Antibody response to SARS-CoV-2 infection in humans: A systematic review
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Abstract
Progress in characterising the humoral immune response to Severe Acute Respiratory Syndrome 2 (SARS-CoV-2) has been rapid but areas of uncertainty persist. Assessment of the full range of evidence generated to date to understand the characteristics of the antibody response, its dynamics over time, its determinants and the immunity it confers will have a range of clinical and policy implications for this novel pathogen. This review comprehensively evaluated evidence describing the antibody response to SARS-CoV-2 published from 01/01/2020-26/06/2020.
Methods
Systematic review. Keyword-structured searches were carried out in MEDLINE, Embase and COVID-19 Primer. Articles were independently screened on title, abstract and full text by two researchers, with arbitration of disagreements. Data were double-extracted into a pre-designed template, and studies critically appraised using a modified version of the Public Health Ontario Meta-tool for Quality Appraisal of Public Health Evidence (MetaQAT) tool, with resolution of disagreements by consensus. Findings were narratively synthesised.
Results
150 papers were included. Most studies (113 or 75%) were observational in design, were based wholly or primarily on data from hospitalised patients (108, 72%) and had important methodological limitations. Few considered mild or asymptomatic infection. Antibody dynamics were well described in the acute phase, up to around three months from disease onset, but the picture regarding correlates of the antibody response was inconsistent. IgM was consistently detected before IgG in included studies, peaking at weeks two to five and declining over a further three to five weeks post-symptom onset depending on the patient group; IgG peaked around weeks three to seven post-symptom onset then plateaued, generally persisting for at least eight weeks. Neutralising antibodies were detectable within seven to 15 days following disease onset, with levels increasing until days 14–22 before levelling and then decreasing, but titres were lower in those with asymptomatic or clinically mild disease. Specific and potent neutralising antibodies have been isolated from convalescent plasma. Cross-reactivity but limited cross-neutralisation with other human coronaviridae was reported. Evidence for protective immunity in vivo was limited to small, short-term animal studies, showing promising initial results in the immediate recovery phase.
Conclusions
Literature on antibody responses to SARS-CoV-2 is of variable quality with considerable heterogeneity of methods, study participants, outcomes measured and assays used. Although acute phase antibody dynamics are well described, longer-term patterns are much less well evidenced. Comprehensive assessment of the role of demographic characteristics and disease severity on antibody responses is needed. Initial findings of low neutralising antibody titres and possible waning of titres over time may have implications for sero-surveillance and disease control policy, although further evidence is needed. The detection of potent neutralising antibodies in convalescent plasma is important in the context of development of therapeutics and vaccines. Due to limitations with the existing evidence base, large, cross-national cohort studies using appropriate statistical analysis and standardised serological assays and clinical classifications should be prioritised.
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SciScore for 10.1101/2020.08.25.20178806: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
Antibodies Sentences Resources We focused on studies reporting measured titres (total antibody, IgA, IgG and/or IgM) with follow-up duration of greater than 28 days (which we defined as the limit of the acute phase of illness). IgA, IgGsuggested: NoneSoftware and Algorithms Sentences Resources Identification of studies: Keyword-structured searches were performed in MEDLINE, Embase, MEDLINEsuggested: (MEDLINE, RRID:SCR_002185)Embasesuggested: (EMBASE, RRID:SCR_001650)The adapted MetaQAT tool was used to gather both … SciScore for 10.1101/2020.08.25.20178806: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
Antibodies Sentences Resources We focused on studies reporting measured titres (total antibody, IgA, IgG and/or IgM) with follow-up duration of greater than 28 days (which we defined as the limit of the acute phase of illness). IgA, IgGsuggested: NoneSoftware and Algorithms Sentences Resources Identification of studies: Keyword-structured searches were performed in MEDLINE, Embase, MEDLINEsuggested: (MEDLINE, RRID:SCR_002185)Embasesuggested: (EMBASE, RRID:SCR_001650)The adapted MetaQAT tool was used to gather both qualitative feedback on study quality, and scaled responses (yes/no/unclear) for answers to key questions around study reliability, internal and external validity, and applicability, among other fields. MetaQATsuggested: NoneResults from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:Strengths and limitations: Our review is the first to provide an overview and critical appraisal of literature published since the beginning of 2020 on the immune response in the round. Our findings are nevertheless limited both by aspects of the review methodology and by shortcomings in the included literature. The comprehensiveness of systematic reviews is always dependent on search strategy, and some results relevant to the research question may have been missed. As with all systematic reviews, our findings cannot account for unpublished negative results. Limitations of the underlying evidence base were considerable. A majority of included studies were of moderate quality. Study populations were highly variable, as were the assays used, along with the rigour with which they were described, verified and validated against their target populations. There are efforts in the UK to standardise laboratory SARS-CoV-2 assays use through the National External Quality Assessment Service (NEQAS), but these are early stage and no comparable international initiatives yet exist to support comparability of research findings. Longitudinal follow-up for durations greater than 50-60 days was rare. Many studies did not perform statistical analysis of findings; in particular, studies of putative correlates of immune response usually failed to control for the effects of potential confounders. Small sample sizes were common, as were study populations selected by convenience which, although commo...
Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
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