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Prognostic value of anti-SARS-CoV-2 antibodies: a systematic review

  • Sylvia Mink EMAIL logo , Patrick Reimann ORCID logo and Peter Fraunberger
Published/Copyright: February 13, 2024
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Clinical Chemistry and Laboratory Medicine (CCLM)
From the journal Clinical Chemistry and Laboratory Medicine (CCLM) Volume 62 Issue 6

Abstract

Objectives

Globally, over 772 million cases of COVID-19 have been reported. New variants of interest with corresponding spikes in case numbers continue to be identified. Vulnerable patients, including older adults or patients with severe comorbidities, continue to be at risk. A large body of evidence has been accumulated regarding anti-SARS-CoV-2-antibodies and COVID-19 but the usefulness of antibody measurements remains unclear. This systematic review aims to assess the prognostic value of anti-SARS-CoV-2-antibodies and their usefulness for guiding booster vaccinations.

Methods

Studies in English and published between January 2020 and October 2023 were included. Studies that relied on multiparameter-models or comprised fewer than 100 participants were excluded. PubMed and via the WHO COVID-19 research database, Embase and Medline databases were searched. Study selection and quality assessment was conducted independently by two researchers.

Results

After screening 1,160 studies, 33 studies comprising >30 million individuals were included. Anti-SARS-CoV-2-antibodies were strongly associated with reduced risk of SARS-CoV-2-infection and better outcomes, including mortality. Risk of infection and COVID-19 severity decreased with increasing antibody levels.

Conclusions

Anti-SARS-CoV-2-antibodies are useful for early identification of high-risk patients and timely adjustment of therapy. Protective thresholds may be applied to advise booster vaccinations but verification in separate cohorts is required.

Keywords: COVID-19; anti-SARS-CoV-2 antibodies; correlate of protection; spike; nucleocapsid; neutralizing antibodies

Introduction

Globally, more than 772 million confirmed cases of COVID-19 have been reported to the World Health Organization [1]. Although testing for SARS-CoV-2 infections has substantially declined [2] and infection numbers are no longer reported in detail, new variants of interest (VOI) with corresponding spikes in case numbers continue to be registered [3]. The latest two VOI include EG.5, a sublineage of XBB.1.9.2, that has led to a global increase in case numbers [4] and currently accounts for approximately 52 % of global SARS-CoV-2 variant proportions, and BA2.86, a variant that was first assessed by the World Health Organization (WHO) in November 2023, and has since steadily grown from a global proportion of 1.8–8.9 % [5].

Vulnerable patient subsets, such as older adults, obese patients or patients with multiple or severe comorbidities have exhibited the highest infection fatality rates throughout the pandemic and continue to be at risk from the currently prevailing and comparatively milder Omicron variant [6], [7], [8], [9], [10].

Global vaccination programs have played a major part in curbing mortality rates and reducing the risk of adverse outcomes [11], [12], [13], [14], [15]. However, current recommendations on booster vaccinations are broad [16] and may be insufficient for patients with additional risk factors or for older adults who are known to have reduced quality, strength and durability of vaccine-induced antibody responses [17], [18], [19], [20], [21], [22].

While a large body of evidence has been accumulated regarding COVID-19, data on the usefulness of antibody measurements is conflicting. In order to best protect vulnerable patients and enable informed decisions on the timing of booster vaccinations, it is necessary to understand if and to what extent anti-SARS-CoV-2 antibodies confer protection against SARS-CoV-2 infection and severe COVID-19, including COVID-19 related mortality.

This systematic review therefore aims to evaluate the prognostic value of anti-SARS-CoV-2 antibodies for identifying patients at high risk of adverse outcomes in a clinical setting and their potential usefulness as a correlate of protection for guiding future booster vaccinations.

Methods

Search methods and study selection

This systematic review was conducted according to PRISMA guidelines [23]. The PubMed database was searched on November 6, 2023 using the following search terms: ((“COVID-19” [Title/Abstract] OR “SARS-CoV-2” [Title/Abstract]) AND (antibodies [Title/Abstract] OR antibody [Title/Abstract] OR vaccine [Title/Abstract])) AND (outcome [Title/Abstract] OR severity [Title/Abstract] OR mortality [Title/Abstract] OR prognosis [Title/Abstract]) while filtering for human probands and publications in English.

The WHO COVID-19 research database [24] was searched on December 1, 2023 using the search terms “prognosis OR mortality OR severity OR outcome” while filtering for publications from MEDLINE and EMBASE, and publications in English. The complete search was defined as follows: “prognosis OR mortality OR severity OR outcome AND db: (“MEDLINE” OR “EMBASE”) AND mj: (“Antibodies, Viral” OR “Antibodies, Neutralizing”) AND type_of_study: (“prognostic_studies” OR “observational_studies” OR “experimental_studies” OR “cohort_studies” OR “rct” OR “diagnostic_studies”) AND la: (“en”)”.

To widen our search, references of included manuscripts were also screened for relevant studies. Peer reviewed observational studies, case control studies, clinical trials and randomized controlled trials published between January 2020 and October 2023 were eligible for inclusion.

Studies not pertinent to our review question were excluded. Thus, studies that did not examine the prognostic value of antibody measurements either preceding COVID-19 or at the onset of COVID-19 infection but focused on antibody kinetics following COVID-19 were excluded. Studies that relied on multiparameter models to predict prognosis and studies that comprised fewer than 100 participants were also excluded. We further excluded studies not written in English, preprints, letters to the editor and short communications and studies without available full text.

Literature screening and data analysis

The Rayyan platform for systematic reviews [25] was used to organize studies and conduct the screening process. After removal of duplicates, title and abstract were screened independently by SM and PR. Full text screening and data extraction were also performed independently by both SM and PR. Conflicts were resolved through discussion.

We collected data on study characteristics, year of publication, journal, author, study cohort, type of antibody measured, outcome, and study results. Data was sought on the following outcomes – immunity against COVID-19 infections and COVID-19 severity.

Risk assessment for bias of cohort studies was conducted independently by SM and PR using the respective Critical Appraisal Skills Programme (CASP) Checklist for cohort studies and case control studies [26, 27]. Randomized controlled trials were assessed with the Cochrane Risk of Bias (ROB) 2.0 Tool [28]. Due to the high heterogeneity of the included studies, the high variability in reported risk measures, and the fact that several studies did not provide any risk measures, conducting sensitivity analyses or a metaanalysis was not considered feasible.

Results

A total of 1,160 eligible studies were identified from PubMed and via the WHO COVID-19 research database, from Embase and Medline databases. After removal of duplicates, 1,113 articles were screened, of which 84 were retrieved. Full text perusal yielded 33 studies that met the inclusion criteria. Figure 1 outlines the process of study identification and selection.

Figure 1: PRISMA 2020 flow chart for study selection.
Figure 1:

PRISMA 2020 flow chart for study selection.

We identified 11 studies that evaluated the role of anti-SARS-CoV-2 antibodies in the prevention of reinfection or breakthrough infections, 20 studies that focused on the association between preexisting antibody levels and disease severity and 2 studies that gave results on both aspects. Data on the latter two studies will be reported both for the association of antibodies with immunity and for the association of antibodies with COVID-19 severity. With regard to studies on the conferral of immunity against COVID-19, two phase 3 clinical trials, 3 retrospective and 8 prospective cohorts were included. Studies on the association between antibodies and COVID-19 severity comprised 16 prospective and 6 retrospective cohorts. Table 1 summarizes the included studies regarding anti-SARS-CoV-2 antibodies and immunity against SARS-CoV-2 infection and Table 2 lists included studies pertaining to anti-SARS-CoV-2 antibodies and COVID-19 severity.

Table 1:

Included studies regarding the association of anti-SARS-CoV-2 antibody levels with immunity against SARS-CoV-2 infection sorted by patient count.

First author, country Year n Study type Study population Antibody type Antibody assay Outcome Main result Potential sources of bias Score
Reynolds [29], U.S. 2023 27,070,023 Retrospective cohort General Not specified Not specified Reinfection 87 % lower risk of reinfection among index-positive than index-negative individuals Retrospective analysis; antibody assays not specified High
Harvey [30], U.S. 2021 3,257,478 Retrospective cohort General Not specified, >91 % IgG Not specified Reinfection Seropositivity is associated with protection from infection. Retrospective analysis; serological assays not specified High
Fong [31], U.S. 2022 44,325 Phase 3 clinical trial; immunogenicity cohort Adults ID50; spike, RBD IgG Pseudo-virus neutralization; ECLIA Breakthrough infection COVID-19 risk decreased with increasing antibody marker tertile; significant for ID50, not for spike and RBD antibodies Spike and RBD antibody ranges may have been too low to detect significant differences Moderate
Hall [32], U.K. 2021 25,661 Prospective cohort Healthcare workers Not specified Not specified Reinfection Patients with antibodies from previous infections are less likely to be reinfected may be subject to some recall bias; serological assays not specified High
Gilbert [33], U.S. 2022 14,064 Phase 3 clinical trial; cohort vaccine recipients Adults RBD, spike IgG ECLIA Breakthrough infection COVID-19 risk of vaccine recipients decreases as antibody marker levels increase Relatively short follow-up time of 4 months High
Lumley [34], U.K. 2021 12,541 Prospective cohort Healthcare workers Spike, nucleocapsid IgG ELISA, CLIA Reinfection The presence of antibodies was associated with a substantially reduced risk of reinfection in the ensuing 6 months may be subject to some selection bias High
Quiroga [35], Spaina 2023 2,186 Prospective cohort Chronic kidney disease Spike IgG CLIA Breakthrough infection Admission for breakthrough COVID-19 was associated with low anti-spike antibody titers. Underlying therapy may limit generalisability to other countries High
Havervall [36], Sweden 2021 1935 Prospective cohort Adults Spike IgG Bead-based multiplex assay Reinfection The presence of anti-spike IgG antibodies is associated with a substantially reduced risk of reinfection up to 9 months following asymptomatic to mild COVID-19. Low chance of recall bias High
Jeffery-Smith [37], U.K. 2021 1,625 Prospective cohort Care home residents Spike, nucleocapsid IgG; neutralizing antibodies ELISA, CLIA; live virus neutralization Breakthrough infection Reinfection was associated with no or low neutralising antibody before reinfection Potentially some bias from comparing older residents to younger, healthier staff High
Pinana [38], Spaina 2023 1,551 Prospective cohort Hematological patients Nucleocapsid IgG, spike IgG ELISA, CLIA Breakthrough infection A serological cut-off of 250 BAU/mL was able to discriminate the risk of being infected and the disease severity may not be generalisable to patients on different treatment regimes; used different testing systems at different test centers High
Liu [39], U.K. 2023 1,228 Prospective cohort Inflammatory bowel disease Neutralizing anti-bodies Pseudo-virus neutralization assay Breakthrough infection Higher antibodies associated with lower HR and hence longer time to breakthrough infection may not be generalisable to patients on different treatment regimes High
Jeffery-Smith [40], U.K. 2021 209 Prospective cohort Care home residents RBD, nucleocapsid IgG EIA Reinfection Only 1.1 % of seropositive vs. 24.7 % of seronegative patients were reinfected Potentially some bias from comparing older residents to younger, healthier staff High
Wand [41], Israel 2022 115 Retrospective cohort Hemodialysis Spike IgG CMIA Breakthrough infection Patients with <50 AU/mL had 5.8 times higher odds of infection Retrospective analysis; low patient number High

  1. aStudies that included information on both immunity and COVID-19 severity and were thus included in both listings. AU antibody unit, BAU, binding antibody unit; COVID-19, coronavirus disease 2019; CLIA, chemiluminescent immunoassay; CMIA, chemiluminescent microparticle immunoassay; ECLIA, electrochemiluminescence immunoassay; ELISA, enzyme-linked immunosorbent assay; EIA, enzyme immunoassay; RBD, receptor binding domain; ICU, intensive care unit.

Table 2:

Included studies regarding the association of anti-SARS-CoV-2 antibody levels with COVID-19 severity, sorted by patient count.

First author, country Year n Study type Study population Antibody type Antibody assay Outcome Main result Potential sources of bias Score
Feng [42], U.K. 2021 4,372 Prospective cohort ChAdOx1 nCoV-19 correlates population Spike, RBD IgG Not specified Symptomatic infection The risk of symptomatic COVID-19 decreased with increasing antibody levels Soft endpoint that may be subject to assessment bias High
Quiroga [35], Spaina 2023 2,186 Prospective cohort Chronic kidney disease Spike IgG CLIA Hospital admission Admitted patients had prior titers <620 IU/mL and lower median values than non-admitted patients Underlying therapy may limit generalisability to other countries High
Pinana [38], Spaina 2023 1,551 Prospective cohort Hematological patients Nucleocapsid IgG, spike IgG ELISA, CLIA Symptomatic infection, pneumonia, hospitalization, oxygen, mortality A serological cut-off value of 250 BAU/mL was able to discriminate the risk of being infected and the disease severity Except for mortality soft endpoints which may be subject to assessment bias; used different testing systems at different test centers High
Mink [43], Austria 2023 1,152 Prospective cohort Hospitalized patients Spike IgG Immunoassay In-hospital mortality Antibody levels at hospital admission are inversely associated with mortality. Patients infected with the omicron variant were 4 times more likely to die if antibodies were <1,200 U/mL Limited to hospitalized patients High
Mink [44], Austria 2023 1,046 Prospective cohort Type 2 diabetes (T2D) Spike IgG Immunoassay Mortality, ICU admission, oxygen administration Mortality risk increased two-fold with each standard deviation-decrease of antibody levels; T2D patients requiring oxygen administration, intubation and ICU admission had significantly lower antibody levels than those who did not Limited to hospitalized patients High
Sananez [45], Argentina 2021 730 Prospective cohort Hospitalized children Spike IgM and IgG ELISA Severe COVID-19 Severe COVID-19 in children is associated with a defective antibody response during acute infection may be subject to some assessment bias; comprised different patient groups, not all with acute infection Moderate
Sanghavi [46], U.S. 2022 627 Retrospective cohort Hospitalized patients Spike IgG Immuno-assay ICU admission, mortality In breakthrough cases, low-titer patients had higher need for ICU care and higher mortality than high-titer patients (>132 U/mL). may be subject to some assessment bias regarding ICU admission High
Sulaiman [47], U.S. 2021 589 Prospective cohort Critically ill adults Spike + RBD IgG, IgM and IgA Not specified Mortality Antibody levels were significantly lower in the deceased group as compared patients who survived may be subject to some selection bias; bronchoalveolar lavage sample material High
Yang [48], China 2022 580 Retrospective cohort Hospitalized patients Spike IgG CMIA Severe COVID-19 Compared with the unvaccinated group, the vac + IgG + group had a 0.05 (0–0.63)-fold risk of suffering from severe cases. Retrospective analysis; may be subject to some assessment bias High
Secchi [49], Italy 2020 509 Prospective cohort Hospitalized patients RBD IgG LIPS Mortality The development of SARS-CoV-2 RBD IgG antibodies was associated with improved patient survival did not adjust for all potential confounders (e.g. BMI) High
Ruytinx [50], Belgium 2023 434 Retrospective cohort Hospitalized patients S1 IgM, IgG ELISA Hospital mortality Increased baseline antibody response was associated with decreased odds for hospital mortality. Retrospective analysis High
Paggi [51], Italy 2023 420 Retrospective cohort Vaccinated hospitalized patients Spike IgG Not specified Mortality Vaccinated seronegative patients’ in-hospital mortality was significantly higher than vaccinated seropositive patients Retrospective; time of antibody measurement not given Moderate
Bernal [52], Spain 2023 232 Prospective cohort Hospitalized patients Spike IgG CMIA Mortality, ventilation Vaccination but not antibody titers protected from adverse events Composite endpoint of ventilation and death; Low
Lucas [53], U.S. 2021 229 Prospective cohort Adults Neutralizing anti-bodies Not specified Mortality Delayed antibody production in lethal COVID-19; early neutralizing antibodies correlate with COVID-19 recovery May be subject to some selection bias; details for antibody assay not specified High
Klineova [54], U.S. 2023 209 Prospective cohort MS, MS related Spike IgG Various Hospitalization Postvaccination antibody response was not associated with hospitalization risk Different antibody assays, antibody levels only available in 79 patients; threshold may have been too low Low
Dispinseri [55], Italy 2021 162 Prospective cohort Hospitalized patients Neutralizing anti-bodies Pseudo-virus neutralization Mortality The lack of neutralizing capacity correlates with an increased risk of a fatal outcome. Comparatively low patient count High
Al-Muhaiteeb [56], Kuwait 2022 138 Prospective cohort Hemodialysis Spike IgG CLIA Hospitalization Hospitalized patients had lower antibody titers than those who were not hospitalized In addition to PCR tests, antigen self tests were admissible as proof of infection Moderate
Nagura-Ikeda [57], Japan 2021 130 Retrospective cohort Hospitalized patients Spike total and IgG CLIA Severity (clinical symptoms of pneumonia) Prevalence or concentration of total or IgG antibody on admission were not associated with disease prognosis Low patient count with positive IgG antibodies on admission; assessment bias due to soft endpoint; retrospective analysis Moderate
Yang [58], U.S. 2021 120 Retrospective cohort Hospitalized patients RBD total Bio-sensor assay Mortality Total antibody positivity rate at hospital admission was significantly higher for the patients who survived than for patients who died Retrospective analysis; not all potential confounders were taken into account High
Malahe [59], Netherlands 2023 114 Prospective cohort Immuno-compromised Spike IgG CLIA Hospitalization A low SARS-CoV-2 antibody response (<300 BAU/mL) at diagnosis were associated with hospital admission Retrospective; different adjustment models – not all potential confounders were included in 1 model High
Shrivastava [60], India 2021 109 Prospective cohort Hospitalized patients Neutralizing anti-bodies Plaque reduction neutralization test Severe disease (ICU + oxygen saturation <93 % at ambient air) Seropositivity in severe disease patients was higher than in mild disease and asymptomatic categories. Healthcare access not equal in India – potential selection bias; outcome is subject to some assessment bias Moderate
Lerum [61], Norway 2021 108 Prospective cohort Hospitalized patients RBD IgG Multiplexed bead-based flow cytometric assay Poor pulmonary outcome Low antibody levels at admission were predictors of poorer pulmonary outcome after 3 months. Adjusted for age, sex, treatment, and smoking but not BMI High

  1. aStudies that included information on both immunity and COVID-19 severity and were thus included in both Tables 1 and 2. BAU, binding antibody unit; COVID-19, coronavirus disease 2019; CLIA, chemiluminescent immunoassay; CMIA, chemiluminescent microparticle immunoassay; ECLIA, electrochemiluminescence immunoassay; ELISA, enzyme-linked immunosorbent assay; EIA, enzyme immunoassay; LIPS, luciferase immune precipitation; RBD, receptor binding domain; ICU, intensive care unit; MS, multiple sclerosis.

In total, 30,443,905 individuals were included, of which 30,432,941 pertained to studies on immunity and 14,701 to studies on COVID-19 severity. Observed heterogeneity among studies was high, with a wide variety of antibody types, antibody testing systems, and outcomes. Evaluated antibody types comprised neutralizing antibodies, anti-SARS-CoV-2 spike antibodies, anti-RBD antibodies and anti-nucleocapsid antibodies. Severity outcomes included symptomatic infections, hospitalization, oxygen administration, invasive ventilation, development of pneumonia, ICU admission, mortality, in-hospital mortality and 28-day mortality. Similarly to outcomes, reported risk measures were highly heterogeneous, and not provided in 15 of 33 studies.

Quality assessment scores based on CASP checklists were divided in thirds to discriminate low, moderate and high quality scores. Of 33 included studies, 2 ranked in the low category, 6 in the moderate and 25 in the high category. Potential sources of bias are listed in Table 1. Figure 2 illustrates details on study origin, patient cohorts, outcomes, measured antibody types and quality scores.

Figure 2: Study characteristics. (A) Origin of studies on prognostic value of anti-SARS-CoV-2 antibodies in COVID-19, (B) origin of studies on anti-SARS-CoV-2 antibodies and immunity against SARS-CoV-2 infection, (C) origin of studies on anti-SARS-CoV-2 antibodies and COVID-19 severity. (D) Study cohorts and quality scores (low/moderate/high) of studies on prognostic value of anti-SARS-CoV-2 antibodies in COVID-19, (E) study cohorts and quality scores for studies on immunity against COVID-19, (F) study cohorts and quality scores for studies on COVID-19 severity; (G) study outcomes with quality scores of studies on prognostic value of anti-SARS-CoV-2 antibodies in COVID-19, (H) study outcomes with quality scores for studies on immunity against COVID-19, (I) study outcomes with quality scores for studies on COVID-19 severity. (J) Antibody type and quality scores of studies on prognostic value of anti-SARS-CoV-2 antibodies in COVID-19, (K) antibody type and quality scores of studies on immunity against COVID-19, (L) antibody type and quality scores of studies on COVID-19 severity. (M) Antibody type and outcome of studies on prognostic value of anti-SARS-CoV-2 antibodies in COVID-19, (N) antibody type and outcome of studies on immunity against COVID-19, (O) antibody type and outcome of studies on COVID-19 severity. Studies with multiple outcomes or antibody types were counted in each category.
Figure 2:

Study characteristics. (A) Origin of studies on prognostic value of anti-SARS-CoV-2 antibodies in COVID-19, (B) origin of studies on anti-SARS-CoV-2 antibodies and immunity against SARS-CoV-2 infection, (C) origin of studies on anti-SARS-CoV-2 antibodies and COVID-19 severity. (D) Study cohorts and quality scores (low/moderate/high) of studies on prognostic value of anti-SARS-CoV-2 antibodies in COVID-19, (E) study cohorts and quality scores for studies on immunity against COVID-19, (F) study cohorts and quality scores for studies on COVID-19 severity; (G) study outcomes with quality scores of studies on prognostic value of anti-SARS-CoV-2 antibodies in COVID-19, (H) study outcomes with quality scores for studies on immunity against COVID-19, (I) study outcomes with quality scores for studies on COVID-19 severity. (J) Antibody type and quality scores of studies on prognostic value of anti-SARS-CoV-2 antibodies in COVID-19, (K) antibody type and quality scores of studies on immunity against COVID-19, (L) antibody type and quality scores of studies on COVID-19 severity. (M) Antibody type and outcome of studies on prognostic value of anti-SARS-CoV-2 antibodies in COVID-19, (N) antibody type and outcome of studies on immunity against COVID-19, (O) antibody type and outcome of studies on COVID-19 severity. Studies with multiple outcomes or antibody types were counted in each category.

Antibodies and immunity against SARS-CoV-2 infection

All of 13 identified studies regarding immunity against SARS-CoV-2 reported an association between anti-SARS-CoV-2 antibodies and reduced rates of reinfection or breakthrough infections.

Seropositivity

A large retrospective study from the U.S. analysing data from over 27 million patients calculated that risk of reinfection was substantially reduced in antibody positive individuals compared to antibody negative individuals (HR 0.13, 95 % CI 0.13–0.13) for a duration of at least 5 months and up to one year after primary infection [29]. These results are substantiated by a further study comprising over 3 million individuals that found seropositivity to be associated with protection from reinfection [30]. Two comparatively large studies on British healthcare workers report concordant results [32, 34]. Firstly, a multicenter study that included 25,661 participants from publicly funded hospitals found that individuals with antibodies from previous infections were less likely to have a reinfection [32]. Secondly, a British study on 12,541 healthcare workers stated that the presence of anti-spike IgG antibodies markedly reduced the risk of reinfection in the ensuing 6 months with an adjusted incidence rate ratio of 0.11 (95 % CI 0.03–0.44) [34]. Similar results were obtained by a Swedish study comprising 1,935 adults that purported reduced risks of reinfection for up to 9 months in IgG positive individuals, with a protective effect of 95.2 % (95 % CI 81.9–99.1 %) [36]. A smaller study of 209 care home residents also reports concordant results [40].

Antibody levels

In addition, antibody levels were found to be significantly lower in patients who experienced reinfection or breakthrough infections than in those who did not [35, 37]. Several studies further suggest that higher antibody levels correlate with longer time to breakthrough infection [39] and that post-vaccination COVID-19 risk decreases as antibody levels increase [33]. Accordingly, a study on 1,551 hematological patients reported that a serological titer of less than 250 BAU/mL of anti-SARS-CoV-2 spike antibodies was predictive of breakthrough infection and its severity [38].

Conflicting evidence

One study found an association between ID 50 titers from a pseudovirus neutralization assay and occurrence of breakthrough infection but could not confirm this association for spike and RBD antibodies. However, these results may have been affected by the relatively low antibody thresholds used for the latter tests, which classified patients with more than 59 BAU/mL as having high antibody levels [31].

Antibodies and COVID-19 severity

18 of 22 identified studies reported an association between antibody levels prior to or at the onset of COVID-19 infection and ensuing COVID-19 severity. Severity measures were highly heterogeneous, ranging from symptomatic infection to hospitalization, pneumonia, ICU admission and death. Figure 2I summarizes the different outcomes. Several studies examined more than one severity measure.

Symptomatic infection

A study published in Nature Medicine examining vaccine efficacy in 4,372 individuals reported 90 % vaccine efficacy at 899 BAU/mL for anti-spike IgG as well as decreasing risk of symptomatic COVID-19 with increasing levels of anti-spike and anti-RBD antibodies [42].

Hospitalization

In 2,186 patients with chronic kidney disease from Spain, patients who were admitted to the hospital had prior anti-spike antibody titers below 620 IU/mL and lower median values than patients who were not hospitalized [35]. These data are supported by a smaller study of 114 immunocompromised patients infected with the Omicron variant that found higher anti-spike antibody levels (>300 BAU/mL) at the time of diagnosis were associated with reduced risk of hospital admission (OR 0.053, 95 % CI 0.006–0.44, p=0.006) [59]. Another prospective cohort study from Spain on 1,551 hematological patients further reported that antibody levels below 250 BAU/mL were associated with higher risk of symptomatic SARS-CoV-2 infection, pneumonia, hospital admission, oxygen requirement and death [38].

Severe COVID-19

Several medium sized studies also report an association between lower antibody levels and elevated risks of severe COVID-19. In a cohort of 730 hospitalized children from Argentina of which 550 had an acute SARS-CoV-2 infection, low antibody concentrations within 4 days of hospital admission were associated with severe COVID-19, characterized by pneumonia, respiratory distress, lethargy and convulsions [45]. In addition, a retrospective Chinese study examining anti-spike IgG on hospital admission of 580 patients noted that, in comparison to unvaccinated patients, vaccinated seropositive patients had adjusted odds ratios of 0.05 (95 % CI 0–0.63) to 0.14 (95 % CI 0.02–0.87) for developing severe COVID-19 pneumonia depending on the adjustment model [48]. Accordingly, in a Norwegian study, low antibody levels at hospital admission were associated with poorer pulmonary outcome after three months [61].

Moreover, a prospective multicenter cohort study on 275 patients with type 2 diabetes (T2D) noted that patients who required oxygen administration, endotracheal intubation and ICU admission had significantly lower anti-SARS-CoV-2 spike antibodies on hospital admission than patients who did not [44]. With regard to ICU admission, a retrospective study on 627 hospitalized patients further reported that low-titer patients (<132 U/mL) had higher need for ICU care (24 [51.1 %] vs. 22 [11.0 %], p=0.034) than high-titer patients (>132 U/mL) in breakthrough cases [46].

Mortality

In a prospective multicenter cohort study on 1,152 hospitalized COVID-19 patients, anti-SARS-CoV-2 spike antibodies measured on admission were inversely associated with in-hospital mortality. In patients infected with the Omicron variant, mortality risk was 4 times higher if antibody levels were below 1,200 BAU/mL (aOR 4.08, 95 % CI 1.81–9.20, p<0.001) [43].

Further, in T2D patients, mortality risk increased two-fold with each standard deviation decrease of antibody levels (aHR 1.99, 95 % CI 1.23–3.22, p=0.005). Comparable results were observed for the control group of 877 non-diabetic individuals [44].

This is supported by another study comprising 589 critically ill adults from the U.S. that found IgG levels of anti-spike and anti-RBD antibodies were significantly lower in the deceased group as compared to the levels found in patients who survived [47]. A retrospective study of 627 hospitalized U.S. patients further reported that low-titer patients had higher mortality (10 [21.3 %] vs. 5 [6.8 %], p=0.025) than high-titer patients (>132 U/mL)[46].

Accordingly, another retrospective cohort study of 434 hospitalized patients described lower odds of in-hospital mortality for patients with higher baseline anti-spike antibody levels [50]. A smaller study from Italy including 152 vaccinated patients with anti-spike IgG measurements also found significantly lower mortality in seropositive vs. seronegative patients (10.7 vs. 33.3 %, p=0.005)[51]. Similar results were obtained by four other medium sized studies comprising between 120 and 509 patients that reported an association between antibody levels and lower mortality [49, 53, 55, 58].

Conflicting evidence regarding hospitalization and severe disease

In contrast to the above, we identified four smaller studies that could not confirm an association between antibody levels and COVID-19 severity [52, 54, 57, 60]. Participant counts ranged from a total of 109–232 individuals, however the number of antibody positive patients was below 100 in each study, with one study [57] comprising only 34 seropositive individuals. Of note, due to various potential sources of bias, these studies were either graded in the lowest or in the moderate scoring tertile according to the CASP checklist (compare Table 1).

One study examining multiple sclerosis patients did not find an association between antibody levels and hospitalization. However, the results of this study may have been affected by several potential sources of bias. Firstly, antibody measurements were only available for 79 of 209 patients, suggesting a potential selection bias. Secondly, antibody measurements were conducted using more than one assay and thirdly, the time of measurement spanned a period of 6 months preceding infection, which may have introduced assessment bias [54].

Another study analyzing 232 hospitalized patients, of whom 91 were seropositive for anti-spike antibodies, did not find an association between antibody titers and the composite outcome of ventilation and death [52]. The composite endpoint of these two outcomes may have resulted in some degree of assessment bias.

Finally, a small study from India comprising 109 hospitalized patients, of whom antibody measurements were conducted in 82 patients, could not confirm an association between neutralizing antibodies and development of severe disease as defined by ICU admission and reduced oxygen saturation at ambient air [60]. Apart from the low patient count, unequal healthcare access in India may have resulted in some degree of selection bias. In addition, the study was conducted between April and June 2020 when vaccines were not yet available, suggesting that the antibody response measured in this population was formed entirely in response to the infection present at the time of the study.

Discussion

In this systematic review that included 33 studies and over 30 million individuals, we found that anti-SARS-CoV-2 antibodies were consistently associated with reduced risk of reinfection or breakthrough infection for 5–12 months after primary infection and for at least 4 months after vaccination. With regard to anti-SARS-CoV-2 antibody levels and reduced COVID-19 severity, the overwhelming majority of identified studies observed significantly better outcomes in seropositive vs. seronegative patients. We further found that both risk of infection and COVID-19 severity decreased with increasing antibody levels.

Interpretation

These results are in accordance with evidence from large vaccine efficacy studies that did not report antibody measurements. For instance, a study comprising over 4.5 million individuals from Israel aged 16 years or older noted that rates of confirmed infection were approximately 10 times lower after booster vaccination than in non-boostered individuals [12]. In boostered patients aged 60 years or older, rates of severe illness and mortality were 17.9 (95 % CI 15.1–21.2) and 14.7 (95 % CI 10.0–21.4) times lower after booster vaccination. Accordingly, a study including 1.2 million older adults showed that a fourth dose lowered rates of severe COVID-19 by a factor of 3.5 (95 % CI 2.7–4.6) [13]. A meta-analysis of 10 studies encompassing close to 10 million individuals also showed that primary infection was associated with a weighted average risk reduction of 90.4 % for reinfection (standard deviation 7.7 %, p<0.01) [62].

In line with results from this systematic review, previous studies show that risk of SARS-CoV-2 infection was reduced following vaccination or preceding infection but protection was not absolute and the duration was relatively short lived [12, 62]. In contrast, protection against adverse outcomes appeared to last longer [12] and lower antibody levels were sufficient to confer protection [63].

While included studies primarily reported anti-SARS-CoV-2 spike and/or RBD antibody levels, these antibodies have been shown to correlate well with neutralizing potency and therefore constitute a good surrogate for measuring neutralizing antibodies [55, 64].

This systematic review found similar results by studies conducted at the beginning of the pandemic, when Alpha and Delta variants were prevalent, and more recent studies based on infections with the Omicron variant, suggesting that antibody measurements are useful as a prognostic tool irrespective of the prevailing virus variant. However, antibodies formed against wild-type SARS-CoV-2 have been shown to lose some neutralizing potency against the Omicron variant [65, 66]. While, sufficiently high antibody levels were still found to be protective, this suggests that not all antibody levels are equally efficient and that regular booster vaccinations with updated vaccines are required in order to best protect vulnerable patient groups. In addition, antibody levels decline more quickly in older adults [17], [18], [19], [20], [21], [22] and antibody affinity is known to decrease with age due to a combination of factors including reduced somatic hypermutation and lower rates of spontaneous mutations in variable regions [67, 68]. Hence, antibody thresholds for guiding booster vaccinations need to be set high enough to account for this variability in efficiency.

Importantly, antibody levels that are present at the onset of an infection seem to confer protection against severe courses and COVID-19 related mortality and may thus be useful for early identification of high-risk patients and timely adjustment of therapy. However, as severe courses elicit stronger antibody responses than mild disease, antibody levels measured in the course of COVID-19 are no longer indicative of protection but appear to reflect the current disease severity [53, 69], [70], [71], [72]. Thus, the prognostic usefulness of anti-SARS-CoV-2 antibodies depends on the time of measurement.

Limitations of included evidence

A high degree of heterogeneity was present among the studies that were included in this systematic review. Sources of heterogeneity included different antibody testing systems, different antibody types, a wide range in the timing of antibody measurements, different follow up periods and different severity measures. Risk measures were also highly heterogeneous and only reported in a fraction of studies.

Although the number of studies included with regard to immunity against SARS-CoV-2 and COVID-19 severity were similar, the total number of included individuals was substantially lower for studies on COVID-19 severity (30,432,941 vs. 14,701).

All currently available evidence is based on observational cohort studies. Two studies were classified as phase 3 clinical trials; however, the antibody analysis conducted by these studies was based on a cohort and is thus also observational in character. The presence of some degree of reporting bias cannot be excluded, particularly with regard to immunity against SARS-CoV-2 infection as no studies reporting negative results could be identified.

Included studies consistently reported an inverse association between higher antibody levels and reduced rates of infection or reinfection, as well as between higher antibody levels and lower rates of symptomatic infection and COVID-19 mortality. However, while several larger and medium-sized studies also observed reduced rates of hospitalisation and severe courses, there was some conflicting evidence from four smaller studies with regard to the latter two outcomes.

Differences in study results may stem from various factors, most notably low patient count and wide ranges in the timing of antibody measurements. In addition, studies based on softer endpoints such as disease severity depend on subjective clinical assessments and are thus more prone to assessment bias than studies based on hard endpoints like patient mortality [73].

Vaccination status may also affect results as studies conducted during the early phases of the pandemic primarily included non-vaccinated patients without previous SARS-CoV-2 contact, whose antibody levels were solely formed in response to the present infection and hence not indicative of pre-existing protection.

In addition, current evidence shows that protection against infection and adverse outcomes increases incrementally with higher antibody levels [33, 44]. Accordingly, several studies that have found better outcomes with higher antibody levels have suggested relatively high antibody thresholds [35, 42, 43]. Thus, studies employing very low thresholds may have been unable to detect a potential protective effect because antibody levels were insufficient.

Several studies that were included in this systematic review did not provide details on the antibody assays that were used in their work. For instance, a large, comprehensive study on more than 27 million individuals by Reynolds et al. [29], only reported that anti-SARS-CoV-2 antibodies were measured but did not describe the assays that were employed by the respective study centres.

In addition, while some studies did report binding antibody units (BAU), it has to be noted that, contrary to the original intention of introducing this unit, significant differences have been described between assays and a complete harmonization of test results has not yet been achieved [74]. While the variability between different assays is unlikely to affect the overall outcome of the studies included in this systematic review, it may limit the comparability between studies and compound the challenge of defining protective antibody thresholds.

Strengths and limitations of the review process

We conducted a comprehensive search of PubMed, and via the WHO COVID-19 research database of Embase and Medline databases, screening over 1,160 studies. While we cannot exclude that studies only available on other platforms may have been missed, this systematic review comprises over 30 million individuals from a total of 33 studies, thus providing a broad basis of evidence. In addition, each step of the study selection and quality assessment process was conducted independently by two researchers to limit the risks of selection and assessment bias.

Implications

The highly concurrent results and considerable patient counts do support a positive association between antibodies and reduced risk of SARS-CoV-2 infection. While the evidence is not quite as strong with regard to COVID-19 severity, high quality studies comprising high patient counts also support an association between higher antibody levels and better outcomes.

This suggests that defining antibody thresholds for efficient application of booster vaccinations would be useful for best protecting vulnerable patient groups, including older adults, obese or highly comorbid patient subsets. In addition, these cut-offs would be useful for early identification of high-risk patients at hospital admission and would allow for timely adjustment of therapy.

Thus far, several cut-offs have been suggested, most notably 250 BAU/mL for immunity [38] and 1,200 BAU/mL for protection against COVID-19 mortality [43]. However, additional data from separate cohorts is urgently needed to define and clarify protective thresholds for clinical use including advising susceptible patients on future booster vaccinations and identifying patients at high risk of adverse outcomes.

Corresponding author: Sylvia Mink, MD, Central Medical Laboratories, Carinagasse 41, 6800 Feldkirch, Austria; and Private University in the Principality of Liechtenstein, Triesen, Principality of Liechtenstein, Phone: +0043 5522 3480 340, Fax: +0043 5522 3480 9340, E-mail:

  1. Research ethics: Not applicable.

  2. Informed consent: Not applicable.

  3. Author contributions: PF and SM were responsible for conceptualisation and methodology. SM and PR conducted the study selection, data extraction and quality assessment of included studies. The original draft was drawn up by SM. Critical review and editing of the manuscript was performed by all authors. All authors had full access to the underlying data. All authors contributed important intellectual content during manuscript drafting and or revision, and accept accountability for the overall work. All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  4. Competing interests: The authors state no conflict of interest.

  5. Research funding: None declared.

  6. Data availability: The raw data can be obtained on request from the corresponding author.

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Received: 2023-12-27
Accepted: 2024-02-02
Published Online: 2024-02-13
Published in Print: 2024-05-27

© 2024 Walter de Gruyter GmbH, Berlin/Boston

Articles in the same Issue

  1. Frontmatter
  2. Editorial
  3. SARS-CoV-2 is here to stay: do not lower our guard
  4. Reviews
  5. SARS-CoV-2 subgenomic RNA: formation process and rapid molecular diagnostic methods
  6. Prognostic value of anti-SARS-CoV-2 antibodies: a systematic review
  7. Presence of SARS-CoV-2 RNA in COVID-19 survivors with post-COVID symptoms: a systematic review of the literature
  8. Opinion Papers
  9. Harmonizing the post-analytical phase: focus on the laboratory report
  10. Blood-based biomarkers in Alzheimer’s disease – moving towards a new era of diagnostics
  11. A comprehensive review on PFAS including survey results from the EFLM Member Societies
  12. General Clinical Chemistry and Laboratory Medicine
  13. Report from the HarmoSter study: different LC-MS/MS androstenedione, DHEAS and testosterone methods compare well; however, unifying calibration is a double-edged sword
  14. An LC–MS/MS method for serum cystatin C quantification and its comparison with two commercial immunoassays
  15. CX3CL1/Fractalkine as a biomarker for early pregnancy prediction of preterm premature rupture of membranes
  16. Elevated S100B urine levels predict seizures in infants complicated by perinatal asphyxia and undergoing therapeutic hypothermia
  17. The correlation of urea and creatinine concentrations in sweat and saliva with plasma during hemodialysis: an observational cohort study
  18. Tubular phosphate transport: a comparison between different methods of urine sample collection in FGF23-dependent hypophosphatemic syndromes
  19. Reference Values and Biological Variations
  20. Monocyte distribution width (MDW): study of reference values in blood donors
  21. Data mining of reference intervals for serum creatinine: an improvement in glomerular filtration rate estimating equations based on Q-values
  22. Hematology and Coagulation
  23. MALDI-MS in first-line screening of newborns for sickle cell disease: results from a prospective study in comparison to HPLC
  24. Cardiovascular Diseases
  25. To rule-in, or not to falsely rule-out, that is the question: evaluation of hs-cTnT EQA performance in light of the ESC-2020 guideline
  26. Temporal biomarker concentration patterns during the early course of acute coronary syndrome
  27. Diabetes
  28. Proteomic analysis of diabetic retinopathy identifies potential plasma-protein biomarkers for diagnosis and prognosis
  29. Infectious Diseases
  30. Serum biomarkers of inflammation and vascular damage upon SARS-Cov-2 mRNA vaccine in patients with thymic epithelial tumors
  31. A high throughput immuno-affinity mass spectrometry method for detection and quantitation of SARS-CoV-2 nucleoprotein in human saliva and its comparison with RT-PCR, RT-LAMP, and lateral flow rapid antigen test
  32. Evaluation of inflammatory biomarkers and vitamins in hospitalized patients with SARS-CoV-2 infection and post-COVID syndrome
  33. The CoLab score is associated with SARS-CoV-2 viral load during admission in individuals admitted to the intensive care unit: the CoLaIC cohort study
  34. Development and evaluation of a CRISPR-Cas13a system-based diagnostic for hepatitis E virus
  35. Letters to the Editor
  36. Crioplast® is a reliable device to ensure pre-analytical stability of adrenocorticotrophin (ACTH)
  37. Falsely decreased Abbott Alinity-c gamma-glutamyl transferase-2 result from paraprotein and heparin interference: case report and subsequent laboratory experiments
  38. Impact of hemolysis on uracilemia in the context of dihydropyrimidine dehydrogenase deficiency testing
  39. Value of plasma neurofilament light chain for monitoring efficacy in children with later-onset spinal muscular atrophy under nusinersen treatment
  40. Analytical evaluation of the Snibe β-isomerized C-terminal telopeptide of type I collagen (β-CTX-I) automated method
  41. Acute myeloid leukemia with blue-green neutrophilic inclusions have different outcomes: two cases and review of the literature
  42. Congress Abstracts
  43. The 10+1 Santorini Conference
  44. 14th National Congress of the Portuguese Society of Clinical Chemistry, Genetics and Laboratory Medicine
  45. 15th National Congress of the Portuguese Society of Clinical Chemistry, Genetics and Laboratory Medicine
  46. ISMD2024 Thirteenth International Symposium on Molecular Diagnostics
https://doi.org/10.1515/cclm-2023-1487
Keywords for this article
COVID-19; anti-SARS-CoV-2 antibodies; correlate of protection; spike; nucleocapsid; neutralizing antibodies

Articles in the same Issue

  1. Frontmatter
  2. Editorial
  3. SARS-CoV-2 is here to stay: do not lower our guard
  4. Reviews
  5. SARS-CoV-2 subgenomic RNA: formation process and rapid molecular diagnostic methods
  6. Prognostic value of anti-SARS-CoV-2 antibodies: a systematic review
  7. Presence of SARS-CoV-2 RNA in COVID-19 survivors with post-COVID symptoms: a systematic review of the literature
  8. Opinion Papers
  9. Harmonizing the post-analytical phase: focus on the laboratory report
  10. Blood-based biomarkers in Alzheimer’s disease – moving towards a new era of diagnostics
  11. A comprehensive review on PFAS including survey results from the EFLM Member Societies
  12. General Clinical Chemistry and Laboratory Medicine
  13. Report from the HarmoSter study: different LC-MS/MS androstenedione, DHEAS and testosterone methods compare well; however, unifying calibration is a double-edged sword
  14. An LC–MS/MS method for serum cystatin C quantification and its comparison with two commercial immunoassays
  15. CX3CL1/Fractalkine as a biomarker for early pregnancy prediction of preterm premature rupture of membranes
  16. Elevated S100B urine levels predict seizures in infants complicated by perinatal asphyxia and undergoing therapeutic hypothermia
  17. The correlation of urea and creatinine concentrations in sweat and saliva with plasma during hemodialysis: an observational cohort study
  18. Tubular phosphate transport: a comparison between different methods of urine sample collection in FGF23-dependent hypophosphatemic syndromes
  19. Reference Values and Biological Variations
  20. Monocyte distribution width (MDW): study of reference values in blood donors
  21. Data mining of reference intervals for serum creatinine: an improvement in glomerular filtration rate estimating equations based on Q-values
  22. Hematology and Coagulation
  23. MALDI-MS in first-line screening of newborns for sickle cell disease: results from a prospective study in comparison to HPLC
  24. Cardiovascular Diseases
  25. To rule-in, or not to falsely rule-out, that is the question: evaluation of hs-cTnT EQA performance in light of the ESC-2020 guideline
  26. Temporal biomarker concentration patterns during the early course of acute coronary syndrome
  27. Diabetes
  28. Proteomic analysis of diabetic retinopathy identifies potential plasma-protein biomarkers for diagnosis and prognosis
  29. Infectious Diseases
  30. Serum biomarkers of inflammation and vascular damage upon SARS-Cov-2 mRNA vaccine in patients with thymic epithelial tumors
  31. A high throughput immuno-affinity mass spectrometry method for detection and quantitation of SARS-CoV-2 nucleoprotein in human saliva and its comparison with RT-PCR, RT-LAMP, and lateral flow rapid antigen test
  32. Evaluation of inflammatory biomarkers and vitamins in hospitalized patients with SARS-CoV-2 infection and post-COVID syndrome
  33. The CoLab score is associated with SARS-CoV-2 viral load during admission in individuals admitted to the intensive care unit: the CoLaIC cohort study
  34. Development and evaluation of a CRISPR-Cas13a system-based diagnostic for hepatitis E virus
  35. Letters to the Editor
  36. Crioplast® is a reliable device to ensure pre-analytical stability of adrenocorticotrophin (ACTH)
  37. Falsely decreased Abbott Alinity-c gamma-glutamyl transferase-2 result from paraprotein and heparin interference: case report and subsequent laboratory experiments
  38. Impact of hemolysis on uracilemia in the context of dihydropyrimidine dehydrogenase deficiency testing
  39. Value of plasma neurofilament light chain for monitoring efficacy in children with later-onset spinal muscular atrophy under nusinersen treatment
  40. Analytical evaluation of the Snibe β-isomerized C-terminal telopeptide of type I collagen (β-CTX-I) automated method
  41. Acute myeloid leukemia with blue-green neutrophilic inclusions have different outcomes: two cases and review of the literature
  42. Congress Abstracts
  43. The 10+1 Santorini Conference
  44. 14th National Congress of the Portuguese Society of Clinical Chemistry, Genetics and Laboratory Medicine
  45. 15th National Congress of the Portuguese Society of Clinical Chemistry, Genetics and Laboratory Medicine
  46. ISMD2024 Thirteenth International Symposium on Molecular Diagnostics
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