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\begin{document}

\title{How did we get here? A short history of~ COVID-19 and other
coronavirus-related epidemics~~~~}



\author[1]{Miriam N. Lango, MD}%
\affil[1]{The University of Texas MD Anderson Cancer Center}%


\vspace{-1em}



  
  \date{May 24, 2024}


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\selectlanguage{english}
\begin{abstract}
The COVID-19 epidemic was not the first coronavirus epidemic of this
century and represents one of the increasing number of zoonoses from
wildlife to impact global health. SARS CoV-2, the virus causing the
COVID-19 epidemic is distinct from, but closely resembles SARS CoV-1,
which was responsible for the severe acute respiratory syndrome (SARS)
outbreak in 2002. SARS CoV-1 and 2 share almost 80\% of genetic
sequences and use the same host cell receptor to initiate viral
infection. However, SARS predominantly affected individuals in close
contact with infected animals and health care workers. In contrast,
CoV-2 exhibits robust person to person spread, most likely by means of
asymptomatic carriers, which has resulted in greater spread of disease,
overall morbidity and mortality, despite its lesser virulence. We review
recent coronavirus-related epidemics and distinguish clinical and
molecular features of CoV-2, the causative agent for COVID-19, and
review the current status of vaccine trials.%
\end{abstract}%



\sloppy


\subsection*{Miriam N. Lango MD}

{\label{956113}}

Department of Head and Neck Surgery,

MD Anderson Cancer Center

Houston, Texas

\textbf{~Acknowledgements of research support}

N/A

~\textbf{Corresponding Author}

Miriam Lango, MD MD Anderson Cancer Center

1515 Holcombe Blvd

Houston, Texas 77030

{MNLango@mdanderson.org}

~

\textbf{Running head}:

Short History COVID-19 Epidemic Review

\textbf{Disclaimers:} none

Number pages: 9 total

Total words: 1681 (without references)

Number of figures: 1

Number of tables: None

~

\par\null

~In early December 2019, Li Wenliang, a physician from Wuhan, a large
metropolitan area in China's Hubei province, reported in a group chat
that he noticed a series of patients showing signs of a severe acute
respiratory syndrome or SARS-like illness which was subsequently
reported to the WHO Country Office in China on December 31, 2019. On
Jan. 12, Chinese scientists published the genome of the virus, and the
World Health Organization (WHO) asked a team in Berlin to use that
information to develop a diagnostic test to identify active infection,
which was developed and shared four days later. On~January 30, 2020, the
outbreak was declared by the WHO a Public Health Emergency of
International Concern (PHEIC). The first case of the disease due
to~local person to person spread in the US was confirmed in mid-February
2020. On March 11, WHO declared COVID-19 a pandemic.

\subsection*{\texorpdfstring{\emph{Links to prior coronaviruses causing
Severe Acute Respiratory Syndromes
(SARS)}}{Links to prior coronaviruses causing Severe Acute Respiratory Syndromes (SARS)}}

{\label{439538}}

Because of the genome's homology with the coronavirus that caused the
SARS outbreak (SARS-Coves) in China in 2002 to 2003, this virus was
renamed SARS-CoV-2. Coronaviruses are known to be the causative agent
for the ``common cold,'' accounting for up to 30\% of upper respiratory
tract infections in adults. Coronaviruses, like other RNA viruses,
mutate frequently and evolve in vast animal reservoirs. The overwhelming
majority of coronaviruses pose no threat to humans, but recombination
events, natural selection and genetic drift permit particularly virulent
coronaviruses to jump to human hosts and to subsequently acquire the
capacity for efficient person to person spread \textsuperscript{1}.

For reasons that are not well understood, zoonoses from wildlife has
been increasing over the last half-century, and represent the most
significant, growing threat to global health of all emerging infectious
diseases \textsuperscript{1}. Geographic hotspots, or maps reflecting
zoonotic infectious disease risk have been identified in South American,
Africa and South Asia\textsuperscript{2} (Figure 1). Both SARS-CoV-1 and
2 arose in one of these `hot-spots'. Future outbreaks are believed to be
all but inevitable\textsuperscript{1,3}.

\subsection*{\texorpdfstring{~\emph{A new
epidemic?}}{~A new epidemic?}}

{\label{466857}}

The SARS-Cove epidemic in 2002-3 was the first coronavirus pandemic in
modern times, which spread to two dozen countries with approximately
8000 cases and 800 deaths before it was contained\textsuperscript{4}. In
2012, another outbreak, referred to as MERS for the Middle Eastern
Respiratory Syndrome, in 2012, also caused by a coronavirus, resulted in
over 1000 infections and 400 deaths through 2015. Since SARS and MERS
coronavirus exhibited reduced person to person spread, its global impact
was ultimately limited. Health care settings were the most frequent
sites of person to person disease transmission\textsuperscript{5,6}.
Health care workers and those in close contact with infected individuals
were at greatest risk of contracting and succumbing to disease, while
the general public was relatively spared during these outbreaks. In
particular, otolaryngologists were at particular risk of infection due
to shedding of virus from nasal and pharyngeal mucosa\textsuperscript{7}
The implementation of infection control methods, aggressive contact
tracing and isolation limited the spread of disease in 2003 and 2012.
Antiviral treatments and vaccines were never developed.

The virus which causes COVID19 is similar to, but not identical with the
SARS-Cove virus, which caused the SARS epidemic originating in China in
2002-3.~ Full-length genome sequences obtained from infected Chinese
patients in 2019 showed 79.6\% sequence homology to
SARS-CoV\textsuperscript{8}.~ SARS-CoV-2 is more closely related to
two~bat-derived severe acute respiratory syndrome (SARS)-like
coronaviruses,~bat-SL-CoVZC45 and~bat-SL-CoVZXC21, collected in 2018 in
Zhoushan, eastern China(with 88\% identity), and a strain isolated from
pangolins (99\% identity) than to SARS-Cove, than SARS-Cove, suggesting
SARS-CoV-2 should be considered a~new~human-infecting coronavirus,
rather than re-emergence of SARS-CoV\textsuperscript{9}. Transmission is
believed to have occurred from bat-Cove to an intermediate host after
which the virus jumped to human hosts at live animal
markets\textsuperscript{10}. Suggestions that CoV-2 was constructed in a
laboratory have been discredited\textsuperscript{11,12}.

The infectivity of CoV-2, relative to CoV-1, is likely accounted for by
relatively high rates of asymptomatic carriers which promote the spread
of infection to susceptible populations\textsuperscript{13}, rather than
greater stability of virus in aerosolized droplets or on surfaces
\textsuperscript{14}. Despite variations and limitations in testing,
CoV-2 appears to be less virulent than CoV-1\textsuperscript{15}. ~

\subsection*{\texorpdfstring{\emph{SARS-CoV2: Conserved sequences and
genetic
drift}}{SARS-CoV2: Conserved sequences and genetic drift}}

{\label{191553}}

While the viral genome continues to evolve since entering the human
population, sequences critical to human transmission are preserved. All
coronaviruses exhibit a spike on its surface, which gives it the
appearance of a crown (i.e. Corona in Latin) on electron micrographs,
mediates binding to host cell receptors, determines viral host range and
tissue tropism, and induces host immune response. SARS-CoV2, like
SARS-Cove, gain entry into human cells via the angiotensin 1 converting
enzyme 2 (ACE2) receptor, expressed on human lung and other tissues
(Zhou, Yang et al. 2020). This receptor mediates the effects of
angiotensin, which affects vasoconstriction and hypertension in the
lungs, heart, kidneys and intestines. An identical ACE receptor is also
found in some animals; this permit cross-species
infection\textsuperscript{10}.

The spike or S protein, expressed on the surface of coronaviruses plays
an important role in the first step of viral infection by binding to the
host ACE-2 receptor, and initiating virus-host membrane fusion. The
amino acid sequences of the protein, particularly its receptor-binding
domains (RBDs) are highly conserved, since they are necessary to
propagate the infection in person to person spread. The amino acid
sequence of the SARS-CoV-2 spike (S) protein, particularly its RBD,
serves as an antigen for the immune system, which could be used in the
development of serologic tests and vaccines. So-called ``escape
mutants'', viruses with amino acid alterations just flanking but not
disrupting the receptor binding domain could potentially compromise
durable immunity and the effectiveness of vaccines against SARS-CoVs
\textsuperscript{16}. The clinical significance of escape mutations in
coronaviruses is uncertain. In general, immune responses to coronavirus
infections confer prolonged immunity. Neutralizing antibodies to CoV-1,
that prevent viral infection by preventing binding of the S protein to
the host cell receptor, have been detected in SARS patients almost 20
years after recovering from disease suggesting that patients retain
protection over long periods after mounting an immune response
\textsuperscript{17}.

While the genetic sequences critical to transmission are preserved,
non-critical viral sequences have undergone genetic drift. Compared to
CoV-2 sequences isolated in January in China, strains from other parts
of the world exhibited genetic sequences which distinguish European from
Asian CoV-2 coronavirus strains\textsuperscript{18}. Differences between
viral strains has permitted evaluations of the effectiveness of public
health interventions. For example, analyses of different strains showed
that predominance of COVID-19 cases in the New York City area resulted
largely from infected patients who flew in from Europe, rather than
Asia. Consequently, barring US entry to recent visitors to China on
January 31\textsuperscript{st}, and from European countries on March
11th was largely ineffective in preventing the COVID outbreak in the
US\textsuperscript{19}.

\subsection*{\texorpdfstring{\emph{Serological testing and vaccine
development}}{Serological testing and vaccine development}}

{\label{878740}}

The identification of viral epitopes that stimulate the production of
antibodies that serve as markers of an immune response to CoV-2
infection are necessary for the development of serologic testing and
vaccines. Currently numerous serologic tests using antibodies against
specified antigens are commercially available, but most have not been
adequately validated. At best, tests reflect an immune response without
necessarily indicating host immunity\textsuperscript{20}. The
availability of conserved epitopes also allows the structure-based
design of a SARS-CoV-2 vaccine. However, not all antibodies prevent
viral infection, despite targeting virus specific epitopes. For example,
antibodies raised against SARS CoV-1 cross-react with the CoV-2 viral
epitopes, but do not prevent CoV-2 binding to ACE-1 receptors; these
antibodies may provide some clinical protection or attenuate the disease
without actually preventing infection\textsuperscript{21,22}.
Neutralizing antibodies that prevent viral attachment to host cell
receptors protect against viral infection. However, subtle amino acid
alterations may provide a ``back door'' for viral escape mutants(Rockx
et al., 2008; Sui et al., 2004; Mitsuki et al., 2008; Sui et al., 2008;
ter Meulen et al., 2006). A cocktail of viral epitopes to stimulate a
robust neutralizing immunologic response has been recommended to address
this phenomenon\textsuperscript{23}.

Currently, the need for a safe and effective vaccine against
coronaviruses is generally appreciated. Numerous human vaccine trials
for are under way targeting CoV-2. ~Historically, support for vaccine
development after the SARS epidemic was short-lived.~ Vaccine
development for SARS included a Phase 1 clinical trial of a SARS-CoV-1
vaccine which showed that the vaccine was safe, and effectively
stimulated the production of neutralizing
antibodies\textsuperscript{24}. Unfortunately, when the SARS epidemic
ended, vaccine development was abandoned \textsuperscript{25}. The
impact of the COVID-19 epidemic suggests that interest in the
development of a vaccine will be more successful.

Nevertheless, potential impediments to vaccine development, noted during
the SARS, remain potentially problematic. For example, concerns about
vaccine -mediated immune enhancement were raised during the vaccine
development for SARS. Anecdotal reports of individuals developing more
severe disease after exposure in individuals vaccinated against SARS
CoV-1 raised concerns about vaccine safety and
efficacy\textsuperscript{26}. Animal models demonstrated an analogous
effect. Prior immunization with severe acute respiratory syndrome
(SARS)-associated coronavirus (SARS-Cove) nucleocapsid protein caused
severe pneumonia in mice infected with SARS-CoV\textsuperscript{27}.
Demonstrations of safety and efficacy of vaccines against CoV-2 are
crucial but take time. In the meantime, other forms of prevention
(social distancing, protective device use) will limit transmission
rates, and ultimately morbidity and mortality.

\par\null

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~

~

~\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure1/Figure1}
\caption{{Heat maps of predicted relative risk distribution of zoonotic emerging
disease threats. The CoV-2 coronavirus arose in one of these
``hot-spots''\textsuperscript{2}
{\label{781710}}%
}}
\end{center}
\end{figure}

\selectlanguage{english}
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