The novel coronavirus and its possible treatment by vaccines, therapeutics and drug delivery systems: Current status and future perspectives

Madhurya Kadavakollu1, Veera Venkata Satyanarayana Reddy Karri*1, Kuppusamy Gowthamarajan1, Arun Radhakrishnan1, Dhanabal Palanisamy2, Somanathan Balasubramanian3, Suresh Bhojraj3 1Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, Nilgiris, Tamil Nadu, India 2Department of Pharmacognosy, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, Nilgiris, Tamil Nadu, India 3 JSS Academy of Higher Education & Research, Mysuru, Karnataka, India


THE ORIGIN AND TRANSMISSION
At the end of December 2019, people of Wuhan presenting to regional hospitals with severe pneumonia of unknown cause. Most of the primary cases had a common exposure to the Huanan seafood market that traded alive animals. On 31st December 2019, China reported the outbreak to the WHO followed by the closure of the Huanan seafood market on 1st January. On 7th January the virus was identi ied as a coronavirus that had 79.5% similarity with the SARS-CoV and 96.2% homology with the bat coronavirus RaTG13.SARS-CoV-2 belongs to β-coronavirus (β-CoV), which is an enclosed non-segmented positive-sense RNA virus (subgenus-sarbecovirus, and subfamily-Ortho coronavirinae) . CoVs are classiied into 4 genera, which includes α,β,γ, and δ-CoV. Mammals are infected by α-and β-CoV, while birds tend to get infected by γ-and δ-CoV. Earlier, 6 CoVs were recognized as a human-prone virus, amongst which α-CoVs (HCoV-229E & HCoV-NL63), and β- OngoingClinical Trailsby Government agencies and Academic institutions.
CoVs (HCoV-HKU1 & HCoV-OC43) are with weak pathogenicity, induce light respiratory symptoms alike to the common cold, respectively. The other two known β-CoVs (SARS-CoV& MERS-CoV) head to critical and potentially lethal infections of the respiratory tract. (Zhu et al., 2019). SARS is a zoonosis caused by SARS-CoV, the irst emergence of SARS-CoV was in 2002 in China before passing to around 29 regions through a global outbreak with 8,098 cases with 9.6% of fatality rate. The primary reservoir for SARS-CoV transmission was bats and civet cats were the intermediary source in wet markets and Nosocomial transmission was common (Yin and Wunderink, 2018) Bats have been suspected as the natural hosts for the SARS-CoV-2 origins based on the results of genomic sequencing and evolutionary analysis and maybe transferred from bats through anonymous intermediary hosts to infect humans. Now, it is obvious that SARS-CoV-2 uses the Angiotensin-converting enzyme 2 (ACE2)receptors which are abundantly expressed in the epithelial cells of the lungs to infect the human (Hui and Zumla, 2019;Zhou et al., 2020).

Structure
CoV contains 4 main structural proteins: 1) Spike (S)-(150 kDa), 2) Membrane (M)-(25-30 kDa), 3) Envelope (E)-(8-12 kDa), and 4) Nucleocapsid (N) proteins. All these are encoded within the 3 ′ end of viral genome.The outstanding peculiarity of coronavirus is it's club-shaped like spike projections originating of the virion's surface. The S protein uses an N-terminal signal sequence to get access to the Endoplasmic reticulum (ER) and it is N-linked glycosylated massively. These spikes are the de ining peculiarity of the virion and provide an appearance of a solar corona, proposing the name, coronaviruses. The most abounding structural protein in the virion is M protein.
It is a small protein with 3 transmembrane domains (Guo et al., 2020) and is responsible for virion shape. The E protein is seen in small quantities within the virion. The E proteins of CoV are highly variant but have a common structure (Armstrong et al., 1984). Though the E protein membrane topology is not completely resolved most data suggest that it is a transmem-brane protein. A helically symmetrical nucleocapsid is present within the virion envelope which is not common with (+)sense RNA viruses still considerably common with (-)sense RNA viruses. The N protein is the only protein existing in the nucleocapsid, which is comprised of an N-terminal domain (NTD) and a C-terminal domain (CTD),2 separate domains that are capable of in vitro binding of RNA, but uses distinct mechanisms for RNA binding. Another structural protein, the hemagglutinin-esterase (HE), also present in the β-CoVs subgroup. (Godet et al., 1992). These actions enhance the entry of S proteinmediated and mucosal virus transmission (Klausegger et al., 1999). Structurally, SARS-CoV has a distinct organization composing 14 binding residues that directly interact with human ACE2. Amongst certain amino acids, 8 have been maintained in SARS-CoV-2. (Cornelissen et al., 1997)

Epidemiology and symptoms
All ages are susceptive to SARS-CoV-2. The infection primarily transmitted through large droplets of saliva or from the nose discharge during cough and sneeze, respectively by symptomatic and asymptomatic people. (Fehr and Perlman, 2015). The infection can be acquired either by inhalating or touching these droplets or its contaminated surfaces followed by touching nose, mouth, and eyes. Pneumonia was the primary clinical sign of the SARS-CoV-2-related disease COVID-19 which supported case detection. Investigations so far suggest 5 days as a mean incubation period (Bastola et al., 2020) and 3 days as the median incubation period of 3 days (range: 0-24 days) (Thompson, 2020). The clinical manifestations in symptomatic patients, the infection, usually begins in not more than a week, the primary symptoms include fever, cough, nasal congestion, fatigue and indications of upper respiratory tract infections. The infection advances to critical conditions like dyspnoea and critical chest symptoms resembling pneumonia in about 75% of cases, being detected by computed tomography on admittance (Thompson, 2020). Mostly Pneumonia transpires in the irst 3 weeks of asymptomatic patients. Human transmission of coronavirus happens principally among family members, include relatives and friends that personally reached with sufferers or incubation transmitters. 33-42% of SARS cases are healthcare workers (Guan et al., 2020). Personal contact with the intermediate host animals or wild animals consumption was assumed to be the main course of SARS-CoV-2 transmission. However, the rise and transmission of SARS-CoV-2 remain mysterious.

Facts on Corona virus disease (COVID-19) Pandemic by WHO
1. Pneumonia vaccines, like pneumococcal or Haemophilus in luenza type B, not provide any protection against the SARS-CoV-2 2. Smokers are more likely vulnerable to SARS-CoV-2 due to their reduced lung capacity and as the means of smoking are ingers and lips which may increase the chance of virus transmission from hand to mouth.

Antibiotics don't act against COVID-19, they only control bacterial infections. COVID-19 is a viral infection.
4. Receiving a package from any reported COVID-19 area is safe as the package that has been transferred, traveled, and exposed to various conditions and low temperatures.

5.
No reported evidence regarding an animal (dog, cat or any pet) that can transmit SARS-CoV-2 while, there has been only one instance yet that a dog being infected in Hong Kong.
6. COVID-19 is not airborne until unless you are within 1 meter of a COVID-19 person. As the primary mode of transmission is through the droplets of cough or sneeze of an infected person. These droplets are too heavy to hang in the air. They immediately fall on grounds or surfaces.
7. COVID-19 virus can be transmitted in all areas with hot and humid climates from the so far evidence.
8. Thermal scanners are ef icient in recognizing people with developed fever, they cannot detect people infected with SARS-CoV-2 All ages of people can be infected by SARS-CoV-2. Elder people and people with pre-existing medical conditions like asthma, diabetes, heart disease are more vulnerable to become severely ill.
9. Alcohol consumption does not protect from COVID-19 and can be hazardous 10. Holding breath for 10 seconds/ more without coughing does not mean free from  or any other lung disease.
11. Exposing to the sun or higher temperature than 25 c does not prevent COVID-19.
12. The novel coronavirus cannot be transmitted through the mosquito bites.
13. Hot shower doesn't prevent theCOVID-19. Coronavirus treatment: Vaccines, 2020) The ambiguous SARS-CoV-2 outbreak in the Wuhan (a China city), currently known as COVID-19, and its rapid roll out to several other countries, risk thousands of lives. This pandemic has catalyzed this advancement of novel SARS-CoV-2 vaccines over the biotech industries, and also pharmaceutical companies and research organizations Tables 1, 2, 3 and 4 shows,

Challenges of coronavirus disease 2019
COVID-19, presenting a global challenge, particularly in the rapid spread of infection, the raise in critically ill patients with pneumonia and the absence of de initive treatment therapy. Till 04/04/2020 around 1,051,635 con irmed COVID-19 cases and 56,985 con irmed deaths been reported according to COVID-19 Situation Report -75 by WHO. One major concern is how well the health systems of the world are prepared and respond to this outbreak. To prepare for and respond to the outbreaks of infectious disease. The following challenges are being brought, which include political and institutional, social, environmental, technological, and pathogen-related, to the proximity by COVID-19 outbreak. Currently, there is no vaccine or speci ic antiviral drug moiety available to treat critically ill patients. Healthcare management mainly concentrates on the provision of supportive care like oxygenation, ventilation, and luid management. However, no approved antiviral treatment for coronaviruses, and notwithstanding the two outbreaks of novel coronaviruses in the past two decades, the development of the vaccine is still in infancy. For critical management of COVID-19, several potential treatments are recommended, including baricitinib (a Janus kinase inhibitor), combination therapy of low systematic dose of corticosteroids with the antivirals and atomization inhalation of IF have been suppoerted (Chowell et al., 2015). Hence, there is an essential need to develop ef icient diagnostics,

INO-4700 (GLS-5300) for MERS-CoV
Ef icacy against the94% MERS-CoV patients in early-stage CT in July 2019. Vaccine therapeutics, and vaccines. Unlike the previous outbreaks of infectious diseases, the complete genomic sequence of coronavirus had received and shared broadly by the middle of January, attainment not possible at such a short period. WHO has stated that the SARS-CoV-2 vaccine should be available within 18 months, but to achieve, this requires funding and attention of the public to be maintained even if the threat level drops. (Liu et al., 2020; Lid The Challenges of coronavirus disease 2019, 2020)

Drug delivery systems for the delivery of vaccine/drugs
Currently, no vaccines are approved for the infection caused due to SARS-CoV-2. Trials are being executed for vaccines delivery by carriers in order to attain sustain release and reach the target site as they regulate the antigen's spatial and temporal offering to the immune system. Hence, weak immunogens of low doses can be delivered ef iciently to excite the immune responses and eradicate the need for the frequency of administration like prime dose and booster doses as a replacement of the conventional vaccination regimenand provide long term therapy. Since Lungs are the most targeted organ for SARS-CoV-2, the drug administration through the oral route by the aerosol may produce an immediate therapeutic response. Immu-nization through the Intranasal route is the only delivery mechanism to succeed both mucosal and systemic immune responses. Intranasal vaccines currently being used against in luenza types group B meningococcal attenuated respiratory syncytial and parain luenza 3 virus. Moreover, the inhalation of Nitric oxide gas given for the SARS-CoV-2 patient, which showed greater antiviral activity against the SARS-CoV in 2003Cunningham et al. (2020. Hence the same treatment was suggested by the health professionals and the respective clinical trials were also in progress for the COVID 19 treatment according to (US National Library of Medicine). Crown proteins of the SARS CoV-2 possess a similar receptorbinding domain to the SARS CoV in the ACE 2 receptor. Now, it is obvious that SARS-CoV-2 uses the Angiotensin-converting enzyme 2 (ACE2)receptors which are abundantly expressed in the epithelial cells of the lungs to infect the human (Chen et al., 2004;Xu et al., 2020). Intranasal immunization would be the bene icial route of delivery to treat upper respiratory tract infections and also produce systemic immunity (Zhang et al., 2020).

Feature perspectives
Researchers are working on safe, active and speci ic vaccine moieties and therapeutics for managing the inevitable COVID-19. To date, there are no spe-ci ic vaccines or active antiviral drugs for COVID-19 available, where few are currently beneath the evaluation and development. Therefore, special attention and efforts are required to reduce the possible risk of transmission in susceptive peoples like children, elderly people, health care providers, and public services by implementing strict preventive control measures. (Pires et al., 2009).

CONCLUSIONS
Outcomes received from recent in vitro study against SARS-CoV-2 using Remdesivir and chloroquine are promising since these drugs are highly effective in infection control. Therefore, direct clinical trials can be performed on COVID-19 infected patients as these drugs are already being used for treating other disease conditions and also have well-established safety pro iles which makes further drug evaluation much easier. Based on several preclinical studies, S protein is identi ied as a pivotal viral antigen for developing the vaccine. Though the researches are in progress to enhance prevention, treatment strategies, and control of transmission of COVID-19. Additional research should be focused on the study of SARS-CoV-2 in proper animal models for investigating the viral replication, transmission, and pathogenesis by understanding the mechanistic cause of COVID-19 by SARS-CoV-2 and immunopathological response in the host.