Immune Antibodies Research Articles

Resilience of Spike-Specific Immunity Induced by COVID-19 Vaccines against SARS-CoV-2 Variants.

The outbreak of SARS-CoV-2 leading to the declaration of the COVID-19 global pandemic has led to the urgent development and deployment of several COVID-19 vaccines. Many of these new vaccines, including those based on mRNA and adenoviruses, are aimed to generate neutralizing antibodies against the spike glycoprotein, which is known to bind to the receptor angiotensin converting enzyme 2 (ACE2) in host cells via the receptor-binding domain (RBD). Antibodies binding to this domain can block the interaction with the receptor and prevent viral entry into the cells. Additionally, these vaccines can also induce spike-specific T cells which could contribute to providing protection against the virus. However, the emergence of new SARS-CoV-2 variants can impair the immunity generated by COVID-19 vaccines if mutations occur in cognate epitopes, precluding immune recognition. Here, we evaluated the chance of five SARS-CoV-2 variants of concern (VOCs), Alpha, Beta, Gamma, Delta and Omicron, to escape spike-specific immunity induced by vaccines. To that end, we examined the impact of the SARS-CoV-2 variant mutations on residues located on experimentally verified spike-specific epitopes, deposited at the Immune Epitope Database, that are targeted by neutralizing antibodies or recognized by T cells. We found about 300 of such B cell epitopes, which were largely overlapping, and could be grouped into 54 B cell epitope clusters sharing ≥ 7 residues. Most of the B cell epitope clusters map in the RBD domain (39 out of 54) and 20%, 50%, 37%, 44% and 57% of the total are mutated in SARS-CoV-2 Alpha, Beta, Gamma, Delta and Omicron variants, respectively. We also found 234 experimentally verified CD8 and CD4 T cell epitopes that were distributed evenly throughout the spike protein. Interestingly, in each SARS-CoV-2 VOC, over 87% and 79% of CD8 and CD4 T cell epitopes, respectively, are not mutated. These observations suggest that SARS-CoV-2 VOCs—particularly the Omicron variant—may be prone to escape spike-specific antibody immunity, but not cellular immunity, elicited by COVID-19 vaccines.

Evaluation of a recombinant five-antigen Staphylococcus aureus vaccine: The randomized, single-centre phase 1a/1b clinical trials

BackgroundStaphylococcus aureus is an important pathogen that causes hospital and community infections. To control Staphylococcus aureus infection and reduce the usage of antibiotics, we evaluated the safety and immunogenicity of a recombinant five-antigen Staphylococcus aureus vaccine (rFSAV) in healthy adults. MethodsWe conducted a randomized, double-blind, placebo-controlled phase 1a study and a randomized, open-label phase 1b study. In phase 1a, we randomly allocated 144 healthy participants in a ratio of 1:1:1:1 to receive the low-(60 μg), middle-(120 μg), and high-dose (240 μg) vaccine or placebo at day 0, 3, 7 and 14. In phase 1b, 144 healthy participants were randomly allocated at a ratio of 1:1:1:1 to receive 0–3–7, 0/0–7, 0/0–3–7, 0/0–7–14 regimens to estimate the optimal strategy. The primary study endpoint was the incidence of solicited adverse events post-vaccination. The immunogenicity endpoints included the level of specific antibodies to five antigens after vaccination, as well as the cellular immune responses and functional antibodies. ResultsThere were 31 (86%), 30 (83%), and 32 (89%) of 36 participants in the low-, middle-, and high-dose group reported solicited adverse events, respectively, most of the adverse events were mild or moderate. In phase 1b, the dose-adjusted rFSAV (90 μg) showed a better safety profile in the four immune procedures, and no vaccine-related serious adverse events were reported. The antigen-specific binding antibodies started to increase at day 7 and reached the peak around day 14 to 21. The cellular immune responses and functional antibodies also were substantially above background levels. ConclusionsrFSAV is safe, well tolerated in healthy adults, elicits rapid and robust specific humoral and cellular immune responses with unconventional immunization procedure in phase 1a and 1b. It deserves to be noted and further explored.Clinical Trials Registration: NCT02804711 and NCT03966040.

How important are COVID-19 vaccine responses in patients with MS on disease-modifying therapies?

How important are COVID-19 vaccine responses in patients with MS on disease-modifying therapies?

Safety and Immunogenicity of COVID-19 BBIBP-CorV Vaccine in Children 3-12 Years Old.

Background and Objectives: In the current COVID-19 pandemic, children below the age of 12 could manifest COVID-19 symptoms and serve as a reservoir for the virus in the community. The present study was conducted to evaluate the reactogenicity, and immunogenicity of BBIBP-CorV, prior to involving this age group in the vaccination program in the kingdom of Bahrain. Subjects and Methods: The study included 582 children from 3 to 12 years old of Bahraini and non-Bahraini nationality, all of which contributed to the reactogenicity study. Of those, 401 contributed to the immunogenicity study. All children received 2 doses of BBIBP-CorV inactivated virus 3 weeks apart. To assess reactogenicity, children were followed up for 5 weeks to evaluate any vaccine-related adverse events (AE). To assess immunogenicity, blood was collected on day 0 and day 35 to assess antibody titer against S, N, and neutralizing antibody. Results: Of the 582 participants, (45.4%) were female, (54.61%) were male, with 49% in 9–12 age group. Of the 401 children contributing to the immunogenicity study, 274 (68.3%) had no prior exposure to COVID-19. The overall incidence of AE was 27.7%. No significant difference was found among different age groups. The most frequent AE was local (at the injection site) and occurred in 16% of children, followed by fever in 9.3%. No serious adverse events were reported. The Seroconversion rate was 100% among children with no prior exposure to COVID-19. Children with previous COVID-19 exposure had higher averages of anti-S (2379 U/mL compared to 409.1), anti-N (177.6 U/mL compared to 30.9) and neutralizing antibody (93.7 U/mL compared to 77.1) than children with no prior exposure at day 35. Conclusions: Two doses of COVID-19 BBIBP-CorV on the subjects aged between 3 to 12 has good safety and tolerance and can induce an effective immune response and neutralizing antibody titer.

Corneal confocal microscopy in the evaluation of immune-related motor neuron disease syndrome

BackgroundTo investigate the sensitivity and specificity of corneal confocal microscopy (CCM) in the diagnosis of immune-related motor neuron disease syndrome and evaluation of the response to immunosuppressive therapy.MethodsSeventy-two patients with clinical manifestations of motor neuron disease (MND) were analysed. According to whether they had concomitant rheumatic immune disease or rheumatic immune antibody abnormalities, they were divided into an MND group (33 patients) and an immune-related MND syndrome group (39 patients). Another 10 healthy adults were selected as the control group. All individuals were examined by CCM.ResultsFor Langerhans cell(LC) density, the area under the receiver operating characteristic(ROC)curve was 0.8, the best cut-off was 67.7 cells/mm2, the sensitivity was 79.5%, and the specificity was 72.7%. For inferior whorl length (IWL), the area under the ROC curve was 0.674, the best cut-off was 17.41 mm/mm2, the sensitivity was 69.2%, and the specificity was 66.7%. After immunosuppressive therapy in 5 patients with immune-related MND syndrome, the LCD was significantly reduced (P < 0.05), and there was no statistically significant change in the IWL (P > 0.05).ConclusionThe LC density and IWL are ideal for distinguishing MND from immune-related MND syndrome. The LC density reflects the immunotherapy response sensitively.

The Role of Myeloid Cells in Hepatotoxicity Related to Cancer Immunotherapy.

Simple SummaryImmune-modulating cancer treatments have proved to be highly effective in a wide range of tumour types. They interrupt the usual communication between cells in the immune system, encouraging them to become more active in identifying and destroying cancer cells. Although these therapies are very successful in treating cancer, patients frequently experience liver injury as a side effect related to over activation of the immune system. If cancer patients develop this side effect, they need to stop their cancer therapy and be given strong immunosuppressants. Researchers are now working on understanding the mechanisms involved in the development of liver inflammation. In this review we will summarise findings identifying classes of immune cells that are of particular importance in this context and highlight ways in which we can use this knowledge to improve the safety of these new cancer drugs.Drug-related hepatotoxicity is an emerging clinical challenge with the widening use of immunotherapeutic agents in the field of oncology. This is an important complication to consider as more immune oncological targets are being identified to show promising results in clinical trials. The application of these therapeutics may be complicated by the development of immune-related adverse events (irAEs), a serious limitation often requiring high-dose immunosuppression and discontinuation of cancer therapy. Hepatoxicity presents one of the most frequently encountered irAEs and a better understanding of the underlying mechanism is crucial for the development of alternative therapeutic interventions. As a novel drug side effect, the immunopathogenesis of the condition is not completely understood. In the liver, myeloid cells play a central role in the maintenance of homeostasis and promotion of inflammation. Recent research has identified myeloid cells to be associated with hepatic adverse events of various immune modulatory monoclonal antibodies. In this review article, we provide an overview of the role of myeloid cells in the immune pathogenesis during hepatoxicity related to cancer immunotherapies and highlight potential treatment options.

Recurrent pneumonia related to a Haemophilus influenzae-specific antibody deficiency and its alleviation by vaccination

Recurrent bacterial infections, such as pneumonia, can be considered unusual and generally represent an anatomic or structural pulmonary defect, aspiration, or underlying immune deficiency.1,2 Some immune disorders, such as common variable immune deficiency and specific antibody deficiency (SAD), are among the more common disorders seen in the outpatient setting.3 In general, antibody deficiency is diagnosed by looking at the pattern and type of microbial infection and evaluating the immune response.

Basic immunology for routine clinical practice

Das Immunsystem ist ein den äußeren Gegebenheiten anpassbares und nahezu ubiquitär vorhandenes Abwehrsystem höherer Organismen, das vor allem Schädigungen durch Krankheitserreger oder Toxine verhindern soll. Zudem kann es fehlerhafte oder entartete körpereigene Zellen erkennen und zerstören. Das immunologische Netzwerk des Menschen besteht aus verschiedenen Organen und Organsystemen, verschiedenen immunaktiven Zelltypen sowie extra- und intrazellulären Signalmolekülen und Signalkomplexen. Unterteilt wird das Immunsystem in das angeborene und erworbene Immunsystem. Pathologische Zustände, die kurz oder länger andauern können, reichen von den angeborenen Störungen der Autoinflammationserkrankungen bis hin zu den zahlreichen Autoimmunerkrankungen. Diese überschießenden Immunreaktionen werden durch verschiedenste Stimuli getriggert. Therapeutisch können bei überschießenden Reaktionen unspezifische Immunsuppressiva oder direkte Immunzellhemmer bzw. Antikörper eingesetzt werden.

Effectiveness, Adverse Events, and Immune Response Following Double Vaccination with BNT162b2 in Staff at the National Comprehensive Cancer Center (NCCC).

Vaccination remains the leading strategy against COVID-19 worldwide. BNT162b2 is among the first licensed vaccines with high effectiveness. However, the role of antibody and cell immunity response monitoring after vaccination remains unclear. We conducted a 6-month prospective study involving the employees of NCCC in Slovakia, who were tested for IgG antibody and cell immune responses after double vaccination with BNT162b2. IgG antibodies were detected at 3, 7, and 26 weeks, respectively. At 6 months, blood samples were tested by two different interferon-γ release assays to determine responses to spike protein antigen and nucleocapsid protein antigen of the novel coronavirus. Results were stratified by gender and body mass index (BMI). Statistical significance was set at p = 0.05. The medical records of 94 respondents (71 females) were analyzed. The mean age was 40.2 years and the mean BMI was 26.4 kg/m2. At 6 months after double vaccination, effectiveness was 97.9%. The side effects of the BNT162b2 vaccine were similar after both doses, with no serious adverse events or new safety signals recorded. The IgG index declined rapidly (p < 0.0001), and 42.6% of subjects had positive and 57.4% borderline or negative immune cell response at 6 months (p < 0.0001). Both T cell activation and IgG counts were lower in morbidly obese patients when compared to some other BMI categories. This study confirmed an acceptable toxicity profile and the high efficacy of BNT162b2 despite a rapid decline of IgG level and negative cell-mediated immunity response in most subjects. An individualized approach to vaccination could be considered in morbidly obese individuals.

Th1/Th17-mediated Immunity and Protection from Peripheral Neuropathy in Wildtype and IL10-/- BALB/c Mice Infected with a Guillain-Barré Syndrome-associated Campylobacter jejuni Strain.

Campylobacter jejuni is an important cause of bacterial gastroenteritis worldwide and is linked to Guillain-Barré syndrome (GBS), a debilitating postinfectious polyneuropathy. The immunopathogenesis of GBS involves the generation of antibodies that are cross reactive to C. jejuni lipooligosaccharide and structurally similar peripheral nerve gangliosides. Both the C. jejuni infecting strain and host factors contribute to GBS development. GBS pathogenesis is associated with Th2-mediated responses in patients. Moreover, induction of IgG1 antiganglioside antibodies in association with colonic Th2-mediated immune responses has been reported in C. jejuni-infected C57BL/6 IL10-/- mice at 4 to 6 wk after infection. We hypothesized that, due to their Th2 immunologic bias, BALB/c mice would develop autoantibodies and signs of peripheral neuropathy after infection with a GBS patient-derived strain of C. jejuni (strain 260.94). WT and IL10-/- BALB/c mice were orally inoculated with C. jejuni 260.94, phenotyped weekly for neurologic deficits, and euthanized after 5 wk. Immune responses were assessed as C. jejuni-specific and antiganglioside antibodies in plasma and cytokine production and histologic lesions in the proximal colon. Peripheral nerve lesions were assessed in dorsal root ganglia and their afferent nerve fibers by scoring immunohistochemically labeled macrophages through morphometry. C. jejuni 260.94 stably colonized both WT and IL10-/- mice and induced systemic Th1/Th17-mediated immune responses with significant increases in C. jejuni-specific IgG2a, IgG2b, and IgG3 plasma antibodies. However, C. jejuni 260.94 did not induce IgG1 antiganglioside antibodies, colitis, or neurologic deficits or peripheral nerve lesions in WT or IL10-/- mice. Both WT and IL10-/- BALB/c mice showed relative protection from development of Th2-mediated immunity and antiganglioside antibodies as compared with C57BL/6 IL10-/- mice. Therefore, BALB/c mice infected with C. jejuni 260.94 are not an effective disease model but provide the opportunity to study the role of immune mechanisms and host genetic background in the susceptibility to post infectious GBS.

Molecularly Targeted Therapy towards Genetic Alterations in Advanced Bladder Cancer.

Simple SummaryIn recent years, there have been several advances in the care of advanced bladder cancer, highlighted by the addition of immune checkpoint inhibitors to the care of advanced disease. Despite these advances, there is a need for further improvement; the morbidity and mortality associated with advanced bladder cancer remain high. With the recent incorporation of advanced molecular techniques, there is more clarity regarding key genetic alterations of the disease. Therapies directed at specific genetic aberrations in bladder cancer provide both proven and potential paths forward. This review discusses the key targetable genetic aberrations and summarizes the current status of targeted therapies in muscle-invasive bladder cancer.Despite the introduction of immune checkpoint inhibitors and antibody–drug conjugates to the management of advanced urothelial carcinoma, the disease is generally incurable. The increasing incorporation of next-generation sequencing of tumor tissue into the characterization of bladder cancer has led to a better understanding of the somatic genetic aberrations potentially involved in its pathogenesis. Genetic alterations have been observed in kinases, such as FGFRs, ErbBs, PI3K/Akt/mTOR, and Ras-MAPK, and genetic alterations in critical cellular processes, such as chromatin remodeling, cell cycle regulation, and DNA damage repair. However, activating mutations or fusions of FGFR2 and FGFR3 remains the only validated therapeutically actionable alteration, with erdafitinib as the only targeted agent currently approved for this group. Bladder cancer is characterized by genomic heterogeneity and a high tumor mutation burden. This review highlights the potential relevance of aberrations and discusses the current status of targeted therapies directed at them.

Quantitative Estimation of Anti-Spike SARS-CoV-2 IgG Antibody Response After Covishield Vaccination in Healthcare Workers

Background: Most studies of COVID vaccination focused on cell-mediated immunity and serum IgG antibodies, overlooking the role of anti-Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) neutralizing IgA antibodies in preventing viral infection. SARS-CoV-2 vaccine generates variable Anti-Spike IgG responses following one or two vaccine doses in almost all individuals for protection. Aim: The study aimed to quantify and estimate the Anti-Spike SARS-CoV-2 IgG antibody response after the second dose of the Covishield vaccine in healthcare workers (HCWs) over the time frame of one, three, and six months. Material and Methods: 30 HCWs who had received both doses of the Covishield vaccine were selected and divided into three groups based on the time elapsed after the second dose of vaccine for serological analysis. Post-vaccination antibody responses were measured using the SARS-CoV-2 IgG Quantitative assay (detection threshold: ≥50 AU/ml) using chemiluminescent microparticle immunoassay (CMIA). Data were analyzed using the Kolmogorov-Smirnov test, Kruskal-Walli's test, and Mann-Whitney U test. Result: Vaccination leads to measurable anti-spike IgG antibodies in HCWs. Only 1 individual was seronegative. The highest antibody titer was reported after one month of the second dose (3615.3 AU/ml). The lowest antibody titer (491.5 AU/ml) was seen after six months of the second dose of Covishield is statistically significant. Conclusion: Anti-Spike SARS-CoV-2 IgG antibody determination is necessary for an immune response after vaccination. This titer decreases with time consequently as the duration after the second dose of the Covishield vaccine increases. This helps assess the requirement of a booster dose for effective immunity against coronavirus.

N-glycosylation, a leading role in viral infection and immunity development.

N-linked protein glycosylation is an essential co-and posttranslational protein modification that occurs in all three domains of life; the assembly of N-glycans follows a complex sequence of events spanning the (Endoplasmic Reticulum) ER and the Golgi apparatus. It has a significant impact on both physicochemical properties and biological functions. It plays a significant role in protein folding and quality control, glycoprotein interaction, signal transduction, viral attachment, and immune response to infection. Glycoengineering of protein employed for improving protein properties and plays a vital role in the production of recombinant glycoproteins and struggles to humanize recombinant therapeutic proteins. It considers an alternative platform for biopharmaceuticals production. Many immune proteins and antibodies are glycosylated. Pathogen’s glycoproteins play vital roles during the infection cycle and their expression of specific oligosaccharides via the N-glycosylation pathway to evade detection by the host immune system. This review focuses on the aspects of N-glycosylation processing, glycoengineering approaches, their role in viral attachment, and immune responses to infection.Supplementary InformationThe online version contains supplementary material available at 10.1007/s11033-022-07359-4.

Molecular identification, histopathological analysis and immunohistochemical characterization of non- pigmented Aeromonas salmonicida subsp. salmonicida in Mugil carinatus (Valenciennes, 1836)

Aeromonas salmonicida was isolated for the first time from Mugil carinatus fish sampled from Suez Gulf, Suez governorate, Egypt. Fish samples were identified bacteriologically, molecularly and histopathologically. Biochemical identification of A. salmonicida was performed using API 20 NE kits. The universal 16 S rRNA gene of Aeromonas species was used for the molecular identification of retrieved isolates by producing amplicons at 461 bp. Serine protease (ser) and aerolysin-like protein (act) virulent genes were detected in retrieved isolates at 211 bp and 232 bp, respectively. DNA sequence analysis showed high identity with A. salmonicida subsp. salmonicida strains listed in the GenBank database. Histopathological analysis revealed localization of basophilic bacterial colonies in liver and kidney. Congestion, hepatocellular necrosis and renal tubular necrosis were the marked pathological lesions in liver and kidney tissues of infected fish. An immunohistochemistry technique was used for confirming the presence of A. salmonicida antigen. Immune positive antigen antibody reaction was observed as brown coloration in liver parenchyma and kidney sections of M. carinatus.

Determinants of B-Cell Compartment Hyperactivation in European Adolescents Living With Perinatally Acquired HIV-1 After Over 10 Years of Suppressive Therapy.

BackgroundDespite a successful antiretroviral therapy (ART), adolescents living with perinatally acquired HIV (PHIV) experience signs of B-cell hyperactivation with expansion of ‘namely’ atypical B-cell phenotypes, including double negative (CD27-IgD-) and termed age associated (ABCs) B-cells (T-bet+CD11c+), which may result in reduced cell functionality, including loss of vaccine-induced immunological memory and higher risk of developing B-cells associated tumors. In this context, perinatally HIV infected children (PHIV) deserve particular attention, given their life-long exposure to chronic immune activation.MethodsWe studied 40 PHIV who started treatment by the 2nd year of life and maintained virological suppression for 13.5 years, with 5/40 patients experiencing transient elevation of the HIV-1 load in the plasma (Spike). We applied a multi-disciplinary approach including immunological B and T cell phenotype, plasma proteomics analysis, and serum level of anti-measles antibodies as functional correlates of vaccine-induced immunity.ResultsPhenotypic signs of B cell hyperactivation were elevated in subjects starting ART later (%DN T-bet+CD11c+ p=0.03; %AM T-bet+CD11c+ p=0.02) and were associated with detectable cell-associated HIV-1 RNA (%AM T-bet+CD11c+ p=0.0003) and transient elevation of the plasma viral load (spike). Furthermore, B-cell hyperactivation appeared to be present in individuals with higher frequency of exhausted T-cells, in particular: %CD4 TIGIT+ were associated with %DN (p=0.008), %DN T-bet+CD11c+ (p=0.0002) and %AM T-bet+CD11c+ (p=0.002) and %CD4 PD-1 were associated with %DN (p=0.048), %DN T-bet+CD11c+ (p=0.039) and %AM T-bet+CD11c+ (p=0.006). The proteomic analysis revealed that subjects with expansion of these atypical B-cells and exhausted T-cells had enrichment of proteins involved in immune inflammation and complement activation pathways. Furthermore, we observed that higher levels of ABCs were associated a reduced capacity to maintain vaccine-induced antibody immunity against measles (%B-cells CD19+CD10- T-bet+, p=0.035).ConclusionWe identified that the levels of hyperactivated B cell subsets were strongly affected by time of ART start and associated with clinical, viral, cellular and plasma soluble markers. Furthermore, the expansion of ABCs also had a direct impact on the capacity to develop antibodies response following routine vaccination.

Direct and indirect engagement of dendritic cell function by antibodies developed for cancer therapy.

Dendritic cells (DC) are crucial for the priming of T cells and thereby influence adaptive immune responses. Hence, they also represent important players in shaping anti-tumour immune responses. Cancer immunotherapy has been driven over many years by the aim to harness the T-cell stimulatory activity of these crucial antigen-presenting cells (APC). Efficient antigen delivery alone is not sufficient for full engagement of the T-cell stimulatory activity of DC and the inclusion of adjuvants triggering appropriate DC activation is essential to ensure effective anti-tumour immunity induction. While the direct engagement of DC function is a powerful tool for tumour immunotherapy, many therapeutic antibodies, such as antibodies directed against tumour-associated antigens (TAA) and immune checkpoint inhibitors (ICI) have been shown to engage DC function indirectly. The induction of anti-tumour immune responses by TAA-targeting and immune checkpoint inhibitory antibodies is thought to be integral to their therapeutic efficacy. Here, we provide an overview of the immunotherapeutic antibodies in the context of cancer immunotherapy, that has been demonstrated to directly or indirectly engage DC and discuss the current understanding of the functional mechanisms underlying anti-tumour immunity induction by these antibody therapies. In the future, the combination of therapeutic strategies that engage DC function directly and/or indirectly with strategies that allow tumour infiltrating immune effector cells to exert their anti-tumour activity in the tumour microenvironment (TME) may be key for the successful treatment of cancer patients currently not responding to immunotherapeutic antibody treatment.

AstraZeneca COVID-19 vaccine induces robust broadly cross-reactive antibody responses in Malawian adults previously infected with SARS-CoV-2

BackgroundBinding and neutralising anti-Spike antibodies play a key role in immune defence against SARS-CoV-2 infection. Since it is known that antibodies wane with time and new immune-evasive variants are emerging, we aimed to assess the dynamics of anti-Spike antibodies in an African adult population with prior SARS-CoV-2 infection and to determine the effect of subsequent COVID-19 vaccination.MethodsUsing a prospective cohort design, we recruited adults with prior laboratory-confirmed mild/moderate COVID-19 in Blantyre, Malawi, and followed them up for 270 days (n = 52). A subset of whom subsequently received a single dose of the AstraZeneca COVID-19 vaccine (ChAdOx nCov-19) (n = 12). We measured the serum concentrations of anti-Spike and receptor-binding domain (RBD) IgG antibodies using a Luminex-based assay. Anti-RBD antibody cross-reactivity across SARS-CoV-2 variants of concern (VOC) was measured using a haemagglutination test. A pseudovirus neutralisation assay was used to measure neutralisation titres across VOCs. Ordinary or repeated measures one-way ANOVA was used to compare log10 transformed data, with p value adjusted for multiple comparison using Šídák's or Holm-Šídák's test.ResultsWe show that neutralising antibodies wane within 6 months post mild/moderate SARS-CoV-2 infection (30–60 days vs. 210–270 days; Log ID50 6.8 vs. 5.3, p = 0.0093). High levels of binding anti-Spike or anti-RBD antibodies in convalescent serum were associated with potent neutralisation activity against the homologous infecting strain (p < 0.0001). A single dose of the AstraZeneca COVID-19 vaccine following mild/moderate SARS-CoV-2 infection induced a 2 to 3-fold increase in anti-Spike and -RBD IgG levels 30 days post-vaccination (both, p < 0.0001). The anti-RBD IgG antibodies from these vaccinated individuals were broadly cross-reactive against multiple VOCs and had neutralisation potency against original D614G, beta, and delta variants.ConclusionsThese findings show that the AstraZeneca COVID-19 vaccine is an effective booster for waning cross-variant antibody immunity after initial priming with SARS-CoV-2 infection. The potency of hybrid immunity and its potential to maximise the benefits of COVID-19 vaccines needs to be taken into consideration when formulating vaccination policies in sub-Saharan Africa, where there is still limited access to vaccine doses.

Hypoxia-inducible factor-1α inhibition augments efficacy of programmed cell death 1 antibody in murine prostatic cancer models.

This study was designed to explore whether hypoxia-inducible factor-1α (HIF-1α) inhibitor could enhance immunotherapy efficacy in prostate cancer. Western blot was used to detect the expression of HIF-1α in the tumor and peritumor tissues from prostate cancer patients. The analysis from Cancer Genome Atlas database was used to show an association between HIF-1α expression and survival rate in prostate cancer patients. Murine prostate cell-derived xenograft (CDX) model was set up in both nude mice and BALB/c mice to observe the therapeutic effect of HIF-1α inhibitor IDF-11774. Protein expression of HIF-1α, as well as changes in the immune microenvironment, was detected. Moreover, the synergistic antitumor effect of IDF-11774 and PD-1 antibody was detected in another murine prostate cancer model. HIF-1α was found to have higher expression in prostate cancer tumor tissue than in peritumor tissue, and the expression level was negatively correlated with survival rate (P = 0.0157). HIF-1α inhibitor IDF-11774 reduced tumor volume and exhibited better efficacy in BALB/c mouse model (P < 0.0001) with normal immune system, with the same suppression level against HIF-1α. HIF-1α inhibitor reduced CD45+CD11b+Gr-1+ myeloid-derived suppressor cells (P = 0.0027) and CD45+ CD11b+F4/80+CD206hi M2 macrophages (P = 0.0059) but increased the abundance of CD45+CD3+CD8+ T cells (P = 0.0002) and CD45+CD3+CD4+ T cells (P = 0.0001) in tumor-infiltrating immune cells. The same synergistic effect was observed in RM-1 murine prostate CDX tumor model. HIF-1α inhibition augmented the antitumor efficacy of immune checkpoint inhibitor PD-1 antibody in murine prostate cancer models, probably through modulating the immunosuppressive microenvironment.

Augmented neutralization of SARS-CoV-2 Omicron variant by boost vaccination and monoclonal antibodies.

Effective vaccines and monoclonal antibodies have been developed against coronavirus disease 2019 (COVID‐19) caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). However, the appearance of virus variants with higher transmissibility and pathogenicity is a major concern because of their potential to escape vaccines and clinically approved SARS‐CoV‐2‐ antibodies. Here, we use flow cytometry‐based binding and pseudotyped SARS‐CoV‐2 neutralization assays to determine the efficacy of boost immunization and therapeutic antibodies to neutralize the dominant Omicron variant. We provide compelling evidence that the third vaccination with BNT162b2 increases the amount of neutralizing serum antibodies against Delta and Omicron variants, albeit to a lower degree when compared to the parental Wuhan strain. Therefore, a third vaccination is warranted to increase titers of protective serum antibodies, especially in the case of the Omicron variant. We also found that most clinically approved and otherwise potent therapeutic antibodies against the Delta variant failed to recognize and neutralize the Omicron variant. In contrast, some antibodies under preclinical development potentially neutralized the Omicron variant. Our studies also support using a flow cytometry‐based antibody binding assay to rapidly monitor therapeutic candidates and serum titers against emerging SARS‐CoV‐2 variants.

Neurotoxic and cardiotoxic effects of N-methyl-1-(naphthalen-2-yl)propan-2-amine (methamnetamine) and 1-phenyl-2-pyrrolidinylpentane (prolintane)

Two synthetic phenylethylamines, N-methyl-1-(naphthalen-2-yl)propan-2-amine (MNA) and 1-phenyl-2-pyrrolidinylpentane (prolintane), are being abused by people seeking hallucinogens for pleasure. These new psychotropic substances may provoke problems because there is no existing information about their toxicity and pharmacological behaviors. Therefore, we evaluated the safety of nerves and cardiovascular systems by determining toxicity after MNA and prolintane drugs administrations to mice and rat. Consequently, side effects such as increased spontaneous motion and body temperature were observed in oral administration of MNA. In addition, both substances reduced motor coordination levels. The IHC tests were conducted to see whether the immune response also shows abnormalities in brain tissue compared to the control group. It has been confirmed that the length of allograft inflammatory factor 1(IBA-1), an immune antibody known as microglia marker, has been shortened. We identified that a problem with the contact between synapses and neurons might be possibly produced. In the assessment of the cardiac toxicity harmfulness, no substances have been confirmed to be toxic to myocardial cells, but at certain concentrations, they have caused the QT prolongation, an indicator of ventricular arrhythmia. In addition, the hERG potassium channel, the biomarker of the QT prolongation, has been checked for inhibition. The results revealed that the possibility of QT prolongation through the hERG channel could not be excluded, and the two substances can be considered toxic that may cause ventricular arrhythmia. In sum, this study demonstrated that the possibility of toxicity in MNA and prolintane compounds might bring many harmful effects on nerves and hearts.