Key Summary Points
Why carry out this study? |
Previous studies have shown that inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine is safe and effective in patients with systemic lupus erythematosus and rheumatoid arthritis. |
Information regarding the response to inactivated vaccine in patients with rheumatic and musculoskeletal diseases (RMDs) is insufficient. |
What was learned from this study? |
After Omicron infection, the serum immunoglobulin G concentration of SARS-CoV-2 neutralizing antibody in patients who received two or more doses of inactivated SARS-CoV-2 vaccine was significantly higher than that in patients who were unvaccinated or received one dose of inactivated vaccine. |
Inactivated SARS-CoV-2 vaccine is safe and effective in patients with RMDs. Healthcare providers should encourage vaccination with inactivated SARS-CoV-2 vaccine in patients with RMDs. |
Introduction
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the coronavirus disease (COVID-19) pandemic [1]. COVID-19 was deemed a public health emergency of international concern by the World Health Organization on January 30, 2020 and as a pandemic on March 11, 2020. The ongoing COVID-19 pandemic is a threat to global public health.
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Patients with rheumatic and musculoskeletal diseases (RMDs) are more likely than the general population to experience severe illness during COVID-19 [2], making early treatment or prevention crucial for the management of this patient population [3‐5]. The development and promotion of multiple vaccine types have decreased COVID-19-associated morbidity and mortality, globally [6]. Patients with RMDs who received the SARS-CoV-2 mRNA (messenger RNA) vaccine have similar serum antibody titers and a similar incidence of vaccine-related adverse events as healthy individuals [7]. Our earlier research showed that administering inactivated SARS-CoV-2 vaccine to patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) was safe and the vaccine was immunogenic as the antibody titers and incidence of adverse events did not differ significantly from those of healthy controls (HCs) [8]. Patients with RMDs in mainland China are currently vaccinated with inactivated SARS-CoV-2 vaccine; however, information regarding its safety and efficacy compared to those in HCs is insufficient. Many patients with RMDs refused the vaccination because of concerns about the effectiveness and side effects of inactivated SARS-CoV-2 vaccine [9]. However, the prevalence of vaccine hesitancy among people with RMDs fell significantly between 2021 and 2022 from 16.5 to 5.1% [10, 11]. To optimize immunization management in patients with RMDs, assessing the safety and effectiveness of inactivated SARS-CoV-2 vaccines is necessary.
Thus, to this end, this study aimed to evaluate the effectiveness and safety of the inactivated SARS-CoV-2 vaccine by evaluating the serum anti-SARS-CoV-2 immunoglobulin G (IgG) and immunoglobulin M (IgM) antibody titers in patients with RMDs and HCs in mainland China after two doses of vaccine and by comparing vaccination-related adverse events between the two groups. To further confirm the protective effects of the vaccine, we also aimed to assess changes in neutralizing antibody titers in the serum in patients with RMDs and HCs following infection with the SARS-CoV-2 Omicron variant.
Methods
Study Participants
Patients with RMDs attending the Rheumatology and Immunology Department of Anqing Medical Center (Anqing Municipal Hospital), Anhui Medical University, were enrolled in this study. From August 10, 2021 to September 30, 2021, 403 patients with RMDs complying with the RMD classifications from the American College of Rheumatology and/or the European League Against Rheumatism were recruited. HCs (134) were selected from healthy volunteers without RMDs using age and sex as matching criteria. All HCs and patients with RMDs had received two doses of the inactivated SARS-CoV-2 vaccine (Vero cell-based) 2 weeks prior to serum collection and had no prior history of COVID-19.
Between February 20, 2023 and March 1, 2023, 180 patients who had been infected with the Omicron variant within 12 weeks were recruited. The patients included 42 patients with RA, 31 with SLE, 27 with progressive systemic sclerosis (pSS), 15 with ankylosing spondylitis (AS), eight with inflammatory myopathy, nine with vasculitis, 18 with other connective tissue diseases (CTD), and 30 HCs.
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Ethical Statement
This study was carried out in accordance with the Helsinki Declaration of 1964 and its later amendments. The ethics committee of Anqing Municipal Hospital approved the study protocol (Medical Ethics Audit (2021) No. 07). All participants gave informed consent.
Study Methods
Age, sex, and body mass index (BMI) were obtained from hospital medical records. Additionally, data were also collected on clinical presentation (duration, comorbidities, and type of treatment), routine laboratory findings (autoantibodies, C-reactive protein, and erythrocyte sedimentation rate), and vaccination-related information (vaccination date, vaccine type, and adverse events).
Sample Preparation and Antibody Detection
On the morning of the day on which the questionnaire was administered, approximately 4–5 ml of whole blood was collected from each participant, and the serum was separated and refrigerated at − 80 °C until analysis. The samples were tested for SARS-CoV-2 IgG and IgM antibodies using a chemiluminescent immunoassay (CMIA) kit (CMU0302/CMU0402, 100 T/kit; Autobio Diagnostics Co., Zhengzhou, China), as previously described [12, 13]. Anti-human IgG or IgM antibodies coated with particles and labeled with haptoglobin-related protein (HPR)-labeled SARS-CoV-2 antigen were used to create enzyme conjugates. Immunoreactions resulted in the formation of solid-phase secondary anti-IgG or anti-IgM antibody-labeled antigen complexes. Catalysis of the substrate by the complexes resulted in a chemiluminescent reaction that was proportional to the concentration of SARS-CoV-2 IgG or IgM antibodies. For IgG, the kit's sensitivity and specificity were 89% and 100%, respectively, whereas for IgM, the sensitivity and specificity were 90% and 100%, respectively. IgM and IgG had cut-off values of 0.1 and 0.2, respectively. The average relative luminescence units (RLU) of the positive control wells, or the cut-off factor, were used to calculate the cut-off value for the kit. To assess whether a sample was positive for IgG or IgM antibodies to SARS-CoV-2, the S/CO value was computed using the equation: RLU/cut-off value of the test sample. If the signal-to-cut-off (S/CO) ratio was < 1.00, the result was positive. Otherwise, the result was reported as negative.
Statistical Analysis
SPSS version 23.0 (IBM Corp., Armonk, NY, USA) was used to perform statistical analysis. The mean and standard deviation were used to describe continuous data that followed a normal distribution, and the median and interquartile range were used to describe data with a skewed distribution. One-way analysis of variance or independent sample t tests were used for comparisons of continuous variables (such as age, BMI, and duration) between groups. The chi-squared test was used to compare categorical data, such as the seroprevalence of IgG and IgM antibodies against SARS-CoV-2, sex, and adverse events. The level of statistical significance was set at P < 0.05.
Results
Clinical Data
During the first data collection, 134 HCs and 269 patients with RMDs, including 70 patients with RA, 60 patients with SLE, 57 patients with pSS, 28 patients with AS, 17 patients with inflammatory myopathies, 12 patients with vasculitis, and 25 patients with other CTDs participated. The inactivated SARS-CoV-2 vaccine (Vero Cell) was administered twice to all trial participants. Patients in both groups were well matched in terms of age, BMI, and sex (P > 0.05) (Table 1). The interval between the first and second doses of vaccine and the second dose of vaccine and the post-vaccination blood draw did not substantially differ between the two groups (P = 0.452, P = 0.324). All patients with RMDs received ongoing treatment for their individual chronic diseases throughout the vaccination period. We found no significant differences in vaccination-related adverse events between the two groups (P = 0.276), with fever and myalgia being the most frequent self-reported vaccination-related adverse events. None of the study subjects had a SARS-CoV-2 infection (Table 1).
Table 1
Incidence of self-reported adverse events associated with Neocon vaccination
RA (N = 70) | SLE (N = 60) | pSS (N = 57) | AS (N = 28) | IIM (N = 17) | Vasculitis (N = 12) | CTD (N = 25) | HCs (N = 134) | Statistical values | P | |
|---|---|---|---|---|---|---|---|---|---|---|
Age (years), mean ± SD | 42.6 ± 15.4 | 38.7 ± 11.4 | 42.6 ± 15.4 | 31.2 ± 10.7 | 42.5 ± 11.6 | 52.4 ± 11.8 | 42.2 ± 12.9 | 43.4 ± 12.6 | 0.260 | 0.611 |
Sex (M/F) | 17/53 | 7/53 | 10/47 | 17/11 | 9/8 | 5/7 | 7/18 | 38/96 | 0.114 | 0.735 |
Self-reported vaccination-related adverse events | 15 | 15 | 12 | 6 | 5 | 3 | 7 | 25 | 1.189 | 0.276 |
Rash | 3 | 1 | 2 | 1 | 1 | 0 | 2 | 7 | 0.502 | 0.478 |
Fever | 4 | 3 | 1 | 1 | 0 | 1 | 0 | 6 | 0.136 | 0.713 |
Edema | 2 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 1.506 | 0.220 |
Muscle pain | 0 | 3 | 1 | 0 | 1 | 0 | 3 | 2 | 0.811 | 0.368 |
Joint pain | 3 | 2 | 3 | 2 | 2 | 2 | 1 | 7 | 0.022 | 0.883 |
Diarrhea | 1 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 1.001 | 0.317 |
Fatigue | 1 | 4 | 4 | 1 | 1 | 0 | 1 | 2 | 2.350 | 0.125 |
Nauseating | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0.499 | 0.480 |
Headaches | 0 | 0 | 1 | 1 | 0 | 0 | 0 | 1 | 0.000 | 0.998 |
History of COVID-19 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | – | – |
The second data collection included participation of 42 patients with RA, 31 with SLE, 27 with pSS, 15 with AS, eight with idiopathic inflammatory myopathy (IIM), nine with vasculitis, 18 with other CTDs, and 30 HCs. All the participants were infected with the Omicron variant within 12 weeks. Age, BMI, and sex differences between the RMD and HC patient groups were sufficiently balanced (P > 0.05). Among patients with RMDs, 173 (96.1%) had a mild disease, and seven (3.9%) had a severe disease. In contrast, one patient (3.3%) had a severe disease, and 29 (96.7%) had a mild disease in the HC group.
Comparison of Serological Tests for IgG and IgM Antibodies Against SARS-CoV-2
IgG and IgM antibodies against SARS-CoV-2 were examined in the first cohort of patients who received two doses of the inactivated SARS-CoV-2 vaccine. Among the study population, 40 patients with RA (57.1%), 30 with SLE (50.0%), 38 with pSS (66.7%), 19 with AS (67.8%), seven with IIM (41.2%), five with vasculitis (41.7%), 13 with other CTDs (52.0%), and 85 HCs (63.4%) tested positive for SARS-CoV-2 IgG antibodies. No significant difference was found between the patients with RMDs and HCs in the seroprevalence of SARS-CoV-2 IgG antibodies (P = 0.183) (Table 2). In addition, six patients with RA (8.6%), five with SLE (8.3%), four with pSS (7.0%), four with AS (14.3%), 0 with IIM (0.0%), one with vasculitis (8.3%), one with other CTDs (4.0%), and ten HCs (7.5%) tested positive for anti-SARS-CoV-2 IgM antibodies. No significant difference was found in the seroprevalence of anti-SARS-CoV-2 IgM antibodies (P = 0.903) (Table 2).
Table 2
Comparison of serum anti-SARS-CoV-2 IgG and IgM antibodies in patients with rheumatic and musculoskeletal diseases and healthy controls after two doses of SARS-CoV-2 inactivated vaccine
RA (N = 70) | SLE (N = 60) | pSS (N = 57) | AS (N = 28) | IIM (N = 17) | Vasculitis (N = 12) | CTD (N = 25) | Total | HCs | c2 | P | |
|---|---|---|---|---|---|---|---|---|---|---|---|
Serum anti-SARS-CoV-2 IgG antibody | 40 | 30 | 38 | 19 | 7 | 5 | 13 | 152 | 85 | 1.772 | 0.183 |
Serum anti-SARS-CoV-2 IgM antibody | 6 | 5 | 4 | 4 | 0 | 1 | 1 | 21 | 10 | 0.015 | 0.903 |
The second cohort of patients that included 42 patients with RA, 31 with SLE, 27 with pSS, 15 with AS, 8 with IIM, 9 with vasculitis, 18 with other CTDs, and 30 HCs infected with the Omicron variant, showed significantly higher serum IgG concentrations of neutralizing antibodies against SARS-CoV-2 than did patients who received two or more doses of vaccine (235.71 ± 117.76 vs 110.95 ± 114.91, P < 0.001) (Table 3). A total of 173 (96.1%) mild and 7 (3.9%) severe disease cases were observed following Omicron variant infection in the RMD group, along with 29 (96.7%) mild and 1 (3.3%) severe disease cases following Omicron variant infection in the HC group.
Table 3
Comparison of serum anti-SARS-CoV-2 IgG antibodies in patients with rheumatic and musculoskeletal diseases and healthy controls following infection with the SARS-CoV-2 Omicron variant
RA (N = 42) | SLE (N = 31) | pSS (N = 27) | AS (N = 15) | IIM (N = 8) | Vasculitis (N = 9) | CTD (N = 18) | RMD Total | HC (N = 30) | P | |
|---|---|---|---|---|---|---|---|---|---|---|
Serum anti-SARS-CoV-2 IgG antibody | 237.66 ± 120.07 | 236.97 ± 96.13 | 223.48 ± 107.09 | 267.00 ± 129.97 | 218.93 ± 91.86 | 294.06 ± 132.98 | 221.87 ± 101.35 | 243.64 ± 112.19 | 293.64 ± 112.19 | < 0.001 |
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In participants with previous Omicron variant infection, serum IgG concentrations of neutralizing antibodies against SARS-CoV-2 were significantly lower in the RMD group than in the HC group (293.64 ± 112.19 vs. 243.64 ± 112.19; P < 0.001).
The serum anti-SARS-CoV-2 IgG and IgM antibody concentrations of the RMD and HC groups after receiving two doses of the inactivated SARS-CoV-2 vaccine are shown in Table 2. Demographics and information relating to SARS-CoV-2 vaccination and the incidence of adverse events in each group at baseline are shown in Table 1.
Discussion
Studies have reported that the new SARS-CoV-2 vaccines are safe and effective in the general population. However, limited information is available on the safety and effectiveness of vaccines in susceptible populations, such as those with systemic autoimmune and inflammatory diseases (SAIDs), those taking immunosuppressive medications, and pregnant women [14]. We aimed to determine whether the efficacy and safety of the inactivated vaccine in patients with RMDs are comparable to those in HCs.
According to one of our previous studies, the safety and efficacy of the SARS-CoV-2 inactivated vaccine in patients with RA and SLE were comparable to those in HCs [8]. In this study, no notable differences were observed between the RMD and HC groups in the rate of seroconversion. A previous study found that the effectiveness of SARS-CoV-2 vaccines was lower in immunosuppressed individuals than in the general population [15]. However, the immunosuppressed study participants were not limited to patients with RMDs taking immunosuppressive drugs, and this could account for the observed discrepancies. However, the previous studies suggest that immunosuppressed populations require additional protection against COVID-19 and related diseases and therefore should be prioritized when implementing additional and/or future SARS-CoV-2 vaccine dosing recommendations.
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In this study, the frequency of vaccination-related adverse events was 23.4% and 18.7% in the RMD and HC groups, respectively, with fever and myalgia being the most frequently reported side effects. Concerns about vaccination-related adverse events were also one of the most common reasons for many patients with RMDs refusing vaccination. Another cross-sectional study found that patients with SAIDs were more likely to experience certain mild side effects. However, the absolute risk was very modest [16]. Overall, the adverse events were significantly higher in patients with SAIDs than in HCs. However, among vaccinated individuals the incidence of adverse events and hospitalization rates did not differ significantly between groups [16]. Another clinical investigation found a higher incidence of rash in individuals with idiopathic inflammatory myopathies [14]. Adjuvants and immune activators in vaccines can also cause immunological thrombosis, demyelinating events, and episodes of autoimmune disease. However, no similar unfavorable outcomes were noted in this study. In vaccine studies, fever (46%), weariness (44%), headache (39%), and muscle pain (17%) are the most frequently reported systemic adverse effects [17]. Active measures should be taken to ensure that patients with RMDs are vaccinated, as adverse vaccination events are easily manageable and the risk of hospitalization as a result of vaccination is minimal.
Among the participants of this study with previous Omicron variant infection, the occurrence of mild disease in many patients in the RMD group may be a consequence of chronic administration of immunosuppressive drugs, resulting in their immune systems not responding promptly and dramatically to the viral infection. SARS-CoV-2 vaccines are effective in preventing hospitalization and death [18, 19], severe COVID-19, and COVID-19 pneumonia, with no statistically significant difference between the vaccine types [20]. In patients infected with the Omicron variant, upper airway symptoms and nonspecific symptoms are the predominant clinical characteristics. The most frequent symptom is fever, which is followed by a light, dry cough [21]. According to a Korean study, fever (20%) and sore throat (25%) are the most typical signs and symptoms. In that study, patients infected with the Omicron variant had a 91.33% vaccination rate, indicating no correlation between infection with the Omicron variant and the COVID-19 vaccine. The numerous mutations in the Omicron variant cause immunological escape from the vaccine [22]. However, in another serum neutralization trial, the escape was incomplete, with relatively high neutralizing antibody titers against the Omicron variant being detected in vaccinated patients [23].
The antibody titers produced by patients with RMDs infected with the Omicron variant were lower than those produced by HCs. Many immunosuppressive agents used to treat RMDs impair the immunogenicity of the vaccine. The degree of reduction in antibody titers varies according to the immunosuppressant being used. For example, the immunogenicity of the mRNA COVID-19 vaccination may be reduced in patients treated with certain drugs, including methotrexate [24], MMF, and abatacept [25]. When used alone or in conjunction with methotrexate, rituximab significantly lowered the humoral response to vaccination [26]. The degree of B-cell recovery after vaccination coincides with the degree of humoral response to vaccination, and seroprotective effects can, therefore, still be acquired following vaccination [25]. Patients with insufficient humoral responses may still be protected by T-cell-mediated immunity because defense against SARS-CoV-2 depends on both humoral and cellular immunity. Patients with RMDs infected with the Omicron variant produce lower antibody titers than do HCs, but these are still sufficient to provide protection from the virus.
Patients with RMDs who received two or more doses of the inactivated vaccine had significantly greater serum concentrations of neutralizing antibody IgG against SARS-CoV-2 than did those who received one or no dose of the vaccine. Clinical studies of inactivated vaccines and changes in serum antibody concentrations resulting from mRNA vaccination [27] have shown the value of increasing the number of doses of vaccine to improve SARS-CoV-2 neutralizing antibody responses [28, 29]. Patients with RMDs should be encouraged to receive a second, third, or even fourth dose of the vaccine.
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This study has certain limitations. First, antibody titers may not reflect the total efficacy of the vaccine, but only a portion of the overall response. The antibody levels required for vaccination to be effective remain unclear. Further studies are required to clarify the relationship between antibody titers and vaccine efficacy. Second, the relatively small sample size of the study population, of which only 111 participants were fully vaccinated with the inactivated SARS-CoV-2 vaccine and only 111 were infected with the Omicron variant, may undermine the robustness of the study. Finally, there is a risk of selection bias. Most of the patients with RMDs who had available data in the outpatient and inpatient departments were in the group with relatively high adherence to medication, and most of the data on those who did not have regular follow-up visits is lacking.
Conclusions
The symptoms of the Omicron variant infection are expected to decrease with increasing population immunity owing to vaccination and infection. To effectively combat Omicron variants and outbreaks, vaccination must be emphasized, particularly in vulnerable populations (e.g., the older and immunocompromised individuals). Infection with the Omicron variant can currently be effectively prevented by administering three doses of vaccine, despite the small number of symptomatic infections. However, vaccination is urgently required. Given that the protection of the third dose wanes over time and that the fourth dose boosts antibody levels, some nations have approved the use of a fourth dose of the vaccine. Consequently, vulnerable populations must be administered with the third and fourth doses of the vaccine as soon as possible and in a timely manner. In the long run, additional booster doses will be required to maintain the antibody levels and protect oneself [30].
Acknowledgements
Thanks to the foundation for the support of this research, thanks to the volunteers for their cooperation in our research, and thanks to the teachers for their guidance in this research. We would like to thank Editage (www.editage.cn) for the English language editing.
Declarations
Conflict of Interest
Xiaowei Zhang, Yifei Li, Chunqing Dai, Yaya Chu, Chaoqi Luan, and Guihong Wang declare they have no competing interests.
Ethical Approval
This study was carried out in accordance with the Helsinki Declaration of 1964 and its later amendments. The ethics committee of Anqing Municipal Hospital approved the study protocol (Medical Ethics Audit (2021) No. 07). All participants gave informed consent.
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