Immunotherapy: ALLOGENEIC UMBILICAL CORD BLOOD REGULATORY T CELLS DECREASE INFLAMMATION AND PRESERVE ANTI-TUMOR ACTIVITY OF CAR T CELLS

Background & Aim: With larger accessibility and increased number of patients being treated with CART cell therapy, real-world toxicity continues to remain a significant challenge to its widespread adoption. We have previously shown that allogeneic umbilical cord blood derived (UCB) regulatory T cells (Tregs) can resolve uncontrolled inflammation and can treat acute and immune mediated lung injury in a xenogenic model as well as in patients suffering from COVID-19 acute respiratory distress syndrome. The unique properties of UCB Tregs including: i) lack of plasticity when exposed to inflammatory micro-environments;ii) no requirement for HLA matching;iii) long shelf life of cryopreserved Tregs;and iv) immediate product availability for on demand treatment, makes them an attractive source for treating acute inflammatory syndromes. Therefore, we hypothesized that add-on therapy with UCB derived Tregs may resolve uncontrolled inflammation responsible for CART cell therapy associated toxicity. Methods, Results & Conclusion(s): UCB Tregs were added in 1:1 ratio to CART cells, where no interference in their ability to kill CD19+ Raji cells, was detected at different ratios : 8:1 (80.4% vs. 81.5%);4:1 (62.0% vs. 66.2%);2:1 (50.1% vs. 54.7%);1:1 (35.4% vs. 44.1%) (Fig 1A). In a xenogenic B cell lymphoma model, multiple injections of Tregs were administered after CART injection (Fig 1B), which did not impact distribution of CD8+ T effector cells (Fig 1C) or CART cells cells (Fig 1D) in different organs. No decline in the CAR T levels was observed in the Tregs recipients (Fig 1E). Specifically, no difference in tumor burden was detected between the two arms (Fig 2A). No tumor was detected in CART+Tregs in liver (Fig 2B) or bone marrow (Fig 2C). A corresponding decrease in multiple inflammatory cytokines in peripheral blood was observed in CART+Tregs when compared to CART alone (Fig 2D). Here we show "proof of concept" for add-on therapy with Tregs to mitigate hyper-inflammatory state induced by CART cells without interference in their on-target anti-tumor activity. The timing of Tregs administration after CART cells have had sufficient time for forming synapse with tumor cells allows for preservation of their anti-tumor cytotoxicity, such that the infused Tregs home to the areas of tissue damage to bind to the resident antigen presenting cells which in turn collaborate with Tregs to resolve inflammation. Such differential distribution of cells allow for a Treg "cooling blanket" and lays ground for clinical study. [Figure presented]Copyright © 2023 International Society for Cell & Gene Therapy

Cholinergic deficiency in the cholinergic system as a pathogenetic link in the formation of various syndromes in COVID-19.

According to recent data, several mechanisms of viral invasion of the central nervous system (CNS) have been proposed, one of which is both direct penetration of the virus through afferent nerve fibers and damage to the endothelium of cerebral vessels. It has been proven that the SARS-CoV-2 virus affects pathologically not only the human cardiorespiratory system but is also associated with a wide range of neurological diseases, cerebrovascular accidents, and neuromuscular pathologies. However, the observed post-COVID symptom complex in patients, manifested in the form of headache, "fog in the head," high temperature, muscle weakness, lowering blood pressure, does it make us think about the pathophysiological mechanisms that contribute to the development of this clinical picture? One possible explanation is a disruption in the signaling of the acetylcholine system (AChS) in the body. Viral invasions, and in particular COVID-19, can negatively affect the work of the AChS, disrupting its coordination activities. Therefore, the main goal of this literature review is to analyze the information and substantiate the possible mechanisms for the occurrence of post-COVID syndrome in people who have had COVID-19 from the standpoint of AChS dysfunctions.

NOISE POLLUTION AND ARTERIAL HYPERTENSION

Environmental noise significantly impacts human health and well-being. It is a widespread problem in Europe, where at least one in five people are exposed to harmful levels of noise. Hearing loss is the most known health effect related to noise exposure. There is, however, growing data that links noise exposure to hypertension, coronary artery disease, and stroke. According to some theories, this relationship may be explained by the indirect pathway of noise exposure, which can cause sympathetic and endocrine activation, as well as several cognitive and emotional responses, including annoyance. Noise exposure leads to stress reactions independent of cognitive involvement. There is a possibility that noise exerts its effects directly through synaptic interactions, as well as through cognitive and emotional effects. Epidemiological studies indicate that nocturnal noise exposure has more profound health consequences. Nighttime noise exposure is associated with an increase in heart rate due to sympathetic activation or parasympathetic withdrawal, and with an increase in blood pressure as well as endothelial dysfunction. Hypertension is a common condition and is an important risk indicator for other cardiovascular diseases. Previous studies showed an association between noise exposure, blood pressure and arterial hypertension. Meta-analysis of cross-sectional studies found an increase of hypertension prevalence per 10 dB increase in daytime average road traffic noise level. There is, however, some heterogeneity among these studies. Prospective studies have also found an association between aircraft noise exposure and hypertension, supporting the cross-sectional findings. The analyses, of data from the large Hypertension and Exposure to Noise near Airports (HYENA) study, showed that an increase in nocturnal aircraft noise exposure per 10 dB was associated with an increased incidence of hypertension. The meaningful effect of night-time aircraft noise on arterial hypertension was also observed in the prospective observation of the subset of individuals from that study. In a longitudinal observation of 420 participants, higher aircraft noise exposure during the night significantly associated with the incidence of hypertension. Previous cross-sectional case-control study conducted in 2015, in 2 suburban areas of Krakow, Poland, revealed an increase in blood pressure and arterial stiffness as determined by carotid - femoral pulse wave velocity in individuals exposed to increased aircraft noise levels. However, even short-term noise reduction, as experienced during the COVID-19 lockdown, may reverse those unfavorable effects. As a result of these observations, noise mitigation strategies are important for cardiovascular health.

SARS-CoV-2 Spike protein induces TLR4-mediated long-term cognitive dysfunction recapitulating post-COVID-19 syndrome in mice.

Cognitive dysfunction is often reported in patients with post-coronavirus disease 2019 (COVID-19) syndrome, but its underlying mechanisms are not completely understood. Evidence suggests that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Spike protein or its fragments are released from cells during infection, reaching different tissues, including the CNS, irrespective of the presence of the viral RNA. Here, we demonstrate that brain infusion of Spike protein in mice has a late impact on cognitive function, recapitulating post-COVID-19 syndrome. We also show that neuroinflammation and hippocampal microgliosis mediate Spike-induced memory dysfunction via complement-dependent engulfment of synapses. Genetic or pharmacological blockage of Toll-like receptor 4 (TLR4) signaling protects animals against synapse elimination and memory dysfunction induced by Spike brain infusion. Accordingly, in a cohort of 86 patients who recovered from mild COVID-19, the genotype GG TLR4-2604G>A (rs10759931) is associated with poor cognitive outcome. These results identify TLR4 as a key target to investigate the long-term cognitive dysfunction after COVID-19 infection in humans and rodents.

IMMUNO-PSYCHIATRY AND INFLAMMATION

: The discovery that the immune system can influence brain function and structure has profoundly changed the landscape of psychiatry. Repeated report of association of pro-inflammatory cytokines with major psychiatric disorders led to exploration of the causes and consequences of this inflammatory background. This low-grade inflammation has been shown to be the consequence of interaction between environmental factors such as infections, stress, pollution, unhealthy lifestyle with immune-genetic background. Association with particular immune-genetic variants of Toll-like receptor genes possibly explain diminished response to infections (TLR, NOD), association with mitochondrial genes contribute to maintenance of inflammation, while association with particular HLA haplotypes explains induction of auto-immune phenomena and/or exaggerated synaptic pruning. For example, association with the complement genes can induce abnormal pruning and microglial activation thereby increasing the risk of neurodevelopmental disorders such as early onset schizophrenia. In the context of the SARS-Cov2 pandemic, increased severity of COVID-19 in psychiatric patients is probably due to their reduced ability to fight infection. Systemic inflammation and persistent infections induce different pathways paving the way to biomarker-guided personalized medicine. One of the best examples is the identification of “autoimmune psychosis” defined by presence of anti-neuronal antibodies that has been confounded for long with atypical, mild, or attenuated forms of autoimmune encephalitis. Persistent infections are associated to activation of Human endogenous retrovirus (HERV). Systemic inflammation induced by microbial infection or psychosocial factors can also be at the origin of the activation of human endogenous retrovirus. Inflammation is also known to be associated with gut dysbiosis and disturbance of the integrity of the digestive barrier leading to behavioral abnormalities. One last example can be found in the immune-metabolic abnormalities that pave the way to metabolic syndrome associated with psychiatric disorders. Although many aspects of the complex relationship between immunity and brain function are not yet fully elucidated, the findings that have accumulated so far have transformed our understanding of psychiatric disorders and favored the consideration of other possible cellular and molecular targets for their treatment than just alterations in neuronal transmitters. Disclosure: Nothing to disclose.

Immune Mediated Bulbar Myasthenia Gravis Incited by SARS-CoV2 mRNA Vaccination

Objective: NA Background: A 32 year-old man with no medical history and no prior documented SARS-CoV2 infection developed malaise, dyspnea, and exercise intolerance in the days following first dose SARS-CoV2 vaccine administration (Pzifer-BioNTECH mRNA). Dysarthria and dysphagia manifested within hours of the second vaccine dose administration, and progressed to severe bifacial weakness with reduced eyelid and mouth closures within one week's time. Design/Methods: NA Results: Severe dysphagia prompted hospitalization and neurology consultation. At an outside hospital, IVIG (2 gm/kg) and pyridostigmine were initiated for empiric treatment of suspected myasthenia gravis. The patient's facial strength, dysphagia and dysarthria improved. Anti-AChR and anti-MuSK serologic studies were non-reactive. A thymoma was not identified. MR brain, cerebrospinal fluid, and ganglioside antibody serologic studies were without explanatory pathological findings. A nerve conduction study, obtained in the outpatient setting, demonstrated decrement in facial nerve-nasalis CMAPs with low frequency repetitive stimulation, consistent with a post-synaptic neuromuscular disorder. Monthly IVIG infusions and pyridostigmine were prescribed. The patient's symptoms worsened and he was rehospitalized. A repeat nerve conduction study revealed post-exercise and repetitive stimulation-induced decrements in median-abductor policus brevis and spinal accessorytrapezius CMAPs, confirming a systemic post-synaptic neuromuscular disorder. AChR binding and blocking antibodies were ultimately detected through repeat serologic testing, consistent with autoimmune myasthenia gravis. Plasma exchange and prednisone therapies engendered near full symptom resolution. Conclusions: While myasthenia gravis symptom exacerbation and crisis in the setting of vaccination are well described, no cases of new-onset myasthenia gravis following vaccination are reported to date. Further, the patient's bifacial weakness with impaired eyelid closure was atypical in contrast to ptosis and diploia typically observed in oculo-bulbar forms of myasthenia gravis. The immune-mediated mechanism and clinical phenotype of SARS-CoV2 vaccinationassociated myasthenia gravis require further investigation.

Addressing Diaphragm Dysfunction in Lung Transplant Recipients: The Expanding Role of Diaphragm Pacing

Purpose: Diaphragmatic dysfunction is documented after lung transplantation and can affect up to 62% patients. Diaphragm pacing (DP) prevents ventilator induced diaphragm dysfunction (VIDD) while on mechanical ventilation (MV) and has been shown via functional electrical stimulation to improve phrenic nerve recovery. We report the largest experience of DP in lung transplantation recipients. Methods: This is a retrospective analysis of an IRB approved prospective, non-randomized interventional experience at a single institution with two DP systems. A chronic DP system [NeuRx, Synapse Biomedical] was implanted laparoscopically in those with phrenic nerve injury or difficulty with weaning from MV remotely after their transplant. A temporary DP system [TransAeris, Synapse Biomedical] was implanted at the time of transplantation or laparoscopically. In both types of implantation, diaphragm stimulation ensued if needed to wean from MV or for nerve recovery. Results evaluated radiographically and with diaphragm electromyography (dEMG). Results: DP was utilized in16 patients with no device adverse events. Of those, 5 patients had chronic DP system: a) 1 patient one year post transplant shows no recovery of phrenic nerve injury, still pacing;b) 3 patients showed recovery of phrenic nerve/diaphragm function through pacing;c) 1 patient 2 years post-transplant sustained hip fracture requiring surgery, developed pneumonia and became tracheostomy MV dependent;DP allowed complete diaphragm recovery, decanullation of tracheostomy and removal of DP wires. 11 patients had temporary DP electrodes placed: a) 1 recipient(two months post-transplant) had DP use during ECMO for COVID- 19 sepsis and respiratory failure and subsequently expired when family withdrew therapy;b) 10 implanted at time of lung transplant. Of those 10, 3 patients had bilateral dEMG identified post-operatively with uneventful recovery and removal of electrodes;7 patients had diaphragm abnormalities identified post-operatively and underwent DP. Of those 7, 5 showed recovery and DP electrodes removed and 2 are still pacing 1 and 9 months post-transplant. Conclusion: DP was safely used in lung transplantation to identify and improve recovery of phrenic nerve injuries, wean from MV and prevent VIDD. DP shows promise in addressing diaphragm dysfunction after lung transplantation and improving outcomes.

All-in-One Metal-Oxide Heterojunction Artificial Synapses for Visual Sensory and Neuromorphic Computing Systems

An all-in-one artificial synapse integrating central nervous and sensory nervous functions utilizing low-dimensional metal-oxide heterojunction is demonstrated in this work. With an ion-electrolyte gate, synaptic emulations modulated by electrical and photonic stimulus have been integrated into one high-performance three-terminal artificial synapse. Various long-term and short-term synaptic plasticity functions have been achieved by altering the electrolyte-gate stimulus amplitude/width/frequency/number. The linear potentiation behavior and maintained states enable artificial synapses for neuromorphic computing. Simulated artificial neural network based on the artificial synapses achieved Covid-19 chest image recognition (>85%). The photo-sensing metal-oxide heterojunction enables the synaptic functions mimicking the biological visual sensory functions responding to optical and UV stimulus. Photonic synaptic plasticity modulations responding to photonic stimulus wavelength/power/width/number are investigated, and short-term/long-term synaptic plasticity transition was achieved. Dual-mode modulation combining photonic stimulus and gate stimulus was examined, along with a ‘AND Gate’ demonstration with electrical and photonic inputs. Finally, an artificial neural network was demonstrated based on the synapses with dual-mode synaptic weight modulation, indicating the potential of the artificial synapse for compact artificial intelligence systems combing neuromorphic computing and visual sensory nervous functions.

Ganglioside binding domains in proteins: Physiological and pathological mechanisms.

Gangliosides are anionic lipids that form condensed membrane clusters (lipid rafts) and exert major regulatory functions on a wide range of proteins. In this review, we propose a new view of the structural features of gangliosides with special emphasis on emerging properties associated with protein binding modes. We analyze the different possibilities of molecular associations of gangliosides in lipid rafts and the role of cholesterol in this organization. We are particularly interested in amide groups of N-acetylated sugars which make it possible to neutralize the negative charge of the carboxylate group of sialic acids. We refer to this effect as "NH trick" and we demonstrate that it is operative in GM1, GD1a, GD1b and GT1b gangliosides. The NH trick is key to understand the different topologies adopted by gangliosides (chalice-like at the edge of lipid rafts, condensed clusters in central areas) and their impact on protein binding. We define three major types of ganglioside-binding domains (GBDs): α-helical, loop shaped, and large flat surface. We describe the mode of interaction of each GBD with typical reference proteins: synaptotagmin, 5HT1A receptor, cholera and botulinum toxins, HIV-1 surface envelope glycoprotein gp120, SARS-CoV-2 spike protein, cellular prion protein, Alzheimer's ß-amyloid peptide and Parkinson's disease associated α-synuclein. We discuss the common mechanisms and peculiarities of protein binding to gangliosides in the light of physiological and pathological conditions. We anticipate that innovative ganglioside-based therapies will soon show an exponential growth for the treatment of cancer, microbial infections, and neurodegenerative diseases.

RNA sequencing of blood in coronary artery disease: involvement of regulatory T cell imbalance.

BACKGROUND: Cardiovascular disease had a global prevalence of 523 million cases and 18.6 million deaths in 2019. The current standard for diagnosing coronary artery disease (CAD) is coronary angiography. Surprisingly, despite well-established clinical indications, up to 40% of the one million invasive cardiac catheterizations return a result of 'no blockage'. The present studies employed RNA sequencing of whole blood to identify an RNA signature in patients with angiographically confirmed CAD. METHODS: Whole blood RNA was depleted of ribosomal RNA (rRNA) and analyzed by single-molecule sequencing of RNA (RNAseq) to identify transcripts associated with CAD (TRACs) in a discovery group of 96 patients presenting for elective coronary catheterization. The resulting transcript counts were compared between groups to identify differentially expressed genes (DEGs). RESULTS: Surprisingly, 98% of DEGs/TRACs were down-regulated ~ 1.7-fold in patients with mild to severe CAD (> 20% stenosis). The TRACs were independent of comorbid risk factors for CAD, such as sex, hypertension, and smoking. Bioinformatic analysis identified an enrichment in transcripts such as FoxP1, ICOSLG, IKZF4/Eos, SMYD3, TRIM28, and TCF3/E2A that are likely markers of regulatory T cells (Treg), consistent with known reductions in Tregs in CAD. A validation cohort of 80 patients confirmed the overall pattern (92% down-regulation) and supported many of the Treg-related changes. TRACs were enriched for transcripts associated with stress granules, which sequester RNAs, and ciliary and synaptic transcripts, possibly consistent with changes in the immune synapse of developing T cells. CONCLUSIONS: These studies identify a novel mRNA signature of a Treg-like defect in CAD patients and provides a blueprint for a diagnostic test for CAD. The pattern of changes is consistent with stress-related changes in the maturation of T and Treg cells, possibly due to changes in the immune synapse.

Corrigendum: Blocking of the High-Affinity Interaction-Synapse Between SARS-CoV-2 Spike and Human ACE2 Proteins Likely Requires Multiple High-Affinity Antibodies: An Immune Perspective.

[This corrects the article DOI: 10.3389/fimmu.2020.570018.].

Potential neurobiological links between social isolation and Alzheimer's disease risk.

It is estimated that 40% of dementia cases could be prevented by modification of lifestyle factors that associate with disease risk. One of these potentially modifiable lifestyle factors is social isolation. In this review, we discuss what is known about associations between social isolation and Alzheimer's disease, the most common cause of dementia. This is particularly relevant in the time of the COVID-19 pandemic when social isolation has been enforced with potential emerging negative impacts on cognition. While there are neurobiological mechanisms emerging that may account for the observed epidemiological associations between social isolation and Alzheimer's disease, more fundamental research is needed to fully understand the brain changes induced by isolation that may make people vulnerable to disease.

Neurological consequences of neurovascular unit and brain vasculature damages: potential risks for pregnancy infections and COVID-19-babies.

Intragravidic and perinatal infections, acting through either direct viral effect or immune-mediated responses, are recognized causes of liability for neurodevelopmental disorders in the progeny. The large amounts of epidemiological data and the wealth of information deriving from animal models of gestational infections have contributed to delineate, in the last years, possible underpinning mechanisms for this phenomenon, including defects in neuronal migration, impaired spine and synaptic development, and altered activation of microglia. Recently, dysfunctions of the neurovascular unit and anomalies of the brain vasculature have unexpectedly emerged as potential causes at the origin of behavioral abnormalities and psychiatric disorders consequent to prenatal and perinatal infections. This review aims to discuss the up-to-date literature evidence pointing to the neurovascular unit and brain vasculature damages as the etiological mechanisms in neurodevelopmental syndromes. We focus on the inflammatory events consequent to intragravidic viral infections as well as on the direct viral effects as the potential primary triggers. These authors hope that a timely review of the literature will help to envision promising research directions, also relevant for the present and future COVID-19 longitudinal studies.

FIB-SEM as a Volume Electron Microscopy Approach to Study Cellular Architectures in SARS-CoV-2 and Other Viral Infections: A Practical Primer for a Virologist.

The visualization of cellular ultrastructure over a wide range of volumes is becoming possible by increasingly powerful techniques grouped under the rubric "volume electron microscopy" or volume EM (vEM). Focused ion beam scanning electron microscopy (FIB-SEM) occupies a "Goldilocks zone" in vEM: iterative and automated cycles of milling and imaging allow the interrogation of microns-thick specimens in 3-D at resolutions of tens of nanometers or less. This bestows on FIB-SEM the unique ability to aid the accurate and precise study of architectures of virus-cell interactions. Here we give the virologist or cell biologist a primer on FIB-SEM imaging in the context of vEM and discuss practical aspects of a room temperature FIB-SEM experiment. In an in vitro study of SARS-CoV-2 infection, we show that accurate quantitation of viral densities and surface curvatures enabled by FIB-SEM imaging reveals SARS-CoV-2 viruses preferentially located at areas of plasma membrane that have positive mean curvatures.

Neuroinflammation and Brain Development: Possible Risk Factors in COVID-19-Infected Children.

COVID-19, a disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) betacoronavirus, affects children in a different way than it does in adults, with milder symptoms. However, several cases of neurological symptoms with neuroinflammatory syndromes, such as the multisystem inflammatory syndrome (MIS-C), following mild cases, have been reported. As with other viral infections, such as rubella, influenza, and cytomegalovirus, SARS-CoV-2 induces a surge of proinflammatory cytokines that affect microglial function, which can be harmful to brain development. Along with the viral induction of neuroinflammation, other noninfectious conditions may interact to produce additional inflammation, such as the nutritional imbalance of fatty acids and polyunsaturated fatty acids and alcohol consumption during pregnancy. Additionally, transient thyrotoxicosis induced by SARS-CoV-2 with secondary autoimmune hypothyroidism has been reported, which could go undetected during pregnancy. Together, those factors may pose additional risk factors for SARS-CoV-2 infection impacting mechanisms of neural development such as synaptic pruning and neural circuitry formation. The present review discusses those conditions in the perspective of the understanding of risk factors that should be considered and the possible emergence of neurodevelopmental disorders in COVID-19-infected children.

NMDA and AMPA Receptor Autoantibodies in Brain Disorders: From Molecular Mechanisms to Clinical Features.

The role of autoimmunity in central nervous system (CNS) disorders is rapidly expanding. In the last twenty years, different types of autoantibodies targeting subunits of ionotropic glutamate receptors have been found in a variety of patients affected by brain disorders. Several of these antibodies are directed against NMDA receptors (NMDAR), mostly in autoimmune encephalitis, whereas a growing field of research has identified antibodies against AMPA receptor (AMPAR) subunits in patients with different types of epilepsy or frontotemporal dementia. Several in vitro and in vivo studies performed in the last decade have dramatically improved our understanding of the molecular and functional effects induced by both NMDAR and AMPAR autoantibodies at the excitatory glutamatergic synapse and, consequently, their possible role in the onset of clinical symptoms. In particular, the method by which autoantibodies can modulate the localization at synapses of specific target subunits leading to functional impairments and behavioral alterations has been well addressed in animal studies. Overall, these preclinical studies have opened new avenues for the development of novel pharmacological treatments specifically targeting the synaptic activation of ionotropic glutamate receptors.

Blocking of the High-Affinity Interaction-Synapse Between SARS-CoV-2 Spike and Human ACE2 Proteins Likely Requires Multiple High-Affinity Antibodies: An Immune Perspective.

The pandemic of Coronavirus Disease 2019 (COVID-19) caused by SARS-CoV-2 has induced global eagerness to develop vaccines and therapeutics for treating COVID-19, including neutralizing antibodies. To develop effective therapeutic antibodies against SARS-CoV-2, it is critical to understand the interaction between viral and host's proteins. The human ACE2 (hACE2) protein is the crucial target for the SARS-CoV's Spike protein that allows the virus to adhere to host epithelial cells. X-ray crystal structures and biophysical properties of protein-protein interactions reveal a large interaction surface with high binding-affinity between SARS-CoV-2 and hACE2 (18 interactions), at least 15-fold stronger than between SARS-CoV-1 and hACE2 (eight interactions). This suggests that antibodies against CoV-1 infection might not be very efficient against CoV-2. Furthermore, interspecies comparisons indicate that ACE2 proteins of man and cat are far closer than dog, ferret, mouse, and rat with significant differences in binding-affinity between Spike and ACE2 proteins. This strengthens the notion of productive SARS-CoV-2 transmission between felines and humans and that classical animal models are not optimally suited for evaluating therapeutic antibodies. The large interaction surface with strong affinity between SARS-CoV-2 and hACE2 (dG-12.4) poses a huge challenge to develop reliable antibody therapy that truly blocks SARS-CoV-2 adherence and infection. We gauge that single antibodies against single epitopes might not sufficiently interfere with the strong interaction-synapse between Spike and hACE2 proteins. Instead, appropriate combinations of high-affinity neutralizing antibodies against different epitopes might be needed, preferably of IgA-class for optimal and prolonged activity at epithelial layers of respiratory and intestine tracts.