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Medical News & Perspectives
April 17, 2020

The Promise and Peril of Antibody Testing for COVID-19

JAMA. 2020;323(19):1881-1883. doi:10.1001/jama.2020.6170

As coronavirus disease 2019 (COVID-19) raged around the globe in late March, hundreds of San Miguel County, Colorado, residents turned out for a blood test. Standing 6 feet apart outside a Telluride school gym, they waited for the blood draw that would tell them whether they had mounted an immune response to the disease-causing virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)—a sign that they’d been infected.

In the first such community-wide campaign in the US, the San Miguel County Department of Health offered the voluntary screening to most of the area’s 8000 residents over 2 weeks. Just 8 of the 986 individuals tested on March 26 and 27 were positive for SARS-CoV-2 antibodies. Another 23 were borderline, suggesting that they’d recently been exposed to the virus and were just starting to make antibodies against it. But those were early days. The screenings, paid for by test manufacturer United Biomedical Inc and the county, eventually would be repeated to see how much things had changed.

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    4 Comments for this article
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    Does IVIG Cause False Positive Serologies?
    Philip Schiffman, MD | Rutgers-Robert Wood Johnson Medical School
    As antibody-positive individuals increase in the donor population, will patients receiving immunoglobulin therapy (IVIG and subcutaneous IG) be prone to false positive antibody tests? Will those patients have blunted immune response to COVID-19?
    CONFLICT OF INTEREST: None Reported
    SARS-CoV-2 antibody testing
    Peter Maple, Ph.D | University of Nottingham, School of Medicine, Queen's Medical Centre, Nottingham, UK
    An excellent article by Jennifer Abbasi which reflects the high quality of coverage by JAMA. Just a few thoughts as follows. Firstly, I have had serious doubts about point of care/rapid tests being available anytime soon. One particular manufacturer was offering COVID-19 lateral flow assay devices at just over $3 per device and could supply 50,000 per week. Very tempting if you are not experienced in evaluating the performance of such devices. I asked for their validation report and they had compared the results of 120 samples from positive cases and negatives with another manufacturer's test device. The problem is that you don't know how good the comparator device is and so you run the risk of comparison against an assay which has limited sensitivity and specificity. I am always suspicious of devices that claim to detect IgM as it can be an unreliable marker of infection, resulting either in false positives (1) or false negatives.

    Regarding the performance of ELISAs, I note that the JAMA commentary refers to a non-peer reviewed pre-print by Amanat and colleagues (2). If this is the same as the pre-print I have then only four COVID-19 positive samples were tested about which, if I was reviewing the paper, I would have concerns. An underlying theme relating to both these examples is the lack of use of reference assays. See the excellent review by Benjamin Meyer and colleagues (3). It would be really useful to have standardized serum and characterized positive and negative serum control panels for SARS-CoV-2 antibody assays. This is something that the WHO has done with national reference laboratories in the past.

    Finally, specific antibody testing can pick up asymptomatic people, so evaluations should include these. Additionally, nucleic acid testing lacks sensitivity outside a certain time window, and detecting seroconversion is useful for diagnosis. I think we live in a different world now, and that coronaviruses will deserve the same attention as influenza - while focussing on the next flu pandemic, coronavirus caught us unawares. One of the best defenses is high-quality scientific communication together with close co-operation between the commercial sector and the medical and scientific communities.

    REFERENCES

    1. Wang Q et al.J. Clin. Microbiol. doi:10.1128/JCM.00375-20
    2. https://www.medrxiv.org/content/10.1101/2020.03.17.20037713v2
    3. Virus Research 2014; 194: 175-183

    CONFLICT OF INTEREST: None Reported
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    COVID-19 Serology
    Kamran Kadkhoda, Ph.D., D(ABMM), D(ABMLI) | Cleveland Clinic
    Employees with a positive IgG may still remain sick and shed the virus through their respiratory secretions and/or through stool. Upper respiratory samples may remain positive for RNA for a few weeks post-onset when patients are already supposed to be IgG seropositive (per initial results from the IgG ELISAs and a  limited number of plaque reduction neutralization tests (PRNTs))(1). The shedding has been reported even up to 47 days in stool, therefore speaking against the neutralizing capacity of tissue-transudated IgG and secretory IgA antibodies (2). Although one might argue that RNA detected from virus that far out probably were from dead viruses it has at least been shown that stool tested positive for SARS-CoV-2 15 days post-onset (3) to the point that donors are deferred for at least a few weeks before donating stool samples. SARS-CoV (SARS-CoV-2’s sister virus) was grown from upper respiratory samples in 54% and 16% of cases, 2 and 3 weeks post onset of symptoms, respectively, despite documented seroconversion in more than 92% of patients assessed by PRNT assays that detect “neutralizing antibodies” (4). 

    Re: COVID-19, the correlate of protection is not known yet. This has to be established via large and well-designed randomized controlled trials. As a common example, the correlate of protection for Hepatitis B is very well known as a surface antibody level at or very close to 10 mIU/ml which is routinely used for occupational health purposes. In a very recent study using golden hamsters as an animal model for COVID-19, the authors showed that injection of hamsters with serum samples from other hamsters with a PRNT titer of ≥427, although it led to a significant decrease in lung viral load, did not decrease lung pathology, highly suggesting the role of tissue damage brought upon by hyper-activated immune response rather than by the virus itself (5). A similar outcome was also seen in a very recent case series from France using the investigational antiviral drug remdesivir in COVID-19 patients, further strengthening the role of immunopathology in the disease process (6). Therefore, determination of “immune status” of individuals including healthcare workers to SARS-CoV-2 cannot be established at this point using serology. It is definitely awaiting outcomes of clinical trials. To further cofound matters, all individuals can be infected and become sick with common CoVs in the community almost every season and sometimes several times during a season. This suggests that immunity to coronaviruses is typically short-lived and a lingering IgG from the previous season(s) does NOT mean an individual is necessarily immune to infection with CoVs. We do not know if what is measured by EIAs (aka ELISAs) has a very good correlation with PRNT results (i.e., ELISA antibodies vs. neutralizing antibodies), and if we do, and they correlate well, then secondly, we do not know if the so-called “neutralizing antibodies” are neutralizing enough if they in fact confer immunity. In a recent publication in JAMA, critically-ill patients were infused with 400 ml of convalescent plasma collected 22-26 days post-onset from donors with clinically-resolved COVID-19 (7). Interestingly the critically ill patients’ neutralization titers where about one dilution factor different than those of donors. This begs the question as to why patients who already have mounted “neutralizing antibody” titers (median of 80) were still critically ill (8).

    REFERENCES
    1. https://www.ncbi.nlm.nih.gov/pubmed/32235945
    2. https://www.thelancet.com/journals/langas/article/PIIS2468-1253(20)30083-2/fulltext
    3. https://www.cdc.gov/coronavirus/2019-ncov/hcp/faq.html 
    4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3322905/
    5. https://academic.oup.com/cid/article/doi/10.1093/cid/ciaa325/5811871
    6. https://jamanetwork.com/journals/jama/fullarticle/2764727
    7. https://jamanetwork.com/journals/jama/fullarticle/2763983
    8. https://www.ccjm.org/content/covid-19-curbside-consults#Kadkhoda_serologic%20testing
    CONFLICT OF INTEREST: None Reported
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    No “Immunity Passport” nor “Risk-Free Certificate”
    Antonio Aceti, Professor | Sapienza University Rome, AOU Sant'Andrea, Rome
    It must be said very clearly that at present serologic assys for SARS-CoV-2 antibodies should only be used for epidemiologic purposes. These cannot have diagnostic meaning nor can they be used as a marker of immunity against the virus. It is often not known which antigens are used in serological testing nor which of these antigens evokes a protective anti-viral response. Several studies show that people who have recovered from infection have antibodies to the virus, but some of these people have very low levels of neutralizing antibodies in their blood (1). In viral infections the cellular immune-response plays an important role that may be also critical for recovery. No study has evaluated whether the presence of antibodies to SARS-CoV-2 confers immunity to subsequent infection by this virus in humans. Serologic tests that detect antibodies to SARS-CoV-2 in people, including rapid immunodiagnostic tests, have not been validated. We don’t known their accuracy and reliability. They may falsely label people who have been infected as negative, and people who have not been infected are falsely labelled as positive. Both errors have serious consequences and will affect control efforts. These tests also need to accurately distinguish between past infections from SARS-CoV-2 and those caused by the known set of six human coronaviruses. Four of these viruses cause the common cold and circulate widely. The remaining two are the viruses that cause Middle East Respiratory Syndrome and Severe Acute Respiratory Syndrome. People infected by any one of these viruses may produce antibodies that cross-react with antibodies produced in response to infection with SARS-CoV-2. For these reasons at this time, no “immunity passport” or “risk-free certificate” is justified (2).

    References
    1. Wu F, Wang A, Liu M, et al. Neutralizing antibody responses to SARS-CoV-2 in a COVID-19 recovered patient cohort and their implications. medRxiv 2020: 2020.03.30.20047365.
    2. WHO/2019-nCoV/Sci_Brief/Immunity_passport/2020.1
    CONFLICT OF INTEREST: None Reported
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