\documentclass[twocolumn,twoside]{article}
\makeatletter\if@twocolumn\PassOptionsToPackage{switch}{lineno}\else\fi\makeatother

\usepackage{amsfonts,amssymb,amsbsy,latexsym,amsmath,tabulary,graphicx,times,xcolor}

%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%
% Following additional macros are required to function some 
% functions which are not available in the class used.
%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%
\usepackage{url,multirow,morefloats,floatflt,cancel,tfrupee}
\makeatletter


\AtBeginDocument{\@ifpackageloaded{textcomp}{}{\usepackage{textcomp}}}
\makeatother
\usepackage{colortbl}
\usepackage{xcolor}
\usepackage{pifont}
\usepackage[nointegrals]{wasysym}
\urlstyle{rm}
\makeatletter

%%%For Table column width calculation.
\def\mcWidth#1{\csname TY@F#1\endcsname+\tabcolsep}

%%Hacking center and right align for table
\def\cAlignHack{\rightskip\@flushglue\leftskip\@flushglue\parindent\z@\parfillskip\z@skip}
\def\rAlignHack{\rightskip\z@skip\leftskip\@flushglue \parindent\z@\parfillskip\z@skip}

%Etal definition in references
\@ifundefined{etal}{\def\etal{\textit{et~al}}}{}


%\if@twocolumn\usepackage{dblfloatfix}\fi
\usepackage{ifxetex}
\ifxetex\else\if@twocolumn\@ifpackageloaded{stfloats}{}{\usepackage{dblfloatfix}}\fi\fi

\AtBeginDocument{
\expandafter\ifx\csname eqalign\endcsname\relax
\def\eqalign#1{\null\vcenter{\def\\{\cr}\openup\jot\m@th
  \ialign{\strut$\displaystyle{##}$\hfil&$\displaystyle{{}##}$\hfil
      \crcr#1\crcr}}\,}
\fi
}

%For fixing hardfail when unicode letters appear inside table with endfloat
\AtBeginDocument{%
  \@ifpackageloaded{endfloat}%
   {\renewcommand\efloat@iwrite[1]{\immediate\expandafter\protected@write\csname efloat@post#1\endcsname{}}}{\newif\ifefloat@tables}%
}%

\def\BreakURLText#1{\@tfor\brk@tempa:=#1\do{\brk@tempa\hskip0pt}}
\let\lt=<
\let\gt=>
\def\processVert{\ifmmode|\else\textbar\fi}
\let\processvert\processVert

\@ifundefined{subparagraph}{
\def\subparagraph{\@startsection{paragraph}{5}{2\parindent}{0ex plus 0.1ex minus 0.1ex}%
{0ex}{\normalfont\small\itshape}}%
}{}

% These are now gobbled, so won't appear in the PDF.
\newcommand\role[1]{\unskip}
\newcommand\aucollab[1]{\unskip}
  
\@ifundefined{tsGraphicsScaleX}{\gdef\tsGraphicsScaleX{1}}{}
\@ifundefined{tsGraphicsScaleY}{\gdef\tsGraphicsScaleY{.9}}{}
% To automatically resize figures to fit inside the text area
\def\checkGraphicsWidth{\ifdim\Gin@nat@width>\linewidth
	\tsGraphicsScaleX\linewidth\else\Gin@nat@width\fi}

\def\checkGraphicsHeight{\ifdim\Gin@nat@height>.9\textheight
	\tsGraphicsScaleY\textheight\else\Gin@nat@height\fi}

\def\fixFloatSize#1{}%\@ifundefined{processdelayedfloats}{\setbox0=\hbox{\includegraphics{#1}}\ifnum\wd0<\columnwidth\relax\renewenvironment{figure*}{\begin{figure}}{\end{figure}}\fi}{}}
\let\ts@includegraphics\includegraphics

\def\inlinegraphic[#1]#2{{\edef\@tempa{#1}\edef\baseline@shift{\ifx\@tempa\@empty0\else#1\fi}\edef\tempZ{\the\numexpr(\numexpr(\baseline@shift*\f@size/100))}\protect\raisebox{\tempZ pt}{\ts@includegraphics{#2}}}}

%\renewcommand{\includegraphics}[1]{\ts@includegraphics[width=\checkGraphicsWidth]{#1}}
\AtBeginDocument{\def\includegraphics{\@ifnextchar[{\ts@includegraphics}{\ts@includegraphics[width=\checkGraphicsWidth,height=\checkGraphicsHeight,keepaspectratio]}}}

\DeclareMathAlphabet{\mathpzc}{OT1}{pzc}{m}{it}

\def\URL#1#2{\@ifundefined{href}{#2}{\href{#1}{#2}}}

%%For url break
\def\UrlOrds{\do\*\do\-\do\~\do\'\do\"\do\-}%
\g@addto@macro{\UrlBreaks}{\UrlOrds}



\edef\fntEncoding{\f@encoding}
\def\EUoneEnc{EU1}
\makeatother
\def\floatpagefraction{0.8} 
\def\dblfloatpagefraction{0.8}
\def\style#1#2{#2}
\def\xxxguillemotleft{\fontencoding{T1}\selectfont\guillemotleft}
\def\xxxguillemotright{\fontencoding{T1}\selectfont\guillemotright}

\newif\ifmultipleabstract\multipleabstractfalse%
\newenvironment{typesetAbstractGroup}{}{}%

%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%

\usepackage[authoryear]{natbib}



\newif\ifnokeywords\nokeywordsfalse

\makeatletter\input{size10-pointfive.clo}\makeatother%
\definecolor{kwdboxcolor}{RGB}{242,242,242}
\usepackage[hidelinks,colorlinks=true,allcolors=blue]{hyperref}
\linespread{1}                 
\def\floatpagefraction{0.8}

\usepackage[paperheight=11.69in,paperwidth=8.26in,top=1in,bottom=1in,left=1in,right=.75in,headsep=24pt]{geometry}

\usepackage{multirow-custom}

\makeatletter

\def\hlinewd#1{%
  \noalign{\ifnum0=`}\fi\hrule \@height #1%
  \futurelet\reserved@a\@xhline}
\def\tbltoprule{\hlinewd{1pt}\\[-14pt]}
\def\tblbottomrule{\noalign{\vspace*{6pt}}\hline\noalign{\vspace*{2pt}}}
\def\tblmidrule{\hline\noalign{\vspace*{2pt}}}



\let\@articleType\@empty
\let\@journalDoi\@empty
\let\@journalVolume\@empty
\let\@journalIssue\@empty
\let\@crossMarkLink\@empty
\let\@receivedDate\@empty
\let\@acceptedDate\@empty
\let\@revisedDate\@empty
\let\@publishedDate\@empty
\let\@copyrightYear\@empty
\let\@firstPage\@empty
\def\articleType#1{\gdef\@articleType{#1}}
\def\journalDoi#1{\gdef\@journalDoi{#1}}
\def\crossMarkLink#1{\gdef\@crossMarkLink{#1}}
\def\receivedDate#1{\gdef\@receivedDate{#1}}
\def\acceptedDate#1{\gdef\@acceptedDate{#1}}
\def\revisedDate#1{\gdef\@revisedDate{#1}}
\def\publishedDate#1{\gdef\@publishedDate{#1}}
\def\copyrightYear#1{\gdef\@copyrightYear{#1}}
\def\journalVolume#1{\gdef\@journalVolume{#1}}
\def\journalIssue#1{\gdef\@journalIssue{#1}}
\def\firstPage#1{\gdef\@firstPage{#1}}
\let\@issuelogo\@empty%
\let\@issuelogoex\@empty%
\def\issuelogo#1{\gdef\@issuelogo{#1}}
\def\issuelogoex#1{\gdef\@issuelogoex{#1}}


\def\author#1{%
  \gdef\@author{%
    \hskip-\dimexpr(\tabcolsep)\hskip5pt%
    \parbox{\dimexpr\textwidth-1pt}%
    {\fontsize{11}{13}\selectfont\raggedright #1}%
  }%
}


\usepackage{pharmascope-abs}
\usepackage{caption}
\usepackage{lastpage}
\usepackage{fancyhdr}
\usepackage[noindentafter,explicit]{titlesec}
\usepackage{fontspec}

\setmainfont[%
BoldFont=cambriab.ttf,%
ItalicFont=CAMBRIAI.TTF,%
BoldItalicFont=CAMBRIAZ.TTF]{Cambria.ttf}
\lefthyphenmin = 3

\def\title#1{%
  \gdef\@title{%
      \vspace*{-40pt}%
       \ifx\@articleType\@empty\else{\fontsize{10}{12}\scshape\selectfont\hspace{8pt}\@articleType\hfill\mbox{}\par\vspace{2pt}}\fi%
       \minipage{\linewidth}
         \hrulefill\\[-0.7pt]%%{\includegraphics[width=75pt,height=50pt]{ijrps_logo.png}}\hfill
         \mbox{~}\hspace{5pt}\parbox{.1\linewidth}{\IfFileExists{images/\@issuelogo.\@issuelogoex}{\includegraphics[width=79pt,height=61pt]{images/\@issuelogo.\@issuelogoex}}{\includegraphics[width=75pt,height=50pt]{ijrps_logo.png}}}\hfill
         \fcolorbox{kwdboxcolor}{kwdboxcolor}{\parbox{.792\linewidth}{%
          \begin{center}\fontsize{17}{17}\selectfont\scshape\vskip-7pt International Journal of Research in Pharmaceutical Sciences\hfill\end{center}%
          \vspace*{-10pt}\hspace*{4pt}{\fontsize{8}{9}\selectfont Published by JK Welfare \& Pharmascope Foundation\hfill  Journal Home Page: \href{www.ijrps.com}{\color{blue}\underline{\smash{www.ijrps.com}}}}\hspace*{4pt}\mbox{}}}%
       \par\vspace*{-1pt}\rule{\linewidth}{1.3pt}%
       \endminipage%
    \par\vspace*{9.2pt}\parbox{.98\linewidth}{\linespread{.9}\raggedright\fontsize{14}{17}\selectfont #1}%
    \vspace*{-8pt}%
  }
}


\setlength{\parindent}{0pt}
\setlength{\parskip}{0.4pc plus 1pt minus 1pt}

\def\abbrvJournalTitle{Int. J. Res. Pharm. Sci.}

\fancypagestyle{headings}{%
  \renewcommand{\headrulewidth}{0pt}%
  \renewcommand{\footrulewidth}{0.3pt}
  \fancyhf{}%
  \fancyhead[R]{%
    \fontsize{9.12}{11}\selectfont\RunningAuthor,\ \abbrvJournalTitle,\ \ifx\@journalVolume\@empty X\else\@journalVolume\fi%
    \ifx\@journalIssue\@empty\else(\@journalIssue)\fi%
    ,\ \ifx\@firstPage\@empty 1\else\@firstPage\fi-\pageref*{LastPage}%
  }%
  \fancyfoot[LO,RE]{\fontsize{9.12}{11}\selectfont\textcopyright\ International Journal of Research in Pharmaceutical Sciences}%
  \fancyfoot[RO,LE]{\fontsize{9.12}{11}\selectfont\thepage}
}\pagestyle{headings}

                                                         
\fancypagestyle{plain}{%
  \renewcommand{\headrulewidth}{0pt}%
  \renewcommand{\footrulewidth}{0.3pt}%
  \fancyhf{}%
  \fancyhead[R]{%
    \fontsize{9.12}{11}\selectfont\RunningAuthor,\ \abbrvJournalTitle,\ \ifx\@journalVolume\@empty X\else\@journalVolume\fi%
    \ifx\@journalIssue\@empty\else(\@journalIssue)\fi%
    ,\ \ifx\@firstPage\@empty 1\else\@firstPage\fi-\pageref*{LastPage}%
  }%
  \fancyfoot[LO,RE]{\fontsize{9.12}{11}\selectfont\textcopyright\ International Journal of Research in Pharmaceutical Sciences}%
  \fancyfoot[RO,LE]{\fontsize{9.12}{11}\selectfont\thepage}
  \ifx\@firstPage\@empty\else\setcounter{page}{\@firstPage}\fi
}


\def\NormalBaseline{\def\baselinestretch{1.1}}
\usepackage{textcase}
\setcounter{secnumdepth}{0}

\titleformat{\section}[block]{\bfseries\boldmath\NormalBaseline\filright\fontsize{10.5}{13}\selectfont}
{\thesection}
{6pt}
{\MakeTextUppercase{#1}}
[]
\titleformat{\subsection}[block]{\bfseries\boldmath\NormalBaseline\filright\fontsize{10.5}{12}\selectfont}
{\thesubsection}
{6pt}
{#1}
[]
\titleformat{\subsubsection}[block]{\NormalBaseline\filright\fontsize{10.5}{12}\selectfont}
{\thesubsubsection}
{6pt}
{#1}
[]
\titleformat{\paragraph}[block]{\NormalBaseline\filright\fontsize{10.5}{10}\selectfont}
{\theparagraph}
{6pt}
{#1}
[]
\titleformat{\subparagraph}[block]{\NormalBaseline\filright\fontsize{10.5}{12}\selectfont}
{\thesubparagraph}
{6pt}
{#1}
[]

\titlespacing{\section}{0pt}{.5\baselineskip}{.5\baselineskip}  
\titlespacing{\subsection}{0pt}{.5\baselineskip}{.5\baselineskip}  
\titlespacing{\subsubsection}{0pt}{.5\baselineskip}{.5\baselineskip}  
\titlespacing{\paragraph}{0pt}{.5\baselineskip}{.5\baselineskip}  
\titlespacing{\subparagraph}{0pt}{.5\baselineskip}{.5\baselineskip}

\captionsetup[figure]{skip=1.4pt,font=bf,labelsep=colon,justification=raggedright,singlelinecheck=false}
\captionsetup[table]{skip=1.4pt,font=bf,labelsep=colon,justification=raggedright,singlelinecheck=false}

\def\bibyear#1{#1}
%\def\bibjtitle#1{#1}   %%Publisher request
\def\bibauand{}
\setlength\bibsep{3pt}
\setlength\bibhang{8pt}

\makeatother
\date{}


\usepackage[flushleft]{threeparttablex}

\usepackage{longtable}

\makeatletter
\AtBeginDocument{\@ifpackageloaded{rotating}{\PassOptionsToPackage{figuresright}{rotating}}{\usepackage[figuresright]{rotating}}\setlength{\rotFPtop}{0pt plus 1fil}\setlength{\rotFPbot}{0pt plus 1fil}}
\makeatother

\makeatletter
 \AtBeginDocument{%
  \@ifpackagewith{endfloat}{figuresonly}
  {\DeclareDelayedFloatFlavor{sidewaysfigure}{figure}}%true
  {\@ifpackagewith{endfloat}{tablesonly}{\DeclareDelayedFloatFlavor{sidewaystable}{table}\DeclareDelayedFloatFlavor{longtable}{table}\DeclareDelayedFloatFlavor{landscape}{table}}%true
  {\@ifpackageloaded{endfloat}{\DeclareDelayedFloatFlavor{sidewaysfigure}{figure}\DeclareDelayedFloatFlavor{sidewaystable}{table}\DeclareDelayedFloatFlavor{longtable}{table}\DeclareDelayedFloatFlavor{landscape}{table}}{}}%false
  }%false
  }
\makeatother

\begin{document}


\def\RunningAuthor{Noah M Bose et al.}
\firstPage{1840}
\articleType{Review Article}
\receivedDate{09 Feb 2021}
\acceptedDate{25 Mar 2021}
\revisedDate{20 Mar 2021}
\journalVolume{2021, 12}
\journalIssue{3}
\journalDoi{ijrps.v12i3.4721}
\copyrightYear{2021}
\def\authorCount{4}
\def\affCount{1}

\def\journalTitle{International Journal of Research in Pharmaceutical Sciences}

\title{\textbf{Current update on COVID-19 vaccines}}
\author{Abisri~Suresh,  
            Amal~Mathew,  
            Narottam~Tiwari, 
            Noah~M~Bose\textsuperscript{*}~\\[5pt]{Department of Pharmacy Practice, Karavali College of Pharmacy, Mangalore - 575028, Karnataka, India}}

\begin{abstract}
Novel Coronavirus, also known as SARS-CoV-2, is an infectious disease that primarily affects the respiratory tract and gastrointestinal tract. The viral spread occurs through respiratory droplets produced while coughing and sneezing. Major vaccine targets for COVID-19 are spike protein, M protein, envelope protein, receptor binding domain, nucleic acids etc. Different mechanisms through which a vaccine can be developed to evoke an immune response include virus inactivated vaccine, live attenuated vaccine, subunit vaccines, virus-like particles, replicating and non-replicating viral vectors and nucleic acid-based vaccines. The mainstay of COVID-19 treatment is supportive and symptomatic therapy with dexamethasone, hydroxychlorquine and anti-viral agents like Darunavir, Ribavirin, Remdesivir, Interferons. Maintaining social distance, personal hygiene, use of N-95 masks aids in limiting the spread of the infection. There is a vital requirement for an ideal and potent vaccine with a favorable benefit-risk profile to evoke an immune response against SARS-CoV-2 infection. There are currently 11 approved vaccines in the market of which the Pfizer/ BioNTech vaccine have produced the most efficacy (95\%), followed by Moderna (94\%), Sputnik (91.6\%), Covaxin (90\%), Janssen (90\%) and Astra Zeneca (70\%). Vaccine hesitancy, vaccine-related adverse reactions and the high cost of the vaccine can be a major barrier to public acceptance and global access to the vaccine.
\end{abstract}\def\keywordstitle{Keywords}

\begin{keywords}COVID-19 Vaccines,\newline Virology,\newline Platform technologies,\newline SARS-CoV-2,\newline Spike protein,\newline Vaccine safety
\end{keywords}
\twocolumn[ \maketitle {\printKwdAbsBox}]
\makeatletter{\raggedright\textsuperscript{*}Corresponding Author\par Name:\ Noah~M~Bose~\\ Phone:\ 8884857579~\\  Email:\ nmb7bose@gmail.com
        \par}\vspace*{-11pt}\hrulefill\par{\fontsize{12}{14}\selectfont ISSN: 0975-7538}\par% 
        \textsc{DOI:}\ \href{https://doi.org/10.26452/\@journalDoi}{\textcolor{blue}{\underline{\smash{https://doi.org/10.26452/\@journalDoi}}}}\par%
        \vspace*{-11pt}\hrulefill\\{\fontsize{9.12}{10.12}\selectfont Production and Hosted by}\par{IJRPS |~\href{www.ijrps.com}{www.ijrps.com}}\par%
        \vspace*{-2pt}{\fontsize{9.12}{10.12}\selectfont\textcopyright\ \@copyrightYear\ $|$ All rights reserved.}\par%
        \vspace*{-11pt}\rule{\linewidth}{1.2pt}
        \makeatother
        
    
\section{Introduction}
Severe acute respiratory syndrome-CoV-2 (SARS CoV-2) is a highly pathogenic virus with a zoonotic origin identified initially in Wuhan, China which subsequently spread all over the world, turning out to be a pandemic termed as COVID-19. Coronavirus belongs to a diverse family of RNA viruses called Coronaviridae, causing a wide array of clinical manifestations on the upper respiratory, gastrointestinal, hepatic and central nervous system \unskip~\citep{1054473:21827239}. 

The novel SARS Coronavirus-2 has 90\% similar amino acids (except Spike protein) as that of SARS, with 79\% of its genomic sequence indistinguishable from SARS-CoV. The arrangement of SARS-CoV-2 comprises a densely enveloped trimeric glycoprotein called the Spike protein (S-protein), expressed superficially on the virus and is the lead hope for vaccine development as it binds to ACE 2 receptors on host cells resulting in attachment and penetration to host cells. The S-protein has two core subunits S1 and S2; S1 controls receptor binding whereas S2 governs membrane fusion, these spike proteins also undergo a conformational change from pre-fusion to post-fusion state attained by dragging and fusing the host cell with viral membranes together \unskip~\citep{1054473:21827241}. 

Current treatment modalities for the management of COVID-19 focus on symptomatic treatment such as oxygen therapy, fluid management, anticoagulation and ventilator support. Virus-specific therapies include antiviral medications such as protease inhibitors, monoclonal antibodies and anti-cytokines \unskip~\citep{1054473:21827240}.\textbf{\space }

However, COVID-19 can be restrained from being transmitted by developing herd immunity either with an effective vaccine or with at least 80\% of the population getting infected, the latter of which can come with quite a serious societal impact \unskip~\citep{1054473:21827243}. Thus, there is an urgent need for an efficacious and economic vaccine at present to develop the necessary herd immunity to prevent further spread of the virus and the development of more potent infections strains. 

\textbf{Methodology}

A thorough literature search was conducted in Pubmed to detect relevant articles pertaining to the research question. Studies published in Pubmed till February 2021 corresponding to the search criteria were included for consideration. Article search was conducted to identify original research articles related to the current vaccines in the pipeline, vaccine target platforms, the public perception towards vaccines, vaccine hesitancy and safety regarding the currently marketed COVID-19 vaccines. The search terms used were: SARS-CoV-2 AND COVID-19 vaccines OR virology OR immunology OR vaccine platforms OR vaccine targets. Letters to editors, narrative reviews and data presented at conferences were excluded from consideration. Once all the relevant articles were extracted, relevant studies addressing the current status of COVID-19 vaccines were selected. 

\textbf{Virology of SARS-COV-2}

Structurally, the SARS-CoV-2 genome has a polarity of +28kb to +32kb with non-structural and structural poly-proteins. The non-structural poly-proteins undergo cleavage to generate 16 non-structural proteins and the four structural proteins, along with five accessory proteins (ORF3a, 6, 7, 8, 83 9) which make up the final protein ensemble in the virus. The four structural proteins are the spike surface glycoprotein (S), membrane protein (M), envelope (E), nucleocapsid protein (N). The spike protein is essential for host cell attachment and penetration into the cell and therefore is an appropriate target against the virus for vaccine development. The exact mechanism behind the activation of the silent COVID-19 infection in an asymptomatic person into an active infection characterized by respiratory symptoms is not clearly understood. 

It is assumed that the spike protein, which binds to the host cell receptor (ACE-2 in lungs) and undergoes division with the help of a host protease enzyme into 2 subunits, N-terminal S1 subunit and C-terminal S2 subunit (membrane-bound), plays a vital role in the pathophysiology and virulence mechanism of the virus. 

Binding of S1 subunit to ACE-2 receptor results in the shedding of a part of the S1 subunit (`down' conformation of S1 subunit) and the shift of the S2 subunit into a highly steady post-fusion conformation state and the receptor binding domain (RBD) of S1 subunit undergo a hinge-like conformation which is the primary determinant of the receptor binding (`up' conformation of S1 subunit) \unskip~\citep{1054473:21827245}. 

Although SARS-CoV and SARS-CoV-2 are structurally similar, variations in the spike protein in SARS-CoV-2 increases its affinity towards the ACE-2 receptor 10-20 times that of SARS-CoV making them highly infectious. 

Thus, S-protein and receptor-binding domain (RBD) are prominent central targets for the development of vaccines.

Once entered into the pulmonary alveolar epithelial cells through ACE-2 receptors, SARS-CoV-2 undergoes rapid replication. The viral RNA strands then undergo translation and invade adjacent cells \unskip~\citep{1054473:21827242}. 

This elicits a vigorous immune response leading to cytokine storm syndrome and subsequent pulmonary tissue damage, acute respiratory distress syndrome (ARDS) and multiple organ impairment. Hyperactivity of cytokines leads to functionally exhausted T-cells producing a decline in immune function and worsening prognosis \unskip~\citep{1054473:21827244}. 

\textbf{Introduction to Vaccine Development}

Developing a COVID-19 vaccine in 1-2 years is a significant challenge as it normally takes 10-15 years to develop a vaccine. Vaccine development has principally 5 stages: Exploratory, Preclinical, Development, Regulatory Review and Approval and the final step is the Manufacturing and Quality control \unskip~\citep{1054473:21827246}. 

The exploratory stage of vaccine development includes fundamental laboratory research and computational modeling to identify natural and synthetic antigens that can be transformed into potential vaccine candidates. 


\begin{table*}[!htbp]
\caption{\boldmath {Vaccine Candidates based on Platforms in Clinical Phase} }
\label{tw-0717ca8c91f3}
\centering 
\begin{threeparttable}

\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.1525\linewidth-2\tabcolsep}p{\dimexpr.3268\linewidth-2\tabcolsep}p{\dimexpr.2707\linewidth-2\tabcolsep}p{\dimexpr.25\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}\multicolumn{2}{p{\dimexpr(.4793\linewidth-2\tabcolsep)}}{\cAlignHack Platform} & \cAlignHack Candidates (No.) & \cAlignHack Candidates (\%)\\
\tblmidrule 
PS &
  Protein subunit &
  \cAlignHack 20 &
  \cAlignHack 32\%\\
VVnr &
  Viral Vector (non-replicating) &
  \cAlignHack 10 &
  \cAlignHack 16\%\\
DNA &
  DNA vaccines &
  \cAlignHack 8 &
  \cAlignHack 13\%\\
IV &
  Inactivated Vaccines &
  \cAlignHack 9 &
  \cAlignHack 14\%\\
RNA &
  RNA vaccines &
  \cAlignHack 7 &
  \cAlignHack 11\%\\
VVr &
  Viral Vector (replicating) &
  \cAlignHack 3 &
  \cAlignHack 5\%\\
VLP &
  Virus Like Particles &
  \cAlignHack 2 &
  \cAlignHack 3\%\\
VVr+ APC &
  VVr + Antigen Presenting Cell &
  \cAlignHack 2 &
  \cAlignHack 3\%\\
LAV &
  Li ve Attenuated Virus &
  \cAlignHack 1 &
  \cAlignHack 2\%\\
VVnr+ APC &
  VVnr + Antigen Presenting Cell &
  \cAlignHack 1 &
  \cAlignHack 2\%\\
\tblbottomrule 
\end{tabulary}\par 
\begin{tablenotes}\footnotesize 
    
\item{\unskip~\citep{1054473:21827266}}
\end{tablenotes}
\end{threeparttable}

\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {FDA approved marketed COVID-19 vaccines} }
\label{tw-6c35800ea4f5}
\centering 
\begin{threeparttable}

\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.06590000000000001\linewidth-2\tabcolsep}p{\dimexpr.20990000000000002\linewidth-2\tabcolsep}p{\dimexpr.2015\linewidth-2\tabcolsep}p{\dimexpr.3536\linewidth-2\tabcolsep}p{\dimexpr.0867\linewidth-2\tabcolsep}p{\dimexpr.08240000000000002\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}S. No.  & \cAlignHack Name & \cAlignHack Vaccine platform & \cAlignHack Primary developer and country of origin & \cAlignHack Doses & \cAlignHack Storage\\
\tblmidrule 
\cAlignHack 1. &
  COVID-19 Vaccine Astra Zeneca; also known as Covishield  &
  Adenovirus vaccine &
  BARDA, OWS (UK) &
  \cAlignHack 2 &
  \cAlignHack 2-8\ensuremath{^\circ}C\\
\cAlignHack 2. &
  Covaxin &
  Inactivated vaccine &
  Bharath Biotech, ICMR (India) &
  \cAlignHack 2 &
  \cAlignHack -20\ensuremath{^\circ}C\\
\cAlignHack 3. &
  BBIBP-CorV &
  Inactivated vaccine &
  Beijing institute of Biological Products; Sinopharm (China) &
  \cAlignHack 2 &
  \cAlignHack 2-8\ensuremath{^\circ}C\\
\cAlignHack 4. &
  Convidicea &
  Recombinant vaccine (Adenovirus type 5 vector) &
  CanSino Biologics (China) &
  \cAlignHack 1 &
  \cAlignHack 2-8\ensuremath{^\circ}C\\
\cAlignHack 5. &
  EpiVacCorona &
  Peptide Vaccine &
  Federal Budgetary Research Institute State Research Centre of Virology and Biotechnology (Russia) &
  \cAlignHack 2 &
  \cAlignHack 2-8\ensuremath{^\circ}C\\
\cAlignHack 6. &
  Sputnik V  &
  Non-replicating viral vector &
  Gamaleya Research Institute, Acellena Contract Drug Research and Development (Russia) &
  \cAlignHack 2 &
  \cAlignHack  -18\ensuremath{^\circ}C - 0\ensuremath{^\circ}C \\
\cAlignHack 7. &
  Moderna COVID-19 Vaccine  &
  mRNA-based vaccine &
  Moderna, BARDA, NIAID (US) &
  \cAlignHack 2 &
  \cAlignHack -20\ensuremath{^\circ}C\\
\cAlignHack 8. &
  Comirnaty &
  mRNA-based vaccine  &
  Pfizer, BioNTech, Fosun Pharma (Multinational) &
  \cAlignHack 2 &
  \cAlignHack -70\ensuremath{^\circ}C\\
\cAlignHack 9. &
  CoronaVac &
  Inactivated vaccine (formalin with alum adjuvant) &
  Sinovac (China) &
  \cAlignHack 2 &
  \cAlignHack 2-8\ensuremath{^\circ}C\\
\cAlignHack 10. &
  No name &
  Inactivated Vaccine &
  Wuhan Institute of Biological Products, Sinopharm (China)  &
  \cAlignHack 3 &
  \cAlignHack 2-8\ensuremath{^\circ}C\\
\cAlignHack 11. &
  JNJ-78436725; also known as (Ad26.CoV2.S) &
  Non- replicating viral vector &
  Janssen vaccines {\textendash} Johnson and Johnson (Netherlands,US) &
  \cAlignHack 1 &
  \cAlignHack 2-8\ensuremath{^\circ}C\\
\tblbottomrule 
\end{tabulary}\par 
\begin{tablenotes}\footnotesize 
    
\item{\unskip~\citep{1054473:21827247}}
\end{tablenotes}
\end{threeparttable}

\end{table*}

\begin{ThreePartTable}

\centering 
\begingroup
\makeatletter\if@twocolumn\@ifundefined{theposttbl}{\gdef\TwoColDocument{true}\onecolumn\onecolumn}{}\fi\makeatother 
\begin{TableNotes}\footnotesize 
    
\item{\unskip~\citep{1054473:21827247}}
\end{TableNotes}\setlength\LTcapwidth{\textwidth}
\begin{longtable}{p{\dimexpr.0888\linewidth-2\tabcolsep}p{\dimexpr.17990000000000002\linewidth-2\tabcolsep}p{\dimexpr.2864999999999999\linewidth-2\tabcolsep}p{\dimexpr.2216000000000001\linewidth-2\tabcolsep}p{\dimexpr.22319999999999993\linewidth-2\tabcolsep}}
\caption{\boldmath {Current status of COVID-Vaccine candidates in pipeline} }
\label{tw-19986b1e4bbd}
\def\arraystretch{1.1}\\\endfirsthead \hline \noalign{\vskip3pt} \noalign{\textit{Table \thetable\ continued}} \noalign{\vskip3pt} \hline \endhead \hline \noalign{\vskip3pt} \noalign{\textit{\hfill Continued on next page}} \noalign{\vskip3pt} \endfoot \insertTableNotes \endlastfoot 
\tbltoprule \rowcolor{kwdboxcolor}\cAlignHack S. No.  & \cAlignHack Candidate Name & \cAlignHack  Vaccine Platform & \cAlignHack Status & \cAlignHack Sponsor\\
\tblmidrule 
\cAlignHack 1. &
  CVnCoV &
  mRNA- based vaccine &
  \cAlignHack Phase 2b/3 &
  CureVac; GSK\\
\cAlignHack 2. &
  NVX-CoV2373 &
  Nanoparticle vaccine &
  \cAlignHack Phase 3 &
  Novavax\\
\cAlignHack 3. &
  ZF2001 &
  Recombinant vaccine &
  \cAlignHack Phase 3 &
  Anhui Zhifei longcom Biopharmaceutical Institute of the Chinese Academy of science\\
\cAlignHack 4. &
  Bacillus Calmette- Guerin (BCG) vaccine &
  Live attenuated vaccine &
  \cAlignHack Phase 2b/3 &
  University of Melbourne and Murdoch Children's Research Institute: Radbund University Medical Center Z;Faustman Lab at Massachusetts General Hospital\\
\cAlignHack 5. &
  ZyCoV-D &
  DNA Vaccine (plasmid) &
  \cAlignHack Phase 3 &
  Zydus Cadila\\
\cAlignHack 6. &
  INO-4800 &
  DNA Vaccine (plasmid) &
  \cAlignHack Phase 2/3 &
  Inovio Pharmaceuticals\\
\cAlignHack 7. &
  VIR\--7831 &
  Plant -based adjuvant vaccine &
  \cAlignHack Phase 2/3 &
  Medico\\
\cAlignHack 8. &
  No Name &
  Adenovirus-based vaccine &
  \cAlignHack Phase 2/3 &
  ImmunityBio; NantKwest\\
\cAlignHack 9. &
  UB-612 &
  Multitope peptide- based DNA Vaccine (plasmid)vaccine  &
  \cAlignHack Phase 2/3 &
  COVAXX\\
\cAlignHack 10. &
  Abdala CIGB66) &
  Protein subunit vaccine &
  \cAlignHack Phase 2 &
  Finlay institute of Vaccine\\
\cAlignHack 11. &
  BNT162 &
  mRNA- based vaccine &
  \cAlignHack Phase 1/2/3 &
  Pfizer,BioNTech\\
\cAlignHack 12. &
  AdCLD - CoV19 &
  Adenivirus -based vaccine &
  \cAlignHack Phase 1/2a &
  Korea University Guro Hospital\\
\cAlignHack 13. &
  Nanocovax &
  Recombinant vaccine (spike protein) &
  \cAlignHack Phase 1/2 &
   Nanogen Biopharmaceutical\\
\cAlignHack 14. &
  EuCorVac-19 &
  Nanoparticle vaccine &
  \cAlignHack Phase 1/2 &
  EuBiologics\\
\cAlignHack 15. &
  Mambisa (CIGB 669) &
  Protein subunit vaccine &
  \cAlignHack Phase 1/2 &
  Finlay institute of Vaccine\\
\cAlignHack 16. &
  IIBR -100 &
  V Vesicular stomatitis virus (rVSV) vaccine &
  \cAlignHack Phase 1/2 &
  Israel Institute for Biological Research\\
\cAlignHack 17. &
  No Name &
  SF9 cell vaccine candidate  &
  \cAlignHack Phase 1/ 2 &
  Westchina Hospital, Sichuan University\\
\cAlignHack 18. &
  Soberana 1 and 2 &
  Monovalent/Conjugate vaccine &
  \cAlignHack Phase 1/ 2 &
  Finlay institute of Vaccine\\
\cAlignHack 19. &
  VLA2001 &
  Inactivated Vaccine &
  \cAlignHack Phase1/2 &
  Valneva; National institute For Health Research (NIHR \\
\cAlignHack 20. &
  No Name &
  Adjuvanted Protein subunit Vaccine &
  \cAlignHack Phase 1/2 &
  CEPI\\
\cAlignHack 21. &
  AGO301-COVID-19 &
  DNA Vaccine &
  \cAlignHack Phase 1/2 &
  AnGes, Inc.\\
\cAlignHack 22. &
  GX-19N &
  DNA Vaccine &
  \cAlignHack Phase 1/2 &
  Genexine\\
\cAlignHack 23. &
  ARCT-021 (LUNAR -COV-19) &
  Self -replicating RNA Vaccine &
  \cAlignHack Phase 1/2 &
  Arcturus Therapeutics Duke -NUS Medical School\\
\cAlignHack 24. &
  No Name &
  Protein subunit vaccine &
  \cAlignHack Phase 1/2 &
  Sanofi GlaxoSmithKline\\
\cAlignHack 25. &
  No Name &
  Inactivated Vaccine &
  \cAlignHack Phase 1/2 &
  Chinese Academy of Medical sciences,Institute of Medical Biology\\
\cAlignHack 26. &
  HDT-301(HGC019) &
  RNA Vaccine &
  \cAlignHack Phase 1/2 &
  University of National Institutes of Health Rocky Mountain Laboratories: HDT Bio Corp; Genova Biopharmaceuticals\\
\cAlignHack 27. &
  AV-COVID-19 &
  Dendritic cell vaccine &
  \cAlignHack Phase 1b/2 &
  Aivita Biomedical,Inc.\\
\cAlignHack 28. &
  PTX COVID-19-B &
  mRNA- based vaccine &
  \cAlignHack Phase 1 &
  Providence Therapeutics;Canadian government\\
\cAlignHack 29. &
  COV-VAC &
  Intranasal vaccine &
  \cAlignHack Phase 1 &
  Codagenix; Serum Institute of India\\
\cAlignHack 30. &
  CORVax12 &
  DNA Vaccine (plasmid) &
  \cAlignHack Phase 1 &
  Onco Sec; Providence Cancer Institute\\
\cAlignHack 31. &
  MVA-SARS-2-S &
  Modified vaccinia virus ankara (MVA) Vector vaccine candidate &
  \cAlignHack Phase 1 &
  UniversitatsklinikumHamburg- Eppendorf; German Center for University Marburg Medical center, Ludwig-Maximilians-University of Munich\\
\cAlignHack 32. &
  COH04S1 &
  Modified vaccinia virus ankara (MVA) Vector vaccine candidate &
  \cAlignHack Phase 1 &
  City of Hope Meical Center; National cancer Institute\\
\cAlignHack 33. &
  pVAC &
  Multiple-peptide vaccine candidate &
  \cAlignHack Phase 1 &
  University Hospital Tubingen \\
\cAlignHack 34. &
  AdimrSC-2f &
  Protein subunit vaccine &
  \cAlignHack Phase 1 &
  Adimmune\\
\cAlignHack 35. &
  bacTRL-Spike &
  Monovalent oral vaccine (bifdobacteria) &
  \cAlignHack Phase 1 &
  Symvivo\\
\cAlignHack 36. &
  COVAX-19 &
  Monovalent recombinant protein vaccine &
  \cAlignHack Phase 1 &
  Vaxine Pty.Ltd\\
\cAlignHack 37. &
  DelNS1-2019-nCoV &
  Replicating Viral Vector &
  \cAlignHack Phase 1 &
  Xiamen University, Beijing Wantai Biological Pharmacy\\
\cAlignHack 38. &
  GRAd-COV2 &
  Adenovirus-based vaccine &
  \cAlignHack Phase 1 &
  ReiThera; Leukocare; Univercells\\
\cAlignHack 39. &
  UQ-CSLV451 &
  Protein subunit vaccine &
  \cAlignHack Phase 1 &
  CSL; The University of Queensland\\
\cAlignHack 40. &
  SCB-2019 &
  Protein subunit vaccine &
  \cAlignHack Phase 1 &
  Glaxosmithkline, Sanofi, Clover Biopharmaceuticals, Dynavax and Xiamen Innovax CEPI \\
\cAlignHack 41. &
  VXA-CoV2-1 &
  Recombinant vaccine (Adenovirus type 5 vector) &
  \cAlignHack Phase 1 &
  Vaxart\\
\cAlignHack 42. &
  AdCOVID &
  Intranasal vaccine &
  \cAlignHack Phase 1 &
  Altimmune\\
\cAlignHack 43. &
  AAVCOVID &
  Gene -based vaccine &
  \cAlignHack Pre-Clinical &
  Massachusetts Eye and Ear; Massachusetts General Hospital University of Pennsylvania\\
\cAlignHack 44. &
  ChAd-SARS-CoV-2-S &
  Adenovirus-based vaccine &
  \cAlignHack Pre-Clinical &
  Washington University School of Medicine in St. Louis\\
\cAlignHack 45. &
  HaloVax &
  Self- assembling vaccine &
  \cAlignHack Pre-Clinical &
  Voltron Therapeutics Inc; Hoth Therapeutics Inc.\\
\cAlignHack 46. &
  Linea DNA &
  DNA Vaccine &
  \cAlignHack Pre-Clinical &
  Takis Biotech\\
\cAlignHack 47. &
  MRT5500 &
  mRNA- based vaccine &
  \cAlignHack Pre-Clinical &
  Sanofi, Translate Bio\\
\cAlignHack 48. &
  No Name &
  li-Key peptide COVID-19 Vaccine &
  \cAlignHack Pre-Clinical &
  Generex Biotechnology\\
\cAlignHack 49. &
  No Name &
  Protein subunit vaccine &
  \cAlignHack Pre-Clinical &
  University of Sasktechewan Vaccine and Infectious Disease Oranization {\textendash} International Vaccine Centre\\
\cAlignHack 50. &
  No Name &
  mRNA- based vaccine &
  \cAlignHack Pre-Clinical &
  Chulalongkorn University's Center of Excellence in Vaccine Research and Development\\
\cAlignHack 51. &
  No Name &
  Gp96-based vaccine  &
  \cAlignHack Pre-Clinical &
   Heat Biologics\\
\cAlignHack 52. &
  No Name &
  Inactivated Vaccine &
  \cAlignHack Pre-Clinical &
  Shenzhen Kangtai Biological Product\\
\cAlignHack 53. &
  PittCoVacc &
  Recombinant Protein subunit vaccine (delivered through microneedle array) &
  \cAlignHack Pre-Clinical &
  UPMC/University of Pittsburgh School of Medicine \\
\cAlignHack 54. &
  T-COVIDTM &
  Intranasal vaccine &
  \cAlignHack Pre-Clinical &
  Altimmune\\
\cAlignHack 55. &
  LNP-nCoVsaRNA &
  Self- amplifying RNA vaccine &
  \cAlignHack No longer being studied &
  Imperial College London\\
\cAlignHack 56. &
  V590 &
  Recombinant vaccine (Vesicular stomatitis virus) &
  \cAlignHack No longer being studied &
  Merck; IAVI\\
\cAlignHack 57. &
  V591 &
  Measles vector vaccine &
  \cAlignHack No longer being studied &
  University of Pittsburgh; Themis Bioscience; Institute Pasteur\\
\tblbottomrule 
\end{longtable}
\endgroup
\end{ThreePartTable}

\makeatletter\@ifundefined{TwoColDocument}{}{\twocolumn}\makeatother 
Preclinical-stage encompasses cell or tissue culturing and conducting vaccine trials on animals to determine the ability of the vaccine candidate to evoke an immune response along with a preliminary assessment of safety and efficacy \unskip~\citep{1054473:21827241}. In the clinical stages of development, vaccines are tested on humans, giving a more enhanced understanding of vaccine safety and efficacy from the animal data \unskip~\citep{1054473:21827246}.

\textbf{Vaccine Platform Technologies}

These technologies vary from inactivated and target attenuated live pathogens to delivering synthetic peptide agents and recombinant protein antigens, nucleic-acid based vaccines, replicating and non-replicating viral vectors, polysaccharide-protein conjugation and Virus-like Particles(VLPs) \unskip~\citep{1054473:21827247}. Some of the techniques used in vaccine development include inactivated virus vaccines, adenovirus vector, mRNA based vaccines, DNA vaccines, protein vaccines \unskip~\citep{1054473:21827248}. The list of vaccine candidate based on platform technologies is listed in Table~\ref{tw-0717ca8c91f3}.

\textbf{Inactivated Vaccine}

These are developed by inactivating the live organism using formalin or phytochemical method using UV light and riboflavin, which selectively targets nucleic acids preserving the viral antigens and protein integrity of the virus, which will evoke an immune response in the individual without causing the disease. This methodology has been followed for the preparation of SolaVAX by the University of Colorado. These vaccines primarily induce immunity through the production of protective antibodies against epitopes on the hemagglutinin S-glycoprotein binding site \unskip~\citep{1054473:21827250}.

The conventional development of inactivated vaccines possess major safety concerns as it requires bio-safety level 3 facilities to culture high titers of the SARS-CoV-2, also incomplete virus inactivation would lead to a disease outbreak among the vaccinated individuals, which can potentially lead to a health care crisis \unskip~\citep{1054473:21827247}. 

\textbf{Live Attenuated Vaccines}

 Live attenuated vaccine utilizes a weakened live pathogen to generate an immune response without causing an infection, thereby mimicking the properties of a natural infection. This type of vaccine can induce a strong lifelong humoral and cellular immune response compared to the inactivated vaccine with two doses. The vaccine formulated against COVID-19 by the Serum Institute of India has utilized the viral gene deoptimization method, which involves computer-aided gene design with chemical synthesis.

Live attenuated vaccines on intranasal administration can produce IgA and provide a local mucosal immunity \unskip~\citep{1054473:21827250}. They have several advantages over other vaccine platforms as they can induce an immune reaction against several variations of the antigens formed by the virus \unskip~\citep{1054473:21827247}. 

Despite its effectiveness and advantages, these vaccines are not devoid of disadvantages. As the SARS-CoV-2 virus is excreted through faeces, the live attenuated strains may also get excreted post-administration through the same route. Thus it can potentially generate an infection in unvaccinated individuals or via recombination of live attenuated strains with any wild type CoV post elimination in the faeces produce virulent strains \unskip~\citep{1054473:21827247}. 

\textbf{Protein Subunit Vaccines}

These vaccines are generated based on recombinant proteins or synthetic peptides of the target pathogen. They use only specific viral antigenic fragments and are devoid of any other components of the pathogenic virus thus surpassing any potential pathogenic effect incurred when administering whole viral particle. This type of vaccine candidates possesses additional advantages such as a better safety profile, cost-effectiveness and long-lasting therapeutic immune response with adjuvants \unskip~\citep{1054473:21827250}. These vaccines can only produce a humoral response.

Clover Biopharmaceuticals has developed a SARS-CoV-2 S-trimer subunit vaccine candidate and the University of Queensland had used molecular clamp stabilized spike protein technology for the development of the COVID-19 vaccine \unskip~\citep{1054473:21827250}. The University of Pittsburgh has used a micro-needle array based recombinant technology, which comprises administering recombinant immunogens.

\textbf{Viral-vectored Vaccines}

This technique involves a modified virus used as a vector to deliver a gene that instructs cells to produce SARS-CoV-2 spike protein, expressing it on the surface of human cells, thereby triggering an antibody production evoking an immune response. 

Several viruses such as influenza, stomatitis virus, measles virus have been used to develop viral vector vaccines \unskip~\citep{1054473:21827251,1054473:21827249}. Adenovirus and poxviruses can be used in both replicating and non-replicating viral vector forms. The replicating viral vectors include measles virus, poliovirus, yellow fever virus and vesicular stomatitis virus and non-replicating vectors include adenovirus, alphavirus and herpes virus \unskip~\citep{1054473:21827250}. 

Lately, Adenovirus is also used as one of the viral vectors as it can be produced on a large scale, are easy to design and can generate high levels of recombinant protein expression. One of the major drawbacks of these vectored vaccines is if the vaccine fails to provide an immune response, then using the same vector vaccine for any other infection in those patients can trigger an immune response against viral vector making the subsequent vaccine ineffective to evoke an immune response \unskip~\citep{1054473:21827247}. 

The vaccines developed by Oxford University- AstraZeneca is an example of viral vector vaccines and has been approved by WHO and marketed as ``Covishield'' for use among frontline healthcare workers and public and comes in two doses and should be refrigerated at 2-8\ensuremath{^\circ}C.

\textbf{DNA Vaccine}

A DNA vaccine delivers genes that encode immunogenic antigens to the host cell through vectors such as DNA plasmids, which can induce both humoral and cell-mediated immune response. This kind of formulation provides genetic instructions which reach the host cell nucleus and instructs it to build harmless spike proteins. Antigen presenting cells receive the genetic material, after which the mammalian promoter gets stimulated and initiates the transcription of the gene. Some of the advantages of DNA vaccines are low-cost production, high stability, can be stored for a long time with less need for refrigeration at very low temperatures and can be produced efficiently on a large-scale \unskip~\citep{1054473:21827252}. 

\textbf{mRNA Vaccine}

Messenger RNAs are a significant and viable therapeutic tool for vaccine development. It is a non-integrating and emerging vaccine platform with less or reduced risk of insertional mutagenesis. The mode of action and efficacy of mRNA vaccines are superior as it does not need to reach inside the cell nucleus \unskip~\citep{1054473:21827252}. Messenger RNA is an unstable molecule but can be designed and developed into a nucleoside-modified mRNA enclosed in lipid nanoparticles to improve its stability, induce a defensive and protective antibody response and improve the efficiency of protein translation. These vaccines consist of an mRNA that codes for a protein antigen. When entered into the body, the host cells can take in the mRNA and initiate translation into proteins \unskip~\citep{1054473:21827254,1054473:21827257}. 

There are currently two mRNA vaccines from Pfizer/BioNTech and Moderna approved for marketing. Moderna vaccine is permitted for use in 18 years and older and Pfizer vaccine allowed for use in people of 16 years or older by WHO.

\textbf{Virus-Like Particles (VLPs)}

These are multimeric structures that are assembled similar to viral structural proteins to trigger immune cells instantly by mimicking the 3D conformation of the SARS COV-2 virus. Though they do not hold any genetic material, they morphologically resemble the SARS-CoV-2 virus, thereby triggering an immune response \unskip~\citep{1054473:21827256}. These vaccines can penetrate the host cell using a functional viral protein (Spike protein) therefore ensuring cell entry. They induce a humoral immune response by stimulating antibody production via a high density B {\textendash}cell epitope and intracellular T-cell epitope, respectively. VLPs are safer than attenuated and inactivated form of vaccines \unskip~\citep{1054473:21827259}. Studies have revealed that using a mammalian expression system would help in sustaining the exact configuration of glycosylated proteins \unskip~\citep{1054473:21827260,1054473:21827262}. 

Premas Biotech in India used a triple antigen vaccine, which involves co-expressing recombinant S, M and E protein in genetically engineered \textit{Saccharomyces cerevisiae }\unskip~\citep{1054473:21827264}. 

\textbf{Current Status of Vaccine Candidates In Pipeline}

Currently, there are more than 50 vaccine candidates on the run with 3 frontrunner vaccines developed by Pfixer/BioNTech, Moderna and Oxford/AstraZeneca. As of 4\ensuremath{^{th}} March 2021, there are 177 vaccines in Pre-clinical trials, 19 vaccines in Phase 1, 25 vaccines has reached Phase 2 and 21 vaccines have entered Phase 3 \unskip~\citep{1054473:21827265}. FDA approved marketed vaccines and the current status of vaccine candidates in the pipeline is listed in Table~\ref{tw-6c35800ea4f5}, Table~\ref{tw-19986b1e4bbd} respectively.

\textbf{Vaccine Safety}

Vaccine related adverse effects are one of the major public concerns. An extensive and thorough analysis should be done to avoid any immuno-potentiation reaction \unskip~\citep{1054473:21827248}.

A clinical trial conducted on the safety and efficacy of Pfizer (Germany/US) vaccine has shown that the vaccine has 95\% efficacy against COVID-19 infection in people older than 16 years. Mild adverse vaccine reactions such as fatigue, mild-moderate pain at the site of injection and headaches were noted, which improved within 2-3 days \unskip~\citep{1054473:21827265}. 

Moderna vaccine (US) has shown 94.1\% efficacy against COVID-19, whereas the safety profile included mild local and systemic reactions during the second dose and serious adverse events were rare \unskip~\citep{1054473:21827268}. 

Clinical Trials of Oxford/AstraZeneca (UK/US) have shown that the vaccine induces a peak T-cell response by the 14\ensuremath{^{th}} day and IgG response was identified on the 28\ensuremath{^{th}} day after the 1\ensuremath{^{st}} dose, which was further improved with the second dose of immunization. 91\% of antibody neutralization response was seen after the first dose and 100\% antibody neutralization after the second shot. The efficacy of this vaccine was found to be 70.1\% and the safety profile reveals adverse effects such as fever, headache, generalized weakness and body ache. It was found that these effects subsided with a dose of Acetaminophen \unskip~\citep{1054473:21827267}. It can be administered in pregnant women as well.

Janssen Vaccine (Netherlands/US) in Phase2a trials had exhibited 90\% neutralizing antibodies with first dose immunization. Fever and injection-site pain is common vaccine-related systemic adverse effect along with muscle pain, fatigue and headache \unskip~\citep{1054473:21827264}. 

Sputnik V Vaccine (Russia) and Novavax (US/UK) has shown a strong immune response with a good safety and efficacy profile. Phase 3 trial data revealed 91.6\% vaccine efficacy against SARS-CoV-2 infection. 94\% of the participants have shown Grade1 reaction towards vaccine \unskip~\citep{1054473:21827270}. 

A clinical trial of Covaxin (India) has shown an interim clinical efficacy of 81\% in preventing SARS-CoV-2 infection with a 2 dose regimen, 28 days apart. The preclinical trial has demonstrated strong immunogenicity and protective efficacy in animals. Covaxin is developed by inactivating whole-virion in Vero cell \unskip~\citep{1054473:21827265}. Contraindication of this vaccine includes a history of drug/food allergies, fever, bleeding disorder, those who are on anticoagulants or antiplatelet medication, immune-compromised individuals, pregnant women and lactating mothers \unskip~\citep{1054473:21827271}.
    
\section{Conclusions}
COVID-19 has become a dreadful pandemic affecting millions of lives all over the world and has contributed to a wide array of psychiatric illness. Vaccine mediated immunity is essential to prevent the spread of the SARS-CoV-2 virus. Developing a vaccine with high efficacy, mild or no adverse effects, single-dose suitable for all ages, lactating and pregnant women is important. Discovering an appropriate and acceptable target for vaccine development is vital to produce a safe and efficacious vaccine. Protein subunit technology is used in majority of the vaccines (32\%). Currently, there are 11 vaccines approved for use and approximately 60 vaccines are under clinical development and over 170 candidates are in the pre-clinical phase. As of 23\ensuremath{^{rd}} February 2021, approximately 12 million doses of vaccines have been given in India.

\textbf{Funding Support}

The authors declare that they have no funding support for this study.

\textbf{Conflict of interest}

The authors declare that there is no conflict of interest for this study.
    

\bibliographystyle{pharmascope_apa-custom}

\bibliography{\jobname}
\end{document}
