Cell-mediated and Neutralizing Antibody Responses to the SARS-CoV-2 Omicron BA.4/BA.5-adapted Bivalent Vaccine Booster in Kidney and Liver Transplant Recipients.

Background: The immunogenicity elicited by the Omicron BA.4/BA.5-adapted bivalent booster vaccine after solid organ transplantation (SOT) has not been characterized. Methods: We assessed cell-mediated and neutralizing IgG antibody responses against the BA.4/BA.5 spike receptor-binding domain at baseline and 2 wk after the administration of an mRNA-based bivalent (ancestral strain and BA.4/BA.5 subvariants) vaccine among 30 SOT recipients who had received ≥3 monovalent vaccine doses. Previous coronavirus disease 2019 history was present in 46.7% of them. We also recruited a control group of 19 nontransplant healthy individuals. Cell-mediated immunity was measured by fluorescent ELISpot assay for interferon (IFN)-γ secretion, whereas the neutralizing IgG antibody response against the BA.4/BA.5 spike receptor-binding domain was quantified with a competitive ELISA. Results: The median number of BA.4/BA.5 spike-specific IFN-γ-producing spot-forming units (SFUs) increased from baseline to 2 wk postbooster (83.8 versus 133.0 SFUs/106 peripheral blood mononuclear cells; P = 0.0017). Seropositivity rate also increased (46.7%-83.3%; P = 0.001), as well as serum neutralizing activity (4.2%-78.3%; P < 0.0001). Patients with no prior coronavirus disease 2019 history experienced higher improvements in cell-mediated and neutralizing responses after booster vaccination. There was no correlation between BA.4/BA.5 spike-specific IFN-γ-producing SFUs and neutralizing activity. Nontransplant controls showed more robust postbooster cell-mediated immunity than SOT recipients (591.1 versus 133.0 IFN-γ-producing SFUs/106 peripheral blood mononuclear cells; P < 0.0001), although no differences were observed for antibody responses in terms of postbooster seropositivity rates or neutralizing activity. Conclusions: Booster with the BA.4/BA.5-adapted bivalent vaccine generated strong subvariant-specific responses among SOT recipients. Booster-induced cell-mediated immunity, however, remained lower than in immunocompetent individuals.

Decreased breadth of the antibody response to the spike protein of SARS-CoV-2 after repeated vaccination.

Introduction: The rapid development of vaccines to prevent COVID-19 has raised the need to compare the capacity of different vaccines in terms of developing a protective humoral response. Previous studies have shown inconsistent results in this area, highlighting the importance of further research to evaluate the efficacy of different vaccines. Methods: This study utilized a highly sensitive and reliable flow cytometry method to measure the titers of IgG1 isotype antibodies in the blood of healthy volunteers after receiving one or two doses of various vaccines administered in Spain. The method was also used to simultaneously measure the reactivity of antibodies to the S protein of the original Wuhan strain and variants B.1.1.7 (Alpha), B.1.617.2 (Delta), and B.1.617.1 (Kappa). Results: Significant differences were observed in the titer of anti-S antibodies produced after a first dose of the vaccines ChAdOx1 nCov-19/AstraZeneca, mRNA-1273/Moderna, BNT162b2/Pfizer-BioNTech, and Ad26.COV.S/Janssen. Furthermore, a relative reduction in the reactivity of the sera with the Alpha, Delta, and Kappa variants, compared to the Wuhan strain, was observed after the second boosting immunization. Discussion: The findings of this study provide a comparison of different vaccines in terms of anti-S antibody generation and cast doubts on the convenience of repeated immunization with the same S protein sequence. The multiplexed capacity of the flow cytometry method utilized in this study allowed for a comprehensive evaluation of the efficacy of various vaccines in generating a protective humoral response. Future research could focus on the implications of these findings for the development of effective COVID-19 vaccination strategies.

Inborn Error of STAT2-Dependent IFN-I Immunity in a Patient Presented with Hemophagocytic Lymphohistiocytosis and Multisystem Inflammatory Syndrome in Children.

Human inborn errors of immunity (IEI) affecting the type I interferon (IFN-I) induction pathway have been associated with predisposition to severe viral infections. Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening systemic hyperinflammatory syndrome that has been increasingly associated with inborn errors of IFN-I-mediated innate immunity. Here is reported a novel case of complete deficiency of STAT2 in a 3-year-old child that presented with typical features of HLH after mumps, measles, and rubella vaccination at the age of 12 months. Due to the life-threatening risk of viral infection, she received SARS-CoV-2 mRNA vaccination. Unfortunately, she developed multisystem inflammatory syndrome in children (MIS-C) after SARS-CoV-2 infection, 4 months after the last dose. Functional studies showed an impaired IFN-I-induced response and a defective IFNα expression at later stages of STAT2 pathway induction. These results suggest a possible more complex mechanism for hyperinflammatory reactions in this type of patients involving a possible defect in the IFN-I production. Understanding the cellular and molecular links between IFN-I-induced signaling and hyperinflammatory syndromes can be critical for the diagnosis and tailored management of these patients with predisposition to severe viral infection.

Defending against SARS-CoV-2: The T cell perspective.

SARS-CoV-2-specific T cell response has been proven essential for viral clearance, COVID-19 outcome and long-term memory. Impaired early T cell-driven immunity leads to a severe form of the disease associated with lymphopenia, hyperinflammation and imbalanced humoral response. Analyses of acute SARS-CoV-2 infection have revealed that mild COVID-19 course is characterized by an early induction of specific T cells within the first 7 days of symptoms, coordinately followed by antibody production for an effective control of viral infection. In contrast, patients who do not develop an early specific cellular response and initiate a humoral immune response with subsequent production of high levels of antibodies, develop severe symptoms. Yet, delayed and persistent bystander CD8+ T cell activation has been also reported in hospitalized patients and could be a driver of lung pathology. Literature supports that long-term maintenance of T cell response appears more stable than antibody titters. Up to date, virus-specific T cell memory has been detected 22 months post-symptom onset, with a predominant IL-2 memory response compared to IFN-γ. Furthermore, T cell responses are conserved against the emerging variants of concern (VoCs) while these variants are mostly able to evade humoral responses. This could be partly explained by the high HLA polymorphism whereby the viral epitope repertoire recognized could differ among individuals, greatly decreasing the likelihood of immune escape. Current COVID-19-vaccination has been shown to elicit Th1-driven spike-specific T cell response, as does natural infection, which provides substantial protection against severe COVID-19 and death. In addition, mucosal vaccination has been reported to induce strong adaptive responses both locally and systemically and to protect against VoCs in animal models. The optimization of vaccine formulations by including a variety of viral regions, innovative adjuvants or diverse administration routes could result in a desirable enhanced cellular response and memory, and help to prevent breakthrough infections. In summary, the increasing evidence highlights the relevance of monitoring SARS-CoV-2-specific cellular immune response, and not only antibody levels, as a correlate for protection after infection and/or vaccination. Moreover, it may help to better identify target populations that could benefit most from booster doses and to personalize vaccination strategies.

Development of an Effective Immune Response in Adults With Down Syndrome After Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Vaccination.

BACKGROUND: Immune dysregulation in individuals with Down syndrome (DS) leads to an increased risk for hospitalization and death due to coronavirus disease 2019 (COVID-19) and may impair the generation of protective immunity after vaccine administration. METHODS: The cellular and humoral responses of 55 individuals with DS who received a complete SARS-CoV-2 vaccination regime at 1 to 3 (visit [V 1]) and 6 (V2) months were characterized. RESULTS: SARS-CoV-2-reactive CD4+ and CD8+ T lymphocytes with a predominant Th1 phenotype were observed at V1 and increased at V2. Likewise, an increase in SARS-CoV-2-specific circulating Tfh (cTfh) cells and CD8+ CXCR5+ PD-1hi lymphocytes was already observed at V1 after vaccine administration. Specific immunoglobulin G (IgG) antibodies against SARS-CoV-2 S protein were detected in 96% and 98% of subjects at V1 and V2, respectively, although IgG titers decreased significantly between both time points. CONCLUSIONS: Our findings show that DS individuals develop an effective immune response to usual regimes of SARS-CoV-2 vaccination.

Cellular and humoral immune responses and breakthrough infections after three SARS-CoV-2 mRNA vaccine doses.

Background: SARS-CoV-2 vaccination has proven the most effective measure to control the COVID-19 pandemic. Booster doses are being administered with limited knowledge on their need and effect on immunity. Objective: To determine the duration of specific T cells, antibodies and neutralization after 2-dose vaccination, to assess the effect of a third dose on adaptive immunity and to explore correlates of protection against breakthrough infection. Methods: 12-month longitudinal assessment of SARS-CoV-2-specific T cells, IgG and neutralizing antibodies triggered by 2 BNT162b2 doses followed by a third mRNA-1273 dose in a cohort of 77 healthcare workers: 17 with SARS-CoV-2 infection prior to vaccination (recovered) and 60 naïve. Results: Peak levels of cellular and humoral response were achieved 2 weeks after the second dose. Antibodies declined thereafter while T cells reached a plateau 3 months after vaccination. The decline in neutralization was specially marked in naïve individuals and it was this group who benefited most from the third dose, which resulted in a 20.9-fold increase in neutralization. Overall, recovered individuals maintained higher levels of T cells, antibodies and neutralization 1 to 6 months post-vaccination than naïve. Seventeen asymptomatic or mild SARS-CoV-2 breakthrough infections were reported during follow-up, only in naïve individuals. This viral exposure boosted adaptive immunity. High peak levels of T cells and neutralizing antibodies 15 days post-vaccination associated with protection from breakthrough infections. Conclusion: Booster vaccination in naïve individuals and the inclusion of viral antigens other than spike in future vaccine formulations could be useful strategies to prevent SARS-CoV-2 breakthrough infections.

Immunogenicity of Anti-SARS-CoV-2 Vaccines in Common Variable Immunodeficiency.

Common variable immunodeficiency (CVID) is characterized by hypogammaglobulinemia and/or a defective antibody response to T-dependent and T-independent antigens. CVID response to immunization depends on the antigen type, the vaccine mechanism, and the specific patient immune defect. In CVID patients, humoral and cellular responses to the currently used COVID-19 vaccines remain unexplored. Eighteen CVID subjects receiving 2-dose anti-SARS-CoV-2 vaccines were prospectively studied. S1-antibodies and S1-specific IFN-γ T cell response were determined by ELISA and FluoroSpot, respectively. The immune response was measured before the administration and after each dose of the vaccine, and it was compared to the response of 50 healthy controls (HC). The development of humoral and cellular responses was slower in CVID patients compared with HC. After completing vaccination, 83% of CVID patients had S1-specific antibodies and 83% had S1-specific T cells compared with 100% and 98% of HC (p = 0.014 and p = 0.062, respectively), but neutralizing antibodies were detected only in 50% of the patients. The strength of both humoral and cellular responses was significantly lower in CVID compared with HC, after the first and second doses of the vaccine. Absent or discordant humoral and cellular responses were associated with previous history of autoimmunity and/or lymphoproliferation. Among the three patients lacking humoral response, two had received recent therapy with anti-B cell antibodies. Further studies are needed to understand if the response to COVID-19 vaccination in CVID patients is protective enough. The 2-dose vaccine schedule and possibly a third dose might be especially necessary to achieve full immune response in these patients.

Longitudinal dynamics of SARS-CoV-2-specific cellular and humoral immunity after natural infection or BNT162b2 vaccination.

The timing of the development of specific adaptive immunity after natural SARS-CoV-2 infection, and its relevance in clinical outcome, has not been characterized in depth. Description of the long-term maintenance of both cellular and humoral responses elicited by real-world anti-SARS-CoV-2 vaccination is still scarce. Here we aimed to understand the development of optimal protective responses after SARS-CoV-2 infection and vaccination. We performed an early, longitudinal study of S1-, M- and N-specific IFN-γ and IL-2 T cell immunity and anti-S total and neutralizing antibodies in 88 mild, moderate or severe acute COVID-19 patients. Moreover, SARS-CoV-2-specific adaptive immunity was also analysed in 234 COVID-19 recovered subjects, 28 uninfected BNT162b2-vaccinees and 30 uninfected healthy controls. Upon natural infection, cellular and humoral responses were early and coordinated in mild patients, while weak and inconsistent in severe patients. The S1-specific cellular response measured at hospital arrival was an independent predictive factor against severity. In COVID-19 recovered patients, four to seven months post-infection, cellular immunity was maintained but antibodies and neutralization capacity declined. Finally, a robust Th1-driven immune response was developed in uninfected BNT162b2-vaccinees. Three months post-vaccination, the cellular response was comparable, while the humoral response was consistently stronger, to that measured in COVID-19 recovered patients. Thus, measurement of both humoral and cellular responses provides information on prognosis and protection from infection, which may add value for individual and public health recommendations.

A Short Corticosteroid Course Reduces Symptoms and Immunological Alterations Underlying Long-COVID.

Despite the growing number of patients with persistent symptoms after acute SARS-CoV-2 infection, the pathophysiology underlying long-COVID is not yet well characterized, and there is no established therapy. We performed a deep immune profiling in nine patients with persistent symptoms (PSP), before and after a 4-day prednisone course, and five post-COVID-19 patients without persistent symptoms (NSP). PSP showed a perturbed distribution of circulating mononuclear cell populations. Symptoms in PSP were accompanied by a pro-inflammatory phenotype characterized by increased conventional dendritic cells and augmented expression of antigen presentation, co-stimulation, migration, and activation markers in monocytes. The adaptive immunity compartment in PSP showed a Th1-predominance, decreased naïve and regulatory T cells, and augmentation of the PD-1 exhaustion marker. These immune alterations reverted after the corticosteroid treatment and were maintained during the 4-month follow-up, and their normalization correlated with clinical amelioration. The current work highlights an immunopathogenic basis together with a possible role for steroids in the treatment for long-COVID.

SARS-CoV-2-specific T-cell responses after COVID-19 recovery in patients with rheumatic diseases on immunosuppressive therapy.

BACKGROUND: In patients with immune-mediated rheumatic diseases (RMD), the development of T-cell responses against SARS-CoV-2 may be impaired by either the immune disturbances associated with the disease, or by the effects of immunosuppressive therapies. We aimed at determining the magnitude of SARS-CoV-2-specific interferon (IFN)-γ-producing T-cell response after COVID-19 recovery in a cohort of patients with RMD on different immunosuppressive therapies. PATIENTS AND METHODS: 53 adult patients with inflammatory or autoimmune RMD and 61 sex and age-matched non-RMD patients with confirmed COVID-19 were included. Peripheral blood mononuclear cells were obtained and T-cell-IFN-γ antigen-specific responses against the S1 domain of the spike glycoprotein, the nucleoprotein (N) and the membrane (M) protein from SARS-CoV-2 were assessed by FluoroSpot assay. RESULTS: Patients with RMD and COVID-19 showed positive T-cells-IFN-γ responses to SARS-COV-2 antigens, in a similar proportion and magnitude as non-RMD patients at a median of 298 [151-316] and 165 [162-167] days after COVID-19 respectively. Among RMD patients 83%, 87% and 90%, and among non-RMD patients, 95%, 87% and 93% responded to S1, N and M protein respectively. Similar responses were observed in the different diagnostic and therapeutic groups, including conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs), TNF-α inhibitors, IL-17 inhibitors, rituximab, JAK inhibitors or other immunosuppressants. CONCLUSION: T-cell responses to the main SARS-CoV-2 antigens are present after COVID-19 recovery in most patients with RMD and are not impaired by immunosuppressive therapies.