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A comprehensive overview of vaccines developed for pandemic viral pathogens over the past two Cite this: RSC Adv.,2021,11, 20006 decades including those in clinical trials for the current novel SARS-CoV-2

Kannan Damodharan, ab Gandarvakottai Senthilkumar Arumugam,b Suresh Ganesan,b Mukesh Doble *b and Sathiah Thennarasua

The unprecedented coronavirus disease 2019 (COVID-19) is triggered by a novel strain of coronavirus namely, Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2). Researchers are working around the clock to control this pandemic and consequent waves of viral reproduction, through repurposing existing drugs as well as designing new vaccines. Several countries have hastened vaccine design and clinical trials to quickly address this outbreak. Currently, more than 250 aspirants against SARS-CoV-2 are in progress, including mRNA- replicating or non-replicating viral vectored-, DNA-, autologous dendritic cell-based-, and inactivated virus- Creative Commons Attribution-NonCommercial 3.0 Unported Licence. vaccines. Vaccines work by prompting effector mechanisms such as cells/molecules, which target quickly replicating pathogens and neutralize their toxic constituents. Vaccine-stimulated immune effectors include adjuvant, affinity, avidity, affinity maturation, antibodies, antigen-presenting cells, B lymphocytes, carrier protein, Received 13th November 2020 CD4+ T-helper cells. In this review, we describe updated information on the various vaccines available over the Accepted 14th January 2021 last two decades, along with recent progress in the ongoing battle developing 63 diverse vaccines against SARS- DOI: 10.1039/d0ra09668g CoV-2. The inspiration of our effort is to convey the current investigation focus on registered clinical trials (as of rsc.li/rsc-advances January 08, 2021) that satisfy the safety and efficacy criteria of international wide vaccine development.

This article is licensed under a aDepartment of Organic and Bioorganic Chemistry, CSIR-Central Leather Research bBioengineering and Drug Design Lab, Department of Biotechnology, Indian Institute Institute (CLRI), Chennai, 600020, India of Technology Madras (IITM), Chennai, 600032, India. E-mail: mukesh.doble0@ gmail.com; [email protected] Open Access Article. Published on 08 June 2021. Downloaded 9/28/2021 7:21:02 PM.

Kannan completed his B.Sc. Senthilkumar obtained chemistry degree at A. V. C. his M.Sc. chemistry at Bhar- College, Mayiladuthurai, aﬃli- athidasan University, where he ated to Bharathidasan Univer- was involved in mechanistic sity, and M.Sc. in chemical studies of anticancer drugs. He sciences at Pondicherry Univer- then explored new drug sity, India. He obtained his PhD discovery and development from (organic chemistry) at the marine and medicinal plants, University of Madras, India. and their synthesis which is been Later, he took a research asso- developed at IIT Madras, IISc ciate position at the Department Bangalore and IIT Kanpur. He of Biotechnology, IIT Madras, developed variegated drug then moved to Taiwan for candidates at IIT Madras, such research at Tamkang University, Taiwan. Then he was employed as phosphate binder resin, sevcar (two patents); and tolvaptan, as a SERB-post-doctoral fellow at the CSIR-Central Leather hyponatremia and cystagon; and drugs from Terminalia arjuna. Research Institute, Chennai, India. He has synthesized substituted He then engaged in the peptidomimetic domain for antitumor alkynylated hybrid molecules and utilized them for NIR and EL screening at IISc Bangalore. Then back at IIT Madras worked on applications; and liquid crystalline-, steroidal-based materials for transitmycin, which is in phase-II pre-clinical trials. He has also sensor and biomedical applications; he also worked on the char- discovered new blood, breast, and liver cancer drugs, and diabetic acterization of natural product transitmycin. treatments. Recently, he also discovered, arjunetin, that is a better candidate for COVID-19 treatment than FDA approved drugs.

Introduction Chemically, adjuvants are a highly heterogeneous group of compounds (including Al salts). One of the most successful therapeutic strategies to prevent or Antibiotics. Used in lower amounts during the develop- control various diseases is by “vaccination” protocol.1,2 Millions ment phase, to circumvent bacterial infection during tissue of lives have been saved because of vaccinations, which cover culture cells where the viruses are grown. MMR (measles, a number of diseases including certain types of cancer, HIV and mumps, rubella) and IPV (inactivated polio vaccine) associ- many viral infections.3 Vaccination was initially accomplished ated vaccines have a minimum amount (<25 mg) of neomycin by Edward Jenner, who was the pioneer for smallpox in the late for each dose. 18th century.4 In the 1980s, the development of vaccines to ght The MMR vaccine was developed by Maurice Hilleman in against pathogenic microorganisms was tentatively introduced. 1971. Mumps, like measles infections, are caused by an RNA Vaccines are now employed to improve and increase the based virus from the Paramyxoviridae family. Moreover, protection capability (immunity) of the body to ght severe measles and mumps belong to the genus Rubulavirus, it is infection and disease,5 and moreover, primarily intend to make a human disease with no animal reservoirs. Generally, the MMR ff immunity stronger and reduce resistivity of diseases by vaccine exhibits side e ects of a painful arm from the shot, reducing the reproduction of target pathogens. The majority of minor rashes, generally in teen/adult women who have no vaccines actively exist in the immune system, since anti-bodies earlier immunity; then the rubella vaccine component can ff are constantly generated in the body to sustain a healthy result in joint and tendon sti ness. This vaccine is also asso- immunity system.6,7 ciated with the minor threat of seizures/jerking instigated by fever, but is not connected with any enduring effects. The threat of febrile seizures increases as infants get older, hence this General components of vaccines vaccine is recommended at a young age. Some people may A vaccine consists of an antigen, stabilizer, adjuvant, antibiotic, experience cheek/neck inammation, impermanent low 8

Creative Commons Attribution-NonCommercial 3.0 Unported Licence. preservative, and chemical reagents such as formaldehyde. The platelet counts that generally do not require treatment and are advantages and disadvantages of vaccinations9a are listed in also not life threatening.9b Table 1. In 1955, Jonas Salk initiated an inactivated polio vaccine Antigen. The component matching the structural array of (IPV), aer that, Albert Sabin further developed the live, OPV. disease-oriented organisms, wherein, they are identied by the Even though poliovirus has three serotypes, both vaccines are immune system as ‘foreign’ and cause an active immune trivalent and oﬀer good resistivity against poliomyelitis, response. a limited number of countries have continuously provided IPV. Stabilizer. This module is employed to assist the vaccine by Sabin’s OPV vaccine is underused in most countries due to sustaining its eﬃciency during storage. Instability of the minimising oral management, but it advances immunity in the This article is licensed under a vaccine can lead to reduced antigenicity and decreased infec- intestine, which is capable of spreading to others, and is asso- tivity of live attenuated vaccine (LAV). Magnesium chloride ciated with lower cost.9c

(MgCl2) for oral polio vaccine (OPV), magnesium sulfate Preservatives. They are added in multi-dose vaccines, which

Open Access Article. Published on 08 June 2021. Downloaded 9/28/2021 7:21:02 PM. (MgSO4) in measles vaccines, and lactose and gelatin associated can be used to control bacterial and fungal growth, including with sorbitol, are current representatives of stabilizing factors. thiomersal (sodium(2-carboxylatophenyl)sulfanyl-ethyl Adjuvant. They are responsible for enhancing the eﬃcacy of mercury), formaldehyde, or phenolic derivatives. In fact, form- the vaccine by motivating the generation of antibodies. aldehyde is responsible for inactivating the viruses (e.g. IPV) and removing toxicity in bacterial strains, including the toxin employed in diphtheria and tetanus vaccines. Doble is a professor (Emeritus) in the Department of Biotechnology at the Indian Institute of Tech- Types of vaccines nology Madras (IITM). He Various kinds of vaccines are available and those which are worked for 23 years at Imperial administered to infants and adults can be classied (Fig. 1) as Chemical Industries and General follows: Electric Technology centers. His Live-attenuated. areas of interest are biomate- Inactivated. rials, drug design, bioreactors Toxoid. and bioremediation. He holds B. Conjugate. Tech and M. Tech degrees in Subunit. chemical engineering (IITM), and Live attenuated vaccines. These vaccines are adapted from a PhD (University of Aston, Bir- the existing bacteria or virus, they have been weakened, and mingham, UK) and has postdoctoral experience (University of thus will not result in serious disease in people with strong Cambridge, UK, and Texas A & M, USA). He has authored 320 immunity. LAV vaccines are more similar to the actual infec- technical papers, 10 books, and led 15 patents and is a director of tion. A few representative examples are the MMR and varicella two startup biotechnology companies. (chickenpox) vaccines. Albeit, it is eﬃcient, but not everyone

Table 1 Advantages and disadvantages of vaccines

Advantages Disadvantages

Protection of inhabitants against disease Uncertainty about complete protection Preventing epidemic and pandemic diseases May have some possible side eﬀects Prevents diseases spreading to others Requires NHS/individual outlay Avoids large cost for the treatment of infected patients Injections are not pleasant/more immune booster injections are inconvenient Creative Commons Attribution-NonCommercial 3.0 Unported Licence.

Fig. 1 Pictorial representation of vaccine types.

can be administered these vaccines, including children and germ,theyhavelesssideeﬀects. The DTaP vaccine-pertussis

This article is licensed under a patients undergoing chemotherapy as their immune system is (whooping cough) module is a paradigm of subunit vaccines. too weak. Inactivated vaccines. These vaccines are made from inactivated or dead organisms. The polio vaccine is an example of an Common characteristics of vaccines Open Access Article. Published on 08 June 2021. Downloaded 9/28/2021 7:21:02 PM. inactivated vaccine, which generates an immune response Live attenuated vaccines are typically grown in animal cell lines ff through various routes di erent to the live attenuated vaccine. under poor development conditions. The development of an It requires a higher dosage to increase and/or sustain immunity. inactivated vaccine involves use of thermal or chemical Toxoid vaccines. This vaccine prevents the disease resulting methods in the beginning, and its mode of action involved in from the toxins released by a virus into the body. Since the toxic conferring immunity is not fully known. However, the live substances administered are weak they are unable to cause the attenuated or execution of entire organism-supported vaccines illness, while the immune system which encounters this toxoid have shown a lot of success in the control and inhibition of vaccine, becomes able to repel the natural toxin. The DTaP severe transmittable diseases in human, including animal vaccine for diphtheria and tetanus toxoids falls into this infectious cattle plague, classic swine fever, equine infectious category. anaemia, measles, mumps, polio, rubella, smallpox, and so on. Conjugate vaccines. They defend the system against In recent times, the use of LAVs, subunit and peptide based ff di erent kinds of bacteria which have antigens that are surface vaccines have become possible because of progressive tech- coated with polysaccharide units. It is obvious, that this sugar nologies in molecular biology. LAVs are based on the mecha- coated unit masks the antigen. These vaccines append (or nism of action associated with the immune response. conjugate) themselves to the polysaccharide units on the anti- Inactivated vaccines, based on antibodies have been mostly  gens. Haemophilus in uenzae type B (Hib) vaccine is an example used to prevent and manage microbial infectious diseases. LAVs of the conjugate type. introduce stronger cell immune responses that are decisive to Subunit vaccines. These vaccines are made up of simple remove several intracellular viral pathogens. However, these fractions of the virus/bacteria or subunits, rather than the pathogens sometimes bypass inactivated vaccines9d by mutating complete germ. Since the subunit vaccines have an essential peripheral antigens. On the other hand, subunit and peptide antigen only and are not the molecular array constituting the based vaccines are less efficient in drawing a strong CD8+ immune response.

Progressive vaccination involves the use of non-viral CD8+ T cells do not inhibit infection but work to minimize, distributed nucleic acid-supported vaccines, which imitate regulate, and remove intracellular pathogens through: live microorganism infection- or immunization. This leads to (a) direct destruction of infected cells (discharge of perforin – T-helper cellular immune responses.Inaddition,thisvaccine a pore forming cytolytic protein present in cytotoxic T development9e,f is harmless and consumes less. It does not lymphocytes (CTLs) and natural killer (NK) cells), granzyme require extreme infectious organisms, so is safe from infec- (serine proteases delivered through cytoplasmic granules inside tivity through live transmittable agents and the discharge of cytotoxic T cells and NK cells); harmful pathogenic organisms. These vaccines ll the gap (b) destroy infected cells with antimicrobial cytokine release. between a virus outbreak and design of a desirable vaccine, CD4+ T cells do not inhibit infection, however they contribute wherein they are classied as DNA/RNA based pentose-carbon in the minimization, regulation, and renement of extra- and sugar motif. The remarkable growth of RNA-associated intra-cellular pathogens with their control and cytokine- vaccines resulted in the growth of mRNA based vaccines. It development capabilities. The main examples of CD4+ Tcellsare: is quite signicant to note that mRNA vaccines provide many (a) Follicular T-helper (T) cells yielding predominantly valuable benets when compared to viral vectored- and DNA interleukin (IL)-21 and providing assistance to B-cells; vaccines.10 (b) T-helper 1 (Th1) effector cells yield interferon (IFN)-g, (TNF)-a/TNF-b, IL-2, and provide a major role in controlling intracellular pathogens e.g., viruses and bacteria such as M. Proceedings of vaccination against tuberculosis; viral diseases (c) Th2 effector cells generate IL-4, IL-5, IL-13, and impact extracellular pathogens such as bacteria and helminths; In 1970, to evade the prevalent spread of foot and mouth (d) Th9 effector cells generate IL-9 and also defend against disease, scientists discovered a vaccine using a single protein extracellular pathogens; from the virus. Despite their achievements in virology, in ff Creative Commons Attribution-NonCommercial 3.0 Unported Licence. (e) Th17 e ector cells generate IL-17, IL-22, and IL-26 and particular vaccine studies and their development, the lack of participate in mucosal protection (for example against, S. understanding of immunological mechanisms of action during pneumoniae, B. pertussis, M. tuberculosis). induced defensive immunity, has prevented the use of existing vaccines during global pandemic outbreaks of related diseases ff with similar viral pathogens. The immune system protects Main e ectors of vaccine responses against various pathogens, including distinctive units of T- Vaccines prevent disease by inducing effector modes of action helper cells that are useful to protect against various unusual in cells/molecules to reduce the development of pathogens and

pathogens. Besides, the follicular T-helper cells (TFH cells) deactivate their toxic effects. Vaccine-stimulating immune This article is licensed under a generate interleukins (ILs) and support the partition of B cells effectors are resourceful antibodies generated by B lympho- (they are lymphocytes, and take part in the humoral immune cytes’ ability to interact to a particular toxin/pathogen. A response) and generation of Memory B cells. Furthermore, pictographic representation of vaccine immunological function  + + Open Access Article. Published on 08 June 2021. Downloaded 9/28/2021 7:21:02 PM. Memory T cells can be sub classi ed as CD4 /CD8 T cells is shown in Fig. 2. (Cluster of Differentiation) and their functionalities are (a) Isotype switching. Control of immunoglobulin (Ig) expres- central memory and (b) effectors memory, which provide sion and production from IgM yielding IgG, IgA, or IgE that various responses upon vaccination against different patho- ensues through B-cell differentiation by DNA recombination. gens.11 Different vaccines attempted for identical pathogens Marginal zone. The zone between the spleen’s red pulp and depend on the perceptions of the scientist,12 many healthcare white pulp is known as marginal zone. Its main function is to professionals do not pay sufficient attention to vaccines, which catch particulate antigens from the circulation and distribute may result in uncertainty in their efficacy, side effects and them to lymphocytes. toxicity. Table 2 lists the various vaccines discovered that are Pattern recognition receptors. These germline-encoded available in the current market for protection against viral receptors sense the existence of infection through the identi- infections. They are listed on the basis of various factors,13,14 cation of pathogenic microbe molecular arrays, and stimulate including the apparent protection level, plausible mechanism innate immune responses. of action, possibility of usage for other diseases.15,16 Regulatory T cells-t. T cells secrete cytokines (IL-10, trans- forming growth factor [TGF]-b/surface markers) and react to reduce immune system response through different modes of Mode of action stimulated by vaccines action, this sustains immune homeostasis and tolerance to Normally antibodies prevent/minimize infections from extra- self-antigens. cellular pathogens: Resident memory T cells. Effector memory T cells exist in (a) use enzymatic active sites to fuse to toxins to break their particular tissues (such as the lungs, gut, and skin) and are an diffusion; instant and early line of protection against various viral and (b) prophylactic action preventing viral replication; bacterial pathogens. (c) facilitate opsonophagocytosis of extracellular bacteria; Somatic hypermutation. This is a process which intercalates (d) inducing the complement cascade. unsystematic mutations in the B-cell receptor region (i.e.,

Table 2 The various antiviral vaccines available in the last two decades, and their characteristics

Characteristic vaccines

S. Treatment for other Year of no. Generic name Trade name Type Mode of action diseases approval Ref.

1 AJ vaccines Picovax IPV vaccine, Inactivated Polio IPV provides serum Diphtheria, whooping 2019 17 Danish Medicines Vaccine (IPV) immunity to each cough, tuberculosis, Agency poliovirus (three types) tetanus, polio and and defence against any bladder cancer ensuing paralysis causative disease (poliomyelitis). The mucosal immunity level in the intestine is less than that aﬀorded by OPV, this diﬀerence may slightly show in the pharyngeal mucosal lining. Prevents poliovirus in the nervous system; immunostimulant 2 Grippol plus Quadrivalent AbbVie Polymer supported Vaccine primes To treat inuenza virus 2018 18 inactivated inuenza advanced meticulous infection (A/H1N1 + A/ vaccine 3-valent, egg anti-inuenza immunity H3N2)

Creative Commons Attribution-NonCommercial 3.0 Unported Licence. derived adjuvanted formation; inuenza vaccine, immunostimulant polyoxidonium as a distinct adjuvant 3 Ys-On-001 Yivyka polyinosinic- Cancer vaccines anti- B-cell stimulant, Cancer vaccines 2017 19 polycystidylic acid/ neoplastics cytokines stimulant, pancreatic cancer inactivated rabies virus dendritic cell stimulant, Yisheng Biopharma immune-modulator, macrophage modulator, natural cell stimulant,

This article is licensed under a regulatory T lymphocyte inhibitor, Th1 cell stimulant 4 Adimmune’s Adimu-S (QIS)BioB2B Monovalent vaccine, Immunostimulants; Inuenza A (H1N1) 2017 20  Open Access Article. Published on 08 June 2021. Downloaded 9/28/2021 7:21:02 PM. quadrivalent u vaccine Taiwan egg-based inactivated inactivated virus from vaccine during (4142) split virus, inuenza chick embryo culture pregnancy H1N1 vaccine split virus 5 Quadrivalent inuenza Vaxigrip Tetra QIVSano Split inuenza virus Induces the humeral Potent immunization 2017 21 vaccine (J0&BB02) Pasteur vaccine antibodies against against the four hemagglutinins inuenza virus strains (A inhibition (HAI) within and B types have two 2–3 weeks; antibodies each) neutralize the inuenza viruses 6 NBP-608 SKY Zoster Attenuated zoster-, Inducing both humoral Varicella-zoster virus 2017 22 varicella-type vaccine and cellular immune (VZV), a human response, which creates neurotropic alpha- an IgG humoral immune herpes-virus. Major response; varicella- infection causes zoster specically varicella (chickenpox) activate CD4+ T-helper and CD8+ T-lymphocyte cells 7 HBV-ISS (Dynavax) Heplisav-B Hepatitis B virus used Immune-stimulatory Treatment of HBV-, HIV 2017 23 for vaccine development DNA sequence (ISS) ISS- viruses 1018, adjuvant proceeds TLR-9 agonist, which is used for potential prevention and treatment of HIV infection

Table 2 (Contd.)

Characteristic vaccines

S. Treatment for other Year of no. Generic name Trade name Type Mode of action diseases approval Ref.

8 GSK-1437173A Shingrix GSK Non-live, recombinant Antigen IgE and adjuvant To prevent herpes zoster 2017 24 subunit vaccine; system AS01B develop (HZ) infection varicella vaccine herpes VZV-specic immune zoster (Hz/su) response in a weakening 2q4vaccine candidates immune system. Generates a long-term immune response, Shingrix helps to address age-related decline in shingles immunity 9 DTPa-hepB-IPV-Hib EasySix, Hexaxim 6 in 1 combination The body produces its Diphtheria, DTP, 2017 25 Panacea Biotech Infanrix hexa whole cell own antibodies to Hepatitis B, Hib, IPV, pertussis antigen protect against bacteria Pertussis, Polio, Tetanus and viruses causing vaccine diﬀerent infections 10 Ad5-EBOVJ07BX02 ErveboBIB, CanSinoBIO Glycoprotein Recombinant To treat Ebola virus 2017 26 recombinant adenovirus replication decient type 5 Ebola virus human Ad5 vector vaccine stimulating immune responses and

Creative Commons Attribution-NonCommercial 3.0 Unported Licence. defending against the Ebola virus 11 Tetravalent inactivated Vaxiu-4 Zydus Cadila Inuenza vaccine To increase immunity by Treating inuenza 2017 27 inuenza vaccine (TIV) generating antibody viruses-H1N1, H3N2, proteins, which defend Type B (Brisbane and against infection caused Phuket) by the virus present in the vaccine 12 Flu Vac Qs 2019–20 (4 Yr Flucelvax Quadrivalent Cell based u vaccines Vaccine motivates the To prevent inuenza A 2016 28 Up) CD,BL-125408 Seqirus, Inc body to produce its own and B viruses

This article is licensed under a immunity (antibodies) against the virus 13 Quadrivalent inuenza Vaxigrip TetraSano Inactivated inuenza To enhance the To protect against 2016 29 vaccine (QIV) (GQM-10) vaccine (split version) protection from inuenza (u) viruses

Open Access Article. Published on 08 June 2021. Downloaded 9/28/2021 7:21:02 PM. circulating inuenza B viruses 14 Live attenuated FluMist Quadrivalent Attenuated virus LAIVs induce T cell To prevent common u; 2016 30 inuenza vaccine (LAIV) Inuenza Tetra- antibody-reactions inuenza A-(H1N1), J07BB03 Medimmune against the surface (H3N2), and B-viruses protein of HA and NA; LAIVs provide hetero- subtype protection in humans 15 Enterovirus type 71 Inlive SINOVAC Inactivated EV 71 virus Generate immune To prevent hand-foot- 2016 31 vaccine (Vero cells) antigen vaccine reactions against EV71 mouth disease (HFMD) virus caused by EV-71 16 Inactivated inuenza Cadiu-S CBL Inactivated vaccine To develop immunity To prevent inuenza 2016 32 vaccine Biologicals Pvt. Ltd against the disease by and protect against its forming antibodies eﬀects 17 Inactivated quadrivalent Auria Quad 2020 Inuenza quadrivalent Against inuenza-A and To prevent inuenza A 2016 33 inuenza vaccine (split Seqiruspty Ltd vaccine 2020 inuenza-B type viruses and B viruses version) 18 Riv-4 (RIV4) Flublok-QSono Pasteur Quadrivalent Humoral immune To prevent inuenza A 2016 34 recombinant inuenza response measured by (H1N1) and B (H3N2) vaccine hemagglutination inhibition antibodies 19 Gam Evac Combi Combined Vector Based Heterologous VSV and Heterologous prime- To prevent Ebola viral 2015 35 Vaccine adenovirus type-5 boost vaccine humoral disease (EVD) vectored Ebola virus immune response, cell facilitated immune response to Ebola

Table 2 (Contd.)

Characteristic vaccines

S. Treatment for other Year of no. Generic name Trade name Type Mode of action diseases approval Ref.

20 In32 Activated Sabin Ai Bi Wei IMB China Inactivated Poliomyelitis Inactivated vaccines To prevent polio in new 2015 36 polio vaccine (IPV) oﬀer immunity by born babies delivering an inactivated antigen. This vaccine cannot cause disease, thus, it may be administered to an immuno-compromised host 21 Rotavirus Orv-116E ROTAVAC 5D Vero cells Rotavirus vaccine live Rotarix (vaccine To prevent rotavirus 2015 37 Derived Bharath Biotech attenuated monovalent prevents rotavirus gastroenteritis vaccine infectivity) reproduces in the small intestine and induces immunity; the particular mechanistic action of immunology by rotarix against rotavirus gastroenteritis is unknown

Creative Commons Attribution-NonCommercial 3.0 Unported Licence. 22 NBP-607-QIV SKY cell u Quadrivalent Cell cultured Immunity for inuenza To treat inuenza virus 2015 38 SK Bioscience quadrivalent inactivated viruses A and B infections subunit inuenza subtypes. Sero- vaccine protection is generally obtained within three weeks 23 GC-3110A, GC-3110B GCu Quad GC Pharma Quadrivalent inuenza Hemagglutination To treat inuenza virus 2015 39 virus vaccine inhibition antibody infections response 24 Chimerivax-dengue Dengvaxia Sano Live attenuated Antibody dependent To prevent Dengue 2015 40

This article is licensed under a (CYD-TDV) Pasteur tetravalent chimeric improvement virus-1, 2, 3 and 4 fever vaccine in humans 25 H5N1 inuenza (avian Audenz Vn-101 Sonali Egg based H5N1 Induces immunity To treat inuenza virus 2014 41 u) vaccine (Rx) Pasteur GSK vaccines, inactivated (antibodies), which act

Open Access Article. Published on 08 June 2021. Downloaded 9/28/2021 7:21:02 PM. inuenza virus vaccine against viral HA in the vaccine, aer interrupting viral attachment to human respiratory cells, provides immunity to inuenza A virus subtype H5N1 26 9-Valent HPV vaccine [9v GARDASIL 9 Recombinant virus Prevent HPV through Prevention of cervical, 2014 42 HPV] humoral immune vuvar, vaginal, anal, or responses induced by pharyngeal, head and the vaccine neck cancer; by preventing papilloma virus (HPV) infection 27 Cell cultured-H5N1 GSK Emulsion cell culture Antibody titer calculated To prevent inuenza A 2014 43 vaccine KD-295 inuenza HA vaccine through virus H5N1 (Prototype) hemagglutination inhibition (HI): high- titer virus generation led to suspension of growth of MDCK (Madin–Darby Canine Kidney) and Vero cells in a serum-free distribution

Table 2 (Contd.)

Characteristic vaccines

S. Treatment for other Year of no. Generic name Trade name Type Mode of action diseases approval Ref.

28 Live modied vaccine IMVANEX/IMVAMUNE Non-replicating small Non-replicating and To prevent smallpox 2013 44 virus Ankara Ankara- JYNNEOS pox vaccine capable of generating Bavarian Nordic (MVA- humoral and cellular BN)-J07BX immune response to orthopox-viruses 29 Japanese encephalitis JENVAC Bharath Biotech Inactivated Vero cell- JENVAC is suﬃcient to To protect against 2013 45 vaccine BBIL/JEV derived viral vaccine elicit an immune Japanese encephalitis response virus (JEV) 30 Fluzone quadrivalent BL FLUZONE Quadrivalent Inactivated quadrivalent Stimulates the Prevents inuenza 2013 46 103914/J07B B Sano Pasteur Inc. inuenza virus vaccine production of specic diseases, type A and B type A and type B (split antibodies version) 31 FLU-Q-QIV u laval FluLaval™ Quadrivalent Inuenza virus vaccine Vaccines which improve Prevents inuenza 2013 47 quadrivalent GSK- Glaxo Smith Kline (GSK) immunity against the diseases, type A and B 2282511A viral pathogen leading to inuenza: they induce the generation of antibodies 32 DTa-IPV-HePB- Hexyon, Infanrix, Vaxelis Hexavalent vaccine Booster vaccination To treat DTaP, hepatitis 2013 48 HibHexavalent vaccine6- B, polio, haemophilus

Creative Commons Attribution-NonCommercial 3.0 Unported Licence. in-1 vaccine J07CA09 inuenza diseases 33 GSK-2282512a BL Fluarix Quadrivalent Inactivated inuenza Increases immunity for Prevents disease 2012 49 125127 (FLU Q-QIV) Glaxo Smith vaccine, quadrivalent, treatment of disease triggered by inuenza A Kline Biologicals seasonal originating from subtype and type B inuenza-A subtype and viruses type B viruses 34 ChimeriVax™-JE IMOJEV Sano Live attenuated IMOJEV is highly To prevent yellow fever 2012 50 Japanese encephalitis immunogenic and able virus vaccine (JEV), to induce continuing monovalent immunity through both

This article is licensed under a preclinical and clinical trials 35 Prepandemic inuenza Vepacel Inactivated u strain Overall the vaccine Protect against inuenza 2012 51 vaccine (H5N1) J07BB01 known as A/Vietnam/ primes the immune H5N1 (bird u)

Open Access Article. Published on 08 June 2021. Downloaded 9/28/2021 7:21:02 PM. 1203/2004 (H5N1) whole system virion, derived from inactivated Vero cells 36 Medi-3250STN: 125020 FLUMIST Quadrivalent Inuenza vaccine, live To provide immunity Protects against 2012 52 Med-Immune attenuated inuenza against inuenza virus inuenza vaccine (LAIV) caused by subtypes A and B 37 Hepatitis E hecolin Hecolin Xiamen Innovax Non enveloped virus HEV 239 treatment Fights against hepatitis- 2012 53 (HEV-239) Biotech with positive sense HEV induces a strong anti- E virus vaccine, a recombinant HEG IgG response, vaccine through early antibody mobilisation 38 Measles/rubella vaccine German measles Live attenuated Immunostimulant, Prevent MMR viruses 2011 54 (weakened) viruses produces antibodies (associated proteins ght and kill measles, mumps, and rubella (MMR) viruses 39 Human inactivated HNVAC (Bharath Inactivated Inuenza A Active immunization Activity against 2010 55 inuenza vaccine Biotech) virus vaccine (H1N1). agent, which acts inuenza A (H1N1) 2009 vaccine. Cell culture derived against the inuenza A Pandemic inuenza vaccine (H1N1) 2009 virus strain A/California/7/ 2009/nyMC X-179A

Table 2 (Contd.)

Characteristic vaccines

S. Treatment for other Year of no. Generic name Trade name Type Mode of action diseases approval Ref.

40 Inuenza A virus 2009 Inuenza A Monovalent vaccine, Active immunization for To prevent inuenza A 2010 56 (H1N1), monovalent (H1N1), Sonali Pasteur adjuvant preventing disease viral disease vaccine caused by inuenza virus A (H5N1) 41 Quadrivalent u vaccine FLUCELVAX Cellular inuenza Active immunization for To defend against four 2010 57 vaccine preventing inuenza diﬀerent strains of subtypes A and B inuenza for both causative diseases subtypes A and B 42 Inuenza vaccine (whole Vaxiu-S Fluzone Zydus Inactivated inuenza Active immunization for To assist in protection 2010 58 virion). Inactivated Cadila Healthcare Ltd vaccine (NZ) preventing Vaxiu-X against inuenza combination 43 H1N1 pandemic Celvapan Baxter Whole virion in Vero Motivates the immune To protect against the 2009 59 inuenza vaccine H5N1 International cell-based inuenza system to produce inuenza strains of strain of the u virus A/ vaccine, inactivated antibodies when H5N1 virus Vietnam/1203/2004Flu exposed to the virus strain/California/07/ 2009 (H1N1) virus 44 Inuenza A virus vaccine Fluval P-H5N1 Fluart innovative Fluval aﬀords active To prevent inuenza 2009 60 H5N1 Omninvest vaccine immunization against a (H5N1) four virus strains; two

Creative Commons Attribution-NonCommercial 3.0 Unported Licence. for inuenza A subtype, and two for B type 45 Non adjuvant inuenza Panenza Sano-Pasteur Non-adjuvanted Induces a high immune To prevent inuenza A 2009 61 A (H1N1) 2009 pandemic vaccine (antibody) response, (H5N1) monovalent vaccine. three weeks post- Inuenza vaccination hemagglutinin (HA) A/ California/07/2009 (H1N1) V-like virus 46 Monovalent, cell culture- Celtura MF-59 adjuvanted cell MF-59 induces a strong Induces an immune 2009 62

This article is licensed under a derived, inactivated cultured derivative A/ response in adults and response for protection subunit inuenza H1N1 pandemic substantially develops against inuenza virus vaccine. Produced from inuenza vaccine the response with A/California/07/2009 growth of HA-specic + Open Access Article. Published on 08 June 2021. Downloaded 9/28/2021 7:21:02 PM. (H1N1) with adjuvant T (CD4 , ICOS+, MF-59 CXCR5+, IL-21+) cells 47 Pandemic (H1N1) ASO3 Pandremix GSK Combination of H1N1 Enhances the natural To prevent inuenza A 2009 63 adjuvanted inuenza virus antigen and immunity of the body (H1N1), swine u viral vaccine adjuvant system of infections H1N1 48 Inuenza vaccine Focetria Surface antigen Vaccine acts by priming To protect against 2009 64 (H1N1) u strain from A/ (hemagglutinin and the immune system inuenza type A (H1N1) California/7/2009 neuraminidase) 2009 virus (H1N1) derived strain inactivated adjuvant NYMC-181 J07BB02 49 Cell culture-derived Grippol NeoSolvay Cell based adjuvanted Activates the endosomal To prevent inuenza 2009 65 adjuvanted inuenza pharmaceutical AbbVie inuenza vaccine receptor, which leads virus infections virus vaccine (Grippol non-specic activation TC of the surface TLRs, which induce the intracellular signals contributing to the antiviral mechanism 50 Inactivated H5N1 Pan-u (Sinovac Single shot vaccine Body reacts by creating To prevent H5N1 2008 66 inuenza (avian u) Biotech) against H1N1 inuenza antibodies pandemic inuenza vaccine A/Vietnam/1194/ 2003/(H5N1) RG

Table 2 (Contd.)

Characteristic vaccines

S. Treatment for other Year of no. Generic name Trade name Type Mode of action diseases approval Ref.

51 Pandemic inuenza Panvax H1N1 vaccine Split virion inactivated Panvax, is an inactive Inuenza virus (H1N1), 2008 67 vaccine vaccine viral part of H1N1, the swine u infections immune system responds by developing antibodies to the virus particle 52 Pre-pandemic inuenza Prepandrix GSK Split virion, inactivated, Potential immunization Inuenza (H5N1) virus, 2008 68 vaccine H5N1 (split adjuvanted; against inuenza A swine u infection virion, adjuvanted, hemagglutinin, antigen, subtype H5N1 virus inactivated) AS03-H5N1 adjuvanted vaccine A/Vietnam/1194/ 2004; or A/Indonesia/5/ 2005 GSK-1562902a 53 Inuenza vaccine Optau Flucelvax TETRA Inuenza virus surface Optau comprising Prevent inuenza viral 2008 69 (surface antigen, Novartis antigens, hemagglutinin diﬀerent strain surface infection inactivated, prepared in and neuraminidase regions of the u virus. cell cultures) J07BB02 subunit vaccines Vaccine causes immune system to recognize the unknown viral components and

Creative Commons Attribution-NonCommercial 3.0 Unported Licence. produce antibodies against them 54 Smallpox (vaccinia) Acam-2000 Sano The vaccine is made Possessing potent Prevention of smallpox 2007 70 vaccine ACAM2000 Pasteur Biologics Co. from a live virus, immunization against vaccinia smallpox 55 Inactivated quadrivalent Auria Seqirus Pty. Ltd. Quadrivalent split Immunity against 3 To stop infection caused 2007 71 inuenza vaccine (split virion, inuenza virus (type A (2) and type B (1)) by inuenza virus virion) hemagglutinin as the or 4 (type A (2) and type active ingredient. B (2)) microbial strains. Suitable for the annual

This article is licensed under a u season 56 H5N1 avian u vaccine, Fluzone Sano Pasteur Inactivated inuenza Provides protection To prevent infection 2007 72 avian inuenza or bird virus vaccine against the H5N1 caused by inuenza u, vaccine is derived inuenza virus virus

Open Access Article. Published on 08 June 2021. Downloaded 9/28/2021 7:21:02 PM. from A/Vietnam/1203/ stimulating the immune 2004 inuenza virus response 57 Adjuvanted H5N1 pre- Daronix, GSK Second generation Prepare the body’s Prevent common u 2007 73 pandemic vaccine pandemic vaccine immune system to disease prevent a u epidemic 58 Inuenza vaccine Optau Vaccine containing u Enhances the body’s To prevent infection 2007 74 surface antigen, surface antigen defence system, priming caused by inuenza inactivated, prepared in the immune system to virus cell culture: A/ make antibodies against California/7/2009 the u virus (H1N1) pdm09-like strain, A/Switzerland/ 9715293/2013 (H3N2)- like strain, B/Phuket/ 3073/2013-like strain 59 Birch pollen allergy Oralgen Birch Pollen Peptide based vaccine Suppression of allergic To prevent allergy 2007 75 vaccine ALK-Abello reactions aer immunization with fusion protein, which is caused by releasing the immune messenger interleukin-10 (IL-10), an autologous cytokine, functioning to decrease the overacting immune response

Table 2 (Contd.)

Characteristic vaccines

S. Treatment for other Year of no. Generic name Trade name Type Mode of action diseases approval Ref.

60 Inuenza vaccine, split Anu Sinovac Split virion, inactivated Body generates To prevent infection 2006 76 virion, inactivated immuno-reactions caused by inuenza hemagglutinin of A/ against inuenza virus virus California/7/2009 Hemagglutinin of A/ Victoria/210/2009 Hemagglutinin of B/ Brisbane/60/2008 61 Rec hepatitis B vaccine Supervax Hepatitis B vaccine, Active immunization of To prevent infection 2006 77 immunoglobulin (HBIG) hepatitis B vaccine against hepatitis B virus induces the immune system to create anti- HBs without an active infection risk 62 Antirabies vaccine RABIRIX Bharath Vero cell based rabies Inactivated virus vaccine To prevent infection 2006 78 Biotech vaccine (PVRV) boosts immunization against rabies virus against rabies 63 Live herpes zoster Zostavax Merck Live attenuated virus Enhancing VZV – Treatment for herpes 2006 79 vaccine vaccine specic immunity zoster/postherpetic against zoster neuralgia (PHN),

Creative Commons Attribution-NonCommercial 3.0 Unported Licence. a neuropathic pain 64 Rotavirus vaccine, live RotaTeq Bharath Live attenuated, oral, Active immunization for To protect against 2006 80 rotavirus 116E strain Biotech monovalent infants from the age of 6 rotavirus gastro-enteritis derived in Vero cells weeks disease in infants and young children 65 Human papillomavirus Gardasil, Cervarix Merck Protein subunit Body’s immune system To protect against either 2006 81 quadrivalent (type 6, 11, quadrivalent, identies the viral two or four or nine types 16, and 18) vaccine (HPV recombinant proteins in Gardasil, of HPV (cervical, vaginal vaccine) J07BM01 develops antibodies and vulvar in females) against them

This article is licensed under a 66 Rotavirus vaccine with ROTARIX Live, attenuated, oral Usually to develop Rotarix vaccine assists to 2005 82 ve strains of rotavirus, immunity against prevent this disease in from both human and rotavirus-based disease children animal sources

Open Access Article. Published on 08 June 2021. Downloaded 9/28/2021 7:21:02 PM. 67 Hepatitis B (r DNZ) Fendrix GSK Adjuvanted, absorbed, Vaccine works by Prevents hepatitis B 2005 83 vaccine, adjuvanted, recombinant DNA priming the immune virus infection absorbed J07BC01 technology system 68 MR vaccine freeze-dried, Mearubik, Mitsubishi Live vaccine for measles, Immune system induced To prevent rubella virus 2005 11 live, attenuated, Tanabe Pharma rubella to produce antibodies measles-rubella Corporation (proteins that ght and combined vaccine also kills the rubella virus) 69 Inactivated hepatitis A Bilive Sinovac Recombinant DNA Suboptimal immune Prevents hepatitis B viral 2005 84 and hepatitis B (rDNA) – technology response to the vaccine infection HAB adsorbed vaccine 70 Virosomal inuenza Invivac Solvay Adjuvant The virosome To treat inuenza 2004 85 vaccine, Invivac Pharmaceuticals mechanism remains inuenza vaccine complex; it is the transporter as well as an immune stimulant 71 Inuenza virus (live) Flumist Wild-type Disease-causing viruses Protects against 2003 86 (LAIV), inactivated has been attenuated and infection from inuenza inuenza vaccine (IIV) inactivated, using the viruses inuence of heat/ chemicals such as formaldehyde 72 Hepatitis A and B Vac Ambirix Vaccine based B-lymphocytes anti-HBs Immunization against 2003 87 DB10989, DB11627 antibodies hepatitis A and B viral infectivity

Fig. 2 General features of vaccine immunology.

immunoglobulin) at a particularly high rate throughout the (g) Can be produced on a huge scale; proliferation of B-cells. This mechanistic process occurs as an (h) Should be economical and easily available. eﬀect of the cytidine deaminase enzyme and results in antibody Herein we consider the COVID-19 pandemic, the main diversication. resolution of vaccination against SARS-CoV-2 are: T lymphocytes. Cells that mature in the thymus, and become (a) Inhibition of characteristic clinical symptoms so hospi-

Creative Commons Attribution-NonCommercial 3.0 Unported Licence. stimulated in the spleen or nodes if their T-cell receptors talization is avoided, and reduces severe infectivity; interact with an antigen marked with MHC molecules, and they (b) Prevention of disease spreading before the corresponding obtain supplementary co-stimulation indications motivating antibodies are produced (sero conversion) them to kill the infected cell (mainly CD8+ T cells)/secondary (c) Producing a strong neutralizing immune response able to (mainly CD4+ T cells) roles. link with the viral protein spike (S) that must prevent it from T-Independent B-cell responses. This B cell differentiation attaching to human cells. pathway is mostly triggered by polysaccharides, in the marginal From this perspective, the various immunological response zone and extra-follicular regions of the spleen or nodes. It effects which neutralize antibodies and CD8+ T cells are most provides a fast response (days), and generates transient (over signicant. This article is licensed under a months) low affinity antibodies without impacting immune The antibodies of anti-SARS-CoV-2 alert the host organism’s memory. immune response to the presence of the virus; such antibodies T-Dependent B-cell responses. This B cell differentiation are immunoglobulins, which are appropriately split into IgA,

Open Access Article. Published on 08 June 2021. Downloaded 9/28/2021 7:21:02 PM. occurs due to protein antgens which recruit T and B cells into IgM, IgG, and less frequently IgD. Prior serological antibody germinal centers of the spleen/nodes. It is slower (weeks), but model responses to viral infections have usually proven the provides enduring stimulation (years) with high affinity anti- subsequent sequence of these antibodies resulting from virus bodies formation and immune memory. infection: the antibodies of IgA are primary, which are followed Toll-like receptors. A cluster of 10 receptors (TLR1 to TLR10) by IgM, IgG-type continues at high levels for a longer time than existing at immune cell external regions, which identify path- the preceding ones (IgA and IgM). For certain viruses, some- ogens and trigger characteristic immunity. times the antigen (the virus itself) co-occurs with antibodies, The main target of immunization through vaccination is to particularly with the antibodies of primary IgA and IgM. inhibit specic infections and their unavoidable difficulties. Further, viruses have a “serological window,” i.e., a period The best vaccine is the one which concomitantly accomplishes between the initial arrival of the antigen (in the blood) and the the following criteria such as: antibody response, thus phase intervals of infection occur. (a) Actively inhibit the infective disease or else minimize the Eventually, IgG-type antibodies are specic to the novel coro- adverse effects of the disease; navirus (SARS-CoV-2) and can be examined through chem- (b) Offer a strong and continuing defence against a specic iluminescence immunological routes, which is an automated disease; laboratory process using enzyme-linked immunosorbent assays (c) Improves immunity through a minimum quantity of with higher arrangement. The examination mostly identies administrations; the body’s immune response to SARS CoV-2 infection. (d) Deliver abundant antigens to afford wide-ranging safety against infection; Signicant characteristics of (corona) virus (e) Never results in side effects, or keeps them to a minimum; (f) Remains stable under storage conditions, preferably mild Before 2019, there were two pandemics caused in the past two storage conditions, for its shelf-life; decades by coronavirus; namely SARS during 2002–2003 and Middle East Respiratory Syndrome (MERS) in 2011. According

to the International Committee on Taxonomy of Viruses (ICTV), knowledge to repurpose signicant drugs appropriately, and the coronaviruses (CoVs) are sub-classied as Othocoronavir- provide cheap drugs with the minimum toxicity prole.91b,c inae, which in turn consist of four categories – alpha-CoV, beta- CoV, gamma-CoV, and delta-CoV. The alpha- and beta-CoVs transmit disease in mammals such as bats, pigs, cats and The manufacture of SARS-CoV-2 vaccines through various mice. Gamma- and delta-CoVs usually infect birds. In addition, approaches the seven diﬀerent types of human CoVs – which include HCoV- Vaccines have to be approved based on suﬃcient evidence. 229E, HCoV-NL63 – belong to alpha-CoVs. The HCoV-OC43, Many scientic researchers have reviewed the current literature HCoV-HKU1, SARS-, MERS- CoVs, and the current pandemic and worked towards the development of a specic treatment for SARS-CoV-2 belong to beta-CoVs, and the genus of such beta COVID-19. Current studies have exposed several benecial coronavirus occurrences are zoonotic infections. The December opportunities, a few of them are more established and are in 2019 outbreak coronavirus, which leads to the respiratory- preclinical trials in addition to some in clinical trials.92,93 associated syndrome, originated from Wuhan, China, and is Vaccines endeavor to represent the antibody to the antigen, and called the novel corona virus disease 2019 or nCOVID-19, and its they should help the immune system (innate and adaptive genome is fully sequenced.88 The genetic sequential arrange- immune responses, Fig. 3). ment of SARS-CoV-2 has an identical genomic array of SARS-/ MERS-CoV.89,90 Initially, the taxonomy of coronaviruses are split in to three Virus vaccines groups, on account of genetic and serological interactions, the A number of vaccines are being developed for SARS-CoV-2, rst set (Group-1) comprised several viruses including the including inactivated and weakened, replicating and non- porcine epidemic diarrhoea virus (PEDV), porcine transmissible replicating viral vectors, and the tentative use of nucleic acid gastroenteritis virus (TGEV), canine coronavirus (CCoV), feline in the form of DNA and RNA. Now, we can distinguish each 

Creative Commons Attribution-NonCommercial 3.0 Unported Licence. infectious peritonitis virus (FIPV), the previously identi ed vaccine characteristic as follows: coronavirus of HCoV-229E, and HCoV-NL63. Whilst the second Weakened virus. Viruses cause disease by reproducing in combination (Group-2) consists of murine hepatitis virus a rapid manner. A weakened virus reproduces inside the human (MHV), bovine coronavirus (BCoV), human coronavirus OC43 or animal host very poorly thereby decreasing its virulence and (HCoV-OC43), rat sialodacryoadenitis virus (SDAV), porcine disease causing ability. One pharmaceutical company in the hemagglutinating encephalomyelitis virus (PHEV), canine USA (Codagenix, New York) is collaborating with an Indian respiratory coronavirus (CRCoV), and equine coronavirus research team (Serum Institute at Pune) for the manufacture of (ECoV). In a similar pattern, the third group (Group-3) contains SARS-CoV-2 with changed genetic sequence – making viral the avian infectious bronchitis virus (IBV) and Turkey corona- proteins with lower potency.

This article is licensed under a virus (TCoV). Now, the SARS coronaviruses (SARS-CoV) cannot Inactivated virus. Chemicals such as formaldehyde, or be associated with any of these representative groups, however thermal heating, are applied to inactivate a virus which is then they possess some similarities along with the second group used as a vaccine. 91a Open Access Article. Published on 08 June 2021. Downloaded 9/28/2021 7:21:02 PM. coronaviruses. Viral-vector vaccines. In this technique other virus types are The battle between scientists and viral infections is modied to render them safe and then used as a vaccine. They a perpetual process and thus the identication of specic combine the qualities of DNA vaccines with those of live potential drugs with high efficiency and low toxicity is attenuated vaccines. The viral vector vaccine consists of a live a continuous aim. Globally, this is the rst time, that scientic attenuated virus which is genetically modied to carry the DNA researchers, diplomats, politicians, and capitalists have encoding protein antigens from a different organism. For convened to work towards a common objective. The FDA example, the virus belonging to measles/adenovirus is geneti- approved drugs chloroquine and hydroxychloroquine to be cally modied and thus made safe. Currently there are products utilized in critical illness cases, but clinical practices were still for veterinary use but not for human use. There are two types of becoming overwhelmed by CoV cases. The suggestion to employ viral vectors,94 one is still able to replicate inside the cells, while extensive use of these antiviral drugs was not sufficient. Certain the other is non-replicating, since the key genes have been polymerase nucleoside/nucleotide inhibitors are promising rendered inoperative. agents. Favipiravir a selective viral RdRp inhibitor, has been Replicating viral vector (weakened measles). One of the tested in clinical trials against COVID-19. Furthermore, the approved Ebola vaccines is a typical paradigm for a viral-vector antiviral drugs lopinavir, ritonavir, remdesivir, nelnavir, serine vaccine. Even if replication occurs inside cells, this vaccine is based protease inhibitors of nafamostat, camostat, efficient safe and will intensify the immune response. lipid reducing statin, rosovastatin, TNF alpha inhibitors, Non-replicating viral vector (adenovirus variety). In general, interleukin 1 receptor antagonists; Janus associated kinases viral vectors are genetically transformed to generate defective (JAK) as well as monoclonal antibodies, tocilizumab, baricitinib replications which are termed non-replicating vectors. and ruxolitinib etc., along with their combinations and other Numerous viruses like adenovirus, adeno-linked, measles, and antiviral components, are also under investigation in clinical human parainuenza viruses has been extensively utilized as studies to combat COVID-19. In the future, researchers are viral vectors. Ultimately, the virus attains an attenuated state in requested to accumulate their results to provide more which they can activate the anticipated human immune

Fig. 3 Pictorial representation of characteristic immunity. Creative Commons Attribution-NonCommercial 3.0 Unported Licence.

responses, however, they are unable to reproduce in human Virus-like particles. Shells (outer regions) of an empty virus cells. resemble the CoV structure, however, it is non-transmittable Nucleic-acid vaccines. A number of groups are aspiring to due to the absence of the genetic factors. Several research utilize gene sequences (based on DNA or RNA) for a coronavirus groups are engaged in vaccines based on virus-like particles that protein to instantaneously provide an immune response. The can activate a good immune response, however it is quite majority of these vaccines focus on the spike protein present in complex to synthesize such particles, and 70% of the teams 95

This article is licensed under a the virus. directing their research in this way are from industry or private Protein-based vaccines. Several researchers have focused on companies rather than academic laboratories.97,98 injecting proteins present in coronavirus into the body. Also, Table 3 and 4 provide a comprehensive overview of the current protein fragments or shells of protein as copies of the corona- development of vaccines for SARS-CoV-2, their mode of action, Open Access Article. Published on 08 June 2021. Downloaded 9/28/2021 7:21:02 PM. virus’ surface could also be utilized. their utility and the name of the manufacturer.99 More than 10 Protein subunits. Nearly 28t groups are working on vaccines vaccines have almost reached the approval stage, while many are using subunits of viral proteins, predominantly on the spike in the preclinical stage. Fig. 4 portrays the number of vaccine protein at the receptor binding arena. Vaccines for protecting aspirants which are under clinical (63 drug aspirants) and monkeys against SARS virus infection are available which have preclinical (172 drug aspirants) stages against nCOVID-19.99a not been examined for humans. In fact, to employ such Protein-based techniques seem to be the most popular among vaccines, adjuvant-immune-stimulation drug molecules should the various mechanisms (see https://www.who.int/publications/ be administered together with the vaccine.96 m/item/dra-landscape-of-covid-19-candidate-vaccines).

Fig. 4 nCOVID-19 vaccine aspirants at the clinical (63 drug aspirants) and preclinical (172 drug aspirants) stage.

Table 3 COVID-19 aspirant developers and their significant details99a a Comparison between previous vaccines and COVID-19 vaccines Comparing COVID-19 vaccine novelty may seem challenging, but it is normal for queries to arise on a vaccine’s overall potential, safety, toxicity and its side effects etc.,100a and some of the efficacy, efficiency and safety of the COVID-19 frontrunner vaccines can be determined by comparison with other vaccines, like u vaccines. For example, Pzer/BioNTech released their COVID-19 vaccine initially in the UK and USA, and the rest of the world could see their effectiveness. However, prior to this demonstration the three prominent COVID-19 vaccines – Pzer/ BioNTech claims an efficacy of 95%, the Oxford/AstraZeneca provides 70%, and the Moderna is stated as 94.1% efficacy – were compared with other available vaccines such as the u, polio, and measles, which helped provide their effectiveness and efficiency predictions. It is important to discuss here that “effectiveness” and “efficacy” are different.100b Efficacy states how a vaccine performs in ideal lab circumstances, like those present in clinical trials. Whereas, effectiveness means how the vaccine works in normal, non-controlled conditions. For example, in a clinical trial, 90% efficacy refers to 90% lower disease rates in

Creative Commons Attribution-NonCommercial 3.0 Unported Licence. the group getting the vaccine compared with the sample group. But, the members in a group selected for a clinical trial have to be in good health and young and they usually have no under- lying health conditions. Besides, medical researchers will not generally consider some demographics in these clinical research studies like children/pregnant women. Thus, once a vaccine is able to prevent disease in clinical trials, we may observe the effectiveness drop when directed to different demographics. This article is licensed under a Vaccines do not necessarily need high effectiveness to protect several thousands of lives from disease. For instance, the vaccine for u100c has 40–60% effectiveness according to Open Access Article. Published on 08 June 2021. Downloaded 9/28/2021 7:21:02 PM. CDC data. During 2018–19, this vaccine prevented millions of inuenza cases and its associated illness, but determining the exact effectiveness rate is challenging. Dosages can also increase effectiveness for some vaccines. The two doses of a vaccine can give a protection boost, nevertheless this advantage is sometimes limited to only certain groups like children/ organ transplanted people. The booster dosage may not provide an advantage in people aged 65 years. Through comparing vaccines, like the ones for polio and measles, we see heavy dosages are needed to realize effectiveness. Polio vaccines100d should be up to 100% effective. According to the CDC, “Two inactivated polio vaccine (IPV) dosages have 90% effectiveness; three dosages are 99–100% effective.” The IPV vaccine prevents poliomyelitis (poliovirus), which can activate infection in the brain and spinal cord leading to paralysis. The MMR vaccine100e defends against measles, mumps, and rubella, which tends to have up to 97% effectiveness at inhib- iting measles once directed in two dosages. A single dose is a Vaccine candidate list and relevant information shown according to around 93% effective, as reported by the CDC. They suggest to the World Health Organization (WHO) statistical data for COVID-19 during 2019–2020. Clinical research data (last updated on January 08, give the initial dose at “12–15 months of age, followed by the 2021) may be variable. second dose at 4–6 years.”

Table 4 Range of SARS-CoV-2 vaccine aspirants and their representative data16a,b,99c

Vaccine Characteristic division Vaccine sector Vaccine category nature of Vaccine utility ID acronym description and composition vaccination Producers Clinical phases for other viruses Ref.

1 IV Inactivated virus Vaccines of Based on an Sinovac R&D Co. Ltd Phase III NCT04456595, Phase Vaccine being 101 CoronaVac, inactivated 1/2 NCT04383574, developed for PiCoVaccine, pathogen, body NCT04352608 treatment of based on vaccine generates a varied SARS-CoV-2 cultured in Vero immune response cells, inactivated against several viral pathogen antigens, producing neutralizing antibodies 2 IV Inactivated virus Inactivated Vaccine from non- Sinopharm + WIBP Phase 3, Phase-I/II/III Vaccine being 102 vaccine, Vero cell living viral particles, ChiCTR2000031809 developed for based bacteria, and other treatment of pathogens which are SARS-CoV-2 developed in a culture medium. No potential for infection, but induces an immune system response 3 IV Inactivated virus Inactivated and The foremost Sinopharm + BIBP Phase 3 ChiCTR2000032459 Vaccine being 92d similar to virus vaccine, does not developed for

Creative Commons Attribution-NonCommercial 3.0 Unported Licence. vaccine based on exhibit any adverse treatment of Vero cells side eﬀects with similar viruses favored immunogenicity and safety; also an inactivated new crown vaccine which completely neutralizes the antibodies in 28 days

This article is licensed under a 4 VVnr Viral vector (non- Covishield Adenovirus vector AstraZeneca + Oxford Phase 3 ISRCTN89951424, MERS, inuenza, 103 replicating) ChAdOx1-S- based on University Phase2b/3 2020-001228-32, TB, (AZD1222) chimpanzee Phase 1/2 Chikungunya, adenovirus PACTR2020069221651322020- Zika, MenB,

Open Access Article. Published on 08 June 2021. Downloaded 9/28/2021 7:21:02 PM. 001072-15 plague 5 VVnr Viral vector (non- Ad5-nCoV Recombinant Beijing Phase 2 ChiCTR2000031781, EBOV (Ebola 104 replicating) recombinant adenovirus type 5 Biotechnology Phase 1 ChiCTR2000030906 virus) vaccine for CoV vector based vaccine Institute/CanSino aspirant, which is Biological Inc. genetically modied with replication- decient groups, mimics SARS-CoV-2 spike protein 6 VVnr Viral vector (non- Gam-COVID-Vac Develop immunity Gamaleya Research Phase-I/III NCT04436471, Vaccine being 105 replicating) adeno-based against the Institute; Ministry of NCT04437875 developed for (rad26-S+rAd5-S), coronavirus, and Health, Russian treatment of Russian COVID- strengthens the Federation SARS-CoV-2 19 vaccine, immune system adenovirus based, and non- replicating 7 VVnr Viral vector (non- Ad26.COV2.S Activates specic Janssen Phase 3 NCT04505722, Vaccine being 106 replicating) recombinant acquired immunity Pharmaceutical NCT04614948 developed for serotype 26, for Ebola virus treatment of adenovirus similar viruses vectors, multivalent vaccine

Table 4 (Contd.)

Vaccine Characteristic division Vaccine sector Vaccine category nature of Vaccine utility ID acronym description and composition vaccination Producers Clinical phases for other viruses Ref.

8 PS Protein subunit SARS-CoV-2 rS/ Matrix-M, an Novavax Phase 3 NCT04611802, Ebola, Lassa, 107 Matrix M1- adjuvant which NCT04583995 MERS, Nipah, adjuvant (full improves the Ri Valley Fever size recombinant immune response and SARS CoV-2 GP and induces Chikungunya nanoparticle advanced based vaccine neutralizing with Matrix Mas antibodies adjuvant) 9 RNA RNA based Moderna mRNA- A vaccine with Moderna + NIAID Phase 3 NCT04470427, Phase Multiple agents 108 vaccine 1273 vaccine, mRNA encapsulated 2 NCT04405076, Phase 1 LNP in LNP, encoding for NCT04283461 encapsulated cell perfusion stabilized bank; mRNA, spike (S) protein. VAX (non- Host generates an replicating viral immune response vector) against the spike protein on SARS- CoV-2 10 RNA mRNA based BNT162 (3 LNP- BNT162 contains BioNTech + Fosun Phase 2/3 NCT04368728 To be 109 vaccine mRNAs) a nucleoside Pharma; Jiangsu implemented Creative Commons Attribution-NonCommercial 3.0 Unported Licence. modied mRNA Provincial CDC + (modRNA) encoding Pzer the viral spike (S) glycoprotein 11 PS Protein subunit Recombinant Increases rate of new Anhui Zhifei Phase-I NCT04453852, Vaccine being 110 COVID-19 coronavirus Longcom NCTo4445194, Phase 3 developed for vaccine, CHO neutralizing S Biopharmaceutical + NCT04646590 treatment of (Chinese protein antibody IMCAS SARS-CoV-2 hamster ovary) (IgG) and RBD cell system, protein antibody

This article is licensed under a prevents CoVs (IgG) 12 RNA mRNA based CVnCoV vaccine Nucleotides without CureVac AG NCT04449276 Phase 1, CureVac’s 111 vaccine chemical NCT04515147 Phase 2, vaccine modications in the NCT04674189 Phase 3 candidate

Open Access Article. Published on 08 June 2021. Downloaded 9/28/2021 7:21:02 PM. mRNA against SARS- CoV-2 13 IV Inactivated virus Vaccine for SARS- ELISA derived IMB + CAMS Phase 3 NCT04659239, Phase To be 112 CoV-2 based on antibodies (IgGs) 1/2 NCT04470609, implemented Vero cells and neutralizing NCT04412538 antibodies, target the spike protein, N protein virion and the specic positive CTL responses against N, S and virion antigens 14 IV Inactivated virus QazCovid-in®- There are specic RIBSP, Republic of Phase 1/2 NCT04530357 Vaccine being 113 COVID-19 antibodies that Kazakhstan developed for inactivated activate upon treatment of vaccine receiving small SARS-CoV-2 dilutions given in the vaccine, they constantly counterbalance the novel coronavirus with a virulence dose of 3000 TCD50

Table 4 (Contd.)

Vaccine Characteristic division Vaccine sector Vaccine category nature of Vaccine utility ID acronym description and composition vaccination Producers Clinical phases for other viruses Ref.

15 DNA DNA based INO-4800 + DNA plasmids Inovio Phase 1 NCT04336410, Multiple agents, 114 vaccine electroporation distribute by electro- Pharmaceuticals + NCT04447781, Phase 2 Cancer, HBV, vaccine with permeabilization IVI ChiCTR2000040146, Phase 2/ HIV, HPV, Lassa, DNA–plasmid (electro-transfer), 3 NCT04642638 Nipah, Zika, based a computationally connecting sequenced design to electroporation produce a specic device immune response 16 DNA DNA based AG0301- Plasmid DNA AnGes + Takara Bio + Phase 2/3 NCT04655625, To be 115 vaccine COVID19 vaccine developed Osaka University Phase 1/2 NCT04463472, implemented through an NCT04527081 intradermal gene transfer targeting the S protein, which increases the eﬃciency of gene expression and antibody production 17 DNA DNA based nCov vaccine Progression of DNA Cadila Healthcare Phase 1/2 CTRI/2020/07/ To be 116 vaccine viral vector, vaccine with the viral Ltd. 026352 implemented membrane membrane protein Creative Commons Attribution-NonCommercial 3.0 Unported Licence. protein based liable for CoV cell vaccine entry; plasmid DNA incorporated into the host cell changes the viral protein, leading to a strong immune response intervened by cellular and humoral immunity. Also used

This article is licensed under a to produce live attenuated recombinant measles viral vector

Open Access Article. Published on 08 June 2021. Downloaded 9/28/2021 7:21:02 PM. vaccine 18 DNA DNA based GX-19 Designed to make Genexine Phase-1/2 NCT04445389 To be 117 vaccine antigens by adding Consortium implemented nucleic acids into the body, the antigens then produce an immune response 19 IV Inactivated virus Whole-virion Isolated from Bharat Biotech Phase 1/2 NCT04471519, Vaccine being 118 inactivated asymptomatic International Phase 3 NCT04641481; CTRI/ developed for vaccine COVID-19 patient at Limited 2020/11/028976 treatment of (BBV152), NIV Pune, India SARS-CoV-2 Covaxin for SARS-CoV-2, India’s trials on nCoV-19 vaccine 20 PS Protein subunit KBP-COVID-19 A distinctive plant- KBP., Inc. Phase 1/2 NCT04473690 To be 119 (RBD-based), based vaccine implemented plant based technology for the technology generation of antigens to various diseases

Table 4 (Contd.)

Vaccine Characteristic division Vaccine sector Vaccine category nature of Vaccine utility ID acronym description and composition vaccination Producers Clinical phases for other viruses Ref.

21 PS Protein subunit Adjuvanted — Sano Pasteur + Phase 1/2 NCT04537208 120 vaccine of SARS- Glaxo SmithKline CoV-2 plc. formulation spike protein (baculovirus production) 22 RNA RNA based ARCT-021 Powerful single Arcturus Phase 1/2 NCT0448095 Vaccine being 121 vaccine dose, vaccine is Therapeutics developed for based upon self- treatment of replicating mRNA, SARS-CoV-2 self-transcribing and replicating RNA along with its liquid- enabling and resolving nucleo- monomer facilitator altered RNA 23 VLP Virus like RBD SARS-CoV-2 Neutralizing SII + Accelagen Pty Phase 1/2 Vaccine being 122 particle HBsAg VLP antibodies response ACTRN12620000817943 developed for vaccine in pigs, treated treatment of Creative Commons Attribution-NonCommercial 3.0 Unported Licence. together with SARS-CoV-2 pseudo type lentivirus and live SARS-CoV-2 viruses. Immunoglobulin (IgG) response observed aer booster immunization 24 VVnr + Viral vector (non- SARS-CoV-2 Shenzhen Geno- Phase 1/2 NCT04276896 Vaccine for SARS- 123

This article is licensed under a APC replicating) + vaccine Immune Medical CoV-2 APC IV (inactivated) Institute inactivated virus 25 VVnr Viral vector (non- GRAd-COV2 Able to generate ReiThera + Phase 2 ChiCTR2000039462 Ebola and RSV 124

Open Access Article. Published on 08 June 2021. Downloaded 9/28/2021 7:21:02 PM. replicating) replication using immune response Leukocare + (respiratory defective simian (antibodies and T Univercells syncytial virus) adenoviral vector cells) (GRAd), encodes full length CoV spike protein 26 VVnr Viral vector (non- VXA-CoV2-1 Ad5 Vaccine mainly Vaxart Phase 1 NCT04563702 Inuenza 125 replicating) adjuvanted oral provides mucosal infection H1N1 vaccine platform immunity, this vital factor targets mucosal pathogens, including the current coronavirus. Stimulates antigen- specic CD4+ and CD8+ T cells at low and high dosage levels

Table 4 (Contd.)

Vaccine Characteristic division Vaccine sector Vaccine category nature of Vaccine utility ID acronym description and composition vaccination Producers Clinical phases for other viruses Ref.

27 VVnr Viral vector (non- MVA-SARS-2-S Immune responses University of Munich Phase 1 NCT04569383 Infectious 126 replicating) and neutralizing (Ludwig- diseases and antibodies directing Maximilians) cancer the S antigen used to defend against infectivity. The double recombinant sMVA-CoV-2 vectors give S-specic CD8+ and CD4+ T cells to both S and N antigens in Balb/c mice, respectively 28 PS Protein subunit SCB-2019 + AS03/ S-Trimer, antigen Clover Phase 1 NCT04405908 Vaccine being 127 CpG 1018 used to target the Biopharmaceuticals developed for adjuvant plus antibodies of novel Inc./GSK/Dynavax treatment of alum adjuvant CoV spike protein SARS-CoV-2 (similar to native and is in ACE2-viable trimeric subunit human convalescent spike protein sera samples, vaccine) obtained from Creative Commons Attribution-NonCommercial 3.0 Unported Licence. recovered COVID-19 patients 29 PS Protein subunit COVID19 vaccine Eﬀective T cells and Vaxine Pty Ltd. + Phase 1 NCT04453852 Vaccine being 128 neutralizing Medytox developed for antibody response treatment of SARS-CoV-2 Protein subunit MF59 adjuvanted Advanced antibodies CSL Ltd. + Seqirus + Phase 1, development was Vaccine SARS-CoV-2 S are able to neutralize University of suspended and the candidate production clamp vaccine infectivity through Queensland vaccine was removed from the against similar live virus in the cell summary analysis viruses is on hold

This article is licensed under a culture 30 PS Protein subunit MVC-COV1901 High titer of Medigen Vaccine Phase 1 NCT04487210 Vaccine being 129 (S-2P protein + neutralizing Biologics Corp + developed for CpG 1018) antibodies are NIAID + Dynavax treatment of

Open Access Article. Published on 08 June 2021. Downloaded 9/28/2021 7:21:02 PM. prompted against SARS-CoV-2 pseudo type novel CoV in sera of immunized mice 31 PS Protein subunit FINLAY-FR anti- It has the capability Instituto Finlay de Phase 2 RPCEC00000347, Vaccine being 130 SARS-CoV-2 to generate Vacunas Phase 1/2 RPCEC00000332, developed for vaccine (RBD + a substantial Phase 1 RPCEC00000338 treatment of adjuvant) immune reaction SARS-CoV-2 32 PS Protein subunit EpiVacCorona, This antigens-based Federal Budgetary Phase 1/2 NCT04527575 Vaccine being 131 based on peptide preparation Research Institution developed for antigens stimulates the SRC VB VECTOR treatment of immune reaction SARS-CoV-2 33 PS Protein subunit RBD, baculovirus Specic immune WCH, Sichuan Phase 2 NCT04640402, Vaccine being 132 production blotting RBD, S-WT University ChiCTR2000039994, Phase 1 developed for expressed in Sf9 and S-2P, motivates NCT04530656 treatment of cells, high neutralization SARS-CoV-2 recombinant titers SARS-CoV-2 vaccine (Sf9 cell) 34 PS Protein subunit IMP CoVac-1 University Hospital Phase 1 Vaccine being 133 (SARS-CoV-2 Tuebingen (UKT) developed for HLA-DR treatment of peptides) SARS-CoV-2

Table 4 (Contd.)

Vaccine Characteristic division Vaccine sector Vaccine category nature of Vaccine utility ID acronym description and composition vaccination Producers Clinical phases for other viruses Ref.

35 PS Protein subunit UB-612, This vaccine has the COVAXX + United Phase 1 NCT04545749 Vaccine being 134 multitope immunity potential Biomedical Inc developed for peptide based S1- to reduce future treatment of RBD-protein pandemic rates SARS-CoV-2 based vaccine 36 VVr Viral vector V591-001- Attains the target Merck & Co., Phase 1 CT04498247, Phase1/ Vaccine being 135 (replicating) measles-vector immune response in Themis + Sharp & 2 NCT04497298NCT04569786 developed for based (TMV-o38) humans Dohme + Pasteur treatment of Institute + Pittsburgh SARS-CoV-2 University 37 VVr Viral vector DelNS1-2019- SARS-CoV-2 RBD Jiangsu Provincial Phase 2 ChiCTR2000039715, Vaccine being 136 (replicating) nCoV-RBD- protein based CDC Phase 2 ChiCTR2000037782 developed for OPT1, intranasal vaccine used to treatment of u-based-RBD motivate cross- SARS-CoV-2 reactivity or cross- neutralizing antibodies; moreover it blocks previous CoV pseudovirus and the advanced novel CoV Creative Commons Attribution-NonCommercial 3.0 Unported Licence. pseudovirus into hACE2 expressing ¼ 293 T cells (IC50 4.1 and 11.63 mg ml 1) 38 RNA RNA based LNP-nCoVsaRNA The saRNA vaccine Imperial College Phase 1 ISRCTN17072692 Vaccine being 137 vaccine can activate a strong London developed for immune response; it treatment of is suggested that the SARS-CoV-2 IM vaccination

This article is licensed under a antigen is expressed in muscle cells, then moves to antigen presenting cells

Open Access Article. Published on 08 June 2021. Downloaded 9/28/2021 7:21:02 PM. (APC), representing a cross priming mode of potentiality to prominent CD8+ T cells 39 RNA RNA based SARS-CoV-2 — Shulan (Hangzhou) Phase 1 Vaccine being 138 vaccine mRNA vaccine Hospital and CDC at developed for Guangxi Zhuang treatment of Autonomous Region SARS-CoV-2 40 VLP Virus-like Coronavirus-like Provides immunity Medicago Inc. Phase 2/3 Vaccine being 139 particle particle COVID- by generating developed for 19 (CoVLP) a harmless spike treatment of protein member, similar viruses reduces severe infection eﬀects 41 VVr + Viral vector COVID-19/aAPC Articial antigen- Shenzhen Phase 1 NCT04299724 Vaccine being 140 APC (replicating) + vaccine pathogen-specic Genoimmune developed for APC produced from vaccine, which uses Medical Institute treatment of a variation of the spike protein SARS-CoV-2 lentivirus with binding to the ACE2 immune receptor; the vaccine modulatory utilizes the modied genes and viral minigenes to direct minigenes to the viral proteins, vary aAPCs aAPC, and trigger T- cells

Table 4 (Contd.)

Vaccine Characteristic division Vaccine sector Vaccine category nature of Vaccine utility ID acronym description and composition vaccination Producers Clinical phases for other viruses Ref.

42 VVnr + Viral vector (non- LV-SMENP-DC Vaccine directed Same medical Phase 1/2 NCT04276896 Vaccine being 141 APC replicating) + vaccine. with antigen-specic institute developed for APC Dendritic cells CTLs treatment of are modied similar viruses with lentivirus vectors transmitting COVID-19 minigene SMENP and immune modulatory genes. Cytotoxic T lymphocytes (CTLs) are activated by LV- DC oﬀering COVID-19 specic antigens. 43 PS Protein subunit AdimrSC-2f — Adimmune Phase 1 NCT04522089 Vaccine being 142 (recombinant Corporation developed for Creative Commons Attribution-NonCommercial 3.0 Unported Licence. RBD treatment of aluminium) SARS-CoV-2 44 DNA DNA based Covigenix VAX- Induces neutralizing Entos Phase 1 NCT04591184 Vaccine being 143 vaccine 001 antibody levels and Pharmaceuticals Inc. developed for stable T helper cell treatment of immunity SARS-CoV-2 45 DNA DNA based CORVax CORVax12 initiates Providence Health & Phase 1 NCT04627675 Vaccine being 144 vaccine a coordinated Services developed for vaccine response, treatment of able to expose the similar viruses

This article is licensed under a innate adaptive humoral and cellular arms. These cellular immune responses

Open Access Article. Published on 08 June 2021. Downloaded 9/28/2021 7:21:02 PM. have the potential to generate a strong antiviral response 46 RNA RNA based ChulaCov19 The mRNA based Chulalongkorn Phase 1 NCT04566276 Vaccine being 145 vaccine mRNA vaccine vaccine encodes University developed for a protein antigen, treatment of while RNA is similar viruses considered to be unstable; the design and development of this novel vaccine is improving its constancy and protein translation eﬃcacy, so it eﬃciently enhances immune response

Table 4 (Contd.)

Vaccine Characteristic division Vaccine sector Vaccine category nature of Vaccine utility ID acronym description and composition vaccination Producers Clinical phases for other viruses Ref.

47 DNA DNA based bacTRL-Spike Symvivo’s bacTRL Symvivo Corporation Phase 1 NCT04334980 Vaccine being 146 vaccine gene therapy developed for platform associates treatment of an advanced gene- similar viruses expression plasmid with a probiotic bacterium to resolve restrictions and distribute the DNA vaccine directly to the gut. The bacterium triggers the immune response 48 VVnr Viral vector (non- hAd5-S-Fusion + A viral spike protein. ImmunityBio, Inc. Phase 1 NCT04591717, Vaccine being 147 replicating) N-ETSD vaccine Virus enters the host NCT04710303, NCT04732468 developed for cells through the treatment of ACE2 receptor with similar viruses a fusion linker, S is antigenic, and generates an Creative Commons Attribution-NonCommercial 3.0 Unported Licence. eﬃcient immune response 49 VVnr Viral vector (non- COH04S1 (MVA- Vaccine holds the City of Hope National Phase 1 NCT04639466 Vaccine in 148 replicating) SARS-2-S) SARS-CoV-2 spike Medical Center development and nucleocapsid proteins inserted into the MVA platform that can replicate DNA within cells. Thus it

This article is licensed under a generates novel CoV protein expression to trigger host immunity against

Open Access Article. Published on 08 June 2021. Downloaded 9/28/2021 7:21:02 PM. the virus 50 VVr Viral vector rVSV-SARS-CoV- rVSV-DG-spike IIBR, Israel Phase 1/2 NCT04608305 Vaccine in 149 (replicating) 2-S vaccine stimulated a safe, development eﬃcient and adequate neutralizing antibody. Vaccination leads to lower morbidity, protects lungs, and provides fast viral clearance 51 VVr + Viral vector Dendritic cell Produced from Aivita Biomedical, Phase 1/2 NCT04690387 Vaccine in 150 APC (replicating) + vaccine AV- isolated peripheral Inc. NCT04386252 development APC COVID-19: blood monocytes contains from patients. autologous Monocytes are then dendritic cells distinguished into load with dendritic cells with antigens from GM-CSF and IL¼4 SARS-CoV-2, with/without GM-CSF

Table 4 (Contd.)

Vaccine Characteristic division Vaccine sector Vaccine category nature of Vaccine utility ID acronym description and composition vaccination Producers Clinical phases for other viruses Ref.

52 LAV Live attenuated COVI-VAC Codagenix’s Codagenix/Serum Phase 1 NCT04619628 Vaccine in 151 virus synthetic attenuated Institute of India development virus engineering (SAVE) platform utilizes synthetic biology to re-code the virus genes into the vaccine. Since this design involves distributing a benign, live attenuated version of SARS-CoV-2 it may stimulate a strong and enduring immune response 53 PS Protein subunit CIGB-669 (RBD + Stimulates the CIGB Phase 1/2 RPCEC00000345 Vaccine in 130 AgnHB) generation of development antibodies that enable a strong immune response to Creative Commons Attribution-NonCommercial 3.0 Unported Licence. the pathogen 54 PS Protein subunit CIGB-66 (RBD + Stimulates the CIGB Phase 1/2 RPCEC00000346 Vaccine in 130 aluminium generation of development hydroxide) antibodies that boost the targeted immune response to the virus 55 IV Inactivated virus VLA2001 Vero-cell supported Valneva, NIHR, Phase 1/2 NCT04671017 Vaccine in 130 the rened United Kingdom development inactivated

This article is licensed under a candidate, based on Valneva’s JE vaccine, uses the spike protein normal

Open Access Article. Published on 08 June 2021. Downloaded 9/28/2021 7:21:02 PM. structural array with CpG 1018 and can stimulate an immune response with a high titer of neutralizing antibodies 56 PS Protein subunit BECOV2 Candidate based on Biological E Limited Phase 1/2 CTRI/2020/11/ Vaccine in 130 inactivated SARS- 029032 development CoV-2 virus components 57 VVr Viral vector AdCLD-CoV19 Immunotherapeutic Cellid Co., Ltd. Phase 1/2 NCT04666012 Vaccine in 152 (replicating) vaccine based on development cells 58 DNA DNA based GLS-5310 Nucleic acid-based GeneOne Life Phase 1/2 NCT04673149 Vaccine in 152 vaccine vaccine platform Science, Inc. development

Table 4 (Contd.)

Vaccine Characteristic division Vaccine sector Vaccine category nature of Vaccine utility ID acronym description and composition vaccination Producers Clinical phases for other viruses Ref.

59 PS Protein subunit Recombinant Protein subunit Nanogen Phase 1/2 NCT04683484 Vaccine in 153 SARS-CoV-2 containing the Pharmaceutical development spike protein, recombinant SARS- Biotechnology aluminum CoV-2 S1 domain of adjuvanted the spike protein, also integrates either CoVaccine HT™ or alhydrogel. CoVaccine HT™, a single dose stimulated high titers of antigen- binding IgG. This accelerates the aﬃnity maturation and switching of class to higher values, enhancing cell-induced immunity and virus antibodies Creative Commons Attribution-NonCommercial 3.0 Unported Licence. 60 PS Protein subunit Recombinant Vaccine is based on Shionogi Phase 1/2 jRCT2051200092 Vaccine in 130 protein vaccine recombinant protein development S-268019 (based units together with on Baculovirus GSK; development of expression vector mRNA vaccine by system) Sano,in collaboration with Translate Bio. Preclinical data revealed that the two

This article is licensed under a immunizations of the mRNA based vaccine stimulated high neutralizing

Open Access Article. Published on 08 June 2021. Downloaded 9/28/2021 7:21:02 PM. antibody levels equal to those produced in infected humans a Globally, vaccine producers have the ability to achieve rapid development of highly eﬃcient, safe – minimum toxicity – vaccines.

In order to determine the similarities and differences effects on COVID-19, and also for clinical evaluation to control between previously available vaccines and COVID-19 vaccines, the COVID-19 pandemic.99b the Bacillus Calmette–Guérin (BCG) vaccine against tubercu- COVID-19 is a serious respiratory related disease, so the losis is provided as one more example; it confers a wide range of scientic and medicinal community are working hard across immunity against other infections, and it also may minimize the globe to develop a vaccine. Presently, around sixty vaccine the intensity of COVID-19. Moreover one epidemiological candidates are on trial in many countries. Now, nearing twenty analyses provided universal connections between the vaccina- candidate vaccines are in phase 3 clinical trials. Gratifyingly, tions of BCG and COVID-19 mortality: the suggestion of BCG seven vaccines have been approved in many countries. vaccination results on COVID-19 fatality are dominated by socio-economical and demographical variations between countries. In the wake of reducing the manifold distracting Conclusions factors, many substantial connections between the BCG vacci- Globally, as of January 2021, there have been around 88 million nation and decreased COVID-19 fatalities were perceived. COVID-19 cases, including nearly 1.9 million fatalities, WHO Obviously this investigation emphasizes the necessity for an have registered (see WHO Covid-19 case report).99d These intrinsic mechanism of studies supporting BCG vaccination numbers are expected to increase further, so there is an

emergency requirement to produce vaccines to protect people. Acknowledgements Several candidates vaccines are being developed which are in preclinical and clinical trials. The mechanism of action of these KD thanks the Science and Engineering Research Board (SERB), candidates varies signicantly, as better knowledge becomes New Delhi, India for the National Post-Doctoral Fellow (NPDF) available154a about this virus, researchers can adapt their design [Project No. PDF/2017/001743]. so if one candidate shows low efficacy, another one may be more active. Similarly, different demographics may necessitate the need References for designing vaccines with different mechanisms of action. The time required for the various stages of clinical trials needs to be 1 J. M. Ryan, R. L. Jonathan and V. Olivia, Chem. Rev., 2020, shortened (without compromising on the ethics and safety) to 120, 3210–3229. achieve the desired goal in a short period of time.154b Finally, 2 Y. Tingting, Z. Zifu, G.-S. Adolfo, S. Michael and manufacturing such large quantities of the vaccine or vaccines, G. D. G. Bruno, Angew. Chem., Int. Ed., 2020, 59, 18885– quickly (without compromising on the quality, purity and effi- 18897. cacy) and distributing them to all parts of the world is another 3 B. Greenwood, Philos. Trans. R. Soc., B, 2014, 369, 20130433. problem which the present planners have not faced before. This 4 K. A. Smith, Front. Immunol., 2011, 2,1–6. requires sufficient manufacturing capacity, availability of raw 5 A. S. Clem, J. Global Infect. Dis., 2011, 3,73–78. materials, logistics and several other factors. Also, as all 6 L. B. Nicholson, Essays Biochem., 2016, 60, 275–301. resources are diverted towards SARS-CoV-2, epidemiologists 7 J. Lu, G. Lu, S. Tan, J. Xia, H. Xiong, X. Yu, Q. Qi, X. Yu, L. Li, and public health organizations should not lose track of their H. Yu, N. Xia, T. Zhang, Y. Xu and J. Lin, Cell Res., 2020, 30, ght against other viruses.155 936–939. The current assemblage of vaccine developers156a may reward 8 B. E. Eldred, A. J. Dean, T. M. McGuire and A. L Nash, Med. J. –

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