Serology testing in the COVID-19 pandemic response

Abstract

The collapse of global cooperation and a failure of international solidarity have led to many low-income and middle-income countries being denied access to molecular diagnostics in the COVID-19 pandemic response. Yet the scarcity of knowledge on the dynamics of the immune response to infection has led to hesitation on recommending the use of rapid immunodiagnostic tests, even though rapid serology tests are commercially available and scalable. On the basis of our knowledge and understanding of viral infectivity and host response, we urge countries without the capacity to do molecular testing at scale to research the use of serology tests to triage symptomatic patients in community settings, to test contacts of confirmed cases, and in situational analysis and surveillance. The WHO R&D Blue Print expert group identified eight priorities for research and development, of which the highest is to mobilise research on rapid point-of-care diagnostics for use at the community level. This research should inform control programmes of the required performance and utility of rapid serology tests, which, when applied specifically for appropriate public health measures to then be put in place, can make a huge difference.

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www.thelancet.com/infection Published online July 17, 2020 https://doi.org/10.1016/S1473-3099(20)30517-X
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Lancet Infect Dis 2020
Published Online
July 17, 2020
https://doi.org/10.1016/
S1473-3099(20)30517-X
Department of Clinical
Research, London School of
Hygiene & Tropical Medicine,
London, UK
(Prof R W Peeling PhD,
C J Wedderburn MBChB,
N Fongwen MD,
Prof D L Heymann MD);
Neuroscience Institute and
Department of Paediatrics and
Child Health, University of
Cape Town, Cape Town,
South Africa (C J Wedderburn);
Universidad Peruana Cayetano
Heredia, Lima, Peru
(Prof P J Garcia MD); Global
Health Impact Group, Atlanta,
GA, USA (D Boeras PhD); Africa
Centres for Disease Control and
Prevention, Addis Ababa,
Ethiopia (J Nkengasong PhD);
Institut Pasteur Dakar, Dakar,
Senegal (A Sall PhD); and
Federal University of
Rio de Janeiro, Rio de Janeiro,
Brazil (Prof A Tanuri MD)
Correspondence to:
Prof Rosanna W Peeling,
Department of Clinical Research,
London School of Hygiene &
Tropical Medicine,
London WC1E 7HT, UK
rosanna.peeling@lshtm.ac.uk
Serology testing in the COVID-19 pandemic response
Rosanna W Peeling, Catherine J Wedderburn, Patricia J Garcia, Debrah Boeras, Noah Fongwen, John Nkengasong, Amadou Sall, Amilcar Tanuri,
David L Heymann
The collapse of global cooperation and a failure of international solidarity have led to many low-income and middle-
income countries being denied access to molecular diagnostics in the COVID-19 pandemic response. Yet the scarcity
of knowledge on the dynamics of the immune response to infection has led to hesitation on recommending the use
of rapid immunodiagnostic tests, even though rapid serology tests are commercially available and scalable. On the
basis of our knowledge and understanding of viral infectivity and host response, we urge countries without the
capacity to do molecular testing at scale to research the use of serology tests to triage symptomatic patients in
community settings, to test contacts of confirmed cases, and in situational analysis and surveillance. The WHO R&D
Blue Print expert group identified eight priorities for research and development, of which the highest is to mobilise
research on rapid point-of-care diagnostics for use at the community level. This research should inform control
programmes of the required performance and utility of rapid serology tests, which, when applied specifically for
appropriate public health measures to then be put in place, can make a huge dierence.
Diagnostics: the weak link in the COVID-19
pandemic response
The COVID-19 pandemic, now only a few months old,1,2
has brought into sharp focus inequalities within and
among countries. John Nkengasong, Director of the
Africa Centres for Disease Control and Prevention,
reported that “the collapse of global cooperation and a
failure of international solidarity have shoved Africa out
of the diagnostics market”.3 Sadly, the same is true of
many other low-income and middle-income countries
(LMICs) outside Africa.
Why are diagnostics important? In any epidemic
response, diagnostic testing plays a crucial role and this
pandemic is no exception. Because early clinical
presentations of infected patients are non-specific,
testing is needed to confirm the diagnosis of COVID-19
in symptomatic patients, as soon as possible, so
that these patients can be appropriately isolated and
clinically managed.1,4,5 Diagnostic testing is also needed
for individuals who have come into contact with
someone with confirmed COVID-19. Some testing
strategies examine only contacts who have symptoms
or develop illness of any kind during the 14-day period
after contact. Other strategies examine all contacts
when identified, regardless of whether they have any
symptoms. Studies have shown that a large number of
infected individuals might have no symptoms at
all, and there is concern that these individuals are
still able to shed the virus and transmit infection
through saliva droplets as they speak.4–9 Tracking all
contacts of confirmed cases and testing them for severe
acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
is key to successful pandemic control. Diagnostics are
also needed to support rapid serosurveys that establish
whether and to what extent SARS-CoV-2 has circulated
in a community, and sur veillance systems, such as that
for influenza-like illness, that monitor disease trends
over time. Diagnostics can also be used to identify at-
risk populations and assess the eectiveness of control
strategies.
Tedros Adhanom Ghebreyesus, Director-General of
WHO, urged countries to implement a comprehensive
package of measures to find, isolate, test, and treat every
case, and trace every contact. Goodwill between countries
has already been shown through the publishing of the
SARS-CoV-2 genetic sequence and shared laboratory
protocols to detect the virus.10 However, as these molecular
assays require sophisticated labora tory facilities, countries
with insucient infrastructure quickly accumulate a
backlog of testing. The rapid spread of COVID-19 around
the world has led to a global shortage of reagents and
supplies needed for testing. Point-of-care molecular
assays for SARS-CoV-2 detection are now available to
enable community-based testing for COVID-19 in LMICs.
Unfortunately, the production of these test cartridges
takes time and, again, global demand has outstripped
supply, leaving LMICs struggling for access.
Test, test, test
In March, 2020, WHO urged member states to “test, test,
test”.11 Widespread testing can help countries to map the
true extent of the outbreak, including identifying hot
spots and at-risk populations, and monitor the rate at
which the epidemic is spreading. However, most LMICs
find that molecular testing, including point-of-care
testing, is neither scalable nor aordable on a large scale.
Relying solely on centralised testing puts countries at
risk of having nothing to use. What diagnostic alternatives
are available to support decentralised testing that would
allow countries to mount an adequate response to the
pandemic?
Rapid antigen detection tests that are simple to do at
point of care and can give results in less than 30 min
would be viable alternatives to molecular testing for
confirming COVID-19 cases, enabling appropriate case
management, and guiding public health measures, such
as quarantine or self-isolation. However, although scaling
up rapid antigen testing oers an eective means of
triaging symptomatic individuals in community settings,
early evaluations of rapid antigen detection tests show

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suboptimal sensitivity for these tests to be recommended
for clinical diagnosis or triage.12
Rapid antibody detection lateral flow tests are also simple
to use, generally requiring a few drops of whole blood
from a finger prick placed onto the test strip with no
processing needed. These tests take 15–20 min to do with
minimal training and can be done at the point of care as
most do not require any equipment. Rapid antibody testing
is an attractive option for scaling up testing but only if
these tests show satisfactory performance for a clearly
specified use.
SARS-CoV-2 infectivity and immune response
The detection of SARS-CoV-2 infection and immune
response has been described in relation to dierent
diagnostic tests.13 In this section, we summarise the
evidence from studies to date.
Viral infectivity
Studies have shown that SARS-CoV-2 RNA can be
detected 2–3 days before onset of symptoms and can
remain detectable up to 25–50 days after the onset
of symptoms, particularly in patients who remain
symptomatic for an extended period.7,14,15 SARS-CoV-2
RNA can be detected for longer in respiratory samples
from patients with severe disease than in samples from
patients with mild illness.16 Viral RNA concentrations
peak within the first 5 days after onset of symptoms and
decrease slowly with rising antibody concentrations.7,17,18
However, RNA clearance is not always associated with
rising antibody concentrations, particularly in patients
who were critically ill.6,18 An important question for the
potential for spread of COVID-19 is whether individuals
who are RNA-positive are shedding infectious virus. A
small study in nine patients found that viral replication
stopped 5–7 days after onset of symptoms but patients
remained RNA-positive for 1–2 weeks after this point.6
Hence, there remains some uncertainty as to whether a
patient who is RNA-positive is shedding live virus or not.
Immune response to COVID-19 disease
Maturation of the immune response typically takes
40 days with variations in the dynamics of the antibody
response depending on disease severity and other factors
still to be discovered. In most studies of laboratory-
confirmed COVID-19 cases, IgM antibodies start to be
detectable around 5–10 days after onset of symptoms and
rise rapidly.14,18–21 IgG antibody concentrations follow the
IgM response closely. Seroconversion is typically within
the first 3 weeks with the mean time for seroconversion
being 9–11 days after onset of symptoms for total antibody,
10–12 days for IgM, and 12–14 days for IgG.14,18,19,22
COVID-19 antibody response: pathogenic or protective?
Antibodies against the receptor-binding domain of the
spike protein and the nucleocapsid protein have been
associated with neutralising activity.14,23,24 Neutralising
anti bodies to these domains can be detected approximately
7 days after onset of symptoms and rise steeply over the
next 2 weeks.23,24 Several studies showed that patients
can remain RNA-positive despite high concentrations of
IgM and IgG antibodies against the nucleocapsid protein
and the receptor-binding domain of the spike protein.18
Whether the presence of neutralising antibodies trans-
lates into protective immunity in patients with COVID-19
is unclear. Some researchers speculate that antibodies can
enhance infectivity as higher antibody concentrations
have been observed in patients with severe disease than in
those with mild disease.18,25 In one study (n=222), a greater
proportion of patients with high IgG concentrations had
severe disease than did those with low IgG concentrations
(52% vs 32%, p=0·008).26 The role of antibody response in
the pathogenesis of COVID-19 remains unclear pending
further studies.
Ideal testing strategies versus reality
WHO and the Pan American Health Organization have
stated that they do not currently recommend the use of
immunodiagnostic tests except in research settings,27,28
because of scarce information on test performance and
appropriate use when immunity to COVID-19 is not well
under stood. However, many countries are struggling to
scale up testing to implement the key strategies of diag-
nosing all symptomatic patients and tracing all contacts.
Delays in confirming COVID-19 cases allow continued
transmission within communities and can result in failure
to contain the pandemic despite other mea sures such as
physical distancing and travel restrictions.
How can countries move forward?
Countries are assessing all available testing options to
address their range of needs. In settings where challenges
with molecular testing exist or access to laboratories
is scarce, rapid serology tests oer a needed additional
option. A rapid serology test with good performance chara-
cter istics is extremely important to avoid missing true
cases of COVID-19 and imposing unnecessary quaran tine
for people with false-positive results due to cross-reactivity
with seasonal coronaviruses. Studies have shown more
anti body cross-reactivity between the nucleo capsid
proteins of SARS-CoV-2 and common corona viruses than
between their spike proteins.20,22 Tests that use the spike
protein or fragments of the spike protein as targets might
have the least amount of cross-reactivity with common
coronaviruses, on the basis of sequence analysis.22 Clear
articulation of the benefits and limitations of serology tests
will hopefully incentivise manufacturers to improve
performance.29
When is serology testing recommended?
Rapid triage of symptomatic individuals in community
settings
Where there is little or no access to molecular testing,
rapid serology tests provide a means to quickly triage

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suspected cases of COVID-19, provided the test is
highly specific for the disease. A positive result for IgM
in symptomatic patients fulfilling the COVID-19 case
definition is strongly suggestive of SARS-CoV-2 infection.
This approach is probably most eective in individuals
5–10 days after symptom onset.
In Peru, public health facilities for molecular testing are
sparse and only 500 beds in intensive care units exist for a
population of 32 million. The Ministry of Health has set up
a hotline and website for individuals who have symptoms
to be interviewed by a health professional for possible
follow-up, prioritising the visits according to age, risk
factors, and severity of symptoms. A testing team visits the
individual at home to do the rapid anti body test. Individuals
who are IgM and IgG positive and have mild symptoms
are quarantined, whereas people who need critical care are
referred to hospital. All contacts are also tested with the
rapid serology test. Anyone who tests negative in the
antibody test has a swab collected for molecular testing.
As of May 2, 2020, 355 604 people had been triaged in
Peru with 42 534 testing positive, 26 362 of whom were
found to be positive by use of a rapid test.30 This approach
has allowed a large number of sympto matic individuals
and contacts to be rapidly tested in the community,
relieving the backlog, reducing waiting time for molecular
testing, and preventing the health-care system from being
overwhelmed.
Experience in China has also shown that, in sympto-
matic patients, the use of IgM tests or total antibody tests
can increase the sensitivity of COVID-19 case detection.18
Further research should explore the performance and
utility of rapid antigen-IgM and antigen-IgG combo tests
and the timing of testing. In individuals who test negative
for IgG, research should also explore, if resources allow,
the value of doing a follow-up antibody test 10–14 days
later to document a definitive diagnosis through sero-
conversion.
Testing all contacts of people with confirmed COVID-19
Studies have shown that a large number of infected
individuals could have only mild symptoms or no
symptoms at all, but they can still transmit infection, with
as much as 44% of infections being transmitted by pre-
symptomatic individuals.6,7,9 Experience from Singapore
shows that tracking down all contacts of people with
confirmed COVID-19, testing them for evidence of
infection, regardless of symptoms, and putting those
contacts who test positive into isolation is an urgent
priority for interrupting the chain of transmission and
containing the epidemic.31–33 This approach is particularly
important in the early stages when there are only sporadic
or clusters of cases, or for countries coming down from
the peak to continue to reduce the extent of infection
in the community. Only individuals who test negative
should have a throat swab collected for molecular testing,
which will reduce the strain on laboratories doing
these tests.
Situational analysis and surveillance
In countries that have set up syndromic surveillance, such
as surveillance for influenza-like illness or severe acute
respiratory infections, and where blood or throat swabs
are routinely collected at these sentinel sites, collected
samples can be tested for COVID-19 with molecular,
antigen, or serology tests, either alone or in combination.
If any of these samples are positive, it means COVID-19
has been circulating in the community. Where serial
samples are available, it might be possible to date when
COVID-19 established itself in a community or country.
In general, antibody tests can be used to establish
the true extent of an outbreak, map its geographical
distribution, and identify hotspots and populations that
are particularly at risk. This information can in turn
be used to inform public health measures and control
strategies. In this case, researchers need to stick to the
same serology test and test sentinel populations
repeatedly, avoiding the variation in sensitivity between
dierent rapid tests.
When is serology testing not recommended?
Testing the general population
The use of serology tests for population surveys is not
recommended in low prevalence settings as this approach
will probably result in more false-positive than true-
positive results, even if a test with high specificity is used.
For example, if the prevalence of infection is 1% in the
general population, a test with 98% specificity will
identify two false-positive results for every true positive
result. These results could lead to a false sense of security
regarding the extent of immunity in the population and
premature easing of public health measures on the basis
of misleading disease estimates.
Patients at an early stage in the disease course, or
asympto matic or paucisymptomatic patients, might
have low antibody concentrations that could give false-
negative results. Patients’ disease stage and severity are
important points to consider, along with the population
being tested. The estimated level of risk can be considered
before using a serology test, because of the changing false-
positive rate or low positive predictive value across dierent
populations. Among the groups with the highest risk of
the disease are symptomatic patients with clinical presen-
tation of COVID-19, patients with other respiratory
symptoms, contacts of confirmed cases, and health-care
workers in settings with little personal protective equip-
ment. We suggest countries consider risk levels before
using serology tests and creating public health guidance.
Scaling up testing, particularly at the community level,
allows for better estimates of risks, which in turn allows
more eective public health measures to be put into place
than would be otherwise.
Testing to allow health-care workers to return to work
In a pandemic, countries must strive to maintain a
robust health-care workforce. Key workers who develop

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symptoms should be prioritised for molecular testing
and receive care if infected. On recovery, should a
serology test be used to decide when they can safely
return to work? This strategy is based on the assumption
that antibodies confer protective immunity.
Although antibodies against the receptor-binding
domain of the spike protein and the nucleocapsid
protein have been correlated with neutralising activity,14,23,24
the development and duration of immunity has not yet
been established.34,35 Although it is tempting to speculate
that serology tests based on the detection of neutralising
antibodies can be used as markers of protective immunity,
and people who test positive can get a so-called immunity
passport to return to work, studies have shown that a
significant proportion of patients remain RNA-positive
despite high concen trations of antibodies against the
receptor-binding domain of the spike protein and the
nucleocapsid protein.6,15,18,20,21 Wang and colleagues36 found
that elevated serum IgM concentrations are correlated
with poor outcomes in patients with COVID-19
pneumonia, and Tan and colleagues21 found that high
concentrations of IgG antibodies were correlated with
severe disease outcomes. Hence a substantial IgM or IgG
response is not necessarily a surrogate marker of
protective immunity. To date, insucient evidence exists
to recommend the use of serology testing for health-care
workers to return to work. A negative molecular test
remains the safest option to establish whether health-care
workers can work again safely.
A policy brief by the World Bank suggested that serology
testing could potentially have a high net benefit if it can
allow dilution of restrictions for essential workers to return
to work and revive essential segments of the economy.37
The type of tests that can be used for immunity passports
remains unclear. A better understanding of the interaction
between infection and immune response dynamics is
needed before these passports can be considered.
Testing to discharge patients from hospitals
Hospital beds are often in short supply. The recom-
mended criteria for hospital discharge are two negative
molecular tests over several days. However, molecular
testing is often scarce or unavailable. Can serology
tests be used for discharging recovered patients when
molecular testing is not available?
As patients can remain positive for viral RNA despite
rising concentrations of antibodies against the nucleo-
capsid protein and receptor-binding domain of the spike
protein, which are correlated with neutralising activities,
antibody tests cannot be used in the place of molecular
tests to confirm that the patient is virus-free or at least no
longer shedding live virus.
Conclusions
The events over the past few months have taught us that
this pandemic is caused by an extraordinary pathogen
that requires extraordinary measures to combat its
spread and end the pandemic. The latest finding that as
much as 44% of COVID-19 transmission happens before
index cases become symptomatic7 means that a great
deal still needs to be learnt about this novel pathogen and
its spread through a population. The paucity of
knowledge on the dynamics of the immune response to
infection has led to much hesitation on recommending
the use of rapid immuno diagnostic tests, particularly
serology tests.
On the basis of our current knowledge and understanding
of viral infectivity and host response, we urge countries
with restricted capacity for molecular testing to embark on
research into the use of serology tests in triaging symp-
tomatic patients in community settings, testing contacts of
confirmed cases, and in situational analysis and
surveillance. Rapid and scalable tests are needed to deal
with this pandemic. Rapid serology tests, applied in the
right situation for appropriate public health measures to
be put into place, can make a huge dierence. On
Feb 10, 2020, leading health experts from around the world
identified eight research and development priorities at the
WHO R&D Blue Print meeting in Geneva, Switzerland, of
which the top priority was to “mobilize research on rapid
point of care diagnostics for use at the community level”.38
In line with this decision, research on the use of rapid
serology tests to inform control programmes of their
required performance and utility is an urgent priority in
the COVID-19 pandemic response.
Contributors
RWP wrote the first draft of the manuscript. All authors contributed to
the manuscript conception and supported manuscript revisions.
Declaration of interests
We declare no competing interests.
Acknowledgments
We thank Sergio Carmona and Jilian Sacks of the Foundation for
Innovative New Diagnostics for helpful discussions.
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