COMPARISON OF HOMOLOGOUS AND HETEROLOGOUS BOOSTER SARS-CoV-2 VACCINATION IN AUTOIMMUNE RHEUMATIC AND MUSCULOSKELETAL PATIENTS

BackgroundVaccine-induced immunity is very important for controlling the COVID-19 infection. The vaccination supports humoral and cellular immunity, and this is one of the main strategy for us. Various vaccines approved in the countries have been shown to reduce infection rates, severity, and mortality.ObjectivesWe aimed to compare humoral and cellular immune responses after homologous or heterologous vaccination among patients with aiRMDs at their third vaccination with BNT162b2 or with two vaccinations followed by COVID-19 infection. We detected the anti-SARS-CoV2 antibody levels and measured the SARS-CoV-2 reactive B-, or T-cell mediated immunity in aiRMDs receiving homologous (Hom.), heterologous (Het.) vaccines or became infected (Inf.).MethodsA single center observational study evaluated immunogenicity and safety of the third dose vaccines or after two-dose regimen of vaccine and COVID infection in patients with aiRMDs. Neutralizing anti-RBD antibodies and specific T-cell response were measured.ResultsWe showed that following 4 months of the booster vaccination with the third dose of mRNA-based vaccine or after COVID infection, the positive (>21.8 BAU/mL) neutralizing anti-RBD IgG antibody response was outstanding in all three patient groups, 95.5%, 100% and 100% of the homologous and heterologous as well as the SARS-CoV-2 infected groups. Taken together booster vaccinations or SARS-CoV-2 infection after completing 2 doses of the vaccination can lead to the production of neutralizing antibodies still protective in RMD cases after 4 months of the third antigen exposition. The booster vaccination reduces the frequency of hospital admissions and mortality with ai RMDs. The vaccinations are effective independently from the type of vaccine, the SARS-CoV-2 specific memory B-cell populations showed a statistically not significant but lower frequency in the infection group. Clinical activity of aiRMDs was not increased following booster vaccination.ConclusionPatients, who received a heterologous booster vaccine had a higher level of peripheral memory B-cells compared to those who had COVID-19 infection. Biologic therapy decreased the level of B-cells. Patients with a disease duration of more than 10 years had higher level of CD8+TNF-α+ and CD8+IFN-γ+ T-cells compared to patients who were diagnosed less than 10 years ago. The third booster mRNA-based vaccine was as much effective as in the homologous and heterologous patients groups compared who had COVID infection.References[1] Szebeni, G.J.;Gemes, N.;Honfi, D.;Szabo, E.;Neuperger, P.;Balog, J.A.;Nagy, L.I.;Szekanecz, Z.;Puskas, L.G.;Toldi, G.;et al. Humoral and Cellular Immunogenicity and Safety of Five Different SARS-CoV-2 Vaccines in Patients With Autoimmune Rheumatic and Musculoskeletal Diseases in Remission or With Low Disease Activity and in Healthy Controls: A Single Center Study. Front. Immunol. 2022, 13, 846248.[2]Honfi, D.;Gémes, N.;Szabó, E.;Neuperger, P.;Balog, J.Á.;Nagy, L.I.;Toldi, G.;Puskás, L.G.;Szebeni, G.J.;Balog, A. Comparison of Homologous and Heterologous Booster SARS-CoV-2 Vaccination in Autoimmune Rheumatic and Musculoskeletal Patients. Int. J. Mol. Sci. 2022, 23, 11411Acknowledgements:NIL.Disclosure of InterestsNone Declared.

Precise Epitope Organization with Self‐adjuvant Framework Nucleic Acid for Efficient COVID‐19 Peptide Vaccine Construction

Peptide vaccines have advantages in easy fabrication and high safety, but their effectiveness is hampered by the poor immunogenicity of the epitopes themselves. Herein, we constructed a series of framework nucleic acids (FNAs) with regulated rigidity and size to precisely organize epitopes in order to reveal the influence of epitope spacing and carrier rigidity on the efficiency of peptide vaccines. We found that assembling epitopes on rigid tetrahedral FNAs (tFNAs) with the appropriate size could efficiently enhance their immunogenicity. Further, by integrating epitopes from SARS‐CoV‐2 on preferred tFNAs, we constructed a COVID‐19 peptide vaccine which could induce high titers of IgG against the receptor binding domain (RBD) of SARS‐CoV‐2 spike protein and increase the ratio of memory B and T cells in mice. Considering the good biocompatibility of tFNAs, our research provides a new idea for developing efficient peptide vaccines against viruses and possibly other diseases.

The Role of Active Immunity and its Types

When a pathogen activates B cells and T cells, memory B cells and memory T cells form, and the major immune response happens as a result. These memory cells "remember" every unique pathogen an animal encounters over the course of its lifetime and can develop a potent secondary response if the pathogen is discovered again. Due to the immune system's proactive self-preparation, this sort of immunity is both active and adaptable. The innate immune system and both the cell-mediated and humoral components of immunity are frequently involved in active immunity. Here, Maiorino discusses the naturally and artificially acquired active immunity.

Vaccination provides superior in vivo recall capacity of SARS-CoV-2-specific memory CD8 T cells.

Memory CD8 T cells play an important role in the protection against breakthrough infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Whether the route of antigen exposure impacts these cells at a functional level is incompletely characterized. Here, we compare the memory CD8 T cell response against a common SARS-CoV-2 epitope after vaccination, infection, or both. CD8 T cells demonstrate comparable functional capacity when restimulated directly ex vivo, independent of the antigenic history. However, analysis of T cell receptor usage shows that vaccination results in a narrower scope than infection alone or in combination with vaccination. Importantly, in an in vivo recall model, memory CD8 T cells from infected individuals show equal proliferation but secrete less tumor necrosis factor (TNF) compared with those from vaccinated people. This difference is negated when infected individuals have also been vaccinated. Our findings shed more light on the differences in susceptibility to re-infection after different routes of SARS-CoV-2 antigen exposure.

Effector memory T cell subset CD45RA−CCR7−CD27−CD28− EM3 increases in direct proportion to the disease severity of COVID‐19

COVID‐19, which emerged in December 2019 and continues to wreak havoc, has led to the death of many people around the world. In this study, we aimed to uncover the variables underlying the exacerbation of the disease by considering the changes in T cell subsets in adults and juveniles with different disease severity of COVID‐19. Peripheral blood samples of 193 patients (128 adults and 65 juveniles) diagnosed with COVID‐19 were evaluated in a flow cytometer, and a broad T cell profile was revealed by examining T cell subsets in terms of exhaustion and senescence. We found remarkable differences in the effector memory (EM;CD45RA−CCR7−) cell subsets of severe pneumonia cases. The frequencies of EM2 CD4+ T, EM3 CD4+ T, EM3 CD8+ T, EM2 DN T and EM3 DN T cells were found to increase in severe pneumonia cases. Consistently, these cells were found in juveniles and uncomplicated adults in similar or lower proportions to healthy controls. The findings of our study provide a view of the T cell profile that may underlie differences in the course of COVID‐19 cases in juveniles and adults and may provide new insights into the development of effective treatment strategies.

Atypical Inflammatory Syndrome Triggered by SARS-CoV-2 in Infants With Down Syndrome

PURPOSE OF THE STUDY: The aim of this study was to identify unique clinical features and immune markers in infants with Down Syndrome (DS) affected by multisystem inflammatory syndrome (MIS-C). STUDY POPULATION: Cases were 2 unrelated infant girls with DS ages 6 months (P1) and 8 months (P2) admitted to the hospital for MIS-C illness for over 4 months (n = 2). The first control group included infants without DS with MIS-C illness (n = 2) from an outpatient setting. The second control group included 10 children with DS unaffected by MIS-C illness from an outpatient setting. METHODS: This was a case-control study that compared the clinical characteristics including immune phenotyping between infants with Down Syndrome (DS) affected by MIS-C and age-matched controls with or without DS. Clinical characteristics were collected from P1 and P2 by chart review, and literature review was done for clinical characteristics of children with MIS-C without DS. Samples of blood were collected from the 2 cases and controls. Subsequently, both mass cytometry and multiplex cytokine analysis were performed. Unpaired t-tests were used to assess the significances of differences in quantitative variables between 2 groups. RESULTS: Both patients with DS and MIS-C had significant neutrophilia and profound B-cell lymphopenia when compared with children with DS without MIS-C (P = .008). Specifically, both patients had decreased memory and plasma B cell subsets, whereas naïve B cells were increased. Control patients with acute MIS-C without DS had normal B cell counts. Activated CD4 T cells were decreased in both patients. P1's neutrophils and monocytes had markedly increased intracellular interleukein-8 and interleukin-1β, but this was not seen in P2. Both patients had markedly elevated inflammatory and immune activation markers. CONCLUSIONS: Children with Down Syndrome affected by MIS-C can have an atypical and severe presentation compared with children affected by MIS-C without DS, hallmarked by significant B cell depletion, younger age of onset, prolonged hospital stay, and refractoriness to treatment.

SARS-CoV-2−Reactive Mucosal B Cells in the Upper Respiratory Tract of Uninfected Individuals

PURPOSE OF THE STUDY: To investigate the role of the mucosal immune system of the upper respiratory tract in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection by exploration of the presence of pre-existing mucosal SARS-CoV-2-reactive B cells in tonsillar tissue specimens. STUDY POPULATION: Tonsillar tissue from pediatric patients who underwent tonsillectomy at The Hospital for Sick Children in Toronto, Canada in 2015 to 2016, before the COVID-19 pandemic. METHODS: Using flow cytometry and fluorescently labeled tetramers to the SARS-CoV-2 Spike protein (S-protein), SARS-CoV-2-reactive B cells were isolated from tonsillar tissue. Monoclonal antibodies (mAbs) recognizing the SARS-CoV-2 S-protein were generated from these B-cells using single-cell real time-polymerase chain reaction and RNA sequencing. Human embryonic kidney derived cell lines expressing SARS-CoV-2 S protein were used for in vitro assays assessing the mAbs' SARS-CoV-2 recognition and Ag binding. RESULTS: Pre-existing SARS-CoV-2-reactive B cells were identified and isolated from prepandemic human tonsillar tissue. The mAbs generated from these B cells recognized the S-protein of the wild-type SARS-CoV-2 virus. Additionally, the mAbs originated from naïve B cells as well as Ag-experienced memory B cells, germinal center B cells, and plasma cells. These mAbs were able to partially block binding in vitro by consistently showing >20% inhibition of S-protein binding. The antibodies did not react to the S-proteins of endemic coronaviruses, human coronavirus-OC43 and human coronavirus-229E. The antibodies also demonstrated significantly reduced recognition of the SARS-CoV-2 B.1.1.7 and B1.315 variants. CONCLUSIONS: B cells contained in the lymphoid tissues of the upper respiratory tract can contain pre-existing SARS-CoV-2 reactive antibodies. Monoclonal antibodies generated by these B-cells demonstrated in vitro SARS-CoV-2 recognition and neutralizing potential. However, these mAbs had reduced binding to the Spike proteins of SARS-CoV-2 variants and did not recognize endemic coronaviruses. The existence of these antibodies may explain the variation in COVID-19 symptom severity since these pre-existing Abs may lead to rapid engagement of the SARS-CoV-2 pathogen as the mucosal surface of the respiratory tract is a main point of contact.

Heterologous Booster Dose with CORBEVAX following Primary Vaccination with COVISHIELD Enhances Protection against SARS-CoV-2.

Despite effective vaccination programs, waning immunity in the vaccinated populations and the emergence of variants of concern posed a risk of breakthrough infections. A booster dose was demonstrated to provide substantially increased protection against symptomatic disease and hospitalization. We aimed to evaluate immune memory and the efficacy of reducing the rate of SARS-CoV-2 infection post heterologous booster with CORBEVAX after primary vaccination with two doses of COVISHIELD. SARS-CoV-2 S1/S2 spike IgG and RBD-specific antibody responses were elicited with both booster vaccines, with a greater response in individuals receiving heterologous booster. T and B memory responses were increased with booster dose, whereas B memory needed a longer duration to develop in individuals who received a homologous booster (90 days) in comparison to a heterologous booster (30 days). RBD-specific B memory and antibody-secreting (non-memory) B lymphocytes were enhanced with both boosters; however, the duration of response was longer with the heterologous booster compared to the homologous, indicating greater protection with the heterologous booster. The rate of infection 14 days after administration of the heterologous booster was comparatively lower than that of the homologous booster, with the symptoms being much less or asymptomatic.

Tissue immunity to SARS-CoV-2: Role in protection and immunopathology.

The SARS-CoV-2 pandemic has demonstrated the importance of studying antiviral immunity within sites of infection to gain insights into mechanisms for immune protection and disease pathology. As SARS-CoV-2 is tropic to the respiratory tract, many studies of airway washes, lymph node aspirates, and postmortem lung tissue have revealed site-specific immune dynamics that are associated with the protection or immunopathology but are not readily observed in circulation. This review summarizes the growing body of work identifying immune processes in tissues and their interplay with immune responses in circulation during acute SARS-CoV-2 infection, severe disease, and memory persistence. Establishment of tissue resident immunity also may have implications for vaccination and the durability of immune memory and protection.

COVID19 disease severity influences the expression of markers of durability in memory B cells

OBJECTIVES/GOALS: Studies have shown that SARS-CoV-2 specific memory B cells can be maintained at least a year after exposure. However, reports show an altered B cell response during infection in severe COVID-19 cases. This study aims to describe the B cell response during COVID-19 convalescence with a focus on signatures that contribute to durable and robust immunity. METHODS/STUDY POPULATION: Our study cohort consisted of individuals who had recovered from non-severe (hospitalized) or severe (hospitalized and requiring invasive mechanical ventilation) COVID-19. In our comparative analysis, samples from both groups were carefully matched to fall within 4-5 weeks post-symptom onset. We also performed a longitudinal analysis of non-severe patients with sampling ending 5 months post-symptom onset. Using high parameter flow cytometry, we characterized the phenotype of memory B cells using 19 distinct cell markers and fluorescently labeled probes to identify B cells reactive with SARS-CoV-2 spike and receptor-binding domain protein. Additionally, serum collected from individuals was used to quantify antibody titers. RESULTS/ANTICIPATED RESULTS: The frequency of spike-specific B cells and serum antibody titers were similar between severe and non-severe groups. However, we observed that individuals recovered from severe COVID-19 have a significantly reduced frequency of spike specific IgG+ memory B cells expressing Tbet and FcRL5 (markers associated with long lived immunity). In the non-severe patients, we observed IgG+Tbet+ B cells targeting the spike protein peak at 2-3 weeks post-symptom onset, decrease by almost fifty percent 4-5 weeks post-symptom onset, and return to baseline 5 months post-symptom onset. Our study also validated previous findings of a short-lived primary response of IgM+ B cells targeting the spike protein. DISCUSSION/SIGNIFICANCE: Our findings highlight potential implications for long-term immunity against re-infection or severity of the resulting disease in patients with severe COVID-19. Further investigation will be necessary to determine whether the maintenance of immunological protection is hindered in patients who overcame severe COVID-19.

ROLE of the CELLULAR IMMUNITY in the FORMATION of the IMMUNE RESPONSE in CORONAVIRUS INFECTIONS

The data obtained during previous epidemics caused by coronaviruses, and current pandemic indicate that assessing the role of certain immune interactions between these viruses and the macroorganism is the main pre-requisite for development of diagnostic test systems as well as effective medical drugs and preventive measures. The review summarizes the results of studying patho- and immunogenesis of SARS-CoV, MERS-CoV, and SARS-CoV-2 infections. These coronaviruses were proven to suppress development of adaptive immune response at the stage of its induction, affecting the number and functional activity of lymphocytes, effectors of cellular immunity, causing impairment of lymphopoiesis, apoptosis and «depletion» of these cells, thus leading to longer duration of the disease and increased viral load. Information about the role of cellular immunity in development of immune response to coronaviruses is presented. It was proven that the causative agents of SARS, MERS and COVID-19 trigger adaptive immune response in the macroorganism according to both humoral and cellular types. Moreover, the synthesis of specific immunoglobulins does not yet point to presence of protective immune response. Activation of the cellular link of immunity is also important. A high degree of antigenic epitope homology in SARS-CoV, MERS-CoV and SARS-CoV-2 is described, thus suggesting an opportunity for cross-immunity to coronaviruses. The review addresses issues related to the terms of specific memory immune cells to SARS-CoV, MERS-CoV and SARS-CoV-2, and their role in providing long-term protection against these infections. Given that specific antibodies to SARS and MERS pathogens persisted for a year, were often not detected or briefly registered in patients with mild and asymptomatic infections, we can talk about important role of the cellular immune response in providing immunity to these coronaviruses. It was shown that, in contrast to antibodies, the antigen-specific memory T cells were registered in patients with SARS virus for 4 to 11 years, and Middle East Respiratory Syndrome - up to two years. Further research is needed to determine presence and number of memory T cells in COVID-19. A comparative analysis of data obtained during previous epidemics with respect to formation of adaptive immunity to coronaviruses. Description of proteins and epitopes recognized by human T lymphocytes will be useful in monitoring immune responses in COVID-19 patients, as well as in developing informative tests to study T cell immune response to SARS-CoV-2 and new preventive drugs. © 2021 Russian Association of Allergologists and Clinical Immunologists, St. Petersburg Regional Branch (SPb RAACI). All rights reserved.

SARS-CoV-2 Vaccine Induced Atypical Immune Responses in Antibody Defects: Everybody Does their Best.

BACKGROUND: Data on immune responses to SARS-CoV-2 in patients with Primary Antibody Deficiencies (PAD) are limited to infected patients and to heterogeneous cohorts after immunization. METHODS: Forty-one patients with Common Variable Immune Deficiencies (CVID), six patients with X-linked Agammaglobulinemia (XLA), and 28 healthy age-matched controls (HD) were analyzed for anti-Spike and anti-receptor binding domain (RBD) antibody production, generation of Spike-specific memory B-cells, and Spike-specific T-cells before vaccination and one week after the second dose of BNT162b2 vaccine. RESULTS: The vaccine induced Spike-specific IgG and IgA antibody responses in all HD and in 20% of SARS-CoV-2 naive CVID patients. Anti-Spike IgG were detectable before vaccination in 4 out 7 CVID previously infected with SARS-CoV-2 and were boosted in six out of seven patients by the subsequent immunization raising higher levels than patients naïve to infection. While HD generated Spike-specific memory B-cells, and RBD-specific B-cells, CVID generated Spike-specific atypical B-cells, while RBD-specific B-cells were undetectable in all patients, indicating the incapability to generate this new specificity. Specific T-cell responses were evident in all HD and defective in 30% of CVID. All but one patient with XLA responded by specific T-cell only. CONCLUSION: In PAD patients, early atypical immune responses after BNT162b2 immunization occurred, possibly by extra-follicular or incomplete germinal center reactions. If these responses to vaccination might result in a partial protection from infection or reinfection is now unknown. Our data suggests that SARS-CoV-2 infection more effectively primes the immune response than the immunization alone, possibly suggesting the need for a third vaccine dose for patients not previously infected.

Exhausted NK cells and cytokine storms in COVID-19: Whether NK cell therapy could be a therapeutic choice.

The global outbreak of coronavirus-2019 (COVID-19) still claims more lives daily around the world due to the lack of a definitive treatment and the rapid tendency of virus to mutate, which even jeopardizes vaccination efficacy. At the forefront battle against SARS-CoV-2, an effective innate response to the infection has a pivotal role in the initial control and treatment of disease. However, SARS-CoV-2 subtly interrupts the equations of immune responses, disrupting the cytolytic antiviral effects of NK cells, while seriously activating infected macrophages and other immune cells to induce an unleashed "cytokine storm", a dangerous and uncontrollable inflammatory response causing life-threatening symptoms in patients. Notably, the NK cell exhaustion with ineffective cytolytic function against the sources of exaggerated cytokine release, acts as an Achilles' heel which exacerbates the severity of COVID-19. Given this, approaches that improve NK cell cytotoxicity may benefit treatment protocols. As a suggestion, adoptive transfer of NK or CAR-NK cells with proper cytotolytic potentials and the lowest capacity of cytokine-release (for example CD56dim NK cells brightly express activating receptors), to severe COVID-19 patients may provide an effective cure especially in cases suffering from cytokine storms. More intriguingly, the ongoing evidence for persistent clonal expansion of NK memory cells characterized by an activating phenotype in response to viral infections, can benefit the future studies on vaccine development and adoptive NK cell therapy in COVID-19. Whether vaccinated volunteers or recovered patients can also be considered as suitable candidates for cell donation could be the subject of future research.

Tapping the immunological imprints to design chimeric SARS-CoV-2 vaccine for elderly population.

The impact of SARS-CoV-2 and COVID-19 disease susceptibility varies depending on the age and health status of an individual. Currently, there are more than 140 COVID-19 vaccines under development. However, the challenge will be to induce an effective immune response in the elderly population. Analysis of B cell epitopes indicates the minor role of the stalk domain of spike protein in viral neutralization due to low surface accessibility. Nevertheless, the accumulation of mutations in the receptor-binding domain (RBD) might reduce the vaccine efficacy in all age groups. We also propose the concept of chimeric vaccines based on the co-expression of SARS-CoV-2 spike and influenza hemagglutinin (HA) and matrix protein 1 (M1) proteins to generate chimeric virus-like particles (VLP). This review discusses the possible approaches by which influenza-specific memory repertoire developed during the lifetime of the elderly populations can converge to mount an effective immune response against the SARS-CoV-2 spike protein with the possibilities of designing single vaccines for COVID-19 and influenza. HighlightsImmunosenescence aggravates COVID-19 symptoms in elderly individuals.Low immunogenicity of SARS-CoV-2 vaccines in elderly population.Tapping the memory T and B cell repertoire in elderly can enhance vaccine efficiency.Chimeric vaccines can mount effective immune response against COVID-19 in elderly.Chimeric vaccines co-express SARS-CoV-2 spike and influenza HA and M1 proteins.

Coronavirus infection: An immunologists' perspective.

Coronavirus infections are frequent viral infections in several species. As soon as the severe acute respiratory syndrome (SARS) appeared in the early 2000s, most of the research focused on pulmonary disease. However, disorders in immune response and organ dysfunctions have been documented. Elderly individuals with comorbidities exhibit worse outcomes in all the coronavirus that cause SARS. Disease severity in SARS-CoV-2 infection is related to severe inflammation and tissue injury, and effective immune response against the virus is still under analysis. ACE2 receptor expression and polymorphism, age, gender and immune genetics are factors that also play an essential role in patients' clinical features and immune responses and have been partially discussed. The present report aims to review the physiopathology of SARS-CoV-2 infection and propose new research topics to understand the complex mechanisms of viral infection and viral clearance.

COVID-19 convalescent plasma composition and immunological effects in severe patients.

Convalescent plasma (CP) has emerged as a treatment for COVID-19. However, the composition and mechanism of action are not fully known. Therefore, we undertook a two-phase controlled study in which, first the immunological and metabolomic status of recovered and severe patients were evaluated. Secondly, the 28-day effect of CP on the immune response in severe patients was assessed. Nineteen recovered COVID-19 patients, 18 hospitalized patients with severe disease, and 16 pre-pandemic controls were included. Patients with severe disease were treated with CP transfusion and standard therapy (i.e., plasma recipients, n = 9) or standard therapy alone (n = 9). Clinical and biological assessments were done on day 0 and during follow-up on days 4, 7, 14, and 28. Clinical parameters, viral load, total immunoglobulin (Ig) G and IgA anti-S1-SARS-CoV-2 antibodies, neutralizing antibodies (NAbs), autoantibodies, cytokines, T and B cells, and metabolomic and lipidomic profiles were examined. Total IgG and IgA anti-S1-SARS-CoV-2 antibodies were key factors for CP selection and correlated with NAbs. In severe COVID-19 patients, mostly interleukin (IL)-6 (P = <0.0001), IL-10 (P = <0.0001), IP-10 (P = <0.0001), fatty acyls and glycerophospholipids were higher than in recovered patients. Latent autoimmunity and anti-IFN-α antibodies were observed in both recovered and severe patients. COVID-19 CP induced an early but transient cytokine profile modification and increases IgG anti-S1-SARS-CoV-2 antibodies. At day 28 post-transfusion, a decrease in activated, effector and effector memory CD4+ (P < 0.05) and activated and effector CD8+ (P < 0.01) T cells and naïve B cells (P = 0.001), and an increase in non-classical memory B cells (P=<0.0001) and central memory CD4+ T cells (P = 0.0252) were observed. Moreover, IL-6/IFN-γ (P = 0.0089) and IL-6/IL-10 (P = 0.0180) ratios decreased in plasma recipients compared to those who received standard therapy alone. These results may have therapeutic implications and justify further post-COVID-19 studies.

Cell-mediated and humoral adaptive immune responses to SARS-CoV-2 are lower in asymptomatic than symptomatic COVID-19 patients.

The characterization of cell-mediated and humoral adaptive immune responses to SARS-CoV-2 is fundamental to understand COVID-19 progression and the development of immunological memory to the virus. In this study, we detected T-cells reactive to SARS-CoV-2 proteins M, S, and N, as well as serum virus-specific IgM, IgA, IgG, in nearly all SARS-CoV-2 infected individuals, but not in healthy donors. Virus-reactive T cells exhibited signs of in vivo activation, as suggested by the surface expression of immune-checkpoint molecules PD1 and TIGIT. Of note, we detected antigen-specific adaptive immune response both in asymptomatic and symptomatic SARS-CoV-2 infected subjects. More importantly, symptomatic patients displayed a significantly higher magnitude of both cell-mediated and humoral adaptive immune response to the virus, as compared to asymptomatic individuals. These findings suggest that an uncontrolled adaptive immune response contribute to the development of the life-threatening inflammatory phase of the disease. Finally, this study might open the way to develop effective vaccination strategies.