Strategies and Challenges in the Development of Coronavirus Disease-2019 Vaccine

Pratibha Gupta

Department of Biotechnology, Radha Govind University, Ramgarh 829122, Jharkhand, IndiaIndia

DOI: https://doi.org/10.17140/epoj-6-122 · Published 2021-06-30 · Licence: https://creativecommons.org/licenses/by/4.0 · © 2021 The Author(s)

Also available as PDF (figures and tables appear in the PDF).

Keywords: SARS-CoV-2; Vaccine development; Clinical trials

Introduction

he outbreak of coronavirus disease-2019 (COVID-19) was first reported in Wuhan, Hubei Province of China in late T 2019. The disease was caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which spread to almost all parts of the globe. The symptoms include fever, cough, chest tightness, and fatigue upon exertion. Most patients experience mild symptoms whereas some are asymptomatic (have no clear or confirmed symp- 1,2 toms). Long incubation, high infection rates and mild to moderate symptoms make COVID-19 a troubling disease. The World Health Organization (WHO) declared this outbreak a pandemic on 30 January 2020. Physical distancing and other transmission mitigation strategies were implemented in most countries to prevent citizens from being infected. The SARS-CoV-1 outbreak in 2003 caused similar respiratory symptoms and amassed 774 deaths. Middle Eastern respiratory syndrome coronavirus (MERS-CoV) often involves similar symptomatology and infections in Saudi Arabia in

cc Copyright 2021 Gupta P. This is an open-access article distributed under Creative Commons Attribution 4.0 International License (CC BY 4.0), which allows 2012 were circulated between bats and camels before transmission to humans (“zoonotic” transmission).3

The coronavirus is an enveloped and positive sense single stranded ribonucleic acid (RNA) genome. It belongs to the Betacoronavirus genus containing 30 kb genome with 14 open reading frames (ORF). The ORFs includes four viral structural proteins: Membrane (M), Spike (S), Nucleocapsid (N) and Envelope (E) 4-7 protein.4-7 The S protein is functionally composed of two subunits, 8,9 S1 (receptor binding) and S2 (cell membrane fusion). During infections, host cell proteases process the S protein at the S1/S2 cleavage site. Proteolytically processed S protein cleaves into two subunits, the N-terminal at the S1 subunit and the C-terminal of the S2 subunit. The S1 subunit consists of N-terminal, signal peptide, and receptor binding domains. The S2 subunit consists of a C-terminal domain, conserved peptide sequences, proteolytic sites, 10-12 a transmembrane domain and a cytoplasmic domain. As the virus enters the host cell, another cleavage occurs for the fusion of

membranes and the cleavage is mediated by endolysosomal proteases.8 Furin is highly expressed in lungs and the S protein contains the potential cleavage site for furin protease. Furin like cleavage appears to be the important for the activation of S protein which leads to the efficient entry of the virus into the host cell.13

Coronavirus (CoVs) can infect a range of host species such as animals, birds and humans. Different CoVs like SARS- CoV, MERS-CoV and SARS-CoV-2 have intricate host receptor recognition patterns, which indicate the structural diversity in the receptor binding domain of the S protein. The interaction between the S-protein and the angiotensin-converting enzyme 2 (ACE-2) receptor present on the host cell is the probable mechanism of the infection that is caused by SARS-CoV-2.14

According to WHO guidelines, the COVID-19 infected patients should receive supportive body system-focused therapies like fluid therapy, oxygen therapy and antibiotics. The major therapeutics drugs include lopinavir, ritonavir, remdesivir along with interferons, monoclonal antibodies and convalescent plasma for the treatment. Remdesivir was originally developed for the treatment of Ebola virus infection. It prevents the viral infection by premature termination of RNA transcription. Remdesivir is a nucleoside analogue drug which is in Phase III of clinical investigation against COVID-19 (NCT04292730, NCT04315948, NCT04257656). An open-label, randomized Phase II clinical trial found that triple antiviral therapy (lopinavir, ritonavir and interferon beta-1b) was safe in alleviating symptoms and shortening the duration of viral shedding. There is an unprecedented need to develop and distribute safe and effective vaccine to protect the entire global community from continued mortality from COVID-19 should be intact. The wide geographic diversity of the pandemic requires an effective vaccine approach, for this the collaboration between biotechnologist and pharmaceutical companies is needed which brings the convergence of a variety of vaccine development approaches. Over the past decade, the vaccine industry and scientific community responded urgently to several epidemics such as H1N1 influenza, Ebola, Nipah virus as well as against CoVs including MERS- and SARS-CoVs. Developing vaccine against H1N1 influenza is relatively rapid as influenza vaccine technology is well-established and key regulators were already decided. Many efforts have been directed to develop vaccine against CoVs infection but the limiting factor is most often the degree of crossreactivity. Immune response by the body against SARS-CoV-2 vaccine plays a vital role for preventing the pathogen’s entry into human cells. However, an unregulated immune response may lead to immunopathogenesis.

There is a challenge in developing safe and effective vaccines, but manufacturing, distributing and administering it to the population within a short time frame is an extraordinary challenge. Approximately, 321 COVID-19 vaccine candidates are available, out of these 66 vaccines are in activeclinical trials (Table 1) and 176 are in the pre-clinical (animal) phase of testing.21

An ideal vaccine should be safe even to immunocompromised people, inexpensive, free from toxicity, have high thermal stability and should confer long-term protection.22 Various scientific communities are using multiple approaches to shorten the development phase which include efficiency gains via over-laying on one other of the traditional, sequential clinical “phases” of progressive testing prior to approval. This, while accomplishing research objectives more quickly than is usual, must be carefully monitored for rigor and reliability of conclusions reached at such previously-unexpected speeds. In addition to the more usual scientifically cautious approach to study and conclusion-drawing, these diverse types of vaccine candidates face a variety of challenges that are related to development, manufacturing, storage, and distribution, to mass vaccination.

Vaccine Design Strategies

The SARS-CoV-2 pandemic created a devastating situation across the globe.14 Children and adults above 65-years of age are more vulnerable to COVID-19. Vaccination enable the natural viral infection defense system, which is the only way to control the CO- VID-19 outbreak. Vaccine design includes the selection of a target antigen key in the virus’ infection process, a “vehicle” (viral, genetic/recombinant, chemical, etc.) for vaccine delivery into patients, and the intended or optimal vaccination administration route (oral, 16 nasal, injection, etc.). The selection of a target antigen is based upon the structural and pathobiology information of SARS-CoV-2. The genome of SARS-CoV-2 is a single stranded positive sense RNA. The positive sense genome can act as messenger RNA that can be directly translated into viral protein by the host cell ribosome. The structural proteins present in the virus include Nucleocapsid (N) protein, spike (S) protein, membrane (M) protein and envelop (E) protein. N protein coats the positive stranded RNA genome which is enclosed in a lipid envelop into which S, M and E protein are inserted. The S protein located at the outer surface of virus binds with an ACE-2 receptor on the host cell surface, allowing receptor mediated endocytosis of the virus (Figure 1).23 S protein plays an important role in the virus life cycle that enables it to enter human cells, so the spike protein is a rational priority prime target for most of the COVID-19 vaccines. Based on crystallography ACE2 binding patterns in SARS-CoV and SARS-CoV-2 are the same.24 Previ- 17-19 ously, while developing vaccine against SARS-CoV, liver damage was observed when a full-length S protein was used as a vaccine antigen.25 Thus, the fragment of S-protein, the receptor binding domain (RBD), was seen as a safer choice as a vaccine candidate for COVID-19. However, RBD-based vaccines face problems arising from low immunogenicity, identifying possible appropriate adjuvant(s), establishing an immunization schedule, and partial versus full fragment length approaches.26 Vaccine candidates in development have several advantage and disadvantages. The most important features that should be considered to develop vaccine candidate are antigen-specific cellular immunity, long-term protection and the ability to induce a reliable and sufficient systemic im- 27,28 mune system response. Vaccine candidates for COVID-19 were classified into vector-based vaccines, recombinant protein-based vaccines, deoxyribonucleic acid (DNA) vaccines, messenger RNA (mRNA) vaccines, recombinant protein vaccines, inactivated vaccines, live attenuated vaccines and viral vector-based vaccines.

Deoxyribonucleic Acid Based Vaccine

Deoxyribonucleic acid vaccines are encoded with an antigen-pre-

Table 1. Vaccine Candidates against COVID-19 in Development with Stage

Candidate Vaccine Characteristic DNA-Based Approach

ZyCoV-D DNA vaccine DNA plasmid that encodes S protein delivered by INO-4800 electroporation AG0301-COVID19 DNA vaccine that encodes S protein DNA vaccine that encodes S protein delivered by GX-19 electroporation or needle free

RNA-Based Approach

mRNA-BNT162 LNP-encapsulated mRNA that encodes stabilised S antigen Pfizer/BioNTech Phase II/III NCT04368728 mRNA mRNA encoding the RBD mRNA-1273 LNP-encapsulated mRNA that encodes S protein LNP-encapsulated self-replicating mRNA that encodes ARCT-021 prefusion S protein LNP-encapsulated self-amplifying RNA that encodes the S LNP-nCoVsaRNA protein CVnCoV LNP-encapsulated mRNA that encodes the S protein

Protein-Based Approach

Recombinant SARS-COV-2 spike protein with Advax-SM Covax-19 adjuvant Recombinant SARS-CoV-2 trimeric S protein subunit SCB-2019 vaccine Recombinant SARS-COV-2 spike protein ‘molecular clamp’ UQ-1-SARS-CoV2-Sclamp plus MF59 adjuvant NVXCoV2373 Stable, prefusion protein, includes MatrixM™ adjuvant Adjuvantedrecombinant Recombinant protein-based S protein vaccine together protein-based vaccine with ASO3 EpiVacCorona Synthesized peptide antigens of SARS-CoV-2 proteins Coronavirus-like particle Plant-derived virus-like particle with/without ASO3 or COVID-19 vaccine CPG1018 adjuvant Recombinant new Recombinant SARS-CoV-2 RBD protein subunit vaccine Phase II NCT04466085 coronavirus vaccine (CHO cell) Recombinant SARS-CoV-2 Recombinant SARS-CoV-2 vaccine (Sf9 cell) vaccine

Inactivated Virus Approach

BBV 152 Whole-virion inactivated

Inactivated SARS-CoV-2 Inactivated novel coronavirus (2019-CoV) vaccine vaccine Inactivated SARS-CoV-2 Inactivated novel coronavirus Pneumonia vaccine vaccine (Vero cells) Inactivated SARS-CoV-2 SARS-CoV-2 inactivated vaccine vaccine Adsorbed COVID-19 SARS-CoV-2 inactivated vaccine (inactivated) vaccine

Viralvector-Based Approach

V591 Measles virus vector Ad5-nCoV Adenovirus type 5 vector that expresses S protein Recombinant adenovirus vector based on the human Gam-COVID-Vac adenovirus type 5, 26, containing S protein GRAd-COV2 Gorilla adenovirus vector that expresses S protein AZD1222 ChAdOx1 vector that expresses S protein Ad26.COV2-S Adenovirus type 26 vector that expresses S protein DCs modified with lentiviral vector expressing synthetic LV-SMENP-DC minigene based on domains of selected viral proteins aAPCs modified with lentiviral vector expressing synthetic Pathogen-specific aAPC minigene based on domains of selected viral proteins

Sponsor/Lead Partner Clinical Stage Registration Number

ZydusCadila Phase I/II CTRI/2020/07/026352 Inovio Pharmaceuticals Phase I/II NCT04336410 Osaka University/ AnGes Phase I/II NCT04463472 Genexine Consortium Phase I/II NCT04445389

Walvax Biotechnology Phase I ChiCTR2000034112 Moderna Therapeutics/NIAID Phase III NCT04470427 the Arcturus Therapeutics Phase I/II NCT04480957

Imperial College London Phase I/II ISRCTN17072692 CureVac Phase I NCT04449276

Vaxine Pty/Medytox Phase I NCT04453852

Clover Biopharmaceuticals Phase I NCT04405908

University of Queensland/CSL Phase I ACTRN12620000674932p Novavax Phase II NCT04368988 Sanofi / GSK Phase I/II NCT04537208 FBRI SRC VB VECTOR Phase I/II NCT04527575 Medicago Phase I NCT04450004 Anhui ZhifeiLongcom Biopharmaceutical/ IMCAS Sichuan University Phase I ChiCTR2000037518

Bharat Biotech, Indian Council of Medical Research, National Phase I/II CTRI/2020/07/026300 Institute of Virology Beijing Institute of Phase I/II ChiCTR2000032459 Biotechnology/ Sinopharm Wuhan Institute of Biological Phase III ChiCTR2000034780 Products/ Sinopharm Institute of Medical Biology, Chinese Academy of Medical Phase I/II NCT04470609 Sciences Sinovac Biotech Phase III NCT04456595

Merck Sharp &Dohme Phase I NCT04497298 CanSino Biological/ Beijing Phase II ChiCTR2000031781 Institute of Biotechnology Gamaleya Research Institute Phase III NCT04530396 ReiTheraSrl Phase I NCT04528641 AstraZeneca/Oxford Phase III NCT04516746 University J&J–Janssen Phase I/II NCT04436276 Shenzhen GIMI Phase I/II NCT04276896

Shenzhen GIMI Phase I NCT04299724

Figure 1. SARS-CoV-2 Vaccine Strategy:S Protein of SARS-CoV-2 is the Target for Vaccine Development

peptide that elicits CD8 T-cell response. DNA plasmids cross the plasma and nuclear membrane, enter the target cell, reach the nucleus and achieve transcription and thus propagates the desired and validated immune response (Figure 2). DNA vaccines have various advantages such as eliminating the use of live viruses, ease of production scaling, lower production costs when compared to protein vaccine production, more stability for storage and transportation and they may even be administered to immuno-compromised patients. Manufacturing DNA based vaccines is relatively straight forward and is more stable than viral protein and RNA vaccines. The only pro-inhibitory factor is the low immunogenicity 31,32 that sometimes requires multiple booster doses. Overcoming the immunogenic issues of DNA vaccines, immunostimulants and adjuvants maybe required. Combined use of granulocyte-macrophage colony-stimulating factor (GM-CSF) and a cytokine-based therapy directed against interleukin-4 (IL-4) have proven useful in enhancing immune response in some medical settings.33 DNA vaccines show promising effects against several emerging viral dis-

eases such as Dengue, MERS, and Chikungunya. Yet, no DNA vaccine has been licensed for use in human. DNA-based vaccines encoding S protein from SARS-CoV-2 appears to be in clinical Phase I/II testing on the pathway to approval.37

Ribonucleic Acid Based Vaccines

Messenger RNA (mRNA) sequences that code for disease specific antigens enclosed with lipid nanoparticles (LNPs) are the current, most widely pursued mechanism of action for approved COV- ID-19 vaccines.38 Once the LNP is phagocytosed (eaten/incorporated) by the human cell, the RNA condensing lipid nanoparticle punctures the endosome and allows the mRNA molecule to release into the cytosolinside the human cell (Figure 3). Messenger RNA vaccines are synthesized by in vitro transcription and are noninfectious. This feature of mRNA vaccines does provide advantages that differentiate it from recombinant viral vector vaccines, live attenuated viral vaccines and inactivated viral vaccines that enable inexpensive and rapid production of vaccine doses.39 The mRNA vaccine does not integrate permanently into the human host genome and does not produce any live infectious particles that elicit immune responses and this further reduces safety concerns.

Moderna’s COVID-19 vaccine candidate mRNA-1273, encodes SARS-CoV-2 S protein encapsulated in lipid nanoparticles, and is in Phase III clinical trials.

Protein Vaccines

Protein vaccines contain partial or full-length SARS-CoV-2 S pro-

Figure 3. Graphical Illustration of RNA Based Vaccine 34-36 + tein that induces a CD4 TH-cell and antibody response. Unlike nucleic acid-based vaccine, protein subunit vaccines could have improper epitope conformation, until they are produced by mam- 37 40

malian cells.40 Protein vaccines are designed to provoke the immune response towards neutralizing epitopes, thus preventing the production of non-neutralizing antibodies that may promote antibody- dependent enhancement (ADE) of disease.41 Protein subunits (when used alone) are poorly immunogenic and thus serve as + poor activators of the CD8+ T-cell response, which requires adjuvant and repeated administrations. Recombinant proteins are enclosed in a virus like particles (VLPs) devoid of viral genome. The VLPs generate high numbers of antigenic epitope copies, thereby preserving viral immunogenicity, enabling the ability to crosslink to B-cell receptors on the B-cell surface and facilitate uptake by 42,43 the antigen presenting cells (APCs) (Figure 4). In protein-based vaccines, subunits are taken up by the antigen presenting cells for B-cell recognition through B cell receptor (BCR) and for major histocompatibility complex (MHC) presentation. In viral-vector vaccines, (replicating and non-replicating) viral vectors or cellular vehicles, carrying a desired gene, are delivered and facilitate the expression of heterologous antigen within the cell. The viral vector retains the capacity to produce viral particles that infect the host cell and that lead to transgene expression and antigen presentation. Live virus vaccines retain the ability to replicate inside the host cell and mimic the natural infectionprocess. The inactivated virus vaccines deploy virus cells that were once alive and have been completely attenuated, yet still generate an infectious state. They do so by using certain chemicals that induce specific neutralizing antibodies in response to what the viral vaccine presents to the human body.

Figure 4. Graphical Representation for Vaccine Design Strategies: Protein Based Vaccines-Subunits are Taken-up by the Antigen Presenting Cells for B-Cell Recognition through BCR and for MHC Presentation Viral vector vaccines (replicating and non-replicating) viral vector carrying a desired gene is delivered and allows the expression of heterologous antigen within the cell, the viral vector retains the capacity to produce viral particles that infect the host cell and leads to transgene expression and antigen presentation. Attenuated viruses retain the ability to replicate inside the host cell and mimic the natural infectionprocess. Inactivated virus generates an infectious state using certain chemicalsthatinduce specific neutralizing antibodies.

Attenuated and Inactivated Virus Vaccine

The attenuated vaccines are obtained by mutating a virus, which infects the human cell until a substantial number of cells adopt the mutation that generates the desired immune response (Figure 4). Their most important advantage is that they offer more than one antigenic component to host, thus inducing or mobilizing various immunological effectors against the virus.44 The drawback associated with attenuated vaccines are potential safety concerns. They often have high reactogenicity compared to protein-based vaccines.45 Several successful vaccines such as bacillus-calmette-guerin (BCG) and measles vaccines are based on attenuated strains of the viruses.46 The coronavirus genome has various genes that are not required for replication and can be deleted. Deletion of various genes that code for non-structural proteins and structural E proteins may also be used as a strategy to design new vaccines. Therefore, deletion of the virulence factor and the induced codon deoptimization (where nucleic acid sequence is modified that encodes the wild type of amino acid sequence, and slows the translation of viral protein) may be a suitable mechanism of attenuation. A codon deoptimization approach yields vaccine-ready virus that is highly attenuated in vivo and in vitro and can replicate if the correct viral protein(s) is/are selected forde-optimization.

In inactivated vaccines, the whole pathogen is killed either by exposure to chemical (formaldehyde) or heat induced inactivation.51 Inactivated viruses have been used traditionally for vaccine development and were found to be safe and effective for prevention of diseases caused by the hepatitis influenza, and polioviruses. They are generally less immunogenic and require multiple doses or 52,53 an additional adjuvant (Figure 4). Currently there are five vaccine candidates for SARS-CoV-2 (Table 1) apart from that there are nine inactivated vaccine that is in preclinical stage (WHO). Inactivated vaccine candidate (NCT04456595) developed by Sinovac Biotech Ltd in China, is currently in phase III clinical trials.54

Viral Vector Based Vaccines

Viral vector-based vaccines use either replicating or non-replicating viruses (Figure 4) to induce the human immune response. It represent the biotechnological evolution of inactivated and attenuated vaccines, which are viral backbones devoid of replication machinery and used as a vehicle to deliver in vivo and express antigens derived from target pathogens. The viral- based vaccine has ability 45,47,48 to induce strong T-cell responses without the need forany adju- 55,56 vants. One of the drawbacks of viral vector vaccines is that it requires multiple immunizations to achieve the level of immunogenicity and thus protection against the virus but may also lead to ahost response against the structural viral protein, thus limiting the efficacy of immunization (called a neutralizing antibody).55 This limitation is overcome by using aheterologous prime boost regi- 49,50 57 men that is introduced in several clinical trials.

Heterologous prime-boost vaccine regimens means to deliver the same or similar antigens through different vaccine types, the first to prime and the second to boost the immune system.

Currently there are eight viral-based vaccine candidates

is in clinical trials (Table 1). Ad5-nCoV (NCT04341389) is a viral vector-based vaccine candidate that has been in Phase III of clinical trials. The replicating viral vaccine candidates are based ona vaccine strain derived from the human pathogen. It is important to consider this very specifically, if the potential recipient of the vaccine has pre-existing exposure and presumed subsequent immunity against the virus. Pre-existing antibodies can impair the ability of vaccine to elicit the immune response required for protection. Non-replication viral vector vaccine candidates are mostly based on adenovirus (Ad5) and express the S protein or receptor binding domain (RBD) of SARS-CoV-2.

Safety Measures for Coronavirus Disease-2019 Vaccines

COVID-19 cases do not seem to be declining and the ebb and flow of cases are mostly driven by human attitude towards physical distancing and protective measures. All eyes remain on pharmaceutical companies and research institute involved in vaccine development. Traditionally new vaccine development and approval requires 10-12-years, and there are enormous pressures and challenges to minimize that time frame. The safety of a vaccine is generally determined by the choice of adjuvant, nature of vaccine platform, mode and route of vaccine administration, status of pre-existing vaccine immunity and age of vaccines. In the particular case of SARS-CoV-2, the individual is either symptomatic or asymptomatic, and COVID-19 vaccines are developed with a goal of mass immunization or protection and not addressing symptomatology. Any loophole in the lack of safety considerations may support the mobilization of anti-vaccination movements or messaging, which would jeopardize the effect of achieving mass immunization.

As other respiratory viral infections, vaccine strategies for COVID-19 require additional safety vigilance. There is a possibility of antibody-dependent enhancement (ADE) of disease if an insufficient immune response is mounted in a situation of the unresolving, active, and serious disease. Over production of proinflammatory cytokines in lung immunopathology that cause additional damage when vaccines cannot stop SARS-CoV-2 pathology early in the process. In this regard, COVID-19 vaccine trials were initially conducted in healthy adults with age of 55-years or younger and later stage trial includes seniors.

Discussion

The COVID-19 pandemic emerged as wide spread SARS-CoV-2 infection in December 2019, according to most estimates. Several challenges exist in the development of vaccines against COVID-19 as the novel SARS-CoV-2 is undergoing several genomic changes, even as of the time of this writing. Developed vaccine candidates include approaches with inactivated viruses, live attenuated viruses, virus nucleic acid-based vaccine, and protein subunit vaccines. All are in different clinical phases. Moderna’s vaccine; the inactivated virus vaccine being developed by Sinopharm, the Wuhan institute of Biological products; and Sinovac Biotech are on the market as of this writing. According to WHO Global Advisory Committee, AstraZeneca (adenovirus vector vaccine) is that, it is safe and effective for protecting people from the serious risk of COVID-19. The ideal vaccine candidate for COVID-19 should be safe, effective and have a good immunogenicity profile among all age groups and be safe for including pregnant women and immuno compromised individuals. For ease of success, the effective vaccine should generate humoral and cellular immunity with a single dose of vaccination. Generating effective vaccines has required initiating a large number of official projects by the WHO, various companies, universities and laboratories. Approval of the first COVID-19 vaccine in increased the enthusiasm and possibilities for developing second and third generation vaccine approaches and candidates for 60,61 approval. COVID-19 eradication programme is time taking after vaccination, as the various mutant strains are available now e.g. South Africa variant (501Y.V2), which show different symptoms in infected humans than previous strains.

Conclusion And Future Guideance

Various companies and institutes are in the position to offer several treatment strategies against the COVID-19 pandemic. Tireless and ongoing scientific efforts have led to the development of 242 COVID-19 vaccines candidates. We are in the early stage of SARS- CoV-2 identification and adequate vaccine preparation, manufacturing, and distribution to populations. Based on previous studies, it may be inferred that the COVID-19 vaccines approved thus far provide acceptable (if not higher than previously experienced) immunity and protection via a durable neutralizing antibody and a lasting T-cell response.

Various vaccine strategies are being pursued now with attendant advantages and disadvantages. According to the WHO, the vaccine must be of high efficacy and producing only mild or transient adverse effects an acceptable and benefit-risk contour. Various vaccine platforms depend upon adjuvants for inducing the T-cell response. Live attenuated vaccines are not recommended, as a delivery vector increases the risk of pathogen conversion to actual viral infection. Viral vectored vaccines are effective in inducing T-cell response but sometimes their efficiency is affected by cross-reactive immunity (antibodies that neutralize the antibodies mobilized by the vaccine). Nucleic acid based vaccines are also a successful candidate but they need specific delivery vehicles or adjuvants. In many countries, emergence of new cases and transmis- 58,59 sion of COVID-19 diseases is significantly declining whereas in some countries the number of new cases increase day-by-day. Approved vaccines must be suitable for persons of all ages, pregnant mother, lactating mother as well as immunocompromised person. To meet the need or demand of less wealthy countries, the funding committed through the COVAX program (COVID-19 Vaccine Global Access) and coalition for epidemic preparedness innovation (CEPI) unite rich and low- income countries to achieve rapid and fair access to the most effective COVID-19 vaccines. Since vaccines alone cannot combat the pandemic and assure its elimination, prevention strategies and social strategies will remain needed and such strategies will also help us to face future pandemics.

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