The ongoing SARS-CoV-2 pandemic has raised concerns surrounding immunological protection against the virus, particularly for people with inborn errors of immunity (IEI). While COVID-19 vaccination induces robust antibody, memory B-cell, and T-cell responses in healthy individuals, how well vaccination protects people with IEI against infection and severe disease remains unclear – especially in the context of new viral variants and vaccine formulations – leading to anxiety, ongoing self-isolation, and repeated vaccination with limited evidence of increased efficacy. Whilst most people with IEI generate some level of cellular and/or humoral immunity to COVID-19 vaccination, the level of protection and durability of the response are unclear. Alongside vaccination, antibody-based therapeutics are aimed at limiting infection and severe disease in this cohort. Immunoglobulin replacement therapy (IgRT) provides passive immunity in antibody-deficient individuals. However, to successfully prevent SARS-CoV-2 infection, a sufficient number of neutralizing antibodies must be present in product. While antibodies against circulating variants are eventually present in IgRT products (both from natural infection and vaccination of the donors), evidence of their capacity to recognize new variants is limited. Furthermore, while antibody-based pre- and post-exposure prophylaxis can be effective, they are susceptible to decreased efficacy in the context of variant evolution. This review provides an in-depth overview of current knowledge about COVID-19 vaccine efficacy in IEIs, the efficacy of SARS-CoV-2-specific antibody products, and knowledge and technological advances required for continued protection of people with IEI.

The study evaluated the immune response to the Janssen Ad26.COV2.S COVID-19 vaccine in a Ugandan cohort, focusing on spike (S) and nucleocapsid (N) protein-directed antibodies. The aim was to assess the longevity and robustness of the elicited antibodies, aligning with breakthrough infections and prior exposure to SARS-CoV-2. The study involved 319 specimens collected over 12 months from 60 vaccinees aged 18 to 64. Binding antibodies were quantified using a validated ELISA method to measure SARS-CoV-2-specific IgG, IgM, and IgA levels against the S and N proteins. The results showed that baseline seropositivity for S-IgG was high at 67%, increasing to 98% by day 14 and consistently stayed above 95% for up to 12 months. However, S-IgM responses remained suboptimal. An increased S-IgA serpositivity rate doubled from 40% at baseline to 86% just two weeks following the initial vaccine dose, indicating sustained and robust mucosal immunity. An increase in N-IgG levels at nine months post-vaccination suggested breakthrough infections in eight cases. Baseline cross-reactivity influenced spike-directed antibody responses, with those with pre-existing S-IgG antibodies showing higher responses. The vaccine demonstrated robust and long-lasting immune responses, with significant implications for regions where administering follow-up doses is challenging.

Background: Newer personalized medicine including targeted therapies such as PARP inhibitors and CDK 4/6 inhibitors have shown to improve survival of breast and gynaecological cancer patients. However, efficacy outcomes may be hampered by treatment discontinuation due to targeted therapy-related adverse drug reactions or resistance. Studies suggest that add-on mistletoe (Viscum album L., VA) improves quality of life and ameliorates cytotoxic side effects of standard oncological therapy in cancer patients. The primary objective of this real-world data study was to determine the safety profile of targeted therapy in combination with add-on Helixor® VA therapy in breast and gynecological cancer patients. Methods: The present study is a real-world data study utilizing demographic and treatment data from the accredited national Network Oncology (NO) registry. The study has received ethics approval. The safety profile of targeted with or without Helixor® VA therapy as well as safety - associated variables were evaluated by univariate and adjusted multivariable regression analyses. Results: All stage breast or gynecological cancer patients (n = 242) were on average 54.5±14.2 years old. One hundred and sixty patients (66.1%) were in the control (CTRL, targeted therapy) and 82 patients (33.9%) in the combinational (COMB, targeted plus Helixor® VA therapy) group. The addition of Helixor® VA did not hamper the safety profile (χ2 = 0.107, p-value = 0.99) of targeted therapy. Furthermore, no adverse events and a trend towards an improved targeted therapy adherence were observed in the COMB group. Conclusions: The present study is the first of its kind showing the applicability of Helixor® VA in combination with targeted therapies. The results indicate that add-on Helixor® VA does not negatively alter the safety profile of targeted therapies in breast and gynaecological cancer patients.

Despite being a rare disease worldwide, rabies has the highest morbidity and mortality rates, with nearly all symptomatic cases leading to coma and death. Rabies represents an infectious disease caused by the Rabies virus (RABV), which is part of the Lyssavirus group and the Rhabdoviridae family, and it mainly spreads through the bite and scratch of an infected mammal, but particularly of wild animals, such as bats, foxes, wolves and racoons, and of domestic animals, such as dogs and cats, in rabies-prone areas of the world. Airborne transmission has been deemed as extremely rare, and no clinical case as such has been recorded worldwide yet, except in the enclosed environment, such as research laboratories and caves where infected bats are present. Domestic mammals, such as dogs and ferrets, represent other important reservoirs of disease transmission, and the human cases of Asia and Africa amount approximately 95% of all human cases worldwide. Infected animals most commonly start transmitting the virus once the first symptoms have occurred, and if they experience disease aggravation and death within 10 days, a case of rabies is registered, more easily if the incidence occurred in the urban area and then, any person or animal that had been potentially exposed are strongly recommended to receive the inoculation. It is rare for asymptomatic mammals to transmit the illness. Most First-World and several Second-World countries have recently been declared dog rabies-free by the World Health Organization. The disease can only be treated prophylactically, with three doses of a vaccine containing an inactivated form of RABV, or with five doses of the vaccine and two doses of anti-RABV immunoglobulins within 28 days if the patient is believed to have been exposed to the virus beforehand. It has been projected that, once the viral load reaches elements of the central nervous system, prophylactic approaches are no longer effective, even if symptoms have not begun yet, and this highlights the urgent trait of the medical condition, strongly recommending exposed people to receive the prophylactic doses immediately after the potential exposure to the virus. The pathogen first infects the bodily fluids, before reaching the peripheral nervous system, from where it will gradually move toward the spinal cord or the encephalon, at a speed of movement ranging from 1 to 40 cm per day. It was also found, in extremely rare circumstances, to infect the nasopharyngeal cavity and the lungs. The primary cause of a successful, gradual advance of the viral load toward the point of clinical no-return for the patient - the CNS - is a complex mechanism of induced innate immune evasion, with the interferon system being heavily targeted and silenced by RABV proteins. The ‘Milwaukee’ protocol is locally believed to decrease the mortality rate of the clinical illness to approximately 80%, although significantly more research is required in this sense. First-line immune evasion represents the central mechanism developed by viruses during their evolutionary process to gain control over human immunity, so it could be the development and adjustment of a counter-offensive to this evolutionary operating system that could address the core elements of the problem. Human recombinant Type I and Type III Interferons were found to be significant vaccine adjuvants and to considerably delay the clinical onset of the disease. Despite their central role in natural immunity-based prophylaxis, vaccine support and, in often cases, vaccination per se, a local administration of IFNs as such may not be enough to tackle the core problem of the endemic disease, and a specific and systemic treatment of potential host cells with IFN I and III, as well as IFN-stimulating proteins, may constitute a major research requirement in the coming years of disease investigation, as the inoculation efforts with the inactivated virus and immunoglobulin administration continue. The administration of a relatively low dosage of somatic Natural Killer cells, gamma-interferon and perhaps, of somatic helper CD4+ and somatic cytotoxic CD8+ T-lymphocytes treated with alpha-, beta- and lambda-interferon could be merged with the administration of a similar dosage of alpha-, beta- and lambda-interferon during the efforts to develop an effective and less costly prophylactic vaccine against rabies. A combination of a nasal substance containing a low dosage of IFN I and III with a reduced concentration of neutralized RABV copies, and/or with a low dose of anti-RABV IgA antibodies, could also be tested for humans for the purposes of pre- and post-exposure prophylaxis.

Alzheimer’s disease (AD) and the therapies of AD with anti-amyloid1-42 (Aβ) monoclonal antibodies are associated with the vascular complications of brain edema, hemorrhage, and cerebral amyloid angiopathy (CAA) termed amyloid-related imaging abnormalities (ARIAs). The neuropathology of normal and AD brains demonstrates that monocyte/macrophages (MMs) are critical in successful brain clearance in healthy brain by up-loading, transporting, and degrading Aβ but fail degradation and clearance in AD patients by releasing Aβ into vessels at the blood-brain barrier, causing vasculitis and ARIAs. The naturally-formed epoxides (EpFAs) of polyunsaturated fatty acids (PUFA’s), including arachidonic, docosahexaenoic, and eicosapentaenoic fatty acids, may repair degradation of Aβ by regulating Aβ-degrading enzymes, inflammatory cytokines, and unfolded protein response (UPR) to endoplasmic reticulum stress in a homeostatic fashion. EpFAs are, however, degraded by the soluble epoxide hydrolase enzyme (sEH) but are protected by the sEH inhibitor (sEHI) TPPU. In the cultures of AD patients’ macrophages, TPPU with the epoxide EEQ, and the cGAS/STING inhibitor H-151 increased uptake of Aβ at 2 hours and degradation of Aβ at 24 hours. In conclusion, the soluble epoxide hydrolase inhibitor TPPU with omega-3 fatty acids and the cGAS/STING inhibitor H-151 increase Aβ uptake and degradation in macrophages of AD patients, and potentially enhancing Aβ clearance in the AD brain.

HLA class-I (HLA-I) polyreactive monoclonal antibodies (mAbs) reacting to all HLA-I alleles were developed by immunizing HLA-E monomeric heavy chain (HC) (Open Conformers, OCs). Two of the mAbs (TFL-006 and TFL-007) bound to the HC’s coated on a solid matrix. The binding was inhibited by a peptide 117AYDGKDY123, present in all alleles of the six HLA-I isoforms but masked by 2-microglobulin -m) in intact HLA-I trimers (Closed Conformers, CCs). Identical HLA-I polyreactivity is observed in IVIg administered to lower anti-HLA antibodies (Abs) in HLA-sensitized patients, but the mechanism is unknown. We hypothesized that the mAbs that mimic IVIg HLA-I polyreactivity might mimic the immunomodulatory functions of IVIg. We tested the relative binding affinity of the mAbs and IVIg for both OCs- and CCs and compared their effects on (a) the phytohemagglutinin (PHA)-activation T-cells, (b) the production of anti-HLA-II antibody (Ab) by B-memory cells, and anti-HLA-I Ab by immortalized B-cells, and (c) the upregulation of CD4+, CD25+, and Fox P3+ T-regs. The mAbs bound only to OCs, whereas IVIg is bound to both CCs and OCs. The mAbs suppressed blastogenesis and proliferation of PHA-activated T-cells, anti-HLA Ab production by B-cells and expanded the T-regs, better than IVIg. We conclude that a humanized version of the TFL-mAbs could be an ideal therapeutic IVIg-mimetic.

The COVID-19 pandemic has created huge damage to society and brought panics around the world. Such panics can be ascribed to the seemingly deceptive features of the COVID-19: compared to other deadly viral outspreads, it has medium transmission and mortality rates. As a result, the severity of the causative coronavirus, SARS-CoV-2, was deeply underestimated by the society at the beginning of the COVID-19 outbreak. Based on this, in this review, we define the viruses with features similar to those of SARS-CoV-2 as the Panic Zone viruses. To contain those viruses, accurate and fast diagnosis followed by effective isolation and treatment of patients are pivotal at the early stage of virus breakouts. This is especially true when there is no cure or vaccine available for a transmissible disease, which is the case for current COVID-19 pandemic. As of January 2021, more than two hundred kits for the COVID-19 diagnosis on the market are surveyed in this review, while emerging sensing techniques for SARS-CoV-2 are also discussed. It is of critical importance to rationally use these kits for the efficient management and control of the Panic Zone viruses. Therefore, we discuss guidelines to select diagnostic kits at different outbreak stages of the Panic Zone viruses, SARS-CoV-2 in particular. While it is of utmost importance to use nucleic acid-based detection kits with low false negativity (high sensitivity) at the early stage of an outbreak, the low false positivity (high specificity) gains its importance at later stages of the outbreak. When a society is set to reopen from the lock-down stage of the COVID-19 pandemic, it becomes critical to have antibody based immunoassay kits with high specificity to identify people who can safely return to the society after their recovery of SARS-CoV-2 infections. Given that the emergence of mutant viruses at the beginning of 2021 has complicated current battle against the COVID-19, we also discussed approaches and guidelines to detect viral mutants in the middle of the second wave of the pandemic that started at the end of 2020. Finally, since a massive attack from a viral pandemic requires a massive defense from the whole society, we urge both government and private sectors to research and develop more affordable and reliable point-of-care testing (POCT) kits, which can be used massively by the general public (and therefore called as massive POCT) to contain Panic Zone viruses in future.

Crosslinking of proteins for their irreversible immobilization on surfaces is a proven and popular method. However, many protocols lead to random orientation and the formation of undefined or even inactive by-products. Most concepts to obtain a more targeted conjugation or immobilization requires the recombinant modification of at least one binding partner, which is often impractical or prohibitively expensive. Here a novel method is presented, which is based on the chemical preactivation of Protein A or G with selected conventional crosslinkers. In a second step, the antibody is added, which is subsequently crosslinked in the Fc part. This leads to an oriented and covalent immobilization of the immunoglobulin with a very high yield. Protocols for Protein A and Protein G with murine and human IgG are presented. This method may be useful for the preparation of columns for affinity chromatography, immunoprecipitation, antibodies conjugated to magnetic particles, permanent and oriented immobilization of antibodies in biosensor systems, microarrays, microtitration plates or any other system, where the loss of antibodies needs to be avoided, and maximum binding capacity is desired. This method is directly applicable even to antibodies in crude cell culture supernatants, raw sera or protein-stabilized antibody preparations without any purification nor enrichment of the IgG. This new method delivered much higher signals as a traditional method and, hence, seems to be preferable in many applications.

The human antibody response to influenza virus infection or vaccination is as complicated as it is essential for protection against flu. The constant antigenic changes of the virus to escape human herd immunity hinder the yearly selection of vaccine strains since it is hard to predict which virus strains will circulate for the coming flu season. A "universal" influenza vaccine that could induce broad cross-influenza subtype protection would help to alleviate this burden. However, the human antibody response is intricate and often obscure, with factors like antigenic seniority or original antigenic sin "OAS", and back-boosting ensuring that each person mounts a unique immune response to infection or vaccination with any new influenza virus strain. Notably, the effects of existing antibodies on cross-protective immunity after repeated vaccinations are unclear. More research is needed to characterize the mechanisms at play, but traditional assays such as hemagglutinin inhibition (HAI) and microneutralization (MN) are excessively limited in scope and too resource-intensive to effectively meet this challenge. In the past ten years, new multiple dimensional assays (MDAs) have been developed to help overcome these problems by simultaneously measuring antibodies against a large panel of influenza hemagglutinin (HA) proteins with a minimal amount of sample in a high throughput way. MDAs will likely be a powerful tool for accelerating the study of the humoral immune response to influenza vaccination and the development of a universal influenza vaccine.

In an era of rapid technological advancements, complex global challenges, and intense market competition, the ability to generate and scale innovative solutions has become a critical imperative for organizations, policymakers, and societies worldwide. However, the existing academic landscape has lacked a cohesive, multidisciplinary framework for comprehensively understanding the multifaceted nature of innovation. Innovationology, a newly established scientific discipline, aims to address this gap by providing a unifying, transdisciplinary approach to the study and practice of transformative innovation. This comprehensive article introduces Innovationology as a cutting-edge science that integrates insights from diverse fields, including management, psychology, sociology, economics, and technology studies. Innovationology posits that innovation is a multilayered, context-dependent phenomenon, shaped by the intricate interplay of individual, team, organizational, and ecosystem-level factors. By synthesizing the latest theoretical advancements and empirical evidence, this article presents a holistic model of Innovationology that illuminates the key determinants of radical, game-changing innovations capable of disrupting existing industries and creating new market spaces. The article delves deep into the individual cognitive, behavioral, and motivational drivers of innovativeness, the team dynamics and organizational structures that foster collaborative innovation, and the ecosystem-level characteristics that catalyze the emergence and scaling of transformative innovations. Importantly, the article explores the crucial role of contextual factors, such as socio-cultural norms, institutional support, and resource availability, in shaping innovation outcomes. This article also establishes the epistemological foundations of Innovationology, grounding it in a transdisciplinary, holistic, and pragmatic approach to knowledge generation. Innovationology embraces a pluralistic epistemology that acknowledges the complexity and context-dependence of innovation, drawing on diverse methodological approaches to capture the multifaceted nature of this phenomenon. Furthermore, the article outlines the object of Innovationology, which is to provide a comprehensive, evidence-based understanding of the drivers, processes, and outcomes of transformative innovation. Innovationology seeks to elucidate the multilevel determinants of innovation, the dynamic interplay between various factors, and the contextual influences that shape innovation trajectories. By establishing a unifying, transdisciplinary framework, Innovationology aims to bridge the gap between innovation theory and practice, empowering a wide range of stakeholders to unlock the transformative potential of innovation. Importantly, this article outlines the practical applications of Innovationology, providing comprehensive strategies and evidence-based interventions for cultivating innovative mindsets, designing innovation-conducive organizational systems, and navigating the challenges of innovative ecosystems. The implications of Innovationology for entrepreneurs, corporate leaders, policymakers, and innovation scholars are discussed in detail. By establishing Innovationology as a distinct, authoritative scientific discipline, this article sets the foundation for a more holistic, context-sensitive understanding of innovation and its multifaceted drivers. The insights generated by this new science can empower global organizations, institutions, and policymakers to address the complex, interconnected challenges of the 21st century through the strategic deployment of transformative innovations.