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Ann Rheum Dis ; 2022 Mar 11.
Article in English | MEDLINE | ID: covidwho-1741594


OBJECTIVE: To determine the immunogenicity of the third dose of CoronaVac vaccine in a large population of patients with autoimmune rheumatic diseases (ARD) and the factors associated with impaired response. METHODS: Adult patients with ARD and age-balanced/sex-balanced controls (control group, CG) previously vaccinated with two doses of CoronaVac received the third dose at D210 (6 months after the second dose). The presence of anti-SARS-CoV-2 S1/S2 IgG and neutralising antibodies (NAb) was evaluated previously to vaccination (D210) and 30 days later (D240). Patients with controlled disease suspended mycophenolate mofetil (MMF) for 7 days or methotrexate (MTX) for 2 weekly doses after vaccination. RESULTS: ARD (n=597) and CG (n=199) had comparable age (p=0.943). Anti-S1/S2 IgG seropositivity rates significantly increased from D210 (60%) to D240 (93%) (p<0.0001) in patients with ARD. NAb positivity also increased: 38% (D210) vs 81.4% (D240) (p<0.0001). The same pattern was observed for CG, with significantly higher frequencies for both parameters at D240 (p<0.05). Multivariate logistic regression analyses in the ARD group revealed that older age (OR=0.98, 95% CI 0.96 to 1.0, p=0.024), vasculitis diagnosis (OR=0.24, 95% CI 0.11 to 0.53, p<0.001), prednisone ≥5 mg/day (OR=0.46, 95% CI 0.27 to 0.77, p=0.003), MMF (OR=0.30, 95% CI 0.15 to 0.61, p<0.001) and biologics (OR=0.27, 95% CI 0.16 to 0.46, p<0.001) were associated with reduced anti-S1/S2 IgG positivity. Similar analyses demonstrated that prednisone ≥5 mg/day (OR=0.63, 95% CI 0.44 to 0.90, p=0.011), abatacept (OR=0.39, 95% CI 0.20 to 0.74, p=0.004), belimumab (OR=0.29, 95% CI 0.13 to 0.67, p=0.004) and rituximab (OR=0.11, 95% CI 0.04 to 0.30, p<0.001) were negatively associated with NAb positivity. Further evaluation of COVID-19 seronegative ARD at D210 demonstrated prominent increases in positivity rates at D240 for anti-S1/S2 IgG (80.5%) and NAb (59.1%) (p<0.0001). CONCLUSIONS: We provide novel data on a robust response to the third dose of CoronaVac in patients with ARD, even in those with prevaccination COVID-19 seronegative status. Drugs implicated in reducing immunogenicity after the regular two-dose regimen were associated with non-responsiveness after the third dose, except for MTX.Trial registration number NCT04754698.

EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-305026


Background: Limited information is available on response to Covid-19 vaccines in autoimmune rheumatic disease patients(ARD) previously exposed to the SARS-CoV-2. We compared the dynamics of vaccine induced antibody production after immunization with CoronaVac in SARS-CoV-2 - seropositive ARD patients(ARD+) with two age/sex balanced groups: SARS-CoV-2 naïve ARD patients(NAÏVE-ARD) and SARS-CoV-2-seropositive control group(CTRL+).Methods: Participants of this phase 4 prospective controlled study were vaccinated with two doses of CoronaVac(28-days interval). Primary objective was immunogenicity dynamics evaluated by median neutralizing activity(NAb-activity)/anti-SARS-Cov-2 ln(IgG) titers[ln(IgG)] from D0-D28 and from D28-D69. Secondary objectives included safety and other immunogenicity parameters.Findings: Disease and therapy were similar in ARD+ and NAÏVE-ARD groups(p>0·05). A comparable dynamics was observed for ARD+ and CTRL+ with a plateau increase occurring from D0-D28[ARD+, NAb-activity:59·1% to 81·8%, mean difference -12·1%,p=0·002 and anti-S1/S2-GMT:52·3 to 128·9, ln(IgG) mean difference -0·9,p<0·001] and [CTRL+, NAb-activity:57·5 to 91·9%, mean difference -25·2%,p<0·001 and anti-S1/S2-GMT: 53·3 to 202·0, ln(IgG) mean difference -1·33,p<0·001]. Insignificant increments occurred from D28-D69 for ARD+ and CTRL+ regarding NAb-activity(p>0·999) and anti-S1/S2-GMT(p<0·999). In contrast, a distinct pattern was observed for NAÏVE-ARD with negligible increase from D0-D28 [NAÏVE-ARD: NAb-activity:15 vs. 15%, mean difference -8·3%,p<0·001 and anti-S1/S2-GMT:2·3 vs. 5·7, ln(IgG) mean difference -0·93,p<0·001] and a moderate increase from D28-D69[NAÏVE-ARD: NAb-activity:15·0 vs. 39·4%, mean difference -19·2%,p<0·001 and anti-S1/S2-GMT:5·7 vs. 29·6, ln(IgG) mean difference -1·65,p<0·001]. Supporting these findings, significant differences in NAb activity/ln(IgG) anti-S1/S2-GMT were observed between ARD+ vs. NAÏVE-ARD at D0:43·8%/3·14,p<0·001, D28:47·5%/3·12,p<0·001 and D69:29%/1·53,p<0·001, whereas no difference occurred between ARD+ vs. CTRL+ at D0:-0·5%/-0·02,p>0·999 and D69:-12·3%,p=0·167/0·32%,p=0·258 with minor difference at D28:-13·6%, p=0·067/-0·45,p=0·006.Interpretation: ARD+ patients mount a robust plateau response after a single dose of inactivated SARS-CoV-2 vaccine, independent of pre-existing ARD/therapy, whereas NAÏVE-ARD patients require the second dose to ensure a moderate antibody production. Our findings raise the possibility of a single dose regimen in ARD patients previously exposed to SARS-CoV-2.[]Funding: FAPESP/CNPq/B3-Bolsa de Valores-Brasil.Declaration of Interest: The authors declare no competing interests.Ethical Approval: The protocol was approved by the National and Institutional Ethical Committee (CAAE: 42566621.0.0000.0068)

Lancet Rheumatol ; 4(2): e113-e124, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1649499


BACKGROUND: We aimed to examine the immunogenicity pattern induced by the inactivated SARS-CoV-2 vaccine CoronaVac (Sinovac Life Sciences, Beijing, China) in SARS-CoV-2 seropositive patients with autoimmune rheumatic diseases compared with seropositive controls, seronegative patients with autoimmune rheumatic diseases, and seronegative controls. METHODS: CoronavRheum is an ongoing, prospective, controlled, phase 4 study, in which patients aged 18 years or older with autoimmune rheumatic diseases, and healthy controls were recruited from a single site (Rheumatology Division of Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo) in São Paulo, Brazil Participants were vaccinated with two doses of CoronaVac (intramuscular injection, 3 µg in 0·5 mL of ß-propiolactone inactivated SARS-CoV-2) on day 0 and on day 28. Blood samples were taken pre-vaccination on day 0, day 28, and also on day 69. For this subgroup analysis, participants were defined as being SARS-CoV-2 seropositive or seronegative prevaccination via anti-SARS-CoV-2 spike (S)1 or S2 IgG (cutoff of 15·0 arbitrary units [AU] per mL) or neutralising antibody titres (cutoff of ≥30%) and were matched for age and sex, via convenience sampling, in a 1:3:1:1 ratio (seropositive patients to seronegative patients to seropositive controls to seronegative controls). The primary outcomes were rates of anti-SARS-CoV-2 S1 and S2 IgG seropositivity and SARS-CoV-2 neutralising antibody positivity at day 28 and day 69 and immunogenicity dynamics assessed by geometric mean titres (GMTs) of IgG and median neutralising activity in seropositive patients with autoimmune rheumatic diseases compared with seronegative patients and seropositive and seronegative controls. We assessed safety in all participants randomly selected for this subgroup analysis. This study is registered with, NCT04754698, and is ongoing for long-term immunogenicity evaluation. FINDINGS: Between Feb 4 and Feb 8, 2021, 1418 patients and 542 controls were recruited, of whom 1685 received two vaccinations (1193 patients and 492 controls). After random sampling, our immunogenicity analysis population comprised 942 participants, of whom 157 were SARS-CoV-2 seropositive patients with autoimmune rheumatic diseases, 157 were seropositive controls, 471 were seronegative patients, and 157 were seronegative controls; the median age was 48 years (IQR 38-56) and 594 (63%) were female and 348 (37%) were male. For seropositive patients and controls, an increase in anti-SARS-CoV-2 S1 and S2 IgG titres (seropositive patients GMT 52·3 [95% CI 42·9-63·9] at day 0 vs 128·9 [105·6-157·4] at day 28; seropositive controls 53·3 [45·4-62·5] at day 0 vs 202·0 [174·8-233·4] at day 28) and neutralising antibody activity (seropositive patients 59% [IQR 39-83] at day 0 vs 82% [54-96] at day 28; seropositive controls 58% [41-79] at day 0 vs 92% [79-96] at day 28), was observed from day 0 to day 28, without further increases from day 28 to day 69 (at day 69 seropositive patients' GMT was 137·1 [116·2-161·9] and neutralising antibody activity was 79% [57-94]); and seropositive controls' GMT was 188·6 [167·4-212·6] and neutralising antibody activity was 92% [75-96]). By contrast, for seronegative patients and controls, the second dose was required for maximum response at day 69, which was lower in seronegative patients than in seronegative controls. GMTs in seronegative patients were 2·3 (95% CI 2·2-2·3) at day 0, 5·7 (5·1-6·4) at day 28, and 29·6 (26·4-33·3) at day 69, and in seronegative controls were 2·3 (2·1-2·5) at day 0, 10·6 (8·7-13·1) at day 28, and 71·7 (63·5-81·0) at day 69; neutralising antibody activity in seronegative patients was 15% (IQR 15-15) on day 0, 15% (15-15) at day 28, and 39% (15-65) at day 69, and in seronegative controls was 15% (15-15) at day 0, 24% (15-37) at day 28, and 61% (37-79) at day 69. Neither seronegative patients nor seronegative controls reached the GMT or antibody activity levels of seropositive patients at day 69. INTERPRETATION: By contrast with seronegative patients with autoimmune rheumatic diseases, seropositive patients have a robust response after a single dose of CoronaVac. Our findings raise the possibility that the reduced immunogenicity observed in seronegative patients might not be the optimum response potential to SARS-CoV-2 vaccination, and therefore emphasise the importance of at least a single booster vaccination in these patients. FUNDING: Fundação de Amparo à Pesquisa do Estado de São Paulo, Conselho Nacional de Desenvolvimento Científico e Tecnológico, and B3-Bolsa de Valores do Brasil. TRANSLATION: For the Portuguese translation of the abstract see Supplementary Materials section.

EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-294296


We provide novel data on anti-SARS-CoV-2 immunogenicity decay and incident cases six months after the 2nd dose of Sinovac-CoronaVac inactivated vaccine(D210) in 828 autoimmune rheumatic diseases(ARD) patients compared with 223 age/sex-balanced control group(CG). From D69 to D210, anti-S1/S2IgG positivity and GMT reduced 23.8% and 38% in ARD(p<0.001/p<0.001) and 20% and 51% in CG(p<0.001/p<0.001). From D69 to D210 NAb positivity and activity declined 41% and 54% in ARD(p<0.001/p<0.001) and 39.7% and 47% in CG(p<0.001/p<0.001). Multivariate logistic regression analysis showed that male(OR=0.56;95%CI0.40-0.79;p<0.001), prednisone(OR=0.56;95%CI0.41-0.76;p<0.001), anti-TNF(OR=0.66;95%CI0.45-0.96;p=0.031), abatacept(OR=0.29;95%CI0.15-0.56;p<0.001) and rituximab(OR=0.32;95%CI0.11-0.90;p=0.031) use were associated with a substantial reduction on IgG response at D210 in ARD patients. A decrease of COVID-19 cases(from 27.5 to 8.1/100 person-years;p<0.001) occurred during the study despite the Delta variant spread. In conclusion, after 6-months of Sinovac-CoronaVac 2nd dose, immunogenicity of ARD patients was markedly reduced, particularly in males and those under prednisone/biological therapies, without a concomitant rise in COVID-19 cases(NCT04754698).