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\begin{document}

\title{ZeroRabiesApp: Enhancing~ human post-exposure rabies prophylaxis in
canine rabies endemic regions with an~ interactive web solution}



\author[1,2]{Aniruddha Belsare}%
\author[3]{Deborah Briggs}%
\author[4]{Gyanendra Gongal}%
\author[5]{Reeta S. Mani}%
\author[1,2,6]{Charles E. Rupprecht}%
\affil[1]{College of Forestry, Wildlife and Environment, Auburn University, Auburn, AL 36849 USA}%
\affil[2]{College of Veterinary Medicine, Auburn University, Auburn, AL 36849 USA}%
\affil[3]{Department of Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506, USA}%
\affil[4]{World Health Organization, WHO Regional Office for South-East Asia, New Delhi, 110002 India}%
\affil[5]{Department of Neurovirology, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, 560030 India}%
\affil[6]{LYSSA LLC, Lawrenceville, GA 30044 USA}%


\vspace{-1em}



  
  \date{May 27, 2024}


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\textbf{Abstract}

Despite the availability of effective biologics, rabies continues to
impact several lower and middle-income countries. More than 50,000
people ~succumb to rabies every year due to lack of timely and
appropriate post-bite care. To combat this, integrating accurate
information about availability of rabies biologics and prophylaxis into
user-friendly apps can offer a simple, real-time, and local solution to
prevent human rabies deaths following potentially rabid exposures like
dog bites.

\textbf{Keywords}: dog, prophylaxis, rabies, Shiny app, zoonosis

Rabies is a neglected disease, disproportionately affecting impoverished
communities in Africa and Asia, despite the availability of effective
vaccines for both animals and humans for over a century. Domestic dogs
are the primary reservoirs of the rabies virus in these regions.
Unfortunately, concerted efforts to control rabies among dog populations
have been lacking in many countries in Asia and Africa. As a result,
each year, tens of thousands of human lives in lower- and middle-income
countries (LMICs) are lost to dog-mediated rabies. India, in particular,
grapples with an alarming estimate of 17.4 million dog-bite cases
annually \textsuperscript{{[}1{]}}.

Human rabies prevention in India has encountered significant hurdles,
primarily stemming from limited knowledge about proper postexposure
prophylaxis (PEP) and inconsistent access to rabies biologics
\textsuperscript{{[}2,3{]}}. Regrettably, the lack of readily available
guidance on the clinical management of human rabies condemns individuals
to endure excruciating suffering, ultimately culminating in a tragic and
inevitable loss of life \textsuperscript{{[}4{]}}.

The prompt administration of appropriate PEP following a dog bite is
critical to prevent rabies~\textsuperscript{{[}5{]}}. However, many
healthcare workers in low- and middle-income countries (LMICs) often
lack the necessary knowledge about proper PEP~\textsuperscript{{[}2{]}}.
Additionally, rabies biologics, such as the rabies vaccine (RV), rabies
immune globulin (RIG), and Rabies Human Monoclonal antibody (mAb) used
in PEP are frequently scarce in developing regions, particularly in
Africa and Asia \textsuperscript{{[}6,7{]}}.

Typically, dog-bite patients or their caregivers, often residing in
remote rural areas, must embark on arduous journeys to acquire these
biologics for PEP, resulting in delays or even the inability to receive
treatment. In addition to promoting public awareness about dog bite
prevention and proper medical care after such incidents, there is a
pressing need for a mechanism to track the real-time availability of PEP
products.

To address these challenges, we have created an online web application
called ZeroRabiesAPP (ZRA), utilizing the Shiny package in R software.
ZRA has been designed as an interactive point-of-care tool for
bite-management, granting users access to the latest guidelines
developed by the World Health Organization
(\url{https://www.who.int/news-room/fact-sheets/detail/rabies}) and the
U.S. Advisory Committee on Immunization Practices
(\url{https://www.cdc.gov/rabies/medical\_care/vaccine.html}).

Furthermore, the ZRA can generate a customized PEP schedule based on the
user-provided bite date (day of exposure), as illustrated in Figure 1.
This customized PEP schedule can then be saved as a snapshot (if
accessed on a smartphone) or printed (if accessed on a computer) for
sharing with a healthcare provider. The PEP schedule generated by the
ZRA eliminates any uncertainty regarding the timing of rabies biologics
administration.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Picture1/fig1}
\caption{{Screenshot of the ZeroRabiesApp (ZRA) illustrating the personalized
postexposure prophylaxis (PEP) schedule generated for the exposure date
entered by the user.~
{\label{819374}}%
}}
\end{center}
\end{figure}

Along with the customized PEP schedule, the ZRA lists the RV, RIG and
mAb brands available in the region (Figure 2). The ZRA also offers
access to the rabies biologics database, which can be used to locate the
nearest places where PEP products are currently in stock, ensuring
timely access to necessary treatment (Tab: RV/RIG Availability Map).

As an illustrative example, we have integrated the ZRA with another
online web application called ZeroRabiesPEP (ZRP). The ZRP serves as a
crowdsourcing tool dedicated to compiling and continuously updating a
comprehensive database of facilities in India where these products
(pharmacies, clinics, hospitals etc.) are presently available. The ZRP
allows for the easy submission of PEP availability information along
with the contact details of the facility (Figure 3). The data provided
by citizens through ZRP is carefully reviewed and integrated into the
rabies biologics database, ensuring its accuracy and usefulness.

The RV/RIG/mAb availability map is connected to the rabies biologics
database and shows the information as a marker on the map. The user can
click on a marker to access contact details of the pharmacy/healthcare
facility (Figure 4).

In the ZRA, the RV/RIG/mAb availability map is superimposed with a grid
consisting of 50 km x 50 km patches, as depicted in Figure 4. The
primary objective is to record the accessibility of PEP products,
thereby reducing the time and energy required to locate these biologics
following a potential exposure. Our target is to ensure that there is at
least one marker indicating the availability of these products within
each square patch on the RV/RIG/mAb availability map in the ZRA.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Picture2/Picture2}
\caption{{List of Rabies Vaccine (RV), Rabies Immune Globulin (RIG) and Rabies
Human Monoclonal antibody (mAbs) brands available in India.
{\label{968411}}%
}}
\end{center}
\end{figure}

The overarching goal of the ZRA is to support the global strategic plan
to end human deaths from dog-mediated rabies by 2030 (Zeroby30;
\url{https://iris.who.int/handle/10665/272756}). The ZRA is freely
available at: \url{https://anyadoc.shinyapps.io/ZeroRabiesINDIA/} and
the ZRP is freely available at:
\url{https://anyadoc.shinyapps.io/ZeroRabiesPEP/}.{}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Picture3/Picture3}
\caption{{The ZeroRabiesPEP (ZRP)nis designed to facilitate citizen involvement in
the process of developing rabies biologics database.
{\label{529741}}%
}}
\end{center}
\end{figure}

The ZRA addresses the problem of poor PEP compliance by creating a
freely accessible rabies biologics database. This initiative also serves
to identify regions where dog-bite victims might have to travel
considerable distances to obtain PEP products. Furthermore, the rabies
biologics database can be employed to formulate strategies tailored to
local needs aimed at enhancing the affordability and accessibility of
rabies PEP, such as exploring options for intradermal vaccination.{}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Picture4/Picture4}
\caption{{The RV/RIG/mAb Availability Map in the ZeroRabiesAPP(ZRA) is connected
with a rabies biologics database. The user can click on a marker to
access information as illustrated.
{\label{273981}}%
}}
\end{center}
\end{figure}

These apps are designed to be customizable and adaptable to different
regions where canine rabies is a prevalent concern. As an example, they
have already been successfully modified and implemented for use in
Nigeria, demonstrating their versatility in addressing the specific
needs of various areas affected by canine rabies
(\url{https://anyadoc.shinyapps.io/ZeroRabiesNigeria/}). These apps
would be particularly useful in reducing the risk of rabies infection
for travelers visiting dog rabies-endemic countries.

Both the ZRA and ZRP applications are accessible via smartphones and
computers, offering users flexibility and convenience. One limitation is
that both ZRA and ZRP require an active internet connection to run. We
are currently working on an Interactive Voice Response (IVR) to ensure
access to point-of-care bite management guidelines as well as the rabies
biologics database without an active internet connection.{}

Citizen scientists are playing an ever-growing role in identifying and
addressing local problems that benefit the public. The use of precise,
up-to-date, and freely accessible information to prevent infectious
diseases like rabies empowers the communities most impacted at the local
level. Indeed, when combined with large-scale canine vaccination efforts
and the provision of suitable human PEP, the utilization of real-time
databases, as demonstrated in these instances, constitutes an
additional, highly effective measure for enhancing the response to
rabies in regions where the disease is widespread. This approach aligns
with the overarching principles of the One Health framework, benefiting
both local residents and visitors alike.

\textbf{Authors' contributions}

Developed the Shiny Apps: Belsare A. Made substantial contributions to
conception and design of the study, and wrote the manuscript: Belsare A,
Briggs D, Gongal G, Mani R, Rupprecht C.

\textbf{Availability of data and materials}

Shiny App code will be made available upon request.

\textbf{Financial support and sponsorship}

None

\textbf{Conflicts of interest}

All authors declared that there are no conflicts of interest.

\textbf{Ethical approval and consent to participate}

Not applicable.

\textbf{Consent for publication}

Not applicable.

\textbf{References}

1.~~~ Gongal G, Wright AE. Human Rabies in the WHO Southeast Asia
Region: Forward Steps for Elimination. \emph{Adv Prev Med}.
2011;2011:383870. doi: 10.4061/2011/383870. Epub 2011 Sep 21. PMID:
21991437; PMCID: PMC3178116.\textbf{{}}

\textbf{~}

2.~~~ Kole AK, Roy R, Kole DC. Human rabies in India: a problem needing
more attention. \emph{Bull World Health Organ} 2014; Apr 1;92(4):230.
doi: 10.2471/BLT.14.136044. PMID: 24700986; PMCID: PMC3967582.{}

~

3.~~~ Thiagarajan K. Why did rabies control fail in India? \emph{BMJ}
2022; Sep 28;378:o2284. doi: 10.1136/bmj.o2284. PMID: 36170986.

~

4.~~~ Warrell MJ. The dilemma of managing human rabies encephalitis.
\emph{Trop Med Int Health} 2016; Apr;21(4):456-7. doi:
10.1111/tmi.12668. Epub 2016 Feb 9. PMID: 26799263.{}

~

5.~~~ Whitehouse ER, Mandra A, Bonwitt J, Beasley EA, Taliano J, Rao AK.
Human rabies despite post-exposure prophylaxis: a systematic review of
fatal breakthrough infections after zoonotic exposures\emph{. Lancet
Infect Dis} 2023; May;23(5):e167-e174. doi:
10.1016/S1473-3099(22)00641-7. Epub 2022 Dec 16. PMID: 36535276.{}

~

6.~~~ Sreenivasan N, Li A, Shiferaw M, Tran CH, Wallace R, Blanton J, et
al. Working group on Rabies PEP logistics. Overview of rabies
post-exposure prophylaxis access, procurement and distribution in
selected countries in Asia and Africa, 2017-2018. \emph{Vaccine} 2019
Oct 3;37 Suppl 1(Suppl 1):A6-A13. doi: 10.1016/j.vaccine.2019.04.024.
Epub 2019 Aug 27. PMID: 31471150; PMCID: PMC10351478.{}

~

7.~~~ Yasmeen, A. Patients hit as government hospitals run out of
antirabies vaccine. \emph{The Hindu}. 2019, June 24.
https://www.thehindu.com/news/national/karnataka/patients-hit-as-government-hospitals-run-out-of-anti-rabies-vaccine/article28119449.ece\textbf{{}}

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