key: cord-0705622-ounx3wzv
authors: Malik, Jonaid Ahmad; Mulla, Almas Hanif; Farooqi, Tahmeena; Pottoo, Faheem Hyder; Anwar, Sirajudheen; Rengasamy, Kannan R.R.
title: Targets and strategies for vaccine development against SARS-CoV-2
date: 2021-01-28
journal: Biomed Pharmacother
DOI: 10.1016/j.biopha.2021.111254
sha: 3edff68a37d1bb26bc0cb93a756dbb235d8c0c29
doc_id: 705622
cord_uid: ounx3wzv

The SARS-CoV-2, previously called a novel coronavirus, that broke out in the Wuhan city of China caused a significant number of morbidity and mortality in the world. It is spreading at peak levels since the first case reported and the need for vaccines is in immense demand globally. Numerous treatment and vaccination strategies that were previously employed for other pathogens including coronaviruses are now beingbeen adopted to guide the formulation of new SARS-CoV-2 vaccines.Several vaccine targets can be utilized for the development ofthe SARS-CoV-2 vaccine. In this review, wehighlightedthe potential of various antigenic targets and other modes of formulating an effective vaccine against SARS-CoV-2. There are a varying number of challenges encountered during developing the most effective vaccines, andmeasures for tackling such challenges will assist in fast pace development of vaccines. This review will give a concise overview of various aspects of the vaccine development process against SARS-CoV-2 including 1) potential antigen targets 2) different vaccination strategies from conventional to novel platforms, 3) ongoing clinical trials, 4) varying challenges encountered during developing the most effective vaccine and the futuristicapproaches.

The SARS-CoV-2, previously called as novel coronavirus, that broke out in the Wuhan city of China, is causing significant number of deathsand morbidity in the human population worldwide characterizing fever, respiratory illness, pneumonia [1] [2] [3] [4] .After China, countries that were affected disproportionately were South Korea, Iran, consequently the USA, India, Brazil, Spain, Italy, Germany, Turkey, Russia, United Kingdom and the France [5] .Thereafter 74,864,905 cases were reported in which 1,661,450 deaths took place worldwide as of December 17, 2020 [6] . The Beta-coronavirus is the genus and Coronavirdae is the family to which SARS-CoV-2 belongs. The SARS-CoV-2 is anSSRV having a 30 kb genome with fourteen ORF consisting of 4 major structural proteins that are nucleocapsid (N), Spike (S), membrane (M), and envelope (E) proteins [7] [8] [9] [10] . Rhinolophusaffinisbat coronavirus RaTG13 hasa J o u r n a l P r e -p r o o f 6 93.1% nucleotide sequence identical to that of Spike gene sequence of SARS-CoV-2 strains, however only less than 75% nucleotide sequence similarity to that of SARS-CoV. The SARS-CoV-2 viral S sequences as compared to SARS-CoV have 3 extra short insertions in the N terminal domain & 4 out of 5 key residues changes in the RBM of S protein RBD [9, 10] . The SARS-CoV-2 as well as SARS-CoV share similar HCR ACE-II, however,SARS-CoV-2 is more rapidly transmitted from humans to humans [1, 7, 11] . For the development of COVID-19 vaccine, the protein S that is a spikeprotein has become a major target, mainly based on the elicitation of viral neutralizing antibodies. The current scenario regarding the vaccine developmental process consists of, 1) 47 vaccine candidates in clinical trial 2) 155 vaccine candidate atpre-clinical stage [12] . and loss of TGFβ [25] . For the inactivated vaccines of the RSV and MERS-CoV after viral challenge, it has been documented that the Th2is associated with immunopathology [13, [26] [27] [28] [13] . It is therefore necessary that vaccines developed against COVID-19 should be carefully assessed while conducting clinical trials [29] . The epitope-rich S1 or RBD part of S protein is considered as a target instead of a whole full-length Spike for the development of a vaccine against MERS-CoV.

Owing to the dramatic rise in the number of cases of COVID-19 worldwide, numerous attempts have been stimulated to develop vaccines against this deadly J o u r n a l P r e -p r o o f SARS-CoV-22 virus.. About 47 vaccines qualified for clinical-stage entry and more than 155 vaccines are under investigation in the pre-clinical stages [30] .

None of the vaccines is having a license for any other coronavirus affecting human subjects like SARS or MERS. One of the significant reasons for the absence of vaccines is due to financial constraints. However other reasons also exist, including the design of the vaccines, transient immune-responsiveness, and toxicity concerns in pre-clinical models [31] . Due to several challengesoccurringin the development of the vaccine; discussed further in section 5.0 of this paper, developing a vaccine against COVID-19 is an onerous task to perform.Multiple methodologies are adopted for developing vaccines including both the next generation as well as conventional techniques. In the case of coronavirus, live attenuated vaccines has safety concerns however inactivated ones have been successful up to pre-clinical in the primate models [32] . In the case of COVID-19, within seven days, the immunized macaques challenged with SARS-CoV-2 were shielded from extreme ailment & virus levels, while placebo-subjected macaques endured SIN.The human phase I and II clinical trials of the inactivated vaccine are ongoing in China [30] .

The S protein of SARS-CoV-22 is the subject of several efforts. The S protein is an essentialmolecule for viral entry into the host cells, being present on the outer layer of the virus. The antibodies targeting the S protein will prevent the virus from entering the host cell, thereby preventing the virus from replicating inside the host cell machinery. [33] . On the 10 th of January 2020, the full genetic sequence of S protein was released globally providing an idea for the development of a vaccine [4, 10, 33] . The SARS-CoV-2 vaccines in the UK are based on S protein. The researchers at the University of Oxford have modified a chimp adenovirus vector that carries genes encoding this Spike protein.

Infecting human cells with this adenovirus will lead to the production of spike protein and became a valid target for the immune response. Approximately J o u r n a l P r e -p r o o f 8 1,000 subjects were recruited by the sponsor for phase 1 human clinical trial, initiated on 23 April 2020. [30] . A phase I/II preliminary study performed on the patient between 23 April and 21 May 2020 was published by the same sponsor in August.The vaccine has been reported to have a good safety profile along with both cellular and humoral responses produced. [34] .As of 11 th November 2020, the trial is under phase III, results of which are awaiting.The novel strategy for vaccine development is the use of mRNA; however, no licensed vaccines have previously used this methodology. The concept for mRNA is based on injecting mRNA encoding S protein and allowing host cell machinery to prepare the said protein. The merit of this methodology is allowing rapid scale production with a straightforward route. In the USA, mRNA vaccines against COVID-19 have entered clinical trials and interim findings from phase III clinical trials have indicated 90 per cent effectiveness in participants with no previous exposure to SARS-CoV-2 infection. [35] .

The vaccines which are already being developed for other ailmentsare repurposed for COVID-19 as an alternative means of virus control. There areseveral vaccines for other ailments other than COVID-19 globally, which are being re-investigated for coronavirus control. The BCG vaccine which is already marketed against tuberculosis can boost the immune system offering some protection in many ailments, from influenza to bladder tumors [36, 37] .

Many investigations have suggested an epidemiological correlation between reduced national occurrence of COVID-19 and community coverage of BCG. [38, 39] . There are about 5 clinical trials recruiting healthcare professionals to study whether BCG shows any protection against SARS-CoV-2 [30] . The other repurposed vaccines consist of OPV & MMR vaccine [40, 41] .

The scientists are now hypothesizing that BCG can offer protection to COVID-19, and some publications support this claim [42] . The basic crux behind the J o u r n a l P r e -p r o o f hypothesis is that the US and Italy have suffered high mortality because of COVID-19 than BCG vaccinated countries like Japan, South Korea [43] .

However,other multiple factors can give rise to COVID infection-related mortality in different places of the world. Many clinical investigations are ongoing to estimate BCG vaccination's effect on the possible responses from SARS-CoV-2 like in the Netherlands, The US, and Australia in the high-risk subjects (health care workers and older), whether it might provide protection [44] from COVID [42] . A study in Germany are investigating VPM1000, which is an rDNA vaccine candidate derived from BCG, could prevent older or health care professionals from SARS-Cov-2 [42] 

The relation of MMR vaccination and COVID associated death rate hasbeen suggested by the worldwide epidemiological data [44] . Several investigators did not agree to this statement for the live MMR vaccines other than BCG. Many countries like Latin American (Argentina, Ecuador, Chile) and Iran maintained more than ninety percent vaccine coverage from 1985 till the high death rate from SARS-CoV2 [44] . The MMR is a live attenuated virus-based vaccine.

MMR is currently in phase III clinical trial (NCT04357028) against COVID-19.

The hypothesis regarding the repurposing of the MMR vaccine is that antibodies can be generated against measles, which may cross-react with SARS-CoV2 [45] .

Much effort is being made to develop vaccine against COVID-19 on accounts to Table 1and Table 2 spleen. Delivery can also be done using the electroporation method [50] . There are some groups, on the other hand, working on a needle-free delivery system, for example, Immunomic Therapeutics, Inc./EpiVax, Inc./PharmaJet [51] . RNAbased vaccines are classified as conventional and self-amplifying RNAs.

Traditionally mRNA-based vaccines encode the antigen of interest and contain untranslated regionsfrom 5ʹ and 3ʹ, whist self-amplifying RNAs(same RNAs) encode viral replication mechanism in addition to viral antigen permitting intracellular RNA amplification and profuse protein synthesis [52] .Notwithstanding the numerous advantages of nucleotide vaccines,there are no approved mRNA/DNA vaccines so far available for the public used. If any vaccine for COVID-19 happens to be from this category then it will be the first of its kind. November 2020, Pfizer and BioNTech announced that their vaccine candidate demonstrated evidence of efficacy in 90% of participants, who were not exposed to SARS-CoV-2 infectionbefore injection,based on the first interim efficacy analysis from the Phase 3 clinical study [35] .

Vectored vaccines are constructed from a carrier such as adeno or pox virus which has been modified to contain a gene from the virus of interest [58] . The platform is broadly classified as replicating and NRVV.

Ads are extensively studied vectors for vaccine development attributable for its few potential benefits including their capacity to taint a wide range of hosts and to initiate elevated levels of transgene expression without the capability of the infectious viral gene being incorporated into the host genome; moreover, Ads can be fabricated safely and cheaply. Adenoviral vectors can be made nonreplicating by removal of the fundamental gene for replication (E1 genes).

J o u r n a l P r e -p r o o f genes.Asthe E1 gene stays intact, as an outcome, these vectors have restricted ability for foreign gene insertion in comparison to RDV [59] .

Extensively studied Ads are human Ads serotype 5(AdHu5) but because ofthe high frequency of AdHu5 neutralizing antibodies (NAs) found across the human populace, the efficiency of gene transfer by the vector is affected leading to diminishing potency of the vaccine. To beat this issue, Ads procured from numerous different species are tried to fill in as potential immunization vectors.

Ads derived from chimpanzees were found to be advantageous as AdCs can be easily produced in a human cell line. Moreover, in comparison to human serotypes of Ad (AdHus),their seroprevalence in the human population is low, because they rarely circulated in humans [60] AdCsare currentlybeing utilized forthe development of the COVID-19

vaccine, for instance, asingledose of avaccine candidate, ChAdOx1 nCoV-19

(Oxford University/ AstraZeneca) has demonstrated to protect six rhesus macaques from the incidence of pneumonia invoked by the virus. The vaccine manifested safety profile within an acceptable range and subsequent booster doses increased antibody immune responses in phase I/II single-blind, randomized control trials [34] . There are many more vectors being investigated for their efficiency as vaccine candidates. 

Subunit vaccines incorporate just the parts, or antigens, that best invigorate the immune system framework. Since there is no live fragment involve, there is no danger of prompting a disease [61] . Subunit antibodies can be additionally classified into Protein-based subunit vaccines, Polysaccharide vaccines, and Conjugate subunit vaccines [48] . Protein subunit vaccines are more steady and safer than live attenuated and inactivated/killed vaccines. They can be manufactured in a more cost-efficient manner as compared to other types of vaccines [47] . A shortcoming of this strategy is that if isolated proteins get denatured, may bind to different antibodies than the targeted protein of the pathogen [48] . Centre are testing their unique ADDomerTM multiepitope display vaccine tech in animals. ADDomer is an ADMP-based self-assembling nanoparticle scaffold constructed to promote the plug-and-play display of numerous immunogenic epitopes from pathogens. What is unique about ADDomer-based vaccines is that it is thermostable thus making it free from cold storagerequirements [66] .

However, safety and efficacy in preventing SAR-CoV 2 infection are not proved yet. 

The passive immunization is an old procedure however reegrading SARS-CoV2 it is gaining scientific importance. The non availability of therapies against COVID-19 has triggered a pandemic, and now every scientific way is is being utilized to takle this crisis. The available reports of passive immunization against COVID-19 was intiated by Chinese and south Korea researchers [68] . A lot of publications have reported that passive immunization could be a great alternative unless and until some effective treatments are available like vaccines [69] . It was reported by Shen et al. that the application of convalescent plasma could be an available approach against COVID-19 subjects suffering from respiratory failure and with this approach they reported success in JAMA. In about five patients the passive immunization was effective with a decrease in viral load within 12 days after the transfusion however these antiviral drugs were not showing any effect [69] .

It has been reported that MSC therapy could act as a potential candidate for COVID-19 by treating ARDS and the hypercytokinemia [70] . There are about thirty-one clinical trials registered on the NIH CTD which are going on, that are selectively for COVID-19 despite the absence of any pre-clinical evidences in covid models [70] . Due to COVID-19 the death rate is rising the MSC are being investigated in the clinical settings to find out that whether it can show some proming outcome in the corona positive subjects. The subjects who received the MSC demonstrated lower TNF-α and high IL-10 levels as compared to placebo, but only three subjects were included in the study, so MSC can have a great potential in treating COVID-19 [70] .

Structural proteins that are coveringthe SARS-CoV-2 surface serveas potential vaccination targets. These structures include the protein S, the protein E, protein M and the protein N [46] Table 4 ). The potential components of S protein for use as antigens include the FLSP, the RBD domain, the S1 subunit, the S2 subunit, the N-terminal domain (NTD), and membrane fusion peptide (FP) [72] The S protein of coronaviruses is essential in promoting viral entry into target cells. Several researchers have discoveredS2RBD in S protein and found that the RBD protein firmly binds to hACE2 receptors. The investigation further affirmed SARS-CoVRBD(S-RBD) generated antibodies that cross-react with S2-RBD protein, and S-RBD-actuated antisera cross-kill SARS-CoV-2, recommending the possibility to create SARS-CoV RBD-based immunizations for counteraction of SARS-CoV2 infection [73] Most advanced spike protein-based candidate, ChAdOx 1 vaccine developed by the University of Oxford Jenner Institute. The vaccine contains the optimized full-length surfaceS glycoprotein sequence of SARS-CoV-2, with a TPA asa leader sequence. It uses a RDCA to deliver a SARS-CoV-2 S protein to induce a protective immune response [34] . The evidence for the effectiveness of the ChAdOx 1 was increased after researchers confirmed that the single-dose protected 6 rhesus macaques from the incidence of pneumoniainvoked by the SAR-COV-2 [74] . 

No vaccine that is explicitly focusing on nucleocapsid protein has entered clinical trials, however, ImmunityBio, Inc. &NantKwest Inc. vaccine candidate that is a Human Adenovirus Type 5 Vector (hAd5) encoding Spike (S) + Nucleocapsid (N) have entered phase I of a human clinical trial [12] . 

The M protein of coronavirus has a vital role in virus assemblage [80] . M is positioned amidst S proteins in the virus envelope alongside modest quantities of E and is the prime component in initiating the virus budding process. In the course of viral assembly, M interacts with several other SPsincluding N protein, with E protein, S protein, and also with itself [81] . Significant CD4+ and CD8+

T cells mediated immune responses were identified against S2M protein during the recent studies conducted in the virus-infected and recovered patients. S2M

was recognized significantly and notable reactivity was observed [82] . Past function in viral pathogenesis [84] . A group recently designed the TCEBPIfor COVID-19 using the envelope protein as a target by utilizing an immunoinformatics approach. The designed vaccine however requires thorough testing to guarantee its safety and immunogenic profile [85] . S2E protein is 100% homologous to bat coronavirus and the pangolin coronavirus. Also, lessthan 95% of sequence similarity was noted between the S2E protein and the E protein sequence of SARS-CoV [84] . It is therefore suggested to carry out J o u r n a l P r e -p r o o f further investigation to determine and confirm the immunogenicity and efficacy of E protein as a potential vaccine target.

Nsp3 contains several functional domains that are important in assisting viral pathogenesis. During the phylogeneticand MSA study of nsp3 protein, It was reported that this protein in SARS-CoV-2 was more analogous to the human coronaviruses (SARS and MERS), and bat coronaviruses (HKU3, HKU4, and HKU9).nps3 can serve as a potential vaccine target, further,an investigation is therefore suggested to validate its potential [78] 

i) Should be safe, even in immunocompromised people. ii) Should be highly effective and optimally induce 'sterilizing' immunity [86] . iii) Should retail immunogenicity despite adverse storage. iv)Inexpensive v) Free from toxicity and adverse effects vi) Should give long term protection vii) Should have high thermal stability.Vaccine development is a lengthy, expensive process and many challenges arise during the development, manufacturing, and mass distribution.

The major challenge in developing COVID 19 vaccine is the fast-tracking of every step in the discovery, development, and evaluation process. This was not the case before the pandemic, asfor any new vaccine to enter a commercial market and be widely available in the public domain, follows extensive safety and efficacy evaluation which usually requiresa minimum duration of 5 years.

However, due to an expedited increase in the number of COVID -19 cases worldwide, vaccine regulatory authorities both at international and national J o u r n a l P r e -p r o o f levels are forced to fast track every process of development to meet the world's immediate vaccine requirement. Thescientificcommunities are using multiple approaches to shorten development phase including overlapping clinical phase and using advanced computer-aided and biotechnological tools.

The fast-tracking ofprocesses arisethe risk of increased side effects. There is an immense possibility that some essential data might go missing or unnoticed at this accelerated speed of development. Researchers are concern about the risk to instances of polio, leaving 200 youngsters with differing degrees of paralysis and several deaths [87] . Therefore manufacturing methodology has to be extremely audited and validated; manufacturers should be extremelymeticulous in producing large quantities of doses of vaccine. This will be challenging during the present race to license the first COVID-19 vaccine and mass-produce a large number of doses.

Ideally, vaccination should provide long term protection. However, immunization induced resistance blurs after some time and the loss of protection varies with every disease [88] . Two doses of inactivated polio antibody (IPV) are 90% effective or more against polio and three doses are 99%

to 100% effective and the duration of protection lasts for several years to decades [89] . Most promising SARS-CoV2 vaccine candidates in clinical trials require booster doses. It is too early to say any of it provides long term protection.

Reinfection is another major aspect affecting theprotection period. A very recent study has confirmed reinfection with genomic evidence. It was concluded that SARS-CoV-2 might flow among the human populace regardless of crowd insusceptibility on account of general infection or immunization.

Additionalmonitoring of patients with reinfection will help optimized vaccine design against SARS-CoV2 [90]

In the early pandemic situation, there was concern among the scientific community over mutations arising in SARS-CoV-2. However recent studies have indicated no cause for concern.The outcomes of phylogenetic examination of various SARS-CoV-2 strains procured from various nations showed that all the glycoproteins of various strains of SARS-CoV-2, obtained from various nations were strongly related to each other; hence antibody structured against one strain would be successful against the various strains of SARS-CoV-2 from various nations.Nevertheless, it is essential to continuously monitor genomic sequence given the knowledge of previous experience on virus mutation rate [91] . 

Even if a single vaccine is proven safe and efficacious, large scale manufacturing and distribution will be challenging especially if vaccine candidate belongs to novel technologies as very few manufacturing plant have previous experiences in mass production. The establishment will have to comply with the GLP guidelines for the particular vaccine candidate. Setting up new premises and infrastructures for vaccine production which is meeting complete quality guidelines will have cost involving. Also in the current global rush to develop a vaccine, there is a possibility that this very crucial compliance step might miss adequate attention; posing a potential danger.The challenge is to vaccinate the entire world population. Experts worry that this might be physically difficult to achieve owing to resource scarcity. Also, there should be production balanced against the need for other vaccines. The kind of infrastructure needed for production will depend on the type of vaccine. The world's governments and companies need to invest enough money so that vaccines can be made quickly available. Financial losses may also occur if the pandemic is ended before development phases are completed as experienced from previous epidemics like SARS.

So far researchers have assured vaccines for SARS-CoV2 will be ready within a few months. If the first licensed vaccine happens to be from a novel technology platform, it will lead to a revolution in the vaccine development landscape.

Since these platforms utilize machine learning,immunoinformatics, biotechnological tools,genomesequencing, and other in-silicoapproaches to J o u r n a l P r e -p r o o f arrive at the most promising hit molecule, aiding in the reduction of the duration of vaccine development significantly. It will change how we will respond to future emerging virus infection. Some of these candidates have loosened animal toxicity studies and started directly dosing in humans. If such vaccines are successful in justifying such a break from the usual protocol, usage of animal models will also change. International and national vaccine regulatory authorities might be required come up with newer guidelines in conducting preclinical and clinical evaluation studies with thecondition that novel vaccine candidate is successful in providing immunity against the virus for a more extended period.

Post-licensure vaccine safety assessment is a long term assessment of adverse event occurring post-vaccination. It is necessary for detecting vaccinerelated rare and LTAEs and keeping uppeople'scertitude in vaccines and following immunization schedules [95] . Such surveillance has to be conducted meticulously using either active or passive methods to determine AEFI/ADE or if there is a decrease of immunity.

Keeping entire hope on a vaccine to end the pandemic should not be encouraged. Because of the wide challenges highlighted above, it will not be a quick process to reach the vaccine shots to each individual. According to WHO, world leaders andthe public must follow and come up with a novel social measure to reduce viral concentrates within the human populace.

More study is required urgently to reach the most successful vaccine candidate in order to minimize the increasingly growing number of cases of COVID-19

that have exceeded 74,864,905 worldwide to date (17 th , December 2020).The need for thorough review of testing methodologies is just as critical as its urgent obligation to ensure that vaccines produced are free from long-term and short-J o u r n a l P r e -p r o o f term toxicity and adverse effects.Since the vaccine alone cannot combat the pandemic, modern preventive social strategies are needed so that the world can battle the present pandemic and be able to face another pandemic if it occurs in the future.

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We are highly thankful to AICTE,NIPER-Hyderabad, NIPER-Guwahati, and IIT-Ropar for the fellowships.J o u r n a l P r e -p r o o f