Absent or suboptimal response to booster dose of COVID-19 vaccine in patients with autoimmune systemic diseases

Abstract

Autoimmune systemic diseases (ASD) show impaired immunogenicity to COVID-19 vaccines. Our prospective observational multicenter study aimed at evaluating the seroconversion elicited by COVID-19 vaccine over the entire vaccination cycle including the booster dose. Among 478 unselected ASD patients originally evaluated at the end of the first vaccination cycle (time 1), 344 individuals were re-evaluated after a 6-month period (time 2), and 244 after the booster vaccine dose (time 3). The immunogenicity of mRNA COVID-19 vaccines (BNT162b2 and mRNA-1273) was assessed by measuring serum IgG-neutralizing antibody (NAb) on samples obtained at the three time points in both patients and 502 age-matched controls. In the 244 ASD group that received booster vaccine and monitored over the entire follow-up, the mean serum NAb levels (time 1, 2, and 3: 696.8 ± 52.68, 370.8 ± 41.92, and 1527 ± 74.16SD BAU/mL, respectively; p < 0.0001) were constantly lower compared to controls (p < 0.0001), but they significantly increased after the booster dose compared to the first two measurements (p < 0.0001). The percentage of patients with absent/suboptimal response to vaccine significantly decreased after the booster dose compared to the first and second evaluations (time 1, 2, and 3: from 28.2% to 46.3%, and to 7.8%, respectively; p < 0.0001). Of note, the percentage of patients with absent/suboptimal response after the booster dose was significantly higher compared to controls (19/244, 7.8% vs 1/502, 0.2%; p < 0.0001). Similarly, treatment with immune-modifiers increased the percentage of patients exhibiting absent/suboptimal response (16/122, 13.1% vs 3/122, 2.46%; p = 0.0031). Overall, the above findings indicate the usefulness of booster vaccine administration in ASD patients. Moreover, the persistence of a significantly higher percentage of individuals without effective seroconversion (7.8%), even after the booster dose, warrants for careful monitoring of NAb levels in all ASD patients to identify those with increased risk of infection. In this particularly frail patients' setting, tailored vaccination and/or therapeutic strategy are highly advisable.

Keywords: Autoimmune systemic diseases; Booster vaccine; COVID-19 vaccine; Cryoglobulinemic vasculitis; Neutralizing antibodies; Rheumatoid arthritis; Systemic lupus; Systemic sclerosis; Systemic vasculitis.

Fig. 1

Flow-chart reporting the number of patients investigated for COVID-19 immunogenicity at different time-points. Figure 1 legend: At the beginning, a series of 478 ASD patients were analyzed as regards the humoral immunogenicity of COVID-19 vaccine [15]; over one quarter (27.9%) of individuals developed valuable levels of serum NAb within the first month after the vaccination cycle (first step). During the present study (second step), we evaluated the NAb titers in 344 ASD patients after the first 6-month follow-up period; a marked increase of the absent/suboptimal responder rate (from 27.9% to 41.85%) was recorded. Successively, the booster dose of vaccine was administered to 244 ASD patients leading to a significant reduction of the impaired seroconversion rate.

Fig. 2

Booster dose immunogenicity in the 244 ASD patients compared to healthy controls. Figure 2 legend: The figure focuses on the immunogenicity elicited by the booster dose of COVID-19 vaccine the main clinical features of the 244 ASD patients after the booster dose of COVID-19 vaccine. The serum levels of NAb are shown in the panel A, while panels B & C report the non-responder/suboptimal responder rates in the whole series and in each disease subgroups. Finally, the relationship of vaccine-related immunogenicity is correlated with the immunomodulating treatments in panel D. ASD patients showed significantly lower NAb titers compared to control group (ASD = 1527(±74.16) BAU/ml vs Controls = 2470(±10.74) BAU/ml p < 0.0001, panel A), as well the single ASD subgroups (RA = 1444(±136.9) BAU/ml, SLE = 1785(±255.7) BAU/ml, SSc = 1528(±99.28) BAU/ml, CV = 1442(±241) BAU/ml; always <0.0001). Similar findings was observed for the percentage of both non-responders (panel B) and sub-optimal responders (panel C). The cumulative number of patients with absent/suboptimal response was significantly higher in subjects treated with immune-modifiers compared to those without (panel D) (16/122(13.1%) and 3/122(2.46%) p = 0.0031). RA: rheumatoid arthritis, SLE: systemic lupus erythematosus, SSc: systemic sclerosis, CV: cryoglobulinemic vasculitis; IS: immuno-suppressors.

Fig. 3

Immunogenicity of booster dose of COVID-19 vaccine in individual ASD patients. Figure 3 legend: The immunogenicity to COVID-19 vaccines is largely variable and often unpredictable among ASD patients. It may be influenced by the single patient's conditions, namely the genetically-driven immune-system reactivity, older age, type of ASD, presence of comorbidities, and mostly by recent/ongoing immunomodifier treatments. The figure shows the response to first COVID-19 vaccination and to booster dose observed in different types of ASD. Panel A: a 22-year-old woman affected by systemic lupus erythematosus (SLE) with complicating severe glomerulonephritis treated since 2019 with mycophenolate mofetil (2 g/day) who developed a mild, delayed response after the first 2 doses of COVID-19 vaccine (BNT162b2), followed by a robust NAb production with the administration of a booster dose of the same vaccine. Panel B: a 44-year-old woman affected by diffuse cutaneous systemic sclerosis (SSc) complicated by interstitial lung involvement, undergoing long-term mycophenolate mofetil (2 g/day). The patients revealed as non-responder at the first 2 determination of serum NAb (within the first 4 weeks after the initial vaccination cycle and 6 months later), while a clear-cut seroconversion was recorded after the booster dose of vaccine (BNT162b2). This late response might be correlated with the previous cycle of rituximab treatment (10 months before the first vaccination). Panel C: a 53-year-old woman affected by rheumatoid arthritis (RA) undergoing long-term anti-TNFα treatment (Adalimumab). As observed in the patient described in panel B, the booster dose of COVID-19 vaccine (BNT162b2) was able to induce a valid seroconversion. Panel D: a 22-year-old woman affected by systemic lupus erythematosus (SLE) was undergoing long-term combined therapy with Belimumab, cyclosporin A, and hydroxychloroquine; the follow-up of serum NAb titers revealed a persistent inadequate response to COVID-19 vaccine (BNT162b2), including the booster dose administration. Timing 1: after the first 4 weeks from initial vaccination cycle; 2: after six-month follow-up; 3: within the first 4 weeks after booster dose.