Protocols of Standard of Care for Adult Patients with Primary Antibody Deficiencies Will Improve Timing of Diagnosis, Survival, and Quality of Life.

The majority of primary immunodeficiencies (PIDs) are antibody deficiencies (PADs), and not all of them are rare diseases; As an example, Caucasian individuals suffer from selective IgA deficiency at a frequency of 1:500. In addition to infections, symptomatic patients with PAD are more likely to develop neoplastic, autoimmune, and allergic diseases. In the event that PAD is neglected or delayed for more than ten years, complications develop, eventually resulting in death. No studies have been conducted to devise and report detailed ready-to-use protocols for managing PAD to date. This study aimed to propose protocols and guidelines for the adult PAD patients' standard care. Preparing the protocol, we considered the frequency and type of laboratory tests, imaging, endoscopic examinations, specialist consultations, and standardized recommendations for further care in the place of residence.  As a result of the proposed monitoring scheme, patients can be provided with complete care in terms of their underlying conditions and comorbidities, as well as early detection of complications. This protocol will serve as a guide for physicians dealing with these patients and enable comparisons of patient groups across a variety of treatment centers, even far away from each other. A national consultant in the field of clinical immunology verified the protocol mainly developed by Polish experts from reference immunology centres for adults.

Relationship between Selective IgA Deficiency and COVID-19 Prognosis.

The prevalence and mortality rates of coronavirus disease 2019 (COVID-19) widely vary among populations. Mucosal immunity is the first barrier to the pathogen's entry into the body. Immunoglobulin A (IgA) is the primary antibody responsible for mucosal immunity. We explored the relationship between selective IgA deficiency (SIgAD) and COVID-19 severity. We included 424 patients (203 women) with COVID-19. Eleven patients had SIgAD. Laboratory data of patients with SIgAD and normal IgA levels were compared. The relationship between SIgAD and severe COVID-19 infection was explored using logistic regression analysis. In the univariate logistic regression analysis, the risk of severe COVID-19 disease in patients with SIgAD was approximately 7.7-fold higher than that in other patients (odds ratio [OR], 7.789; 95% confidence interval [CI], 1.665-36.690, P = 0.008), while it was 4-fold (OR, 4.053; 95% CI, 1.182-13.903, P = 0.026) higher in the multivariate logistic regression analysis. Serum IgA levels were positively correlated with total lymphocyte counts and negatively correlated with C-reactive protein levels, which was a risk factor for severe COVID-19. In patients with SIgAD, the number of severe acute respiratory coronaviruses 2 that pass through mucosal membranes may be increased, leading to complications such as cytokine storm syndrome and acute respiratory distress syndrome.

Intranasal pediatric parainfluenza virus-vectored SARS-CoV-2 vaccine candidate is protective in macaques (preprint)

SUMMARY Pediatric SARS-CoV-2 vaccines are needed that elicit immunity directly in the airways, as well as systemically. Building on pediatric parainfluenza virus vaccines in clinical development, we generated a live-attenuated parainfluenza virus-vectored vaccine candidate expressing SARS-CoV-2 prefusion-stabilized spike (S) protein (B/HPIV3/S-6P) and evaluated its immunogenicity and protective efficacy in rhesus macaques. A single intranasal/intratracheal dose of B/HPIV3/S-6P induced strong S-specific airway mucosal IgA and IgG responses. High levels of S-specific antibodies were also induced in serum, which efficiently neutralized SARS-CoV-2 variants of concern. Furthermore, B/HPIV3/S-6P induced robust systemic and pulmonary S-specific CD4 + and CD8 + T-cell responses, including tissue-resident memory cells in lungs. Following challenge, SARS-CoV-2 replication was undetectable in airways and lung tissues of immunized macaques. B/HPIV3/S-6P will be evaluated clinically as pediatric intranasal SARS-CoV-2/parainfluenza virus type 3 vaccine. One-Sentence Summary Intranasal parainfluenza virus-vectored COVID-19 vaccine induces anti-S antibodies, T-cell memory and protection in macaques.

Elevated levels of IL-6 in IgA nephropathy patients are induced by an epigenetically driven mechanism triggered by viral and bacterial RNA (preprint)

ABSTRACT Recently, several models have been proposed to describe the pathogenesis of Immunoglobulin A nephropathy (IgAN), and among them the multihit and the gut-microbiota. Newly, the role of IL-6 in pathogenesis is becoming increasingly important but reason why levels of IL-6 are elevated in IgAN patients is not well understood. One attainable hypothesis on high levels of IL-6 in IgAN comes out from our recent whole genome DNA methylation screening in IgAN patients, that identified, among others, a hypermethylated region comprising Vault RNA 2-1 (VTRNA2-1), a non-coding RNA. Consistently, the VTRNA2-1 expression was found down-regulated in IgAN patients. Here we confirm that VTRNA2-1 is low expressed in IgAN subjects compared to HS and we found that also in transplanted IgAN patients (TP-IgAN), compared to non-IgAN transplanted patients (TP), the VTRNA2-1 transcript was expressed at level very low. We found that in IgAN patients with downregulated VTRNA2-1, PKR is overactivated, coherently with the role of the VTRNA2-1 that binds to PKR and inhibits its phosphorylation. The loss of the VTRNA2-1 natural restrain caused the activation of CREB by PKR, a classical cAMP-inducible CRE-binding factor interacting with a region of the IL-6 promoter and leading to IL-6 production. We found higher CREB phosphorylation levels and IL-6 levels both in IgAN and in TP-IgAN patients. Since PKR is normally activated by bacterial and viral RNA, we hypothesized that these microorganisms can further activate the PKR/CREB/IL-6 pathway leading to an excess of IL-6 production, explaining both the high levels of IL-6, both infection involvement in the disease, both cases of IgAN associated with COVID-19 infection and with COVID-19 RNA-vaccination. Effectively, we found that both the RNA poly(I:C) and the COVID-19 RNA-vaccine stimulation significantly increase the IL-6 levels in IgAN patient PBMCs. In conclusion, the discovery of the upregulated VTRNA2-1/PKR/CREB/IL-6 pathway in IgAN patients may provide novel approach to treat the disease and may be useful for development of precision nephrology and personalized therapy, possibly by checking the VTRNA2-1 methylation level in IgAN patients.

Clinicopathological and Immunological Features of Patients With New Onset Kidney Disease After Inactivated SARS-CoV-2 Vaccination: An Observational Cohort Study (preprint)

Background: The onset of various kidney diseases have been reported after COVID-19 vaccination. However, detailed clinical and pathological examination of kidney injury in patients receiving inactivated vaccines are lacking.Methods: We screened and analyzed patients with newly diagnosed kidney diseases after inactivated SARS-CoV-2 vaccination in Peking University First Hospital from January 2021 to August 2021. We obtained samples of blood, urine, and renal biopsy tissues. Clinical and laboratory information, as well as light microscopy, immunostaining and ultrastructural observation were described. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Spike protein and Nucleoprotein were stained using immune-fluorescence technique in the kidney biopsy samples. SARS-CoV-2 specific antibodies were tested using magnetic particle chemiluminescence immunoassay.Findings: The study group included 17 patients, including immune complex mediated kidney diseases (IgA nephropathy, membranous nephropathy and lupus nephritis), podocytopathy (minimal change disease and focal segmental glomerulosclerosis) and others (antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, anti-GBM nephritis, acute tubulointerstitial nephritis, and thrombotic microangiopathy). Seven patients (41.18%) developed renal disease after the first dose and 10 (58.82%) after the second dose. We found no definitive evidence of SARS-CoV-2 Spike protein or Nucleoprotein deposition in the kidney biopsy samples. Serological markers implicated abnormal immune responses in predisposed individuals. Treatment and follow-up (median = 86 days) showed that biopsy diagnosis informed treatment and prognosis in all patients.Interpretation: We observed various kidney diseases following inactivated SARS-CoV-2 vaccine administration. Our findings provide an evidence against direct vaccine protein deposition as the major pathomechanism, but implicate abnormal immune responses in predisposed individuals. These findings expand our understanding of inactivated SARS-CoV-2 vaccine renal safety.Funding: This study was funded by National Natural Science Foundation of China (91742205, 82170711, 81800636, 82070733, 81625004), Clinical Medicine Plus X—Young Scholars Project of Peking University (PKU2021LCXQ017), the Fundamental Research Funds for the Central Universities, CAMS Innovation Fund for Medical Sciences (2019-I2M-5-046), Yunnan Provincial Science and Technology Department (202102AA100051 and 202003AC100010, China), and Beijing Young Scientist Program (BJJWZYJH01201910001006).Declaration of Interest: The authors declare no competing interests.Ethical Approval: This study was approved by the institutional review board of Peking University First Hospital (2021-352) and the Committee on Human Subject Research and Ethics of Yunnan University (CHSRE2021020). Written Informed Consent Form was obtained from each participant.

IgA Antibodies and IgA Deficiency in SARS-CoV-2 Infection.

A large repertoire of IgA is produced by B lymphocytes with T-independent and T-dependent mechanisms useful in defense against pathogenic microorganisms and to reduce immune activation. IgA is active against several pathogens, including rotavirus, poliovirus, influenza virus, and SARS-CoV-2. It protects the epithelial barriers from pathogens and modulates excessive immune responses in inflammatory diseases. An early SARS-CoV-2 specific humoral response is dominated by IgA antibodies responses greatly contributing to virus neutralization. The lack of anti-SARS-Cov-2 IgA and secretory IgA (sIgA) might represent a possible cause of COVID-19 severity, vaccine failure, and possible cause of prolonged viral shedding in patients with Primary Antibody Deficiencies, including patients with Selective IgA Deficiency. Differently from other primary antibody deficiency entities, Selective IgA Deficiency occurs in the vast majority of patients as an asymptomatic condition, and it is often an unrecognized, Studies are needed to clarify the open questions raised by possible consequences of a lack of an IgA response to SARS-CoV-2.

Chimeric hPIV2/Corona-Spike Nasal Vaccine Robustly Protects the Upper and Lower Airways Against SARS-CoV-2 (preprint)

We developed an intranasal vaccine against SARS-CoV-2 using the replication-incompetent human parainfluenza virus type 2 (hPIV2) vector BC-PIV, which can deliver ectopic gene as stable RNA and ectopic protein on the envelope. BC-PIV expressing the full-length prefusion-stabilized spike gene of SARS-CoV-2, S2PM, possessed a corona-like viral envelope. Intranasal vaccination of mice with BC-PIV/S2PM induced high levels of neutralizing IgG and mucosal IgA antibodies against the spike protein. While BC-PIV showed hemagglutinating activity, BC-PIV/S2PM lacked such activity, in accordance with the presence of the massive spike protein on the viral surface. Furthermore, single-dose intranasal vaccination of hamsters with BC-PIV/S2PM completely protected the lungs from SARS-CoV-2 at 11 weeks post-immunization, and prime-boost vaccination conferred virtually complete protection of the nasal turbinates against SARS-CoV-2 challenge at 11 weeks post-priming. Thus, this chimeric hPIV2/spike intranasal vaccine is one of the strong candidates for an ultimate vaccine against SARS-CoV-2 to curtail virus transmission.Funding: This work was supported in part by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology in Japan (17K19652, 20K21614), by a Research Program on Emerging and Re-emerging Infectious Diseases from the Japan Agency for Medical Research and Development (AMED) (JP19fk0108113), Mie University (for research institutes of excellence), Mie Prefecture, Junior Chamber International Yokkaichi, and MediciNova, Inc.Conflict of Interest: J.O., M.F., M.Im., R.O., S.Y., Y.Kaw., and T.N. are patent applicants for recombinant BCPIV vaccine against SARS-CoV-2. M.F. is a founder of BioComo, Inc., and J.O. is an employee of BioComo, Inc. J.O., M.F., M.M., and T.N. have shares of stock in Biocomo, Inc. M.M. is a scientific advisor of JEOL Ltd. T.N. is a scientific advisor of MediciNova, Inc. The other authors declare no competing interests.Ethical Approval: Recombinant DNA experiments with SARS-CoV-2 S gene fragments were approved by the Ministry of Education, Culture, Sports, Science and Technology in Japan (Approved No. 2019-728, 729; 2020-362, 373, 948). The animal studies were approved by the Animal Care Committees of Mie University(Approved No. 23-33) and the Animal Experiment Committee of the Institute of Medical Science, the University of Tokyo (Approved No. PA19-75), and all methods were performed under institutional regulations of animal experiments in accordance with the current national guidelines. Animal experiments using SARS-CoV-2 S gene fragments orSARS-CoV-2 were also approved by the Ministry of Education, Culture, Sports, Science and Technology in Japan (Approved No. 2019-728, 729; 2020-362, 373, 2020-948).

History of the Discovery and Development of Biomodulina T (InmunyVital®), a Useful Immunomodulator with a Broad Range of Clinical Applications (preprint)

Biomodulina T, the active ingredient in InmunyVital®, is a polypeptide thymic factor that modulates immune responses and inflammation. Biomodulina T stimulates the differentiation, maturation and proliferation of CD3 T cell populations and CD4 and CD8 T cell subpopulations. Additionally, Biomodulina T improves the ability of T cells to produce cytokines, therefore enhancing T lymphocyte function. Additionally, Biomodulina T stimulates the thymus gland and, thus, promotes the recovery of normal thymus mass and size in children with thymic hypoplasia and restores the functions of immunosenescent T cells in aging people.The thymus gland slowly shrinks with age, and the levels of the thymic factors it produces decrease in the blood. Moreover, thymus-dependent immunity, including T cell immunity and thymus- dependent antibody production, decreases with thymus size in adult people. For that reason, older adults are generally at a higher risk of becoming severely ill from infectious diseases, such as influenza, COVID-19 and other diseases. As people age, “immunosenescence” occurs; immunosenescence means that with age, the ability to produce vigorous responses to infections gradually diminishes compared to that observed at younger ages during which the thymus gland, thymic factor levels, and immune responses are healthy and strong. In addition, in older adults, low-grade, chronic systemic inflammation, called “inflamm-aging”, occurs, and this phenomenon increases susceptibility to age-related inflammatory diseases.In 1984, with the aim of developing biological response modifiers, I established the laboratory of Biomodulators in Havana, where I created and developed the immunomodulatory thymic factor that I called “Biomodulina T”. The biological activity of Biomodulina T was demonstrated in several in vitro and in vivo studies in our laboratory and in independent laboratories. An extensive series of preclinical toxicological studies were conducted in different species, such as mice, rats, guinea pigs, rabbits and dogs. All these studies demonstrated that Biomodulina T is an active and safe thymic factor.We conducted clinical trials with Biomodulina T in patients with multiple sclerosis, chronic hepatitis B, rheumatoid arthritis, Crohn's disease, Behcet's syndrome, and selective deficiency of IgA as well as in geriatric populations. In 1994, I obtained the sanitary registration of Biomodulina T as an immunomodulatory drug.Since that time, we conducted other clinical trials in children with repeated infections and primary immunodeficiencies and in adults with systemic lupus erythematosus, uveitis, myasthenia gravis, chronic obstructive pulmonary disease (COPD), and respiratory infections.This article identifies the milestones involved in the creation and development of Biomodulina T. Since its discovery 35 years ago, the first and recent reports of new scientific advances show that Biomodulina T (InmunyVital®) is a modulator of immune responses and inflammation that is very useful for restoring the immune system in young and elderly people with allergies, asthma, immunodeficiency, autoimmune diseases, and infectious diseases. Biomodulina T is also useful as an immunotherapeutic agent for improving immune responses in the context of cancer and vaccines, for reversing immunosenescence and for improving the healthspan in general aging.

A High Content Screen for Mucin-1-Reducing Compounds Identifies Fostamatinib as a Candidate for Rapid Repurposing for Acute Lung Injury During the COVID-19 Pandemic (preprint)

Drug repurposing is the only method capable of delivering treatments on the shortened time-scale required for patients afflicted with lung disease arising from SARS-CoV-2 infection. Mucin-1 (MUC1), a membrane-bound molecule expressed on the apical surfaces of most mucosal epithelial cells, is a biochemical marker whose elevated levels predict the development of acute lung injury (ALI) and respiratory distress syndrome (ARDS), and correlate with poor clinical outcomes. In response to the pandemic spread of SARS-CoV-2, we took advantage of a high content screen of 3,713 compounds at different stages of clinical development to identify FDA-approved compounds that reduce MUC1 protein abundance. Our screen identified Fostamatinib (R788), an inhibitor of spleen tyrosine kinase (SYK) approved for the treatment of chronic immune thrombocytopenia, as a repurposing candidate for the treatment of ALI. In vivo, Fostamatinib reduced MUC1 abundance in lung epithelial cells in a mouse model of ALI. In vitro, SYK inhibition by Fostamatinib promoted MUC1 removal from the cell surface. Our work reveals Fostamatinib as a repurposing drug candidate for ALI and provides the rationale for rapidly standing up clinical trials to test Fostamatinib efficacy in patients with COVID-19 lung injury.Drug repurposing is the only method capable of delivering treatments on the shortened time-scale required for patients afflicted with lung disease arising from SARS-CoV-2 infection. Mucin-1 (MUC1), a membrane-bound molecule expressed on the apical surfaces of most mucosal epithelial cells, is a biochemical marker whose elevated levels predict the development of acute lung injury (ALI) and respiratory distress syndrome (ARDS), and correlate with poor clinical outcomes. In response to the pandemic spread of SARS-CoV-2, we took advantage of a high content screen of 3,713 compounds at different stages of clinical development to identify FDA-approved compounds that reduce MUC1 protein abundance. Our screen identified Fostamatinib (R788), an inhibitor of spleen tyrosine kinase (SYK) approved for the treatment of chronic immune thrombocytopenia, as a repurposing candidate for the treatment of ALI. In vivo, Fostamatinib reduced MUC1 abundance in lung epithelial cells in a mouse model of ALI. In vitro, SYK inhibition by Fostamatinib promoted MUC1 removal from the cell surface. Our work reveals Fostamatinib as a repurposing drug candidate for ALI and provides the rationale for rapidly standing up clinical trials to test Fostamatinib efficacy in patients with COVID-19 lung injury.Funding: FWKT has received research project grants from Rigel Pharmaceuticals, and has consultancy agreements with Rigel Pharmaceuticals, and is the Chief Investigator of an international clinical 290trial of a SYK inhibitor in IgA nephropathy (ClinicalTrials.gov NCT02112838), funded by Rigel Pharmaceuticals. Conflict of Interest: The authors declare no competing interests.