Phase 1/2 trial of SARS-CoV-2 vaccine ChAdOx1 nCoV-19 with a booster dose induces multifunctional antibody responses

Barrett, Jordan R.; Belij‐Rammerstorfer, Sandra; Dold, Christina; Ewer, Katie; Folegatti, Pedro M.; Gilbride, Ciaran; Halkerston, Rachel; Hill, Jennifer; Jenkin, Daniel; Stockdale, Lisa; Verheul, Marije K.; Aley, Parvinder K.; Angus, Brian; Bellamy, Duncan; Berrie, Eleanor; Bibi, Sagida; Bittaye, Mustapha; Cavell, Breeze E.; Clutterbuck, Elizabeth A.; Edwards, Nick J.; Flaxman, Amy; Fuskova, Michelle; Gorringe, Andrew; Hallis, Bassam; Kerridge, Simon; Lawrie, Alison M.; Linder, Aline; Liu, Xinxue; Madhavan, Meera; Makinson, Rebecca; Mellors, Jack; Minassian, Angela M.; Moore, Maria; Farooq, Yama G; Plested, Emma; Poulton, Ian; Ramasamy, Maheshi; Robinson, Hannah; Rollier, Christine S.; Song, Rinn; Snape, Matthew D; Tarrant, Richard; Taylor, Stephen; Thomas, Kelly M.; Voysey, Merryn; Watson, Marion E. E.; Wright, Daniel; Douglas, Alexander D.; Green, Catherine; Avs., Hill; Lambe, Teresa; Gilbert, Sarah C.; Pollard, Andrew J.; Aboagye, Jeremy; Alderson, Jennifer; Ali, Aabidah; Allen, Elizabeth; Allen, Lauren; Anslow, Rachel; Arancibia‐Cárcamo, Carolina V.; Arbe-Barnes, Edward H.; Baker, Megan; Baker, Philip; Baker, Natalie; Baleanu, Ioana; Barnes, Eleanor; Bates, Louise; Batten, Alexander; Beadon, Kirsten; Beckley, Rebecca; Beveridge, Amy; Bewley, Kevin R.; Bijker, Else M.; Blackwell, Luke; Blundell, Caitlin L.; Bolam, Emma; Boland, Elena; Borthwick, Nicola; Boyd, Amy; Brenner, Tanja; Brown, Philip N.; Brown-O’Sullivan, Charlie; Brunt, Emily; Burbage, Jamie; Buttigieg, Karen; Byard, Nicholas; Puig, Ingrid Cabrera; Camara, Susana; Cao, Michelangelo; Cappuccini, Federica; Carr, Melanie; Carroll, Miles W.; Chadwick, Jim; Chelysheva, Irina; Cho, Jee-Sun; Cifuentes, Liliana; Clark, Elizabeth; Colin-Jones, Rachel; Conlon, Christopher P.; Coombes, Naomi; Cooper, Rachel; Crocker, Wendy E. M.; Cunningham, Christina J.; Damratoski, Brad E.; Datoo, M; Datta, Chandrabali; Davies, H. Dele; Demissie, Tesfaye; Maso, Claudio Di; DiTirro, Danielle; Dong, Tao; Donnellan, Francesca R.; Douglas, Naomi; Downing, Charlotte; Drake, Jonathan; Drake-Brockman, Rachael; Drury, Ruth; Dunachie, Susanna; Muhanna, Omar El; Elias, Sean C.; Elmore, Michael J.; Emary, Katherine R. W.; English, Marcus Rex; Felle, Sally; Feng, Shuo; Silva, Carla Ferreira Da; Field, Samantha; Fisher, Richard; Ford, Karen; Fowler, Jamie; Francis, Emma; Frater, John; Furze, Julie; Galian-Rubio, Pablo; Garlant, Harriet; Godwin, Kerry; Gorini, Giacomo; Gracie, Lara; Gupta, Gaurav; Hamilton, Elizabeth; Hamlyn, Joseph; Hanumunthadu, Brama; Harris, Stephanie A.; Harrison, Daisy; Hart, Thomas C.; Hawkins, Sophia; Henry, John A.; Hodges, Gina; Hodgson, Susanne H.; Hou, Mimi M.; Howe, Elizabeth; Howell, Nicola; Huang, Ben; Humphries, Holly E.; Iveson, Poppy; Jackson, Susan; Jackson, Frederic; Jauregui, Sam; Jeffery, Katie; Jones, Elizabeth; Jones, Kathryn L.; Kailath, Reshma; Keen, Jade; Kelly, Sarah; Kelly, Dearbhla M.; Kelly, Elizabeth J.; Kerr, David; Khan, Liaquat; Khozoee, Baktash; Killen, Annabel; Kinch, Jasmin; King, Thomas; King, Lloyd; Kingham-Page, Lucy; Klenerman, Paul; Knight, Julian C.; Knott, Daniel; Koleva, Stanislava; Larkworthy, Colin W.; Larwood, Jessica P. J.; Lees, Emily A.; Lelliott, Alice; Leung, Stephanie; Li, Yuanyuan; Lias, Amelia M.; Lipworth, Samuel; Liu, Shuchang; Loew, Lisa; Ramon, Raquel Lopez; Mallett, Garry; Mansatta, Kushal; Marchevsky, N; Marinou, Spyridoula; Marlow, Emma; Marshall, Julia; Matthews, Philippa C.; McEwan, J; McGlashan, Joanna; McInroy, Lorna; Meddaugh, Gretchen; Mentzer, Alexander J.; Mirtorabi, Neginsadat; Morey, Ella; Morgans, Roisin; Morris, Susan; Morrison, Hazel; Morshead, Gertraud; Morter, Richard; Moya, Nathifa; Mukhopadhyay, Ekta; Muller, Jilly; Munro, Claire; Murphy, Sarah; Mweu, Philomena; Noé, Andrés; Nugent, Fay L.; Nuthall, Elizabeth; O’Brien, Katie M.; O’Connor, Daniel; O’Donnell, Denise; Oguti, Blanché; Olchawski, Vicki; Oliveria, Catarina; O’Reilly, Peter; Osborne, P; Owino, Nelly; Parker, Kaye; Parracho, Helena; Patrick-Smith, Maia; Peng, Yanchun; Penn, Elizabeth J.; Álvarez, Marco Polo Peralta; Perring, James; Petropoulos, Christos J.; Pfafferott, Katja; Pipini, Dimitra; Phillips, Daniel J.; Proud, Pamela C.; Provstgaard-Morys, Samuel; Pulido, David; Radia, Kajal; Rajapaksa, Durga; Lopez, Fernando Ramos; Ratcliffe, Helen; Rawlinson, Thomas A.; Pabon, Emilia Reyes; Rhead, Sarah; Ritchie, Adam; Roberts, Hannah; Roche, Sophie; Rudiansyah, Indra; Salvador, Stephannie; Sanders, Helen; Sanders, Katherine; Satti, Iman; Schmid, Annina; Schofield, Ella; Screaton, Gavin; Sedik, Cynthia; Shaik, Imam H.; Sharpe, Hannah; Shea, Adam; Silk, Sarah E.; Silva-Reyes, Laura; Skelly, Donal; Smith, Catherine C.; Smith, David J.; Spencer, Alexandra J.; Stafford, E. E.; Szigeti, Anna; Tahiri-Alaoui, Abdessamad; Tanner, Rachel; Taylor, Iona J.; Taylor, Keja; Naudé, Rebecca te Water; Themistocleous, Andreas C.; Themistocleous, Andreas; Thomas, Merin; Thomas, Tonia M.; Thompson, Amber; Tinh, Lan; Tomić, Adriana; Tonks, Susan; Towner, James; Tran, Nguyen; Tree, Julia A.; Truby, Adam; Turner, Cheryl; Turner, Nicola; Ulaszewska, Marta; Varughese, Rachel; Vichos, Iason; Walker, Laura; Wand, Matthew E.; White, Caroline; White, Rachel; Williams, Paul V.; Worth, Andrew; Wrin, Terri; Yao, Xin; Zizi, Dalila

doi:10.1038/s41591-020-01179-4

Cited by 284 publications

(280 citation statements)

References 55 publications

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“…In a phase I clinical trial of heterologous prime-boost regime for an Ebola virus vaccine, administering the lowest dose of a chimpanzee adenovirus (ChAd3, 1 × 10 10 vp) primed for a substantially stronger IgG and neutralizing antibody response subsequent to an MVA boost, compared to priming with 2.5 × 10 10 vp or 5 × 10 10 vp of ChAd3, although the low number of volunteers in each group prevents statistical analysis [6]. Repeated use of an adenovirus-based COVID-19 vaccine, namely ChAdOx1-nCoV-19 [56], or malaria vaccine, namely ChAd3-METRAP [57], did not boot T cell responses in either study, but was demonstrated to be capable of increasing antibody titre and modulating antibody effector function to the spike antigen of SARS-CoV2 [56], but not to the malaria antigen [58]; however robust statistical analyses was not feasible in the former study. It is well recognized that T cell receptor (TCR) stimulation strength affects the phenotype of T cell responses; including the generation and function of follicular helper T cells, which are critical to modulating the induction of B cell responses [57].…”

Section: Discussionmentioning

confidence: 99%

Low Adenovirus Vaccine Doses Administered to Skin Using Microneedle Patches Induce Better Functional Antibody Immunogenicity as Compared to Systemic Injection

et al. 2021

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Adenovirus-based vaccines are demonstrating promising clinical potential for multiple infectious diseases, including COVID-19. However, the immunogenicity of the vector itself decreases its effectiveness as a boosting vaccine due to the induction of strong anti-vector neutralizing immunity. Here we determined how dissolvable microneedle patches (DMN) for skin immunization can overcome this issue, using a clinically-relevant adenovirus-based Plasmodium falciparum malaria vaccine, AdHu5–PfRH5, in mice. Incorporation of vaccine into patches significantly enhanced its thermostability compared to the liquid form. Conventional high dose repeated immunization by the intramuscular (IM) route induced low antigen-specific IgG titres and high anti-vector immunity. A low priming dose of vaccine, by the IM route, but more so using DMN patches, induced the most efficacious immune responses, assessed by parasite growth inhibitory activity (GIA) assays. Administration of low dose AdHu5–PfRH5 using patches to the skin, boosted by high dose IM, induced the highest antigen-specific serum IgG response after boosting, the greatest skewing of the antibody response towards the antigen and away from the vector, and the highest efficacy. This study therefore demonstrates that repeated use of the same adenovirus vaccine can be highly immunogenic towards the transgene if a low dose is used to prime the response. It also provides a method of stabilizing adenovirus vaccine, in easy-to-administer dissolvable microneedle patches, permitting storage and distribution out of cold chain.

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Section: Discussionmentioning

confidence: 99%

Low Adenovirus Vaccine Doses Administered to Skin Using Microneedle Patches Induce Better Functional Antibody Immunogenicity as Compared to Systemic Injection

et al. 2021

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“…In contrast, one -CoronaVac -that showed approximately 50% e cacy, had been reported to induce neutralising titres several-fold lower than those found in convalescent patients 17 . The two remaining vaccines, BBIP-CorV and AZD1222 (ChAdOx-1 nCoV-19), had intermediate values of both clinical e cacy and relative potency in generating neutralising antibody responses 18,19 . mRNA and Adenovirus-vectored vaccines generate high magnitude SARS-CoV-2 multispeci c CD4+ and CD8+ T cells responses.…”

Section: Introductionmentioning

confidence: 99%

Vaccine-induced immunity provides more robust heterotypic immunity than natural infection to emerging SARS-CoV-2 variants of concern.

Skelly¹,

Harding²,

Gilbert‐Jaramillo³

et al. 2021

Preprint

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Both natural infection with SARS-CoV-2 and immunization with a number of vaccines induce protective immunity. However, the ability of such immune responses to recognize and therefore protect against emerging variants is a matter of increasing importance. Such variants of concern (VOC) include isolates of lineage B1.1.7, first identified in the UK, and B1.351, first identified in South Africa. Our data confirm that VOC, particularly those with substitutions at residues 484 and 417 escape neutralization by antibodies directed to the ACE2-binding Class 1 and the adjacent Class 2 epitopes but are susceptible to neutralization by the generally less potent antibodies directed to Class 3 and 4 epitopes on the flanks RBD. To address this potential threat, we sampled a SARS-CoV-2 uninfected UK cohort recently vaccinated with BNT162b2 (Pfizer-BioNTech, two doses delivered 18-28 days apart), alongside a cohort naturally infected in the first wave of the epidemic in Spring 2020. We tested antibody and T cell responses against a reference isolate (VIC001) representing the original circulating lineage B and the impact of sequence variation in these two VOCs. We identified a reduction in antibody neutralization against the VOCs which was most evident in the B1.351 variant. However, the majority of the T cell response was directed against epitopes conserved across all three strains. The reduction in antibody neutralization was less marked in post-boost vaccine-induced than in naturally-induced immune responses and could be largely explained by the potency of the homotypic antibody response. However, after a single vaccination, which induced only modestly neutralizing homotypic antibody titres, neutralization against the VOCs was completely abrogated in the majority of vaccinees. These data indicate that VOCs may evade protective neutralising responses induced by prior infection, and to a lesser extent by immunization, particularly after a single vaccine, but the impact of the VOCs on T cell responses appears less marked. The results emphasize the need to generate high potency immune responses through vaccination in order to provide protection against these and other emergent variants. We observed that two doses of vaccine also induced a significant increase in binding antibodies to spike of both SARS-CoV-1 & MERS, in addition to the four common coronaviruses currently circulating in the UK. The impact of antigenic imprinting on the potency of humoral and cellular heterotypic protection generated by the next generation of variant-directed vaccines remains to be determined.Authorship note: Donal T. Skelly and Adam C. Harding contributed equally; Miles W. Carroll and William S. James contributed equally

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“…In contrast, one -CoronaVac -that showed approximately 50% e cacy, had been reported to induce neutralizing titres several-fold lower than those found in convalescent patients 21 . The two remaining vaccines, Sinopharm/BBIBP-CorV and AstraZeneca/AZD1222 (ChAdOx-1 nCoV-19), had intermediate values of both clinical e cacy against symptomatic infection and relative potency in generating neutralizing antibody responses 22,23 . mRNA and adenovirus-vectored vaccines generate high magnitude SARS-CoV-2 multispeci c CD4+ and CD8+ T cells responses.…”

Section: Introductionmentioning

confidence: 99%

Two doses of SARS-CoV-2 vaccination induce more robust immune responses to emerging SARS-CoV-2 variants of concern than does natural infection.

Skelly¹,

Harding²,

Gilbert‐Jaramillo³

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

Both natural infection with SARS-CoV-2 and immunization with vaccines induce protective immunity. However, the extent to which such immune responses protect against emerging variants is of increasing importance. Such variants of concern (VOC) include isolates of lineage B.1.1.7, first identified in the UK, and B.1.351, first identified in South Africa. Our data confirm that VOC, particularly those with substitutions at residues 484 and 417, escape neutralization by antibodies directed to the ACE2-binding Class 1 and the adjacent Class 2 epitopes but are susceptible to neutralization by the generally less potent antibodies directed to Class 3 and 4 epitopes on the flanks of the receptor-binding domain. To address the potential threat posed by VOC, we sampled a SARS-CoV-2 uninfected UK cohort recently vaccinated with BNT162b2 (Pfizer-BioNTech, two doses delivered 18-28 days apart), alongside a cohort sampled in the early convalescent stages after natural infection in the first wave of the pandemic in Spring 2020. We tested antibody and T cell responses against a reference isolate of the original circulating lineage, B, and the impact of sequence variation in the B.1.1.7 and B.1.351 VOC. Neutralization of the VOC compared to B isolate was reduced, and this was most evident for the B.1.351 isolate. This reduction in antibody neutralization was less marked in post-boost vaccine-induced responses compared to naturally induced immune responses and could be largely explained by the potency of the homotypic antibody response. After a single vaccination, which induced only modestly neutralizing homotypic antibody titres, neutralization against the VOC was completely abrogated in the majority of vaccinees. Importantly, high magnitude T cell responses were generated after two vaccine doses, with the majority of the T cell response directed against epitopes that are conserved between the prototype isolate B and the VOC. These data indicate that VOC may evade protective neutralizing responses induced by prior infection, and to a lesser extent by immunization, particularly after a single vaccine dose, but the impact of the VOC on T cell responses appears less marked. The results emphasize the need to generate high potency immune responses through vaccination in order to provide protection against these and other emergent variants.

show abstract

Phase 1/2 trial of SARS-CoV-2 vaccine ChAdOx1 nCoV-19 with a booster dose induces multifunctional antibody responses

Cited by 284 publications

References 55 publications

Low Adenovirus Vaccine Doses Administered to Skin Using Microneedle Patches Induce Better Functional Antibody Immunogenicity as Compared to Systemic Injection

Low Adenovirus Vaccine Doses Administered to Skin Using Microneedle Patches Induce Better Functional Antibody Immunogenicity as Compared to Systemic Injection

Vaccine-induced immunity provides more robust heterotypic immunity than natural infection to emerging SARS-CoV-2 variants of concern.

Two doses of SARS-CoV-2 vaccination induce more robust immune responses to emerging SARS-CoV-2 variants of concern than does natural infection.

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