Growing attention of immunogenicity among patients with autoimmune diseases post-SARS-CoV-2 vaccination: meta-analysis and systematic reviews of the current studies
Vaccines for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were developed during the emergence of SARS-CoV-2, and various vaccine types and subtypes had been produced in such short period as well . Mainstream vaccine types including messenger RNA (mRNA) platforms, adenoviral vectors, and inactivated virus vaccines have been vaccinated in many countries and cities . The widespread promotion of vaccine platforms significantly bolstered public confidence in acquiring immunological protection amid viral spread. However, vaccines have indefinite efficiency and safety in among large and complex populations worldwide, such as healthy populations and patients who are immunocompromised. One study has emphasized that type and composition of mRNA formulation was linked to difference between safety of BNT162b2 and mRNA-1273 vaccines . Haidar et al.  have reported higher antibody level in patients with hematologic malignancy who received mRNA-1273 than those who received BNT162b2 after the third dose. Additionally, another study has indicated that patients who are immunocompromised do not exhibit a striking pattern of increase in immunogenicity following mRNA vaccine compared to healthy population . Moreover, inactivated vaccines have a certain probability of exerting harmful effects in patients rather than providing protection from the virus . Thus, this can lead to the hypothesis that distinct vaccine types and combination protocol patients applied could be potentially shaped the strong or weak immune response after immunizations. Therefore, the influence of various vaccine types on patients with autoimmune diseases including homologous and heterogeneous vaccine scheme needs to be explored. For patients who are immunocompromised, no unified definition scope exists. Moreover, unpredicted SARS-CoV-2 variants of concern might threaten the immunity of patients who are immunocompromised . Since patients with autoimmune diseases take immunosuppressive drugs and receive biological therapy, referring to multiple administrations of treatments (e.g. anti-tumor necrosis factor (TNF), methotrexate, ustekinumab, secukinumab, and prednisone) with different diseases associated with efficiency of SARS-CoV-2 vaccines . Several studies have reported on the considerable differences in the effectiveness between variants and proved that vaccine recipients have decreased effectiveness during emergence of the Delta variant, such as the B.1.617.2 variant . The influence of different types of SARS-CoV-2 on the immunogenicity of patients who are immunocompromised is another potential point of interest. Overall, various strategies regarding SARS-CoV-2 vaccination have been proposed, and whether various efficiency of SARS-CoV-2 vaccines types, vaccine doses (first dose, second dose, third dose and even forth dose), history of previous SARS-CoV-2 infection, SARS-CoV-2 variants of concerns, utilized immunoassay, administration of immunosuppression treatments, and different kind of autoimmune disease patients diagnosed could possibly affect humoral response among those patients with autoimmune diseases is controversial. Although several previous meta-analyses and systematic reviews have revealed that some patients with autoimmune inflammatory diseases (AIDs) receive more benefits of SARS-CoV-2 vaccines than harmful effects, sufficient data on these patients are also lacking . A recent retrospective study  has highlighted that not all individuals who are immunocompromised have strong serological responses after receiving mRNA vaccines following the third dose with 6 months of follow-up. Nevertheless, no comprehensive and acquired meta-analysis was published on autoimmune disease (such as AIDs, immune mediated inflammatory diseases [IMIDs], autoimmune rheumatic diseases [ARDs], and inflammatory bowel disease [IBD]), except for patients who received organ transplantation, those with cancer, and those with acquired immune deficiency syndrome [AIDS]. Thus, we performed a meta-analysis and systematic reviews focused on the abovementioned concerns to explore the efficiency of mainstream SARS-CoV-2 vaccines on patients with autoimmune diseases in terms of outcomes including seroconversion rate; antibody response; antibody titer; seropositive incidence of immunoglobin G (IgG); serological IgG titer; seropositive incidence of neutralizing antibody (NAb), NAb inhibitor serological NAb, or NAb inhibitor titer; and breakthrough infection. Materials and methods This meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines  to reveal flow of identifying eligible studies. No ethical approval was required for the study. Search strategy The PubMed, Embase, and Cochrane Library databases were searched from inception until October 07, 2022 using the terms ‘COVID-19’, ‘COVID-19 virus’, ‘SARS-CoV-2’, ‘SARS2’, ‘Coronavirus Disease 2019’, ‘2019-nCoV’, ‘2019 Novel Coronavirus’, ‘SARS Coronavirus 2’, ‘vaccines’, ‘immunocompromised’, and ‘autoimmune diseases’ to obtain full texts and abstracts published in the English language. References in the included studies were manually searched to supplement the electronic search. Two reviewers independently evaluated all full-text manuscripts for eligibility. Any disagreements between them were resolved by a third reviewer. Eligibility criteria The inclusion criteria for included articles were as follows: (1) the exposure group comprises patients with autoimmune diseases including ARDs, AIDs, IMIDs, IBDs, chronic inflammatory diseases (CIDs), and combined variable immune deficiency (CVID) who had been vaccinated with SARS-CoV-2 vaccines; (2) the non-exposure group was defined as the general population (i.e. healthy volunteers); and (3) studies expounding the outcomes involving seroconversion rate, antibody response, seropositive incidence of IgG, antibody (SARS-CoV-2) titer, NAb or NAb inhibition titer, and breakthrough infection. The exclusion criteria were as follows: (1) studies involving patients with hematological malignancy or solid cancer, AIDS or HIV virus, and organs transplant; (2) studies including children or pediatric patients aged <12 years; and (3) publications in languages other than English. Quality assessment Regarding SARS-CoV-2 vaccination trials on patients with autoimmune diseases, randomized controlled trials have not been conducted yet. Thus, the NIH study quality assessment tool  was used to measure the risk of bias in case–control and observational cohort studies. This assessment tool comprises 14 items for observational cohort studies and 12 items for case–control studies. All items could be answered as ‘yes’, ‘no’, ‘not reported’, or ‘not applicable’, and the overall quality of each study could be classified as ‘good’, ‘fair’, or ‘poor’. Data extraction and outcome measures Two reviewers extracted relevant data from each literature, involving key information of eligible literature, that is, the basic information, primary outcomes on the effectiveness of SARS-CoV-2 vaccines. Specifically, information on study characteristics (author, year, study design, sample, and country), participant information (gender, age, therapy regimens, particular diseases, and immunogenicity analysis tools or immunoassay) and SARS-CoV-2 vaccination schemes (vaccine type or subtype, vaccine doses, and seropositive cutoff value) was collected. Literature screening was completed by the two reviewers individually, and any discrepancies were resolved by a third researcher. We included all eligible studies reporting on the effectiveness of SARS-CoV-2 vaccines in patients with autoimmune diseases. The primary outcomes of this study were the seroconversion rate and SARS-CoV-2 antibody titer in patients who are immunocompromised. The secondary outcomes included antibody response, seropositive incidence of IgG, IgG titer, breakthrough infection, seropositive incidence of NAb or NAb inhibitor, and NAb or NAb titer. Statistical analysis The effect size of dichotomous data is presented as risk ratios (RRs) and was calculated using the Mantel–Haenszel method with a corresponding 95% confidence interval (CI). Continuous data, such as IgG titer, are reported as standard mean differences (SMDs) with 95%CI to present the efficiency of SARS-CoV-2 vaccine regimens. Moreover, heterogeneity among original articles was appraised using the Higgins’s I 2 test. When I 2 > 40%, a random effect model was used. Otherwise, a fixed-effects model was used. A subgroup analysis of setting outcomes was performed to evaluate studies based on the vaccine doses, vaccine subtype (BNT162b2, mRNA-1273, AD26.COV2.S and AZD1222, Sinovac-CoronaVac, Vero cell, and BBV152), and type (mRNA, inactivated virus, and adenoviral vector vaccines) received by the recruited people, number of vaccine injections (first, second, third, and fourth SARS-CoV-2 vaccinations), history of SARS-CoV-2 infection, SARS-CoV-2 variants of concern, immunoassay, particular diseases, and therapy regimens. The STATA 15.0 software was used for all subgroup analyses. 

This meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines  to reveal flow of identifying eligible studies. No ethical approval was required for the study. 

The PubMed, Embase, and Cochrane Library databases were searched from inception until October 07, 2022 using the terms ‘COVID-19’, ‘COVID-19 virus’, ‘SARS-CoV-2’, ‘SARS2’, ‘Coronavirus Disease 2019’, ‘2019-nCoV’, ‘2019 Novel Coronavirus’, ‘SARS Coronavirus 2’, ‘vaccines’, ‘immunocompromised’, and ‘autoimmune diseases’ to obtain full texts and abstracts published in the English language. References in the included studies were manually searched to supplement the electronic search. Two reviewers independently evaluated all full-text manuscripts for eligibility. Any disagreements between them were resolved by a third reviewer. 

The inclusion criteria for included articles were as follows: (1) the exposure group comprises patients with autoimmune diseases including ARDs, AIDs, IMIDs, IBDs, chronic inflammatory diseases (CIDs), and combined variable immune deficiency (CVID) who had been vaccinated with SARS-CoV-2 vaccines; (2) the non-exposure group was defined as the general population (i.e. healthy volunteers); and (3) studies expounding the outcomes involving seroconversion rate, antibody response, seropositive incidence of IgG, antibody (SARS-CoV-2) titer, NAb or NAb inhibition titer, and breakthrough infection. The exclusion criteria were as follows: (1) studies involving patients with hematological malignancy or solid cancer, AIDS or HIV virus, and organs transplant; (2) studies including children or pediatric patients aged <12 years; and (3) publications in languages other than English. 

Regarding SARS-CoV-2 vaccination trials on patients with autoimmune diseases, randomized controlled trials have not been conducted yet. Thus, the NIH study quality assessment tool  was used to measure the risk of bias in case–control and observational cohort studies. This assessment tool comprises 14 items for observational cohort studies and 12 items for case–control studies. All items could be answered as ‘yes’, ‘no’, ‘not reported’, or ‘not applicable’, and the overall quality of each study could be classified as ‘good’, ‘fair’, or ‘poor’. 

Two reviewers extracted relevant data from each literature, involving key information of eligible literature, that is, the basic information, primary outcomes on the effectiveness of SARS-CoV-2 vaccines. Specifically, information on study characteristics (author, year, study design, sample, and country), participant information (gender, age, therapy regimens, particular diseases, and immunogenicity analysis tools or immunoassay) and SARS-CoV-2 vaccination schemes (vaccine type or subtype, vaccine doses, and seropositive cutoff value) was collected. Literature screening was completed by the two reviewers individually, and any discrepancies were resolved by a third researcher. We included all eligible studies reporting on the effectiveness of SARS-CoV-2 vaccines in patients with autoimmune diseases. The primary outcomes of this study were the seroconversion rate and SARS-CoV-2 antibody titer in patients who are immunocompromised. The secondary outcomes included antibody response, seropositive incidence of IgG, IgG titer, breakthrough infection, seropositive incidence of NAb or NAb inhibitor, and NAb or NAb titer. 

The effect size of dichotomous data is presented as risk ratios (RRs) and was calculated using the Mantel–Haenszel method with a corresponding 95% confidence interval (CI). Continuous data, such as IgG titer, are reported as standard mean differences (SMDs) with 95%CI to present the efficiency of SARS-CoV-2 vaccine regimens. Moreover, heterogeneity among original articles was appraised using the Higgins’s I 2 test. When I 2 > 40%, a random effect model was used. Otherwise, a fixed-effects model was used. A subgroup analysis of setting outcomes was performed to evaluate studies based on the vaccine doses, vaccine subtype (BNT162b2, mRNA-1273, AD26.COV2.S and AZD1222, Sinovac-CoronaVac, Vero cell, and BBV152), and type (mRNA, inactivated virus, and adenoviral vector vaccines) received by the recruited people, number of vaccine injections (first, second, third, and fourth SARS-CoV-2 vaccinations), history of SARS-CoV-2 infection, SARS-CoV-2 variants of concern, immunoassay, particular diseases, and therapy regimens. The STATA 15.0 software was used for all subgroup analyses. 

Literature identification and characteristics of the included studies In total, 4858 studies were obtained by searching digital databases. We then identified 1079 publications after applying the inclusion and exclusion criteria. Finally, 84 studies [17-100] were included in this meta-analysis and systematic review after full-text screening of 876 potential studies. presents the study inclusion flowchart. Nineteen studies were observational cohort studies, published online from 2020 to 2023, involving diverse populations with various autoimmune diseases. The most commonly received SARS-CoV-2 vaccine subtypes by the targeted patients and healthy volunteers were BNT162b2, mRNA-1273, AZD1222, Vero cell, AD16.COV2.S, and Sinovac-CoronaVac. Nearly all participants received at least one SARS-CoV-2 vaccine dose, and various cut-off values of the positive antibody titer criteria are reported in . Quality assessment The quality of the non-randomized studies was assessed using the NIH quality assessment tool. A total of 17 studies were assessed as good quality with a score of ≥11, whereas as the rest of studies scored <11 score, indicating fair quality ( ). 

In total, 4858 studies were obtained by searching digital databases. We then identified 1079 publications after applying the inclusion and exclusion criteria. Finally, 84 studies [17-100] were included in this meta-analysis and systematic review after full-text screening of 876 potential studies. presents the study inclusion flowchart. Nineteen studies were observational cohort studies, published online from 2020 to 2023, involving diverse populations with various autoimmune diseases. The most commonly received SARS-CoV-2 vaccine subtypes by the targeted patients and healthy volunteers were BNT162b2, mRNA-1273, AZD1222, Vero cell, AD16.COV2.S, and Sinovac-CoronaVac. Nearly all participants received at least one SARS-CoV-2 vaccine dose, and various cut-off values of the positive antibody titer criteria are reported in . 

The quality of the non-randomized studies was assessed using the NIH quality assessment tool. A total of 17 studies were assessed as good quality with a score of ≥11, whereas as the rest of studies scored <11 score, indicating fair quality ( ). 

Serological response post-SARS-CoV-2 vaccination A total of 24 studies have reported a serological response rate of 88% (95%CI: 0.86–0.91) in patients who are immunocompromised ( ). Antibody response post-SARS-CoV-2 vaccination Among the 24 studies, 17 studies provided data on the incidence of antibody response when patients who are immunocompromised received SARS-CoV-2 vaccines. The incidence of antibody response was lower in such patients than in their healthy counterparts (RR = 0.90, 95%CI: 0.87 to 0.94) ( ). Incidence of seropositive IgG post-SARS-CoV-2 vaccination Over 34 studies have reported on the incidence of seropositive IgG after vaccination and significant difference between patients who are immunocompromised and the healthy population (RR = 0.74, 95%CI: 0.69 to 0.80). Of the studies, four have reported producing detectable IgG titer level in both groups ( ). Incidence of seropositive NAb post-SARS-CoV-2 vaccination A total of 12 published studies have reported detectable seropositive NAb titer level when participants received SARS-CoV-2 vaccines, and the pooled incidence of NAb was significantly lower in the healthy group than in vaccinated patients (RR = 0.66, 95%CI: 0.57–0.77) ( ). Antibody titer post-SARS-CoV-2 vaccination This meta-analysis pooled 20 studies reporting various units of antibody titer post-vaccinations and seven articles reporting significant difference in antibody titer with units (U)/ml between patients who are immunocompromised (SMD= −11.23, 95%CI: −13.47 to −9.00) and the healthy group. Regarding antibody titer on arbitrary units (AU)/ml, only five studies have reported that antibody titer in patients who are immunocompromised was slightly lower than that in the healthy group (SMD= −1.39, 95%CI: −2.30 to −0.49). Similarly, the result of the antibody titer in BAU/ml was significantly different between the two groups (SMD= −4.71, 95%CI: −5.86 to −3.57) as reported by six studies. Moreover, other units of antibody titer post-vaccination also showed the same result such as AU/ml, that is, patients who are immunocompromised generated lower antibody titer than the healthy group (one study with mg/ml: SMD= −6.08, 95%CI: −6.78 to −5.38; one study with μg/ml: SMD= −8.12, 95%CI: −9.11 to −7.14; and one study did not indicate the unit: SMD= −0.40, 95%CI: −0.68 to −0.12). All results are presented in . IgG titer post-SARS-CoV-2 vaccination Various units were used for IgG titer level testing post-vaccination, such as AU/ml, binding antibody units (BAU)/ml, U/ml, UA/ml, and optical density (OD). However, this meta-analysis identified significant differences between patients who are immunocompromised and the healthy group (pooled IgG titer: SMD= −0.92, 95%CI: −1.06 to −0.78). Many studies used AU/ml or BAU/ml as a unit of IgG titer level to measure the response to SARS-CoV-2 vaccines and presented similar results (15 studies with AU/ml: SMD= −0.64 95%CI: −0.84 to −0.43 and 12 studies with BAU/ml: SMD= −1.21, 95%CI: −1.45 to −0.98). Meanwhile, other units for IgG titer level were used by several studies. Four published articles using OD have reported slightly significant difference between patients who are immunocompromised and healthy group (SMD= −0.94 95%CI: −1.50 to −0.38) in . NAb inhibitor titer post-SARS-CoV-2 vaccination Overall, the pooled RR for NAb inhibitor titer following vaccination in 12 studies was −0.44 (95%CI: −0.63 to −0.25), which indicates that the healthy group responds to SARS-CoV-2 vaccines on a higher NAb inhibitor level than vaccinated patients. In addition, these indicators were analyzed further in vaccinated patients who are immunocompromised ( ). Breakthrough infection post-SARS-CoV-2 vaccination Only eight studies have reported on the incidence of breakthrough infection after vaccination, and no significant difference was observed between the two groups (RR = 1.71, 95%CI: 0.94–3.08) ( ). 

A total of 24 studies have reported a serological response rate of 88% (95%CI: 0.86–0.91) in patients who are immunocompromised ( ). 

Among the 24 studies, 17 studies provided data on the incidence of antibody response when patients who are immunocompromised received SARS-CoV-2 vaccines. The incidence of antibody response was lower in such patients than in their healthy counterparts (RR = 0.90, 95%CI: 0.87 to 0.94) ( ). 

Over 34 studies have reported on the incidence of seropositive IgG after vaccination and significant difference between patients who are immunocompromised and the healthy population (RR = 0.74, 95%CI: 0.69 to 0.80). Of the studies, four have reported producing detectable IgG titer level in both groups ( ). 

A total of 12 published studies have reported detectable seropositive NAb titer level when participants received SARS-CoV-2 vaccines, and the pooled incidence of NAb was significantly lower in the healthy group than in vaccinated patients (RR = 0.66, 95%CI: 0.57–0.77) ( ). 

This meta-analysis pooled 20 studies reporting various units of antibody titer post-vaccinations and seven articles reporting significant difference in antibody titer with units (U)/ml between patients who are immunocompromised (SMD= −11.23, 95%CI: −13.47 to −9.00) and the healthy group. Regarding antibody titer on arbitrary units (AU)/ml, only five studies have reported that antibody titer in patients who are immunocompromised was slightly lower than that in the healthy group (SMD= −1.39, 95%CI: −2.30 to −0.49). Similarly, the result of the antibody titer in BAU/ml was significantly different between the two groups (SMD= −4.71, 95%CI: −5.86 to −3.57) as reported by six studies. Moreover, other units of antibody titer post-vaccination also showed the same result such as AU/ml, that is, patients who are immunocompromised generated lower antibody titer than the healthy group (one study with mg/ml: SMD= −6.08, 95%CI: −6.78 to −5.38; one study with μg/ml: SMD= −8.12, 95%CI: −9.11 to −7.14; and one study did not indicate the unit: SMD= −0.40, 95%CI: −0.68 to −0.12). All results are presented in . 

Various units were used for IgG titer level testing post-vaccination, such as AU/ml, binding antibody units (BAU)/ml, U/ml, UA/ml, and optical density (OD). However, this meta-analysis identified significant differences between patients who are immunocompromised and the healthy group (pooled IgG titer: SMD= −0.92, 95%CI: −1.06 to −0.78). Many studies used AU/ml or BAU/ml as a unit of IgG titer level to measure the response to SARS-CoV-2 vaccines and presented similar results (15 studies with AU/ml: SMD= −0.64 95%CI: −0.84 to −0.43 and 12 studies with BAU/ml: SMD= −1.21, 95%CI: −1.45 to −0.98). Meanwhile, other units for IgG titer level were used by several studies. Four published articles using OD have reported slightly significant difference between patients who are immunocompromised and healthy group (SMD= −0.94 95%CI: −1.50 to −0.38) in . 

Overall, the pooled RR for NAb inhibitor titer following vaccination in 12 studies was −0.44 (95%CI: −0.63 to −0.25), which indicates that the healthy group responds to SARS-CoV-2 vaccines on a higher NAb inhibitor level than vaccinated patients. In addition, these indicators were analyzed further in vaccinated patients who are immunocompromised ( ). 

Only eight studies have reported on the incidence of breakthrough infection after vaccination, and no significant difference was observed between the two groups (RR = 1.71, 95%CI: 0.94–3.08) ( ). 

Subgroup analysis of diseases of patients who are immunocompromised The subgroup analyses involved up to 20 various immunocompromised diseases. In particular, patients with CVID, ARD, systemic lupus erythematosus (SLE), rheumatic disease (RD), rheumatoid arthritis (RA), spondyloarthritis, autoimmune conditions, and primary immunodeficiency (PID) demonstrated a slightly lower response rate than the healthy group. Significant differences in other diseases were not observed between the two groups. This may be attributable to patients with different diseases having considerably varying reactions in terms of effective and sufficient antibodies after receiving SARS-CoV-2 vaccines. Furthermore, more details of this subgroup analysis are presented in and . More patients in the seven disease groups had a comparable antibody response with healthy people. The lower seropositive IgG incidence was in those diagnosed with RD, ARD, CVID, IBD, IMID, multiple sclerosis (MS), psoriasis, and SLE (RR = 0.84, 0.89, 0.68, 0.71, 0.92, 0.82, 0.58 0.75, and 0.71, respectively). However, patients with ten diseases reported in 19 studies produced non-differential IgG against SARS-CoV-2. Regarding different units of measuring antibody or IgG titer level in the serum samples of participants, this meta-analysis conducted subgroup analysis by vital factor. Specifically, up to 20 disease types were analyzed, and patients had lower antibody titer level in their serum samples, but only in those patients with autoimmune hepatitis (AIH) for AU/ml, primary biliary cholangitis (PBC)/primary sclerosing cholangitis (PSC) for BAU/ml, and autoimmune rheumatic disease (AIRD) for OU, with SMDs of −0.15, −0.07, and −0.35, respectively. Subgroup analysis of patients receiving treatments The subgroup of patients who received anti-CD20 therapy was distinctively smaller than the healthy group, based on pooling two cohort studies on serological response post-vaccination (RR = 0.38, 95%CI: 0.15–0.92) and one study on antibody response (RR = 0.54, 95%CI: 0.40–0.74). Nevertheless, patients on rituximab therapy demonstrated a lower antibody response at 0.47 (95%CI: 0.36–0.59). For seropositive IgG concentrations, those patients who received immunomodulator (RR = 0.88, 95%CI: 0.78, 0.98), anti-CD20 therapy (RR = 0.46, 95%CI: 0.34, 0.62), methotrexate (RR = 0.56, 95%CI: 0.33, 0.95), and infliximab (RR = 0.69, 95%CI: 0.51, 0.93) failed to reach comparable IgG level with that of the healthy group. Patients administered adalimumab (RR = 0.64, 95%CI: 0.47, 0.87) and rituximab (RR = 0.32, 95%CI: 0.17, 0.58) reported decreased NAb incidence compared to those who received infliximab, ustekinumab, methotrexate, or vedolizumab. Many patients who are immunocompromised vaccinated against SARS-CoV-2 during continuous drug treatment had similar detectable serological antibody level with that of the healthy group, and more details of the subgroup analysis are presented in . For continuous data of SARS-CoV-2 antibody titer level, only patients with ustekinumab (SMD= −0.30 (U/ml, 95%CI: −0.88 to 0.27) did not have significantly reduced antibody titer level. However, patients receiving ocrelizumab (SMD= −2.00 AU/ml, 95%CI: −2.30 to −1.71), rituximab (SMD= −2.67 AU/ml, 95%CI: −2.92 to −2.43; SMD= −1.32 U/ml, 95%CI: −1.72 to −0.93), abatacept (SMD= −1.50 BAU/ml, 95%CI: −2.04 to −0.96; SMD= −1.78 U/ml, 95%CI: −2.29 to −1.27), methotrexate (SMD= −1.27 BAU/ml, 95%CI: −1.53 to −1.01; SMD= −1.74 U/ml, 95%CI: −2.24 to −1.24), and continued disease-modifying anti-rheumatic drug (DMARD) therapy (SMD= −0.45 U/ml, 95%CI: −0.70 to −0.20) were not significantly affected, thus suggesting that patients who are immunocompromised could not develop a similar antibody titer level with that of the healthy group. Thus, antibody titer level in patients who are immunocompromised differed depending on drug therapy administration at the time of vaccination ( ). IgG titer level have differences based on immunosuppressive drugs, which many of those illustrated decreased titer in patients who are immunocompromised compared to that in the healthy group. Specifically, IgG titer level were reduced in patients who are immunocompromised and received anti-TNF and methotrexate after the first and second vaccinations compared to the general and sufficient titer leves in the healthy population (SMD= −0.52 AU/ml, 95%CI: −0.83 to −0.22). Ozdede et al. have reported that the titer level of BioNTech or CoronaVac recipients was not significantly different between subgroups of patients on colchicine and the healthy group (SMD = 0.20 AU/ml, 95%CI: −0.16 to 0.56). In addition to combined treatment of anti-TNF and methotrexate, patients on twelve drugs demonstrated significant difference including csDMARDs therapy (SMD= −0.48 AU/ml, 95%CI: −0.71 to −0.26), TNF inhibitor monotherapy (SMD= −0.72 AU/ml, 95%CI: −0.85 to −0.59), adalimumab (SMD= −1.13 AU/ml, 95%CI: −1.71 to −0.55), anti-CD20 therapy (SMD= −0.84 AU/ml, 95%CI: −1.32 to −0.35), anti-CD21 therapy (SMD= −0.89 AU/ml, 95%CI: −1.71 to −0.07), anti-CD22 therapy (SMD= −1.38 AU/ml, 95%CI: −2.22 to −0.53), infliximab (SMD= −1.29 AU/ml, 95%CI: −1.81 to −0.76), methotrexate (SMD= −0.82 AU/ml, 95%CI: −1.03 to −0.61), methotrexate monotherapy (SMD= −0.71 AU/ml, 95%CI: −0.97 to −0.44), non-TNF-α (SMD= −0.25 AU/ml, 95%CI: −0.40 to −0.09), ocrelizumab (SMD= −3.25 AU/ml, 95%CI: −3.85 to −2.65), and ustekinumab (SMD= −0.57, 95%CI: −1.12 to −0.02), as well as those without treatment (SMD= −0.17, 95%CI: −0.29 to −0.04). However, data related to other therapies, such as immunomodulators (SMD = 0.15 AU/ml, 95%CI: −0.38 to 0.68), Janus kinase (JAK) inhibitor (SMD = 0.59 AU/ml, 95%CI: −0.42 to 1.59), prednisone monotherapy (SMD= −0.24 AU/ml, 95%CI: −0.64 to 0.16), and vedolizumab (SMD= −0.57 AU/ml, 95%CI: −1.19 to 0.04) showed nonsignificant differences between the two groups ( ). Other IgG titer results are described in BAU/ml with nine treatments for markedly significant differences between patients who are immunocompromised and the healthy group (bDMARDs/tsDMARDs: SMD= −0.67, 95%CI: −0.93 to −0.42; csDMARDs: SMD= −0.55, 95%CI: −1.09 to −0.02; fingolimod: SMD= −1.51, 95%CI: −1.79 to −1.23; infliximab: SMD= −0.54, 95%CI: −0.90 to −0.16; JAK inhibitor: SMD= −1.82, 95%CI: −2.33 to −1.32; ocrelizumab: SMD= −1.43, 95%CI: −1.69 to −1.18; rituximab: SMD= −2.33, 95%CI: −2.91 to −1.74; TNF inhibitor: SMD= −0.88, 95%CI: −1.15 to −0.60), but not for methotrexate (SMD= −0.58, 95%CI: −1.24 to 0.08) and no treatment (SMD= −0.25, 95%CI: −0.54 to 0.05). Other data on IgG titer level in the subgroup analysis by treatment is presented in . The provided data could provide clinical workers and populations knowledge on medical therapies associated with the effectiveness of SARS-CoV-2 vaccines, and help in clinical decision making ( ). Subgroup analysis of patients who are immunocompromised by SARS-CoV-2 vaccine dose The pooled serological response after the first (RR = 0.73, 95%CI: 0.67 to 0.79), second (RR = 0.92, 95%CI: 0.89 to 0.96), and third vaccine doses (RR = 0.50, 95%CI: 0.27 to 0.93) showed reduced prevalence in patients who are immunocompromised compared to the healthy group. In three studies, with a total of 285 patients who are immunocompromised and 153 immunocompetent people, antibody response detected by immunoassay were high among the healthy group (RR = 0.60, 95%CI: 0.49 to 0.73) following the first vaccine dose as well as in the second dose for 16 studies (RR = 0.93, 95%CI: 0.89 to 0.97), whereas only one study reported a high response after the third dose (RR = 0.85, 95%CI: 0.54 to 1.34). In addition, a subgroup analysis of the incidence of seropositive IgG was also conducted and presented very similar results with antibody response, for more data with various vaccine dose (1st dose for RR = 0.73, 95%CI: 0.66 to 0.79; 2nd dose for RR = 0.87, 95%CI: 0.83 to 0.90; and 3rd dose for RR = 0.84, 95%CI: 0.59 to 1.19). Data on the incidence of serological response, antibody response, and seropositive IgG are summarized in . Interestingly, this meta-analysis also evaluated effectiveness via collecting the incidence of NAb and found results consistent with other qualitative data, which represents immunocompetent people could develop sufficient antibodies against the SARS-CoV-2 virus, whereas patients who are immunocompromised could not. Patients had a breakthrough virus infection following the 2nd and 3rd vaccine doses during subsequent virus attacks, although this was not significantly different with healthy group, with RR of 1.28 and 0.94, respectively (fore, 95%CI: 0.99 to 1.66 and later, 95%CI: 0.70 to 1.26). Further subgroup analysis of quantitative data such as antibody and IgG titer level, with abundant data of various units by vaccine dose, demonstrated showed weak antibody titer after the 2nd (SMD= −1.14, 95%CI: −1.27 to −1.01) and 3rd vaccine doses (SMD= −2.84, 95%CI: −3.58 to −2.10) for AU/ml. For BAU/ml which was commonly used across studies, two studies with four data reported a significant difference in antibody titer level between patients who are immunocompromised and the healthy group (SMD= −0.64, 95%CI: −0.86 to −0.42). This finding is strongly supported by IgG titer level in BAU/ml, demonstrating that patients who are immunocompromised failed to develop similar titer level after immunization (1st dose, SMD= −1.46, 95%CI: −1.65 to −1.28 and 2nd dose, SMD= −0.80, 95%CI: −0.90 to −0.70). Studies using other units of measurement also indicated identical results (2nd dose, SMD= −0.72, 95%CI: −1.12 to −0.31 in relative units (RU)/ml; 1st dose, SMD= −0.83, 95%CI: −1.07 to −0.60 and 2nd dose, SMD= −1.14, 95%CI: −1.39 to −0.90 in UA/ml; 2nd dose, SMD= −1.14, 95%CI: −1.39 to −0.90 as U/ml). Only one study by Shenoy et al., with a total of 102 patients with AIRD and non-AIRD controls reported no marked difference between healthy participants and patients who are immunocompromised without describing the unit of measurement. Subgroup analysis of patients who are immunocompromised by SARS-CoV-2 vaccine type Four vaccine types were considered in this meta-analysis. A significant difference in seroconversion rate was not observed in those vaccinated with inactivated virus and adenoviral vector vaccines (RR = 0.93, 95%CI: 0.85 to 1.01). However, patients who are immunocompromised with homologous vaccine strategy (including adenoviral vector vaccine, inactivated virus vaccine, and mRNA vaccine) or combined strategy of mRNA and adenoviral vector vaccine were presented remarkable difference in serological response comparing with healthy participants (RR = 0.81, 95%CI: 0.70 to 0.94, RR = 0.71, 95%CI: 0.65 to 0.78, RR = 0.76, 95%CI: 0.68 to 0.86, and RR = 0.81, 95%CI: 0.72 to 0.92, respectively). The subgroup analysis by vaccine type in antibody response revealed that patients primed with a combined schedule of adenoviral vector vaccine and inactivated virus vaccine (RR = 1.01, 95%CI: 0.89 to 1.15) or homologous administration of the abovementioned two vaccines (adenoviral vector vaccine, RR = 0.75, 95%CI: 0.39 to 1.41; inactivated vaccine, RR = 0.95, 95%CI: 0.91 to 1.00) could generate nonsignificant response rate with the healthy group as the control. Inconsistent results were observed in the incidence of seropositive IgG for patients primed with mRNA and vector vaccines; no significant difference was observed between patients who are immunocompromised and the healthy group (RR = 0.78, 95%CI: 0.59 to 1.02). Moreover, no significant difference in three SARS-CoV-2 vaccines (adenoviral vector vaccine, RR = 0.89, 95%CI: 0.84 to 0.95; inactivated vaccine, RR = 0.70, 95%CI: 0.62 to 0.80; mRNA vaccine, RR = 0.72, 95%CI: 0.65 to 0.80) were observed. Regarding the incidence of seropositive NAb, significant differences in homologous inactivated vaccine or mRNA vaccines were observed between patients who are immunocompromised and the healthy group (RR = 0.79, 95%CI: 0.67 to 0.94; RR = 0.63, 95%CI: 0.54 to 0.74, respectively). Significant differences in IgG titer post-immunization for each unit including AU/ml (SMD for mRNA vaccine= −0.53, 95%CI: −0.62 to −0.44; SMD for inactivated virus vaccine= −1.96, 95%CI: −2.06 to −1.85, SMD for mRNA and adenoviral vector vaccines= −0.77, 95%CI: −0.86 to −0.67), UA/ml (SMD for inactivated virus vaccine= −0.98, 95%CI: −1.15 to −0.81), U/ml (SMD for mRNA vaccine= −1.20, 95%CI: −1.49 to −0.92), and RU/ml (SMD= −0.72, 95%CI: −1.12 to −0.31) were also observed. In addition, antibody titer level demonstrated distinct difference among unit of AU/ml. Specifically, vaccine strategies involving the use of mRNA vaccine also demonstrated statistically significant differences (SMD for single mRNA vaccine= −1.27, 95%CI: −2.12 to −0.43; SMD for mRNA and adenoviral vector vaccine= −2.67, 95%CI: −2.92 to −2.43), but not inactivated virus vaccine (SMD= −0.19, 95%CI: −1.18 to −0.80) for non-unit. Additionally, statistically significant differences in NAb inhibitor titer among inactivated virus vaccine and mRNA vaccine recipients were observed between groups (SMD= −0.29, 95%CI: −0.43 to −0.14 and SMD= −0.76, 95%CI: −1.25 to −0.28, respectively) ( ). This meta-analysis also further analyzed vaccine subtypes owing to vaccine brands potentially having different efficacies in people who are immunocompromised ( and ). Subgroup analysis of patients who are immunocompromised by SARS-CoV-2 vaccine subtype As several people worldwide received many vaccine brands that could be biased by confounders, subgroup analyses were performed. For serological response, a combined schedule of Pfizer, Moderna, and Janssen reported by Alexander et al. and Haider et al. showed nonsignificant difference between patients who are immunocompromised and the healthy group (RR = 0.96, 95%CI: 0.86 to 1.08), strategy of BBV152 and AstraZeneca by Shenoy et al. (RR = 0.96, 95%CI: 0.72 to 1.28) and vector-based vaccine by Bsteh et al.: RR = 0.89, 95%CI: 0.67 to 1.19) as well. Meanwhile, most vaccine schedules presented a significantly more favorable seroconversion rate after SARS-CoV-2 vaccination in the healthy population than in patients who are immunocompromised (strategy of Pfizer, Moderna, AstraZeneca, and Janssen: RR = 0.87, 95%CI: 0.82 to 0.93; strategy of Pfizer and Moderna: RR = 0.91, 95%CI 0.85 to 0.98; and single Sinovac-CoronaVac: RR = 0.80, 95%CI: 0.74 to 0.87). A vaccine schedule of Pfizer and Moderna and homologous Pfizer vaccine demonstrated significant difference in antibody response as reported in six studies (RR = 0.61, 95%CI: 0.38 to 0.96). Nevertheless, the homologous vaccine strategy of AstraZeneca (RR = 0.75, 95%CI: 0.39 to 1.41) and mixed vaccine schedules of Pfizer, Moderna, AstraZeneca, and Janssen (RR = 0.93, 95%CI: 0.82 to 1.05); BBV152 and AstraZeneca (RR = 1.01, 95%CI: 0.89 to 1.15); and Pfizer, Moderna, AstraZeneca (RR = 0.60, 95%CI: 0.16 to 2.26) showed no significant difference in antibody response between the two groups. A total of 19 studies provided data on only Pfizer and significant difference in the incidence of seropositive IgG were observed between patients who are immunocompromised and the healthy group (RR = 0.72, 95%CI: 0.65 to 0.80). A similar difference in the vaccine schedule primed with Sinovac-CoronaVac for detectable IgG antibody level by pooling the results of nine studies (RR = 0.70, 95%CI: 0.62 to 0.80). The mixed strategy involving two vaccines, namely Pfizer and Moderna (RR = 0.88, 95%CI: 0.68 to 1.14), Pfizer and AstraZeneca (RR = 0.76, 95%CI: 0.53 to 1.08), and Pfizer, Moderna, AstraZeneca, and Janssen (RR = 0.80, 95%CI: 0.49 to 1.30) yielded varying incidence rates for seropositive neutralizing antibodies (NAb). Only the Sinovac-CoronaVac vaccine demonstrated a significant difference (RR = 0.73, 95%CI: 0.67 to 0.79), compared to Pfizer (RR = 0.92, 95%CI: 0.78 to 1.09) and the mixed strategy of Pfizer and Moderna (RR = 0.80, 95%CI: 0.61 to 1.05). For breakthrough SARS-CoV-2 infections, no significant difference in each vaccine subtype (mixed strategy of Pfizer, Moderna, AstraZeneca, and Janssen: RR = 0.97, 95%CI: 0.72 to 1.30; combined strategy of Pfizer and Moderna: RR = 1.30, 95%CI: 0.83 to 2.03; and Pfizer: RR = 1.26 95%CI: 0.91 to 1.73 and Sinovac-CoronaVac vaccine: RR = 1.96, 95%CI: 0.28 to 13.54) was observed between the two groups. The antibody titer and IgG titer level were lower in patients who are immunocompromised than in the healthy group, with the majority of vaccine strategies demonstrating significant differences, except antibody titer level for those who received Pfizer and Moderna by AU/ml (SMD= −0.19, 95%CI: −0.78 to 0.39), mRNA vaccine by AU/ml (SMD= −0.02, 95%CI: −0.31 to 0.26), BBV152 (SMD= −0.19, 95%CI: −1.18 to 0.80), and AstraZeneca by U/ml (SMD= −0.30, 95%CI: −1.07 to 0.46). Detailed results of the subgroup analysis are presented in and . NAb inhibitor titer level by vaccine subtype were analyzed in detail, and the results indicated no statistically significant difference between Pfizer recipients with autoimmune diseases and the healthy group (SMD= −0.36, 95%CI: −0.72 to 0.01). Nevertheless, only one study has reported that the BBV152 vaccine significantly reduces NAb inhibitor titer level in patients with autoimmune diseases (SMD= −0.78, 95%CI: −1.15 to −0.40), whereas several studies have reported the same result for Sinovac-CoronaVac and mixed schedule of Pfizer (SMD= −0.25, 95%CI: −0.40 to −0.11) and Moderna (SMD= −1.34 95%CI: −2.62 to −0.06) ( ). Subgroup analysis of patients who are immunocompromised by history of SARS-CoV-2 infection Because many studies have not reported on the history of SARS-CoV-2 infection, the present study collected and analyzed existing data and noted that patients with a history of viral infection had lower response rates of seroconversion (RR = 0.79, 95%CI: 0.70 to 0.89) and antibody response (RR = 0.62, 95%CI: 0.47 to 0.84) following vaccination than those without a viral infection history. However, history of previous infection in terms of incidence of seropositive IgG (RR = 0.87, 95%CI: 0.76 to 1.00) and NAb (RR= 0.91, 95%CI: 0.75, 1.09) was not significantly different between the two groups. Statistically significant differences in serological response (RR = 0.82, 95%CI: 0.75 to 0.90), incidence of seropositive IgG (RR = 0.71, 95%CI: 0.63 to 0.80), and seropositive NAb (RR = 0.68, 95%CI: 0.57 to 0.81) were observed in patients who are immunocompromised without a history of infection. The rest of the results on unknown previous history of SARS-CoV-2 infection with significant differences involved dichotomous data (the incidence of serological response, antibody response, seropositive IgG, and Nab). The subgroup analysis results are summarized in . Several studies have not described whether the participants recruited in their cohort had prior history of SARS-CoV-2 infection, who were classified as the unknown subgroup based on various units of measurement relating to antibody titer level. The findings associated with subgroup of unknown prior medical history showed significant differences in any unit of IgG titer between the two groups (SMD= −0.69 AU/ml, 95%CI: −0.79 to −0.59; pooling seven studies for SMD= −0.95 BAU/ml, 95%CI: −1.07 to −0.84; one study for SMD= −1.82 OD, 95%CI: −2.63 to −1.02, SMD= −0.82U/ml, 95%CI: −1.21 to −0.43, and SMD= −0.72 RU/ml, 95%CI: −1.12 to −0.31). Additionally, the results from IgG titer with or without medical information history on previous SARS-CoV-2 infection demonstrated significant difference and concordantly favored the healthy group among all units in the included studies (with history of SARS-CoV-2 infection: SMD= −0.68 AU/ml, 95%CI: −0.77 to −0.60; SMD= −0.44 BAU/ml, 95%CI: −0.72 to −0.15; SMD = 0.84 OD, 95%CI: −1.06 to −0.62; SMD= −1.62 U/ml 95%CI: −2.03 to −1.21; without history of SARS-CoV-2 infection: SMD= −1.88 AU/ml, 95%CI: −1.99 to −1.77; SMD= −1.10 BAU/ml, 95%CI: −1.26 to −0.94; SMD= −1.03 OD, 95%CI: −1.36 to −0.70; SMD= −0.98 UA/ml, 95%CI: −1.15 to −0.81). Considering antibody titer level, which differed across situations that participants had during the research period, history of SARS-CoV-2 infection was not significantly different between patients who are immunocompromised and the healthy group (SMD = 0.11 AU/ml, 95%CI: −were classified as the unknown subgroup based on various units of he remaining groups related to antibody titer regardless of history of infection ( ). Further analysis of NAb inhibitor titer level reported by Signorelli et al. with first and second doses, presented nonsignificant difference in patients with a history of SARS-CoV-2 infection (SMD= −0.02, 95%CI: −0.31 to 0.26), whereas reduced NAb inhibitor titer was observed in patients who are immunocompromised without a history of SARS-CoV-2 infection (SMD= −0.31 95%CI: −0.39 to −0.22) and those with unknown medical coronavirus infections (SMD= −0.42, 95%CI: −0.71 to −0.12) ( ). Subgroup analysis of patients who are immunocompromised by SARS-CoV-2 variant of concern Variants of concerns were considered into this meta-analysis. Few studies have reported the Delta (B.1.617.2) and B.1.1.7 variants as critical factors triggering vaccine immunogenicity against the SARS-CoV-2 virus. Nonetheless, a significantly remarkable difference was observed in any condition of variants of concern and even in those of unknown periods. Thus, reduced effectiveness was observed against the Delta and B.1.1.7 variants in patients who are immunocompromised compared to that in the healthy group ( and ). Patients who are immunocompromised and received SARS-CoV-2 vaccines against the Delta (B.1.617.2) variant had significantly lower IgG titer (SMD= −1.02 AU/ml, 95%CI: −1.18 to −0.86) and antibody titer level than the healthy group (SMD= −2.67, 95%CI: −2.92 to −2.43). Subgroup analysis of patients who are immunocompromised by SARS-CoV-2 immunoassay Immunoassay after immunization was analyzed using various assays, such as enzyme-linked immunosorbent assay (ELISA) and indirect chemiluminescence immunoassay (CLIA), that laboratory diagnosis to SARS-CoV-2 infection, might have influence on detective seropositive antibody rate. Hence, this subgroup analysis of serological response illustrated that most studies used immunoassays or kits were ELISA (RR = 0.86, 95%CI: 0.79 to 0.94) or CLIA (RR = 0.89, 95%CI: 0.84 to 0.95), and showed significant differences between the two groups, except for the combined ELISA and CLIA method (RR = 0.99, 95%CI: 0.86 to 1.14). Beck Coulter by Haider et al. also revealed nonsignificant difference for seroconversion rate between patients who are immunocompromised and the healthy group (RR = 0.92, 95%CI: 0.79 to 1.07). Using electrochemiluminescence immunoassay analyzer (ECLIA) or CLIA as measure tool for detecting antibody response in their bodies showed a significant difference between patients who are immunocompromised and the healthy group (RR = 0.83 95%CI: 0.74 to 0.93, RR = 0.83 95%CI: 0.74 to 0.93, respectively). The study by Verstappen et al. adopted indirect CLIA and luminescent immunoassay microparticles (MIA) analyzed involved patients for antibody response illustrated statistical difference between two groups (RR = 1.00, 95%CI: 0.74 to 1.34). Immunoassay tools including ELISA, CLIA, and chemiluminescent immunoassay microparticles (CMIA) used to detect seropositive IgG against coronavirus demonstrated significant differences between the two groups (RR = 0.73, 95%CI: 0.64 to 0.83; RR = 0.69, 95%CI: 0.61 to 0.78; RR = 0.82, 95%CI: 0.65 to 1.03, respectively), except for ECLIA in four studies (RR = 0.92, 95%CI: 0.86 to 0.99). NAb incidence was significantly different with ELISA (RR = 0.70, 95%CI: 0.60 to 0.82) and CLIA (RR = 0.32, 95%CI: 0.17, 0.60) tools between patients who are immunocompromised and the healthy group. Many studies adopting the CLIA method for measuring antibody titer post-vaccination showed significant differences on various units (AU/ml: SMD= −2.26, 95%CI: −2.43 to −2.08; BAU/ml: SMD= −1.63, 95%CI: −1.78 to −1.47; U/ml: SMD= −0.45, 95%CI: −0.70 to −0.20). The inconsistent results in antibody titer were revealed using ELICA for different units. In particular, no statistically significant difference was observed when using the unit BAU/ml (SMD= −0.02, 95%CI: −0.31 to 0.26), compared to ELICA in U/ml (SMD= −1.06, 95%CI: −1.25 to −0.86) and mg/ml (SMD= −6.08, 95%CI: −6.78 to −5.38) between the two groups. Only one study by Duengelhoef et al. published in 2020 reported contradictory results when using the mixed method of two units of measurement, demonstrating significant differences in BAU/ml (SMD= −7.36, 95%CI: −13.13 to −1.59) and nonsignificant difference in AU/ml (SMD = 0.11, 95%CI: −0.09 to 0.30). Ten studies used the CLIA tool to detect IgG titer, and showed favorable result between the two groups (SMD= −1.07 AU/ml, 95%CI: −1.89 to −0.24). Two studies with eight available data used the CLIA and ELISA tools throughout the first and second vaccine doses in patients on TNF treatment (SMD= −0.65 AU/ml, 95%CI: −1.25 to −0.05). The ECLIA method was used for participants who received CoronaVac or BioNTech vaccines, and nonsignificant difference was noted between the two groups (SMD= −0.13 AU/ml, 95%CI: −0.35 to 0.09). However, some studies used ELISA for IgG titer, not ECLIA, thus yielding a significant difference between the two groups (SMD= −0.78 AU/ml, 95%CI: −1.03 to −0.54). In addition, serval immunoassays used BAU/ml to detect IgG titer following vaccines which presented significant difference (CLIA in seven studies: SMD= −1.29, 95%CI: −1.65 to −0.93; ELISA in two studies: SMD= −0.54 95%CI: −0.84 to −0.24) ( and ) . Two studies utilized the ECLIA tool for IgG titer with the U/ml (SMD= −1.27, 95%CI: −1.55 to −0.98) and CLIA for UA/ml (SMD= −0.99, 95%CI: −1.29 to −0.68), with both reporting significant differences between the two groups. Furthermore, almost all of studies adopted the ELSA method to detect NAb inhibitor titer against SARS-CoV-2 virus post-immunization, which presented statistically significant difference between the two groups in a pooled result of SMD −0.40 with 95%CI of −0.57 to −0.23 ( ). 

The subgroup analyses involved up to 20 various immunocompromised diseases. In particular, patients with CVID, ARD, systemic lupus erythematosus (SLE), rheumatic disease (RD), rheumatoid arthritis (RA), spondyloarthritis, autoimmune conditions, and primary immunodeficiency (PID) demonstrated a slightly lower response rate than the healthy group. Significant differences in other diseases were not observed between the two groups. This may be attributable to patients with different diseases having considerably varying reactions in terms of effective and sufficient antibodies after receiving SARS-CoV-2 vaccines. Furthermore, more details of this subgroup analysis are presented in and . More patients in the seven disease groups had a comparable antibody response with healthy people. The lower seropositive IgG incidence was in those diagnosed with RD, ARD, CVID, IBD, IMID, multiple sclerosis (MS), psoriasis, and SLE (RR = 0.84, 0.89, 0.68, 0.71, 0.92, 0.82, 0.58 0.75, and 0.71, respectively). However, patients with ten diseases reported in 19 studies produced non-differential IgG against SARS-CoV-2. Regarding different units of measuring antibody or IgG titer level in the serum samples of participants, this meta-analysis conducted subgroup analysis by vital factor. Specifically, up to 20 disease types were analyzed, and patients had lower antibody titer level in their serum samples, but only in those patients with autoimmune hepatitis (AIH) for AU/ml, primary biliary cholangitis (PBC)/primary sclerosing cholangitis (PSC) for BAU/ml, and autoimmune rheumatic disease (AIRD) for OU, with SMDs of −0.15, −0.07, and −0.35, respectively. 

The subgroup of patients who received anti-CD20 therapy was distinctively smaller than the healthy group, based on pooling two cohort studies on serological response post-vaccination (RR = 0.38, 95%CI: 0.15–0.92) and one study on antibody response (RR = 0.54, 95%CI: 0.40–0.74). Nevertheless, patients on rituximab therapy demonstrated a lower antibody response at 0.47 (95%CI: 0.36–0.59). For seropositive IgG concentrations, those patients who received immunomodulator (RR = 0.88, 95%CI: 0.78, 0.98), anti-CD20 therapy (RR = 0.46, 95%CI: 0.34, 0.62), methotrexate (RR = 0.56, 95%CI: 0.33, 0.95), and infliximab (RR = 0.69, 95%CI: 0.51, 0.93) failed to reach comparable IgG level with that of the healthy group. Patients administered adalimumab (RR = 0.64, 95%CI: 0.47, 0.87) and rituximab (RR = 0.32, 95%CI: 0.17, 0.58) reported decreased NAb incidence compared to those who received infliximab, ustekinumab, methotrexate, or vedolizumab. Many patients who are immunocompromised vaccinated against SARS-CoV-2 during continuous drug treatment had similar detectable serological antibody level with that of the healthy group, and more details of the subgroup analysis are presented in . For continuous data of SARS-CoV-2 antibody titer level, only patients with ustekinumab (SMD= −0.30 (U/ml, 95%CI: −0.88 to 0.27) did not have significantly reduced antibody titer level. However, patients receiving ocrelizumab (SMD= −2.00 AU/ml, 95%CI: −2.30 to −1.71), rituximab (SMD= −2.67 AU/ml, 95%CI: −2.92 to −2.43; SMD= −1.32 U/ml, 95%CI: −1.72 to −0.93), abatacept (SMD= −1.50 BAU/ml, 95%CI: −2.04 to −0.96; SMD= −1.78 U/ml, 95%CI: −2.29 to −1.27), methotrexate (SMD= −1.27 BAU/ml, 95%CI: −1.53 to −1.01; SMD= −1.74 U/ml, 95%CI: −2.24 to −1.24), and continued disease-modifying anti-rheumatic drug (DMARD) therapy (SMD= −0.45 U/ml, 95%CI: −0.70 to −0.20) were not significantly affected, thus suggesting that patients who are immunocompromised could not develop a similar antibody titer level with that of the healthy group. Thus, antibody titer level in patients who are immunocompromised differed depending on drug therapy administration at the time of vaccination ( ). IgG titer level have differences based on immunosuppressive drugs, which many of those illustrated decreased titer in patients who are immunocompromised compared to that in the healthy group. Specifically, IgG titer level were reduced in patients who are immunocompromised and received anti-TNF and methotrexate after the first and second vaccinations compared to the general and sufficient titer leves in the healthy population (SMD= −0.52 AU/ml, 95%CI: −0.83 to −0.22). Ozdede et al. have reported that the titer level of BioNTech or CoronaVac recipients was not significantly different between subgroups of patients on colchicine and the healthy group (SMD = 0.20 AU/ml, 95%CI: −0.16 to 0.56). In addition to combined treatment of anti-TNF and methotrexate, patients on twelve drugs demonstrated significant difference including csDMARDs therapy (SMD= −0.48 AU/ml, 95%CI: −0.71 to −0.26), TNF inhibitor monotherapy (SMD= −0.72 AU/ml, 95%CI: −0.85 to −0.59), adalimumab (SMD= −1.13 AU/ml, 95%CI: −1.71 to −0.55), anti-CD20 therapy (SMD= −0.84 AU/ml, 95%CI: −1.32 to −0.35), anti-CD21 therapy (SMD= −0.89 AU/ml, 95%CI: −1.71 to −0.07), anti-CD22 therapy (SMD= −1.38 AU/ml, 95%CI: −2.22 to −0.53), infliximab (SMD= −1.29 AU/ml, 95%CI: −1.81 to −0.76), methotrexate (SMD= −0.82 AU/ml, 95%CI: −1.03 to −0.61), methotrexate monotherapy (SMD= −0.71 AU/ml, 95%CI: −0.97 to −0.44), non-TNF-α (SMD= −0.25 AU/ml, 95%CI: −0.40 to −0.09), ocrelizumab (SMD= −3.25 AU/ml, 95%CI: −3.85 to −2.65), and ustekinumab (SMD= −0.57, 95%CI: −1.12 to −0.02), as well as those without treatment (SMD= −0.17, 95%CI: −0.29 to −0.04). However, data related to other therapies, such as immunomodulators (SMD = 0.15 AU/ml, 95%CI: −0.38 to 0.68), Janus kinase (JAK) inhibitor (SMD = 0.59 AU/ml, 95%CI: −0.42 to 1.59), prednisone monotherapy (SMD= −0.24 AU/ml, 95%CI: −0.64 to 0.16), and vedolizumab (SMD= −0.57 AU/ml, 95%CI: −1.19 to 0.04) showed nonsignificant differences between the two groups ( ). Other IgG titer results are described in BAU/ml with nine treatments for markedly significant differences between patients who are immunocompromised and the healthy group (bDMARDs/tsDMARDs: SMD= −0.67, 95%CI: −0.93 to −0.42; csDMARDs: SMD= −0.55, 95%CI: −1.09 to −0.02; fingolimod: SMD= −1.51, 95%CI: −1.79 to −1.23; infliximab: SMD= −0.54, 95%CI: −0.90 to −0.16; JAK inhibitor: SMD= −1.82, 95%CI: −2.33 to −1.32; ocrelizumab: SMD= −1.43, 95%CI: −1.69 to −1.18; rituximab: SMD= −2.33, 95%CI: −2.91 to −1.74; TNF inhibitor: SMD= −0.88, 95%CI: −1.15 to −0.60), but not for methotrexate (SMD= −0.58, 95%CI: −1.24 to 0.08) and no treatment (SMD= −0.25, 95%CI: −0.54 to 0.05). Other data on IgG titer level in the subgroup analysis by treatment is presented in . The provided data could provide clinical workers and populations knowledge on medical therapies associated with the effectiveness of SARS-CoV-2 vaccines, and help in clinical decision making ( ). 

The pooled serological response after the first (RR = 0.73, 95%CI: 0.67 to 0.79), second (RR = 0.92, 95%CI: 0.89 to 0.96), and third vaccine doses (RR = 0.50, 95%CI: 0.27 to 0.93) showed reduced prevalence in patients who are immunocompromised compared to the healthy group. In three studies, with a total of 285 patients who are immunocompromised and 153 immunocompetent people, antibody response detected by immunoassay were high among the healthy group (RR = 0.60, 95%CI: 0.49 to 0.73) following the first vaccine dose as well as in the second dose for 16 studies (RR = 0.93, 95%CI: 0.89 to 0.97), whereas only one study reported a high response after the third dose (RR = 0.85, 95%CI: 0.54 to 1.34). In addition, a subgroup analysis of the incidence of seropositive IgG was also conducted and presented very similar results with antibody response, for more data with various vaccine dose (1st dose for RR = 0.73, 95%CI: 0.66 to 0.79; 2nd dose for RR = 0.87, 95%CI: 0.83 to 0.90; and 3rd dose for RR = 0.84, 95%CI: 0.59 to 1.19). Data on the incidence of serological response, antibody response, and seropositive IgG are summarized in . Interestingly, this meta-analysis also evaluated effectiveness via collecting the incidence of NAb and found results consistent with other qualitative data, which represents immunocompetent people could develop sufficient antibodies against the SARS-CoV-2 virus, whereas patients who are immunocompromised could not. Patients had a breakthrough virus infection following the 2nd and 3rd vaccine doses during subsequent virus attacks, although this was not significantly different with healthy group, with RR of 1.28 and 0.94, respectively (fore, 95%CI: 0.99 to 1.66 and later, 95%CI: 0.70 to 1.26). Further subgroup analysis of quantitative data such as antibody and IgG titer level, with abundant data of various units by vaccine dose, demonstrated showed weak antibody titer after the 2nd (SMD= −1.14, 95%CI: −1.27 to −1.01) and 3rd vaccine doses (SMD= −2.84, 95%CI: −3.58 to −2.10) for AU/ml. For BAU/ml which was commonly used across studies, two studies with four data reported a significant difference in antibody titer level between patients who are immunocompromised and the healthy group (SMD= −0.64, 95%CI: −0.86 to −0.42). This finding is strongly supported by IgG titer level in BAU/ml, demonstrating that patients who are immunocompromised failed to develop similar titer level after immunization (1st dose, SMD= −1.46, 95%CI: −1.65 to −1.28 and 2nd dose, SMD= −0.80, 95%CI: −0.90 to −0.70). Studies using other units of measurement also indicated identical results (2nd dose, SMD= −0.72, 95%CI: −1.12 to −0.31 in relative units (RU)/ml; 1st dose, SMD= −0.83, 95%CI: −1.07 to −0.60 and 2nd dose, SMD= −1.14, 95%CI: −1.39 to −0.90 in UA/ml; 2nd dose, SMD= −1.14, 95%CI: −1.39 to −0.90 as U/ml). Only one study by Shenoy et al., with a total of 102 patients with AIRD and non-AIRD controls reported no marked difference between healthy participants and patients who are immunocompromised without describing the unit of measurement. 

Four vaccine types were considered in this meta-analysis. A significant difference in seroconversion rate was not observed in those vaccinated with inactivated virus and adenoviral vector vaccines (RR = 0.93, 95%CI: 0.85 to 1.01). However, patients who are immunocompromised with homologous vaccine strategy (including adenoviral vector vaccine, inactivated virus vaccine, and mRNA vaccine) or combined strategy of mRNA and adenoviral vector vaccine were presented remarkable difference in serological response comparing with healthy participants (RR = 0.81, 95%CI: 0.70 to 0.94, RR = 0.71, 95%CI: 0.65 to 0.78, RR = 0.76, 95%CI: 0.68 to 0.86, and RR = 0.81, 95%CI: 0.72 to 0.92, respectively). The subgroup analysis by vaccine type in antibody response revealed that patients primed with a combined schedule of adenoviral vector vaccine and inactivated virus vaccine (RR = 1.01, 95%CI: 0.89 to 1.15) or homologous administration of the abovementioned two vaccines (adenoviral vector vaccine, RR = 0.75, 95%CI: 0.39 to 1.41; inactivated vaccine, RR = 0.95, 95%CI: 0.91 to 1.00) could generate nonsignificant response rate with the healthy group as the control. Inconsistent results were observed in the incidence of seropositive IgG for patients primed with mRNA and vector vaccines; no significant difference was observed between patients who are immunocompromised and the healthy group (RR = 0.78, 95%CI: 0.59 to 1.02). Moreover, no significant difference in three SARS-CoV-2 vaccines (adenoviral vector vaccine, RR = 0.89, 95%CI: 0.84 to 0.95; inactivated vaccine, RR = 0.70, 95%CI: 0.62 to 0.80; mRNA vaccine, RR = 0.72, 95%CI: 0.65 to 0.80) were observed. Regarding the incidence of seropositive NAb, significant differences in homologous inactivated vaccine or mRNA vaccines were observed between patients who are immunocompromised and the healthy group (RR = 0.79, 95%CI: 0.67 to 0.94; RR = 0.63, 95%CI: 0.54 to 0.74, respectively). Significant differences in IgG titer post-immunization for each unit including AU/ml (SMD for mRNA vaccine= −0.53, 95%CI: −0.62 to −0.44; SMD for inactivated virus vaccine= −1.96, 95%CI: −2.06 to −1.85, SMD for mRNA and adenoviral vector vaccines= −0.77, 95%CI: −0.86 to −0.67), UA/ml (SMD for inactivated virus vaccine= −0.98, 95%CI: −1.15 to −0.81), U/ml (SMD for mRNA vaccine= −1.20, 95%CI: −1.49 to −0.92), and RU/ml (SMD= −0.72, 95%CI: −1.12 to −0.31) were also observed. In addition, antibody titer level demonstrated distinct difference among unit of AU/ml. Specifically, vaccine strategies involving the use of mRNA vaccine also demonstrated statistically significant differences (SMD for single mRNA vaccine= −1.27, 95%CI: −2.12 to −0.43; SMD for mRNA and adenoviral vector vaccine= −2.67, 95%CI: −2.92 to −2.43), but not inactivated virus vaccine (SMD= −0.19, 95%CI: −1.18 to −0.80) for non-unit. Additionally, statistically significant differences in NAb inhibitor titer among inactivated virus vaccine and mRNA vaccine recipients were observed between groups (SMD= −0.29, 95%CI: −0.43 to −0.14 and SMD= −0.76, 95%CI: −1.25 to −0.28, respectively) ( ). This meta-analysis also further analyzed vaccine subtypes owing to vaccine brands potentially having different efficacies in people who are immunocompromised ( and ). 

As several people worldwide received many vaccine brands that could be biased by confounders, subgroup analyses were performed. For serological response, a combined schedule of Pfizer, Moderna, and Janssen reported by Alexander et al. and Haider et al. showed nonsignificant difference between patients who are immunocompromised and the healthy group (RR = 0.96, 95%CI: 0.86 to 1.08), strategy of BBV152 and AstraZeneca by Shenoy et al. (RR = 0.96, 95%CI: 0.72 to 1.28) and vector-based vaccine by Bsteh et al.: RR = 0.89, 95%CI: 0.67 to 1.19) as well. Meanwhile, most vaccine schedules presented a significantly more favorable seroconversion rate after SARS-CoV-2 vaccination in the healthy population than in patients who are immunocompromised (strategy of Pfizer, Moderna, AstraZeneca, and Janssen: RR = 0.87, 95%CI: 0.82 to 0.93; strategy of Pfizer and Moderna: RR = 0.91, 95%CI 0.85 to 0.98; and single Sinovac-CoronaVac: RR = 0.80, 95%CI: 0.74 to 0.87). A vaccine schedule of Pfizer and Moderna and homologous Pfizer vaccine demonstrated significant difference in antibody response as reported in six studies (RR = 0.61, 95%CI: 0.38 to 0.96). Nevertheless, the homologous vaccine strategy of AstraZeneca (RR = 0.75, 95%CI: 0.39 to 1.41) and mixed vaccine schedules of Pfizer, Moderna, AstraZeneca, and Janssen (RR = 0.93, 95%CI: 0.82 to 1.05); BBV152 and AstraZeneca (RR = 1.01, 95%CI: 0.89 to 1.15); and Pfizer, Moderna, AstraZeneca (RR = 0.60, 95%CI: 0.16 to 2.26) showed no significant difference in antibody response between the two groups. A total of 19 studies provided data on only Pfizer and significant difference in the incidence of seropositive IgG were observed between patients who are immunocompromised and the healthy group (RR = 0.72, 95%CI: 0.65 to 0.80). A similar difference in the vaccine schedule primed with Sinovac-CoronaVac for detectable IgG antibody level by pooling the results of nine studies (RR = 0.70, 95%CI: 0.62 to 0.80). The mixed strategy involving two vaccines, namely Pfizer and Moderna (RR = 0.88, 95%CI: 0.68 to 1.14), Pfizer and AstraZeneca (RR = 0.76, 95%CI: 0.53 to 1.08), and Pfizer, Moderna, AstraZeneca, and Janssen (RR = 0.80, 95%CI: 0.49 to 1.30) yielded varying incidence rates for seropositive neutralizing antibodies (NAb). Only the Sinovac-CoronaVac vaccine demonstrated a significant difference (RR = 0.73, 95%CI: 0.67 to 0.79), compared to Pfizer (RR = 0.92, 95%CI: 0.78 to 1.09) and the mixed strategy of Pfizer and Moderna (RR = 0.80, 95%CI: 0.61 to 1.05). For breakthrough SARS-CoV-2 infections, no significant difference in each vaccine subtype (mixed strategy of Pfizer, Moderna, AstraZeneca, and Janssen: RR = 0.97, 95%CI: 0.72 to 1.30; combined strategy of Pfizer and Moderna: RR = 1.30, 95%CI: 0.83 to 2.03; and Pfizer: RR = 1.26 95%CI: 0.91 to 1.73 and Sinovac-CoronaVac vaccine: RR = 1.96, 95%CI: 0.28 to 13.54) was observed between the two groups. The antibody titer and IgG titer level were lower in patients who are immunocompromised than in the healthy group, with the majority of vaccine strategies demonstrating significant differences, except antibody titer level for those who received Pfizer and Moderna by AU/ml (SMD= −0.19, 95%CI: −0.78 to 0.39), mRNA vaccine by AU/ml (SMD= −0.02, 95%CI: −0.31 to 0.26), BBV152 (SMD= −0.19, 95%CI: −1.18 to 0.80), and AstraZeneca by U/ml (SMD= −0.30, 95%CI: −1.07 to 0.46). Detailed results of the subgroup analysis are presented in and . NAb inhibitor titer level by vaccine subtype were analyzed in detail, and the results indicated no statistically significant difference between Pfizer recipients with autoimmune diseases and the healthy group (SMD= −0.36, 95%CI: −0.72 to 0.01). Nevertheless, only one study has reported that the BBV152 vaccine significantly reduces NAb inhibitor titer level in patients with autoimmune diseases (SMD= −0.78, 95%CI: −1.15 to −0.40), whereas several studies have reported the same result for Sinovac-CoronaVac and mixed schedule of Pfizer (SMD= −0.25, 95%CI: −0.40 to −0.11) and Moderna (SMD= −1.34 95%CI: −2.62 to −0.06) ( ). 

Because many studies have not reported on the history of SARS-CoV-2 infection, the present study collected and analyzed existing data and noted that patients with a history of viral infection had lower response rates of seroconversion (RR = 0.79, 95%CI: 0.70 to 0.89) and antibody response (RR = 0.62, 95%CI: 0.47 to 0.84) following vaccination than those without a viral infection history. However, history of previous infection in terms of incidence of seropositive IgG (RR = 0.87, 95%CI: 0.76 to 1.00) and NAb (RR= 0.91, 95%CI: 0.75, 1.09) was not significantly different between the two groups. Statistically significant differences in serological response (RR = 0.82, 95%CI: 0.75 to 0.90), incidence of seropositive IgG (RR = 0.71, 95%CI: 0.63 to 0.80), and seropositive NAb (RR = 0.68, 95%CI: 0.57 to 0.81) were observed in patients who are immunocompromised without a history of infection. The rest of the results on unknown previous history of SARS-CoV-2 infection with significant differences involved dichotomous data (the incidence of serological response, antibody response, seropositive IgG, and Nab). The subgroup analysis results are summarized in . Several studies have not described whether the participants recruited in their cohort had prior history of SARS-CoV-2 infection, who were classified as the unknown subgroup based on various units of measurement relating to antibody titer level. The findings associated with subgroup of unknown prior medical history showed significant differences in any unit of IgG titer between the two groups (SMD= −0.69 AU/ml, 95%CI: −0.79 to −0.59; pooling seven studies for SMD= −0.95 BAU/ml, 95%CI: −1.07 to −0.84; one study for SMD= −1.82 OD, 95%CI: −2.63 to −1.02, SMD= −0.82U/ml, 95%CI: −1.21 to −0.43, and SMD= −0.72 RU/ml, 95%CI: −1.12 to −0.31). Additionally, the results from IgG titer with or without medical information history on previous SARS-CoV-2 infection demonstrated significant difference and concordantly favored the healthy group among all units in the included studies (with history of SARS-CoV-2 infection: SMD= −0.68 AU/ml, 95%CI: −0.77 to −0.60; SMD= −0.44 BAU/ml, 95%CI: −0.72 to −0.15; SMD = 0.84 OD, 95%CI: −1.06 to −0.62; SMD= −1.62 U/ml 95%CI: −2.03 to −1.21; without history of SARS-CoV-2 infection: SMD= −1.88 AU/ml, 95%CI: −1.99 to −1.77; SMD= −1.10 BAU/ml, 95%CI: −1.26 to −0.94; SMD= −1.03 OD, 95%CI: −1.36 to −0.70; SMD= −0.98 UA/ml, 95%CI: −1.15 to −0.81). Considering antibody titer level, which differed across situations that participants had during the research period, history of SARS-CoV-2 infection was not significantly different between patients who are immunocompromised and the healthy group (SMD = 0.11 AU/ml, 95%CI: −were classified as the unknown subgroup based on various units of he remaining groups related to antibody titer regardless of history of infection ( ). Further analysis of NAb inhibitor titer level reported by Signorelli et al. with first and second doses, presented nonsignificant difference in patients with a history of SARS-CoV-2 infection (SMD= −0.02, 95%CI: −0.31 to 0.26), whereas reduced NAb inhibitor titer was observed in patients who are immunocompromised without a history of SARS-CoV-2 infection (SMD= −0.31 95%CI: −0.39 to −0.22) and those with unknown medical coronavirus infections (SMD= −0.42, 95%CI: −0.71 to −0.12) ( ). 

Variants of concerns were considered into this meta-analysis. Few studies have reported the Delta (B.1.617.2) and B.1.1.7 variants as critical factors triggering vaccine immunogenicity against the SARS-CoV-2 virus. Nonetheless, a significantly remarkable difference was observed in any condition of variants of concern and even in those of unknown periods. Thus, reduced effectiveness was observed against the Delta and B.1.1.7 variants in patients who are immunocompromised compared to that in the healthy group ( and ). Patients who are immunocompromised and received SARS-CoV-2 vaccines against the Delta (B.1.617.2) variant had significantly lower IgG titer (SMD= −1.02 AU/ml, 95%CI: −1.18 to −0.86) and antibody titer level than the healthy group (SMD= −2.67, 95%CI: −2.92 to −2.43). 

Immunoassay after immunization was analyzed using various assays, such as enzyme-linked immunosorbent assay (ELISA) and indirect chemiluminescence immunoassay (CLIA), that laboratory diagnosis to SARS-CoV-2 infection, might have influence on detective seropositive antibody rate. Hence, this subgroup analysis of serological response illustrated that most studies used immunoassays or kits were ELISA (RR = 0.86, 95%CI: 0.79 to 0.94) or CLIA (RR = 0.89, 95%CI: 0.84 to 0.95), and showed significant differences between the two groups, except for the combined ELISA and CLIA method (RR = 0.99, 95%CI: 0.86 to 1.14). Beck Coulter by Haider et al. also revealed nonsignificant difference for seroconversion rate between patients who are immunocompromised and the healthy group (RR = 0.92, 95%CI: 0.79 to 1.07). Using electrochemiluminescence immunoassay analyzer (ECLIA) or CLIA as measure tool for detecting antibody response in their bodies showed a significant difference between patients who are immunocompromised and the healthy group (RR = 0.83 95%CI: 0.74 to 0.93, RR = 0.83 95%CI: 0.74 to 0.93, respectively). The study by Verstappen et al. adopted indirect CLIA and luminescent immunoassay microparticles (MIA) analyzed involved patients for antibody response illustrated statistical difference between two groups (RR = 1.00, 95%CI: 0.74 to 1.34). Immunoassay tools including ELISA, CLIA, and chemiluminescent immunoassay microparticles (CMIA) used to detect seropositive IgG against coronavirus demonstrated significant differences between the two groups (RR = 0.73, 95%CI: 0.64 to 0.83; RR = 0.69, 95%CI: 0.61 to 0.78; RR = 0.82, 95%CI: 0.65 to 1.03, respectively), except for ECLIA in four studies (RR = 0.92, 95%CI: 0.86 to 0.99). NAb incidence was significantly different with ELISA (RR = 0.70, 95%CI: 0.60 to 0.82) and CLIA (RR = 0.32, 95%CI: 0.17, 0.60) tools between patients who are immunocompromised and the healthy group. Many studies adopting the CLIA method for measuring antibody titer post-vaccination showed significant differences on various units (AU/ml: SMD= −2.26, 95%CI: −2.43 to −2.08; BAU/ml: SMD= −1.63, 95%CI: −1.78 to −1.47; U/ml: SMD= −0.45, 95%CI: −0.70 to −0.20). The inconsistent results in antibody titer were revealed using ELICA for different units. In particular, no statistically significant difference was observed when using the unit BAU/ml (SMD= −0.02, 95%CI: −0.31 to 0.26), compared to ELICA in U/ml (SMD= −1.06, 95%CI: −1.25 to −0.86) and mg/ml (SMD= −6.08, 95%CI: −6.78 to −5.38) between the two groups. Only one study by Duengelhoef et al. published in 2020 reported contradictory results when using the mixed method of two units of measurement, demonstrating significant differences in BAU/ml (SMD= −7.36, 95%CI: −13.13 to −1.59) and nonsignificant difference in AU/ml (SMD = 0.11, 95%CI: −0.09 to 0.30). Ten studies used the CLIA tool to detect IgG titer, and showed favorable result between the two groups (SMD= −1.07 AU/ml, 95%CI: −1.89 to −0.24). Two studies with eight available data used the CLIA and ELISA tools throughout the first and second vaccine doses in patients on TNF treatment (SMD= −0.65 AU/ml, 95%CI: −1.25 to −0.05). The ECLIA method was used for participants who received CoronaVac or BioNTech vaccines, and nonsignificant difference was noted between the two groups (SMD= −0.13 AU/ml, 95%CI: −0.35 to 0.09). However, some studies used ELISA for IgG titer, not ECLIA, thus yielding a significant difference between the two groups (SMD= −0.78 AU/ml, 95%CI: −1.03 to −0.54). In addition, serval immunoassays used BAU/ml to detect IgG titer following vaccines which presented significant difference (CLIA in seven studies: SMD= −1.29, 95%CI: −1.65 to −0.93; ELISA in two studies: SMD= −0.54 95%CI: −0.84 to −0.24) ( and ) . Two studies utilized the ECLIA tool for IgG titer with the U/ml (SMD= −1.27, 95%CI: −1.55 to −0.98) and CLIA for UA/ml (SMD= −0.99, 95%CI: −1.29 to −0.68), with both reporting significant differences between the two groups. Furthermore, almost all of studies adopted the ELSA method to detect NAb inhibitor titer against SARS-CoV-2 virus post-immunization, which presented statistically significant difference between the two groups in a pooled result of SMD −0.40 with 95%CI of −0.57 to −0.23 ( ). 

This large systematic review was designed to identify an optimal immunization schedule by comparing the effectiveness of SARS-CoV-2 vaccines between patients who are immunocompromised and a healthy group in terms of vaccine dose, brand or subtype, therapeutic schedule, and history of SARS-CoV-2 infection. Majority of the included studies were conducted in the United States, Germany, United Kingdom, Sweden, and Israel. Only a few studies have described the certain ethnicity of their participants. Moreover, the population comprised adults (age > 18 years) who were either healthy or had autoimmune diseases. Patients diagnosed with autoimmune diseases showed reduced seroconversion after vaccination compared to healthy participants, which accords with results from a previous network meta-analysis . Exclusive reliance on seroconversion as single criteria to assess humoral response may result in false negative serological results. Thus, this meta-analysis collected data on seropositive neutralizing antibodies from appropriate studies and reached a similar conclusion for IgG and antibody response. Continuous data such as IgG titer and Nab inhibitor titer level were used to assess the immunity of patients with autoimmune diseases who received SARS-CoV-2 vaccines. The results revealed lower levels in patients who are immunosuppressed than the healthy group. In addition, only breakthrough infection after immunization had no significant difference between the two groups, and few studies have reported on the emergency of new variants of the virus, such as the Delta (B.1.617.2), variant and disease severity . Therefore, further subgroup analyses were conducted to evaluate an optimal vaccine schedule for patients with autoimmune diseases, based on the types of autoimmune disease, administration of specific treatment on autoimmune diseases, vaccine dose, vaccine types or subtypes, immunoassay, variants of concern, and history of prior SARS-CoV-2 infection. Favorable results were observed on seroconversion rate for patients who are immunocompromised with IBD and IMDs; antibody response rate in patients with AID, IBD, neuroimmunologic disease and MS; and incidence of positive IgG in patients with RD, Behçet’s syndrome (BS), CVID, IBD, psoriasis, primary Sjögren’s syndrome (pSS) and systemic sclerosis (SSc). Patients with IBD demonstrated a comparable antibody response with healthy controls. Therefore, patients who are immunocompromised should receive vaccination according to their own disease conditions. Furthermore, the potential influence of immunosuppressants that patients take during SARS-CoV-2 vaccination has not been completely explored yet. Patients taking ustekinumab, infliximab, vedolizumab, tofacitinib, prednisone, hydroxychloroquine, TNF inhibitor monotherapy, methotrexate, anti-TNF and methotrexate, sulfasalazine, leflunomide, and adalimumab developed comparable serological response with the healthy population. In addition, the subgroup analysis revealed that patients on ustekinumab or withheld DMARD therapy had similar antibody titer level with the healthy control. Most drugs administered for autoimmune diseases reduced IgG titer level, as evidenced by the lower IgG titer level in patients who are immunocompromised than in healthy controls, following SARS-CoV-2 vaccination. The subgroup analysis of the history of SARS-CoV-2 infection revealed unfavorable IgG titer level in patients who are immunocompromised, regardless of history of infections, compared to that in healthy controls. Additionally, variants of concern was also identified as an influential factor and presented similar results as the history of SARS-CoV-2 infection, which might be attributed to limited relevant research. In addition, the factors of SARS-CoV-2 vaccines have been considered and analyzed further in terms of dose, type, and subtype. Most results in the subgroup analysis of vaccine dose, revealed weak evidence that patients who are immunocompromised failed to develop sufficient seropositive antibody rate or seroconversion rate compared to healthy controls. However, although the incidence of seropositive IgG with a third vaccine dose showed a different trend, three vaccine doses are necessary for patients with immunodeficiency. However, the optimal strategy for patients who are immunocompromised to develop antibodies for viral invasion close to that of the healthy population who received SARS-CoV-2 vaccines remains unclear. Moreover, this meta-analysis used mainstream vaccines subtype and type, and identified subgroups of inactivated virus and adenoviral vector vaccines in patients who achieved similar titer and seropositive antibody rate with those in the healthy population. Detailed subgroup analysis of vaccine subtype, technically, brands of those in lieu of types, revealed complex results in combined vaccine strategies such as Pfizer, Moderna, AstraZeneca, and Janssen; Pfizer and AstraZeneca; BBV152 and AstraZeneca; and Pfizer and Moderna. Altogether, the results indicate that patients who are immunocompromised receiving multiple vaccine brands or subtypes might generate a similar level of specific antibody and antibody titer as that of the healthy population. However, the main determinant of cell entry and tropism called spike (S) protein of SARS-CoV-2, contains neutralizing epitopes triggering NAb in bodies, was explored by various approaches and techniques throughout many original studies to develop candidate vaccines against coronavirus. Therefore, NAb and its inhibitor titer were also analyzed in this study. Our findings emphasize that patients diagnosed with IBD, pSS, PAPS, and SSc; on vedolizumab, methotrexate, ustekinumab, and infliximab therapy; and with previous history of SARS-CoV-2 infections have similar detected titer level or incidence of seropositive NAb inhibitor with healthy controls. This systematic review and meta-analysis has several strengths. First, this study analyzed some diseases that previous meta-analysis did not . We also further analyzed more detailed patient characteristics including various diseases and treatments, from multidimensional outcomes included in the subgroup analyses. Second, we included SARS-CoV-2 vaccine platforms without any limit of dose and timepoint, which aligns with the meta-analysis of Widhani et al. , wherein eligible studies are non-randomized controlled trials. Regarding immunogenicity results, as patients had lower total antibody level than healthy controls, this was well-matched in this study. Third, this study underscores the strong need of administering SARS-CoV-2 vaccines to patients with autoimmune diseases to face current and future epidemics. This study also provides valuable data for healthcare workers in guiding patients with autoimmune decisions regarding clinical treatment decisions and protective measures. 

First, studies exploring homologous diseases or treatment on SARS-CoV-2 vaccines for patients who are immunocompromised are limited. Second, few studies have described the history of SARS-CoV-2 infection of enrolled participants, which may have biased the results. Lastly, the cuff-off value associated with the incidence of seropositive IgG or NAb, even serological response, is not consistent among included studies. Hence, false negative results may have been missed, and more researchers used various measure tools to avoid missing truly included patients in their own studies. 

Patients with autoimmune diseases who received most vaccines elicited poorer humoral responses and seropositive incidence after receiving SARS-CoV-2 vaccines than healthy individuals. Despite no observable favorable results of patients who are immunocompromised with autoimmune diseases occurred compared to healthy populations, which has trend of effectiveness of SARS-CoV-2 vaccines close to that of the healthy population. A more precise and detailed schedule of SARS-CoV-2 vaccination considering vaccine subtypes, dose(s), variants of concern (epidemic background of patients involved), and immunoassay used (tools or methods) is needed for patients with autoimmune diseases. 

PRISMA checklist.docx 

