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\begin{document}

\title{Advancing Efficient and Timely Community~ Access to SARS-CoV-2 Serology
Testing in Europe: a Multi-stakeholder Consensus}



\author[1,2,3]{Rafael Cantón}%
\author[4,5]{Constance Delaugerre}%
\author[6]{Catherine Hankins}%
\author[7]{Wame Jallow}%
\author[8]{Uwe Gerd Liebert}%
\author[9]{Julieta Villegas}%
\affil[1]{Clinical Microbiology Department, University Hospital Ramón y Cajal, Madrid, Spain }%
\affil[2]{Ramón y Cajal Health Research Institute, University Hospital Ramón y Cajal, Madrid, Spain }%
\affil[3]{Department of Microbiology \& Parasitology, Complutense University of Madrid, Madrid, Spain }%
\affil[4]{Virology, Vaccine Research Institute, Paris, France}%
\affil[5]{Virology Department Saint Louis Hospital, Université de Paris, Paris, France}%
\affil[6]{Amsterdam Institute for Global Health and Development, Amsterdam, The Netherlands}%
\affil[7]{Global Programs and Advocacy, International Treatment Preparedness Coalition, Johannesburg, Republic of South Africa}%
\affil[8]{Institute of Virology, Leipzig University, Leipzig, Germany }%
\affil[9]{Health Policy Division, Policy Wisdom LLC, Miami, (Florida,) United States }%


\vspace{-1em}



  
  \date{May 10, 2024}


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\selectlanguage{english}
\begin{abstract}
\textbf{Background:} Currently there is no clear consensus on the use,
value, benefits, and impact of serology testing as part of a
comprehensive SARS-CoV-2 testing strategy. The lack of clarity on the
use of this strategy in policies and guidelines may have serious
implications on the efforts to curb the pandemic. The aim of this paper
is to elaborate an experts and community consensus on the use of
serology testing as an effective method to respond to and mitigate the
impact of the pandemic. The recommendations herein can help build
community awareness and guide advocacy strategies.

\textbf{Methods:} A desk review was conducted to inform a working
document that was subject to a multistage process of validation and
feedback by a group of renowned experts. The multi-stakeholder group of
experts, representing the European and international levels, convened to
inform and validate the recommendations.

\textbf{Results:} The consensus offered eight policy recommendations
organized in two main themes. The first group of recommendations
provides guidance on the role and value of serology testing to contain
and understand the COVID-19 pandemic. The second group targets health
system strengthening aspects necessary to support the appropriate
delivery of serology testing.

\textbf{Conclusions:} Recommendations seek to indicate how SARS-CoV-2
serology testing may positively impact national health systems, country
economies and local communities. The pertinence of the recommendations
is to communities in Europe, and beyond, and relevant to multiple
stakeholders. Given the rapidly changing scenario, this set of
recommendations should be considered a live document.%
\end{abstract}%



\sloppy


\textbf{Key words:} COVID-19, SARS-CoV-2, severe acute respiratory
syndrome coronavirus 2, COVID-19 diagnostic testing, serologic tests,
consensus, pandemics, health emergency, global health emergency, Europe

\section*{Introduction}

{\label{642713}}\par\null

On December 31, 2019, news released from the city of Wuhan in China,
alerted of an outbreak of cases of an unknown type of viral pneumonia,
later identified as a novel coronavirus and given the name of severe
acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The World Health
Organization (WHO) declared SARS-CoV-2 a public health emergency of
international concern on January 30, 2020 and a global pandemic on March
11. Shortly thereafter, the European region was officially pronounced
one of the epicentres of the pandemic, amounting a death toll of
~701,991 by January 28, 2021 ~{[}1{]}.~

The burden imposed by the SARS-CoV-2 pandemic has directly and
indirectly permeated all sectors of society, with diverse types or
degrees of impact experienced among countries of varying income levels
{[}2,3{]}. Morbidity and mortality rates have been especially elevated
among the high-risk and vulnerable populations {[}4-6{]}, with Europe
being the world region at highest risk due the elevated percentage of
people living with underlying health conditions {[}7{]}. Furthermore,
socio-economic disparities may put segments of the population at higher
risk {[}8-11{]}.

In the absence of effective treatments or universal access to vaccines,
alternatives used to suppress the virus transmission included public
health measures such as nationwide lockdowns. Although strict
non-pharmaceutical measures have been effective in controlling the
spread of the virus {[}12{]}, they are not viable long-term solutions
given their negative socio-economic consequences, such as the loss on
Gross Domestic Product (GDP) and development of human capital due to the
disruption of economic and educational activities, respectively
{[}13-15{]}. In this context, a key prevention and containment strategy
is the detection of SARS-CoV-2 infection through various types of tests
that can support important aspects like diagnosis, case management, and
tracking the spread of the virus.

Among the proposed tests for SARS-CoV-2, there are two main types of
approaches. The first is based on a reverse transcriptase-polymerase
chain reaction (RT-PCR), a molecular-based test method usually employed
to detect an active pathogen in the body. The second is a serology test,
based on an antibody/antigen reaction, which detects a body's humoral
immune responses to a current and/or prior infection. This type of test
shows that the body has produced antibodies following the exposure to
the virus and can help to confirm prior infections even after the immune
system has eliminated the virus.

Currently, there is no clear guidance supporting the use, value,
benefits, and impact of serology testing as part of a comprehensive
SARS-CoV-2 detecting strategy. The lack of clarity on policies and
guidelines regarding the role of serology testing on decisions related
to restriction measures may have serious implications on the efforts to
curb the pandemic. Departing from a sound bibliographic review, this
paper aims to provide an expert and community consensus on the effective
use of serology testing as a method to respond to and mitigate the
impact of the pandemic. Ultimately, the recommendations herein intend to
enable the implementation of SARS-CoV-2 serology testing to support
mitigation strategies at the regional, national, and local levels to
build community awareness, and to guide advocacy strategies.

\par\null

\subsection*{Methodology}

{\label{893201}}\par\null

Five renowned European and international experts on testing policies and
strategies joined an online panel facilitated by Policy Wisdom, LLC.
Their academic backgrounds included microbiology, infectious diseases,
virology, epidemiology, and health policy. Throughout the three months
from August to October 2020, a multistage validation and feedback
process was carried out.~

As the first step, we created a working document from a desk review of
literature, policies, and epidemiological data. The search was guided by
five pre-established topics:

\begin{itemize}
\tightlist
\item
  Medical and scientific perspectives on SARS-CoV-2 serology testing,~
\item
  The impact of the SARS-CoV-2 outbreak on recipients of care within
  society, health systems, and vulnerable communities,~
\item
  The implications of serology testing in Europe, including
  resource-limited settings,
\item
  The economic and labour force impact of the pandemic on various
  sectors such as tourism, trade industries, and education, and how
  serology testing might support decision-making to mitigate the adverse
  effects of resuming activities,
\item
  Existing limitations of SARS-CoV-2 serology tests and barriers to
  their widespread application, and~
\item
  Opportunities and advantages of an effective serology testing
  strategy.
\end{itemize}

Experts convened in a two-session meeting to inform and validate the
contents of the working document and to discuss and propose a set of
recommendations. The paper was then updated using this and subsequent
written feedback. After reaching a consensus, the final document was
approved by all panellists.

\par\null

\section*{Results}

{\label{456248}}\par\null

\subsection*{Impact on population
health}

{\label{849343}}

Morbidity and mortality rates have been especially elevated among the
high-risk and vulnerable populations, while the pandemic has also
worsened conditions for those who regularly need to access health
facilities. Among the highest risk populations for the disease are (1)
the elderly, particularly in long term care facilities (LTCF), (2) those
with comorbidities, including communicable and non-communicable
diseases, (3) vulnerable communities, which include those in
outbreak-prone settings, and (4) healthcare workers. Europe has
documented higher rates of infections among individuals over 70 years
old and higher mortality rates in those above 65 {[}4,5{]}. Regional
reports show figures of up to 88\% mortality among those 65 years of age
and above {[}16{]}. Furthermore, several countries including Italy,
France, Germany, Sweden, Belgium, and the U.K., reported outbreaks in
nursing homes, which accounted for a considerable fraction of their
recorded fatalities {[}6{]}.

Patients with comorbidities or underlying health-compromising
conditions, such as diabetes, cancer, HIV, cardiovascular, chronic
kidney, and chronic respiratory disease as well as other risk factors,
such as obesity or smoking have also been shown to be disproportionately
affected. Europe is the world region with the highest percentage of
population that could be at risk due to underlying health conditions
{[}7{]}. Additionally, those with chronic illnesses and other
health-compromising conditions have had reduced access to healthcare
services and medicines due to the burden on the health system imposed by
the pandemic. Simultaneously, many patients may hesitate to visit health
centres either for fear of infection, unclear communication on whether
they can, and lack of understanding about which type of facility is
safest to visit.

Moreover, socio-economic disparities may carry additional risks to
certain sections of the population, particularly those of lower-income
and/or marginalized communities {[}8{]}. Many low-income individuals
live on daily wages and simply cannot forego employment and/or their
economic livelihood depends on what are deemed as essential jobs. This
situation exposes them to potential infection leading to an increased
risk of outbreaks. Likewise, vulnerable or marginalized communities face
extreme disparities that lead to increased difficulties in accessing
healthcare (including laboratory testing) whether it be for economic
reasons, literacy, transportation, language, cultural, or other barriers
{[}9{]}. Among the most vulnerable populations are migrants (including
seasonal workers that migrate between east and west Europe, and North
Africa), correctional institution inmates, and the homeless {[}10,11{]}.

~Secondary effects of the pandemic may exacerbate the clinical situation
of those who are already suffering mental health conditions, such as
depression, anxiety, and other similar disorders, as well as a surge in
new mental health cases {[}17,18{]}. Stay-at-home measures, loss of
employment as well as the stress associated with a pandemic situation
and risk of infection have contributed to this effect {[}16{]}. Multiple
sources identify healthcare workers among the most affected, including
risk for suicide {[}11,17,19{]}. Lastly, preliminary reports have also
suggested an increase in intimate partner violence in Europe during the
outbreak. {[}20{]}.

\subsection*{Broader Socio-Economic
Impact}

{\label{573788}}

Although essential, imposing stringent non-pharmaceutical interventions
has severe negative effects on country economies. According to the OECD,
it is estimated that for every month that a country is in total
lockdown, it loses up to approximately 2\% of its GDP {[}13{]}. With
most of the workforce under lockdown, unemployment rates have soared
causing a domino effect in which almost all sectors of the economy have
suffered {[}21,22{]}. International trade has slowed significantly and
areas such as travel and tourism, as well as sports, food and
entertainment have been especially affected. According to the World
Travel \& Tourism Council (WTTC), tourism generates 10,3\% of global
GDP, making it an important driver of the global economy. For countries
such as Spain and Italy the contribution of tourism to their GDP is even
higher than the global average, 14,3\% and 13,0\% of their GDP in 2019,
respectively. It is predicted that 13 million jobs in the travel and
tourism sector will be lost in Europe due to the SARS-CoV-2 pandemic,
resulting in a tourism GDP loss of \euro{}633 billion {[}23{]}.

The closure of schools and universities has also had great impact,
limiting access to quality education, and sometimes resulting in
students being unable to continue their studies. The disruption of
classes at schools and universities has also placed an extra burden on
society, causing concern for the short and long-term impact on the
development of human capital and workforce {[}14,15{]}. Women and girls
have been particularly affected by physical distancing measures, with a
heavy loss in employment and lack of access to education. As the UN
reported, decades of progress in women's rights have been scaled back in
a matter of months {[}24,25{]}.

\subsection*{SARS-CoV-2 Serology
Testing}

{\label{938363}}

Several types of serology tests exist and each one has a different use
depending on the setting and application. Currently available serology
tests, or immunoassays, to detect SARS-CoV-2 antibody responses are
designed for the detection of antigens or antibodies. Tests to detect
the two main isotypes of antibodies, immunoglobulin M (IgM) and
immunoglobulin G (IgG), are those most used to determine subject
immunity. IgM represents an early antibody response during the acute
phase of infection and may indicate current or recent infection. On the
other hand, IgG, which are usually produced at a later stage, may
indicate that a patient has been exposed, but was/may also still be
infected, with or without symptoms. Immunoglobulin A (IgA) antibodies
can also be detected in mucosal secretions or in serum samples but are
often associated with earlier production of antibodies, shortly before
IgM, and not associated with longer term immunity. SARS-CoV-2 antibody
production, however, seems to differ from the typical scenario in that
IgM and IgG tend to appear at the same time, while other models depict
IgA and IgM developing simultaneously, with IgA even outlasting IgM
antibodies in some instances {[}26{]}.

Testing methods and setting needed to take and process samples, may also
influence access and turnaround time of results. Antibody tests can be
carried out either by laboratory-based assays or with rapid diagnostic
tests (RDT). While the processing of samples for laboratory-based assays
are more centralized, laboratories can analyse a higher number of
samples. RDTs usually take 15-30 minutes to complete and are easily
conducted and processed in decentralized settings. In general,
laboratory-based assays generate more accurate results as they can
provide qualitative (whether antibodies are present) and quantitative
(amount of antibodies present) data as opposed to RDTs that only provide
qualitative results {[}9{]}. The choice will depend on the application
setting and on the scope of testing. Convenience and easier access to
patients at point-of-care (POC) could be a preferable option of RDTs,
yet it may require additional confirmation from more reliable
laboratory-based assays.~

Certain limitations of antibody tests have raised concerns, including
their reliability or accuracy for detecting SARS-CoV-2 infection due to
possible cross-reactivity {[}27{]}. Antibody test accuracy is evaluated
by its specificity and sensitivity. While specificity measures a test's
ability to correctly generate a negative result (true negative rate),
sensitivity measures how often a test correctly generates a positive
result (true positive rate). In clinical settings no assays reach 100\%
accuracy in both specificity and sensitivity. Based on the prevalence of
infection in a determined population, the specificity and sensitivity of
tests are used to determine the positive predictive value (PPV) and
negative predictive value (NPV). Predictive values permit assessment of
the effectiveness of a specific testing strategy to determine the
accuracy and reliability of serology tests at the individual and at
population levels {[}9{]}. Choosing a test with higher specificity may
be preferable in populations with low prevalence of the disease.
Nevertheless, if not possible, the use of tests with lower specificity
could be accompanied by orthogonal testing algorithms {[}28{]}.

Additional concerns arise from the fact that some individuals may
produce very low levels of antibodies, which may be missed by
serological tests {[}29{]}. Furthermore, there is some indication that a
classic long-term immunity may not exist for SARS-CoV-2 infection. In
fact, some studies have documented reinfections {[}9,30{]}, and others
suggest neutralizing antibodies may wane after two to three months,
especially for those who experience mild or asymptomatic cases
{[}29,31{]}. \textsuperscript{} These ambiguities have implications for
determining herd immunity and understanding the proportion of the
population that must be immune at the community level to cease high
rates of transmission.

\subsection*{Benefits of SARS-CoV-2 Serology
Testing~}

{\label{146416}}

Serology testing can help enrich epidemiological data through
sero-surveillance to inform policymaking at different levels, especially
when asymptomatic cases seem to be high. While some preliminary studies
estimated the proportion of asymptomatic cases at 17.9\%, others go as
high as 40\% {[}32,33{]}.~Although serology tests cannot replace RNA
tests in hospital settings, they may provide additional information to
support decision making on patient clinical diagnosis {[}34{]}. Hence,
conducting serology tests in the clinical setting, when the index of
suspicion is high, but SARS-CoV-2 cannot be detected, represents an
opportunity to determine if a patient had been infected, providing
relevant data that can help complete datasets and enhance preparedness.
Finally,~{i}mplementation of systematic serology testing and
sero-surveillance could also provide an alternative method to less
accessible and affordable lab RNA testing {[}35{]}. To summarize,
evidence suggests that serology testing can be used as one of the tools
to control virus transmission, prevent community spread, and meet public
health and community needs and demands.~

Serology testing might also be beneficial for research purposes,
especially under scenarios where the virus is still new and less prone
to mutations and genetic diversification. The use of serological tests
to assist the development of effective treatments and/or vaccines is
prescribed in this context {[}36{]}, as so is research to identify the
role of neutralizing antibodies {[}37,38{]}{.}

\subsection*{Challenges of SARS-CoV-2 Serology
Testing}

{\label{998857}}

Although WHO has acknowledged the importance of serology testing for
epidemiological surveillance and research purposes, it provides limited
guidance and support on implementation, and lacks emphasis on the value
of other possible benefits. The existing WHO interim guidelines on the
use of POC immunodiagnostic tests recommends molecular testing as a gold
standard {[}37{]}, and in the latest interim guideline indicates
serology testing as complementary in specific cases {[}39{]}.

At the regional level, the European Commission has acknowledged the
overall utility of serology testing {[}40{]}, releasing its guidelines
on SARS-CoV-2 testing in April 2020 {[}41{]}. That same month, the ECDC
published its Strategies for the Surveillance of COVID-19 {[}42{]}.
However, neither of these documents set a clear plan for rolling out
serology testing across the region. Meanwhile, some European countries
have independently implemented serology testing strategies, while others
are still lagging {[}9,43{]} \textsuperscript{} (see Supplementary
Material 1). A list of sero-epidemiological studies conducted in the
region can also be found on the ECDC's website {[}44{]}. The fragmented
initiatives across the region might result in the loss of opportunities
to gather critical information in an organized manner at a crucial time.
Furthermore, in absence of comprehensive guidance, access to quality
testing might be hindered due to insufficient supply and availability,
and, in some cases, limited health systems capacity (effective
infrastructure and a trained health workforce) {[}45{]}.

\subsection*{Policy Recommendations~}

{\label{501526}}

The eight policy recommendations offered in this paper focus on two main
themes: the first four recommendation address the role and value of
serology testing to contain and understand the SARS-CoV-2 pandemic, and
the last four address issues around health system strengthening. As
shown in Fig. 1, serology testing might be a valuable resource and
should be considered as part of a larger comprehensive pandemic
preparedness and mitigation strategy. Currently serology testing is
primarily recommended for sero-surveillance and research purposes;
however, this study found the need to define targeted pathways and a
framework for ultimate introduction of serology testing to complement
the existing strategies along with new scientific and clinical data as
it becomes available. Active promotion of well-designed projects should
facilitate this goal. Moreover, evidence suggests - and this paper
recommends - to prioritize by geographic hotspots and to consider
serology testing as part of national containment strategies to jumpstart
the economy for full control of epidemics.

\par\null\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=1.00\columnwidth]{figures/T11/T11}
\caption{{\textbf{Recommendations on the role and value of serology testing to
contain and understand SARS-CoV-2 pandemic}
{\label{384770}}%
}}
\end{center}
\end{figure}



The introduction of serology testing would also require the
reinforcement of the national health system infrastructure and capacity
for optimal test performance and guarantee supply. Attention needs to be
paid to ensure the use of high-quality serology assays considering both
the analytical (i.e., high-level specificity and sensitivity) and
clinical characteristics of patients. Finally, governments should
clearly communicate and engage with different stakeholders to raise
awareness and ensure access to testing opportunities (see Fig. 2).~

\par\null\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=1.00\columnwidth]{figures/T21/T21}
\caption{{\textbf{Recommendations for health system strengthening to support
appropriate serology testing within the SARS-CoV-2 pandemic}
{\label{174152}}%
}}
\end{center}
\end{figure}

\section*{Discussion}

{\label{392281}}\par\null

Non-pharmaceutical measures taken by countries have varied depending on
specific situation and socio-cultural context. As countries begin to
lift some of these restrictions, different strategies have been
considered. While some European countries are currently only
contemplating occupational health and safety measures in the workplace
and/or learning environments as part their exit strategy, other
countries have recognized the positive role that serological testing
might play. Given the inconsistencies in how serology testing strategies
are being carried out, aligned guidance and a more coherent approach are
necessary to support policy-level decision-making.

Whether a country is experiencing no burden of cases, sporadic cases, a
cluster of cases/outbreaks, or community transmission, it should be
continuously vigilant. Different testing strategies will yield different
outcomes in understanding the true spread and severity of the virus
sub-epidemics between countries and different populations at risk. Since
mild/moderate or asymptomatic cases may go untested, the complete
picture of the epidemiological situation cannot be fully understood in
the absence of tests that can capture these cases. It is important to
generate reliable and comprehensive information by conducting
well-designed, scientifically, and ethically sound studies.

Sero-epidemiological population-based studies on antibody prevalence in
defined communities would be essential for generating supportive data
(such as prevalence, incidence, and fatality rates), and improve
surveillance, monitoring, and forecasting of SARS-CoV-2 infection in
populations, which could support the development of effective public
health intervention strategies. At the community level,
sero-epidemiological information could provide a basis for better
understanding of viral spread in terms of the geographic mechanisms
behind the emergence of local and regional outbreaks. Additionally, it
can provide data on selective distribution among diverse populations,
such as those most vulnerable and sub-populations with higher risk due
to comorbidities.~ Factors such as race, ethnicity, socio-economic
status, and other aspects that can lead to marginalization or
vulnerabilities, should be considered when performing
sero-epidemiological studies and developing health policies. Conducting
serology testing on vulnerable subsets of the population should be
approached in a carefully planned manner so as not to place such
populations at greater risk.

Serological testing can also post additional benefits to control the
pandemic. Detection of mild or asymptomatic cases can provide better
clarity to authorities, identifying true attack and mortality rates, as
well as the potential role of immunity (including herd immunity), which
can help better define and adapt policies to respond to viral patterns
and develop effective prevention and control strategies. Furthermore, it
could help assess the effectiveness of using non-pharmaceutical
interventions in suppressing and containing the virus transmission.

Challenges may also arise from the inclusion of serological testing
among testing strategies. Europe is a heterogeneous region with
different social, economic, political, and cultural ethos and
perspectives that can influence the use and uptake of serology testing.
Further constrains may arise from insufficient supply and availability
of quality tests and health workforce. An increase in demand could also
outweigh the test production capacity, having further cost implications.
A guidance on the role of serological testing must include actions
directed at bringing awareness among policymakers and regulatory
authorities. Dialogue is an essential factor that can enhance community
engagement and coordinated policy action.

\par\null

\section*{Conclusions}

{\label{392333}}

Due to this lack of comprehensive guidance at the global and European
levels, there has been a diverse approach to SARS-CoV-2 testing
policies, weakening the potential benefits that serology testing can
bring to addressing the challenges posed by the pandemic. Europe is a
heterogeneous region that can influence the use and uptake of serology
testing. The global challenge demands the generation of reliable and
accurate epidemiological information that can timely inform policy
making, whether for diagnostic, treatment, and prevention strategies.
Serological testing is critical to respond to this demand.

The policy recommendations offered in this paper intend to enable the
implementation of SARS-CoV-2 serology testing to support mitigation
strategies at the regional, national, and local levels, to build
community awareness and guide advocacy strategies. With the situation
evolving rapidly, it is important to notice that this paper should be
considered a ``live'' document that must be updated as new evidence
emerges.

\section*{}

{\label{967187}}

\section*{Acknowledgements}

{\label{687807}}

The authors acknowledge Katya Nogales for her role in helping finalize
the manuscript. Her assistance was covered by her regular function in
Policy Wisdom LLC.

\section*{\texorpdfstring{Conflict of Interest
Statement{}}{Conflict of Interest Statement}}

{\label{403423}}

While Abbott Laboratories has sponsored the production of this
manuscript, it is fully independent of any influence from the company on
the contributing authors. The included recommendations are based on a
review of literature and publicly available evidence, as well as the
subsequent expert deliberations to reach consensus on the subject
matter.

\section*{Funding Sources}

{\label{414299}}

\textbf{{}}\emph{The authors disclosed receipt of financial support from
Abbott Laboratories} for the research, authorship, and publication of
this article. \emph{} {}

\section*{Author Contributions}

{\label{862382}}

All author contributed equally to this work.

\par\null

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{\label{116191}}

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