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ObjectivesThe emergence of strains of SARS-CoV-2 exhibiting increase viral fitness and immune escape potential, such as the Delta variant (B.1.617.2), raises concerns in immunocompromised patients. We aimed to evaluate seroconversion, cross-neutralisation and T-cell responses induced by BNT162b2 in immunocompromised patients with systemic inflammatory diseases.MethodsProspective monocentric study including patients with systemic inflammatory diseases and healthcare immunocompetent workers as controls. Primary endpoints were anti-spike antibodies levels and cross-neutralisation of Alpha and Delta variants after BNT162b2 vaccine. Secondary endpoints were T-cell responses, breakthrough infections and safety.ResultsSixty-four cases and 21 controls not previously infected with SARS-CoV-2 were analysed. Kinetics of anti-spike IgG after BNT162b2 vaccine showed lower and delayed induction in cases, more pronounced with rituximab. Administration of two doses of BNT162b2 generated a neutralising response against Alpha and Delta in 100% of controls, while sera from only one of rituximab-treated patients neutralised Alpha (5%) and none Delta. Other therapeutic regimens induced a partial neutralising activity against Alpha, even lower against Delta. All controls and cases except those treated with methotrexate mounted a SARS-CoV-2 specific T-cell response. Methotrexate abrogated T-cell responses after one dose and dramatically impaired T-cell responses after two doses of BNT162b2. Third dose of vaccine improved immunogenicity in patients with low responses.ConclusionRituximab and methotrexate differentially impact the immunogenicity of BNT162b2, by impairing B-cell and T-cell responses, respectively. Delta fully escapes the humoral response of individuals treated with rituximab. These findings support efforts to improve BNT162b2 immunogenicity in immunocompromised individuals (ClinicalTrials.gov number, NCT04870411).

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Background. The emergence of strains of SARS-CoV-2 exhibiting increase viral fitness and immune escape potential, such as the Delta variant (B.1.617.2), raises concerns in immunocompromised patients. To what extent Delta evades vaccine-induced immunity in immunocompromised individuals with systemic inflammatory diseases remains unclear. Methods. We conducted a prospective study in patients with systemic inflammatory diseases (cases) and controls receiving two doses of BNT162b2. Primary end points were anti-spike antibodies levels and cross-neutralization of Alpha and Delta variants after BNT162b2 vaccine. Secondary end points were T-cell responses, breakthrough infections and safety. Results. Sixty-four cases and 21 controls not previously infected with SARS-CoV-2 were analyzed. Kinetics of anti-spike IgG and IgA after BNT162b2 vaccine showed lower and delayed induction in cases, more pronounced with rituximab. Administration of two doses of BNT162b2 generated a neutralizing response against Alpha and Delta in 100% of controls, while sera from only one of rituximab-treated patients neutralized Alpha (5%) and none Delta. Other therapeutic regimens induced a partial neutralizing activity against Alpha, even lower against Delta. All controls and cases except those treated with methotrexate mounted a SARS-CoV-2 specific T-cell response. Methotrexate abrogated T-cell responses after one dose and dramatically impaired T-cell responses after 2 doses of BNT162b2. Conclusions. Rituximab and methotrexate differentially impact the immunogenicity of BNT162b2, by impairing B-cell and T-cell responses, respectively. Delta fully escapes the humoral response of individuals treated with rituximab. These findings support efforts to improve BNT162b2 immunogenicity in immunocompromised individuals (Funded by the Fonds IMMUNOV; ClinicalTrials.gov number, NCT04870411).

Multiple myeloma (MM) patients are at risk of fatal outcome after SARS-CoV-2 infection. Preliminary data suggest that MM patients have an impaired response to vaccination. This prospective study analyzed the humoral and cellular immune responses to two doses of BNT162b2 in 72 MM patients, including 48 receiving anti-CD38 immunotherapy. Results evidenced that MM patients display lower levels of SARS-CoV-2 specific IgG and IgA antibodies and decreased neutralization of alpha and delta variants when compared to healthy controls. They also showed decreased numbers of circulating IFNγ-producing Spike SARS-CoV-2 specific T lymphocytes. This defective immune response was particularly marked in patients receiving anti-CD38 immunotherapy. Furthermore, a retrospective investigation of MM patients among COVID-19-related death in the Paris area suggested a limited efficacy of BNT162b2 in patients treated with anti-CD38. Overall, these results show a decreased immunogenicity of BNT162b2 in MM patients and stress the need for novel strategies to improve SARS-CoV-2 prophylaxis in immunocompromised individuals.

This work sought to confirm the human-like expression of exhaustion and senescence markers in a mouse model with a humanized immune system (HIS): the Balb/c Rag2KO IL2rgcKO SirpαNOD Flk2KO HLA-A2HHD (BRGSF-A2) mouse reconstituted with human CD34+ cord blood cells. With regard to senescence markers, the percentage of CD57+ T cells was higher in the bone marrow (BM) than in the spleen or blood. The same was true for KLRG1+ hCD8+ T cells. With regard to exhaustion markers, the percentage of programmed death 1 (PD-1+) T cells was higher in the BM than in the spleen or blood; the same was true for TIGIT+ hCD4+ cells. These tissue-specific differences were related to both higher proportions of memory T cells in BM and intrinsic differences in expression within the memory fraction. In blood samples from HIS mice and healthy human donors (HDs), we found that the percentage of KLRG1+ cells among hCD8+ T cells was lower in HIS compared to HDs. The opposite was true for CD4+ T cells. Unexpectedly, a high frequency of KLRG1+ cells was observed among naive T cells in HIS mice. CD57 expression on T cells was similar in blood samples from HIS mice and HDs. Likewise, PD-1 expression was similar in the two systems, although a relatively low proportion of HIS hCD4+ T cells expressed TIGIT. The BRGSF-A2 HIS mouse's exhaustion and senescence profile was tissue specific and relatively human like; hence, this mouse might be a valuable tool for determining the preclinical efficacy of immunotherapies.

Objective Sarcopenia has been associated with poor outcomes in various medical and surgical conditions. However, its impact in systemic necrotizing vasculitides (SNV) had never been characterized. We aimed to assess the prevalence, associated factors and prognostic impact of sarcopenia in SNV. Methods Patients with SNV were successively included in a prospective longitudinal study assessing comorbidities. At inclusion, we evaluated sarcopenia by assessing skeletal muscle mass index using DXA and muscle strength using handgrip strength. Vasculitis and treatments-related events were recorded and analysed using Cox models. Results One hundred and twenty patients were included. At inclusion, low handgrip strength (<30 kg for men and 20 kg for women) was identified in 28 (23%) patients, while no patient exhibited low skeletal muscle mass index (<7.23 kg/m2 for men and 5.67 kg/m2 for women). Low handgrip strength was associated with age (P <0.0001), type of vasculitis (P =0.01), vasculitis damage index (P =0.01), history of falls (P =0.0002), osteoporosis (P =0.04), low serum albumin (P =0.003) and prealbumin (P =0.0007), high CRP (P =0.001), high FRAX® tool (P =0.002) and low bone mineral density at femoral neck (P =0.0002). After median follow-up of 42 months, low handgrip strength was associated with higher risk of bone fracture [HR 4.25 (1.37–13.2), P =0.01] and serious adverse events [HR 2.80 (1.35–5.81), P =0.006]. Conclusion Handgrip strength is associated in SNV with nutritional status and comorbidities such as bone disease, and seems to predict, as in other medical conditions, the risk of fracture and serious adverse events during follow-up. In contrast, assessment of skeletal muscle mass index in this population remains uncertain.