The Perspective of Covid-19 Vaccines: What Needs to Be Known and Its Expected Effect on the Human Population?

Background: The COVID-19 pandemic is a devastating blow to the entire world community and changes the order of human life. Purpose: All efforts and strategies are being carried out to contain and reduce the spread of the SARS-CoV-2 virus by tightening the health protocol and using vaccines for the public. Currently, several vaccines are available and have passed phase 3 clinical trials, such as vector vaccines (Gamaleya Sputnik V Russia, University of Oxford/AstraZeneca, CanSino, and Janssen Pharmaceutical Companies), mRNA-based vaccines (Moderna/BioNTech/Fosun Pharma/Pfizer), inactivated vaccines (Sinovac and Sinopharm from China, Covaxin from Bharat Biotech India) and adjuvanted recombinant protein nanoparticles (Novavax from the USA), which are expected to be able to suppress the spread of the virus and produce a minimum of 70% herd immunity in a population. This study uses a narrative review from reputable publications and is closely related to the topic. Result: Each vaccine’s efficacy varies from the lowest, namely, the Sinovac vaccine (CoronaVac) 50%, to the highest the Novavax vaccine (NVX-Cov2373) 96% effectivity value. However, further rigorous research is still being carried out to develop an effective and efficient vaccine. Health workers are the last bastion to handle COVID-19 patients. Conclusion: The primary purpose of the present immunization is to prevent and minimize the spread of COVID-19. At this time, the availability of a variety of vaccines is expected to provide strategic answers to the pandemic scenario that has afflicted countries all over the world.


Introduction
The vaccine strategy is an appealing and effective medical approach for controlling the coronavirus type 2 that causes a severe acute respiratory syndrome, stopping its spread, and protecting patients who are at high risk of infection [1].
The vaccination process has taken place in all countries, including Indonesia and Malaysia. Vaccination is anticipated to provide herd immunity to a minimum of 70% or 80% of the population [2].
The evaluation of patients positive for SARS-CoV-2 revealed that the antibody binder and leading bidders targeted receptor-binding domain subunit S1 (Spike 1) [3]. One of the main challenges when making vaccines is how effectively the vaccine can generate an immune response in the human body instead of the vaccine's safety. Characteristic responses such as immunity include the formation of neutralizing antibodies, the construction of T cell responses, and the prevention of disease following immunization (response induced by the vaccine causes an increase in the severity of illness) [4]. Innate immunity, which serves as our immune system's initial line of defense, is critical in defeating SARS-CoV-2 [5].
Medically and biologically, the genetic variety of viruses that result from mutations is very important because it has a big impact on how infectious diseases are prevented and how they can be treated, as well as how vaccines are used [6].  [7] are facilitating rapid viral spread [8] [9] that may interfere with the effectivity of the vaccine program.

COVID-19 Vaccine Development
Vaccines have prevented measles, polio, hepatitis B, and many others as preventive infectious diseases in recent decades. People who get vaccines have a much lower risk of getting sick because they teach the immune system how to look for and fight pathogens like viruses or bacteria [10]. Vaccine development has several clinical stages before being used in humans.
The steps were preclinical studies, clinical trials (Phases I, II, III), marketing surveillance, and human challenge studies. The vaccine is tested in animals for efficacy and shows safety in the preclinical step. In a clinical trial, the vaccine was tested on a small healthy group (Phase I) and then a large group (Phase II) to thousands for efficacy and safety (Phase III) [11]. Ongoing studies after the vaccine are approved and licensed; Phase IV is used to monitor adverse events and study the vaccine's long-term effect on the population. In the last phase, Journal of Biosciences and Medicines studies are given, followed by pathogen administration which the vaccine is designed to protect. Such trials are uncommon in people, as they present considerable ethical challenges [12].
Most research on the COVID-19 vaccine shows that there are more differences in vaccine development. Normal vaccine development for each step-in sequence but fast-track vaccine development for COVID-19 were performed in parallel [13]. This affects several things, such as the financial risk for the industry to product effectiveness and efficacy (Table 1).
There are many different COVID-19 vaccines in development using other technologies. New manufacturing platforms, structure-based antigen design, computational biology, protein engineering, and gene synthesis have provided tools to make vaccines with speed and precision. Antiviral vaccines were classified into two broad categories. Gene-based vaccines deliver gene sequences that encode protein antigens produced by host cells [10]. These include live virus vaccines, recombinant vaccine vectors, or nucleic acid vaccines. Protein-based vaccines include whole-inactivated viruses, individual viral proteins or subdomains, or viral proteins assembled as particles, all of which are manufactured in vitro. Recombinant vaccine vectors and nucleic acid vaccines are best suited for speed because they can be more easily adapted to platform manufacturing technologies in which upstream supply chains and downstream processes are the same for each product. Precision is achieved by knowing the atomic structure of the vaccine antigen and that the targeted epitopes are preserved in the vaccine [16]. Table 1. Advantages and disadvantages of vaccine development methods [14] [15].

Vaccine
Advantages Disadvantages

Viral vector
Highly an innate immune response, induction of T cell immune responses, and cell B. Widely used for MESR-COV.
Induction of anti-vector immunity: cell-based manufacturing. It is integrating into the host genome and induces cancer.

DNA vaccine
Not contagious; shortly stimulation of the innate immune response; free cell and egg; stable, fast, and scalable production; clicking the induction of T cell immune response and B.
Potential for integration into the human genome; low immunogenicity in induces anti-immunoglobulins synthesis.

RNA vaccine
Degradation is natural in the body, not contagious, does not integrate into the human genome, is a noncell egg virus, fast, and scalable production; shortly stimulation of the innate immune response; clicking the induction of T cell immune responses and cell B.
Potential for instability reactogenicity reported.
The method of COVID-19 manufacturing is not yet known, which one will be effective and safe. Data from the global COVID-19 R & D landscape include 115 vaccine candidates, of which 78 are confirmed as active and 37 are unconfirmed, and of the 78 confirmed, active projects, 73 are currently at exploratory or preclinical stages [17]. The WHO data show that as of 26 December 2020, there were 56 COVID-19 vaccine candidates in the clinical evaluation, of which 13 were in Phase III and 166 candidates in the preclinical evaluation. Of the 13 in phase III, four submitted data to regulatory authorities for emergency authority use.
In Indonesia, the Minister of Research and Technology has prepared a 'Merah-Putih' vaccine derived from the domestically made S subunit vaccine. In its construction, the government involved BioFarma, the Eijkman Institute, the Indonesian Institute of Sciences (LIPI), and four major universities. the production journey is still in the preclinical stage; to reach stage III, it will be carried out in 2022 [18] as SARS-CoV-2 is like the highly pathogenic SARS-CoV and MERS-CoV, experiences in the development of vaccines against other beta coronaviruses may facilitate COVID-19 vaccine development [19]. There are many types of COVID-19 vaccines in action using different technologies. Different types being tested include recombinant protein subunit vaccines, nucleic acid vaccines, viral vector vaccines, inactivated viruses, and live attenuated vaccines [20].
A live attenuated vaccine is a conventional method that has a long story of successful application in smallpox and polio. Live attenuated live more like natural infections with a wide range of natural viral antigen production over a long period and are often more immunogenic than nonreplicating vaccines. One live vaccine that improves the immune system and decreases SARS-CoV-2 is the Baccile Calmette-Guerin (BCG) [16] [21] [22]. During the early development of SARS-CoV vaccines, inactivated virus vaccines were once a leading strategy. Studies using UV and formaldehyde-inactivated SARS-CoV can induce neutralizing antibody response, and phase I clinical trial using β-propiolactone inactivated SARS-CoV-2 vaccine demonstrated that it is safe, well-tolerated, and can elicit SARS-CoV-2 specific neutralizing antibodies [23]. The inactivated vaccine for Sinovac also showed safety and effectiveness in producing IgG and reducing virus titters and pathological changes in the lungs without observable antibody-dependent enhancement of infection [22].
Nucleic acid vaccines are genetic vaccines consisting only of DNA or RNA, which are taken up and translated into protein by host cells and elicit immune responses. Because they contain nonviral coats, naked nucleic acids are not generally subject to pre-existing immunity, which can hamper the clinical efficacy of recombinant virus vaccines [24]. mRNA is a minimal and transient information carrier. It does not interact with the host genome, is safe, and can be manufactured rapidly. Any protein can be encoded and expressed by mRNA, which offers maximum flexibility concerning, the development of vaccines for infectious diseases and cancer and protein replacement therapies [25]. Vaccine products from this method include Moderna, BioNTech/Pfizer, Curevac, Arc-Journal of Biosciences and Medicines turus, Academy of Military Sciences of China, Chulalongkorn University, and AstraZeneca/Shenzhen Kangtai, which have entered clinical trials [22].
Protein subunit vaccines comprise purified immunogenic proteins or peptides derived from viruses. In contrast with traditional vaccines, subunit vaccines have fewer side effects and higher safety at the injection site [26]. However, whether immunological memory will be formed correctly is not guaranteed. Therefore, adjuvants and vaccine delivery systems are needed to enhance immune response candidates that constitute minimal structural components of SARS-CoV-2 that can prime protective immune responses in the host when administered with molecular adjuvants for enhanced immunogenicity. For example, contemporary SARS-CoV-2 subunit vaccine candidates are formulations of full-length S protein or S1/S2 subunits with adjuvants. The front runner among developers is Novavax, which initiated a Phase I/II trial on 25 May 2020 [27]. Additionally, Sanofi Pasteur/GSK, Vaccine, Johnson & Johnson, and the University of Pittsburgh announced that they expected to begin. Viral vector vaccines effectively introduce genes encoding viral antigens into host cells. The infected cells produce and release immunogenic antigens within a certain period after vaccination [28]. Subunit vaccines and protein-induced immune responses are usually short-lived, and consequently, multiple injections are typically required to induce and maintain a systemic immune response [22].

Discussion
The   [34]. Each type of vaccine has a different level of efficacy. This can be caused by several factors, including viral mutations, the dynamics of immune cells responsible for developing immunity when exposed to the SARS-CoV-2 virus, or viral-derived antigens such as vaccines [35]. There's a good chance that the severity of this disease is determined by a complex interaction between the host, virus, and environment, which results in varying clinical outcomes [36] [37]. Although in one study, viral vector-based COVID-19 vaccines lower local side events than mRNA-based [38].

mRNA Vaccine
In clinical trials, mRNA-based vaccines were more than 90% effective against SARS-CoV-2, such as Moderna/BioNTech/Fosun Pharma/Pfizer. Although the vaccine may have side effects, this vaccine has high effectiveness, despite the local and systemic reactogenicity to the mRNA vaccine. The advantages of mRNA vaccines are the speed of vaccine production (only a few weeks) and the ability to generate a T H 2 and T H 1 response [39]. T H 1 cells are required for the host's defense against intracellular infections. In contrast, T helper 2 (T H 2) cells organize beneficial to type 2 immune responses, such as those against helminths and tis-sue repair, contributing to chronic inflammatory disorders [40]. T H 2 and T H 1 should be balanced; If a patient's T H 1 immune response is incorrectly organized, an increased immune response leads to a cytokine storm that triggers T H 2 cells, with a poor prognosis [41].

Virus Vector Vaccines
Currently, approximately 25 research groups are working on a viral vector vaccine. Viruses such as rubeola or animal viruses are genetically designed to produce coronavirus proteins within the body. There are two types: people who will still replicate in cells and people who cannot because a key gene has been deactivated [42]. The use of adenovirus vaccines has been used in the USA and Europe, and two vaccines have shown promising initial results, namely, the Sero-

The Vaccine-Inactivated
Inactivated or killed vaccines made from cultured and then chemically inactivated viruses are one path to vaccine production, which can produce native antigenic epitopes (binding to T cell and B cell antibodies) expressed in a stable and conformational manner [43]. One approach used in the production of vaccines from the killed virus is using beta-propiolactone, especially for the vaccines developed by Wuhan Institute of Biological Products/Sinopharm, Beijing Institute of Biological Products/Sinopharm, and Sinovac/Instituto Butantan/BioPharma [22]. Sinopharm and Sinovac are two companies working on this form of the vaccine, which has been tested in a phase 3 trial and received international approval for use as a COVID-19 vaccine [39].
Bharat Biotech (BBV152/Covaxin) from the Indian vaccine industry has succeeded in making a vaccine derived from the intact virion of the SARS-CoV-2 virus that has been killed (inactivated virus). Based on phase 3 clinical trials, the Covaxin vaccine showed high clinical efficacy (81%) against COVID-19, as well as high immunogenicity against some of the variants [44]. The presence of the additive/adjuvant Algel-IMDG can increase the immune response of T cells to COVID-19, which leads to long-term protection [30].

Subunit Vaccine Proteins
As a recombinant protein subunit, Protein S is another approach to vaccine development. This method may protect immunized animals in vitro, but it can  2˚C -8˚C India [44] produce a polarized immune response [45]. An example of vaccines that use this method is Novavax, using adjuvant Matrix-M-based saponin, which has 89.3% efficacy in patients with COVID-19 through phase 3 clinical trials in the UK [46]. SCB-2019 Vaccine was promising and successful against the severity of COVID-19 including the delta variant in the phase 2/3 trial [47]. More than 60% of vaccine development currently uses the protein subunit approach (Table 3) [39].

Impact of Vaccination on the Human Population
COVID-19 outbreaks have resulted in many worldwide illnesses and mortality, as well as jeopardizing people's and community's economic and social well-being.
Despite the high death events, SARS-CoV-2 infection remains a threat to most of society [52]. Vaccination is still an important preventative strategy for lower- People should think about vaccines which have safe and available, the possibility of using two different types of vaccines or boosters, and the types of vaccines that can keep people from getting new infections and multiple kinds of vaccines.

Conclusions
Various vaccinations have been developed around the world to help combat the COVID-19 pandemic. Because of discrepancies in how the vaccines were developed, particularly in terms of efficacy and side effects, vaccination hesitancy and pharmacovigilance may become distinguishing aspects of the COVID-19 pandemic's next stage as supply meets demand. This page will explain some of your questions about vaccines, like where they are made, how many doses they con- The vaccine effort is projected to establish herd immunity in at least 70% of the population, allowing them to quickly recover from the pandemic and resume their usual lives. The presence of viral mutations is one of the elements that can alter vaccine effectiveness, so more research into the efficacy of viral genetic mutations is still needed.