COVID-19 Scientific Advisory Group Rapid Evidence Report
COVID-19 Scientific Advisory Group Rapid Evidence Report
COVID-19 Scientific Advisory Group Rapid Evidence Report
Context
• Questions have arisen around whether a person who has recovered from COVID-19 related
illness can be re-infected by the SARS-CoV-2 virus within a short time period, with implications
for both individual risk and societal pandemic control.
• The media has reported on cases where reinfection was apparently suspected and this has
caused public concern.
• The possibility of reinfection would affect the risk of ongoing exposures to HCW and the public
after recovering from COVID-19
• Demonstrated reinfection would also change the current theories around the likely development
of at least partial immunity from both natural infection and potential future vaccination.
clinical evidence suggests that this likely does not occur (over a short time frame) and if it were to – it is
likely exceedingly uncommon.
• Although most experts feel that recovered individuals will have some degree of immune protection from
reinfection, data on the proportion of individuals expected to develop a detectable antibody response to
SARS-CoV-2, optimal specific testing modalities, and the titer that appears to be required to confer
immunity is still evolving. In addition, the possibility of viral mutation affecting the likelihood of reduced
protection (from natural or eventual immunization related antibodies) is not excluded but has not been
seen with other coronaviruses.
• Relevant information can also be found in Scientific Advisory Group Rapid Reviews on Priorities for
Serologic Testing in COVID-19, and Testing Characteristics of RT-PCR.
Committee Discussion
The committee appreciated the update, with most discussion taking place around the concept of immunity in
different populations. It was suggested that links to existing testing documents be provided, and some concerns
were raised around whether specific immunocompromised populations (e.g. BMT patients) may be at a more
significant risk of actual reinfection, although it is also noted that they would be at risk of prolonged RT-PCR
positivity as well, whether or not there is potentially transmissible virus present as well, and data are lacking in this
group.
Recommendations
There are no specific actionable recommendations. There is an evolving understanding of the immune response
in COVID-19 disease, and the possibility of reinfection with SARS-CoV-2 appears very unlikely but has not been
completely excluded. However, there have been no well substantiated cases of reinfection to date and most of the
suspect cases are likely related to inconsistent detection of prolonged viral RNA shedding. This information may
be useful in public and HCW messaging and this review will need to be updated.
Research Gaps
Characterization of optimal serologic testing methodologies, correlations of antibody titers with the likelihood of
immunity, and further analysis of shedding of transmissible virus in an expanded group of patients including those
with immunocompromise were highlighted as areas to follow to better address this question.
Strength of Evidence
The rapidly changing information and literature related to COVID-19, the current literature on COVID-19 and
particularly reinfection by SARS-CoV-2 is limited primarily to descriptive papers, observational studies, published
letters, and news articles. Not enough time has passed since the introduction of SARS-CoV-2 to the human
population to carry out studies that can show whether immunity occurs after infection, or how long this immunity
may last.
Summary of Evidence
Literature for this review was collected from a pragmatic search of literature on coronaviruses. Key limitations of
this review are related to a few observational studies in peer-reviewed publications focused on SARS-CoV-2, and
limited numbers of studies on SARS-CoV and MERS-CoV in peer-reviewed publications. Some of the information
is from media reports with comments from experts, as well as evidence from preprint, published correspondence,
or observational, with lower rigor than formal studies (epidemiological or clinical trials). This review updates the
Research Question • 3
previous review from March 30, 2020 to May 4, 2020. Literature includes both that from the original search and
newly added references.
The evidence included in this rapid review included a literature search performed by Knowledge Resource
Services (KRS) within AHS and literature collected from internet searches. A total of 13 relevant references (peer-
reviewed and not peer-reviewed) were added after screening for inclusion/exclusion criteria to 19 references from
the March 30 version.
Evolving Evidence
The evidence available to answer this research question is evolving because the human population is naïve to
SARS-CoV-2 infection, and studies of population based antibody responses, and correlation of this with protection
against reinfection are not yet possible. There is limited information on whether individuals develop protective
immunity following COVID-19 recovery.
Three studies at the pre-print (non-peer reviewed) stage may be relevant after quality assessment. The first study
found that monoclonal antibodies from recovering patients' B-cells had neutralizing activity in a pseudovirus model
(Ju et al., 2020). An observational study by Dong et al. (2020) showed that patients discharged from hospital
appeared to have neutralizing antibodies out to a short 2 weeks follow-up, suggesting at least short-term immune
protection, with neutralizing antibody titers higher at discharge than at later follow-up. The third study was a
rechallenge experiment on rhesus macaques, and found that those re-challenged with SARS-CoV-2 after
recovering from their first infection did not develop COVID-19 a second time (Bao et al., 2020). Finally, a recent
detailed laboratory publication of 9 COVID-19 cases in Germany revealed early and prolonged viral RNA
shedding that outlasted symptoms, with live virus only detectable in the first week of illness. Notably, at day 7 half
of the patients had seroconverted with detectable neutralizing antibodies and at 14 days all had developed an
antibody response. This would support an association of an antibody response with infectious viral clearance
(Wölfel et al, 2020).
Several studies have documented of newly positive RT-PCR testing in previously negative patients. In a series of
20 patients, Zheng et al. (2020) showed repeat positive PCR tests in 3 patients on day 7 after discharge after 2
negative salivary and 1 negative fecal PCR tests prior to hospital discharge. The 3 patients had all improved
clinically at the time of repeat testing, were in strict isolation post discharge, and further testing at day 14 after
discharge was negative in all. In a retrospective study of 55 patients, Ye et al. (2020) showed 5 patients (1
asymptomatic, and 4 with symptoms) with a positive test 4-17 days after a negative test, though details on the
timing of the tests in relation to initial symptom onset were lacking.
Some authors suggest that positive PCR testing after a negative test represents recurrent infection, thought to
occur due to age, underlying diseases, clinical status, immune function, (Cao et al., 2020; Luo et al., 2020; Ye et
al., 2020). Cases with recurrence of PCR positivity cases have varied in initial symptom severity (Jiang et al.,
2020). The Korean Centres for Disease Control and Prevention (KCDC) was reported to reassure against such
results representing reinfection, stating that “the SARS-CoV-2 does not get into the nucleus of host cells, so it will
not cause a chronic infection that reoccurs at a later date” (Bo-gyung, 2020). In these cases no viral cultivation or
sequencing was done and the patients did not develop recurrent symptoms.
Research Question • 4
availability and so it is possible a patient may test negative with one assay but positive with another due to
different sensitivity.
A recent media report from Korea suggested that 263 people who tested positive weeks after recovery was the
result of follow up PCR tests picking up ribonucleic acid (RNA) fragments from likely nonviable virus, around the
threshold of detection of the test (so a negative test may be followed by a positive PCR) (Bo-gyung, 2020).
These RNA fragments may be detectable for many weeks and the PCR cannot distinguish between live and dead
virus. The KCDC reports that virus culture tests have not been able to find live virus in recovered patients (Bo-
gyung, 2020).
Finally, a false positive RT-PCR result from a non COVID infection could be followed by actual COVID-19
infection and documentation of a true positive result (Chen et al., 2020). The likelihood of this is felt to be much
lower than the false negative scenario described above during a time of increasing population prevalence.
It is noted that to prove reinfection after recovering from COVID-19, the genomes of the virus from initial and
subsequent infection would need to be sequenced, looking for evidence of different genetic backgrounds
indicating a discrete reinfection (Su, 2020).
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COVID-19 Scientific Advisory Group
Rapid Evidence Report
Appendix
List of Abbreviations
AHS: Alberta Health Services
CDC: Centers for Disease Control and Prevention
COVID-19: Coronavirus Disease-2019
HCW: Healthcare worker
MERS: Middle Eastern Respiratory Syndrome
RT-PCR: reverse transcription polymerase chain reaction
SAG: Scientific Advisory Group
SARS: Severe Acute Respiratory Syndrome
Methods
Literature Search
A literature search was conducted by Lauren Seal from Knowledge Resources Services (KRS) within the
Knowledge Management Department of Alberta Health Services. KRS searched databases for articles published
after the last update, from March 30, 2020 to date of search (May 1, 2020), and included: Medline/Pubmed,
CINAHL, and grey literature sources. Search strategy is available below under “Search Strategy” section.
Identified articles were initially screened by title against the inclusion/exclusion criteria listed in Table 1 below. The
PRISMA diagram in Figure 1 provides the flowchart for the newly added literature review evidence.
Table 1. Inclusion and exclusion criteria for results of the literature search
Table 2 below is a narrative summary of the body of evidence included in this review. The categories, format, and
suggested information for inclusion were adapted from the Oxford Centre for Evidence-Based Medicine, the
Cochrane Library, and the AGREE Trust (Urwin, Gavinder & Graziadio, 2020; Viswanathan et al., 2012; Wynants
et al., 2020; Brouwers et al., 2010).
Description
Volume • 13 articles
o 1 retrospective observational study (peer-reviewed) from China
o 3 observational studies (not peer reviewed, pre-print) from China
o 1 observational study (not peer reviewed, pre-print) from USA
o 2 case reports/presentations (peer-reviewed journal: 1 published, 1 in-
press) from China
o 2 letters to the editor (2 in-press)
o 1 evaluation of tests to detect SARS-CoV-2 (in-press)
o 2 commentaries (not peer-reviewed but in peer reviewed journals)
o 1 commentary about SARS-CoV-1 (SARS) (peer-reviewed)
• 3 grey literature
o 1 magazine article – USA
o 1 newspaper article – Korea
o 1 web site (international health organization)
Quality Given the dearth of evidence available for reinfection, the included articles are
comprised of observational studies, case reports, commentaries, and letters to the
editor (scientific journal). Sample sizes are small, largest in a study was 262 (An et al.,
2020) and the largest in a news report was 263 (Bo-gyung, 2020). The available study
designs are potentially biased given they are observational – most likely impacted by
selection bias and possibly confounding (due to pre-existing conditions in some study
subjects). One study (Zheng et al., 2020) highlighted the limitations from small sample
sizes and public health controls (compliance), emphasizing the need for further
research with larger studies.
Applicability The current evidence is mainly from Asia where they have had more experience with
the SARS-CoV-2 virus and COVID-19. While public health controls may be different
than in Alberta, this does not impact the applicability of the currently available evidence
to Alberta.
Consistency N/A
Research Question • 10
Search Strategy
Database: Medline/PubMed
Date search conducted: May 1, 2020
Search terms used/Strategy:
Database: CINAHL
Date search conducted: May 1, 2020
Search terms used/Strategy:
S1 (MH "Coronavirus+")
S2 (MH "Coronavirus Infections+")
S3 coronaviru*
S4 "corona virus"
S5 ncov*
S6 n-cov*
S7 COVID-19 OR COVID19 OR COVID-2019 OR COVID2019
S8 SARS-COV-2 OR SARSCOV-2 OR SARSCOV2 OR SARSCOV19 OR SARS-COV-19 OR
SARSCOV-19 OR SARSCOV2019 OR SARS-COV-2019 OR SARSCOV-2019
S9 "severe acute respiratory syndrome cov 2" OR "severe acute respiratory syndrome coronavirus*"
S10 "2019 ncov" OR 2019ncov OR Hcov*
S11 S1 OR S2 OR S3 OR S4 OR S5 OR S6 OR S7 OR S8 OR S9 OR S10 4,951
S12 (MH "Recurrence") 50,020
S13 reinfect* OR reccur* OR relaps* OR reoccur* OR recrudescence 35,793
S14 (MH "Immunity+") 40,402
S15 (MH "Antibodies+") 76,587
S16 immunit* OR antibod* 103,188
S17 S12 OR S13 OR S14 OR S15 OR S16 214,498
S18 S11 AND S17 276
S19 S11 AND S17 Limiters - Published Date: 20200101-20201231 48
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