A Review of Covid-19 Vaccines: What needs to be known and its expected effect on the human population?

The COVID-19 pandemic is a devastating blow to the entire world community and changes the order of human life. All efforts and strategies are being carried out to contain and reduce the spread of the SARS-COV-2 virus, both by tightening the health protocol and using vaccines to 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) are expected to be able to suppress the spread of the virus and produce a minimum of 70 percent herd-immunity in a population. 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. Moreover, further rigorous research is still being carried out for the development of an effective and efficient vaccine. Keywords; Vaccine Development; Clinical Trial; COVID-19; SARS-COV-2


INTRODUCTION
Implementation of control measures and protocol health in life are crucially required, such as using masks, physical distancing, testing of persons exposed to or symptomatic, contact tracing and isolation have helped to limit the contagion that has been applied strictly, but such measures have been applied varied and proven yet sufficient in inhibiting the spread of the coronavirus disease 2019 (COVID-19) (Baden et al., 2021).
The vaccination technique is an attractive and powerful medical approach for dominant the severe acute respiratory syndrome coronavirus type 2, preventing the spread, and protecting those who are at high risk of infection (Baden et al., 2021). The process of vaccination has taken place in all countries including Indonesia and Malaysia. Vaccination is anticipated to provide a herd-immunity a minimum of 70% of the population and 80 percent without used other intervention for instance physical distancing (Bartsch et al., 2020).
Based on the evaluation of patients with positive SARS-COV-2 revealed that antibody binder and main bidders targeting the receptor-binding domain subunit S1 (Spike 1) (Premkumar et al., 2020). The main challenge when making vaccines is how effectively the vaccine can generate an immune response in the human body. Characteristics response such immune is the formation of neutralizing antibodies, formation of T-cell responses, and prevention of disease following immunization (response induced by the vaccine causes an increase in severity of disease) (Tseng et al., 2012). At present, the dominant circulating variant of spike protein mutations of the virus from Britain (B.1.1.7, deletion 69-70, deletion 144, N501Y, A570D,  D614G, P681H, T716I, S982A, D1118H, and there are mutations in other genomic regions as  well), South Africa (B.1.351) and Brazil (P.1) are facilitating rapid viral spread (Ecdc, 2020;Faria et al., 2021;Tegally et al., 2020) that may interfere effectivity of vaccine program.
There are enormous direct the development of the vaccine candidates to prevent transmission of COVID-19 consist of 84 trials that are still in clinical assessment (15 of them have been in phase 3 and 5 vaccines under phase 4 clinical trials) and 184 in preclinical analysis with different route of administration, doses, and schedule (  (Baden et al., 2021;Logunov et al., 2021;Polack et al., 2020;Voysey et al., 2021). Based on the preceding description, this review presents of vaccine development with different types ( Table 3) that was provided by pharma industry to combat and eliminate spreading of SARS-COV-2 in a population. Moreover, it develops herd-immunity at least 70% in the community.

METHOD
The review was conducted using the google engine to find the precise literature references (Scopus, PubMed, Medline, WHO Website). The key search terms 'Vaccine Development', 'Clinical Trial', 'COVID-19', 'SARS-COV-2'. The range of period for searching the references for this review's study is 4 November 2020 to 29 March 2021.

RESULT AND DISCUSSION mRNA Vaccine
In clinical trials, mRNA-based vaccines were found to be more than 90% effective against SARS-COV-2 such as Moderna/BioNTech/Fosun Pharma/Pfizer. This high effectiveness of the vaccine is associated with few/rare side effects, 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 TH2 and TH1 response ( Table 2) . Potential for instability, reactogenicity reported

Virus Vector Vaccines
Currently, about 25 research groups are working on a viral vector vaccine. Viruses like rubeola or animal virus are genetically designed in order that they will turn out coronavirus proteins within the body. There are 2 types: people who will still replicate at in cells and people that cannot because of a key gene has been deactivated (Callaway, 2020). The use of adenovirus vaccine has been used in the USA and Europe, two vaccines have shown promising initial results, namely the Serotype 26 adenovirus vector vaccine (Ad26.CoV2. S; Johnson & Johnson) and the ChAdOx of Chimpanzee adenovirus vector vaccine (AstraZeneca) . Both vaccines have efficacy in preventing hospitalization and death of COVID-19 patients, but they are still not maximal in preventing diseases caused by the new variant SARS-CoV-2 . The Sputnik V vaccine (Gam-COVID-Vac) uses a combination of the rAd type 26 (rAd26) and rAd type 5 (rAd5), rAd26-S, and rAd5-S vaccine vectors given separately intramuscularly at 21-day intervals (table 1). Gam-COVID-Vac has a 91.6% efficacy of preventing infection COVID-19 (Logunov et al., 2021).

The Vaccine Inactivated and Subunit Vaccine Proteins
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 (Delrue et al., 2012). One approach that is used in the production of vaccines from the killed virus is UV-inactivated conducted on laboratory Biosafety Level 3 (BSL3), which includes the step of expansion, titration, inactivated, and ultracentrifuge the virus (Lundstrom, 2020). Sinopharm and Sinovac are two of the companies working on this form of vaccine, which has been tested in a phase 3 trial and received international approval for use as a COVID-19 vaccine. .
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 (Ella et al., 2021). 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 (Li & Zhu, 2021).
Protein S as a recombinant protein subunit is another approach to vaccine development. This method may protect immunized animals in vitro, but it has the potential to produce a polarized immune response (Zimmermann & Curtis, 2019). Example of vaccines using this method is Novavax, using adjuvant Matrix-M-based saponin, which has efficacy 89.3 % of patients COVID 19 through clinical trials phase 3 in the UK (Callaway & Mallapaty, 2021). Currently, more than 60% of vaccine development uses the protein subunit approach, even though none has the status as an emergency use authorization .

CONCLUSION
Various vaccines were produced around the world to provide better control of covid-19 pandemic. Due to differences in how the vaccines was developed, it created numerous issues especially related to efficacy and side effects. This article helps to clarify some of the questions regarding the vaccines and its sources of production, the doses and storage form. Health workers are the last bastion in handling COVID-19 patients. The process of preventing and minimizing the spread of COVID-19 is the main goal of the current vaccination. The presence of several types of vaccines at this time is expected to be able to provide strategic solutions to overcome the pandemic situation that has hit various countries in the world. The implementation of the vaccination program is expected to produce a herd-immunity of at least 70% in a population so that they can quickly get out of the pandemic and live normally as before. One of the factors that can affect the effectiveness of vaccines is the presence of virus mutations, so that further research on the effectiveness of viral genetic mutations is still huge necessary.

ACKNOWLEDGMENT
I would like to thank the colleagues of Faculty of Military Pharmacy, Indonesia Defense University and Advanced Medical and Dental Institute, Universiti Sains Malaysia for technical supports on this research.