Progress and Pitfalls in the Quest for Effective SARS-CoV-2 (COVID-19) Vaccines

There are currently around 200 SARS-CoV-2 candidate vaccines in preclinical and clinical trials throughout the world. The various candidates employ a range of vaccine strategies including some novel approaches. Currently, the goal is to prove that they are safe and immunogenic in humans (phase 1/2 studies) with several now advancing into phase 2 and 3 trials to demonstrate efficacy and gather comprehensive data on safety. It is highly likely that many vaccines will be shown to stimulate antibody and T cell responses in healthy individuals and have an acceptable safety profile, but the key will be to confirm that they protect against COVID-19. There is much hope that SARS-CoV-2 vaccines will be rolled out to the entire world to contain the pandemic and avert its most damaging impacts. However, in all likelihood this will initially require a targeted approach toward key vulnerable groups. Collaborative efforts are underway to ensure manufacturing can occur at the unprecedented scale and speed required to immunize billions of people. Ensuring deployment also occurs equitably across the globe will be critical. Careful evaluation and ongoing surveillance for safety will be required to address theoretical concerns regarding immune enhancement seen in previous contexts. Herein, we review the current knowledge about the immune response to this novel virus as it pertains to the design of effective and safe SARS-CoV-2 vaccines and the range of novel and established approaches to vaccine development being taken. We provide details of some of the frontrunner vaccines and discuss potential issues including adverse effects, scale-up and delivery.

[1]  R. Hatchett,et al.  CEPI: Driving Progress Toward Epidemic Preparedness and Response , 2019, Epidemiologic reviews.

[2]  Caitlin E. Mullarkey,et al.  Original Antigenic Sin: How First Exposure Shapes Lifelong Anti–Influenza Virus Immune Responses , 2019, The Journal of Immunology.

[3]  Y. Hu,et al.  Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a randomised, double-blind, placebo-controlled, phase 2 trial , 2020, The Lancet.

[4]  Barney S. Graham,et al.  Rapid COVID-19 vaccine development , 2020, Science.

[5]  J. Wolchok,et al.  The many faces of the anti-COVID immune response , 2020, The Journal of experimental medicine.

[6]  J. Lai,et al.  Peptide-Based Vaccines: Current Progress and Future Challenges , 2019, Chemical reviews.

[7]  A. Levêque,et al.  Effectiveness of influenza vaccines in preventing severe influenza illness among adults: A systematic review and meta-analysis of test-negative design case-control studies. , 2017, The Journal of infection.

[8]  K. Kadkhoda COVID-19: an Immunopathological View , 2020, mSphere.

[9]  David M. Wirth,et al.  COVID-19 vaccine development and a potential nanomaterial path forward , 2020, Nature Nanotechnology.

[10]  J. Anaya,et al.  Original antigenic sin: A comprehensive review. , 2017, Journal of autoimmunity.

[11]  F. Palombo,et al.  SARS-CoV-2 SPIKE PROTEIN: an optimal immunological target for vaccines , 2020, Journal of Translational Medicine.

[12]  G. Gao,et al.  A Novel Coronavirus from Patients with Pneumonia in China, 2019 , 2020, The New England journal of medicine.

[13]  P. Stern Key Steps in Vaccine Development. , 2020, Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology.

[14]  L. Escobar,et al.  BCG vaccine-induced protection from COVID-19 infection, wishful thinking or a game changer? , 2020, medRxiv.

[15]  D. Lynn,et al.  The non-specific and sex-differential effects of vaccines , 2020, Nature Reviews Immunology.

[16]  I. Messaoudi,et al.  Herpes zoster and the search for an effective vaccine , 2017, Clinical and experimental immunology.

[17]  M. Tay,et al.  The trinity of COVID-19: immunity, inflammation and intervention , 2020, Nature Reviews Immunology.

[18]  L. Ren,et al.  Genetic drift of human coronavirus OC43 spike gene during adaptive evolution , 2015, Scientific Reports.

[19]  S. Inoue,et al.  Prior Immunization with Severe Acute Respiratory Syndrome (SARS)-Associated Coronavirus (SARS-CoV) Nucleocapsid Protein Causes Severe Pneumonia in Mice Infected with SARS-CoV1 , 2008, The Journal of Immunology.

[20]  R. Xavier,et al.  BCG-induced trained immunity in NK cells: Role for non-specific protection to infection. , 2014, Clinical immunology.

[21]  Y. Hu,et al.  Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China , 2020, The Lancet.

[22]  Walter Fierz,et al.  Antibody Dependent Enhancement Due to Original Antigenic Sin and the Development of SARS , 2020, Frontiers in Immunology.

[23]  Yusuke Nakamura,et al.  Bioinformatic prediction of potential T cell epitopes for SARS-Cov-2 , 2020, Journal of Human Genetics.

[24]  Y. Shoenfeld,et al.  Convalescent plasma in Covid-19: Possible mechanisms of action , 2020, Autoimmunity Reviews.

[25]  Jianmin Li,et al.  Immune cell profiling of COVID-19 patients in the recovery stage by single-cell sequencing , 2020, Cell Discovery.

[26]  Lisa E. Gralinski,et al.  A Double-Inactivated Severe Acute Respiratory Syndrome Coronavirus Vaccine Provides Incomplete Protection in Mice and Induces Increased Eosinophilic Proinflammatory Pulmonary Response upon Challenge , 2011, Journal of Virology.

[27]  R. Hodges,et al.  Peptide Nanoparticles as Novel Immunogens: Design and Analysis of a Prototypic Severe Acute Respiratory Syndrome Vaccine , 2008, Chemical biology & drug design.

[28]  M. Francis Recent Advances in Vaccine Technologies , 2017, Veterinary Clinics of North America: Small Animal Practice.

[29]  H. Hou,et al.  The laboratory tests and host immunity of COVID-19 patients with different severity of illness. , 2020, JCI insight.

[30]  E. Mohammadi,et al.  Barriers and facilitators related to the implementation of a physiological track and trigger system: A systematic review of the qualitative evidence , 2017, International journal for quality in health care : journal of the International Society for Quality in Health Care.

[31]  Jing Yuan,et al.  Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma. , 2020, JAMA.

[32]  M. Netea,et al.  Considering BCG vaccination to reduce the impact of COVID-19 , 2020, The Lancet.

[33]  K. Shadan,et al.  Available online: , 2012 .

[34]  M. Netea,et al.  Non-specific effects of BCG vaccine on viral infections. , 2019, Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases.

[35]  Ulas Bagci,et al.  Evaluation of candidate vaccine approaches for MERS-CoV , 2015, Nature Communications.

[36]  S. Kent,et al.  Distinct systems serology features in children, elderly and COVID patients , 2020, medRxiv.

[37]  Yongli Yang,et al.  Effect of an Inactivated Vaccine Against SARS-CoV-2 on Safety and Immunogenicity Outcomes: Interim Analysis of 2 Randomized Clinical Trials. , 2020, JAMA.

[38]  H. M. Nielsen,et al.  CAF01 liposomes as a mucosal vaccine adjuvant: In vitro and in vivo investigations. , 2010, International journal of pharmaceutics.

[39]  K. Okuda,et al.  Developments in Viral Vector-Based Vaccines , 2014, Vaccines.

[40]  Shaun Rawson,et al.  Distinct conformational states of SARS-CoV-2 spike protein , 2020, Science.

[41]  J. Borghi,et al.  Epidemiology of COVID‐19: A systematic review and meta‐analysis of clinical characteristics, risk factors, and outcomes , 2020, Journal of medical virology.

[42]  D. Weissman,et al.  mRNA vaccines — a new era in vaccinology , 2018, Nature Reviews Drug Discovery.

[43]  Yan Zhao,et al.  Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. , 2020, JAMA.

[44]  Shao-hua Hu,et al.  Factors Associated With Mental Health Outcomes Among Health Care Workers Exposed to Coronavirus Disease 2019 , 2020, JAMA network open.

[45]  M. Peiris,et al.  Antibodies against trimeric S glycoprotein protect hamsters against SARS-CoV challenge despite their capacity to mediate FcγRII-dependent entry into B cells in vitro , 2006, Vaccine.

[46]  Via Ajnoffthecharts Com Marylyn Ethical Issues. , 2018, The American journal of nursing.

[47]  Linqi Zhang,et al.  Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor , 2020, Nature.

[48]  A. Caplan,et al.  Extraordinary diseases require extraordinary solutions , 2020, Vaccine.

[49]  Shibo Jiang,et al.  Rapid adaptation of SARS-CoV-2 in BALB/c mice: Novel mouse model for vaccine efficacy , 2020, bioRxiv.

[50]  M. Delgado-Rodríguez,et al.  Systematic review and meta-analysis. , 2017, Medicina intensiva.

[51]  Kam Y. J. Zhang,et al.  Design of a peptide-based subunit vaccine against novel coronavirus SARS-CoV-2 , 2020, Microbial Pathogenesis.

[52]  D. Weiner,et al.  Safety and immunogenicity of an anti-Middle East respiratory syndrome coronavirus DNA vaccine: a phase 1, open-label, single-arm, dose-escalation trial , 2019, The Lancet Infectious Diseases.

[53]  A. Casadevall,et al.  Effect of Convalescent Plasma on Mortality among Hospitalized Patients with COVID-19: Initial Three-Month Experience , 2020, medRxiv.

[54]  Mihai G. Netea,et al.  BCG-induced trained immunity: can it offer protection against COVID-19? , 2020, Nature Reviews Immunology.

[55]  William J. Liu,et al.  A human neutralizing antibody targets the receptor-binding site of SARS-CoV-2 , 2020, Nature.

[56]  anonymous,et al.  Comprehensive review , 2019 .

[57]  Maxim Shevtsov,et al.  Nanoparticle Vaccines Against Infectious Diseases , 2018, Front. Immunol..

[58]  P. Knapstein,et al.  MODE OF ACTION OF PROGESTERONE, GESTONORONE CAPRONATE (DEPOSTAT)* AND CYPROTERONE ACETATE (ANDROCUR)* ON THE METABOLISM OF TESTOSTERONE IN HUMAN PROSTATIC ADENOMA: IN VITRO AND IN VIVO INVESTIGATIONS , 1976 .

[59]  J. Blattman,et al.  Retinoic Acid as a Vaccine Adjuvant Enhances CD8+ T Cell Response and Mucosal Protection from Viral Challenge , 2011, Journal of Virology.

[60]  K. Kim,et al.  What Is COVID-19? , 2020, Frontiers for Young Minds.

[61]  P. Woo,et al.  Coronavirus Diversity, Phylogeny and Interspecies Jumping , 2009, Experimental biology and medicine.

[62]  Dominika Hobernik,et al.  DNA Vaccines—How Far From Clinical Use? , 2018, International journal of molecular sciences.

[63]  Hongyang Wang,et al.  Immune cell profiling of COVID-19 patients in the recovery stage by single-cell sequencing , 2020, Cell Discovery.

[64]  L. Moreno-Fierros,et al.  Development of SARS-CoV-2 vaccines: should we focus on mucosal immunity? , 2020, Expert opinion on biological therapy.

[65]  M. Miyasaka,et al.  Is BCG vaccination causally related to reduced COVID‐19 mortality? , 2020, EMBO molecular medicine.

[66]  K.,et al.  Monoclonal antibodies to the spike protein of feline infectious peritonitis virus mediate antibody-dependent enhancement of infection of feline macrophages , 1992, Journal of virology.

[67]  Eriko Padron-Regalado Vaccines for SARS-CoV-2: Lessons from Other Coronavirus Strains , 2020, Infectious Diseases and Therapy.

[68]  Shishir K. Gupta,et al.  Potential adjuvants for the development of a SARS-CoV-2 vaccine based on experimental results from similar coronaviruses , 2020, International Immunopharmacology.

[69]  Fang Li,et al.  Molecular Mechanism for Antibody-Dependent Enhancement of Coronavirus Entry , 2019, Journal of Virology.

[70]  Jo-Eun Seo,et al.  Vaccine adjuvants: smart components to boost the immune system , 2017, Archives of Pharmacal Research.

[71]  Syed Faraz Ahmed,et al.  Preliminary Identification of Potential Vaccine Targets for the COVID-19 Coronavirus (SARS-CoV-2) Based on SARS-CoV Immunological Studies , 2020, Viruses.

[72]  T. West,et al.  Covid-19 in Critically Ill Patients in the Seattle Region — Case Series , 2020, The New England journal of medicine.

[73]  Ji-Ming Chen,et al.  Potential of live pathogen vaccines for defeating the COVID‐19 pandemic: History and mechanism , 2020, Journal of medical virology.

[74]  Shibo Jiang,et al.  Subunit Vaccines Against Emerging Pathogenic Human Coronaviruses , 2020, Frontiers in Microbiology.

[75]  J. Sterne,et al.  Association of BCG, DTP, and measles containing vaccines with childhood mortality: systematic review , 2016, British Medical Journal.

[76]  H. Vennema,et al.  Early death after feline infectious peritonitis virus challenge due to recombinant vaccinia virus immunization , 1990, Journal of virology.

[77]  T. Zhao,et al.  A Mouse Model of SARS-CoV-2 Infection and Pathogenesis , 2020, Cell Host & Microbe.

[78]  Sehee Park,et al.  Original Antigenic Sin Response to RNA Viruses and Antiviral Immunity , 2016, Immune network.

[79]  L. Escobar,et al.  BCG vaccine protection from severe coronavirus disease 2019 (COVID-19) , 2020, Proceedings of the National Academy of Sciences.

[80]  M. Selgelid,et al.  COVID-19 human challenge studies: ethical issues , 2020, The Lancet Infectious Diseases.

[81]  Yan Li,et al.  Adaptation of SARS-CoV-2 in BALB/c mice for testing vaccine efficacy , 2020, Science.

[82]  R. Tripp,et al.  Original Antigenic Sin and Respiratory Syncytial Virus Vaccines , 2019, Vaccines.

[83]  V. Shinde,et al.  First-in-Human Trial of a SARS CoV 2 Recombinant Spike Protein Nanoparticle Vaccine , 2020, medRxiv.

[84]  R. Kream,et al.  An Evidence Based Perspective on mRNA-SARS-CoV-2 Vaccine Development , 2020, Medical science monitor : international medical journal of experimental and clinical research.

[85]  Nguyen H. Tran,et al.  Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial , 2020, The Lancet.

[86]  F. Polack Atypical Measles and Enhanced Respiratory Syncytial Virus Disease (ERD) Made Simple , 2007, Pediatric Research.

[87]  Gary J. Nabel,et al.  A DNA vaccine induces SARS coronavirus neutralization and protective immunity in mice , 2004, Nature.

[88]  Xiangxi Wang,et al.  Rapid development of an inactivated vaccine for SARS-CoV-2 , 2020, bioRxiv.

[89]  A. Rodrigues,et al.  National Immunization Campaigns with Oral Polio Vaccine Reduce All-Cause Mortality: A Natural Experiment within Seven Randomized Trials , 2018, Front. Public Health.

[90]  A. Walls,et al.  Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein , 2020, Cell.

[91]  Hongzhu Cui,et al.  Structural Genomics of SARS-CoV-2 Indicates Evolutionary Conserved Functional Regions of Viral Proteins , 2020, Viruses.

[92]  M. Bachmann,et al.  Major findings and recent advances in virus-like particle (VLP)-based vaccines. , 2017, Seminars in immunology.

[93]  A. Danchin,et al.  The Severe Acute Respiratory Syndrome , 2003 .

[94]  Krishna Shankara Narayanan,et al.  Immunization with inactivated Middle East Respiratory Syndrome coronavirus vaccine leads to lung immunopathology on challenge with live virus , 2016, Human vaccines & immunotherapeutics.

[95]  E. Walsh,et al.  Phase 1/2 Study to Describe the Safety and Immunogenicity of a COVID-19 RNA Vaccine Candidate (BNT162b1) in Adults 18 to 55 Years of Age: Interim Report , 2020, medRxiv.

[96]  Yi Wang,et al.  Mucosal vaccines: Strategies and challenges. , 2020, Immunology letters.

[97]  S. Todd,et al.  Regulatory T Cells in Arterivirus and Coronavirus Infections: Do They Protect Against Disease or Enhance it? , 2012, Viruses.

[98]  E. Holmes,et al.  A new coronavirus associated with human respiratory disease in China , 2020, Nature.

[99]  Fang Li,et al.  Cell entry mechanisms of SARS-CoV-2 , 2020, Proceedings of the National Academy of Sciences.

[100]  S. Klein,et al.  Sex and Gender Differences in the Outcomes of Vaccination over the Life Course. , 2017, Annual review of cell and developmental biology.

[101]  Nguyen H. Tran,et al.  Safety and immunogenicity of a candidate Middle East respiratory syndrome coronavirus viral-vectored vaccine: a dose-escalation, open-label, non-randomised, uncontrolled, phase 1 trial , 2020, The Lancet Infectious Diseases.

[102]  M. Davies,et al.  A Controlled Human Infection Model of Group A Streptococcus Pharyngitis: Which Strain and Why? , 2019, mSphere.

[103]  K. Flanagan,et al.  Effect of sex on vaccination outcomes: important but frequently overlooked , 2018, Current opinion in pharmacology.

[104]  M. V. van Breemen,et al.  Potent neutralizing antibodies from COVID-19 patients define multiple targets of vulnerability , 2020, Science.

[105]  J. Matthijnssens,et al.  A single-dose live-attenuated YF17D-vectored SARS-CoV-2 vaccine candidate , 2020, Nature.

[106]  M. Dominguez-Villar,et al.  Modulation of regulatory T cell function and stability by co-inhibitory receptors , 2020, Nature Reviews Immunology.

[107]  M. Pinkovskiy,et al.  The spread of COVID-19 and the BCG vaccine: A natural experiment in reunified Germany , 2020, The Econometrics Journal.

[108]  Robert J. Fischer,et al.  Importance of Neutralizing Monoclonal Antibodies Targeting Multiple Antigenic Sites on the Middle East Respiratory Syndrome Coronavirus Spike Glycoprotein To Avoid Neutralization Escape , 2018, Journal of Virology.

[109]  Zhènglì Shí,et al.  Origin and evolution of pathogenic coronaviruses , 2018, Nature Reviews Microbiology.

[110]  Jingxin Cao,et al.  Evaluation of modified vaccinia virus Ankara based recombinant SARS vaccine in ferrets , 2005, Vaccine.

[111]  G. Alter,et al.  Dissecting antibody-mediated protection against SARS-CoV-2 , 2020, Nature Reviews Immunology.

[112]  M. Robert-Guroff Replicating and non-replicating viral vectors for vaccine development , 2007, Current Opinion in Biotechnology.

[113]  S. Xiao,et al.  Reverse genetic systems: Rational design of coronavirus live attenuated vaccines with immune sequelae , 2020, Advances in Virus Research.

[114]  V. Munster,et al.  ChAdOx1 nCoV-19 vaccination prevents SARS-CoV-2 pneumonia in rhesus macaques , 2020, bioRxiv.

[115]  C. Birch,et al.  Analysis of human coronavirus 229E spike and nucleoprotein genes demonstrates genetic drift between chronologically distinct strains. , 2006, The Journal of general virology.

[116]  E. MacMahon,et al.  Longitudinal evaluation and decline of antibody responses in SARS-CoV-2 infection , 2020, medRxiv.

[117]  P. Zhou,et al.  Histopathologic Changes and SARS–CoV-2 Immunostaining in the Lung of a Patient With COVID-19 , 2020, Annals of Internal Medicine.

[118]  Molecular structure analyses suggest strategies to therapeutically target SARS-CoV-2 , 2020, Nature Communications.

[119]  R. Schwartz,et al.  Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19 , 2020, Cell.

[120]  Kenneth Lundstrom,et al.  Coronavirus Pandemic—Therapy and Vaccines , 2020, Biomedicines.

[121]  M. Netea,et al.  Two Randomized Controlled Trials of Bacillus Calmette-Guérin Vaccination to reduce absenteeism among health care workers and hospital admission by elderly persons during the COVID-19 pandemic: A structured summary of the study protocols for two randomised controlled trials , 2020, Trials.

[122]  Gordon Ada,et al.  Overview of vaccines and vaccination , 2005, Molecular biotechnology.

[123]  M. Plebanski,et al.  Sex-differential heterologous (non-specific) effects of vaccines: an emerging public health issue that needs to be understood and exploited , 2017, Expert review of vaccines.

[124]  Quanxin Long,et al.  Clinical and immunological assessment of asymptomatic SARS-CoV-2 infections , 2020, Nature Medicine.

[125]  P. T. Ten Eyck,et al.  Recovery from the Middle East respiratory syndrome is associated with antibody and T cell responses , 2017, Science Immunology.

[126]  M. Levine,et al.  Typhoid vaccine development with a human challenge model , 2017, The Lancet.

[127]  M. Chen,et al.  A SARS-CoV-2 surrogate virus neutralization test based on antibody-mediated blockage of ACE2–spike protein–protein interaction , 2020, Nature Biotechnology.

[128]  Emrullah Korkmaz,et al.  Microneedle array delivered recombinant coronavirus vaccines: Immunogenicity and rapid translational development , 2020, EBioMedicine.

[129]  Sara Invitto,et al.  Current state of the science , 2015 .

[130]  S. Klein,et al.  Sex differences in immune responses , 2016, Nature Reviews Immunology.

[131]  Rino Rappuoli,et al.  Correlates of adjuvanticity: A review on adjuvants in licensed vaccines. , 2018, Seminars in immunology.

[132]  J. Mascola,et al.  An mRNA Vaccine against SARS-CoV-2 — Preliminary Report , 2020, The New England journal of medicine.

[133]  D. Fuller,et al.  Amplifying RNA Vaccine Development. , 2020, The New England journal of medicine.

[134]  S. Muller AVOIDING DECEPTIVE IMPRINTING OF THE IMMUNE RESPONSE TO HIV-1 INFECTION IN VACCINE DEVELOPMENT , 2004, International reviews of immunology.

[135]  A. Chit,et al.  Efficacy and effectiveness of high-dose versus standard-dose influenza vaccination for older adults: a systematic review and meta-analysis , 2018, Expert review of vaccines.

[136]  J. Kim,et al.  Immunogenicity of a DNA vaccine candidate for COVID-19 , 2020, Nature Communications.

[137]  V. Munster,et al.  ChAdOx1 nCoV-19 vaccine prevents SARS-CoV-2 pneumonia in rhesus macaques , 2020, Nature.

[138]  J. Lloyd,et al.  Logistical challenges for potential SARS-CoV-2 vaccine and a call to research institutions, developers and manufacturers , 2020, Vaccine.

[139]  R. L. Roper,et al.  SARS vaccines: where are we? , 2009, Expert review of vaccines.

[140]  J. Farrar,et al.  CEPI—a new global R&D organisation for epidemic preparedness and response , 2017, The Lancet.

[141]  Wei Liu,et al.  Two-Year Prospective Study of the Humoral Immune Response of Patients with Severe Acute Respiratory Syndrome , 2006, The Journal of infectious diseases.

[142]  I. Youngster,et al.  SARS-CoV-2 Rates in BCG-Vaccinated and Unvaccinated Young Adults. , 2020, JAMA.

[143]  Y. Hu,et al.  Safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 vectored COVID-19 vaccine: a dose-escalation, open-label, non-randomised, first-in-human trial , 2020, The Lancet.

[144]  Jincun Zhao,et al.  T cell-mediated immune response to respiratory coronaviruses , 2014, Immunologic Research.

[145]  G. Gavazzi [Vaccination in the elderly]. , 2015, Geriatrie et psychologie neuropsychiatrie du vieillissement.

[146]  Dong Yang,et al.  Comparative replication and immune activation profiles of SARS-CoV-2 and SARS-CoV in human lungs: an ex vivo study with implications for the pathogenesis of COVID-19 , 2020, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[147]  D. Burton,et al.  Isolation of potent SARS-CoV-2 neutralizing antibodies and protection from disease in a small animal model , 2020, Science.

[148]  T. Cook,et al.  Deaths in healthcare workers due to COVID‐19: the need for robust data and analysis , 2020, Anaesthesia.

[149]  P. Aaby,et al.  Rapid Protective Effects of Early BCG on Neonatal Mortality Among Low Birth Weight Boys: Observations From Randomized Trials , 2017, The Journal of infectious diseases.

[150]  Chun-Xia Zhao,et al.  Nanoparticle vaccines. , 2014, Vaccine.

[151]  V. Shinde,et al.  Phase 1–2 Trial of a SARS-CoV-2 Recombinant Spike Protein Nanoparticle Vaccine , 2020, The New England journal of medicine.

[152]  R. Sanders,et al.  Anti-SARS-CoV-2 IgG from severely ill COVID-19 patients promotes macrophage hyper-inflammatory responses , 2020, bioRxiv.

[153]  E. von Hofe,et al.  Increasing the potency of MHC class II-presented epitopes by linkage to Ii-Key peptide. , 2000, Vaccine.

[154]  Xiangxi Wang,et al.  Development of an inactivated vaccine candidate for SARS-CoV-2 , 2020, Science.

[155]  M. Addo,et al.  Safety and immunogenicity of a modified vaccinia virus Ankara vector vaccine candidate for Middle East respiratory syndrome: an open-label, phase 1 trial , 2020, The Lancet Infectious Diseases.

[156]  S. Plotkin Vaccines for epidemic infections and the role of CEPI , 2017, Human vaccines & immunotherapeutics.

[157]  K. Kadkhoda COVID‐19: are neutralizing antibodies neutralizing enough? , 2020, Transfusion.

[158]  C. Olsen,et al.  Monoclonal antibody analysis of neutralization and antibody-dependent enhancement of feline infectious peritonitis virus , 1992, Journal of virology.

[159]  M. Merad,et al.  Immunology of COVID-19: Current State of the Science , 2020, Immunity.

[160]  M. Sykes,et al.  Antigen-specific human T-cell responses and T cell-dependent production of human antibodies in a humanized mouse model. , 2008, Blood.

[161]  R. Johnston,et al.  Vaccine Efficacy in Senescent Mice Challenged with Recombinant SARS-CoV Bearing Epidemic and Zoonotic Spike Variants , 2006, PLoS medicine.

[162]  R. Xavier,et al.  Bacille Calmette-Guérin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes , 2012, Proceedings of the National Academy of Sciences.

[163]  L. Roncati,et al.  What about the original antigenic sin of the humans versus SARS-CoV-2? , 2020, Medical Hypotheses.

[164]  A. Domnich,et al.  Effectiveness of MF59-adjuvanted seasonal influenza vaccine in the elderly: A systematic review and meta-analysis. , 2017, Vaccine.

[165]  Qin Ning,et al.  Clinical and immunological features of severe and moderate coronavirus disease 2019 , 2020 .

[166]  G. Gao,et al.  Development of an Inactivated Vaccine Candidate, BBIBP-CorV, with Potent Protection against SARS-CoV-2 , 2020, Cell.

[167]  M. Ravid,et al.  A Six-Year Follow-up Study , 2016 .

[168]  I. Sola,et al.  Molecular Basis of Coronavirus Virulence and Vaccine Development , 2016, Advances in Virus Research.