Approaches and #Challenges in #SARS-CoV-2 #Vaccine #Development (Cell Host Microbe, abstract)

[Source: Cell Host and Microbe, full page: (LINK). Abstract, edited.]

Approaches and Challenges in SARS-CoV-2 Vaccine Development

Gabriel Dagotto ∗, Jingyou Yu ∗, Dan H. Barouch

Published: August 10, 2020 | DOI: https://doi.org/10.1016/j.chom.2020.08.002

 

Abstract

The explosive spread of SARS-CoV-2 suggests that a vaccine will be required to end this global pandemic. Progress in SARS-CoV-2 vaccine development to date has been faster than for any other pathogen in history. Multiple SARS-CoV-2 vaccine candidates have been evaluated in preclinical models and are currently in clinical trials. In this Perspective, we discuss three topics that are critical for SARS-CoV-2 vaccine development: antigen selection and engineering, preclinical challenge studies in non human primate models, and immune correlates of protection.

Publication stage In Press Accepted Manuscript

Identification DOI: https://doi.org/10.1016/j.chom.2020.08.002

Copyright © 2020 Elsevier Inc.

Keywords: SARS-CoV-2; COVID-19; Vaccines.

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An #Alphavirus-derived replicon #RNA #vaccine induces #SARS-CoV-2 neutralizing #antibody and T cell responses in mice and nonhuman primates (Sci Transl Med., abstract)

[Source: Science Translational Medicine, full page: (LINK). Abstract, edited.]

An Alphavirus-derived replicon RNA vaccine induces SARS-CoV-2 neutralizing antibody and T cell responses in mice and nonhuman primates

Jesse H. Erasmus1,2, Amit P. Khandhar2,3, Megan A. O’Connor1,4, Alexandra C. Walls5, Emily A. Hemann6,7, Patience Murapa1, Jacob Archer1,3, Shanna Leventhal8, James T. Fuller1, Thomas B. Lewis1,4, Kevin E. Draves1, Samantha Randall1, Kathryn A. Guerriero4, Malcolm S. Duthie2, Darrick Carter2,3,6, Steven G. Reed2,6, David W. Hawman8, Heinz Feldmann8, Michael Gale Jr.4,6,7, David Veesler5, Peter Berglund2 and Deborah Heydenburg Fuller1,4,6,*

1 Department of Microbiology, University of Washington, Seattle, WA 98109, USA. 2 HDT Bio, Seattle, WA 98102, USA. 3 PAI Life Sciences, Seattle, WA 98102, USA. 4 Washington National Primate Research Center, Seattle, WA 98121, USA. 5 Department of Biochemistry, University of Washington, Seattle, WA 98195, USA. 6 Center for Innate Immunity and Immune Disease, University of Washington, Seattle, WA 98109, USA. 7 Department of Immunology, University of Washington, Seattle, WA 98109, USA. 8 Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840, USA.

*Corresponding author. Email: fullerdh@uw.edu

Science Translational Medicine  05 Aug 2020: Vol. 12, Issue 555, eabc9396 | DOI: 10.1126/scitranslmed.abc9396

 

A replicating RNA vaccine candidate to fight COVID-19

The COVID-19 pandemic caused by the coronavirus SARS-CoV-2 is having a major global public health impact necessitating the rapid development of an effective vaccine. Erasmus et al. report that a replicating RNA vaccine stabilized in a lipid inorganic nanoparticle (LION) formulation induced robust antibody responses after a single intramuscular immunization in mice and after a single intramuscular injection at five different sites in macaques. These antibodies neutralized SARS-CoV-2 at titers comparable to those reported in humans convalescing from COVID-19. Prime/boost vaccination of mice and macaques also induced T cell responses that could potentially contribute to protection. This RNA vaccine also induced robust immune responses in aged mice, suggesting the potential for protection in the elderly. These findings support further development of this COVID-19 vaccine candidate.

 

Abstract

The coronavirus disease 2019 (COVID-19) pandemic, caused by infection with the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is having a deleterious impact on health services and the global economy, highlighting the urgent need for an effective vaccine. Such a vaccine would need to rapidly confer protection after one or two doses and would need to be manufactured using components suitable for scale up. Here, we developed an Alphavirus-derived replicon RNA vaccine candidate, repRNA-CoV2S, encoding the SARS-CoV-2 spike (S) protein. The RNA replicons were formulated with lipid inorganic nanoparticles (LIONs) that were designed to enhance vaccine stability, delivery, and immunogenicity. We show that a single intramuscular injection of the LION/repRNA-CoV2S vaccine in mice elicited robust production of anti–SARS-CoV-2 S protein IgG antibody isotypes indicative of a type 1 T helper cell response. A prime/boost regimen induced potent T cell responses in mice including antigen-specific responses in the lung and spleen. Prime-only immunization of aged (17 months old) mice induced smaller immune responses compared to young mice, but this difference was abrogated by booster immunization. In nonhuman primates, prime-only immunization in one intramuscular injection site or prime/boost immunizations in five intramuscular injection sites elicited modest T cell responses and robust antibody responses. The antibody responses persisted for at least 70 days and neutralized SARS-CoV-2 at titers comparable to those in human serum samples collected from individuals convalescing from COVID-19. These data support further development of LION/repRNA-CoV2S as a vaccine candidate for prophylactic protection against SARS-CoV-2 infection.

Keywords: SARS-CoV-2; COVID-19; Vaccines.

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#Safety and #COVID19 #symptoms in individuals recently vaccinated with #BCG: a retrospective cohort study (Cell Rep Med., abstract)

[Source: Cell Reports Medicine, full page: (LINK). Abstract, edited.]

Safety and COVID-19 symptoms in individuals recently vaccinated with BCG: a retrospective cohort study

Simone J.C.F.M. Moorlag, Rosanne C. van Deuren, Cornelis H. van Werkhoven, Martin Jaeger, Priya Debisarun, Esther Taks, Vera P. Mourits, Valerie A.C.M. Koeken, L. Charlotte J. de Bree, Thijs ten Doesschate, Maartje C. Cleophas, Sanne Smeekens, Marije Oosting, Frank L. van de Veerdonk, Leo A.B. Joosten, Jaap ten Oever, Jos W.M. van der Meer, Nigel Curtis, Peter Aaby, Christine Stabell-Benn, Evangelos J. Giamarellos-Bourboulis, Marc Bonten, Reinout van Crevel, Mihai G. Netea

Open Access | Published: August 05, 2020 | DOI: https://doi.org/10.1016/j.xcrm.2020.100073

 

Highlights

  • Recent BCG vaccination is safe during the COVID-19 pandemic
  • BCG vaccination is not associated with symptoms of hyperinflammation
  • BCG might be associated with reduced incidence of sickness and extreme fatigue
  • Randomized trials of BCG vaccination for the prevention of COVID-19 are warranted

 

Summary

Bacille Calmette-Guérin (BCG) induces long-term boosting of innate immunity, termed trained immunity, and decreases susceptibility to respiratory tract infections. BCG vaccination trials for reducing SARS-CoV-2 infection are underway, but concerns have been raised regarding the potential harm of strong innate immune responses. To investigate the safety of BCG vaccination, we retrospectively assessed coronavirus disease 2019 (COVID-19) and related symptoms in three cohorts of healthy volunteers who either received BCG in the last five years or not. BCG vaccination is not associated with increased incidence of symptoms during the COVID-19 outbreak in the Netherlands. Our data suggest that BCG vaccination might be associated with a decrease in the incidence of sickness during the COVID-19 pandemic (AOR 0.58, P < 0.05), and lower incidence of extreme fatigue. In conclusion, recent BCG vaccination is safe and large randomized trials are needed to reveal if BCG reduces the incidence and/or severity of SARS-CoV-2 infection.

Accepted: July 26, 2020 – Received in revised form: June 12, 2020 – Received: May 15, 2020

Publication stage In Press Accepted Manuscript

Identification DOI: https://doi.org/10.1016/j.xcrm.2020.100073

Copyright © 2020 The Author(s).

Keywords: SARS-CoV-2; COVID-19; BCG; Immunotherapy; Vaccines.

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A novel receptor-binding domain (#RBD)-based #mRNA #vaccine against #SARS-CoV-2 (Cell Res., summary)

[Source: Cell Research, full page: (LINK). Summary, edited.]

A novel receptor-binding domain (RBD)-based mRNA vaccine against SARS-CoV-2

Wanbo Tai, Xiujuan Zhang, Aleksandra Drelich, Juan Shi, Jason C. Hsu, Larry Luchsinger, Christopher D. Hillyer, Chien-Te K. Tseng, Shibo Jiang & Lanying Du

Cell Research (2020)

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Dear Editor, The pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) highlights the need to develop effective and safe vaccines. Similar to SARS-CoV, SARS-CoV-2 recognizes angiotensin-converting enzyme 2 (ACE2) as receptor for host cell entry.1,2 SARS-CoV-2 spike (S) protein consists of S1, including receptor-binding domain (RBD), and S2 subunits.3,4 We previously demonstrated that RBDs of SARS-CoV and MERS-CoV serve as important targets for the development of effective vaccines.5,6

(…)

Keywords: SARS-CoV-2; COVID-19; Vaccines.

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#Replication-competent #VSV #vaccine vector protects against #SARS-CoV-2-mediated pathogenesis in mice (Cell Host Microbe, abstract)

[Source: Cell Host and Microbe, full page: (LINK). Abstract, edited.]

Replication-competent vesicular stomatitis virus vaccine vector protects against SARS-CoV-2-mediated pathogenesis in mice

James Brett Case ∗, Paul W. Rothlauf ∗, Rita E. Chen, Natasha M. Kafai, Julie M. Fox, Brittany Smith, Swathi Shrihari, Broc T. McCune, Ian B. Harvey, Shamus P. Keeler, Louis-Marie Bloyet, Haiyan Zhao, Meisheng Ma, Lucas J. Adams, Emma S. Winkler, Michael J. Holtzman, Daved H. Fremont, Sean P.J. Whelan, Michael S. Diamond

Published: July 30, 2020 | DOI: https://doi.org/10.1016/j.chom.2020.07.018

 

Highlights

  • A replicating VSV-SARS-CoV-2 vaccine induces high-titer neutralizing antibodies
  • Infectious SARS-CoV-2 is undetectable in the lung of vaccinated mice post-challenge
  • SARS-CoV-2-induced lung inflammation and pathology is decreased in vaccinated mice
  • Transfer of vaccine-derived immune sera to naïve mice protects against SARS-CoV-2

 

SUMMARY

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused millions of human infections and an effective vaccine is critical to mitigate coronavirus-induced disease 2019 (COVID-19). Previously, we developed a replication-competent vesicular stomatitis virus (VSV) expressing a modified form of the SARS-CoV-2 spike gene in place of the native glycoprotein gene (VSV-eGFP-SARS-CoV-2). Here, we show that vaccination with VSV-eGFP-SARS-CoV-2 generates neutralizing immune responses and protects mice from SARS-CoV-2. Immunization of mice with VSV-eGFP-SARS-CoV-2 elicits high antibody titers that neutralize SARS-CoV-2 and target the receptor binding domain that engages human angiotensin converting enzyme-2 (ACE2). Upon challenge with a human isolate of SARS-CoV-2, mice expressing human ACE2 and immunized with VSV-eGFP-SARS-CoV-2 show profoundly reduced viral infection and inflammation in the lung, indicating protection against pneumonia. Passive transfer of sera from VSV-eGFP-SARS-CoV-2-immunized animals also protects naïve mice from SARS-CoV-2 challenge. These data support development of VSV-eGFP-SARS-CoV-2 as an attenuated, replication-competent vaccine against SARS-CoV-2.

Accepted: July 27, 2020 – Received in revised form: July 21, 2020 – Received: July 9, 2020

Publication stage In Press Accepted Manuscript

Lead Contact: Michael S. Diamond, M.D., Ph.D.

Identification DOI: https://doi.org/10.1016/j.chom.2020.07.018

Copyright © 2020 Elsevier Inc.

Keywords: SARS-CoV-2; COVID-19; Vaccines; Animal models.

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A single #immunization with nucleoside-modified #mRNA #vaccines elicits strong cellular and humoral immune responses against #SARS-CoV-2 in #mice (Immunity, abstract)

[Source: Immunity, full page: (LINK). Abstract, edited.]

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 III, 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

Published: July 30, 2020 | DOI: https://doi.org/10.1016/j.immuni.2020.07.019

 

Highlights

  • mRNA vaccines induce robust type 1 CD4+ and CD8+ T cells in the spleen and lung
  • Vaccine-induced T cells readily exit the vasculature and enter the lung parenchyma
  • mRNA vaccines elicit strong long-lived plasma cell and memory B cell responses
  • mRNA vaccines induce antibodies with potent anti-SARS-CoV-2 neutralization activity

 

Summary

SARS-CoV-2 infection has emerged as a serious global pandemic. Because of the high transmissibility of the virus and the high rate of morbidity and mortality associated with COVID-19, developing effective and safe vaccines is a top research priority. Here, we provide a detailed evaluation of the immunogenicity of lipid nanoparticle-encapsulated, nucleoside-modified mRNA (mRNA-LNP) vaccines encoding the full length SARS-CoV-2 spike protein or the spike receptor binding domain in mice. We demonstrate that a single dose of these vaccines induces strong type 1 CD4+ and CD8+ T cell responses, as well as long-lived plasma and memory B cell responses. Additionally, we detect robust and sustained neutralizing antibody responses and the antibodies elicited by nucleoside-modified mRNA vaccines do not show antibody-dependent enhancement of infection in vitro. Our findings suggest that the nucleoside-modified mRNA-LNP vaccine platform can induce robust immune responses and is a promising candidate to combat COVID-19.

Accepted: July 23, 2020 – Received in revised form: July 16, 2020 – Received: June 17, 2020

Publication stage In Press Accepted Manuscript

Identification DOI: https://doi.org/10.1016/j.immuni.2020.07.019

Copyright Published by Elsevier Inc.

Keywords: SARS-CoV-2; COVID-19; Vaccines; Animal models.

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Single-shot Ad26 #vaccine protects against #SARS-CoV-2 in rhesus #macaques (Nature, abstract)

[Source: Nature, full page: (LINK). Abstract, edited.]

This is an unedited manuscript that has been accepted for publication. Nature Research are providing this early version of the manuscript as a service to our authors and readers. The manuscript will undergo copyediting, typesetting and a proof review before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers apply.

Single-shot Ad26 vaccine protects against SARS-CoV-2 in rhesus macaques

Noe B. Mercado, Roland Zahn, […] Dan H. Barouch

Nature (2020)

 

Abstract

A safe and effective vaccine for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may be required to end the coronavirus disease 2019 (COVID-19) pandemic1–8. For global deployment and pandemic control, a vaccine that requires only a single immunization would be optimal. Here we show the immunogenicity and protective efficacy of a single dose of adenovirus serotype 26 (Ad26) vector-based vaccines expressing the SARS-CoV-2 spike (S) protein in nonhuman primates. Fifty-two rhesus macaques were immunized with Ad26 vectors encoding S variants or sham control and were challenged with SARS-CoV-2 by the intranasal and intratracheal routes9,10. The optimal Ad26 vaccine induced robust neutralizing antibody responses and provided complete or near-complete protection in bronchoalveolar lavage and nasal swabs following SARS-CoV-2 challenge. Vaccine-elicited neutralizing antibody titres correlated with protective efficacy, suggesting an immune correlate of protection. These data demonstrate robust single-shot vaccine protection against SARS-CoV-2 in nonhuman primates. The optimal Ad26 vector-based vaccine for SARS-CoV-2, termed Ad26.COV2.S, is currently being evaluated in clinical trials.

Keywords: SARS-CoV-2; COVID-19; Vaccines; Animal models.

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ChAdOx1 nCoV-19 #vaccine prevents #SARS-CoV-2 pneumonia in rhesus #macaques (Nature, abstract)

[Source: Nature, full page: (LINK). Abstract, edited.]

This is an unedited manuscript that has been accepted for publication. Nature Research are providing this early version of the manuscript as a service to our authors and readers. The manuscript will undergo copyediting, typesetting and a proof review before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers apply.

ChAdOx1 nCoV-19 vaccine prevents SARS-CoV-2 pneumonia in rhesus macaques

Neeltje van Doremalen, Teresa Lambe, […] Vincent J. Munster

Nature (2020)

 

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in December 20191,2 and is responsible for the COVID-19 pandemic3. Vaccines are an essential countermeasure urgently needed to control the pandemic4. Here, we show that the adenovirus-vectored vaccine ChAdOx1 nCoV-19, encoding the spike protein of SARS-CoV-2, is immunogenic in mice, eliciting a robust humoral and cell-mediated response. This response was predominantly Th1, as demonstrated by IgG subclass and cytokine expression profiling. Vaccination with ChAdOx1 nCoV-19 (prime-only and prime-boost regimen) induced a balanced Th1/Th2 humoral and cellular immune response in rhesus macaques. We observed a significantly reduced viral load in bronchoalveolar lavage fluid and lower respiratory tract tissue of vaccinated rhesus macaques challenged with SARS-CoV-2 compared with control animals, and no pneumonia was observed in vaccinated animals. However, there was no difference in nasal shedding between vaccinated and control animals. Importantly, no evidence of immune-enhanced disease following viral challenge in vaccinated animals was observed. Safety, immunogenicity and efficacy of ChAdOx1 nCoV-19 against symptomatic PCR-positive COVID-19 disease will now be assessed in randomised controlled human clinical trials.

Keywords: SARS-CoV-2; COVID-19; Vaccines; Animal models.

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Developing a #lowcost and accessible #COVID19 #vaccine for global health (PLOS Negl Trop Dis., summary)

[Source: PLOS Neglected Tropical Diseases, full page: (LINK). Summary, edited.]

OPEN ACCESS | VIEWPOINTS

Developing a low-cost and accessible COVID-19 vaccine for global health

Peter J. Hotez , Maria Elena Bottazzi

Published: July 29, 2020 | DOI: https://doi.org/10.1371/journal.pntd.0008548

Citation: Hotez PJ, Bottazzi ME (2020) Developing a low-cost and accessible COVID-19 vaccine for global health. PLoS Negl Trop Dis 14(7): e0008548. https://doi.org/10.1371/journal.pntd.0008548

Editor: Gregory Gromowski, WRAIR, UNITED STATES

Published: July 29, 2020

Copyright: © 2020 Hotez, Bottazzi. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: The authors received no specific funding for this work.

Competing interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: The authors have developed subunit vaccines against SARS and MERS coronavirus infections. They are involved in the process of developing a vaccine against SARS-CoV-2.

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Overview: There is an urgent need to advance safe and affordable COVID-19 vaccines for low- and middle-income countries of Asia, Africa, and Latin America. Such vaccines rely on proven technologies such as recombinant protein–based vaccines to facilitate its transfer for emerging market vaccine manufacturers. Our group is developing a two-pronged approach to advance recombinant protein–based vaccines to prevent COVID-19 caused by SARS-CoV-2 and other coronavirus infections. One vaccine is based on a yeast-derived (Pichia pastoris) recombinant protein comprised of the receptor-binding domain (RBD) of the SARS-CoV formulated on alum and referred to as the CoV RBD219-N1 Vaccine. Potentially, this vaccine could be used as a heterologous vaccine against COVID-19. A second vaccine specific for COVID-19 is also being advanced using the corresponding RBD of SARS-CoV-2. The first antigen has already undergone current Good Manufacturing Practices (cGMP) manufacture and is therefore “shovel ready” for advancing into clinical trials, following vialing and required Good Laboratory Practice (GLP) toxicology testing. Evidence for its potential efficacy to cross-protect against SARS-CoV-2 includes cross-neutralization and binding studies using polyclonal and monoclonal antibodies. Evidence in support of its safety profile include our internal assessments in a mouse challenge model using a lethal mouse-adapted SARS strain, which shows that SARS-CoV RBD219-N1 (when adsorbed to aluminum hydroxide) does not elicit eosinophilic lung pathology. Together, these findings suggest that recombinant protein–based vaccines based on the RBD warrant further development to prevent SARS, COVID-19, or other coronaviruses of pandemic potential.

(…)

Keywords: SARS-CoV-2; COVID-19; Vaccines.

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A #vaccine targeting the #RBD of the S protein of #SARS-CoV-2 induces protective #immunity (Nature, abstract)

[Source: Nature, full page: (LINK). Abstract, edited.]

This is an unedited manuscript that has been accepted for publication. Nature Research are providing this early version of the manuscript as a service to our authors and readers. The manuscript will undergo copyediting, typesetting and a proof review before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers apply.

A vaccine targeting the RBD of the S protein of SARS-CoV-2 induces protective immunity

Jingyun Yang, Wei Wang, […] Xiawei Wei

 

Abstract

The novel Coronavirus SARS-CoV-2 causes a respiratory illness called COVID-19 leading to a pandemic. An effective preventive vaccine against this virus is urgently needed. As the most critical step during infection, SARS-CoV-2 uses its Spike protein receptor-binding domain (S-RBD) to engage with the host cell receptor angiotensin-converting enzyme 2 (ACE2)1,2. Here we showed that a recombinant vaccine comprising residues 319-545 of the S-RBD could induce a potent functional antibody response in the immunized mice, rabbits and non-human primates (Macaca mulatta) as early as 7 or 14 days after a single dose injection. The sera from the immunized animals blocked RBD binding to ACE2 expressed on the cell surface and neutralized the infection by SARS-CoV-2 pseudovirus and live SARS-CoV-2 in vitro. Importantly, the vaccination also provided protection in non-human primates from SARS-CoV-2 challenge in vivo. The elevated RBD-specific antibodies were also found in the sera from patients with COVID-19. Several immune pathways and CD4 T lymphocytes were implicated in the induction of the vaccine antibody response. Our finding highlights the importance of the RBD domain in the SARS-CoV-2 vaccine design and provides the rationale for the development of a protective vaccine through the induction of antibody against the RBD domain.

Keywords: SARS-CoV-2; COVID-19; Vaccines; Animal models.

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