva, Thushan, de Vries, Peter, Deacon, Jillian, Dean, David, Debard, Alexa, Debray, Marie‐Pierre, DeCastro, Nathalie, Dechert, William, Deconninck, Lauren, Decours, Romain, Defous, Eve, Delacroix, Isabelle, Delaveuve, Eric, Delavigne, Karen, Delfos, Nathalie M.; Deligiannis, Ionna, Dell'Amore, Andrea, Delmas, Christelle, Delobel, Pierre, Delsing, Corine, Demonchy, Elisa, Denis, Emmanuelle, Deplanque, Dominique, Depuydt, Pieter, Desai, Mehul, Descamps, Diane, Desvallées, Mathilde, Dewayanti, Santi, Dhanger, Pathik, Diallo, Alpha, Diamantis, Sylvain, Dias, André, Diaz, Juan Jose, Diaz, Priscila, Diaz, Rodrigo, Didier, Kévin, Diehl, Jean‐Luc, Dieperink, Wim, Dimet, Jérôme, Dinot, Vincent, Diop, Fara, Diouf, Alphonsine, Dishon, Yael, Djossou, Félix, Docherty, Annemarie B.; Doherty, Helen, Dondorp, Arjen M.; Donnelly, Maria, Donnelly, Christl A.; Donohue, Sean, Donohue, Yoann, Donohue, Chloe, Doran, Peter, Dorival, Céline, D'Ortenzio, Eric, Douglas, James Joshua, Douma, Renee, Dournon, Nathalie, Downer, Triona, Downey, Joanne, Downing, Mark, Drake, Tom, Driscoll, Aoife, Dryden, Murray, Fonseca, Claudio Duarte, Dubee, Vincent, Dubos, François, Ducancelle, Alexandre, Duculan, Toni, Dudman, Susanne, Duggal, Abhijit, Dunand, Paul, Dunning, Jake, Duplaix, Mathilde, Durante‐Mangoni, Emanuele, Durham, Lucian, Dussol, Bertrand, Duthoit, Juliette, Duval, Xavier, Dyrhol‐Riise, Anne Margarita, Ean, Sim Choon, Echeverria‐Villalobos, Marco, Egan, Siobhan, Eggesbø, Linn Margrete, Eira, Carla, El Sanharawi, Mohammed, Elapavaluru, Subbarao, Elharrar, Brigitte, Ellerbroek, Jacobien, Ellingjord‐Dale, Merete, Eloy, Philippine, Elshazly, Tarek, Elyazar, Iqbal, Enderle, Isabelle, Endo, Tomoyuki, Eng, Chan Chee, Engelmann, Ilka, Enouf, Vincent, Epaulard, Olivier, Escher, Martina, Esperatti, Mariano, Esperou, Hélène, Esposito‐Farese, Marina, Estevão, João, Etienne, Manuel, Ettalhaoui, Nadia, Everding, Anna Greti, Evers, Mirjam, Fabre, Marc, Fabre, Isabelle, Faheem, Amna, Fahy, Arabella, Fairfield, Cameron J.; Fakar, Zul, Fareed, Komal, Faria, Pedro, Farooq, Ahmed, Fateena, Hanan, Fatoni, Arie Zainul, Faure, Karine, Favory, Raphaël, Fayed, Mohamed, Feely, Niamh, Feeney, Laura, Fernandes, Jorge, Fernandes, Marília Andreia, Fernandes, Susana, Ferrand, François‐Xavier, Devouge, Eglantine Ferrand, Ferrão, Joana, Ferraz, Mário, Ferreira, Sílvia, Ferreira, Isabel, Ferreira, Benigno, Ferrer‐Roca, Ricard, Ferriere, Nicolas, Ficko, Céline, Figueiredo‐Mello, Claudia, Finlayson, William, Fiorda, Juan, Flament, Thomas, Flateau, Clara, Fletcher, Tom, Florio, Letizia Lucia, Flynn, Deirdre, Foley, Claire, Foley, Jean, Fomin, Victor, Fonseca, Tatiana, Fontela, Patricia, Forsyth, Simon, Foster, Denise, Foti, Giuseppe, Fourn, Erwan, Fowler, Robert A.; Fraher, Marianne, Franch‐Llasat, Diego, Fraser, John F.; Fraser, Christophe, Freire, Marcela Vieira, Ribeiro, Ana Freitas, Friedrich, Caren, Fry, Stéphanie, Fuentes, Nora, Fukuda, Masahiro, Argin, G.; Gaborieau, Valérie, Gaci, Rostane, Gagliardi, Massimo, Gagnard, Jean‐Charles, Gagneux‐Brunon, Amandine, Gaião, Sérgio, Skeie, Linda Gail, Gallagher, Phil, Gamble, Carrol, Gani, Yasmin, Garan, Arthur, Garcia, Rebekha, Barrio, Noelia García, Garcia‐Diaz, Julia, Garcia‐Gallo, Esteban, Garimella, Navya, Garot, Denis, Garrait, Valérie, Gauli, Basanta, Gault, Nathalie, Gavin, Aisling, Gavrylov, Anatoliy, Gaymard, Alexandre, Gebauer, Johannes, Geraud, Eva, Morlaes, Louis Gerbaud, Germano, Nuno, Ghisulal, Praveen Kumar, Ghosn, Jade, Giani, Marco, Gibson, Jess, Gigante, Tristan, Gilg, Morgane, Gilroy, Elaine, Giordano, Guillermo, Girvan, Michelle, Gissot, Valérie, Glikman, Daniel, Glybochko, Petr, Gnall, Eric, Goco, Geraldine, Goehringer, François, Goepel, Siri, Goffard, Jean‐Christophe, Goh, Jin Yi, Golob, Jonathan, Gomez, Kyle, Gómez‐Junyent, Joan, Gominet, Marie, Gonçalves, Bronner P.; Gonzalez, Alicia, Gordon, Patricia, Gorenne, Isabelle, Goubert, Laure, Goujard, Cécile, Goulenok, Tiphaine, Grable, Margarite, Graf, Jeronimo, Grandin, Edward Wilson, Granier, Pascal, Grasselli, Giacomo, Green, Christopher A.; Greene, Courtney, Greenhalf, William, Greffe, Segolène, Grieco, Domenico Luca, Griffee, Matthew, Griffiths, Fiona, Grigoras, Ioana, Groenendijk, Albert, Lordemann, Anja Grosse, Gruner, Heidi, Gu, Yusing, Guedj, Jérémie, Guego, Martin, Guellec, Dewi, Guerguerian, Anne‐Marie, Guerreiro, Daniela, Guery, Romain, Guillaumot, Anne, Guilleminault, Laurent, Guimarães de Castro, Maisa, Guimard, Thomas, Haalboom, Marieke, Haber, Daniel, Habraken, Hannah, Hachemi, Ali, Hackmann, Amy, Hadri, Nadir, Haidri, Fakhir, Hakak, Sheeba, Hall, Adam, Hall, Matthew, Halpin, Sophie, Hameed, Jawad, Hamer, Ansley, Hamers, Raph L.; Hamidfar, Rebecca, Hammarström, Bato, Hammond, Terese, Han, Lim Yuen, Haniffa, Rashan, Hao, Kok Wei, Hardwick, Hayley, Harrison, Ewen M.; Harrison, Janet, Harrison, Samuel Bernard Ekow, Hartman, Alan, Hasan, Mohd Shahnaz, Hashmi, Junaid, Hayat, Muhammad, Hayes, Ailbhe, Hays, Leanne, Heerman, Jan, Heggelund, Lars, Hendry, Ross, Hennessy, Martina, Henriquez‐Trujillo, Aquiles, Hentzien, Maxime, Hernandez‐Montfort, Jaime, Hershey, Andrew, Hesstvedt, Liv, Hidayah, Astarini, Higgins, Eibhilin, Higgins, Dawn, Higgins, Rupert, Hinchion, Rita, Hinton, Samuel, Hiraiwa, Hiroaki, Hirkani, Haider, Hitoto, Hikombo, Ho, Yi Bin, Ho, Antonia, Hoctin, Alexandre, Hoffmann, Isabelle, Hoh, Wei Han, Hoiting, Oscar, Holt, Rebecca, Holter, Jan Cato, Horby, Peter, Horcajada, Juan Pablo, Hoshino, Koji, Houas, Ikram, Hough, Catherine L.; 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Influenza and Other Respiratory Viruses ; 2022.
Article in English | Web of Science | ID: covidwho-2019369

ABSTRACT

Introduction: Case definitions are used to guide clinical practice, surveillance and research protocols. However, how they identify COVID-19-hospitalised patients is not fully understood. We analysed the proportion of hospitalised patients with laboratory-confirmed COVID-19, in the ISARIC prospective cohort study database, meeting widely used case definitions. Methods: Patients were assessed using the Centers for Disease Control (CDC), European Centre for Disease Prevention and Control (ECDC), World Health Organization (WHO) and UK Health Security Agency (UKHSA) case definitions by age, region and time. Case fatality ratios (CFRs) and symptoms of those who did and who did not meet the case definitions were evaluated. Patients with incomplete data and non-laboratory-confirmed test result were excluded. Results: A total of 263,218 of the patients (42%) in the ISARIC database were included. Most patients (90.4%) were from Europe arid Central Asia. The proportions of patients meeting the case definitions were 56.8% (WHO), 74.4% (UKHSA), 81.6% (ECDC) and 82.3% (CDC). For each case definition, patients at the extremes of age distribution met the criteria less frequently than those aged 30 to 70 years;geographical and time variations were also observed. Estimated CFRs were similar for the patients who met the case definitions. However, when more patients did riot meet the case definition, the CFR increased. Conclusions: The performance of case definitions might be different in different regions and may change over time. Similarly concerning is the fact that older patients often did not meet case definitions, risking delayed medical care. While epidemiologists must balance their analytics with field applicability, ongoing revision of case definitions is necessary to improve patient care through early diagnosis and limit potential nosocomial spread.

10.
Wellcome open research ; 7, 2022.
Article in English | EuropePMC | ID: covidwho-1980498

ABSTRACT

Background: Marked reductions in serum iron concentrations are commonly induced during the acute phase of infection. This phenomenon, termed hypoferremia of inflammation, leads to inflammatory anemia, but could also have broader pathophysiological implications. In patients with coronavirus disease 2019 (COVID-19), hypoferremia is associated with disease severity and poorer outcomes, although there are few reported cohorts. Methods: In this study, we leverage a well characterised prospective cohort of hospitalised COVID-19 patients and perform a set of analyses focussing on iron and related biomarkers and both acute severity of COVID-19 and longer-term symptomatology. Results: We observed no associations between acute serum iron and long-term outcomes (including fatigue, breathlessness or quality of life);however, lower haemoglobin was associated with poorer quality of life. We also quantified iron homeostasis associated parameters, demonstrating that among 50 circulating mediators of inflammation IL-6 concentrations were strongly associated with serum iron, consistent with its central role in inflammatory control of iron homeostasis. Surprisingly, we observed no association between serum hepcidin and serum iron concentrations. We also observed elevated erythroferrone concentrations in COVID-19 patients with anaemia of inflammation. Conclusions: These results enhance our understanding of the regulation and pathophysiological consequences of disturbed iron homeostasis during SARS-CoV-2 infection.

11.
Chest ; 162(5): 1006-1016, 2022 Nov.
Article in English | MEDLINE | ID: covidwho-1944506

ABSTRACT

BACKGROUND: Excessive inflammation is pathogenic in the pneumonitis associated with severe COVID-19. Neutrophils are among the most abundantly present leukocytes in the inflammatory infiltrates and may form neutrophil extracellular traps (NETs) under the local influence of cytokines. NETs constitute a defense mechanism against bacteria, but have also been shown to mediate tissue damage in a number of diseases. RESEARCH QUESTION: Could NETs and their tissue-damaging properties inherent to neutrophil-associated functions play a role in the respiratory failure seen in patients with severe COVID-19, and how does this relate to the SARS-CoV-2 viral loads, IL-8 (CXCL8) chemokine expression, and cytotoxic T-lymphocyte infiltrates? STUDY DESIGN AND METHODS: Sixteen lung biopsy samples obtained immediately after death were analyzed methodically as exploratory and validation cohorts. NETs were analyzed quantitatively by multiplexed immunofluorescence and were correlated with local levels of IL-8 messenger RNA (mRNA) and the density of CD8+ T-cell infiltration. SARS-CoV-2 presence in tissue was quantified by reverse-transcriptase polymerase chain reaction and immunohistochemistry analysis. RESULTS: NETs were found in the lung interstitium and surrounding the bronchiolar epithelium with interindividual and spatial heterogeneity. NET density did not correlate with SARS-CoV-2 tissue viral load. NETs were associated with local IL-8 mRNA levels. NETs were also detected in pulmonary thrombi and in only one of eight liver tissues. NET focal presence correlated negatively with CD8+ T-cell infiltration in the lungs. INTERPRETATION: Abundant neutrophils undergoing NETosis are found in the lungs of patients with fatal COVID-19, but no correlation was found with viral loads. The strong association between NETs and IL-8 points to this chemokine as a potentially causative factor. The function of cytotoxic T-lymphocytes in the immune responses against SARS-CoV-2 may be interfered with by the presence of NETs.


Subject(s)
COVID-19 , Extracellular Traps , Humans , Extracellular Traps/physiology , SARS-CoV-2 , T-Lymphocytes, Cytotoxic , Interleukin-8 , Lung , Neutrophils/pathology , RNA, Messenger/metabolism
12.
Nat Microbiol ; 7(8): 1161-1179, 2022 08.
Article in English | MEDLINE | ID: covidwho-1921616

ABSTRACT

Vaccines based on the spike protein of SARS-CoV-2 are a cornerstone of the public health response to COVID-19. The emergence of hypermutated, increasingly transmissible variants of concern (VOCs) threaten this strategy. Omicron (B.1.1.529), the fifth VOC to be described, harbours multiple amino acid mutations in spike, half of which lie within the receptor-binding domain. Here we demonstrate substantial evasion of neutralization by Omicron BA.1 and BA.2 variants in vitro using sera from individuals vaccinated with ChAdOx1, BNT162b2 and mRNA-1273. These data were mirrored by a substantial reduction in real-world vaccine effectiveness that was partially restored by booster vaccination. The Omicron variants BA.1 and BA.2 did not induce cell syncytia in vitro and favoured a TMPRSS2-independent endosomal entry pathway, these phenotypes mapping to distinct regions of the spike protein. Impaired cell fusion was determined by the receptor-binding domain, while endosomal entry mapped to the S2 domain. Such marked changes in antigenicity and replicative biology may underlie the rapid global spread and altered pathogenicity of the Omicron variant.


Subject(s)
COVID-19 , Spike Glycoprotein, Coronavirus , Antibodies, Viral , BNT162 Vaccine , Humans , Membrane Glycoproteins/metabolism , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Viral Envelope Proteins/metabolism , Virus Internalization
13.
Lancet Microbe ; 3(1): e21-e31, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1915218

ABSTRACT

BACKGROUND: Previous infection with SARS-CoV-2 affects the immune response to the first dose of the SARS-CoV-2 vaccine. We aimed to compare SARS-CoV-2-specific T-cell and antibody responses in health-care workers with and without previous SARS-CoV-2 infection following a single dose of the BNT162b2 (tozinameran; Pfizer-BioNTech) mRNA vaccine. METHODS: We sampled health-care workers enrolled in the PITCH study across four hospital sites in the UK (Oxford, Liverpool, Newcastle, and Sheffield). All health-care workers aged 18 years or older consenting to participate in this prospective cohort study were included, with no exclusion criteria applied. Blood samples were collected where possible before vaccination and 28 (±7) days following one or two doses (given 3-4 weeks apart) of the BNT162b2 vaccine. Previous infection was determined by a documented SARS-CoV-2-positive RT-PCR result or the presence of positive anti-SARS-CoV-2 nucleocapsid antibodies. We measured spike-specific IgG antibodies and quantified T-cell responses by interferon-γ enzyme-linked immunospot assay in all participants where samples were available at the time of analysis, comparing SARS-CoV-2-naive individuals to those with previous infection. FINDINGS: Between Dec 9, 2020, and Feb 9, 2021, 119 SARS-CoV-2-naive and 145 previously infected health-care workers received one dose, and 25 SARS-CoV-2-naive health-care workers received two doses, of the BNT162b2 vaccine. In previously infected health-care workers, the median time from previous infection to vaccination was 268 days (IQR 232-285). At 28 days (IQR 27-33) after a single dose, the spike-specific T-cell response measured in fresh peripheral blood mononuclear cells (PBMCs) was higher in previously infected (n=76) than in infection-naive (n=45) health-care workers (median 284 [IQR 150-461] vs 55 [IQR 24-132] spot-forming units [SFUs] per 106 PBMCs; p<0·0001). With cryopreserved PBMCs, the T-cell response in previously infected individuals (n=52) after one vaccine dose was equivalent to that of infection-naive individuals (n=19) after receiving two vaccine doses (median 152 [IQR 119-275] vs 162 [104-258] SFUs/106 PBMCs; p=1·00). Anti-spike IgG antibody responses following a single dose in 142 previously infected health-care workers (median 270 373 [IQR 203 461-535 188] antibody units [AU] per mL) were higher than in 111 infection-naive health-care workers following one dose (35 001 [17 099-55 341] AU/mL; p<0·0001) and higher than in 25 infection-naive individuals given two doses (180 904 [108 221-242 467] AU/mL; p<0·0001). INTERPRETATION: A single dose of the BNT162b2 vaccine is likely to provide greater protection against SARS-CoV-2 infection in individuals with previous SARS-CoV-2 infection, than in SARS-CoV-2-naive individuals, including against variants of concern. Future studies should determine the additional benefit of a second dose on the magnitude and durability of immune responses in individuals vaccinated following infection, alongside evaluation of the impact of extending the interval between vaccine doses. FUNDING: UK Department of Health and Social Care, and UK Coronavirus Immunology Consortium.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Viral , Antibody Formation , COVID-19/prevention & control , COVID-19 Vaccines , Humans , Immunoglobulin G , Leukocytes, Mononuclear , Prospective Studies , T-Lymphocytes , United Kingdom/epidemiology , Vaccines, Synthetic
17.
Front Immunol ; 13: 912571, 2022.
Article in English | MEDLINE | ID: covidwho-1903032

ABSTRACT

Background: Patients with primary and secondary antibody deficiency are vulnerable to COVID-19 and demonstrate diminished responses following two-dose SARS-CoV-2 vaccine schedules. Third primary vaccinations have been deployed to enhance their humoral and cellular immunity. Objectives: To determine the immunogenicity of the third primary SARS-CoV-2 immunisation in a heterogeneous cohort of patients with antibody deficiency. Methods: Participants enrolled in the COV-AD study were sampled before and after their third vaccine dose. Serological and cellular responses were determined using ELISA, live-virus neutralisation and ELISPOT assays. Results: Following a two-dose schedule, 100% of healthy controls mounted a serological response to SARS-CoV-2 vaccination, however, 38.6% of individuals with antibody deficiency remained seronegative. A third primary SARS-CoV-2 vaccine significantly increased anti-spike glycoprotein antibody seroprevalence from 61.4% to 76.0%, the magnitude of the antibody response, its neutralising capacity and induced seroconversion in individuals who were seronegative after two vaccine doses. Vaccine-induced serological responses were broadly cross-reactive against the SARS-CoV-2 B.1.1.529 variant of concern, however, seroprevalence and antibody levels remained significantly lower than healthy controls. No differences in serological responses were observed between individuals who received AstraZeneca ChAdOx1 nCoV-19 and Pfizer BioNTech 162b2 during their initial two-dose vaccine schedule. SARS-CoV-2 infection-naive participants who had received a heterologous vaccine as a third dose were significantly more likely to have a detectable T cell response following their third vaccine dose (61.5% vs 11.1%). Conclusion: These data support the widespread use of third primary immunisations to enhance humoral immunity against SARS-CoV-2 in individuals with antibody deficiency.


Subject(s)
COVID-19 , Viral Vaccines , Antibodies, Viral , Antibody Formation , COVID-19 Vaccines , ChAdOx1 nCoV-19 , Humans , SARS-CoV-2 , Seroepidemiologic Studies , Vaccination
18.
Cell ; 185(14): 2422-2433.e13, 2022 07 07.
Article in English | MEDLINE | ID: covidwho-1881762

ABSTRACT

The Omicron lineage of SARS-CoV-2, which was first described in November 2021, spread rapidly to become globally dominant and has split into a number of sublineages. BA.1 dominated the initial wave but has been replaced by BA.2 in many countries. Recent sequencing from South Africa's Gauteng region uncovered two new sublineages, BA.4 and BA.5, which are taking over locally, driving a new wave. BA.4 and BA.5 contain identical spike sequences, and although closely related to BA.2, they contain further mutations in the receptor-binding domain of their spikes. Here, we study the neutralization of BA.4/5 using a range of vaccine and naturally immune serum and panels of monoclonal antibodies. BA.4/5 shows reduced neutralization by the serum from individuals vaccinated with triple doses of AstraZeneca or Pfizer vaccine compared with BA.1 and BA.2. Furthermore, using the serum from BA.1 vaccine breakthrough infections, there are, likewise, significant reductions in the neutralization of BA.4/5, raising the possibility of repeat Omicron infections.


Subject(s)
COVID-19 , Viral Vaccines , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/prevention & control , Humans , Neutralization Tests , SARS-CoV-2/genetics , South Africa
19.
Br J Haematol ; 198(4): 668-679, 2022 08.
Article in English | MEDLINE | ID: covidwho-1874397

ABSTRACT

Allogeneic haematopoietic stem cell transplant (HSCT) recipients remain at high risk of adverse outcomes from coronavirus disease 2019 (COVID-19) and emerging variants. The optimal prophylactic vaccine strategy for this cohort is not defined. T cell-mediated immunity is a critical component of graft-versus-tumour effect and in determining vaccine immunogenicity. Using validated anti-spike (S) immunoglobulin G (IgG) and S-specific interferon-gamma enzyme-linked immunospot (IFNγ-ELIspot) assays we analysed response to a two-dose vaccination schedule (either BNT162b2 or ChAdOx1) in 33 HSCT recipients at ≤2 years from transplant, alongside vaccine-matched healthy controls (HCs). After two vaccines, infection-naïve HSCT recipients had a significantly lower rate of seroconversion compared to infection-naïve HCs (25/32 HSCT vs. 39/39 HCs no responders) and had lower S-specific T-cell responses. The HSCT recipients who received BNT162b2 had a higher rate of seroconversion compared to ChAdOx1 (89% vs. 74%) and significantly higher anti-S IgG titres (p = 0.022). S-specific T-cell responses were seen after one vaccine in HCs and HSCT recipients. However, two vaccines enhanced S-specific T-cell responses in HCs but not in the majority of HSCT recipients. These data demonstrate limited immunogenicity of two-dose vaccination strategies in HSCT recipients, bolstering evidence of the need for additional boosters and/or alternative prophylactic measures in this group.


Subject(s)
COVID-19 Vaccines , COVID-19 , Hematopoietic Stem Cell Transplantation , Age Factors , Antibodies, Viral/immunology , BNT162 Vaccine/immunology , BNT162 Vaccine/therapeutic use , Bone Marrow Transplantation/adverse effects , COVID-19/prevention & control , COVID-19/virology , COVID-19 Vaccines/adverse effects , COVID-19 Vaccines/immunology , COVID-19 Vaccines/pharmacology , COVID-19 Vaccines/therapeutic use , ChAdOx1 nCoV-19/immunology , ChAdOx1 nCoV-19/therapeutic use , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Immunity, Cellular/drug effects , Immunity, Cellular/immunology , Immunity, Humoral/drug effects , Immunity, Humoral/immunology , Immunoglobulin G/blood , Immunoglobulin G/immunology , Seroconversion , Transplantation, Homologous/adverse effects , Vaccination/adverse effects
20.
Cell ; 185(12): 2116-2131.e18, 2022 06 09.
Article in English | MEDLINE | ID: covidwho-1850795

ABSTRACT

Highly transmissible Omicron variants of SARS-CoV-2 currently dominate globally. Here, we compare neutralization of Omicron BA.1, BA.1.1, and BA.2. BA.2 RBD has slightly higher ACE2 affinity than BA.1 and slightly reduced neutralization by vaccine serum, possibly associated with its increased transmissibility. Neutralization differences between sub-lineages for mAbs (including therapeutics) mostly arise from variation in residues bordering the ACE2 binding site; however, more distant mutations S371F (BA.2) and R346K (BA.1.1) markedly reduce neutralization by therapeutic antibody Vir-S309. In-depth structure-and-function analyses of 27 potent RBD-binding mAbs isolated from vaccinated volunteers following breakthrough Omicron-BA.1 infection reveals that they are focused in two main clusters within the RBD, with potent right-shoulder antibodies showing increased prevalence. Selection and somatic maturation have optimized antibody potency in less-mutated epitopes and recovered potency in highly mutated epitopes. All 27 mAbs potently neutralize early pandemic strains, and many show broad reactivity with variants of concern.


Subject(s)
Antibodies, Monoclonal , COVID-19 Vaccines/immunology , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Angiotensin-Converting Enzyme 2 , Antibodies, Monoclonal/chemistry , Antibodies, Monoclonal/genetics , Antibodies, Viral , COVID-19 , COVID-19 Vaccines/administration & dosage , Epitopes , Humans , Neutralization Tests , SARS-CoV-2/classification , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/chemistry
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