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COVID-19 Vaccines: A Race Against Time in the Middle of Death and Devastation!

2020; Elsevier BV; Volume: 10; Issue: 6 Linguagem: Inglês

10.1016/j.jceh.2020.06.003

2213-3453

Mohammad Sultan Khuroo, Mohammad Sultan Khuroo, Mehnaaz S. Khuroo, Ahmad Sofi, Mohammad Sultan Khuroo,

Vaccine Coverage and Hesitancy

The coronavirus disease 2019 (COVID-19) has turned into a global human tragedy and economic devastation. Governments have implemented lockdown measures, blocked international travel, and enforced other public containment measures to mitigate the virus morbidity and mortality. As of today, no drug has the power to fight the infection and bring normalcy to the utter chaos. This leaves us with only one choice namely an effective and safe vaccine that shall be manufactured as soon as possible and available to all countries and populations affected by the pandemic at an affordable price. There has been an unprecedented fast track path taken in Research & Development by the World community for developing an effective and safe vaccine. Platform technology has been exploited to develop candidate vaccines in a matter of days to weeks, and as of now, 108 such vaccines are available. Six of these vaccines have entered clinical trials. As clinical trials are "rate-limiting" and "time-consuming", many innovative methods are in practice for a fast track. These include parallel phase I-II trials and obtaining efficacy data from phase IIb trials. Human "challenge experiments" to confirm efficacy in humans is under serious consideration. The availability of the COVID-19 vaccine has become a race against time in the middle of death and devastation. There is an atmosphere of tremendous hype around the COVID-19 vaccine, and developers are using every moment to make claims, which remain unverified. However, concerns are raised about a rush to deploy a COVID-19 vaccine. Applying "Quick fix" and "short cuts" can lead to errors with disastrous consequences. The coronavirus disease 2019 (COVID-19) has turned into a global human tragedy and economic devastation. Governments have implemented lockdown measures, blocked international travel, and enforced other public containment measures to mitigate the virus morbidity and mortality. As of today, no drug has the power to fight the infection and bring normalcy to the utter chaos. This leaves us with only one choice namely an effective and safe vaccine that shall be manufactured as soon as possible and available to all countries and populations affected by the pandemic at an affordable price. There has been an unprecedented fast track path taken in Research & Development by the World community for developing an effective and safe vaccine. Platform technology has been exploited to develop candidate vaccines in a matter of days to weeks, and as of now, 108 such vaccines are available. Six of these vaccines have entered clinical trials. As clinical trials are "rate-limiting" and "time-consuming", many innovative methods are in practice for a fast track. These include parallel phase I-II trials and obtaining efficacy data from phase IIb trials. Human "challenge experiments" to confirm efficacy in humans is under serious consideration. The availability of the COVID-19 vaccine has become a race against time in the middle of death and devastation. There is an atmosphere of tremendous hype around the COVID-19 vaccine, and developers are using every moment to make claims, which remain unverified. However, concerns are raised about a rush to deploy a COVID-19 vaccine. Applying "Quick fix" and "short cuts" can lead to errors with disastrous consequences. The coronavirus infection which originated from Wuhan, China, in December 2019, has turned into a global catastrophe.1Gates B. Responding to Covid-19 - a once-in-a-century pandemic?.N Engl J Med. 2020; https://doi.org/10.1056/NEJMp2003762Crossref PubMed Scopus (700) Google Scholar The virus has been designated as severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) and the disease caused by the agent as coronavirus disease 2019 (COVID-19).2WHO Naming the Coronavirus Disease (COVID-19) and the Virus that Causes it. World Health Organization, Geneva, Switzerland2020https://www.who.int/emergencies/diseases/novel-coronavirus-2019/technical-guidance/naming-the-coronavirus-disease-(COVID-2019)-and-the-virus-that-causes-itGoogle Scholar World Health Organization (WHO) pronounced the disease as a pandemic on March 11, 2020.3WHO Coronavirus Disease (COVID-19) Pandemic. World Health Organization, Geneva, Switzerland2020https://www.who.int/emergencies/diseases/novel-coronavirus-2019Google Scholar As of May 4th, 2020, the infection has spread to 212 countries and territories around the World and 2 international conveyances, with over 3.5 million cases and around 250000 deaths.4Anonymous Worldometer. Covid-19 Coronavirus Pandemic. The United States. Dadax Limited., 2020https://www.worldometers.info/coronavirus/?utm_campaign=homeAdvegas1?Google Scholar The disease on average affects over 33,000 individuals with over 1300 deaths daily. The world community has responded to the challenge of death and devastation with resilience and determination.5Legido-Quigley H. Asgari N. Teo Y.Y. et al.Are high-performing health systems resilient against the COVID-19 epidemic?.Lancet. 2020; 395: 848-850Abstract Full Text Full Text PDF PubMed Scopus (324) Google Scholar Governments have implemented lockdown measures, blocked international travel, and enforced other public containment measures to mitigate the virus morbidity and mortality.6Arun T.K. Coronavirus: is there an alternative to lockdowns?. Economic Times, 2020Google Scholar, 7WHO Coronavirus Disease (COVID-19) Advice for the Public.2020https://www.who.int/emergencies/diseases/novel-coronavirus-2019/advice-for-publicGoogle Scholar, 8WHO Updated WHO Recommendations for International Traffic in Relation to the COVID-19 Outbreak.2020https://www.who.int/news-room/articles-detail/updated-who-recommendations-for-international-traffic-in-relation-to-covid-19-outbreakGoogle Scholar There has been a major understanding of the disease as well as the pathogen, and these data have been generated and widely publicized in a matter of days and weeks rather than years and decades, an unprecedented occurrence in the history of medicine.9Kumar N. Lockdown 2.0: how it impacts the ailing economy. India Times, 2020Google Scholar, 10Nelson R. COVID-19 disrupts vaccine delivery.Lancet Infect Dis. 2020; Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar, 11Shoenfeld Y. 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A decade after SARS: strategies for controlling emerging coronaviruses.Nat Rev Microbiol. 2013; 11: 836-848Crossref PubMed Scopus (519) Google Scholar, 15Assiri A. Al-Tawfiq J.A. Al-Rabeeah A.A. et al.Epidemiological, demographic, and clinical characteristics of 47 cases of Middle East respiratory syndrome coronavirus disease from Saudi Arabia: a descriptive study.Lancet Infect Dis. 2013; 13: 752-761Abstract Full Text Full Text PDF PubMed Scopus (1105) Google Scholar, 16Zumla A.I. Memish Z.A. Middle East respiratory syndrome coronavirus: epidemic potential or a storm in a teacup?.Eur Respir J. 2014; 43: 1243-1248Crossref PubMed Scopus (18) Google Scholar, 17Yong C.Y. Ong H.K. Yeap S.K. Ho K.L. Tan W.S. Recent advances in the vaccine development against Middle East respiratory syndrome-coronavirus.Front Microbiol. 2019; 10: 1781Crossref PubMed Scopus (164) Google Scholar, 18Shereen M.A. Khan S. Kazmi A. Bashir N. Siddique R. COVID-19 infection: origin, transmission, and characteristics of human coronaviruses.J Adv Res. 2020; 24: 91-98Crossref PubMed Scopus (2301) Google Scholar Coronaviruses are enveloped viruses, around 125 nm in diameter, with a positive-sense single-stranded RNA genome of around 30 kb and a nucleocapsid of helical symmetry. This is wrapped in an icosahedral protein shell. The surface has multiple club-shaped spikes, which creates the appearance of solar corona on electron micrsocopy (EM). The viral envelope consists of a lipid bilayer, in which the membrane (M), envelope (E), and spike (S) structural proteins are anchored. All the coronaviruses use angiotensin-converting enzyme 2 receptors as a cellular entry receptor; however, the propensity of SARS-CoV-2 to attach to these receptors is much higher, giving it high infectivity.13Lai M.M. Cavanagh D. The molecular biology of coronaviruses.Adv Virus Res. 1997; 48: 1-100Crossref PubMed Google Scholar There has been an intensive search for an effective drug against the virus or the resultant disease and has not led to any breakthrough agents. Few drugs namely hydroxychloroquine and remdesivir have been advocated as desperate measures to fight COVID-19 based on a few preliminary, contradictory, and inconclusive studies.19NIHNIH Clinical Trial Shows Remdesivir Accelerates Recovery from Advanced COVID-19. National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA2020https://www.niaid.nih.gov/news-events/nih-clinical-trial-shows-remdesivir-accelerates-recovery-advanced-covid-19Google Scholar, 20Wang Yea Remdesivir in adults with severe COVID-19: a randomized, double-blind, placebo-controlled, multicentre trial.Lancet. 2020; (published online April 29)https://doiorg/101016/S0140-6736(20)31022-9Abstract Full Text Full Text PDF Scopus (2481) Google Scholar, 21Rathi S. Ish P. Kalantri A. Kalantri S. Hydroxychloroquine prophylaxis for COVID-19 contacts in India.Lancet Infect Dis. 2020; (PMC7164849)https://doi.org/10.1016/S1473-3099(20)30313-3https://www.ncbi.nlm.nih.gov/pubmed/32311324Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar, 22Raoult D. Hsueh P.R. Stefani S. Rolain J.M. COVID-19 therapeutic and prevention.Int J Antimicrob Agents. 2020; : 105937Crossref PubMed Scopus (21) Google Scholar, 23Khuroo M. Sofi A.A. Khuroo M. Chloroquine and hydroxychloroquine IN coronavirus disease 2019 (COVID-19). FACTS, fiction & the hype. A critical appraisal....2020https://doiorg/106084/m9figshare12177117v1. 2020Google Scholar What we need is a drug that is at least 95% effective to stop the pandemic. These and other drugs may save lives but are nowhere near that power to bring normalcy in the utter chaos caused by the pandemic.24Gates B. The vaccine race, explained. What You Need to Know about the COVID-19 Vaccine GatsNotes the Blog of Bill Gates.2020https://www.gatesnotes.com/Health/What-you-need-to-know-about-the-COVID-19-vaccineGoogle Scholar This leaves us with only one choice namely an effective and safe vaccine that shall be manufactured as soon as possible and available to all countries and populations affected by the pandemic at an affordable price.25Guarascio F.U.N. Calls for the COVID Vaccine, Treatment Available for All. Reuters Health, Brussels2020https://in.reuters.com/article/us-health-coronavirus-eu-virus-un/u-n-calls-for-covid-vaccine-treatment-available-for-all-idINKBN22G1MZGoogle Scholar,26Dyer O. Covid-19: trump sought to buy vaccine developers exclusively for the US, say German officials.BMJ. 2020; 368: m1100Crossref PubMed Scopus (14) Google Scholar A vaccine has the power to generate herd immunity in the communities, which will reduce the incidence of disease, block transmission, and reduce the social and economic burden of the disease. Very high immunization coverage can effectively fight the pandemic, prevent secondary waves of infection, and control the seasonal endemic infection outbursts. Eventually, the disease can be eradicated as has happened in many other diseases that have had even with higher potential than COVID-19 to cause pandemics namely smallpox, poliomyelitis, etc.27Anonymous Vaccine-Preventable Diseases Australian Government. The Dept of Health, July 20, 2010https://www.health.gov.au/news/health-alerts/novel-coronavirus-2019-ncov-health-alertGoogle Scholar,28Anonymous Vaccines for Your Children. Diseases You Almost Forgot about (Thanks to Vaccines). Centre for Diseases Control and Prevention, 2020https://www.cdc.gov/vaccines/parents/diseases/forgot-14-diseases.htmlGoogle Scholar A vaccine is medical preparations ranging from intact organisms (attenuated live or inactivated) to genetically engineered parts of the organisms (antigenic) that induce both arms of the adaptive immune system and stimulate a sufficient number of memory T cells and B lymphocytes.29Aryal S. Vaccines-introduction and Types with Examples Online Microbiology Notes by Sagar Aryal.2020https://microbenotes.com/author/sagararyalnepal/Google Scholar Vaccines should contain antigens necessary to mount the specific response without causing disease. Once challenged with the pathogen, memory cells yield effector T cells and antibody-producing B cells and fight the infection. The antibodies have to be the neutralizing type which binds to the virus and block infection.30Clem A.S. Fundamentals of vaccine immunology.J Glob Infect Dis. 2011; 3: 73-78Crossref PubMed Scopus (243) Google Scholar The virus coated with neutralizing antibodies either cannot interact with the receptor or may be unable to uncoat of the genome. Most currently licensed vaccines induce neutralizing antibody responses capable of mediating long-term protection against lytic viruses such as influenza and smallpox.31Payne S. Chapter 6. Immunity and Resistance to Viruses. Viruses: From Understanding to Investigation. Academic Press, 2017: 61-71Google Scholar The T cell–based responses that recognize and kill infected cells do also fight the infection.32Siegrist C.-A. Chapter 2. Vaccine immunology.in: Plotkin S. Orenstein W. Offit P. Edwards K.M. Plotkin's Vaccines. 7th. ed. Imprint: Elsevier, The United States2017: 1-26Google Scholar Following antigen processing in dendritic cells, the small peptides are displayed at the cell surface at the groove of major histocompatibility complex (MHC) class I and class II molecules. Cytotoxic T cells (CD8+) recognize MHC class I-peptide complexes and differentiate into cytotoxic effector cells capable of killing infected cells or pathogens. Helper T cells (CD4+) recognize MHC class II-peptide complexes and differentiate in effector cells that produce preferentially T helper 1 cells (Th1) or T helper cells 2 (Th2) cytokines (Figure 1). Th1 support CD8+ T cell differentiation, which is in contrast inhibited by Th2-like cytokines. Vaccines against chronic pathogens namely Mycobacterium tuberculosis, malaria, HCV, HIV, etc. more often require cell-mediated immune responses to control the infection.33Esser M.T. Marchese R.D. Kierstead L.S. et al.Memory T cells and vaccines.Vaccine. 2003; 21: 419-430Crossref PubMed Scopus (146) Google Scholar The success of a vaccine against a pathogen is a complex issue and depends on the biology of the virus and the type of immune response elicited by the body against the organism. While vaccines have been successful against several pathogens including 14 major infectious diseases,27Anonymous Vaccine-Preventable Diseases Australian Government. The Dept of Health, July 20, 2010https://www.health.gov.au/news/health-alerts/novel-coronavirus-2019-ncov-health-alertGoogle Scholar,28Anonymous Vaccines for Your Children. Diseases You Almost Forgot about (Thanks to Vaccines). Centre for Diseases Control and Prevention, 2020https://www.cdc.gov/vaccines/parents/diseases/forgot-14-diseases.htmlGoogle Scholar not all infectious diseases are vaccine-preventable.34Randal J. Hepatitis C vaccine hampered by viral complexity, many technical restraints.J Natl Cancer Inst. 1999; 91: 906-908Crossref PubMed Scopus (4) Google Scholar,35Alcorn K. The Search for an HIV Prevention Vaccine.2020http://www.aidsmap.com/about-hiv/search-hiv-prevention-vaccineGoogle Scholar The development of vaccines against HIV and HCV has proved challenging. These viruses have an extreme genetic heterogeneity including the hypervariable regions (target for neutralizing antibodies), and the mutation contributes to immune escape.36Bankwitz D. Steinmann E. Bitzegeio J. et al.Hepatitis C virus hypervariable region 1 modulates receptor interactions, conceals the CD81 binding site, and protects conserved neutralizing epitopes.J Virol. 2010; 84: 5751-5763Crossref PubMed Scopus (189) Google Scholar The mutations lead to a mixture of genomes in the patient over time and from patient to patient. Also, antibodies mounted against such viral infections are predominantly nonneutralizing. Neutralizing antibodies are often either absent or weak to fight the pathogen or neutralize only a narrow range of circulating viral strains and only appear in a subgroup of patients who either recover or are "elite controller".37De Rose R. Kent S.J. Ranasinghe C. Singh M. Salnikova M. Chapter 12 - Prime-Boost Vaccination: Impact on the HIV-1 Vaccine Field. Elsevier Inc., 2015Google Scholar Another aspect to be considered is whether the virus can be grown in cell culture and transmitted to small animals for experimentation. Since HCV has been discovered by molecular cloning in 1989, its propagation in cell culture has been difficult, which hampers the ability of investigators to experiment with various antigenic components of the virus.38Duverlie G. Wychowski C. Cell culture systems for the hepatitis C virus.World J Gastroenterol. 2007; 13: 2442-2445Crossref PubMed Scopus (16) Google Scholar To develop a safe and effective vaccine against COVID-19, we need to consider several things about the SARS-CoV-2 and the immune response against the natural infection and the vaccine. Does SARS-CoV-2 mutate, how fast and will mutations cause a phenomenon of immune escape as is seen in HIV and HCV.34Randal J. Hepatitis C vaccine hampered by viral complexity, many technical restraints.J Natl Cancer Inst. 1999; 91: 906-908Crossref PubMed Scopus (4) Google Scholar,35Alcorn K. The Search for an HIV Prevention Vaccine.2020http://www.aidsmap.com/about-hiv/search-hiv-prevention-vaccineGoogle Scholar SARS-CoV-2 has shown mutations as is true to every RNA virus. However, the mutations are slow and mild, and mutants show nearly similar sequences as in the parent strain. Dorp et al.39Lv Dorp Aeman M. Richard D. Shaw L.P. Ford C.F. Ormond L. Emergence of genomic diversity and recurrent mutations in SARS-CoV-2.Infection, Genetics and Evolution. 2020; https://doi.org/10.1016/j.meegid.2020.104351Crossref Scopus (528) Google Scholar studied genomic diversity of SARS-CoV-2 and recorded 198 filtered recurrent mutations; however, most of the mutations were either neutral or even deleterious and of no clinical significance in vaccine immunity. Ahmad et al.40Ahmed S.F. Quadeer A.A. McKay M.R. Preliminary identification of potential vaccine targets for the COVID-19 coronavirus (SARS-CoV-2) based on SARS-CoV immunological studies.Viruses. 2020; 12Crossref Scopus (848) Google Scholar found no mutations in 120 available SARS-CoV-2 sequences and identified a set of B cell and T cell epitopes derived from the spike (S) and nucleoprotein (N) proteins that map identically to SARS-CoV-2 proteins. These findings provide a screened set of epitopes that can help guide experimental efforts toward the development of vaccines against SARS-CoV-2. What type of immune response occurs in natural COVID-19 and after vaccination and are antibodies neutralizing in nature? SARS-CoV-2 infection evokes a robust adaptive immune response of both T cell and B cell type arms.41Thevarajan I. Nguyen T.H.O. Koutsakos M. et al.Breadth of concomitant immune responses prior to patient recovery: a case report of non-severe COVID-19.Nat Med. 2020; 26: 453-455Crossref PubMed Scopus (748) Google Scholar,42Braun J. Loyal L. Frentsch M. Wendisch D. Georg P. al e Presence of SARS-CoV-2-reactive T cells in 1 COVID-19 patient and healthy donors. medRxiv, April 22, 2020https://doi.org/10.1101/2020041720061440Crossref Google Scholar Furthermore, both IgM and IgG antibodies appear around the 10th day of infection, and most patients seroconvert within 3 weeks. The antibodies are raised against internal nucleoprotein (N) and spike protein (S) of the virion and have neutralizing activity.43Chen Y. Li L. SARS-CoV-2: virus dynamics and host response. vol. 20. 2020: 515www.thelancet.com/infectionGoogle Scholar Now that several candidate vaccines are in the clinical trial, investigators shall study the strength and nature of immune response against the vaccine antigen (mostly spike protein). Are people who recover from COVID-19 infection protected from a second or a third infection? Should re-infections occur, it would imply that immune response against SARS-CoV-2 is not protective, making possibilities of a successful vaccine difficult. There were scary reports from South Korea about patients thought to have recovered from COVID-19 had tested positive again.44Russel A. Can You Catch Coronavirus Twice? South Korea Reports 91 Recovered Patients Tested Positive. Global News, 2020https://globalnews.ca/news/6805414/coronavirus-south-korea-reinfection-canada/Google Scholar An intense debate started about re-activation or re-infections of the virus. Soon these reports were put to rest, and the positive sample were found to be residual dead fragments of the virus, not the virus, which had re-activated or re-infected.45Guzman J. No Evidence of Coronavirus Reinfections, South Korean Researchers Say. South Korea's Infectious Disease Experts Said Thursday Reports of Coronavirus Reinfection Were Likely Testing Errors. The Hill, 2020https://thehill.com/changing-america/well-being/medical-advances/495646-no-evidence-of-coronavirus-reinfections-southGoogle Scholar After these reports, 2 groups of investigators have shown that SARS-CoV-2 antibodies are protective. Bao et al. showed that 2 monkeys who recovered from SARS-CoV-2 infection were protected from re-infection on the challenge during convalescence.46Bao L. Deng W. Gao H. et al.Reinfection could not occur in SARS-CoV-2 infected rhesus macaques.bioRxiy. 2020; (May 5)https://doi.org/10.1101/20200313990226Crossref Google Scholar Gao et al. administered candidate vaccine PiCoVacc Sinovac Biotech to mice, rats, and nonhuman primates. The antibodies raised against the vaccine in animals showed neutralizing ability against SARS-CoV-2 strains. Three immunizations of 2 doses (3 μg or 6 μg per dose) gave partial or complete protection in macaques against SARS-CoV-2.47Gao Q. Bao L. Mao H. et al.Rapid development of an inactivated vaccine candidate for SARS-CoV-2.Science. 2020; https://doi.org/10.1126/science.abc1932https://www.ncbi.nlm.nih.gov/pubmed/32376603Crossref Scopus (997) Google Scholar These data are exciting and if reproducible in humans confirm that vaccines against COVID-19 shall be protective. For the COVID-19 vaccination program to succeed, the antibody response mounted against the virus/vaccine must be long-lasting. As of today, it is not possible to address this question as the virus has been in the community only for the last few months. However, we can take leads from data generated about the duration of immunity against 2 other coronaviruses namely SARS-CoV and MERS-CoV.14Graham R.L. Donaldson E.F. Baric R.S. A decade after SARS: strategies for controlling emerging coronaviruses.Nat Rev Microbiol. 2013; 11: 836-848Crossref PubMed Scopus (519) Google Scholar,17Yong C.Y. Ong H.K. Yeap S.K. Ho K.L. Tan W.S. Recent advances in the vaccine development against Middle East respiratory syndrome-coronavirus.Front Microbiol. 2019; 10: 1781Crossref PubMed Scopus (164) Google Scholar Both these viruses, which are closely related to SARS-CoV-2, induce a robust T cell and B cell immune response which is long-lasting. Many candidate vaccines against both these viruses had gone through successful clinical trials and are safe and immunogenic.48Roper R.L. Rehm K.E. SARS vaccines: where are we?.Expert Rev Vaccines. 2009; 8: 887-898Crossref PubMed Scopus (152) Google Scholar The greatest fear among vaccine developers is to create a vaccine that does not protect from infection but causes disease exacerbation, increased morbidity, and mortality.48Roper R.L. Rehm K.E. SARS vaccines: where are we?.Expert Rev Vaccines. 2009; 8: 887-898Crossref PubMed Scopus (152) Google Scholar, 49Peeples L. News Feature: avoiding pitfalls in the pursuit of a COVID-19 vaccine.Proc Natl Acad Sci U S A. 2020; 117: 8218-8221Crossref PubMed Scopus (102) Google Scholar, 50Hotez P.J. Corry D.B. Bottazzi M.E. COVID-19 vaccine design: the Janus face of immune enhancement.Nat Rev Immunol. 2020; https://doi.org/10.1038/s41577-020-0323-4https://www.ncbi.nlm.nih.gov/pubmed/32346094Crossref Scopus (140) Google Scholar, 51de Alwis R. Chen S. Gan E.S. Ooi E.E. Impact of immune enhancement on Covid-19 polyclonal hyperimmune globulin therapy and vaccine development.EBioMedicine. 2020; 55: 102768Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar Some vaccines can mount antibody-dependent enhancement (ADE), which negates the basic purpose of vaccination.52Smatti M.K. Al Thani A.A. Yassine H.M. Viral-induced enhanced disease illness.Front Microbiol. 2018; 9: 2991Crossref PubMed Scopus (92) Google Scholar This response is mediated by the type of nonneutralizing antibodies mounted against infection or vaccination. The immune response to such vaccines is subverted, leading to exacerbated illness. This could be because of Fc receptor- or complement bearing cells-mediated mechanisms. The Fc-region of the antibody binds to FCγR on the immune cells, which subverts the immune response by reducing TH1 cytokines (interleukin 2 (IL-2), tumour necrosis factor alpha (TNF-a), and interferon gamma (IFN-g)) and skews TH2 cytokines (interleukin 10 (IL-10), interleukin 6 (IL-6), prostaglandin E2 (PGE-2), and interferon alpha (INF-a)) and inhibits signal transducer and activator of transcription protein pathway leading to increased viral replication (Figure 2). ADE is of clinical significance in several viral infections including influenza, RSV, SARS-CoV, MERS-CoV, Dengue virus, Zika virus, and West Nile virus. Considering ADE is a major impediment to vaccine development, efforts to identify highly selected epitopes have been done to avoid the production of antibodies responsible for disease enhancement. ADE has been reported in animals during vaccination trials with SARS-CoV and MERS-CoV.14Graham R.L. Donaldson E.F. Baric R.S. A decade after SARS: strategies for controlling emerging coronaviruses.Nat Rev Microbiol. 2013; 11: 836-848Crossref PubMed Scopus (519) Google Scholar,17Yong C.Y. Ong H.K. Yeap S.K. Ho K.L. Tan W.S. Recent advances in the vaccine development against Middle East respiratory syndrome-coronavirus.Front Microbiol. 2019; 10: 1781Crossref PubMed Scopus (164) Google Scholar,35Alcorn K. The Search for an HIV Prevention Vaccine.2020http://www.aidsmap.com/about-hiv/search-hiv-prevention-vaccineGoogle Scholar Vaccine candidates against coronaviruses based on full-length spike protein induce nonneutralizing antibodies, lack of protection of animals against a viral challenge, and severe disease enhancement presenting as enhanced hepatitis, increased morbidity, and stronger inflammatory response.17Yong C.Y. Ong H.K. Yeap S.K. Ho K.L. Tan W.S. Recent advances in the vaccine development against Middle East respiratory syndrome-coronavirus.Front Microbiol. 2019; 10: 1781Crossref PubMed Scopus (164) Google Scholar As of today, there are no reports of ADE with the use of COVID-19 candidate vaccines in nonhuman primates and humans.51de Alwis R. Chen S. Gan E.S. Ooi E.E. Impact of immune enhancement on Covid-19 polyclonal hyperimmune globulin therapy and vaccine development.EBioMedicine. 2020; 55: 102768Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar However, it is an early period in the development of these vaccines, and as the matter is of major importance in the success of such a vaccine, we need to be vigilant. ADE following COVID-19 vaccination if reported can be prevented by shielding nonneutralizing epitopes of S protein by glycosylation or selecting critical neutralizing epitopes of the S antigen to elicit a more robust protective immunity. Every new vaccine follows a stringent protocol in Research and Development (R&D) which has to be meticulously followed and completed before it is licensed to be marketed (Figure 3). Regulatory authorities namely WHO, U.S. Food and Drug Administration, the European Medicines Agency, and national authorities of many countries have issued guidelines relevant to the clinical evaluation of vaccines.53WHO Guidelines on Clinical Evaluation of Vaccines: Regulatory Expectations. WHO Technical Report Series, No. 1004, 2017. Replacement of Annex 1 of WHO Technical Report Series, No. 924 Geneva, Switzerland.2017https://www.who.int/biologicals/expert_committee/WHO_TRS_1004_web_Annex_9.pdf?ua=1Google Scholar, 54(CHMP). CoHMPGuideline on clinical evaluation of vaccines. EMEA/CHMP/VWP/164653/05 Rev. 1.2018https://www.ema.europa.eu/en/documents/scientific-guideline/draft-guideline-clinical-evaluation-vaccines-revision-1_en.pdfGoogle Scholar, 55FDAGUIDANCE DOCUMENTGeneral Principles for the Development of Vaccines to Protect against Global Infectious Diseases. Guidance