Interim guidelines for COVID-19 antibody testing


SARS-CoV-2 infection with SARS-CoV-2 initiates a cell-mediated humoral immune response that produces antibodies against specific viral antigens such as the nucleocapsid (N) protein and spike (S) protein. These include protein S antibodies that target the S1 subunit and receptor-binding domain (RBD). Antibody tests can detect the presence of these antibodies in your blood serum within days to weeks after an acute infection. However, an antibody test should not be used to diagnose acute SARS infection. Antibody tests can identify people with or past SARS-CoV-2 infection and thus help scientists and public health experts better understand the epidemiology of SARS-CoV-2. Although the immune links to protection are not fully understood, evidence suggests that the development of antibodies after infection likely confers some degree of immunity from subsequent infection for at least 6 months (1, 2). However, it is not known to what extent SARS-CoV-2 variants can affect protection against subsequent infection (3).

Antibody development and immunity


The data indicate that almost all immunocompetent subjects develop an adaptive immune response after SARS-CoV-2 infection, which leads to humoral and humoral antiviral immune responses via B and T cell-mediated immunity (4-6), respectively. Our understanding of the immune response to SARS-CoV-2 is advancing rapidly. In humans, the humoral response includes antibodies directed against the S and N proteins. The S protein contains two subunits, S1 and S2. The S1 subunit contains the RBD that mediates virus binding to susceptible cells. RBD is the main target for neutralizing antibodies. Antibodies—including IgM, IgG, and IgA—against S and its subunits can be detected in serum within 1–3 weeks after infection (7, 8). IgM and IgG antibodies can arise almost simultaneously (7); However, IgM (and IgA) antibodies degrade more rapidly than IgG (7, 9). The clinical significance of serum IgA measurement in SARS-CoV-2 infection is not known; However, IgA secretion plays an important role in protecting mucosal surfaces from pathogens by neutralizing respiratory viruses, including SARS-CoV-2 (10).

IgG antibodies, including IgG against the S and N proteins, persist for at least several months in most people, but the exact length of time the antibodies persist after infection is not known (11). Loss of previously detectable SARS-CoV-2 antibodies (seroconversion) has been reported among people with mild disease (12). People with more severe disease appear to develop a stronger antibody response with IgM, IgG, and IgA, all of which achieve higher titers and show longer persistence (12, 13). The observed stability of antibodies can vary by screening (14), and some studies have found that approximately 5%-10% of people do not develop detectable IgG antibodies after infection (15, 16). Although neutralizing antibodies may not be detected among patients with mild or asymptomatic disease (17), the humoral immune response appears to remain intact even with the loss of specific antibodies over time due to persistence of memory B cells (18). Neutralizing antibodies to SARS-CoV-2 that inhibit viral replication in the laboratory Mainly targeting RBD (5, 6). Efforts to better understand antibody kinetics, longevity of humoral immune responses, association between levels of binding antibody and neutralizing antibodies, and serological alternatives for immunoprotection depend on the broader availability of quantitative binding antibody assays that are standardized and can be traced according to an international standard (19).

SARS-CoV-2 infection has been documented again (20, 21); However, studies show that people with SARS-CoV-2 antibodies are less likely to develop infection or subsequent clinical illness than people without antibodies. Investigations into outbreaks among people on a fishing vessel and at a summer camp in the United States have found that people with pre-existing SARS-CoV-2 antibodies are associated with protection against subsequent infection (22, 23). In consecutive outbreaks among staff and residents of two British nursing homes, people who tested positive for antibodies after the first outbreak were approximately 96% less likely to develop infection during the second outbreak four months later (24). In a prospective British cohort study in people with and without SARS-CoV-2 antibodies, the adjusted incidence rate of subsequent infection was 0.11 among subjects followed by a median of 200 days after a positive antibody test, compared with those who tested negative. SARS-CoV-2 antibodies (2). Another British cohort study found an 84% reduction in the incidence of SARS-CoV-2 infection over seven months among people who tested positive for SARS-CoV-2 antibodies or had a previous infection documented by reverse transcriptase polymerase chain reaction (RT). – PCR) (1). A large study in the United States of commercial lab results linked to medical claims data and electronic medical records found a 90% reduction in infection among people with antibodies compared to people without antibodies (25), and another study of U.S. military recruits found that seropositive persons who had an 82% reduction in the incidence of SARS-CoV-2 infection over a 6-week period (26). Experiments on non-human primates support the above observations in humans. Experimentally infected rhesus macaques that developed humoral and cellular immune responses that were protected from infection again upon reinfection after 35 days (27). Another study found that transfer of purified IgG from rhesus macaques infected with SARS-CoV-2 was effective in protecting naive macaques from infection, and the protection threshold was established, based on binding and neutralizing antibodies. Analyzes of data from two vaccine trials found that higher titers of neutralizing and anti-S antibodies were associated with more effective protection against infection. (28, 29)

Taken together, these findings in humans and non-human primates indicate that SARS-CoV-2 infection and antibody development can lead to a certain level of protection against re-infection of SARS-CoV-2. The extent and duration of protection are not specified. While lifelong immunity has not been observed with endemic seasonal coronaviruses (30), studies in subjects infected with SARS-CoV-1 and MERS-CoV showed measurable antibodies for 18-24 months after infection (31, 32), and the neutralizing antibody was present for 34 months in a small study of patients infected with MERS-CoV (33). It is not known to what extent people infected with SARS-CoV-2 may transmit SARS-CoV-2 to others or whether the clinical spectrum differs from the primary infection.


SARS-CoV-2 infection begins when the RBD of the virus’s S protein binds to the angiotensin-converting enzyme 2 (ACE-2) receptor site in human cells, the first step in virus entry into human cells. Blocking SARS-CoV-2 from binding to ACE-2 receptors in the human respiratory tract can prevent infection and disease (34). This interaction between the S protein of SARS-CoV-2 and ACE-2 receptor sites has been a major focus of vaccine development. A candidate vaccine that has EUA or FDA approval or is in late development is intended to elicit neutralizing antibodies against protein S or RBD (35). Data from two phases of the mRNA vaccine efficacy trials and cohort studies showed an efficacy of up to 95% following a two-dose vaccination series (36–38). It is not known whether infection confers a similar degree of immunity compared to vaccination.

SARS-CoV-2 infection results in the development of antibodies against viral proteins including the N and S proteins. Vaccine-induced antibody development has implications for antibody testing. Prior to the introduction of the vaccine, a SARS-CoV-2 antibody test that detects either N, S, or RBD antibodies may be considered to indicate previous exposure to SARS-CoV-2. A vaccinated person can be serologically positive for the vaccine’s antigen target (S and S subunits, including RBD) but not against other non-target proteins (39, 40). Thus, a history of vaccination and/or a previous infection with SARS-CoV-2 should be considered when interpreting antibody test results.

Currently available antibody tests for SARS-CoV-2 assess IgM and/or IgG for one of two viral proteins: S or N because the COVID-19 vaccine is created to encode the spike protein or part of the spike protein, which is a positive test for S IgM and/ Or IgG could indicate a previous infection and/or vaccination. To evaluate for evidence of previous infection in a person with a history of vaccination against COVID-19, testexternal symbol

Public health considerations and clinical practice

Accumulating evidence indicates that the presence of antibodies after infection provides some level of protection against reinfection. Evidence includes: (1) a lower incidence among people with SARS-CoV-2 antibodies followed by a period of 3 months or longer; (ii) findings from outbreak investigations that detectable pre-existing antibodies are associated with a lower infection rate (22, 23, 26, 41); (3) challenge trials in primates passively immunized with convalescent plasma demonstrating infection prevention (42); (4) inactivation of the virus with the serum of persons after infection (5, 6); (5) data demonstrating that vaccination, which also leads to the production of antibodies, can reduce the incidence of disease (36, 37); and (6) reduce disease severity and even prevent infection associated with administration of monoclonal antibodiesexternal symbol

While it remains uncertain to what degree and for how long people with detectable antibodies are protected from reinfection with SARS-CoV-2 or what concentration of antibodies is needed to provide this protection, cohort studies report an 80% reduction. to 90% in infection at least 6 months after infection among antibody-positive persons (1, 2, 25). Longitudinal patient follow-up studies are underway to measure antibody levels before and after vaccination or infection to determine the association between responses below a certain threshold and vaccine failure or reinfection. These longitudinal patient follow-up studies are expected to clarify the relationship between antibodies and protection against reinfection. In addition, post-infection T-cell-mediated adaptive immunity, although not fully understood, likely contributes to protection against subsequent exposure to SARS-CoV-2 (45). It is also not known whether, and to what extent, viral evolution and the emergence of new variants of SARS-CoV-2 can affect immunity from reinfection. One UK study found that among people with a primary infection >180 days before reinfection, the risk of reinfection with the delta variant was increased compared to reinfection with the alpha variant (46).

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