Clinical GuidelinesApril 2022

What Is the Antibody Response and Role in Conferring Natural Immunity After SARS-CoV-2 Infection? Rapid, Living Practice Points From the American College of Physicians (Version 2)

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    The Scientific Medical Policy Committee (SMPC) of the American College of Physicians (ACP) developed these living, rapid practice points to summarize the current best available evidence on the antibody response to SARS-CoV-2 infection and protection against reinfection with SARS-CoV-2. This is version 2 of the ACP practice points, which serves to update version 1, published on 16 March 2021. These practice points do not evaluate vaccine-acquired immunity or cellular immunity.


    The SMPC developed this version of the living, rapid practice points based on an updated living, rapid, systematic review conducted by the Portland VA Research Foundation and funded by the Agency for Healthcare Research and Quality.

    Practice Point 1:

    Do not use SARS-CoV-2 antibody tests for the diagnosis of SARS-CoV-2 infection.

    Practice Point 2:

    Do not use SARS-CoV-2 antibody tests to predict the degree or duration of natural immunity conferred by antibodies against reinfection, including natural immunity against different variants.

    Retirement From Living Status:

    Although natural immunity remains a topic of scientific interest, this topic is being retired from living status given the availability of effective vaccines for SARS-CoV-2 and widespread recommendations for and prevalence of their use. Currently, vaccination is the best clinical recommendation for preventing infection, reinfection, and serious illness from SARS-CoV-2 and its variants.

    The Scientific Medical Policy Committee (SMPC) of the American College of Physicians (ACP) has been maintaining these living, rapid practice points to summarize the current best available evidence on the antibody response to SARS-CoV-2 infection and protection against reinfection with SARS-CoV-2 (Table 1). This is version 2 of the ACP practice points, which serves to update version 1, published on 16 March 2021 (3, 4). It is based on a focused update of a living, rapid, systematic review conducted by the Portland VA Research Foundation and funded by the Agency for Healthcare Research and Quality (5, 6). The SMPC developed these practice points according to ACP's practice points development process, details of which can be found in ACP's methods paper (7).

    Table 1. Practice Points

    Table 1.

    The intended audience for these practice points includes clinicians, patients, the public, and public health officials. The population includes adults who have been previously infected with SARS-CoV-2.

    This version was approved by the ACP Executive Committee of the Board of Regents on behalf of the Board of Regents on 9 August 2021 and was submitted to Annals of Internal Medicine on 6 August 2021.

    Although vaccine-acquired immunity and cellular immunity are important areas of research, this article does not evaluate them.

    Key Questions Addressed in the Living and Rapid Systematic Review

    Key Question 1 (not updated): What are the prevalence, level, and duration of detectable anti–SARS-CoV-2 antibodies among patients infected with or recovered from reverse transcriptase polymerase chain reaction (RT-PCR)–diagnosed SARS-CoV-2 infection?

    Key Question 1a (not updated): Do the levels and durability of detectable antibodies vary by patient characteristics (for example, age, sex, race/ethnicity, and comorbidities), COVID-19 severity (severity of the initial infection), presence of symptoms, time from symptom onset, or the characteristics of the immunoassay (sensitivity, specificity)?

    Key Question 2 (updated): What is the risk for reinfection with SARS-CoV-2 among adults with prior SARS-CoV-2 infection?

    Key Question 2a (updated): Does the risk for reinfection vary by patient characteristics (for example, age, sex, race/ethnicity, and comorbidities), severity of the initial infection, initial antibody levels, or SARS-CoV-2 variants?

    Key Question 2b (updated): Is there a threshold level of detectable anti–SARS-CoV-2 antibodies necessary to confer natural immunity, and if so, does this threshold vary by patient characteristics (for example, age, sex, race/ethnicity, and comorbidities)?

    Key Question 3 (updated): What is the duration of protection against reinfection among adults with prior SARS-CoV-2 infection?

    Key Question 3a (updated): Does the duration of protection vary by patient characteristics (for example, age, sex, race/ethnicity, and comorbidities), severity of initial infection, initial antibody levels, SARS-CoV-2 variants, or case identification method (for example, surveillance, symptomatic testing only)?

    Key Question 4 (not updated): What are the unintended consequences of antibody testing after SARS-CoV-2 infection?

    Key Questions: Rationale for a Focused Update to the Living and Rapid Systematic Review

    Updates to key questions in the living, rapid, systematic review are prioritized on the basis of identification of new evidence from literature surveillance that will likely substantially modify the conclusions or the certainty of evidence. Based on literature surveillance, the Portland VA Research Foundation and the SMPC determined that there was a signal to perform a focused update of key questions 2, 2a, 2b, 3, and 3a (large population-based studies that included uninfected comparison groups were published) and that the evidence for key questions 1, 1a, and 4 had not matured enough to evaluate the long-term persistence of antibodies, which would substantially modify the conclusions or certainty of evidence in the previous version. Consistent with methods for living systematic reviews and our living, rapid practice points (7), the inclusion criteria were modified to include large longitudinal studies with control groups to evaluate the risk for reinfection, and key questions were modified for clarity (Appendix Table).

    Appendix Table. Key Questions Version History

    Appendix Table.
    Overview of New Evidence

    The evidence update (5, 6) identified 18 new studies (8–25) informing key questions 2, 2a, and 3, for which there were previously no studies that met the inclusion criteria in version 1 (3). These studies were initiated before the emergence of the Delta and Omicron variants and before the U.S. Food and Drug Administration's emergency use authorization of vaccines late in 2020 (5, 6). The new studies compared the risk for symptomatic reinfection (as a primary outcome) among adults with a recent SARS-CoV-2 infection with the risk for infection among adults without a recent infection, with “recent” defined as within 7 months of initial SARS-CoV-2 infection. These studies were designed to evaluate risk for symptomatic reinfection, with risk for asymptomatic reinfection as a secondary outcome. The new studies showed that patients with a recent SARS-CoV-2 infection have a substantially reduced risk for symptomatic reinfection (88% in the general population and 87% in health care workers) compared with those without a recent infection (key question 2) over follow-up of 4 to 13 months. There is also protection for asymptomatic reinfections, but the evidence is unclear about whether the degree of protection for asymptomatic reinfections is as high as it is for symptomatic reinfections. No evidence was identified on threshold levels of antibodies needed to confer protection from reinfection or the contribution of the antibody response to this protection (key question 2b). The systematic review update did not identify evidence from included studies on whether risk for reinfection varied by patient comorbidities (including immunosuppression) or by viral variants other than the Alpha variant (including the Delta and Omicron variants) (key question 2a), or whether the variation in the duration of protection varies by patient or clinical characteristics (key question 3a).

    Updated Practice Points and Rationales (Version 2)

    Evidence continues to emerge about the antibody response to SARS-CoV-2 infection and protection against future reinfection. The following practice points are based on the current best available evidence. The Figure, Table 2, and the accompanying systematic review (5, 6) summarize changes in the findings. Table 3 presents clinical considerations, and Table 4 identifies evidence gaps.

    Figure. Evidence description.

    The evidence search and assessment were conducted by the Portland VA Research Foundation (3, 5, 6). The evidence search was updated through 22 September 2021. PCR = polymerase chain reaction.

    * Observational studies include studies estimating seroprevalence among a given population that includes a small subpopulation known to have SARS-CoV-2 infection; cross-sectional or cohort studies characterizing the antibody response among adults with SARS-CoV-2 infection; and large, population-based observational (cohort, case–control) studies comparing risk for reinfection in adults with and without recent SARS-CoV-2 infection (3,5,6). Immunoassay validation studies include those validating the diagnostic performance of 1 or more immunoassays (3).

    Table 2. Evidence Summary

    Table 2.

    Table 3. Clinical Considerations

    Table 3.

    Table 4. Evidence Gaps

    Table 4.

    We have retired Practice Point 2 from version 1, which stated, “Antibody tests can be useful for the purpose of estimating community prevalence of SARS-CoV-2 infection.” The relevance of this statement is now limited given the increase in vaccinations in the United States and because antibody tests cannot differentiate antibodies that develop due to past SARS-CoV-2 infection from those that develop due to vaccination.

    Practice Point 1: Do not use SARS-CoV-2 antibody tests for the diagnosis of SARS-CoV-2 infection.

    Reaffirmed Rationale

    Studies included in the version 1 systematic review evaluated the prevalence, levels, and duration of different types of antibodies after symptom onset or confirmation of SARS-CoV-2 infection with a positive RT-PCR result (3). These studies showed that most patients develop detectable antibodies after SARS-CoV-2 infection; however, the timing of when different antibodies peak and how long they remain detectable may vary (low to moderate certainty). Furthermore, the antibody response may vary by age, sex, race/ethnicity, and the severity of the initial infection (low certainty), and the evidence is very uncertain (insufficient) as to whether the response varies by comorbidities or type of immunoassay. In addition, the diagnostic test characteristics (for example, sensitivity, specificity, and accuracy) vary substantially across the antibody tests used in the included studies (3–6), contributing to differing risks for false-negative and false-positive results (94, 95). For these reasons, based on the studies included in version 1, antibody tests should not be used for the diagnosis of SARS-CoV-2 infection.

    Practice Point 2: Do not use SARS-CoV-2 antibody tests to predict the degree or duration of natural immunity conferred by antibodies against reinfection, including natural immunity against different variants.

    Updated Rationale

    Because measuring antibodies is an approach for evaluating the immune response, questions arise about the role of antibody testing in assessing natural immunity and protection from reinfection after SARS-CoV-2 infection. Although new evidence (18 new studies) has emerged addressing the risk for reinfection among adults with recent SARS-CoV-2 infection, several important evidence gaps remain in the new body of evidence that limit the clinical role of antibody testing (Table 4).

    Low- to moderate-certainty evidence showed that patients with asymptomatic and symptomatic initial infections develop detectable antibodies (3), and high-certainty evidence from new studies showed that recent initial SARS-CoV-2 infection reduced the risk for symptomatic reinfection by 84% to 90% in adults over follow-up ranging from 4 to 13 months. This degree of protection may be similar across age groups (low certainty), with the Alpha variant (low certainty), in persons in the general population and health care workers, and does not vary according to sex (high certainty). However, these studies do not establish that antibodies are primarily responsible for the observed natural immunity because none of the new studies examined the relationship between antibody levels and degree of natural immunity, including threshold levels of detectable SARS-CoV-2 antibodies necessary to confer natural immunity. Furthermore, the included studies were conducted before the Delta and Omicron variants became the dominant circulating strains. However, the systematic review identified 3 studies that were not yet fully reported (96) or were longitudinal uncontrolled studies (97, 98) and thus did not meet the inclusion criteria; these studies suggest that recent SARS-CoV-2 infection reduced risk for reinfection in adults after the Delta variant became the dominant strain.

    It is important to note that none of the new included studies reported on the variation in risk for reinfection in patients who are immunocompromised or have other comorbidities, and evidence is very uncertain (insufficient) about other factors that may modify risk for reinfection, including initial antibody levels and race/ethnicity. Evidence is also conflicting about risk for reinfection in patients who had an asymptomatic initial infection (5, 6); studies show that risk for reinfection may be higher for patients who had a mild or asymptomatic initial infection compared with those who had a symptomatic initial infection (low certainty). Although evidence suggests a high degree of protection (>80%) against symptomatic SARS-CoV-2 reinfection in the short term (high certainty for up to 7 months and low certainty for 7 to 10 months), the duration of protection beyond 10 months is very uncertain (insufficient), and follow-up in the included studies is constrained by time elapsed since the beginning of the pandemic. Finally, none of the included studies reported on how the duration of protection might vary by such factors as variant strains, initial antibody levels, and patient characteristics.

    Despite evidence that patients develop detectable antibodies (3) and have reduced risk for reinfection after initial SARS-CoV-2 infection, knowledge about the direct association of the antibody response and the degree of natural immunity to SARS-CoV-2 is still limited. In light of these evidence gaps, and considering previously reported insufficient (very uncertain) evidence (3) about the unintended consequences of antibody testing, we advise against antibody testing to evaluate for natural immunity. Patients with current or previous SARS-CoV-2 infection should continue to follow recommended infection prevention and control procedures to slow and reduce transmission of the virus (92, 93, 99).

    Retirement From Living Status

    The SMPC is retiring the ACP living, rapid practice points on the antibody response to SARS-CoV-2 infection and protection against reinfection with SARS-CoV-2 from living status (7), given the widespread availability and use of effective vaccines against SARS-CoV-2 infection in the United States. Vaccination is currently the best clinical recommendation for prevention of SARS-CoV-2 infection and reinfection, including from currently circulating viral variants (1, 2).


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    Jeffrey Fessel MD21 April 2022
    SARS-CoV-2 may cause reduced numbers of oligodendrocytes, leading to cognitive dysfunction or dementia.

    The article by Qaseem et al (Annals, April 2022) regarding the antibody response to SARS-CoV-2 infection, describes its diagnostic value and protection against severity of clinical response or against future infection. Omitted by the article is that antibodies provoked by the infection may cause organ damage. Brain damage is not common because brain’s expression of the ACE2 receptor is ~120-fold less than by the small intestine and ~20-fold less than by the kidneys (1). Nevertheless, besides by infection, the brain may be damaged by antibodies that are provoked by SARS-CoV-2, because several of those antibodies affect surface markers of oligodendrocytes or their precursor cells (OPC). If that happens, it could cause apoptosis and reduce the numbers of myelinating oligodendrocytes, producing an adverse effect on neural tracts.

    Affected surface markers (contact the author for references) with antibodies include PGDF, Olig2, MOG, CXCR1, and CXCR3. Antibodies are not the only cause of reduced oligodendrocyte numbers, because the ACE2 receptor is expressed by OPCs, permitting their infection by SARS-CoV-2.

    That reduction may have important clinical manifestations because abnormalities of myelination involving neural tracts cause microcircuit and brain network dysfunction that affects cognition, as explained by Mattson in an extensive review (2). From 110 healthcare facilities, Qureshi et al identified 10,403 adult patients with new onset pneumonia due to SARS-CoV-2 infection, and matched them for age, gender, and race/ethnicity with 10,403 contemporary, control pneumonia patients without SARS-CoV-2 infection. For patients over age 70, new dementia incidence was 6.4% in those with pneumonia due to SARS-CoV-2 versus 5.0% in the control group (p = .04) (3). In another report that also compared SARS-CoV-2 infected patients with an uninfected control group, concentration or memory issues occurred in 4.1% versus 0.2% (P < 0.0005); those symptoms lasted ≥28 days in 13.3%, ≥8 weeks in 4.5% and ≥12 weeks in 2.3% (4). Past morbidity is important: among 44,779 persons, 18.1% of those with a prior history of a psychiatric diagnosis experienced a new episode during 14 to 90 days after an acute SARS-CoV-2 infection, and 5.8% had a new one among those with no previous psychiatric history; 1.6% of persons over age 65, suffered a first diagnosis of dementia during those 14 to 90 days versus 0.66% in controls (p = .0044) (5).

    In brief, besides the antibodies directed against the virus itself, the antibodies provoked by SARS-CoV-2 infection may be disastrous by causing a major neurocognitive disorder in some patients.


    1. Hikmet F, Méar L, Edvinsson Å, Micke P, Uhlén M, Lindskog C. The protein expression profile of ACE2 in human tissues. Molecular systems biology. 2020;16(7):e9610.
    2. Kapogiannis D, Mattson MP. Disrupted energy metabolism and neuronal circuit dysfunction in cognitive impairment and Alzheimer's disease. The Lancet Neurology. 2011;10(2):187-98.
    3. Qureshi AI, Baskett WI, Huang W, Naqvi SH, Shyu C-R. New-Onset Dementia Among Survivors of Pneumonia Associated With Severe Acute Respiratory Syndrome Coronavirus 2 Infection. Open Forum Infectious Diseases, 2022. Oxford University Press US: ofac115.
    4. Sudre CH, Murray B, Varsavsky T, Graham MS, Penfold RS, Bowyer RC, et al. Attributes and predictors of long COVID. Nature medicine. 2021;27(4):626-31.
    5. Taquet M, Luciano S, Geddes JR, Harrison PJ. Bidirectional associations between COVID-19 and psychiatric disorder: retrospective cohort studies of 62 354 COVID-19 cases in the USA. The Lancet Psychiatry. 2021;8(2):130-40.