Abstract

To this day, coronavirus has not shown signs of ending, and appeared in different variants, so the need for the development of vaccines and drugs has increased. The article describes the latest development, platforms, strategies, and challenges in the development of COVID-19 vaccines.

Keywords

SARS-CoV-2, challenges, platforms, and progress

Background

In late 2019, a type of pneumonia was identified in Wuhan, China, and the cause was reported as a unique betacoronavirus, which was later named SARS-CoV-2. One of the characteristics was that it rapidly spread over 200 countries, with 12.2 million cases and half a million deaths by July 11, 2020, and not only affected health, but also the global economy.

Coronavirus is a positive-sensitive single-stranded virus encapsulated and four classes have been discovered: alpha, beta, gamma, and delta. The virus has 8-10 open reading frames (ORF), translated into proteins (ORF 1a → pp 1a/ ORF 1B → pp 1b), containing RNA-dependent RNA polymerase (RdRp) enzymes. Then, the RNA is replicated creating 6-9 proteins  (envelope - E, membrane - M, nucleocapsid - N, and spike - S).

The virus enters through the S protein to the cell, then, it releases ssRNA which is converted into polyprotein and turned into proteins. SARS-CoV-2 attacks the respiratory system to cause viral pneumonia with gastrointestinal, heart, liver, kidney, and central nervous system disorders, leading to multiorgan failure.

Methodology

The review includes articles from Pubmed, articles from early April 2020, and from the current times related to the genomic characterization of COVID-19 and vaccine-induced immunological responses. 

SARS-CoV-2 Genomic Characterization

Genome analysis from 9 patients showed that SARS-CoV-2 was closely related (90%) to bat-SL-CoVZXC21 and bat-SL-CoVZC45 (bat coronavirus). The genome contains 12 regions and all encoded proteins are the same length, except for the S protein. It is divided into S1 domain protein (binding to the receptor), 63% equal to the bat virus, and the S2 domain protein (cell membrane fusion), 93% equal to the bat virus.

Another comparison was done to the receptor-binding domain (RBD), which binds the virus to the receptor. The RBD of SARS-CoV-2 is more similar to SARS-CoV than to betacoronavirus because it has a core and external subdomain.

B cell epitopes have 10 regions from which, 6 had 90% identity, 2 had 80–90% identity, and 2 others had <80% identity. A test (IEBD) showed that the surface glycoprotein has the highest number of B cells.

6 identical epitopes were identified in the S protein between SARS-CoV and SARS-CoV-2. This similarity suggests that the vaccines can be SARS-CoV-derived epitope-based or SARS-CoV-2 epitope specific.

A recent study showed that SARS-CoV-2 has developed into three variants differentiated by the amino acids. The first variant was the most similar to bat coronavirus but was altered with various mutations. The second variant, adapted itself to resist a larger population and different environment. And the third variant, derived from the second variant with a special mutation to replace nucleotides (Europe, Hong Kong, Taiwan, and South Korea but not China).

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Immunological Mechanism of Vaccines

Vaccines are mostly done with neutralizing antibodies, but T cell-based vaccines ( T cell derives from Naive CD4+) work just as well or even better (used for protection against malaria, HIV, and tuberculosis) because they can persist for long periods and provide protection against subsequent infections.

The memory of T can be controlled by reducing the contraction phase, stabilizing the memory phase, and encouraging the clonal expansion phase. The last one, depends on the mobilization of antigen-specific T cells to dendritic cells (DCs → produce different types of immune responses). These interactions between DC and T cells are influenced by the amount of cytokines secreted by DCs (induce T cells to produce interferon-y (gamma) that is essential for intracell communication)

As T cells can be useful for the production of vaccines, it is important to target their functions.

Regulating the quality and persistence of the antibody responses from a T cell is key in the development of vaccines. These responses occur when activated antigen-specific B cells move toward the surface between B cell follicles and T cell areas, and there is a clonal expansion of B where some B cells turn into plasma cells and others, into gremial centers.

COVID-19 Vaccine Development

Vaccines are the most effective way to prevent infectious diseases and at this time, the development of a SARS-CoV-2 vaccine is urgent. The mapping of S glycoproteins and epitopes of SARS-CoV-2 can accelerate the development. RNA vaccines are shown to be the most effective for this case because vaccines that stimulate antibodies take lots of years to make. 

Challenges in developing COVID-19 vaccines

An ideal platform technology to produce vaccines would accelerate development to 16 weeks, show consistent immune response, and be suitable for large-scale production. But the new technology is not able to do that because the optimization of the S protein antigen is still debated since SARS vaccine candidates showed lung disease susceptibility.

Because vaccine development is a long and expensive process, the developers tend to follow linear stages pausing several times for manufacturing process control and data analysis. However, this rapid development because of the pandemic, required to do steps in parallel without waiting for approval (such as testing in animals before phase 1 is approved), which increased the financial risk. 

The great challenges for the development are the evaluation of safety (does not cause adverse immune response); if there are qualified developers for the vaccine; if the production requirements will be accepted in other countries; and any political and commercial obstacles. 

SARS-CoV-2 vaccines under development

Until 7th July, 2020, more than 160 vaccine candidates were presented. Eight technological platforms and several types of vaccines have been proposed (see Table 1).

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Replicating and non-replicating viral vectors

Viral vectors are tools designed to deliver genetic material into cells, and can be classified as replicating and non-replicating. Replicating Viral Vectors are the measles virus (MV) and vesicular stomatitis virus (VSV). The first one is used for HIV, HBV, mumps, and SARS vaccines because it provides cellular and humoral immunity over long periods (25 years); is genetically stable; and doesn't cause integration. The second one is used for SARS-CoV-2 vaccine because it replicates in the cytoplasm, which avoids modifying DNA; has a high expression of the transgene due to cessation of the translation of host cell mRNA, easy production processes, low level of prior immunity, and ability to be administered through the mucosa. Non-Replicating Viral Vectors are adeno-associated viruses, alphaviruses, and herpesviruses. Furthermore, there are Adenoviruses (Ads), which contain both vectors, and are the most common vector in vaccine development because it is safe, physically and genetically stable, and can infect DCs and dividing or non-dividing cells.

mRNA vaccines

mRNA-based vaccines are limited to infectious diseases and can also be used for cancer. It is convenient because it has a short production cycle, low production cost, and safe delivery; and it is being produced by Moderna, Inc. in silico so that it is performed faster.

DNA vaccines

DNA vaccines inject plasmids encoding antigens to generate a broad immune response. They are considered better than mRNA as they have superior stability and delivery efficiency. However, as they need to get through the nucleus, they can develop a mutation. The primary advantage of this vaccine is its ability to induce antibodies and immune cells through intradermal delivery.

Inactivated and LAVs

Inactivated vaccines and live-attenuated vaccines (LAVs) have antigenic components and can induce a broad immunological response. Although inactivated vaccines, produced from physically or chemically killed microorganisms, cannot always induce an immune response or a long one (many doses should be applied), it has no risk of inducing disease. 

Pathogens in LAVs, created in the 1950s from attenuated viruses and bacteria, can grow to a certain extent in the vaccinated individual, and not cause disease or produce only mild symptoms, which stimulate good immune responses until the stage in which memory cells are formed. However, attenuated pathogens can still return to their original form and get the disease, so individuals with weak immune systems may not be able to get LAVs. It has a wide range of errors.

Virus-like particle vaccines (VLPs)

VLPs are a supramolecular structure of multi-proteins and carry various characteristics of a virus, without having infectious properties (because they don't carry genetic material). They can be produced in bacteria, insects, fungi, mammalian cells, and, interestingly, plant cells; and when induced, they don't cause side effects. HBV and HPV vaccines are currently available. They carry antigens in a dense and repetitive manner and effectively generate crosslinking of B cell receptors (positive). VLP vaccines are designed to target B cells and induce antibody responses.

Protein-subunit vaccines

Subunit vaccines contain one or more antigens with strong immunogenicity. The vaccine is safe and easy to produce but requires the addition of adjuvants to induce a strong immune response. They don't contain living organisms (as inactivated vaccines), but the formation of memory cells is uncertain. Protein-subunit vaccines are divided into protein subunit-based vaccines, polysaccharide vaccines, and conjugate subunit vaccines. As the name explains, these vaccines don't use viruses, they use specific pathogenic protein isolate, but the denaturation of the protein may bond with non-target antibodies. Several institutions are using this platform to develop the COVID-19 vaccine.

Peptides or synthetic epitope-based vaccines have also been investigated, and only contain a few fragments of antigens. However, the low molecular weight and structural complexity of the antigen render its immunogenicity relatively weak, so modifications in its structures are needed.

Conclusion and Future Prospects

COVID-19 pandemic has exceeded original expectations, therefore, the only way to stop it is through vaccine development, which turns it into a global priority. Vaccine making is a long and expensive process so new methods have been introduced to the market. Till date, there are 160 vaccine candidates, of which 21 have passed phases 1, 2, and 3. However, the most important thing is that the vaccines are safe and efficient. High-risk individuals and medical personnel should be the ones to receive it first. And high-income countries must be prohibited from monopolizing global supplies so that the vaccine is accessible to everyone.

References

Sumirtanurdin R. and Barliana M. (2021, April 16). Coronavirus Disease 2019 Vaccine Development: An Overview. Libert Pub.

liebertpub.com/doi/10.1089/VIM.2020.0119