Current Updates on Covid-19 Vaccine Research and an Overview of Therapeutic Drug Research

The world is presently hectic in a battle against the strong and lethal COVID-19 virus, which is not only dangerous to the body but also psychologically distressing due to the growing number of patients infected and dying worldwide. This paper includes a concise overview of the possible therapies as well as the elements associated with intensive care, which have been identified with promising clinical outcomes, based on the knowledge we have gathered so far. Furthermore, as the SARS-CoV-2 virus is better understood, recent drugs focussing certain parts of the virus are being developed, and anti-SARS-CoV-2 vaccines are being researched. This timely study examines the existing condition of COVID-19 across the globe. This topic will bring to light the potential for drug development and vaccination in different parts of the world to combat the epidemic, and some of this may be of use in the future.

The world is facing a deadly pandemic. Primarily, an unidentified etiology caused respiratory illness near Wuhan of 29 cases in china 1 . The Chinese Center for Disease Control and Prevention (CDC) began looking into the novel virus. They initially labeled it as pneumonia with an unclear cause. After research, they addressed this novel virus to be belonged to coronavirus (CoV) family. They termed it as COVID-19, which is nothing but the acronym for coronavirus disease 2019. Soon, this virus spread rapidly all over the world. This COVID-19 is highly contagious, and several million people have been died globally and it's still pandemic in many countries. This novel virus has been evolved over 18 countries among those 4 countries through humanhuman transmission. In the timeline of past twenty years, there were already two 2 deadly epidemics occurred across the world. They were severe acute respiratory syndrome SARS-CoV which was first found in china in the period of 2002-2003 and other one is Middle East respiratory syndrome corona virus (MERS-CoV) Saudi Arabia which occurred first in 2012 2 . In accordance with The International Committee on Taxonomy of Viruses (ICTV), the novel coronavirus (COVID-19) was termed as SARS-CoV-2; considering it's similarity to that of SARA-CoV outburst. The novel coronavirus has got a structure that resembles a positive single stranded RNA virus having a crown like structure visualized under an electron microscope and therefore termed as coronam in Latin it means crown and this is in regards with the spike (S) glycoprotein on the envelope 3 . Genera: 4 types 1. Alpha coronavirus (Alpha CoV) 2. Beta Coronavirus (Beta CoV) 3. Delta Coronavirus (Delta CoV) 4. Gamma Coronavirus (Gamma CoV) According to research, the genomic characterization of bats and rodents has the gene source of alpha CoVs and beta CoVs; avian species have the gene source of delta CoVs and gamma CoVs. Recently, seven humans CoVs has been identified and named as HCoVs which has the capacity to infect humans. Some of the human CoVs are as follows; HCoV-OC43, HCoV-HkU1, HCoV-229F, HCoV-NL63, SARS-CoV, SARS-CoV-2 and MERS-CoV. Most commonly acting human CoVs is SARS-CoV-2 which is accountable for present pandemic outbreak that belongs to beta CoV family.

SARS-CoV-2 Virus
It is a pleomorphic shape with a round or elliptic structure. The diameter ranges between 60 and 140 nanometers. This virus is sensitive to ultraviolent radiation and heat. The studies reveal that, increases in temperature of about 27°C and above can be activate the virulence effect of virus. Although when treated with ether, ethanol, chlorine-containing disinfectant, peroxyacetic acid, and chloroform, these viruses were inhibited. As reported by Chan et al., the new virus SARS-CoV-2 has a single-stranded RNA genome with 29891 nucleotides and 9860 amino acids encoded. For both SARS-CoV and MERS-CoV, an envelope spike (S) glycoprotein binds around the cellular receptors angiotensin converting enzyme 2 (ACE2) and dipeptidyl peptidase (DPP4). The process of this new virus is that the viral RNA genome is delivered into the cytoplasm at first, then replication of viral genome takes place, after that the genomic RNA accompanies with envelope glycoproteins and nucleocapsid protein that results in virion containing vesicles, which finally incorporate into plasma membrane and release the virus.

Statistics -Occurrence of death and recovered Medication Procedure
A novel corona virus were originated in some parts of china, which includes Wuhan, The World Health Organization (WHO) designated this pandemic outbreak as a public health emergency of worldwide concern on January 30, 2020. 7-9 As per the Chinese study, there are six strains of corona virus that are infectious to humans, each named after their appearance with a single stranded RNA genome. 10 They also confirmed that, like SARS and MERS, SARS-CoV-2 is highly infectious and causes serious breathing illness and ultimately death. 11 As long as this SARS-CoV-2 is highly vulnerable to humans it makes even worse with the elderly and other diseased people. [12][13][14] The Chinese researchers employs that it's hard to introduce a new drug, which approximately takes 15 years, so to control this situation they decided to make a new drug manipulating from the existing drug in the market, just to eradicate the occurrence of disease, so as a result they followed Chinese traditional medicine. 15

Traditional Chinese Medicine
The treatment approach for COVID patients is divided into two parts, according to their clinical experience: a medical observation phase and a clinical therapy phase. Confirmed cases were handled during the clinical therapy phase based on four symptoms, which were as follows: Based on the patient's pathological conditions, different medications and treatment were used at different stages. 17-18 According to research, till date 23 different Chinese medicines were approved and given to treat mild, severe and critical symptoms ( Table 2) 19 As listed in the table. 3, above these are the chemical medicines which were widely used to treat mild, severe, critical COVID patients. Along with these medicines there were also some other chemical medicines were gone for clinical trials, which includes Chloroquine Phosphate, Darunavir, Emtricitabine and Denofovir Alafenamide. The Chinese also dealt with some biological medicines and techniques for the treatment of COVID 19 and were listed in the following table. 4 Human immunoglobulin and intestine micro ecological regulator are among the biological medications found on COVID-19. Chinese medicines offer a wide range of applications, particularly in the treatment of minor symptoms.3.2 Evolution of Medicine in India. As per recent research, India, having a population of over 1.36 billion people, is the second-vast nation with a significant number of COVID-19 instances; one of the numerous causes for this abrupt and uncontrollable increase was India's lack of ventilators, which totalled just 49,000 (Mumbai, 2020). Indian government initiated various preventive and precaution measures to control the pandemic. The Ministry of Health and Family  Welfare (MOHFW) have elevated awareness about the present epidemic and implemented a number of necessary steps to combat COVID-19. People who had travelled from China or other countries and had any of the symptoms, such as fever, trouble breathing, sore throat, cough, and dyspnea, were advised to seek medical attention at the local hospital. Seven separate airport authorities have been asked to check and monitor Indian travellers from China and other impacted nations, including those in Chennai, Kochi, Kolkata, New Delhi, Telungana, and Bangalore.
The following figure 5 clearly explains the growth of COVID-19 cases in India and its current scenario and the present active and confirmed cases.
India is popular for its conventional medicines, or AYUSH (Ayurvedic, Yoga & Naturopathy, Unani, Siddha & Homeopathy). One of most promising medication followed by Indians were polyherbal powder Nilavembu Kudineer, which was effectively treating dengue and chikungunya fever 47 . With the collaboration with WHO ICMR decided to work on useful medications to improve the immunity that fight against the corona virus. The researchers of India studied various types of drugs and the therapeutic effects to enhance the people with immunity. There was a evolution of medicines in India from the start of this outbreak.
According to researchers, the COVID-19 therapies is done under two categories which includes antiviral that averts the virus from accumulating and other one is immune modulators that helps the immune system to oppose the virus. 48 Based on the category, the following are the list of COVID-19 antiviral The following is a list of COVID-19 immune modulators on the basis of immune modulators.
There are some more drugs apart from these two categories. They are as follows.
• Colchicine • Fluvoxamine • Angiotensin-converting-enzyme inhibitors/ angiotensin-II receptor blockers The above are the some of the drugs, used for treating the COVID patients which were studied so far by the researchers. 49 Among all these medicines, antiviral, and immune modulators, according to researchers, certain antiviral drugs and immune modulators were effectively used for treating the COVID patients that are listed in the following figures 7(a) & (b).

Remdesivir
Remdesivir is one of the broad-spectrum antiviral medications that was first produced in 2014 to cure hepatitis C and afterwards the Ebola virus. Remdesivir has been shown to have action against SARS-CoV 2 and MERS CoV in in-vitro and animal investigations. [50][51] This remdesivir is an injectable medication that is exclusively available in hospitals. It is mostly utilised for COVID-19 individuals who have been classified as moderate to severe. 52 The US National Institutes of Allergies and Infectious Diseases released preliminary study findings on covid patients' recuperation growth in May 2020, indicating that recovery increased from 15 to 11 days following remdesivir treatment. The Indian Drug Controller General authorised a fiveday remdesivir regimen in June. 53 The WHO issued a provisional guideline about the use of remdesivir in severe patients in November 2020, citing a lack of clear findings that remdesivir enhances therapeutic efficacy and other consequences. 54 The remdesivir had very less influence on the fatality of individuals diagnosed for COVID, according to preliminary data from the solidarity study.

Chloroquine / Hydroxychloroquine
Chloroquine has a history of 70 years for treating chloroquine sensitive malaria, extraintestinal amoebiasis, systemic lupus erythematous (SLE),  Remdesivir has showed good showed the highest inhibitory drug anti-MERS-CoV and effect on COVID-19 in vitro anti-SARS-CoV activity. 27 (EC50 = 0.77 mol/L) of the six antiviral medications studied. 28

Favipiravir
Chemical / The medication was first Favipiravir has emerged as a nucleoside used to treat influenza 30 , viable treatment for COVID-19 antiviral drug 29 but it now has inhibitory patients 33 35 patients. 36 and rheumatoid arthritis. [55][56] Even though, the Chloroquine has some essentials benefits it has adverse side effects that includes at higher doses of chloroquine ophthalmologic reactions namely retinal toxicity, reducedvisual acuity, visual loss, and diplopia, due to the selectivebinding of CQ to retinal melanin. 57 Hydroxychloroquine is a derivative of Chloroquine. Hydroxychloroquine is an antimalarial drug, has a invitro activity against various viruses including SARS-CoV-2. 58 According to researchers, they reveal that the hydroxychloroquine has an increased toxic behaviour which leads to cardiovascular problems. Various investigations have revealed that postexposure treatment with hydroxychloroquine did not demonstrate any benefit against SARS-CoV-2 infection or symptomatic COVID-19 infection in people having good health. 59 Also before the  42 to be employed for critical cases usual treatment of with high inflammatory response COVID-19, except in or children having acute respiratory clinical trials, according distress syndrome 43 to the WHO. 44 Fig. 4. India -Total cases, total deaths, and confirmed cases, with cured cases within states and union territories While Actemra is the brand name in India. The antineoplastic tocilizumab is primarily used to cure rheumatoid arthritis. 67 It's a monoclonal antibody that blocks interleukin-6 (Il-6), a critical component of the immune reaction to SARS-CoV-2. Tocilizumab, an intravenous medication licenced as an off-label therapy for moderate to severe COVID-19 patients, will likewise be available only in hospitals. 68 There were no excellently done studies showing the effectiveness and safety of tocilizumab towards COVID-19, as per the expert. 69 By day 14, tocilizumab can minimise the requirement for mechanical breathing or mortality in patients, but it can't regulate morality by day 28. 70 In India, randomised control trials have commenced. 71

Ritonavir + Lopinavir
This antiviral combination of ritonavir and lopinavir is primarily used to treat HIV patients. It's an HIV type I aspartate inhibitor that's used in combination with several other antiretroviral medicine for treating HIV infection. In vitro, lopinavir inhibits SARS-CoV, but ritonavir, when combined with lopinavir, increases the half-life. Based on the current emerging results from the recovery trials, ritonavir + lopinavir had no positive effect on 28-day fatality in COVID 19 patients as compared to conventional treatment. 72 When triple antiviral therapy was given among the patients that includes (IFN) beta-Ib, ritonavir + lopinavir and ribavirin along with usual care, it was safe and it reduces the duration of viral shedding than ritonavir + lopinavir alone especially in mild to moderate COVID-19 patients. 73 According to certain trials, when ritonavir + lopinavir was administered within 12 days of the beginning of symptoms, there was modest updated accordingly, but no diminution in RNA viral injection, identification of viral longevity, or time from randomization to death. As a result, ritonavir + lopinavir has been discontinued in 13 individuals because to negative side effects 74

Doxycycline + Ivermectin
Ivermectin was an anti-parasitic agent with antiviral activity. In vitro, it has modest inhibitory Dexamethasone is a kind of steroid that reduces inflammation by imitating the body's anti-inflammatory hormones and treating allergic diseases. This is appropriate for individuals who have already been admitted to the hospital and are getting oxygen or mechanical ventilator. This is the first medication to show an increase in COVID-19 survival rates. 77 When dexamethasone is given endovenously along with conventional therapy, it is more effective than normal care alone. For 28 days, it demonstrated a substantial growth in the number of days alive and without respiratory support. 78 The recovery trial results show that this dexamethasone has reduced 35% deaths in ventilated patients and 20 % patients' who received oxygen. The patients who don't have oxygen or respiratory support have no idea how it is effective, it's under research. 79

Convalescent Plasma
The convalescent plasma is predominanatly for severe patients who are having scanty oxygen levels, and those who struggle from cytokine storm.Patients who have healed from extreme COVID-19 give plasma, which is subsequently injected into other critically ill patients to help them recover. 80 There are a few indications that show convalescent plasma may provide advantages in COVID-19 patients, however further randomized clinical trials are needed. 81 COVID-19 development was slowed when moderate patients and aged persons received high-titre convalescent plasma towards SARS-Cov-2. 82 There was no notable change in clinical outcomes, death, or hospital discharge time in individuals treated with convalescent plasma after 28 days. 83 As a result, India's medical progression is achieved.

Drugs Developed and Treated In Europe and America
According to treatment carried out in The following fig. 8, categorize the list of drugs based on their improvement The drug approved by FDA and evidence in cells, animals and humans is Remdesivir. Among 13 tentative or mixed evidence drugs, Favipiravir is one among them and it is evidence in animals, cells, and humans. Some small studies suggested that favipiravir block is the virus replication to its genetic material. Other tentative or mixed evidence drugs are Molnupiravir which can be observed in cells, animals and humans, recombinant ACE-2 which is evidence in cells, Ivermectin attestation in cells and humans and Oleandrin evidence in cells. Molnupiravir, commonly known as MK-4482 or EIDD-2801, is a flu treatment drug. Early investigations in cells and animals suggest that molnupiravir is effective it against coronavirus. However, the outcomes of the clinical trials have yet to be shown. The coronavirus must first enter the cells in order to enter them. This is done by hooking on to a human protein known as ACE-2.Therefore, the scientist created recombinant ACE-2 cells, it shows promising outcomes in cells, yet to evaluate in human and animals. Ivermectin is used to treat river blindness and parasitic worms. Scientists are currently investigating if it can be used to treat viral infections. Lopivir and ritonavir, as well as hydroxychloroquine and chloroquine, were found to be ineffective in both cells and people.FDA approved this lopinavir and ritonavir combination immediately since it stops the replication and culturing of coronavirus. But it could not reveal if the patients need to be hospitalized and prevent them from new coronavirus. Trump promoted hydroxyl chloroquine will be the game changer. But FDA temporarily permitted the use of this drug, since the results from the patients were not satisfied. The above discussed drugs have the characteristic feature of blocking the virus. The immune system is the other important area to consider. These medicines elicit a powerful inflammatory reaction in order to combat the infection. Convalescent plasma is an experimental or mixed-evidence medication that has been authorised for use as an emergency treatment in cells and humans. Monoclonal antibodies are the next medication on the list, which is likewise a preliminary or mixed evidence drug for both animals and people. It is also approved or emergency use. Another tentative or mixed evidence drug is interferons. It evidences in animals and humans. Another category is putting out friendly fire, i.e., the immune system overreacts to the virus. In this category the most promising evidence drugs in humans is dexamethasone. Trump said on October 4, 2020, that he was being medicated with dexamethasone, monoclonal antibodies, and remdesivir. In humans, cytokine inhibitors are a questionable or mixed-evidence medication. Another three tentative or mixed evidence drugs used for humans were blood filtration system, stem cells and Colchicine. These are the drugs widely used by European and American countries.

COVID-19 Vaccines across the World
Initially a vaccine development requires a minimum of 36 months to enter the market after several clinical trials and testing. In this 2020, scientist was forced to design a vaccine for this new dreadful virus. There were totally 67 vaccines undergone clinical trials on humans, 20 vaccines reached testing phase which is the final stage. The following fig. 9 clearly gives the data of vaccines count and their stages.

DISCUSSION
As per Chinese scientists, traditional Chinese medicine was used to treat over 93 percent of the COVID cases in the country, which comprises a variety of therapies ranging from herbal products to acupuncture. Besides all the other Chinese traditional medicines, Lianhua Qingwen, which contains 13 herbs such as Rhodiola rose and Forsythia suspense, and Jinhua Table 5. Leading Vaccines around the world, which is currently approved and in use 86 Qinggan, which progressed during the time of 2009 H1N1 upsurge and contains 12 ingredients such as honeysuckle, liquorice and mint, are two of the most well-known medicines. 87 But according to US national institute of Health and UK based researcher, they manifest that the overall effectiveness of Chinese traditional medicine is not conclusive and therefore it is dangerous, and its use is unjustified. China's National Institute for Food and Drug Control last year discovered fatal toxins in certain Chinese traditional medicine sample. 88 The Chinese government and traditional medicine therapist also added that, these medicines have thousand years of history, with some significant side effects which I need to studied further and using advance research its need to be eradicated. 89 The Drug Controller General of India (DCGI) have approved several repurposed drugs for treating the disease, especially on emergency purpose. But according to scientist, it is unclear; in what way the drugs have been approved and used in the market. The first drug to be approved in India was itolizumab which is mainly used to treat autoimmune disease psoriasis which was approved by Cuba to use for critical patients. The DCGI has approved emergency use of three drugs to treat COVID-19. The influenza drug favipiravir which approved for mild to moderate cases. Second, remdesivir a broad-spectrum antiviral drug and itolizumab to treat moderate to severe acute respiratory distress on people who is suffering from COVID-19. Emergency approvals were permitted based on preliminary evidence of the drugs. But scientists clearly explain that there was only limited evidence been collected stating that favipiravir and itolizumab can treat COVID-19 successfully. India is not alone involved in these fast-tracking CVOID 19 medications. Convalescent plasma treatment, hydroxychloroquine, and remdesivir have all been granted emergency necessity authorizations by the US Food and Drug Administration (FDA). 90 The FDA in May 2020 issued an emergency authorization for remdesivir for the severe and critical patients who need oxygen supply. The FDA authorised the medication in August 2020, based on a study from one trial in which individuals with less severe covid-19 reacted moderately to a five-day surgical procedure with remdesivir. According to the scientist, the FDA approved the drug without robust evidence. Later, October-21 when the president Trump was treated with remdesivir on a 5-day course basis. On the day of October 22, FDA immediately approved the remdesivirfor the patients of 12 years and older. But scientist reveals that there is no statistical evidence for the efficiency of remdesivir. On November 2020, WHO halted the use of remdesivir, as they do not have strong significant evidence against mortality. Favipiravir though played a crucial role in many countries that include Japan, Kenya, Russia, Saudi Arabia and Thailand, there were no large randomized clinical trial conducted, so this favipiravir drug is still under research. FDA immediately created awareness against this ivermectin, to treat COVID-19. Since this animal drug can cause adverse effects to people. 91 The drugs were used to control the spread of disease, but scientist failed to continue with it, so there begins the development of vaccines. Currently, some of the vaccines were introduced into the market waiting for the best result among them. The fig. 10 shows the new addition and recent updates on vaccines all around the world.

CONCLUSION
This new virus outbreak has posed a threat to world's economic, medical, and public health infrastructure, particularly those in its immediate vicinity. How the virus affects our life in India will only be known with time. Following the epidemic in December 2019, several people died in various parts of the our nation and rest of the countries. In order to save the patients, many healthcare workers gave their lives. For twelve months, the whole world was shut down. The production of a vaccine to contain and kill this awful virus has improved recently. In several parts of the our nation and rest of world, ten vaccines are leading, and new additions are undergoing clinical trials but have yet to enter the market. We are hopeful that these vaccines will help to improve the current situation.