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ACADEMIA Letters New Generation Vaccine Strategies against COVID-19 susmita mitra The emergence of a previously unknown virus in Wuhan, China in late 2019 has resulted in the ongoing coronavirus disease 2019 (COVID-19) pandemic. The pathogen that causes COVID19 is the severe acute respiratory syndrome coronavirus (SARS-CoV-2), a beta-coronavirus homologous to SARS-CoV [1] and the Middle East respiratory syndrome CoV (MERS43CoV) [2]. The easy transmission ability of the virus has led to widespread infection and death worldwide. SARS-CoV-2 causes a spectrum of clinical manifestations ranging from asymptomatic, minor flu-like symptoms to acute respiratory distress (ARDS), pneumonia and death. In a bid to control the spread of this disease several vaccine candidates have been generated or are under investigation. Research and development has been fast paced, and the landscape is changing rapidly with many countries now approving and launching vaccination campaigns. 11 approved vaccines are in use, and several in clinical trials. These diverse types of vaccine candidates face challenges related to the development, manufacturing, storage, distribution and mass vaccinations. Development of multiple vaccine candidates boosts confidence that should one vaccine fail in clinical trials there are alternatives available. Safe vaccines that are effective at low doses, simple to produce and stable outside a freezer would facilitate vaccination on a global scale; ethically and equitably. As vaccination progresses the pandemic will subside but the virus is here to stay; once most people are immune, following natural infection or immunization, it will be no more a threat than the common cold. The candidate vaccines being investigated use various technologies and platforms. These ranges from the traditional viral-vectored vaccines: live attenuated and inactivated virus, as well as bacterial vectors; to the new-generation vaccines: protein subunit, nucleic acid (DNA, RNA), virus-like particles and nanoparticles [3]. In viral vector based vaccines, the antigen is cloned into the vector that lacks the ability to multiply. Common vectors include lentivirus, adenovirus and adeno-associated virus. These imitate the viral infection disease state; thereAcademia Letters, April 2021 ©2021 by the author — Open Access — Distributed under CC BY 4.0 Corresponding Author: susmita mitra, susm58@gmail.com Citation: Mitra, S. (2021). New Generation Vaccine Strategies against COVID-19. Academia Letters, Article 656. https://doi.org/10.20935/AL656. 1 fore can produce stronger cellular immune responses [4]. Bacterial vector is another option where the non-pathogenic lactic acid bacteria (LAB) are the most promising candidate [5]. Symvivo’s bacTRL-Spike uses LAB as vector and is currently in clinical trial. It is safe, cheap and can be lyophilized to provide better stability profile. Some of the approved viral vectors for use in the worldwide vaccination drive are the non-replicating viral vectors AZD1222 (Oxford /Astra Zeneca), Sputnik V (Gamaleya), Ad5-nCoV (CanSino), Covishield (Serum Institute of India), Ad26.COV2.S (Janssen) and inactivated viral vectors CoronaVac (Sinovac), Inactivated (Sinopharm), BBIBP-CorV (Sinopharm), Covaxin (Bharat Biotech). The non-replicating vectors introduce a mild infection leading to a strong immunological response with long lasting memory; but they have the potential to infect people with compromised immune systems or revert back to virulent strain [6]. The inactivated vaccine is relatively safe, but a defect in the manufacturing process may cause a disease outbreak. Also it is low on immunogenicity, requiring multiple doses to establish immune memory. The new generation vaccines, including recombinant protein vaccines and non-viral vector based vaccines incorporate a specific antigen /antigens from the pathogen, giving a better safety profile [7]. Designing a successful new-generation vaccine requires a thorough understanding of the structure and immune-pathogenesis of the virus. The SARS-CoV-2 is a single stranded positive-sense RNA virus with four main structural proteins including spike protein (S), envelope protein (E), membrane protein (M) and nucleocapsid protein (N). The S proteins are located at the outer surface and can bind to angiotensin – converting enzyme 2 (ACE2) on the host cell surface allowing receptor-mediated endocytosis [8]. The SARS-CoV-2 spike protein is a trimer of S1-S2 heterodimers. The S1 subunit contains a receptor-binding domain (RBD) that binds to ACE2 on host cells to initiate infection. The S2 subunit consists of a fusion peptide (FP) and heptad repeat regions 1 and 2 (HR1 and HR2). Upon endocytosis the S1 subunit is cleaved off to facilitate the FP insertion into the host membrane, while the remaining S2 refolds to bring HR1 and HR2 together to fuse the viral and host cell membranes. The spike protein harbors all neutralizing antibody epitopes and is the main target for vaccine development against SARS-associated CoVs [9]. Most COVID-19 non-viral vector based vaccine candidates use the S-protein fragment, or the receptor binding domain (RBD) as the antigen. Development of new-generation vaccines was initiated following the publication of the complete genome sequence of SARS-CoV-2 on 10th January 2020 [10]. In theory, the recombinant protein vaccines can be developed solely from the sequence information, using the RBD / RBD fused with carrier protein as antigen [11]. But it usually induces only specific humoral immune response, providing partial protection against infections. Therefore, an adjuvant is required to enhance immunogenicity. Several protein sub-unit vaccines under development are EpiVacCorona (FBRI), RBD-Dimer (Anhui Academia Letters, April 2021 ©2021 by the author — Open Access — Distributed under CC BY 4.0 Corresponding Author: susmita mitra, susm58@gmail.com Citation: Mitra, S. (2021). New Generation Vaccine Strategies against COVID-19. Academia Letters, Article 656. https://doi.org/10.20935/AL656. 2 Zhifei Longcom) and NVX-CoV2373 (Novavax) that has used Matrix-M as the adjuvant [12]. Following endocytosis by the antigen-presenting cells (APC), a small fraction of the digested fragments is presented to the major histocompatibility complex (MHC) II molecules, triggering downstream immune responses. DNA and mRNA vaccines have a better safety profile but have low transfection efficiency. Plasmid DNA is relatively stable and can be freeze dried for long term storage, but requires various transfection modalities [13, 14]. Inovio’s DNA-vaccine INO-4800 uses an electroporation device, CELLECTRA (INOVIO 2020). mRNA vaccines can be produced via solid-phase synthesis process; this is an advantage from a quality standpoint and allows quick product switching in manufacturing facilities. mRNA-1273 (Moderna), BNT162 (BioNTech/Pfizer), CVnCoV (Curevac) are vaccines in use/in-development. To counter the low transfection efficiency of mRNA, lipid nanoparticles (LNPs) are often used. A typical LNP formulation consists of an RNA condensing lipid, helper lipid and lipidized- polymer coating to modify the surface properties [15]. The 1,2-dioleoyl-3trimethylammonium propane (DOTAP) and dilinoleylmethyl-4-dimethylaminobutyrate (DLinMC3-DMA) are the two common commercially available lipids for this purpose. mRNA-1273 is a LNP – encapsulated mRNA vaccine that encodes the S protein, given as two intramuscular injections [6]. The vaccine candidate BNT162b1 encodes the RBD and incorporates modified mRNA and also includes a T4fibritin- derived trimerization domain to enhance immune response [17]. NVX-CoV2373, a recombinant spike protein adjuvanted with lipid nanoparticles (NPs), was reported to elicit high neutralizing antibody titers in human trials that were on average four-fold greater than in convalescent patients [18]. Several SARS-CoV-2 vaccine compositions in the pipeline are using nanotechnology-enabled formulations. A plant-based virus-like particle [VLP] (Medicago) is in Phase III trials. Nanoparticle vaccines balance the effectiveness of viral vector based vaccines with the safety and ease of production of sub-unit vaccines. A silver lining of the COVID-19 pandemic is that the fast-tracked vaccine development has advanced the clinical translation pathway for nanomedicine drug delivery systems. Self-Assembling nanoparticle vaccine candidates have been developed; the molecular structure of the vaccines roughly mimics that of a virus which may account for its ability toprovoke enhanced immune response. An ultra-potent nanoparticle vaccine candidate has been developed using structure –based vaccine design techniques invented at the Institute of Protein Design, School of Medicine,University of Washington, USA. This protein nanoparticle displays 60 copies of the SARS-CoV-2, S-protein receptor binding domain (RBD) in a highly immunogenic array. Immunization with this vaccine induced a strong B-cell response in mice and non-human primates, produced neutralizing antibodies targeting multiple different sites on the SARS-CoV-2 S-protein; this is thought to be critical for immune memory and a durable protective effect. The researchers suggested that this may allow the vaccine to Academia Letters, April 2021 ©2021 by the author — Open Access — Distributed under CC BY 4.0 Corresponding Author: susmita mitra, susm58@gmail.com Citation: Mitra, S. (2021). New Generation Vaccine Strategies against COVID-19. Academia Letters, Article 656. https://doi.org/10.20935/AL656. 3 protect against mutant strains of SARS-CoV-2, should they arise. The potency, stability and manufacturability of this vaccine candidate differentiates it from many others under investigation [19]. Biochemists at Stanford University, California, USA, have created a prototype of a COVID-19 vaccine based on the nanoparticles of Ferritin. The distinctive surface S-proteins of SARS-CoV-2 are attached to the particle subunits. Researchers claim that this is a single shot vaccine that could be shipped and stored in a freeze dried powder form [20]. Most other vaccines farthest in development needs to be stored at cold temperatures [approx. 8oC to 70oC]. A California Institute of Technology group has developed a cage-shaped 60 subunit protein based nanoparticle onto which up to 8 different types of RBD have been attached [21]. This vaccine platform called a mosaic nanoparticle was developed initially by collaborators at the University of Oxford. It produces antibodies that react to a variety of different coronavirus strains; this is an advantage over traditional vaccine methods that are effective against only a single type of virus. Importantly the antibodies were reactive to related strains of coronavirus that was not present on the nanoparticle surface. Unfortunately, SARS-CoV-2 is unlikely to be the last coronavirus to cause a pandemic, there is hope that this technology could be used to protect against COVID-19 and other coronaviruses with pandemic potential. Nanoparticles modulate immune response with higher efficiency than the soluble form of antigens and can be functionalized with the positively charged moieties and ligands of targeted cells, such as dendritic cells, to increase cellular uptake of the antigens and their presentation on the surface of immune cells. The efficacy of nano-based vaccines may be attributed to the improved antigen stability, minimum immuno-toxicity, sustained release, enhanced immunogenicity and the flexibility of physical features of nanoparticles. Based on these, the nano-based vaccines have potential to evoke both cellular and humoral immune responses. Targeted and highly specific immunological pathways required for solid and long lasting immunity may be achieved with specially engineered nano-vaccines. Academia Letters, April 2021 ©2021 by the author — Open Access — Distributed under CC BY 4.0 Corresponding Author: susmita mitra, susm58@gmail.com Citation: Mitra, S. (2021). 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