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SARS-CoV-2 mRNA Vaccines: Immunological Mechanism and Beyond. ​

Literature Information ​

DOI10.3390/vaccines9020147
PMID33673048
JournalVaccines
Impact Factor3.4
JCR QuartileQ2
Publication Year2021
Times Cited156
KeywordsSARS-CoV-2, T follicular helper cells, Th1 cells, adaptive immunity, antibodies
Literature TypeJournal Article, Review
ISSN2076-393X
Issue9(2)
AuthorsEmily Bettini, Michela Locci

TL;DR ​

This review examines the efficacy of SARS-CoV-2 mRNA vaccines in eliciting adaptive immune responses, crucial for protecting against COVID-19, highlighting findings from both pre-clinical animal studies and clinical human trials. The study underscores the importance of both B and T cell responses in achieving effective immunity, emphasizing the mRNA vaccines' rapid development and potent immunogenicity as significant advancements in vaccine technology.

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SARS-CoV-2 · T follicular helper cells · Th1 cells · adaptive immunity · antibodies

Abstract ​

To successfully protect against pathogen infection, a vaccine must elicit efficient adaptive immunity, including B and T cell responses. While B cell responses are key, as they can mediate antibody-dependent protection, T cells can modulate B cell activity and directly contribute to the elimination of pathogen-infected cells. In the unprecedented race to develop an effective vaccine for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the respiratory disease coronavirus disease 2019 (COVID-19), messenger RNA (mRNA) vaccines have emerged as front runners thanks to their capacity for rapid development and ability to drive potent adaptive immune responses. In this review article, we provide an overview of the results from pre-clinical studies in animal models as well as clinical studies in humans that assessed the efficacy of SARS-CoV-2 mRNA vaccines, with a primary focus on adaptive immune responses post vaccination.

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Primary Questions Addressed ​

  1. How do the immunological mechanisms of mRNA vaccines compare to traditional vaccine approaches in eliciting B and T cell responses?
  2. What are the long-term effects of SARS-CoV-2 mRNA vaccines on the adaptive immune system, particularly regarding memory B and T cells?
  3. In what ways can the findings from pre-clinical studies in animal models inform the development of future mRNA vaccines for other infectious diseases?
  4. How does the modulation of B cell activity by T cells influence the overall efficacy of mRNA vaccines against SARS-CoV-2 variants?
  5. What challenges remain in optimizing mRNA vaccine formulations to enhance their immunogenicity and protection against emerging pathogens?

Key Findings ​

Research Background and Purpose ​

The emergence of SARS-CoV-2, the virus responsible for COVID-19, necessitated rapid vaccine development to curb the pandemic. This review focuses on the immunological mechanisms underlying SARS-CoV-2 mRNA vaccines, specifically examining how these vaccines induce adaptive immune responses, including B and T cell activation, and evaluates their efficacy based on preclinical and clinical studies.

Main Methods/Materials/Experimental Design ​

The review outlines the design strategies for mRNA vaccines, including mRNA modifications, antigen selection, and delivery methods.

Mermaid diagram
  1. mRNA Modifications: Modifications like N1-methyl-pseudouridine enhance stability and reduce immunogenicity, improving translation efficiency.
  2. Antigen Selection: The spike protein (S) and its receptor-binding domain (RBD) are chosen due to their critical role in viral entry and immunogenic potential.
  3. Delivery Methods: LNPs are used for effective mRNA delivery, facilitating cellular uptake and protecting mRNA from degradation.

Key Results and Findings ​

  • B Cell Responses: mRNA vaccines induce robust antibody responses, characterized by high levels of binding and neutralizing antibodies (nAbs) against SARS-CoV-2. Long-lived plasma cells (LLPCs) and memory B cells (MBCs) are generated through germinal center (GC) reactions.
  • T Cell Responses: mRNA vaccines elicit significant CD4+ T cell responses, skewed towards a Th1 phenotype, which is favorable for controlling viral infections. Cytotoxic CD8+ T cell responses are also noted but vary among different vaccine candidates.
  • Clinical Efficacy: Phase 1/2 clinical trials demonstrate that mRNA vaccines induce strong humoral and cellular immune responses, with the potential for durable immunity. Both Moderna's mRNA-1273 and BioNTech/Pfizer's BNT162b2 show high efficacy rates (over 94%) in preventing COVID-19.

Main Conclusions/Significance/Innovation ​

SARS-CoV-2 mRNA vaccines represent a novel and effective approach to vaccine development, offering rapid manufacturing capabilities and potent immune responses. The ability to elicit strong B and T cell responses positions mRNA vaccines as a critical tool in combating COVID-19 and potentially future pandemics.

Research Limitations and Future Directions ​

  • Limitations: The review highlights concerns regarding the long-term durability of immunity, the potential for allergic reactions, and the logistical challenges associated with mRNA vaccine storage and distribution.
  • Future Directions: Ongoing studies are necessary to assess the longevity of immune responses and to evaluate the effectiveness of mRNA vaccines against emerging variants of SARS-CoV-2. Further exploration into the optimization of mRNA vaccine formulations and delivery methods could enhance their efficacy and accessibility.
AspectDetails
Vaccine TypemRNA vaccines (e.g., mRNA-1273, BNT162b2)
Key Immune ResponsesRobust B cell (nAbs, LLPCs, MBCs) and T cell (CD4+, CD8+) responses
Efficacy RateOver 94% in clinical trials
Safety ProfileGenerally favorable with mild-to-moderate adverse effects
Research GapsLong-term immunity, allergic reactions, storage challenges

This structured summary encapsulates the critical insights from the review, emphasizing the innovative nature of mRNA vaccines and their significance in public health.

References ​

  1. Immune Responses Induced by mRNA Vaccination in Mice, Monkeys and Humans. - Alberto Cagigi;Karin Loré - Vaccines (2021)
  2. Phase I/II study of COVID-19 RNA vaccine BNT162b1 in adults. - Mark J Mulligan;Kirsten E Lyke;Nicholas Kitchin;Judith Absalon;Alejandra Gurtman;Stephen Lockhart;Kathleen Neuzil;Vanessa Raabe;Ruth Bailey;Kena A Swanson;Ping Li;Kenneth Koury;Warren Kalina;David Cooper;Camila Fontes-Garfias;Pei-Yong Shi;Özlem Türeci;Kristin R Tompkins;Edward E Walsh;Robert Frenck;Ann R Falsey;Philip R Dormitzer;William C Gruber;Uğur Şahin;Kathrin U Jansen - Nature (2020)
  3. A Single Immunization with Nucleoside-Modified mRNA Vaccines Elicits Strong Cellular and Humoral Immune Responses against SARS-CoV-2 in Mice. - Dorottya Laczkó;Michael J Hogan;Sushila A Toulmin;Philip Hicks;Katlyn Lederer;Brian T Gaudette;Diana Castaño;Fatima Amanat;Hiromi Muramatsu;Thomas H Oguin;Amrita Ojha;Lizhou Zhang;Zekun Mu;Robert Parks;Tomaz B Manzoni;Brianne Roper;Shirin Strohmeier;István Tombácz;Leslee Arwood;Raffael Nachbagauer;Katalin Karikó;Jack Greenhouse;Laurent Pessaint;Maciel Porto;Tammy Putman-Taylor;Amanda Strasbaugh;Tracey-Ann Campbell;Paulo J C Lin;Ying K Tam;Gregory D Sempowski;Michael Farzan;Hyeryun Choe;Kevin O Saunders;Barton F Haynes;Hanne Andersen;Laurence C Eisenlohr;Drew Weissman;Florian Krammer;Paul Bates;David Allman;Michela Locci;Norbert Pardi - Immunity (2020)
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  5. Potent neutralizing antibodies from COVID-19 patients define multiple targets of vulnerability. - Philip J M Brouwer;Tom G Caniels;Karlijn van der Straten;Jonne L Snitselaar;Yoann Aldon;Sandhya Bangaru;Jonathan L Torres;Nisreen M A Okba;Mathieu Claireaux;Gius Kerster;Arthur E H Bentlage;Marlies M van Haaren;Denise Guerra;Judith A Burger;Edith E Schermer;Kirsten D Verheul;Niels van der Velde;Alex van der Kooi;Jelle van Schooten;Mariëlle J van Breemen;Tom P L Bijl;Kwinten Sliepen;Aafke Aartse;Ronald Derking;Ilja Bontjer;Neeltje A Kootstra;W Joost Wiersinga;Gestur Vidarsson;Bart L Haagmans;Andrew B Ward;Godelieve J de Bree;Rogier W Sanders;Marit J van Gils - Science (New York, N.Y.) (2020)
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  7. Humoral and circulating follicular helper T cell responses in recovered patients with COVID-19. - Jennifer A Juno;Hyon-Xhi Tan;Wen Shi Lee;Arnold Reynaldi;Hannah G Kelly;Kathleen Wragg;Robyn Esterbauer;Helen E Kent;C Jane Batten;Francesca L Mordant;Nicholas A Gherardin;Phillip Pymm;Melanie H Dietrich;Nichollas E Scott;Wai-Hong Tham;Dale I Godfrey;Kanta Subbarao;Miles P Davenport;Stephen J Kent;Adam K Wheatley - Nature medicine (2020)
  8. A COVID-19 mRNA vaccine encoding SARS-CoV-2 virus-like particles induces a strong antiviral-like immune response in mice. - Jing Lu;Guoliang Lu;Shudan Tan;Jia Xia;Hualong Xiong;Xiaofei Yu;Qingqing Qi;Xiang Yu;Li Li;Hang Yu;Ningshao Xia;Tianying Zhang;Yingjie Xu;Jinzhong Lin - Cell research (2020)
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Literatures Citing This Work ​

  1. Intervention Strategies for Seasonal and Emerging Respiratory Viruses with Drugs and Vaccines Targeting Viral Surface Glycoproteins. - Ralph A Tripp;John Stambas - Viruses (2021)
  2. An Updated Review of SARS-CoV-2 Vaccines and the Importance of Effective Vaccination Programs in Pandemic Times. - Cielo García-Montero;Oscar Fraile-Martínez;Coral Bravo;Diego Torres-Carranza;Lara Sanchez-Trujillo;Ana M Gómez-Lahoz;Luis G Guijarro;Natalio García-Honduvilla;Angel Asúnsolo;Julia Bujan;Jorge Monserrat;Encarnación Serrano;Melchor Álvarez-Mon;Juan A De León-Luis;Miguel A Álvarez-Mon;Miguel A Ortega - Vaccines (2021)
  3. Correlation between BNT162b2 mRNA Covid-19 vaccine-associated hypermetabolic lymphadenopathy and humoral immunity in patients with hematologic malignancy. - Dan Cohen;Shir Hazut Krauthammer;Yael C Cohen;Chava Perry;Irit Avivi;Yair Herishanu;Einat Even-Sapir - European journal of nuclear medicine and molecular imaging (2021)
  4. Rapid Development of Clinically Symptomatic Radiation Recall Pneumonitis Immediately Following COVID-19 Vaccination. - Cole R Steber;Janardhana Ponnatapura;Ryan T Hughes;Michael K Farris - Cureus (2021)
  5. Anti-SARS-CoV-2 Receptor-Binding Domain Total Antibodies Response in Seropositive and Seronegative Healthcare Workers Undergoing COVID-19 mRNA BNT162b2 Vaccination. - Gian Luca Salvagno;Brandon M Henry;Giovanni di Piazza;Laura Pighi;Simone De Nitto;Damiano Bragantini;Gian Luca Gianfilippi;Giuseppe Lippi - Diagnostics (Basel, Switzerland) (2021)
  6. mRNA Innovates the Vaccine Field. - Norbert Pardi - Vaccines (2021)
  7. Unveiling the Potential Role of Nanozymes in Combating the COVID-19 Outbreak. - Jafar Ali;Saira Naveed Elahi;Asghar Ali;Hassan Waseem;Rameesha Abid;Mohamed M Mohamed - Nanomaterials (Basel, Switzerland) (2021)
  8. Trigeminal and cervical radiculitis after tozinameran vaccination against COVID-19. - Kaavya Narasimhalu;Wai Ching Lee;Parag Ratnakar Salkade;Deidre Anne De Silva - BMJ case reports (2021)
  9. SARS-CoV-2 mRNA vaccines induce persistent human germinal centre responses. - Jackson S Turner;Jane A O'Halloran;Elizaveta Kalaidina;Wooseob Kim;Aaron J Schmitz;Julian Q Zhou;Tingting Lei;Mahima Thapa;Rita E Chen;James Brett Case;Fatima Amanat;Adriana M Rauseo;Alem Haile;Xuping Xie;Michael K Klebert;Teresa Suessen;William D Middleton;Pei-Yong Shi;Florian Krammer;Sharlene A Teefey;Michael S Diamond;Rachel M Presti;Ali H Ellebedy - Nature (2021)
  10. Addressing Vaccine-Induced Immune Thrombotic Thrombocytopenia (VITT) Following COVID-19 Vaccination: A Mini-Review of Practical Strategies. - Po-Wei Chen;Zong-Yun Tsai;Ting-Hsing Chao;Yi-Heng Li;Charles Jia-Yin Hou;Ping-Yen Liu - Acta Cardiologica Sinica (2021)

... (146 more literatures)

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