INTRODUCTION
On January 30, 2020, the World Health Organization (WHO) declared a severe respiratory disorder syndrome which originated in Wuhan city as a global public health emergency, and the pandemic declaration by the WHO was made on March 11, 2020.[1] Since its emergence in November 2019, it has spread to 188 countries and 25 territories around the globe, despite elaborate efforts by the WHO and governments to contain the infection, primarily owing to the highly infectious nature of this virus.[2] Structurally, coronaviruses are pleomorphic, enveloped viruses with a characteristic fringe of projections composed of S-protein on their surface equipped with a positive-sense single-stranded RNA genome.[2]
SARS-CoV-2 enters host cell via the angiotensin-converting enzyme 2 receptor (ACE2). The S-protein of CoV, especially the receptor binding domain (RBD), is able to induce neutralizing antibodies (NAbs) and T-cell immune responses.[3] SARS-CoV-2 attacks host immune system, leading to an uncontrolled inflammatory response, lymphocytopenia, high cytokine levels, and increased antibodies.[2] Persons infected with SARS-CoV-2 are frequently asymptomatic, yet they have high respiratory viral loads, and they are major purveyors of viral spread. These factors have led to the current explosion of COVID-19 hospitalizations and deaths. Our only hope is safe and effective vaccines that can be widely deployed to provide herd immunity that can control viral spread.[4]
Vaccines could play an important role by preventing severe diseases and increasing population immunity and reducing the ongoing health crisis.[5] Vaccines stimulate the immune system of an individual to prepare it against a future pathogen. To address the COVID-19 public health emergency, the United States Food and Drug Administration has issued a guidance in June 2020 to assist sponsors in clinical development and licensure of vaccines for the prevention of COVID-19.[6] The WHO has implemented an access to COVID-19 tools accelerator for coordinating global vaccine development program in collaboration with The Global Alliance for Vaccines and The Coalition for Epidemic Preparedness Innovations.[7]
There are multiple methods and platforms being tried for the development of COVID-19 vaccines, such as inactivated or weakened, protein subunit, viral vector, RNA and DNA vaccines, and virus-like particles (VLPs) with each exhibiting advantages and disadvantages.
Inactivated vaccines
They are produced by completely inactivating or killing the pathogen, on injecting it to the host they primarily induce protective antibody against epitopes on hemagglutinin glycoprotein on surface of the virus.[2]
BBIBP-CorV
The candidate vaccine is an inactivated whole SARS-CoV-2 virus vaccine developed by Wuhan Institute of Biological Products and Sinopharm. The Phase I trial was conducted using three doses with 2.5 μg, 5 μg, and 10 μg antigen protein content per dose, and the results showed inactivated vaccine candidate to have better safety profiles.[2] Phase II trial was conducted using 5 μg antigen protein, and the results showed that vaccine candidate effectively produces antibody titers. No serious adverse effects and only mild-to-moderate self-limiting reactions were reported. It is administered intramuscular and can be stored at a temperature of 2°C–8°C.
PiCoVacc/Sinovac/CoronaVac
It is a purified formalin-inactivated alum-adjuvanted SARS-CoV-2 virus vaccine candidate developed by China-based biotechnology company Sinovac Biotech.[6] CoronaVac is currently in Phase 3 clinical trials in a two-dose injection regimen with a 14-day interval, both dosages induced a seroconversion on more than 90% of the individuals immunized, however, no T-cell responses were reported.[8] It can be given intramuscular and can be refrigerated. The vaccine appears to be safe and did not cause any severe side effects. China has approved CoronaVac as a part of an emergency use program in the country for high-risk individuals, such as healthcare workers and essential personnel.[9]
Bharat Biotech's Covaxin
It is India's first inactivated vaccine against SARS-CoV-2 making it safe to be injected into the body developed by Bharat Biotech, Indian Council of Medical Research, National Institute of Virology, Pune, by the name of Covaxin.[2] When administered, immune cells can still recognize the dead virus, prompting the immune system to make antibodies against the pandemic virus. No adverse side effects were reported and vaccine was found to generate robust immune response.[2] The vaccine is also reportedly effective against B.1.1.7 variant of SARS-CoV-2. No life-threatening events were reported in trial. The most common adverse event was pain at the injection site, followed by headache, fatigue, and fever.[10] It is administered intramuscular and can be stored at least a week at room temperature.
Live-attenuated vaccine
DelNS1-SARS-CoV-2 receptor binding domain (University of Hong Kong)
This live-attenuated vaccine is influenza-based vaccine strain with a deletion in the NS1 gene; it is reorganized to express the RBD of SARS-CoV-2 spike protein on its surface and is cultivated in the chick embryos and/or Madin–Darby Canine kidney cells. It is potentially more immunogenic than the wild-type influenza virus and can be administered as a nasal spray.[2]
Nucleic acid vaccines
DNA vaccines
They are noninfectious and nonreplicating. They are easy to produce within a short duration, cost-effective, and stable.[2] DNA vaccines have a great therapeutic potential due to their ability to enhance T-cell induction and antibody production.
Cadila ZyCoV-D
It is India's second vaccine, a type of DNA plasmid vaccine expressing SARS-CoV-2 S-protein developed by Zydus Cadila Healthcare. The candidate has been approved with Phase 3 trials, according to the Drugs Controller General of India.[9] No adverse side effects were reported; it is administered intradermally and can be stored at room temperature for 3 months [Table 1].
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Table 1:
Landscape of rapidly progressing anti-COVID-19 vaccines and its clinical trial stage with its efficacy and dosage: The list of all the vaccine candidates in the pipeline can be assessed from: World Health Organization, Research and Development blueprint team
Ino-4800 (iNOVIO pharmaceuticals)
It is a prophylactic DNA vaccine against SARS-CoV-2 developed by iNOVIO. It uses codon-optimized S-protein sequence of SARS-CoV-2 to which an IgE leader sequence is affixed.[2] The vaccine is injected intradermally at a dose of 1.0 mg to 40 healthy volunteers in Phase 1 trial at baseline and at 4 weeks, followed by electroporation. No adverse side effects were reported and can be stored at room temperature.
RNA vaccines
mRNA-1273/Moderna
The messenger RNA (m-RNA)-1273 vaccine is a lipid nanoparticle-encapsulated nucleoside modified m-RNA–based vaccine developed by Moderna and National Institute of Allergy and Infectious Diseases.[2] It encodes the spike glycoprotein (S-protein) present on the surface of SARS-CoV-2. The safety and efficacy results from the Phase 3 trial of mRNA-1273 were published in the New England Journal of Medicine, confirming the vaccine candidate's 94.1% efficacy and safety profile.[8] Binding antibody responses increased rapidly after the first immunization.[11] The local reactions to vaccination were mild; however, moderate-to-severe systemic side effects, such as fatigue, myalgia, arthralgia, and headache, were noted in about 50% of participants in the mRNA-1273 group after the second dose. These side effects were transient, starting about 15 h after vaccination and resolving in most participants by day 2, without sequelae.[12] It is administered intramuscularly and can be stored till 30 days with refrigeration and for 6 months at −4°F (−20°C).
Comirnaty/BNT162b1
It is a codon-optimized, lipid nanoparticle-encapsulated mRNA vaccine that encodes for the trimerized SARS-CoV-2 RBD, a critical target of the virus NAb developed by BioNTech, Fosun Pharma, and Pfizer, available in the name of Comirnaty. Researchers have administered the BNT162b1 vaccine candidate intramuscularly at three different doses 10 μg, 30 μg, and 100 μg and found that it exhibits acceptable safety profile and elicits adequate antibody titer.[2] A two-dose regimen of BNT162b1 30 μg per dose, given 21 days apart, was found to be safe and 95% effective against COVID-19.[13] In the interval between the first and second doses, the observed vaccine efficacy against COVID-19 was 52%, and in the first 7 days after dose two, it was 91% reaching full efficacy against disease with onset at least 7 days after dose.[14] Most of the reported adverse reactions were mild or moderate in severity and resolved in the first 7 days after each BNT162b1 dose for the prime and boost vaccinations.[15] It showed acceptable safety profile, and long-term assessment of vaccine candidate for efficacy and tolerability is ongoing in Phase 3 trials. It can be stored at −25°C to −15°C [Table 2].
Table 2:
List of COVID-19 vaccine along with its clinical trial remarks, signs and symptoms, storage temperature, and route of administration: The list of all the vaccine candidates in the pipeline can be assessed from: World Health Organization, Research and Development blueprint team
CVnCoV
CureVac is developing an m-RNA–based vaccine, CVnCoV. It works by using nonchemically modified nucleotides within mRNA to provide a strong and balanced activation of the immune system. No life-threatening side effects were reported. It is administered intramuscularly and can be stored for at least for 3 months at 36°F–46°F (2°C–8°C) [Table 2].
Vectored vaccines
Vectored vaccines are generally constructed for a carrier virus, such as an adeno or pox virus, and are engineered to carry a relevant gene from the virus, usually the S-gene for SARS-CoV-2.
Ad5-nCoV/CONVIDICEA
It is a recombinant, replication defective adenovirus type 5 vector (Ad5) expressing the recombinant spike protein of SARS-CoV-2.[2] It was prepared by cloning an optimized full length gene the S-protein along with the plasminogen activator signal peptide gene in the Ad5 vector devoid of E1 and E3 gene developed by CanSino Biologics named Convidicea.[2] The two lower doses of 5 × 1010 and 1 × 1011 viral particles were found to have an acceptable safety and immunogenicity profile and were selected for a Phase 2 trial.[8] No serious adverse reactions were reported and those reported are mild to moderate and resolved within a short period of time maximum by 48 h of reaction onset. The preliminary report suggests the acceptable safety.[2] It can be stored at 2°C–8°C temperature.
Ad26COV2.S/JNJ-78436735
It is nonreplicating viral vector vaccine developed by Janssen Pharmaceutical Companies using their AdVac and PER C6 systems, which were also used to develop the company's Ebola vaccine.[9] The DNA in the adenovirus is modified so that it produces a key part of the SARS-CoV-2 virus particle to which the body then develops an immune response.[14] From the Phase ½ study in humans, a single dose of the vaccine was given intramuscularly that showed immunogenicity and good safety profile. Only mild side effects are reported such as fatigue, fever headache, and pain at injection site, which generally resolve within a day or 2. It was found to be 72% effective in the vaccine candidates. It can be stored up to 2 years frozen at −4°C (−20°C) and up to 3 months refrigerated at 36°F–46°F (2°C–8°C) [Table 2].
CoroFlu (University of Wisconsin-Madison/Flugen/Bharat Biotech)
M2SR is a self-limiting version of the influenza virus, which is modified by insertion of the SARS-CoV-2 gene sequence of the spike protein. It is able to enter into the cell, thereby inducing the immunity against the virus.[2] It shall be administered intranasally mimicking the natural route of viral infection and had higher immunogenicity as compared to the intramuscular injections. No adverse events were reported.
LV-SMENP-DC (Shenzen Geno-Immune Medical Institute)
The LV-SMENP-DC vaccine is prepared by engineering the dendritic cells (DCs) with the lentiviral vector expressing the conserved domains of the SARS-CoV-2 structural proteins and the protease using the SMENP mini genes. The subcutaneous inoculation of the vaccine presents the antigen presenting cells that ultimately activate the cytotoxic T-cell and generate the immune response.[2]
ImmunityBio
ImmunityBio is developing a COVID-19 adenovirus vaccine candidate that targets both spike and nucleocapsid DNA in SARS-CoV-2 with no name announced so far. The interim Phase 1 results showed no serious adverse events in the low-dose group. Route of administration is subcutaneous.
ChAdOX1 nCov 19/AZD122/Covishield/AstraZeneca
It consists of the nonreplicating simian adenovirus vector ChAdOX1 containing the full length structure spike protein of SARS-CoV-2 developed by AstraZeneca and the Oxford Vaccine Group at the University of Oxford in collaboration with Serum Institute of India and goes by the name Covishield.[9] Two vaccines are administered in two doses between 4 and 12 weeks apart. 14 days after first dose of vaccine, cellular response was observed, and after 28 days, humoral responses to spike protein are seen. The vaccine has an overall efficacy of 70%, with vaccine efficacy of 62.1% in a group of participants receiving two standard doses and 90% in a group receiving one half dose followed by a standard dose.[9] No adverse events are reported, and those that are reported are mild to moderate such as fatigue, headache, fever, and pain at injection site which generally resolves within 1–2 days. It is stable in refrigerator for at least 6 months.
Gamaleya's Sputnik V
It is the type of nonreplicating adenovirus (rAd26-S + rAd5-S) type vaccine developed by Gamaleya Research Institute Epidemiology and Microbiology, Health Ministry of the Russian Federation. The vaccine consists of the two components, one with the recombinant adenovirus vector based on the human adenovirus type 26 and another with the adenovirus vector based on the human adenovirus type 5, both containing SARS-CoV-2 S protein gene.[2] The interim results of the Phase 3 Gam-COVID-Vac trial show that the vaccine is 91.6% (95% confidence interval 85.6–95.2) efficacious against COVID-19 (from day 21 after first dose, the day of receiving second dose). rAd26-S and rAd5-S are administered intramuscularly separately with a 21-day interval.[16] No adverse side effects were reported and vaccine induced cellular immunogenic response. It can be stored at a temperature of 2°C–8°C [Table 2].
Protein subunit vaccine
A subunit vaccine is one that is based on the synthetic vaccines or recombinant antigenic proteins, which are necessary for invigorating long-lasting protective/or therapeutic immune response. The virus enters the cell via endocytosis by utilizing the S-protein–mediated ACE2 receptor.[2] Therefore, the S-protein and its antigenic fragments are the prime targets of subunit vaccine.
Molecular clamp-stabilized spike protein vaccine
It is being developed by the University of Queensland in collaboration with GSK and Dynavax.[2] They are developing a stabilized preperfusion, recombinant viral protein subunit vaccine which is based on molecular clamp technology to induce the production of NAbs.
EpiVacCorona
The Federal Budgetary Research Institution State Research Centre of Virology and Biotechnology in Russia has developed a peptide vaccine for COVID-19 called EpiVacCorona.[9] The vaccine relies on chemically synthesized peptide antigens of SARS-CoV-2 proteins, conjugated to a carrier protein and adsorbed on an aluminum-containing adjuvant (aluminum hydroxide). The EpiVacCorona vaccine contributes to developing protective immunity against SARS-CoV-2 coronavirus following two intramuscular administrations spaced 21–28 days apart. A Phase ½ trial for evaluating the efficacy of vaccine was done on 100 participants, and it was found to be 100% effective. No life-threatening adverse events were reported, and it is stable in refrigerator for up to 2 years.
NOVAVAX/NVX-CoV2373
It is a nanoparticle-based immunogenic vaccine which is based upon the recombinant expression of the stable prefusion, coronavirus S-protein.[2] Phase 1 trial participants who received the vaccine developed an antibody response at multiple dose, and vaccine has a favorable safety profile with no adverse events with efficacy of 89%[17] [Table 1]. It is administered intramuscularly and can be stored at a temperature of 2°C–8°C [Table 2].
PittCoVacc (University of Pittsburgh)
It is microneedle array-based recombinant SARS-CoV-2 vaccine which involves the administration of rSARS-CoV-2 S1 and rSARS-CoV-2 S1Frs09 (recombinant immunogens).[2] This array is a fingertip-sized patch of 400 tiny needles that deliver spike protein pieces into the skin, where the immune reaction is the strongest. PittCoVac is still in testing phases. No adverse side effects were reported so far.
Triple-antigen vaccines (Premas Biotech, India)
It is a multigenic VLP vaccine prototype wherein the recombinant spike, membrane, and envelope protein of SARS-CoV-2 have been coexpressed in an engineered Saccharomyces cerevisiae expression platform.[2] It is thought to be safe and easy to manufacture on a mass scale, in a cost-effective manner. Its route of administration is intramuscular.
ZF2001
It is the latest subunit vaccine candidate to enter Phase 3 clinical studies is the adjuvanted RBD-dimeric antigen designed by Anhui Zhifei Longcom Biopharmaceutical and the Institute of Microbiology of the Chinese Academy of Medical Sciences.[8] It is administered intramuscularly which utilizes a harmless fragment of SARS-CoV-2, instead of the complete germ.
Plant-based vaccine
CoVLP
Medicago Inc., recently developed a plant-derived recombinant quadrivalent VLPs coronavirus vaccine named CoVLP. It uses the virus-transfected plant Nicotiana benthamiana to express the prefusion trimeric subunit form of the SARS-CoV-2 S-protein and assemble it on the surface of VLPs, which are harvested and used for immunization.[8] No life-threatening adverse events were reported.
Nasal sray
AdCOVID
AdCOVID is a nasal spray developed by AltImmune a biopharmaceutical company for COVID-19, delivering the Ad5 adenovirus to the airway. On December 22, the company registered a Phase 1 clinical trial of a single dose of the vaccine, which is expected to deliver results in June 2021.[18]
BBV154
This is a nasal spray developed by Bharat Biotech that contains a chimpanzee adenovirus developed by researchers at Washington University. They found that it could produce coronavirus antibodies in mice with just a single dose.[17] The vaccines mentioned in Tables 3 and 4 are in their Phase I and preclinical trials respectively.
Table 3:
List of candidate vaccine in clinical evaluation: It can be assessed from World Health Organization: COVID-19 vaccine updates
CONCLUSION
The world is in dire need of safe effective COVID-19 vaccine. According to the pandemic vaccine development paradigm, the conventional vaccine development has compressed from a time frame of 10–15 years to 1–2 years, with overlapping clinical, preclinical, and manufacturing process occurring in parallel. As a result, crucial information about the longevity and quality of vaccine-induced protective immunity is unavailable.
The COVID-19 vaccines are expected to provide at least some protection against new virus variants and are effective at preventing serious illness and death that is because these vaccines create a broad immune response, and any virus changes or mutations should not make vaccines completely ineffective. If any of these vaccines become less effective against one or more variants, it will be possible to change the composition of the vaccines to protect against these variants.
Therefore, along with focusing on the vaccine development, we should focus on containing the spread of the virus. Until widespread immunity halts the spread of SARS-CoV-2, physical distancing measures, covering a cough or sneeze in your elbow, frequently cleaning your hands, wearing a mask, and avoiding poorly ventilated rooms are needed to control COVID-19. However, control of pandemic coronavirus will only be achieved if the licensure, manufacturing, and distribution of these vaccines can be achieved at an unprecedented scale and vaccination is rolled out to all those who are vulnerable.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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