Immunizing the Imperfect Immune System: COVID-19 Vaccination in Patients with Inborn Errors of Immunity

OBJECTIVE: To update clinicians on current evidence regarding the immunogenicity and safety of COVID-19 vaccines in patients with Inborn Errors of Immunity (IEI). DATA SOURCES: Peer reviewed, published studies in Pubmed, clinical trials listed on clinicaltrial.gov, and professional organization and governmental guidelines. STUDY SELECTIONS: Literature searches on Pubmed and clinicaltrials.gov were performed using a combination of the following keywords: Primary Immunodeficiency, COVID-19, SARS-CoV-2, vaccination RESULTS: Twenty-six studies met criteria and were included in this review. Overall, antibody responses to COVID-19 vaccination were seen in 72% of study subjects, with stronger responses observed following mRNA vaccination. Neutralizing antibodies were detected in IEI patients, though consistently at lower levels than healthy controls. Risk factors for poor antibody responses included diagnosis of common variable immunodeficiency (CVID), presence of autoimmune comorbidities, and use of rituximab. T cells responses were detectable in most patients with IEI, with poorer responses often seen in CVID patients. Safety of COVID-19 vaccines in patients with IEI were acceptable with high rates of reactogenicity but very few serious adverse events, including in patients with immune dysregulation. CONCLUSION: COVID-19 vaccines are safe in patients with IEI and appear to be immunogenic in most individuals, with stronger responses seen following mRNA vaccinations

Transcriptomic analysis reveals optimal cytokine combinations for SARS-CoV-2-specific T cell therapy products

Adoptive T cell immunotherapy has been used to restore immunity against multiple viral targets in immunocompromised patients after bone-marrow transplantation and has been proposed as a strategy for preventing coronavirus 2019 (COVID-19) in this population. Ideally, expanded severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-virus-specific T cells (CSTs) should demonstrate marked cell expansion, T cell specificity, and CD8+ T cell skewing prior to adoptive transfer. However, current methodologies using IL-4 + IL-7 result in suboptimal specificity, especially in CD8 cells. Using a microexpansion platform, we screened various cytokine cocktails (IL-4 + IL-7, IL-15, IL-15 + IL-4, IL-15 + IL-6, and IL-15 + IL-7) for the most favorable culture conditions. IL-15 + IL-7 optimally balanced T cell expansion, polyfunctionality, and CD8+ T cell skewing of a final therapeutic T cell product. Additionally, the transcriptomes of CD4 and CD8 T cells cultured with IL-15 + IL-7 displayed the strongest induction of antiviral type I interferon (IFN) response genes. Subsequently, microexpansion results were successfully translated to a Good Manufacturing Practice (GMP)-applicable format where IL-15 + IL-7 outperformed IL-4 + IL-7 in specificity and expansion, especially in the desirable CD8 T cell compartment. These results demonstrate the functional implications of IL-15-, IL-4-, and IL-7-containing cocktails for therapeutic T cell expansion, which could have broad implication for cellular therapy, and pioneer the use of RNA sequencing (RNA-seq) to guide viral-specific T cell (VST) product manufacturing

SARS-CoV-2-Specific T Cell Responses Are Stronger in Children With Multisystem Inflammatory Syndrome Compared to Children With Uncomplicated SARS-CoV-2 Infection

Background: Despite similar rates of infection, adults and children have markedly different morbidity and mortality related to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Compared to adults, children have infrequent severe manifestations of acute infection but are uniquely at risk for the rare and often severe Multisystem Inflammatory Syndrome in Children (MIS-C) following infection. We hypothesized that these differences in presentation are related to differences in the magnitude and/or antigen specificity of SARS-CoV-2-specific T cell (CST) responses between adults and children. We therefore set out to measure the CST response in convalescent adults versus children with and without MIS-C following SARS-CoV-2 infection. Methods: CSTs were expanded from blood collected from convalescent children and adults post SARS-CoV-2 infection and evaluated by intracellular flow cytometry, surface markers, and cytokine production following stimulation with SARS-CoV-2-specific peptides. Presence of serum/plasma antibody to spike and nucleocapsid was measured using the luciferase immunoprecipitation systems (LIPS) assay. Findings: Twenty-six of 27 MIS-C patients, 7 of 8 non-MIS-C convalescent children, and 13 of 14 adults were seropositive for spike and nucleocapsid antibody. CST responses in MIS-C patients were significantly higher than children with uncomplicated SARS-CoV-2 infection, but weaker than CST responses in convalescent adults. Interpretation: Age-related differences in the magnitude of CST responses suggest differing post-infectious immunity to SARS-CoV-2 in children compared to adults post uncomplicated infection. Children with MIS-C have CST responses that are stronger than children with uncomplicated SARS-CoV-2 infection and weaker than convalescent adults, despite near uniform seropositivity