Comparative analysis of COVID-19 vaccine responses and third booster dose-induced neutralizing antibodies against Delta and Omicron variants

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Abstract

Two COVID-19 mRNA (of BNT162b2, mRNA-1273) and two adenovirus vector vaccines (ChAdOx1 and Janssen) are licensed in Europe, but optimization of regime and dosing is still ongoing. Here we show in health care workers ( n = 328) that two doses of BNT162b2, mRNA-1273, or a combination of ChAdOx1 adenovirus vector and mRNA vaccines administrated with a long 12-week dose interval induce equally high levels of anti-SARS-CoV-2 spike antibodies and neutralizing antibodies against D614 and Delta variant. By contrast, two doses of BNT162b2 with a short 3-week interval induce 2-3-fold lower titers of neutralizing antibodies than those from the 12-week interval, yet a third BNT162b2 or mRNA-1273 booster dose increases the antibody levels 4-fold compared to the levels after the second dose, as well as induces neutralizing antibody against Omicron BA.1 variant. Our data thus indicates that a third COVID-19 mRNA vaccine may induce cross-protective neutralizing antibodies against multiple variants.

Abstract

Vaccination shows efficacy in protecting from COVID-19, but regime and dosing optimization is still ongoing. Here the authors show that BNT162b2, mRNA-1273, or their combination with ChAdOx1 induces similar antibody responses, and those receiving three doses of BNT162b2 induce neutralizing antibodies against the Omicron variant.

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Correlates of protection against symptomatic and asymptomatic SARS-CoV-2 infection

Shuo Feng, Daniel Phillips, Thomas M White … (2021)

The global supply of COVID-19 vaccines remains limited. An understanding of the immune response that is predictive of protection could facilitate rapid licensure of new vaccines. Data from a randomized efficacy trial of the ChAdOx1 nCoV-19 (AZD1222) vaccine in the United Kingdom was analyzed to determine the antibody levels associated with protection against SARS-CoV-2. Binding and neutralizing antibodies at 28 days after the second dose were measured in infected and noninfected vaccine recipients. Higher levels of all immune markers were correlated with a reduced risk of symptomatic infection. A vaccine efficacy of 80% against symptomatic infection with majority Alpha (B.1.1.7) variant of SARS-CoV-2 was achieved with 264 (95% CI: 108, 806) binding antibody units (BAU)/ml: and 506 (95% CI: 135, not computed (beyond data range) (NC)) BAU/ml for anti-spike and anti-RBD antibodies, and 26 (95% CI: NC, NC) international unit (IU)/ml and 247 (95% CI: 101, NC) normalized neutralization titers (NF50) for pseudovirus and live-virus neutralization, respectively. Immune markers were not correlated with asymptomatic infections at the 5% significance level. These data can be used to bridge to new populations using validated assays, and allow extrapolation of efficacy estimates to new COVID-19 vaccines.

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Pathologic Antibodies to Platelet Factor 4 after ChAdOx1 nCoV-19 Vaccination

Marie Scully, Deepak Singh, Robert Lown … (2021)

Background The mainstay of control of the coronavirus disease 2019 (Covid-19) pandemic is vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Within a year, several vaccines have been developed and millions of doses delivered. Reporting of adverse events is a critical postmarketing activity. Methods We report findings in 23 patients who presented with thrombosis and thrombocytopenia 6 to 24 days after receiving the first dose of the ChAdOx1 nCoV-19 vaccine (AstraZeneca). On the basis of their clinical and laboratory features, we identify a novel underlying mechanism and address the therapeutic implications. Results In the absence of previous prothrombotic medical conditions, 22 patients presented with acute thrombocytopenia and thrombosis, primarily cerebral venous thrombosis, and 1 patient presented with isolated thrombocytopenia and a hemorrhagic phenotype. All the patients had low or normal fibrinogen levels and elevated d -dimer levels at presentation. No evidence of thrombophilia or causative precipitants was identified. Testing for antibodies to platelet factor 4 (PF4) was positive in 22 patients (with 1 equivocal result) and negative in 1 patient. On the basis of the pathophysiological features observed in these patients, we recommend that treatment with platelet transfusions be avoided because of the risk of progression in thrombotic symptoms and that the administration of a nonheparin anticoagulant agent and intravenous immune globulin be considered for the first occurrence of these symptoms. Conclusions Vaccination against SARS-CoV-2 remains critical for control of the Covid-19 pandemic. A pathogenic PF4-dependent syndrome, unrelated to the use of heparin therapy, can occur after the administration of the ChAdOx1 nCoV-19 vaccine. Rapid identification of this rare syndrome is important because of the therapeutic implications.

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Safety and immunogenicity of seven COVID-19 vaccines as a third dose (booster) following two doses of ChAdOx1 nCov-19 or BNT162b2 in the UK (COV-BOOST): a blinded, multicentre, randomised, controlled, phase 2 trial

Alasdair Munro, Leila Janani, Victoria Cornelius … (2021)

Background Few data exist on the comparative safety and immunogenicity of different COVID-19 vaccines given as a third (booster) dose. To generate data to optimise selection of booster vaccines, we investigated the reactogenicity and immunogenicity of seven different COVID-19 vaccines as a third dose after two doses of ChAdOx1 nCov-19 (Oxford–AstraZeneca; hereafter referred to as ChAd) or BNT162b2 (Pfizer–BioNtech, hearafter referred to as BNT). Methods COV-BOOST is a multicentre, randomised, controlled, phase 2 trial of third dose booster vaccination against COVID-19. Participants were aged older than 30 years, and were at least 70 days post two doses of ChAd or at least 84 days post two doses of BNT primary COVID-19 immunisation course, with no history of laboratory-confirmed SARS-CoV-2 infection. 18 sites were split into three groups (A, B, and C). Within each site group (A, B, or C), participants were randomly assigned to an experimental vaccine or control. Group A received NVX-CoV2373 (Novavax; hereafter referred to as NVX), a half dose of NVX, ChAd, or quadrivalent meningococcal conjugate vaccine (MenACWY) control (1:1:1:1). Group B received BNT, VLA2001 (Valneva; hereafter referred to as VLA), a half dose of VLA, Ad26.COV2.S (Janssen; hereafter referred to as Ad26) or MenACWY (1:1:1:1:1). Group C received mRNA1273 (Moderna; hereafter referred to as m1273), CVnCov (CureVac; hereafter referred to as CVn), a half dose of BNT, or MenACWY (1:1:1:1). Participants and all investigatory staff were blinded to treatment allocation. Coprimary outcomes were safety and reactogenicity and immunogenicity of anti-spike IgG measured by ELISA. The primary analysis for immunogenicity was on a modified intention-to-treat basis; safety and reactogenicity were assessed in the intention-to-treat population. Secondary outcomes included assessment of viral neutralisation and cellular responses. This trial is registered with ISRCTN, number 73765130. Findings Between June 1 and June 30, 2021, 3498 people were screened. 2878 participants met eligibility criteria and received COVID-19 vaccine or control. The median ages of ChAd/ChAd-primed participants were 53 years (IQR 44–61) in the younger age group and 76 years (73–78) in the older age group. In the BNT/BNT-primed participants, the median ages were 51 years (41–59) in the younger age group and 78 years (75–82) in the older age group. In the ChAd/ChAD-primed group, 676 (46·7%) participants were female and 1380 (95·4%) were White, and in the BNT/BNT-primed group 770 (53·6%) participants were female and 1321 (91·9%) were White. Three vaccines showed overall increased reactogenicity: m1273 after ChAd/ChAd or BNT/BNT; and ChAd and Ad26 after BNT/BNT. For ChAd/ChAd-primed individuals, spike IgG geometric mean ratios (GMRs) between study vaccines and controls ranged from 1·8 (99% CI 1·5–2·3) in the half VLA group to 32·3 (24·8–42·0) in the m1273 group. GMRs for wild-type cellular responses compared with controls ranged from 1·1 (95% CI 0·7–1·6) for ChAd to 3·6 (2·4–5·5) for m1273. For BNT/BNT-primed individuals, spike IgG GMRs ranged from 1·3 (99% CI 1·0–1·5) in the half VLA group to 11·5 (9·4–14·1) in the m1273 group. GMRs for wild-type cellular responses compared with controls ranged from 1·0 (95% CI 0·7–1·6) for half VLA to 4·7 (3·1–7·1) for m1273. The results were similar between those aged 30–69 years and those aged 70 years and older. Fatigue and pain were the most common solicited local and systemic adverse events, experienced more in people aged 30–69 years than those aged 70 years or older. Serious adverse events were uncommon, similar in active vaccine and control groups. In total, there were 24 serious adverse events: five in the control group (two in control group A, three in control group B, and zero in control group C), two in Ad26, five in VLA, one in VLA-half, one in BNT, two in BNT-half, two in ChAd, one in CVn, two in NVX, two in NVX-half, and one in m1273. Interpretation All study vaccines boosted antibody and neutralising responses after ChAd/ChAd initial course and all except one after BNT/BNT, with no safety concerns. Substantial differences in humoral and cellular responses, and vaccine availability will influence policy choices for booster vaccination. Funding UK Vaccine Taskforce and National Institute for Health Research.

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Author and article information

Contributors

Milja Belik:

ORCID: http://orcid.org/0000-0002-4115-3922

milja.j.belik@utu.fi

Ilkka Julkunen:

ORCID: http://orcid.org/0000-0003-0165-2564

ilkka.julkunen@utu.fi

Journal

Journal ID (nlm-ta): Nat Commun

Journal ID (iso-abbrev): Nat Commun

Title: Nature Communications

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2041-1723

Publication date (Electronic): 5 May 2022

Publication date PMC-release: 5 May 2022

Publication date Collection: 2022

Volume: 13

Electronic Location Identifier: 2476

Affiliations

[1 ]GRID grid.1374.1, ISNI 0000 0001 2097 1371, Institute of Biomedicine, University of Turku, ; Turku, Finland

[2 ]GRID grid.14758.3f, ISNI 0000 0001 1013 0499, Finnish Institute for Health and Welfare, ; Helsinki, Finland

[3 ]GRID grid.410552.7, ISNI 0000 0004 0628 215X, Department of Paediatrics and Adolescent Medicine, , Turku University Hospital and University of Turku, ; Turku, Finland

[4 ]GRID grid.15485.3d, ISNI 0000 0000 9950 5666, Department of Infectious Diseases, Meilahti Vaccination Research Center, MeVac, , Helsinki University Hospital and University of Helsinki, ; Helsinki, Finland

[5 ]GRID grid.7737.4, ISNI 0000 0004 0410 2071, Department of Physiology, , University of Helsinki, ; Helsinki, Finland

[6 ]GRID grid.7737.4, ISNI 0000 0004 0410 2071, Department of Virology, , University of Helsinki and HUSLAB, ; Helsinki, Finland

[7 ]GRID grid.7737.4, ISNI 0000 0004 0410 2071, Department of Veterinary Biosciences, , University of Helsinki, ; Helsinki, Finland

[8 ]GRID grid.410552.7, ISNI 0000 0004 0628 215X, Clinical Microbiology, Turku University Hospital, ; Turku, Finland

Author information

Milja Belik http://orcid.org/0000-0002-4115-3922

Pinja Jalkanen http://orcid.org/0000-0001-7218-4732

Lauri Ivaska http://orcid.org/0000-0001-8935-5032

Arja Pasternack http://orcid.org/0000-0002-6088-4245

Tarja Sironen http://orcid.org/0000-0002-2344-2755

Olli Vapalahti http://orcid.org/0000-0003-2270-6824

Pamela Österlund http://orcid.org/0000-0002-2229-6661

Laura Kakkola http://orcid.org/0000-0001-9271-4059

Pekka Kolehmainen http://orcid.org/0000-0001-5997-8167

Ilkka Julkunen http://orcid.org/0000-0003-0165-2564

Article

Publisher ID: 30162

DOI: 10.1038/s41467-022-30162-5

PMC ID: 9072399

PubMed ID: 35513437

SO-VID: 7815645a-69ba-4b62-8ac3-7960e16ff5ba

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 23 December 2021

Date accepted : 19 April 2022

Funding

Funded by: FundRef https://doi.org/10.13039/501100002341, Academy of Finland (Suomen Akatemia);

Award ID: 337530

Award ID: 335527

Award ID: 339512

Award Recipient : Milja Belik

Funded by: FundRef https://doi.org/10.13039/501100004012, Jane ja Aatos Erkon Säätiö (Jane and Aatos Erkko Foundation);

Award ID: 3067-84b53

Award Recipient : Milja Belik

Funded by: FundRef https://doi.org/10.13039/100008723, Suomen Lääketieteen Säätiö (Finnish Medical Foundation);

Funded by: FundRef https://doi.org/10.13039/501100004037, Juho Vainion Säätiö (Juho Vainio Foundation);

Funded by: FundRef https://doi.org/10.13039/501100006306, Sigrid Juséliuksen Säätiö (Sigrid Jusélius Foundation);

Funded by: FundRef https://doi.org/10.13039/100008376, Helsingin ja Uudenmaan Sairaanhoitopiiri (Helsinki University Central Hospital);

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Keywords: vaccines,infectious diseases,antimicrobial responses,sars-cov-2

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ScienceOpen disciplines: Uncategorized

Keywords: vaccines, infectious diseases, antimicrobial responses, sars-cov-2

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Comparative analysis of COVID-19 vaccine responses and third booster dose-induced neutralizing antibodies against Delta and Omicron variants

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Correlates of protection against symptomatic and asymptomatic SARS-CoV-2 infection

Pathologic Antibodies to Platelet Factor 4 after ChAdOx1 nCoV-19 Vaccination

Safety and immunogenicity of seven COVID-19 vaccines as a third dose (booster) following two doses of ChAdOx1 nCov-19 or BNT162b2 in the UK (COV-BOOST): a blinded, multicentre, randomised, controlled, phase 2 trial

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