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Immunity After COVID-19

Research Protocol

This protocol was amended on June 7, 2021. For a summary of the amendments, please refer to Summary of Protocol Amendments.

Condition or Domain Being Studied

Uncertainty exists regarding the immune response in individuals infected with SARS-CoV-2 (the virus which causes the COVID-19 disease) including whether antibodies are protective against reinfection and if so, for how long. Although testing for antibodies to SARS-CoV-2 is becoming more common, how these tests should be utilized and the clinical implications of test results remain unclear. Antibody development in response to infection (adaptive immunity) is only a part of the overall immune response (also comprised of innate immunity), and there is limited understanding of the contribution of antibodies to the overall protection against SARS-CoV-2 reinfection, the duration of the protection, and whether detectable antibodies to SARS-CoV-2 can be used to determine immunity.

The U.S. Agency for Healthcare Research and Quality (AHRQ) intends to commission this rapid living review to synthesize evidence on the prevalence of antibodies to SARS-CoV-2 among adults with COVID-19 or those who have recovered from the disease, whether antibodies are protective against reinfection with the SARS-CoV-2 virus, and the duration of immunity. The American College of Physicians (ACP) nominated this topic for evidence review by the Agency as part of AHRQ's standing work to provide health professional organizations and systems with evidence reviews to support the development of clinical guidance for clinicians. ACP has proposed this to be a living review to continually update their guidance as new practice changing evidence becomes available.

Key Questions

  1. What is the prevalence, level, and duration of detectable antibodies to SARS-CoV-2 among adults infected with or recovered from SARS-CoV-2 infection that has been confirmed with viral RT-PCR?
    1. Does the level and duration of detectable SARS-CoV-2 antibodies vary by patient characteristics (e.g., age, gender, race/ethnicity and comorbidities), COVID-19 disease severity, presence of symptoms, time from symptom onset, or the characteristics of the immunoassay (i.e. sensitivity/specificity)?
  2. Do antibodies to SARS-CoV-2 confer active natural immunity (i.e. immunity due to acquired antibody response to infection rather than immunity from a vaccine) against reinfection with SARS-CoV-2?
    1. Does conferred immunity(assessed as the rate of reinfection) vary by factors such as initial antibody levels, patient characteristics, presence of symptoms, or severity of disease?
    2. Is there a threshold level of detectable SARS-CoV-2 antibodies necessary to confer active natural immunity and if so, does this threshold vary by patient characteristics (e.g., age, gender, race/ethnicity and comorbidities)?
  3. If antibodies to SARS-CoV-2 confer active natural immunity against reinfection with SARS-CoV-2, how long does this immunity last (i.e. what is the rate of reinfection over time)?
    1. Does the duration of immunity vary by factors such as initial antibody levels, patient characteristics, presence of symptoms, or severity of disease?
  4. What are the unintended consequences of antibody testing after SARS-CoV-2 infection?

Table 1. Inclusion and Exclusion Criteria

Study Parameter Inclusion/Exclusion Criteria
Population

Include:

  • KQ 1,4: Adults with viral RT-PCR confirmed SARS-CoV-2 infection who underwent serologic testing for antibodies to SARS-CoV-2 (IgM, IgG, or total antibodies) using an immunoassay authorized by the U.S. Food And Drug Administration (FDA) or prequalified for emergency use by the World Health Organization (WHO) (see Appendix 1 for FDA and WHO information sources).
  • KQ 2-3: Adults with viral RT-PCR confirmed SARS-CoV-2 infection who underwent serologic testing using an immunoassay authorized by the U.S. FDA or prequalified for emergency use by the WHO and demonstrated detectable antibodies to SARS-CoV-2 (IgM, IgG, or total antibodies).

Exclude: Children less than 18 years of age.

Outcomes

KQ 1:

  • Levels of antibodies to SARS-CoV-2
  • Length of time that antibodies remain detectable

KQ 2:

  • Incidence of reinfection (defined by the CDC as new clinical or laboratory evidence of COVID-19 after a documented period of recovery, where recovery is defined as either of the following: (1) two consecutive negative RT-PCR results at least 24 hours apart, (2) resolution of symptoms, or (3) radiographic evidence of recovery

KQ 3:

  • Duration of immunity (i.e. length of time between an initial viral RT-PCR confirmed SARS-CoV-2 infection with clinical recovery to another infection with SARS-CoV-2)

KQ 4:

  • Unintended consequences of antibody testing after SARS-CoV-2 infection
  • We will stratify outcomes by the following factors:
  • Patient characteristics (i.e. age, gender, race/ethnicity, comorbidities)
  • COVID-19 disease severity (i.e. mild, moderate, severe, and critical as defined in NIH COVID-19 treatment guidelines1)
  • Presence of symptoms (asymptomatic or symptomatic)
  • Time from symptom onset to antibody testing
  • Type of test and characteristics of the immunoassay (i.e. name, manufacturer, sensitivity and specificity, test methodology, test kit identifying information, lot number, expiration dates)
Eligible Study Designs

Include: We will include any study design that addresses the key questions and otherwise meets eligibility criteria, including systematic reviews, randomized controlled trials (RCTs), and controlled and uncontrolled observational studies. We will include intervention series (i.e., prospective studies that assess outcomes of interest among a series of patients) but will exclude descriptive case series with <25 subjects and case reports given that these study designs would not be suitable to address our KQs. For systematic reviews, we will assess the timeliness, relevance, and quality (using criteria as described below) of the review and either incorporate all or some of the analyses into our review or utilize the review to identify relevant studies.

Exclude: We will exclude animal studies, in-vitro studies, and studies of infection with coronavirus other than SARS-CoV-2 (e.g., SARS-CoV-1, MERS-CoV, seasonal coronaviruses, etc.)

Study Settings

Any setting (i.e., nursing facility, community, acute care hospital, prison, public health clinic, private clinic, etc.). We will not exclude any study based on setting.

Abbreviations: CoV=coronavirus; COVID-19=coronavirus disease 2019; FDA=food and drug administration; IgM=Immunoglobulin M; IgG=Immunoglobulin G; KQ=key question; MERS=middle east respiratory syndrome; RCT=randomized controlled trial; RT-PCR=reverse transcriptase polymerase chain reaction; SARS=severe acute respiratory syndrome; US=United States; WHO=world health organization.

Literature Search

We will search for systematic reviews and primary studies using the model search strategy outlined in Appendix 2 using the following databases: Ovid Medline ALL, Embase.com, Cumulative Index of Nursing and Allied Health Literature (CINAHL), Covid19reviews.org and ClinicalTrials.gov. The search will be limited to peer-reviewed studies available in the English language.

Study Selection and Data Extraction

Title and abstract review will be performed by one reviewer and checked by another. Full-text article review will be performed by one reviewer and checked by another. Disagreements will be resolved through consensus between the first and second reviewer or consultation with a third reviewer. Data will be extracted into Excel spreadsheets and will include information about author, year, country, setting, study design, study dates, sample size, follow-up duration, patient characteristics (age, gender, race co-morbidities), COVID-19 severity, presence of symptoms, time of symptom onset to antibody testing, antibody test used, characteristics of the immunoassay, and outcomes of interest (listed in Table 1).

Quality Assessment

We will use predefined criteria to rate the internal validity of controlled studies. We will use Cochrane’s Risk of Bias 2 (ROB 2) tool2 to rate RCTs and the Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I) tool3 to rate non-randomized, controlled studies.

Data Synthesis

Data will be compiled into evidence tables and synthesized narratively. We will not conduct meta-analysis. We may prioritize synthesis of studies to accommodate the rapid review timeline using a best-evidence approach according to the hierarchy of evidence pyramid4 (i.e. prioritizing RCTs and controlled observational studies over uncontrolled observational studies). The strength of evidence will be graded for primary outcomes (as listed for each KQ above) using the methods outlined in the AHRQ Effective Health Care Program (EHC) Methods Guide for Effectiveness and Comparative Effectiveness Reviews.5

Literature Surveillance

  • Automated Ovid MEDLINE literature searches will be performed weekly; an updated literature search of all databases will be performed monthly.
  • Status updates will be provided using the AHRQ surveillance report template every 2 months indicating either a) no new studies have been identified; or b) new studies have been identified but do not change the report’s conclusions (i.e. do not change the overall certainty of evidence, or the direction or magnitude of net benefit).
  • We will also monitor the list of FDA-authorized immunoassays every 2 months. If tests are removed, we will include this information in the report status update and discuss it as a limitation to our prior findings.
  • The report will be updated when new studies are identified that change conclusions or at 4 months, whichever is sooner.
  • We will monitor the state of evidence and reconsider value of the key questions/clinical topic on ongoing basis in order to determine when to retire this living review.
  • All evidence updates described above will be housed on a publicly available website (SRDR.ahrq.gov) in addition to being posted online with the journal (if applicable).

External Peer Review

We will have at least two content experts review the draft report.

Definition of Terms

COVID-19=Coronavirus Disease 2019

SARS-CoV-2= Severe Acute Respiratory Syndrome Coronavirus 2

RT-PCR=Reverse Transcriptase Polymerase Chain Reaction

IgM=Immunoglobulin M

IgG=Immunoglobulin G

FDA=U.S. Food and Drug Administration

WHO=World Health Organization

EUA=Emergency Use Authorization

Summary of Protocol Amendments

Date Section Original Protocol Revised Protocol Rationale
6/7/2021 Literature search—databases We will search Ovid Medline ALL, Embase.com, Cumulative Index of Nursing and Allied Health Literature (CINAHL), Covid19reviews.org and ClinicalTrials.gov. We will search Ovid Medline ALL, Covid19reviews.org, WHO COVID database, and ClinicalTrials.gov. Medline and COVID databases will capture the epidemiological studies of interest for our KQ2–3 update. Studies of interest will not likely be published in only CINAHL or Embase and searching these would be duplicative.
6/7/2021 Data synthesis Data synthesized only narratively. Data synthesized for KQ2-3 narratively and with a meta-analysis. High-quality epidemiological studies are now available for quantitative synthesis.
6/7/2021 Table 1: Inclusion and Exclusion Criteria—Eligible study designs Any study design that meets other criteria For this update, our primary analysis will focus on large, population-based observational (cohort or case-control) studies that include an uninfected control group. To address gaps in the evidence, we will consider other study designs as needed. As the field of living reviews on COVID topics has evolved, it has become clear that it is important to focus successive updates on selected key questions, timed to coincide with the emergence of higher quality research publications for each question (called a SWATH review). For the main topic of this update (KQ2), only controlled longitudinal cohorts and case-control designs provide useful estimates of the protection afforded by natural immunity. These studies may also provide the best evidence regarding KQ3 (addressed in this update) and KQ1 (which will be addressed in the update after this one).
6/7/2021 Table 1: Inclusion and Exclusion Criteria—Outcomes KQ 2: Incidence of reinfection defined by the CDC as new clinical or laboratory evidence of COVID-19 after a documented period of recovery, where recovery is defined as either of the following: (1) two consecutive negative RT-PCR results at least 24 hours apart, (2) resolution of symptoms, or (3) radiographic evidence of recovery

KQ 2: Incidence of re-infection. Primary outcome is clinical re-infection; secondary outcomes are any reinfection and severity of reinfection. Re-infection is determined through either:

  • Genomic sequencing;
  • A repeat positive RT-PCR test result 45 or more days following negative RT-PCR testing; or
  • Positive RT-PCR test result 45 or more days following detection of anti-SARS-CoV-2 antibodies
We are interested in population-based epidemiological studies where serial PCR testing of previously positive persons might not have been feasible in early pandemic timepoints. We revised our definition of reinfection to be more representative of testing capabilities in real-world settings of interest.
6/7/2021 Table 1: Inclusion and Exclusion Criteria—Populations KQ 2–3: Adults with viral RT-PCR confirmed SARS-CoV-2 infection who underwent serologic testing using an immunoassay authorized by the U.S. FDA or prequalified for emergency use by the WHO and demonstrated detectable antibodies to SARS-CoV-2 (IgM, IgG, or total antibodies). KQ2-3: Adults with documented COVID-19 infection compared with a concurrent control group. Index infection can be determined by RT-PCR or serologic testing for SARS-CoV-2 in the setting of a wave or outbreak of COVID-19. We decided to expand our criteria to include studies of populations where index infections were determined by PCR or serologic testing to be more representative of potential asymptomatic primary infections in the early pandemic (pre vaccination efforts) timepoints of interest. Early in the pandemic, PCR testing was strictly done on symptomatic patients to conserve resources in most settings.
6/7/2021 Key Question 3

If antibodies to SARS-CoV-2 confer active natural immunity against reinfection with SARS-CoV-2, how long does this immunity last (i.e. what is the rate of reinfection over time)? 

  1. Does the duration of immunity vary by factors such as initial antibody levels, patient characteristics, presence of symptoms, or severity of disease?
What is the duration of protection against reinfection among adults following a primary SARS-CoV-2 infection?
  1. Does the duration of protection vary by factors such as initial antibody levels, patient characteristics, case identification method (e.g., surveillance, symptomatic testing only), presence of symptoms, or COVID-19 severity?
As humoral immunity is not the only mechanism for conferring natural immunity to SARS-CoV-2, it is important to assess whether antibody levels and persistence are related to the duration of protection from natural immunity. We revised our Key Question 3 language to accommodate this fact and indicate that we are interested in the duration of protection regardless of the mechanism.
6/7/2021 Key Question 2

Do antibodies to SARS-CoV-2 confer active natural immunity (i.e. immunity due to acquired antibody response to infection rather than immunity from a vaccine) against reinfection with SARS-CoV-2?

  1. Does conferred immunity (assessed as the rate of reinfection) vary by factors such as initial antibody levels, patient characteristics, presence of symptoms, or severity of disease?
  2. Is there a threshold level of detectable SARS-CoV-2 antibodies necessary to confer active natural immunity and if so, does this threshold vary by patient characteristics (e.g., age, gender, race/ethnicity and comorbidities)?
What is the risk of reinfection from SAR-CoV-2 among adults in the general population compared with the risk of infection in people who have never been infected?
  1. Does the risk of reinfection vary by factors such as initial antibody levels, patient characteristics, presence of symptoms, or severity of disease?

We revised KQ2 to reflect that antibodies are not the only mechanism for which natural immunity could be conferred, and that our analysis aims to identify and estimate the protective effect of natural immunity in the general population.

Although the role of antibodies in conferring natural immunity is still relevant, it is not the only mechanism, and cell-mediated immunity also plays a role.  The most clinically relevant question about reinfection at this time is how the efficacy of protection against infection from natural immunity compares to the protection conferred by vaccination, and whether those who have previously suffered from SARS-CoV-2 infection would have added protection from vaccination. Efficacy of protection from vaccines has been well documented by the Phase 2/3 clinical trials conducted by vaccine manufacturers to receive Emergency Use Authorization from the Food and Drug Administration. By comparing our estimate of efficacy conferred by natural immunity to the estimates of efficacy published by vaccine manufacturers, we will be able to explore whether there might be added protection from vaccination of previously infected persons.

 

References

  1. NIH. Guideline on Management of Persons with COVID-19. NIH; 2020.
  2. Sterne J, Savović J, Page M, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. Bmj. 2019 August 28;366:l4898. doi: 10.1136/bmj.l4898. PMID: 31462531
  3. Sterne J, Hernán M, Reeves B, et al. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. Bmj. 2016 Oct 12;355:i4919. doi: 10.1136/bmj.i4919
  4. Murad M, Asi N, Alsawas M, et al. New evidence pyramid. Evid Based Med. 2016 June 23;21(4):125-7. doi: 10.1136/ebmed-2016-110401. PMID: 27339128
  5. Berkman N., Lohr K., M. A. AHRQ. Grading the strength of a body of evidence when assessing health care interventions for the Effective Health Care Program of the Agency for Healthcare Research and Quality: An Update. 2013 Nov 18.

Appendix 1

We will include studies that used serologic immunoassays that were approved for the detection of antibodies to SARS-CoV-2 either through emergency use authorization from the U.S. FDA or by the emergency use prequalification process by the WHO. The following key resources will be used to determine the regulatory approval status of immunoassays from eligible studies:

Appendix 2

Model Literature Search: We will search for systematic reviews and primary studies using the model search strategy below using the following databases: Ovid MEDLINE ALL, Embase.com, Covid19reviews.org, CINAHL and ClinicalTrials.gov

Ovid MEDLINE ALL 1946 to August 04, 2020

Date searched: August 5, 2020

1 exp Coronavirus/ (24702)

2 exp Coronavirus Infections/ (25370)

3 (coronavirus* or corona-virus* or OC43 or NL63 or 229E or HKU1 or HCoV* or ncov* or covid* or sars-cov* or sarscov* or Sars-coronavirus* or "Severe Acute Respiratory Syndrome").ti,ab,kf. (54179)

4 or/1-3 (60361)

5 4 not (SARS or MERS or MERS-CoV or "Middle East respiratory syndrome" or camel* or dromedar* or equine or coronary or coronal or covidence* or covidien or "influenza virus" or HIV or bovine or calves or TGEV or feline or porcine or BCoV or PED or PEDV or PDCoV or FIPV or FCoV or SADS-CoV or canine or CCov or zoonotic or "avian influenza" or H1N1 or H5N1 or H5N6 or IBV or murine).ti,ab,kf. (32966)

6 ((pneumonia or covid* or coronavirus* or corona virus* or ncov* or 2019-ncov or sars*).mp. or exp pneumonia/) and Wuhan.mp. (2362)

7 (2019-ncov or ncov19 or ncov-19 or 2019-novel CoV or sars-cov2 or sars-cov-2 or sarscov2 or sarscov-2 or Sars-coronavirus2 or Sars-coronavirus-2 or SARS-like coronavirus* or coronavirus-19 or covid19 or covid-19 or covid 2019 or ((novel or new or nouveau) adj2 (CoV or nCoV or covid or coronavirus* or corona virus or Pandemi*2)) or ((covid or covid19 or covid-19) and pandemic*2) or (coronavirus* and pneumonia)).ti,ab,kf. (40627)

8 COVID-19.rx,px,ox. or severe acute respiratory syndrome coronavirus 2.os. (15787)

9 or/5-8 (47964)

10 exp Antibodies/ or exp Immunity/ (1092488)

11 (((active or adaptive or assess* or humoral or long-term or natural or protective or response) adj2 (immune or immunity or immunolog*)) or ((antibody or antibodies) adj5 (attenuat* or complete or detect or detected or detection or detections or level or levels or neutral* or positive)) or convalescent or "false immunity" or "false positive" or "false negative" or IgG or "immunoglobulin G" or IgM or "immunoglobulin M" or immunoassay* or immuno-assay* or postinfection or post-infection or reactivate or reactivated or reactivation or recurrent or recurrence or reinfect* or re-infect* or repositive or re-positive or "second infection*" or seroepidemiolog* or serological or seronegativ* or seropositiv* or seroprevalence or "subsequent infection*" or T-cell or T-cells).ti,ab,kf. (1571174)

12 ("Alinity i SARS-CoV-2 IgG" or "Architect SARS-CoV-2 IgG" or "Assure COVID-19 IgG/IgM" or "Anti-SARS-CoV-2 Rapid Test" or "Babson Diagnostics aC19G1" or "Beckman Coulter Access SARS-CoV-2 IgG" or "WANTAI SARS-CoV-2" or "Platelia SARS-CoV-2" or "Biohit SARS-CoV-2 IgM/IgG" or "qSARS-CoV-2 IgG/IgM" or "LIAISON SARS-CoV-2 S1/S2 IgG" or "Diazyme DZ-Lite SARS-CoV-2 IgG" or "SARS-CoV-2 RBD IgG" or "SARS-COV-2 ELISA" or "RightSign COVID-19" or "LYHER Novel Coronavirus" or "COVID-19 IgG/IgM Rapid Test Cassette" or "SCoV-2 Detect IgG ELISA" or "SCoV-2 Detect IgM ELISA" or "Mt. Sinai Laboratory COVID-19 ELISA" or "VITROS Anti-SARS-CoV-2 IgG" or "VITROS Immunodiagnostic Products Anti-SARS-CoV" or "Elecsys Anti-SARS-CoV-2" or "ADVIA Centaur SARS-CoV-2" or COV2T or "Atellica IM SARS-CoV-2" or "Dimension EXL SARS-CoV-2 Total antibody" or "Dimension Vista SARS-CoV-2 Total antibody" or "Vibrant COVID-19 Ab" or "New York SARS-CoV Microsphere Immunoassay").ti,ab,kf. (19)

13 or/10-12 (2223243)

14 and/9,13 (4373)

15 14 and (202*.dp. or 20200101:20301231.ep.) (2647)

16 exp clinical trial/ or exp cohort studies/ or exp epidemiologic studies/ (3153243)

17 ("controlled clinical trial" or meta-analysis or "observational study" or "randomized controlled trial" or "systematic review").pt. (875867)

18 (cohort or cohorts or (control and (group* or study)) or cross-sectional or follow-up or longitudinal or meta-analy* or metaanaly* or observational or ((evidence or rapid or systematic) adj3 (review or synthesis)) or prospective or prospectively or ((random* or control*) adj3 trial) or retrospective or retrospectively or survey).ti,ab,kf. (4731249)

19 (assess* or ((active or adaptive or assess* or humoral or long-term or natural or protective or response) adj2 (immune or immunity or immunolog*)) or ((antibody or antibodies) adj3 (attenuat* or complete or detect or detected or detection or detections or level or levels or neutral* or positive)) or convalescent or "false immunity" or "false positive" or "false negative" or IgG or "immunoglobulin G" or IgM or "immunoglobulin M" or immunoassay* or immuno-assay* or inciden* or postinfection or post-infection or reactivate or reactivated or reactivation or recurrent or recurrence or reinfect* or re-infect* or repositive or re-positive or "second infection*" or seroepidemiolog* or serological or seronegativ* or seropositiv* or seroprevalence or "subsequent infection*").ti. (776693)

20 or/16-19 (6379286)

21 and/15,20 (1049)

22 21 not ((exp animals/ not humans/) or (animal* or primate*).ti.) (1035)

23 22 not ("in vitro techniques"/ or (case or "in vitro" or man or report or patient or woman).ti. or ("case reports" or comment or editorial or letter).pt.) (801)

Embase.com

Date searched: August 5, 2020

#1 'coronavirus infection'/de OR 'coronavirus disease 2019'/de (38,075)

#2 coronavirus*:ti,ab,kw OR 'corona virus*':ti,ab,kw OR oc43:ti,ab,kw OR nl63:ti,ab,kw OR 229e:ti,ab,kw OR hku1:ti,ab,kw OR hcov*:ti,ab,kw OR ncov*:ti,ab,kw OR covid*:ti,ab,kw OR 'sars cov*':ti,ab,kw OR sarscov*:ti,ab,kw OR 'sars coronavirus*':ti,ab,kw OR 'severe acute respiratory syndrome':ti,ab,kw (53,792)

#3 #1 OR #2 (57,579)

#4 #3 NOT (sars:ti,ab,kw OR mers:ti,ab,kw OR 'mers cov':ti,ab,kw OR 'middle east respiratory syndrome':ti,ab,kw OR camel*:ti,ab,kw OR dromedar*:ti,ab,kw OR equine:ti,ab,kw OR coronary:ti,ab,kw OR coronal:ti,ab,kw OR covidence*:ti,ab,kw OR covidien:ti,ab,kw OR 'influenza virus':ti,ab,kw OR hiv:ti,ab,kw OR bovine:ti,ab,kw OR calves:ti,ab,kw OR tgev:ti,ab,kw OR feline:ti,ab,kw OR porcine:ti,ab,kw OR bcov:ti,ab,kw OR ped:ti,ab,kw OR pedv:ti,ab,kw OR pdcov:ti,ab,kw OR fipv:ti,ab,kw OR fcov:ti,ab,kw OR 'sads cov':ti,ab,kw OR canine:ti,ab,kw OR ccov:ti,ab,kw OR zoonotic:ti,ab,kw OR 'avian influenza':ti,ab,kw OR h1n1:ti,ab,kw OR h5n1:ti,ab,kw OR h5n6:ti,ab,kw OR ibv:ti,ab,kw OR murine:ti,ab,kw) (32,173)

#5 (covid*:ti,ab,kw OR coronavirus*:ti,ab,kw OR 'corona virus*':ti,ab,kw OR ncov*:ti,ab,kw OR '2019 ncov':ti,ab,kw OR sars*:ti,ab,kw OR 'pneumonia'/exp) AND wuhan:ti,ab,kw (2,347)

#6 '2019 ncov':ti,ab,kw OR ncov19:ti,ab,kw OR 'ncov 19':ti,ab,kw OR '2019-novel cov':ti,ab,kw OR 'sars cov2':ti,ab,kw OR 'sars cov 2':ti,ab,kw OR sarscov2:ti,ab,kw OR 'sarscov 2':ti,ab,kw OR 'sars coronavirus2':ti,ab,kw OR 'sars coronavirus 2':ti,ab,kw OR 'sars-like coronavirus*':ti,ab,kw OR 'coronavirus 19':ti,ab,kw OR covid19:ti,ab,kw OR 'covid 19':ti,ab,kw OR 'covid 2019':ti,ab,kw OR (((novel OR new OR nouveau) NEAR/2 (cov OR ncov OR covid OR coronavirus* OR 'corona virus' OR pandemi*2)):ti,ab,kw) OR ((covid:ti,ab,kw OR covid19:ti,ab,kw OR 'covid 19':ti,ab,kw) AND pandemic*2:ti,ab,kw) OR (coronavirus*:ti,ab,kw AND pneumonia:ti,ab,kw) (37,049)

#7 #4 OR #5 OR #6 (45,302)

#8 'antibodies,antisera and immunoglobulins'/exp OR 'immunity'/exp (2,692,035)

#9 (((active OR adaptive OR assess* OR humoral OR 'long term' OR natural OR protective OR response) NEAR/2 (immune OR immunity OR immunolog*)):ti,ab,kw) OR (((antibody OR antibodies) NEAR/5 (attenuat* OR complete OR detect OR detected OR detection OR detections OR level OR levels OR neutral* OR positive)):ti,ab,kw) OR convalescent:ti,ab,kw OR 'false immunity':ti,ab,kw OR 'false positive':ti,ab,kw OR 'false negative':ti,ab,kw OR igg:ti,ab,kw OR 'immunoglobulin g':ti,ab,kw OR igm:ti,ab,kw OR 'immunoglobulin m':ti,ab,kw OR immunoassay*:ti,ab,kw OR 'immuno assay*':ti,ab,kw OR postinfection:ti,ab,kw OR 'post infection':ti,ab,kw OR reactivate:ti,ab,kw OR reactivated:ti,ab,kw OR reactivation:ti,ab,kw OR recurrent:ti,ab,kw OR recurrence:ti,ab,kw OR reinfect*:ti,ab,kw OR 're infect*':ti,ab,kw OR repositive:ti,ab,kw OR 're positive':ti,ab,kw OR 'second infection*':ti,ab,kw OR seroepidemiolog*:ti,ab,kw OR serological:ti,ab,kw OR seronegativ*:ti,ab,kw OR seropositiv*:ti,ab,kw OR seroprevalence:ti,ab,kw OR 'subsequent infection*':ti,ab,kw OR 't cell':ti,ab,kw OR 't cells':ti,ab,kw (2,159,420)

#10 'alinity i sars-cov-2 igg':ti,ab,kw OR 'architect sars-cov-2 igg':ti,ab,kw OR 'assure covid-19 igg/igm':ti,ab,kw OR 'anti-sars-cov-2 rapid test':ti,ab,kw OR 'babson diagnostics ac19g1':ti,ab,kw OR 'beckman coulter access sars-cov-2 igg':ti,ab,kw OR 'wantai sars-cov-2':ti,ab,kw OR 'platelia sars-cov-2':ti,ab,kw OR 'biohit sars-cov-2 igm/igg':ti,ab,kw OR 'qsars-cov-2 igg/igm':ti,ab,kw OR 'liaison sars-cov-2 s1/s2 igg':ti,ab,kw OR 'diazyme dz-lite sars-cov-2 igg':ti,ab,kw OR 'sars-cov-2 rbd igg':ti,ab,kw OR 'sars-cov-2 elisa':ti,ab,kw OR 'rightsign covid-19':ti,ab,kw OR 'lyher novel coronavirus':ti,ab,kw OR 'covid-19 igg/igm rapid test cassette':ti,ab,kw OR 'scov-2 detect igg elisa':ti,ab,kw OR 'scov-2 detect igm elisa':ti,ab,kw OR 'mt. sinai laboratory covid-19 elisa':ti,ab,kw OR 'vitros anti-sars-cov-2 igg':ti,ab,kw OR 'vitros immunodiagnostic products anti-sars-cov':ti,ab,kw OR 'elecsys anti-sars-cov-2':ti,ab,kw OR 'advia centaur sars-cov-2':ti,ab,kw OR cov2t:ti,ab,kw OR 'atellica im sars-cov-2':ti,ab,kw OR 'dimension exl sars-cov-2 total antibody':ti,ab,kw OR 'dimension vista sars-cov-2 total antibody':ti,ab,kw OR 'vibrant covid-19 ab':ti,ab,kw OR 'new york sars-cov microsphere immunoassay':ti,ab,kw (18)

#11 #8 OR #9 OR #10 (3,903,483)

#12 #7 AND #11 (6,621)

#13 #12 AND (2020:py OR 2021:py) (5,292)

#14 'clinical trial'/de OR 'randomized controlled trial'/de OR 'randomization'/de OR 'single blind procedure'/de OR 'double blind procedure'/de OR 'crossover procedure'/de OR 'placebo'/de OR 'prospective study'/de OR ('randomi?ed controlled' NEXT/1 trial*) OR rct OR 'randomly allocated' OR 'allocated randomly' OR 'random allocation' OR (allocated NEAR/2 random) OR (single NEXT/1 blind*) OR (double NEXT/1 blind*) OR ((treble OR triple) NEAR/1 blind*) OR placebo* (2,349,364)

#15 'meta analysis'/exp OR 'systematic review'/de OR 'observational study'/de (542,335)

#17 assess*:ti OR (((active OR adaptive OR assess* OR humoral OR 'long term' OR natural OR protective OR response) NEAR/2 (immune OR immunity OR immunolog*)):ti) OR (((antibody OR antibodies) NEAR/3 (attenuat* OR complete OR detect OR detected OR detection OR detections OR level OR levels OR neutral* OR positive)):ti) OR convalescent:ti OR 'false immunity':ti OR 'false positive':ti OR 'false negative':ti OR igg:ti OR 'immunoglobulin g':ti OR igm:ti OR 'immunoglobulin m':ti OR immunoassay*:ti OR 'immuno assay*':ti OR inciden*:ti OR postinfection:ti OR 'post infection':ti OR reactivate:ti OR reactivated:ti OR reactivation:ti OR recurrent:ti OR recurrence:ti OR reinfect*:ti OR 're infect*':ti OR repositive:ti OR 're positive':ti OR 'second infection*':ti OR seroepidemiolog*:ti OR serological:ti OR seronegativ*:ti OR seropositiv*:ti OR seroprevalence:ti OR 'subsequent infection*':ti (1,023,676)

#16 cohort:ti,ab,kw OR cohorts:ti,ab,kw OR ((control NEAR/3 (group* OR study)):ti,ab,kw) OR 'cross sectional':ti,ab,kw OR 'follow up':ti,ab,kw OR longitudinal:ti,ab,kw OR 'meta analy*':ti,ab,kw OR metaanaly*:ti,ab,kw OR observational:ti,ab,kw OR (((evidence OR rapid OR systematic) NEAR/3 (review OR synthesis)):ti,ab,kw) OR prospective:ti,ab,kw OR prospectively:ti,ab,kw OR (((random* OR control*) NEAR/3 trial):ti,ab,kw) OR retrospective:ti,ab,kw OR retrospectively:ti,ab,kw OR survey:ti,ab,kw (5,907,213)

#18 #14 OR #15 OR #16 OR #17 (7,720,648)

#19 #13 AND #18 (1,561)

#20 #19 NOT ('animal'/exp NOT 'human'/exp OR animal*:ti OR primate*:ti) (1,545)

#21 #20 NOT ('in vitro study'/exp OR case:ti OR 'in vitro':ti OR man:ti OR report:ti OR patient:ti OR woman:ti OR 'editorial'/it OR 'letter'/it OR 'note'/it OR 'case report'/de) (918)

#22 #21 AND [embase]/lim NOT ([embase]/lim AND [medline]/lim) (265)

ClinicalTrials.gov

Date searched: August 5, 2020

Recruiting, Active, not recruiting, Completed Studies | 2019-ncov OR ncov19 OR ncov-19 OR 2019-novel CoV OR sars-cov2 OR sars-cov-2 OR sarscov2 OR sarscov-2 OR Sars-coronavirus2 OR Sars-coronavirus-2 OR SARS-like coronavirus OR coronavirus-19 OR covid19 OR covid-19 OR covid 2019 OR ( ( novel OR new OR nouveau ) AND ( CoV OR nCoV OR covid OR coronavirus OR corona virus OR Pandemic ) ) AND or AND ( ( covid OR covid19 OR covid-19 ) AND pandemic ) OR coronavirus AND pneumonia | immunity OR antibodies OR convalescent OR EXPAND[Concept] "false immunity" OR EXPAND[Concept] "false positive" OR EXPAND[Concept] "false negative" OR IgG OR immunoglobulin OR IgM OR immunoassay or immuno-assay OR postinfection OR post-infection OR reactivated OR recurrent OR reinfection OR re-infection OR repositive OR re-positive OR EXPAND[Concept] "second infection" OR seroepidemiology OR serological OR seronegative OR seropositive OR seroprevalence OR EXPAND[Concept] "subsequent infection" OR T-cell | First posted from 01/01/2020 to 08/05/2020 (171)

Covid19reviews.org

Date searched: August 5, 2020

Keyword searching: immunity, antibody, serological, seroepidemiology, seroprevalence, seropositive, seropositivity, seronegative, seronegativity, post-infection, postinfection, convalescent, recurrent, recurrence, reactivated, reactivation, false, secondary, immunoglobulin, IgG, IgM, immune-assay, immunoassay