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\begin{document}

\title{Pathogenesis Diagnosis, Immune Responses, and Current Treatment
Strategies of COVID-19}



\author[1]{Jabir Ali}%
\author[1]{Ujalla  Tanveer}%
\author[1]{Mohsin Raza}%
\author[1]{Maheen Shafiq}%
\author[2]{Ghulam Nabi}%
\author[3]{Suliman Khan}%
\author[4]{Hafiz Muhammad Asmar Naeem}%
\affil[1]{University of Agriculture Faisalabad}%
\affil[2]{Hebei Normal University College of Life Sciences}%
\affil[3]{Zhengzhou University}%
\affil[4]{Affiliation not available}%


\vspace{-1em}



  
  \date{May 24, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Abstract An ongoing novel highly contagious pneumonia outbreak started
in Wuhan, which is sprawling capital of central china's province, Hubei,
at the late December 2019. World Health Organization on February 12,
2020 officially named this disease as Coronavirus Disease 2019
(COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2
(SARS-CoV-2). The primary host of SARS-CoV-2 is linked with bat specie
however; the intermediate host is still not clear. The COVID-19 spread
rapidly across the world because of person-person transmission. The
SARS-CoV-2 stimulates both the cellular and humoral immunity mediated by
viral specific B and T cells. Cases of COVID-19 infection exhibit
several clinical complications for example fever, tiredness and dry
cough. Diagnosis are mostly depending on epidemiological
characteristics, clinical manifestation, and few through the examination
of auxiliary tissues. In this review, we have provided a brief
introduction of SARS-CoV-2, pathogenesis, diagnosis, immune responses,
and treatments and future perspectives.%
\end{abstract}%



\sloppy


\textbf{Summary:}

SARS-CoV-2 is a highly contagious member of \selectlanguage{greek}β \selectlanguage{english}coronaviruses. It can
cause pneumonia like disease officially named by WHO as COVID-19. It
infects the persons of all ages children, adults and olds. Primarily it
was emerged in late December, 2019 from seafood market of Wuhan, capital
of the Hubei Province of China. Now it has circled the entire world by
having exponential transmission rate human to human. Its transmission
occurs through direct contact, aerosols and air droplets but it can also
spread through shoes, clothes, electrical devices, etc. It cannot spread
through house flies and mosquitoes. Until now, it has infected
approximately 5.5 million people and caused 353334 deaths globally.
Patients infected with COVID-19 harbor three sorts of symptoms; they may
be asymptomatic, show mild or severe symptoms. Persons having medical
complications like cardiovascular diseases, diabetes, kidney diseases,
autoimmune diseases and other related diseases are more susceptible for
serve illness or death. To reduce the damage associated with COVID-19,
there should be complete implementation on recommendations provided by
health care organizations and WHO which include avoiding close contact,
wearing masks and gloves, practicing good hygienic measures and staying
at home. Diagnosis can be made on the bases of epidemiological
characteristics, screening and PCR. There is no FDA approved treatment
available for COVID-19 right now but some antiviral drugs (Leponavir,
Redimedisvir and Favipiravir), antimalarial potential drugs chloroquine
or hypo chloroquine, Monoclonal antibodies, blood plasma transfer, stem
cells, herbal treatments and many vaccines are also under
considerations. Some vaccines like Moderna (mRNA-1273) are showing very
fascinated results. Hopefully, it will be available at the end 2020 if
it has passed all the clinical examinations. Recently, WHO stopped the
clinical trials of chloroquine due to its severe complications observed
in many patients related to heart, kidney and immune system.

\textbf{Introduction}

Coronaviruses are Nidovirales and belong to family of coronaviridae, and
subfamily orthrocoronavirinae (Shereen, Khan, Kazmi, Bashir, \&
Siddique, 2020). Coronavirus shows crown-like spikes on their outer
surface; therefore, it was named as ``Coronavirus''. The Coronaviridae
has the four subgroups Alpha, Beta, Gamma, and Delta (\selectlanguage{greek}α, β, γ \selectlanguage{english}and \selectlanguage{greek}δ\selectlanguage{english})
coronaviruses(Zhong et al., 2003). The newly emerged SARS-CoV-2 belongs
to \selectlanguage{greek}β-\selectlanguage{english}coronaviruses, which is a enveloped, positive (+) sensed RNA virus
(Su et al., 2016). SARS-CoV-2 causes a highly contagious disease called
Coronavirus Disease 2019 (COVID-19) (Adhikari et al., 2020). The
phylogenetic studies shows that SARS-CoV-2 has high resemblance with
Severe Acute Respiratory Syndrome virus (SARS-CoV) and the relatively
poor resemblance with Middle East Respiratory Syndrome virus (MERS-CoV)
(Shereen et al., 2020) (Wang et al., 2020). This is the
3\textsuperscript{rd} zoonotic coronavirus outbreak in the
1\textsuperscript{st} two decades of 21\textsuperscript{st} century.
However, this time disease is rapidly transmitted from person to person
and have raised a global human concern (Xie \& Chen, 2020). Human to
human transmission through close contact, air droplets and asymptomatic
incubation carriers within the families, friends and the community made
it extremely contagious (Guo et al., 2020). By following exponential
growth up to the end of January, 2020, outbreak reached to several
countries grabbing considerable attention in the entire globe (Cucinotta
\& Vanelli, 2020). As of March 11, 2020, WHO announced the epidemic to a
global pandemic because of 13 folds increase in cases outside the China
and number of affected countries also increased 3 folds. A further
increase was is expected (Cucinotta \& Vanelli, 2020).

Unfortunately, the Chinese New Year festival ``Lunar'' holidays, which
is celebrated on the beginning of new year, accord with the outbreak of
COVID-19, is a best celebratory event of the year in China during which
huge number of peoples' migration occurred towards their home towns (Cai
et al., 2020). Approximately 3 billion people in China made close trips
over the 40 days' travel period of ``Chunyun''. About 5 million
individuals travelled from Wuhan, the epicentre of the COVID-19
outbreak, before the implementations of the travel ban on January 23,
2020 (Zu et al., 2020). Therefore, a rapid expansion and spread of
COVID-19 cases transmission observed within the China and outside the
China (Yang, Lu, et al., 2020). This review article highlights the
ongoing challenges of COVID-19, pathogenesis, diagnosis, current and
future treatment strategies, immune responses and future perspectives.

\textbf{1. Pathogenesis:}

The coronaviruses genome structure is best known among all RNA viruses
of virosphere. Two-third (2/3) part of their genome (RNA) encodes for
the viral polymerases (RdRp), material responsible for RNA synthesis,
and two (II) big structural polypeptides are responsible for the host
immune responses modulation (ORF1a-ORF1b). The remaining one-third (1/3)
part of RNA encodes for four (IV) structural proteins. These structural
proteins include spike (S) proteins, envelop (E) proteins, membrane (M)
proteins, and nucleocapsid (N) proteins (Shereen et al., 2020). COVID-19
causes the infection of lower respiratory tract of human and results in
pneumonia (Zhong et al., 2003). Patients infected with COVID-19 had the
higher leukocyte count, respiratory abnormalities, and elevated levels
of plasma proinflammatory cytokines (Cui, Li, \& Shi, 2019). Few
patients can also face headache or hemoptysis and even relatively
asymptomatic. According to Li et al; patients suffering from COVID-19
develop diarrhea (Klopfenstein et al., 2020) with loss of taste and
smell (Menni et al., 2020). Coronavirus causes approximately 15\% of
adult common colds while the same strains of coronaviruses can cause
debilitation and pneumonia in immunocompromised older adults
(Nikolich-Zugich et al., 2020). Affected aged individuals with medical
findings have a greater chance of respiratory failure due to severe
lungs ``alveolar'' damage (Adhikari et al., 2020). These signs and
symptoms are analogous with SARS-CoVs and MERS-CoVs infections. The
bases of initial infections with SARS-CoV-2 are not completely known
until now. Although, pathogenesis mechanism of COVID-19 is inadequately
learnt, however, the same mechanism of SARS-CoVs and MERS-CoVs can
provide us huge information about the SARS-CoV-2 pathogenesis.
Similarly, the attachment of SARS-CoV-2 with lung cells through ACE2
receptors lead to extended production of ACE2, which may catalyze the
destruction of host alveolar cells. Injury to human alveolar cells run a
group of systemic reactions and even death occurres (Hoffmann et al.,
2020) as shown in figure 1. Generally, the coronavirus infection
consists on attachment, entry, replication, translation, virion assembly
and release of virus (Hoffmann et al., 2020) (Shirato, Kawase, \&
Matsuyama, 2018).\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

\textbf{Figure 1:} Person to person transmission of SARS-CoV-2 mainly
depends upon air droplets and direct contact with infected person. After
the transmission the viral particles undergo six step viral replication
in human body such as 1) Viral entry through plasma membrane or
endosomes 2) translation of viral replicating machinery 3) replication
of viral particles 4) structural proteins translation 5) assembly of
virion and 6) release of the viruses. Furthermore, the figure also
explains the immune responses and conditions which develop after the
infection. There are three types of infections; asymptomatic, mild and
severe.

SARS-CoV-2 infection cycle starts from the entry of viral particle into
the host cell. SARS-CoV-2 can enter into host cell in two ways; either
through plasma membrane fusion or through endosomes (Hoffmann et al.,
2020). When the virions enter in to the endosomes, L cathepsin activates
the S protein. Although, the spike protein can also be activated by
cellular serine protease TMPRSS2 in close proximity to the ACE2
receptor, that starts with the fusion of viral membrane and the plasma
membrane (Hoffmann et al., 2020). Viral fusion entry less activates the
immune system therefore, more efficient for viral replication (Shirato
et al., 2018). The S proteins play a vital role in the attachment of
virion with the host cell membrane (Ramanathan et al., 2020). It
consists of two basic subunits S1 and S2. The S1 subunit consists on a
signal peptide (SP) which is proceeded through Receptor Binding domain
(RBD) and N-terminal domain (NTD), while S2 subunit consists on the I
and II heptad repeat (HR), cytoplasmic domain (CPD), Transmembrane
domain (TMD), and fusion peptide (FP) (Cai et al., 2020). Genome
encoding initiates after the entry into human cells (respiratory tract
cells) and facilitates the expression of genes (protein synthesis) which
run the adaptation of CoVs to their human host (Su et al., 2016).

1.2. \textbf{Replication and translation of SAR-CoV-2 Machinery:}

When SARS-CoV-2 enters the body, it releases its RNA into the host lung
cells, and polypeptides immediately undergo translation. Nonstructural
proteins (NPs), that have a very important function in viral RNA and
structural proteins' synthesis, have a very critical role in virion
assembly formed by the viral genomic RNA encoding. Pp1a and pp1ab are
the first polypeptides that are translated to form functional NSPs as
helicase or RdRp (Shin, Jung, Kim, Baric, \& Go, 2018).

1.3. \textbf{Translation of viral structural proteins, virion assembly
and Release:}

RdRp are very important enzymes that are responsible for the replication
of viral structural proteins of RNA. S1, S2, E and M are structural
proteins translated via ribosomes that are attached with endoplasmic
reticulum (ER) and expressed on its surface as preparation of virion
assembly. N proteins remain in cytoplasm and are assembled from genomic
RNA. They bound to the virion precursor which is then transported via
small vesicles from the ER through Golgi Apparatus to cell surface
(Zhong et al., 2003). Virions are then released from the infected cell
through exocytosis which then search for another host cell to infect.

\textbf{Immune response:}

Immune system shows response against COVID-19 into 2 distinct phases (I,
II). Phase I immune response initiates during the incubation and
non-severe stage of SAR-CoV-2. Fully functional and specific adaptive
immune response is required to eliminate SAR-CoV-2 and to stop the
disease progression to severe stages. At this stage of disease,
anti-sera and IFN \selectlanguage{greek}α \selectlanguage{english}treatments are important strategies for the
protective endogenous immune response. Host generally has good health
and appropriate immune genetic background that produce excellent
antiviral immunity (Shi et al., 2020). When the protective immune
response is failed to elicit the disease, the virus propagates to a
severe stage and triggers the phase II immune response. Phase II immune
response includes severe cytokines storms and pro-inflammation (Guo et
al., 2020). According to Lancet reports, the prime factor of causalities
with COVID-19 is the progression of acute respiratory distress syndrome
(ARDS) (Kalkeri, Goebel, \& Sharma, 2020). One of the key mechanism of
ARDS is the massive release of cytokines named as cytokines storm which
leads to abandoned systemic inflammation due to the release of IFN- \selectlanguage{greek}α,
\selectlanguage{english}IFN-g, IL-1b, IL-6, IL-12, IL-18, Il-33, TNF- \selectlanguage{greek}α, \selectlanguage{english}and TGFb and many other
chemokines CCL2, CCL3, CCL5, CXCL8, and CXCL-10, etc. (Ahmed, Shah,
Rahim, Flores, \& O'Linn, 2020). This lead to multi-organ failures like
kidney and lungs (Ahmed et al., 2020), while the immune system of aged
persons bear many age-related consequences that effect nearly each
component of immune system collectively termed as immune senescence
(Nikolich-Zugich et al., 2020). It changes the face themselves and
enhance the morbidity and mortality rate with infectious diseases
especially COVID-19 which affect both adaptive and innate immune system
as well as the cooperation of immune response itself in time and space
which work effectively in young adults but deteriorate with age.
Globally, cytokines signalling, peroxide production, nitric oxide and
phagocytic functions of neutrophils all are reduced in older people
(Nikolich-\selectlanguage{polish}Ž\selectlanguage{english}ugich, 2018). The macrophages ability of phagocytoses also
become limited due to defective phosphorylation of activating enzymes to
limit and delay cytokines secretions (Desai, Grolleau-Julius, \& Yung,
2010). Age related changes disturb the functionality of dendritic cell
(DC, s), to encompass reduced uptake of antigen and diminish the
maturation, migration and formulation of co-stimulatory molecules and
necessary cytokines for T cells stimulations (Nikolich-\selectlanguage{polish}Ž\selectlanguage{english}ugich, 2018).
Furthermore, adaptive immune system is also significantly affected by
age related factors. It diminishes both, B and T cells functions.
Activation of old B cells face serious issues in the initiation of a
vital E47 and AID transcription factor.

Improper induction of these important enzymes, in case of class
switching and somatic cell hyper-mutation, head to decrease avidity of
antibodies in aged patients (Nikolich-\selectlanguage{polish}Ž\selectlanguage{english}ugich, 2018). T --cells are also
affected enormously by age related changes and the proliferation of
T-cells and expression of IL-2 is also reduced. CD4\textsuperscript{+}TN
cells in old humans, whereby, diminish T-cells receptors' (TCR)
signalling and population increment were associated with age linked
destruction of miR-181, an important microRNA 53. MicroRNA commonly
suppresses the phosphatase that attenuate TCR signalling. T-helper cells
and downstream effector molecules like TNF, TNF-\selectlanguage{greek}γ, \selectlanguage{english}granzyme B cells and
others are also reduced (Nikolich-Zugich et al., 2020). A brief
information is beyond this review scope, although, the aggregation of
these alterations leaves aged people particularly susceptible to
emerging infectious disease. This is, because, with advancing age, T and
B-cells production starts dropping and at the age of 40-50 years, only
10\% of T-cells are left as compared to the children and youngsters.
This is the reason that why elderly people are more prone to infections
(Chinn, Blackburn, Manley, \& Sempowski, 2012).

\textbf{CURRENT TREATMENT STRATIGIES FOR COVID-19:}

To date, there is no specific antiviral drug and vaccine recommended for
the treatment of COVID-19, however, UK and Germany are trailing their
vaccines against COVID-19. The only treatment available is oxygen
therapy which constitute the prime treatment intervention for patients
with serious respiratory infections. Moreover, among other therapeutic
strategies and a number of drugs, only a few have been used on patients
with SARS-CoV and MERS-CoV infections and a few are being tested
including remdisivir, baricitnib, hydroxychloroquine and the drugs used
against influenza, favipiravir, chloroquine and others being considered
(Chinn et al., 2012).

Wang et al. disclosed that chloroquine (anti-malarial drug) in
combination with remdesivir is highly effective against the COVID-19.,
because chloroquine results great in in-vitro impacts on the suppression
of uncoating of viruses. It does not allow a virus to uncoat and release
its genome. It also inhibits alteration of post-translational changes of
newly synthesized proteins, it also does suppression of glycosylation in
several viruses, including human immunodeficieny virus (HIV) (Wang et
al., 2020). The advantage of exploring such drugs is that there is
already a large number of information available about the bases of their
usage and safety in humans and it is important that despite the urgency,
the introduction of new therapies should not be pressed at the expense
of safety. Moreover, Chinese traditional medicines have gained wide
adoption, particularly in curing mild symptoms of COVID-19. A Chinese
patent medicine Lianhuaqingwen (LH), which is formed of 13 herbs has
played a positive role in the treatment of COVID-19 as it exerts broad
spectrum impact on the group of influenza viruses by restricting viral
propagation (Runfeng et al., 2020). Furthermore, immunotherapy by
applying IgG in combination with antiviral drugs can be applied to treat
and prevent COVID-19 and to make the immune response stronger against
this virus. The IgG may be applied to neutralize the virus causing
COVID-19 and the efficacy of IgG antibodies would be best if they were
isolated from patients recovered from COVID-19 (Jawhara, 2020).

A research which include four rhesus monkeys introduce that formulating
SARS-CoV-2 saved against future reoccurring of infections. When
scientists re-infected II of the IV monkeys by this virus after 28 days of
initial infection, a total of 96 anal swabs and nasopharyngeal swabs
resulted negative (--ve) after the re-exposure of SARS-CoV-2. The
euthanasia and necropsy findings of I of the II monkeys confirmed these
results. These results suggested that immune response raised by II
animals have saved them from future infection of SARS-CoV-2. Hoffmann et
al; studied, whether antibodies produced by patients who have been
previously diagnosed positive (+) for SARS would prevent SARS-CoV-2
entry into the cell. They also analysed that the antibodies against
SARS-CoV S protein limit how well in the in-vitro model virus with a
SARS-CoV-2 S protein could infect cells (Golchin, Seyedjafari, \&
Ardeshirylajimi, 2020). They also saw similar findings with antibodies
against S proteins produced in rabbits. These findings showed that
neutralizing antibody responses formed against SARS-CoVs could offer
some safety against SARS-CoV-2 infection, which can be used for the
prevention of COVID-19 infection (Hofmann \& P\selectlanguage{ngerman}öhlmann, 2004). Moreover,
the passive immunization with convalescent sera having (Ab)antibodies
from individuals who have recovered from COVID-19, could prevent
COVID-19 infection as argued by Casadevall and Pirofski (Golchin et al.,
2020). Some investigational treatments for COVID-19 are given in table
1.

To reduce the damage linked to COVID-19, global public health and
infection control programs are exigently needed to bound the world wide
transmission of virus. In COVID-19 victim's travel history has great
significance for early discovery and isolation of SARS-CoV-2 pneumonia
cases. It is necessary to reduce person to person transmission in order
to limit secondary infections (Garami, 2020). Currently, prevention is
the only strategy that can limit spread of COVID-19 (Anderson,
Heesterbeek, Klinkenberg, \& Hollingsworth, 2020).

Table 1: \textbf{Investigational treatments of COVID-19}\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
VIRAL DRUGS UNDER CLINICAL TRIALS: & POSSIBILITIES OTHER THAN ANTIVIRAL
DRUGS:\tabularnewline
\midrule
\endhead
Leponavir and ritonavir (Stower, 2020) & Monoclonal antibodies isolation
from patients recovered from COVID-19 (Shanmugaraj, Siriwattananon,
Wangkanont, \& Phoolcharoen, 2020)\tabularnewline
Remedisvir (Grein et al., 2020) & Blood plasma transfers (Duan et al.,
2020)\tabularnewline
Favipiravir (Cai et al., 2020) & Stem cells (Golchin et al.,
2020)\tabularnewline
Chloroquine (Principi \& Esposito, 2020) &\tabularnewline
Hydroxychloroquine (Principi \& Esposito, 2020) &\tabularnewline
\textbf{HERBAL TREATMENTS:} 4 most commonly used herbs in China under
trial are : & \textbf{HERBAL TREATMENTS:} 4 most commonly used herbs in
China under trial are :\tabularnewline
Astragali Radix (Huangqi) (Yang, Islam, Wang, Li, \& Chen, 2020) &
Saposhnikoviae Radix (Fangfeng) (Ang et al., 2020)\tabularnewline
Glycyrrhizae Radix Et Rhizoma (Gancao) (Luo et al., 2020) & Lonicerae
Japonicae Flo (Luo et al., 2020)\tabularnewline
\bottomrule
\end{longtable}

\textbf{Chloroquine as a potential inhibitor among all other
antivirals:}

Chloroquine (CQ) is an acidotropic amine form of quinine. For decades CQ
is being used as a medication for the treatment and prevention of
malaria and for a variety of other viruses such as human
immuneodeficiency virus (HIV), Zika virus, Marburg virus, Dengue virus
and SARS-CoV-1 (Barnard et al., 2006). The reason behind this frequent
use is anti-inflammatory and immunomodulatory effects of this drug which
can be beneficial in treating COVID-19. The China National Centre for
Biotechnology Development found that CQ is I of the III drugs with
encouraging profile against SARS-Cov-2 caused by COVID-19 (Devaux,
Rolain, Colson, \& Raoult, 2020). Chloroquine has multiple mechanisms of
action depending on the type of pathogen interaction. Chloroquine can
limit the pre-entry step of viral replication cycle by interfering with
viral particles binding to their intracellular receptors, it can also
inhibit pH dependent endosome mediated entry of enveloped viruses
(Barnard et al., 2006). This feature can be attributed in treating
COVID-19 as SARS-CoV-2 entry is also reported to be endosome mediated
(Wang et al., 2020). The pH intonation by CQ can diminish the proper
maturation of viral protein and recognition of viral antigens by
receptors. CQ can also inhibit post translational modifications of viral
proteins such as glycosylation which require low pH i.e. HIV and CQ
increase the pH (Vincent et al., 2005). During in-vitro studies CQ has
shown to deficit the glycosylation of angiotensin converting enzyme 2
(ACE2), a viral cell surface receptor (Wang et al., 2020). Chloroquine
works at both, entry and after entry stages of COVID-19 infection. Its
immune-modulating functions synergistically increase its antiviral
effects on animals as it is mostly distributed in the entire body as
well as lungs after oral administration. Recently CQ have been shown by
several studies to reduce SARS-CoV-2 viral load and duration of viremia
(Dong, Hu, \& Gao, 2020). Till now, 15 clinical trials have been
conducted in China where each trial contained 100 patients to define the
safety and efficacy of CQ in treating COVID-19, however, their immune
modulatory effects also play a vital role in treating COVID-19 which
require further investigation (Zhang, Wang, Qi, Shen, \& Li, 2020).
Suddenly, on May 25, 2020 WHO suspended the clinical trials of
chloroquine and hydroxyl-chloroquine as very potential treatment of
COVID-19 due to recent published study in Lancet by Mehra et al;
According to their findings, chloroquine and hydroxyl-chloroquine showed
serious side effects especially heart arrhythmia and many other
complications related cardiovascular diseases (Klopfenstein et al.,
2020).

\textbf{Vaccines:}

Currently, there is no FDA approved vaccine is available for COVID-19,
but, several groups started their work on preparing vaccine shortly
after Chinese scientists shared viral genetic material (Klopfenstein et
al., 2020). These include, MODERNA, INOVIO, CUREVAC BIOTECH COMPANY and
UNIVERSITY OF QUEENSLAND IN AUSTRALIA.

\textbf{MODERNA is a Key Forerunner among all Vaccines:}

At the end of March, 2020 this company started testing its mRNA-1273
vaccine against COVID-19 in Washington on 45 healthy volunteers with
ages between 18-55, this mRNA vaccine when injected into human body
cells, the lymphocytes (B and T cells) in lymph nodules can operate that
mRNA initiates the formulation of protein in just the right way for
other immune cells to mark and identify them for destruction (Grein et
al., 2020).\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

\textbf{Figure 2:} A timeline of Moderna mRNA-1273 vaccine.

This mRNA-1273 consists on the lipid Nano-particles (LNP), encapsulated
mRNA vaccine that encodes for stabilized condition of S proteins before
the fusion. The currently expected dose is 50 mcg. Moderna is ready to
lunch Phase 3 studies by summer, 2020. Hopefully it would be the
1\textsuperscript{st} recommended vaccine against COVID-19 by the end of
2020.

\textbf{INOVIO} : This company has quickly developed vaccine against
COVID-19 as they are working since December on DNA vaccine for MERS,
caused by the same coronavirus. The company is expected to start
clinical trials of COVID-19 vaccine in May 2020 (Grein et al., 2020).

\textbf{UNIVERSITY OF QUEENSLAND IN AUSTRALIA} : Researchers are
developing vaccine by growing viral proteins in cell culture. They
expect to start clinical trials by the end of May 2020 (Duan et al.,
2020).

\textbf{CUREVAC BIOTECH} : This company in Turbingen, Germany will begin
a human trial of mRNA based vaccine in June 2020 (Kirkwood, 2019).

Another trial is by the Kaiser Permanente Washington Health Research
institute in Seattle, USA, which is under consideration. In this trial,
vaccine is injected to 45 healthy volunteers which contain a part of
genetic material duplicated from SARS-CoV-2. Because this vaccine does
not have the actual SARS-CoV-2, the individuals will not develop
COVID-19 (Philippidis, 2020).

In UK, Sarah Gilbert and her colleague at Oxford University begin
imminent trials on humans and animals of ChAdOx1 vaccine and it is
predicted that the vaccine will be accessible in late of 2020 (Alharbi
et al., 2017).

In China CanSino Biologics, in participation with the academy of
Military Medical sciences, is also working to formulate the recombinant
vaccine. A clinical trial has begun among 108 volunteers in Wuhan aged
between 18-60 years (Cohen, 2020).

However, according to the director of the National institute of Allergy
and Infectious Diseases, a vaccine won't be available for widespread use
for at least another 12-18 months (Cai et al., 2020).

\textbf{Myths related to COVID-19:}

There are so many myths wondering around the world related to
transmission, prevention and treatment of COVID-19. According to WHO,
addition of pepper in food, inhalation of disinfectants, alcohols,
bleach, exposure to hot sun, cold weathers, snows, bathing with hot
water, hand dryer, UV-lights, watching nose with saline, eating garlic,
older person susceptibility, vaccines of pneumonia and use of
antibiotics cannot protect from this lethal virus. The only way of
protection is to keep 1-meter distance. WHO also cleared that COVID-19
cannot spread through the house flies and bite of mosquitoes (Shereen et
al., 2020).

\textbf{Conclusion and Future Perspectives:}

There is no proper treatment available for COVID-19 right now.
Therefore, it is spreading rapidly across the globe and has already
paralyzed life in a number of countries. Its spread can be limited only
by having strict implementation on preventive strategies developed by
WHO. Nowadays, it is too early to predict any practical situation, but
it will strongly threat the entire world. Low-income countries like
Pakistan, are facing worst-case scenarios by having very low economic
support to fight against this lethal virus. This is an interesting and
hot topic to develop guidelines, not only for the instant time of
pandemic, but it is also very important to keep an eye on future as
there are upcoming waves looking forward. There is a need for unveiling
the detailed entry processes of SARS-CoV-2 into human cells. In
addition, research work is required to fill the gaps associated with the
transmission of the virus from zoonotic sources to humans. Without
knowing the intermediate zoonotic source that had received the virus
from source of origin and caused the infection in humans, it is almost
impossible to eradicate the infection. Proper strategies should be
applied in healthcare settings with restriction of people to their homes
to mitigate the spread.

\textbf{Conflict of Interest:} No

\textbf{Data Availability Statement:} The authors confirm that the data
supporting the findings of this study are available within the article
and its supplementary materials.

\textbf{Ethical Statement:} The authors confirm that the ethical
policies of the journal, as noted on the journal's author guidelines
page, have been adhered to. No ethical approval was required as this is
a review article with no original research data.

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\textbf{Tables:}

Table 1: \textbf{Investigational treatments of COVID-19}\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
VIRAL DRUGS UNDER CLINICAL TRIALS: & POSSIBILITIES OTHER THAN ANTIVIRAL
DRUGS:\tabularnewline
\midrule
\endhead
Leponavir and ritonavir (Stower, 2020) & Monoclonal antibodies isolation
from patients recovered from COVID-19 (Shanmugaraj et al.,
2020)\tabularnewline
Remedisvir (Grein et al., 2020) & Blood plasma transfers (Duan et al.,
2020)\tabularnewline
Favipiravir (Cai et al., 2020) & Stem cells (Golchin et al.,
2020)\tabularnewline
Chloroquine (Principi \& Esposito, 2020) &\tabularnewline
Hydroxychloroquine (Principi \& Esposito, 2020) &\tabularnewline
\textbf{HERBAL TREATMENTS:} 4 most commonly used herbs in China under
trial are : & \textbf{HERBAL TREATMENTS:} 4 most commonly used herbs in
China under trial are :\tabularnewline
Astragali Radix (Huangqi) (Yang, Islam, et al., 2020) & Saposhnikoviae
Radix (Fangfeng) (Ang et al., 2020)\tabularnewline
Glycyrrhizae Radix Et Rhizoma (Gancao) (Luo et al., 2020) & Lonicerae
Japonicae Flo (Luo et al., 2020)\tabularnewline
\bottomrule
\end{longtable}

\textbf{Figures:}

\textbf{Figure 1:} Person to person transmission of SARS-CoV-2 mainly
depends upon air droplets and direct contact with infected person. After
the transmission the viral particles undergo six step viral replication
in human body such as 1) Viral entry through plasma membrane or
endosomes 2) translation of viral replicating machinery 3) replication
of viral particles 4) structural proteins translation 5) assembly of
virion and 6) release of the viruses. Furthermore, the figure also
explains the immune responses and conditions which develop after the
infection. There are three types of infections; asymptomatic, mild and
severe.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image3/image3}

\end{center}
\end{figure}

\textbf{Figure 2:} A timeline of Moderna mRNA-1273 vaccine.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image4/image4}

\end{center}
\end{figure}

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\textbf{Hosted file}

\verb`Tables.docx`  available at \url{https://authorea.com/users/327853/articles/455249-pathogenesis-diagnosis-immune-responses-and-current-treatment-strategies-of-covid-19}

\selectlanguage{english}
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