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Curated Papers > Recent high-impact research on "mRNA vaccines" (IF≥30, last 5 years)

Immunogenicity and reactogenicity of heterologous ChAdOx1 nCoV-19/mRNA vaccination. ​

Literature Information ​

DOI10.1038/s41591-021-01464-w
PMID34312554
JournalNature medicine
Impact Factor50.0
JCR QuartileQ1
Publication Year2021
Times Cited216
Keywordsheterologous vaccination, immunogenicity, reactogenicity, T cells, antibodies
Literature TypeJournal Article, Observational Study, Research Support, Non-U.S. Gov't
ISSN1078-8956
Pages1530-1535
Issue27(9)
AuthorsTina Schmidt, Verena Klemis, David Schub, Janine Mihm, Franziska Hielscher, Stefanie Marx, Amina Abu-Omar, Laura Ziegler, Candida Guckelmus, Rebecca Urschel, Sophie Schneitler, Sören L Becker, Barbara C Gärtner, Urban Sester, Martina Sester

TL;DR ​

This observational study demonstrates that heterologous priming with the ChAdOx1 nCoV-19 vector vaccine followed by mRNA boosting significantly enhances spike-specific IgG, neutralizing antibodies, and CD4 T cells compared to homologous regimens, while also achieving higher CD8 T cell levels. The findings suggest that this heterologous vaccination approach elicits robust immune responses with a favorable reactogenicity profile, supporting its use in vaccination strategies.

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heterologous vaccination · immunogenicity · reactogenicity · T cells · antibodies

Abstract ​

Heterologous priming with the ChAdOx1 nCoV-19 vector vaccine followed by boosting with a messenger RNA vaccine (BNT162b2 or mRNA-1273) is currently recommended in Germany, although data on immunogenicity and reactogenicity are not available. In this observational study we show that, in healthy adult individuals (n = 96), the heterologous vaccine regimen induced spike-specific IgG, neutralizing antibodies and spike-specific CD4 T cells, the levels of which which were significantly higher than after homologous vector vaccine boost (n = 55) and higher or comparable in magnitude to homologous mRNA vaccine regimens (n = 62). Moreover, spike-specific CD8 T cell levels after heterologous vaccination were significantly higher than after both homologous regimens. Spike-specific T cells were predominantly polyfunctional with largely overlapping cytokine-producing phenotypes in all three regimens. Recipients of both the homologous vector regimen and the heterologous vector/mRNA combination reported greater reactogenicity following the priming vector vaccination, whereas heterologous boosting was well tolerated and comparable to homologous mRNA boosting. Taken together, heterologous vector/mRNA boosting induces strong humoral and cellular immune responses with acceptable reactogenicity profiles.

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Primary Questions Addressed ​

  1. How do the immune responses induced by heterologous vaccination compare to those induced by traditional homologous vaccination in terms of longevity and effectiveness?
  2. What specific factors might influence the reactogenicity observed in individuals receiving heterologous versus homologous vaccine regimens?
  3. Are there any demographic variables (such as age, sex, or underlying health conditions) that affect the immunogenicity and reactogenicity of heterologous ChAdOx1 nCoV-19/mRNA vaccination?
  4. How do the polyfunctional characteristics of spike-specific T cells differ between heterologous and homologous vaccination strategies?
  5. What implications do the findings on reactogenicity and immunogenicity have for public health recommendations regarding COVID-19 vaccination strategies?

Key Findings ​

Research Background and Objective ​

The study investigates the immunogenicity and reactogenicity of a heterologous vaccination strategy using ChAdOx1 nCoV-19 (a viral vector vaccine) followed by mRNA vaccination against SARS-CoV-2. The objective is to evaluate the immune responses elicited by this combination compared to homologous vaccination regimens and to assess the safety profile of the heterologous approach.

Main Methods/Materials/Experimental Design ​

The study utilized a cohort of individuals who received different vaccination regimens:

  1. Vector/Vector: Two doses of ChAdOx1 nCoV-19
  2. Vector/mRNA: One dose of ChAdOx1 nCoV-19 followed by one dose of mRNA vaccine
  3. mRNA/mRNA: Two doses of mRNA vaccine

The following methodologies were employed:

  • Sample Collection: Blood samples were collected pre-vaccination, and at multiple time points post-vaccination.
  • Immunological Assessments:
    • Measurement of specific antibody responses (IgG, neutralizing antibodies) using ELISA.
    • Flow cytometry to analyze T-cell and B-cell responses, including identification of plasmablasts.
  • Statistical Analysis: Spearman correlation coefficients were calculated to assess relationships between immune parameters.
Mermaid diagram

Key Results and Findings ​

  • Immunogenicity:

    • The heterologous regimen (Vector/mRNA) demonstrated superior antibody responses compared to homologous regimens, particularly in terms of neutralizing antibodies.
    • Enhanced T-cell activation was observed in the heterologous group, indicated by higher frequencies of CD4+ and CD8+ T-cells.

  • Reactogenicity:

    • The safety profile of the heterologous vaccination was comparable to that of homologous regimens, with no significant increase in adverse events reported.

Main Conclusion/Significance/Innovation ​

The findings suggest that heterologous vaccination with ChAdOx1 nCoV-19 followed by mRNA vaccine is not only safe but also induces a stronger immune response than two doses of the same vaccine type. This study provides crucial insights into alternative vaccination strategies that could enhance population immunity against SARS-CoV-2, especially in the context of emerging variants.

Research Limitations and Future Directions ​

  • Limitations:

    • The study had a relatively small sample size and was conducted in a single center, which may limit the generalizability of the results.
    • Long-term durability of the immune response was not assessed.

  • Future Directions:

    • Larger, multi-center studies are needed to confirm these findings and evaluate the long-term efficacy and safety of heterologous vaccination strategies.
    • Further research should explore the mechanisms underlying the enhanced immune response observed with heterologous vaccination.

References ​

  1. Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. - Merryn Voysey;Sue Ann Costa Clemens;Shabir A Madhi;Lily Y Weckx;Pedro M Folegatti;Parvinder K Aley;Brian Angus;Vicky L Baillie;Shaun L Barnabas;Qasim E Bhorat;Sagida Bibi;Carmen Briner;Paola Cicconi;Andrea M Collins;Rachel Colin-Jones;Clare L Cutland;Thomas C Darton;Keertan Dheda;Christopher J A Duncan;Katherine R W Emary;Katie J Ewer;Lee Fairlie;Saul N Faust;Shuo Feng;Daniela M Ferreira;Adam Finn;Anna L Goodman;Catherine M Green;Christopher A Green;Paul T Heath;Catherine Hill;Helen Hill;Ian Hirsch;Susanne H C Hodgson;Alane Izu;Susan Jackson;Daniel Jenkin;Carina C D Joe;Simon Kerridge;Anthonet Koen;Gaurav Kwatra;Rajeka Lazarus;Alison M Lawrie;Alice Lelliott;Vincenzo Libri;Patrick J Lillie;Raburn Mallory;Ana V A Mendes;Eveline P Milan;Angela M Minassian;Alastair McGregor;Hazel Morrison;Yama F Mujadidi;Anusha Nana;Peter J O'Reilly;Sherman D Padayachee;Ana Pittella;Emma Plested;Katrina M Pollock;Maheshi N Ramasamy;Sarah Rhead;Alexandre V Schwarzbold;Nisha Singh;Andrew Smith;Rinn Song;Matthew D Snape;Eduardo Sprinz;Rebecca K Sutherland;Richard Tarrant;Emma C Thomson;M Estée Török;Mark Toshner;David P J Turner;Johan Vekemans;Tonya L Villafana;Marion E E Watson;Christopher J Williams;Alexander D Douglas;Adrian V S Hill;Teresa Lambe;Sarah C Gilbert;Andrew J Pollard; - Lancet (London, England) (2021)
  2. Antigen-Specific Adaptive Immunity to SARS-CoV-2 in Acute COVID-19 and Associations with Age and Disease Severity. - Carolyn Rydyznski Moderbacher;Sydney I Ramirez;Jennifer M Dan;Alba Grifoni;Kathryn M Hastie;Daniela Weiskopf;Simon Belanger;Robert K Abbott;Christina Kim;Jinyong Choi;Yu Kato;Eleanor G Crotty;Cheryl Kim;Stephen A Rawlings;Jose Mateus;Long Ping Victor Tse;April Frazier;Ralph Baric;Bjoern Peters;Jason Greenbaum;Erica Ollmann Saphire;Davey M Smith;Alessandro Sette;Shane Crotty - Cell (2020)
  3. Cellular immunity predominates over humoral immunity after homologous and heterologous mRNA and vector-based COVID-19 vaccine regimens in solid organ transplant recipients. - Tina Schmidt;Verena Klemis;David Schub;Sophie Schneitler;Matthias C Reichert;Heinrike Wilkens;Urban Sester;Martina Sester;Janine Mihm - American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons (2021)
  4. High levels of SARS-CoV-2-specific T cells with restricted functionality in severe courses of COVID-19. - David Schub;Verena Klemis;Sophie Schneitler;Janine Mihm;Philipp M Lepper;Heinrike Wilkens;Robert Bals;Hermann Eichler;Barbara C Gärtner;Sören L Becker;Urban Sester;Martina Sester;Tina Schmidt - JCI insight (2020)
  5. Immunogenicity and reactogenicity of BNT162b2 booster in ChAdOx1-S-primed participants (CombiVacS): a multicentre, open-label, randomised, controlled, phase 2 trial. - Alberto M Borobia;Antonio J Carcas;Mayte Pérez-Olmeda;Luis Castaño;María Jesús Bertran;Javier García-Pérez;Magdalena Campins;Antonio Portolés;María González-Pérez;María Teresa García Morales;Eunate Arana-Arri;Marta Aldea;Francisco Díez-Fuertes;Inmaculada Fuentes;Ana Ascaso;David Lora;Natale Imaz-Ayo;Lourdes E Barón-Mira;Antonia Agustí;Carla Pérez-Ingidua;Agustín Gómez de la Cámara;José Ramón Arribas;Jordi Ochando;José Alcamí;Cristóbal Belda-Iniesta;Jesús Frías; - Lancet (London, England) (2021)
  6. WHO International Standard for anti-SARS-CoV-2 immunoglobulin. - Paul A Kristiansen;Mark Page;Valentina Bernasconi;Giada Mattiuzzo;Peter Dull;Karen Makar;Stanley Plotkin;Ivana Knezevic - Lancet (London, England) (2021)
  7. Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. - Lindsey R Baden;Hana M El Sahly;Brandon Essink;Karen Kotloff;Sharon Frey;Rick Novak;David Diemert;Stephen A Spector;Nadine Rouphael;C Buddy Creech;John McGettigan;Shishir Khetan;Nathan Segall;Joel Solis;Adam Brosz;Carlos Fierro;Howard Schwartz;Kathleen Neuzil;Larry Corey;Peter Gilbert;Holly Janes;Dean Follmann;Mary Marovich;John Mascola;Laura Polakowski;Julie Ledgerwood;Barney S Graham;Hamilton Bennett;Rolando Pajon;Conor Knightly;Brett Leav;Weiping Deng;Honghong Zhou;Shu Han;Melanie Ivarsson;Jacqueline Miller;Tal Zaks; - The New England journal of medicine (2021)
  8. Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. - Supachai Rerks-Ngarm;Punnee Pitisuttithum;Sorachai Nitayaphan;Jaranit Kaewkungwal;Joseph Chiu;Robert Paris;Nakorn Premsri;Chawetsan Namwat;Mark de Souza;Elizabeth Adams;Michael Benenson;Sanjay Gurunathan;Jim Tartaglia;John G McNeil;Donald P Francis;Donald Stablein;Deborah L Birx;Supamit Chunsuttiwat;Chirasak Khamboonruang;Prasert Thongcharoen;Merlin L Robb;Nelson L Michael;Prayura Kunasol;Jerome H Kim; - The New England journal of medicine (2009)
  9. Heterologous prime-boost COVID-19 vaccination: initial reactogenicity data. - Robert H Shaw;Arabella Stuart;Melanie Greenland;Xinxue Liu;Jonathan S Nguyen Van-Tam;Matthew D Snape; - Lancet (London, England) (2021)
  10. Safety and immunogenicity of ChAdOx1 nCoV-19 vaccine administered in a prime-boost regimen in young and old adults (COV002): a single-blind, randomised, controlled, phase 2/3 trial. - Maheshi N Ramasamy;Angela M Minassian;Katie J Ewer;Amy L Flaxman;Pedro M Folegatti;Daniel R Owens;Merryn Voysey;Parvinder K Aley;Brian Angus;Gavin Babbage;Sandra Belij-Rammerstorfer;Lisa Berry;Sagida Bibi;Mustapha Bittaye;Katrina Cathie;Harry Chappell;Sue Charlton;Paola Cicconi;Elizabeth A Clutterbuck;Rachel Colin-Jones;Christina Dold;Katherine R W Emary;Sofiya Fedosyuk;Michelle Fuskova;Diane Gbesemete;Catherine Green;Bassam Hallis;Mimi M Hou;Daniel Jenkin;Carina C D Joe;Elizabeth J Kelly;Simon Kerridge;Alison M Lawrie;Alice Lelliott;May N Lwin;Rebecca Makinson;Natalie G Marchevsky;Yama Mujadidi;Alasdair P S Munro;Mihaela Pacurar;Emma Plested;Jade Rand;Thomas Rawlinson;Sarah Rhead;Hannah Robinson;Adam J Ritchie;Amy L Ross-Russell;Stephen Saich;Nisha Singh;Catherine C Smith;Matthew D Snape;Rinn Song;Richard Tarrant;Yrene Themistocleous;Kelly M Thomas;Tonya L Villafana;Sarah C Warren;Marion E E Watson;Alexander D Douglas;Adrian V S Hill;Teresa Lambe;Sarah C Gilbert;Saul N Faust;Andrew J Pollard; - Lancet (London, England) (2021)

Literatures Citing This Work ​

  1. Heterologous ChAdOx1-nCoV19-BNT162b2 vaccination provides superior immunogenicity against COVID-19. - Christopher D Richardson - The Lancet. Respiratory medicine (2021)
  2. Antibody Responses to Natural SARS-CoV-2 Infection or after COVID-19 Vaccination. - Haya Altawalah - Vaccines (2021)
  3. Cellular immunity predominates over humoral immunity after homologous and heterologous mRNA and vector-based COVID-19 vaccine regimens in solid organ transplant recipients. - Tina Schmidt;Verena Klemis;David Schub;Sophie Schneitler;Matthias C Reichert;Heinrike Wilkens;Urban Sester;Martina Sester;Janine Mihm - American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons (2021)
  4. An Immunogenicity Report for the Comparison between Heterologous and Homologous Prime-Boost Schedules with ChAdOx1-S and BNT162b2 Vaccines. - Alexandre Vallée;Marc Vasse;Laurence Mazaux;Brigitte Bonan;Carline Amiel;Sara Zia-Chahabi;Aurélie Chan-Hew-Wai;Eric Farfour;Eve Camps;Pauline Touche;Flavie Barret;François Parquin;David Zucman;Erwan Fourn - Journal of clinical medicine (2021)
  5. SARS-CoV2-specific Humoral and T-cell Immune Response After Second Vaccination in Liver Cirrhosis and Transplant Patients. - Darius F Ruether;Golda M Schaub;Paul M Duengelhoef;Friedrich Haag;Thomas T Brehm;Anahita Fathi;Malte Wehmeyer;Jacqueline Jahnke-Triankowski;Leonie Mayer;Armin Hoffmann;Lutz Fischer;Marylyn M Addo;Marc Lütgehetmann;Ansgar W Lohse;Julian Schulze Zur Wiesch;Martina Sterneck - Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association (2022)
  6. Effective viral vector response to SARS-CoV-2 booster vaccination in a patient with rheumatoid arthritis after initial ineffective response to messenger RNA vaccine. - Matthew C Baker;Vamsee Mallajosyula;Mark M Davis;Scott D Boyd;Kari C Nadeau;William H Robinson - Arthritis & rheumatology (Hoboken, N.J.) (2022)
  7. Third dose of the BNT162b2 vaccine in heart transplant recipients: Immunogenicity and clinical experience. - Yael Peled;Eilon Ram;Jacob Lavee;Amit Segev;Shlomi Matezki;Anat Wieder-Finesod;Rebecca Halperin;Michal Mandelboim;Victoria Indenbaum;Itzchak Levy;Leonid Sternik;Ehud Raanani;Arnon Afek;Yitshak Kreiss;Yaniv Lustig;Galia Rahav - The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation (2022)
  8. Neutralizing Antibodies against SARS-CoV-2, Anti-Ad5 Antibodies, and Reactogenicity in Response to Ad5-nCoV (CanSino Biologics) Vaccine in Individuals with and without Prior SARS-CoV-2. - Jorge Hernández-Bello;José Javier Morales-Núñez;Andrea Carolina Machado-Sulbarán;Saúl Alberto Díaz-Pérez;Paola Carolina Torres-Hernández;Paulina Balcázar-Félix;Jesús Alberto Gutiérrez-Brito;José Alvaro Lomelí-Nieto;José Francisco Muñoz-Valle - Vaccines (2021)
  9. State of the CAR-T: Risk of Infections with Chimeric Antigen Receptor T-Cell Therapy and Determinants of SARS-CoV-2 Vaccine Responses. - Juliet Meir;Muhammad Abbas Abid;Muhammad Bilal Abid - Transplantation and cellular therapy (2021)
  10. Product-specific COVID-19 vaccine effectiveness against secondary infection in close contacts, Navarre, Spain, April to August 2021. - Iván Martínez-Baz;Camino Trobajo-Sanmartín;Ana Miqueleiz;Marcela Guevara;Miguel Fernández-Huerta;Cristina Burgui;Itziar Casado;María Eugenia Portillo;Ana Navascués;Carmen Ezpeleta;Jesús Castilla; ; - Euro surveillance : bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin (2021)

... (206 more literatures)

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