Immune Interference Research Articles

The race toward a universal influenza vaccine: Front runners and the future directions

Influenza virus is the pathogen of influenza (flu) and millions of people suffer from the infection worldwide, posing a significant health risk. The current influenza vaccines induce neutralizing antibodies against hemagglutinin (HA) to achieve strain-specific neutralization. The effectiveness of seasonal vaccines is usually low and unpredictable because of the antigenic variation and genetic plasticity of viruses, as well as the interference of preexisting immunity. A universal influenza vaccine is urgently needed to prevent a wide variety of influenza viruses. Nevertheless, reaching this difficult optimal goal requires a step-by-step approach. Innovative strategies and vaccine platforms are being developed in order to generate robust cross-protective immunity. In this review, we summarize candidate influenza vaccines that meet two criteria: first, they are designed to provide protection against multiple influenza viruses; second, they had passed regulatory evaluations and have entered various stages of clinical trials. We discuss these vaccine candidates based on the different vaccine-production platforms, with the focus on antigen selection, design, adjuvants, immunomodulators, and routes of vaccine delivery in the development of universal influenza vaccines.

MRNA-LNP expressing PfCSP and Pfs25 vaccine candidates targeting infection and transmission of Plasmodium falciparum

Malaria is a deadly disease responsible for between 550,000 and 627,000 deaths annually. There is a pressing need to develop vaccines focused on malaria elimination. The complex lifecycle of Plasmodium falciparum provides opportunities not only to target the infectious sporozoite stage, introduced by anopheline mosquitoes, but also the sexual stages, which are ingested by mosquitoes during blood feeding, leading to parasite transmission. It is widely recognized that a vaccine targeting multiple stages would induce efficacious transmission reducing immunity. Technological advancements offer new vaccine platforms, such as mRNA-LNPs, which can be used to develop highly effective malarial vaccines. We evaluated the immunogenicity of two leading P. falciparum vaccine candidates, Pfs25 and PfCSP, delivered as mRNA-LNP vaccines. Both vaccines induced extremely potent immune responses when administered alone or in combination, which were superior to Pfs25 and PfCSP DNA vaccine formulations. Purified IgGs from Pfs25 mRNA-LNPs immunized mice were highly potent in reducing malaria transmission to mosquitoes. Additionally, mice after three and four immunizations with PfCSP mRNA-LNP provided evidence for varying degrees of protection against sporozoite challenge. The comparison of immune responses and stage-specific functional activity induced by each mRNA-LNP vaccine, administered alone or in combination, also supports the development of an effective combination vaccine without any risk of immune interference for targeting malaria parasites at various life cycle stages. A combination of vaccines targeting both the infective stage and sexual/midgut stages is expected to interrupt malaria transmission, which is critical for achieving elimination goals.

HIV Coinfection Provides Insights for the Design of Vaccine Cocktails to Elicit Broadly Neutralizing Antibodies.

ABSTRACTInduction of broadly neutralizing antibodies (bNAbs) to HIV and other diverse pathogens will likely require the use of multiple immunogens. An understanding of the dynamics of antibody development to multiple diverse but related antigens would facilitate the rational design of immunization strategies. Here, we characterize, in detail, the development of neutralizing antibodies in three individuals coinfected with several divergent HIV variants. Two of these coinfected individuals developed additive or cross-neutralizing antibody responses. However, interference was observed in the third case, with neutralizing antibody responses to one viral variant arising to the near exclusion of neutralizing responses to the other. Longitudinal characterization of the diversity in the Envelope glycoprotein trimer (Env) structure showed that in the individual who developed the broadest neutralizing antibodies, circulating viruses shared a conserved epitope on the trimer apex that was targeted by cross-neutralizing antibodies. In contrast, in the other two individuals, diversity was distributed across Env. Taken together, these data highlight that multiple related immunogens can result in immune interference. However, they also suggest that immunogen cocktails presenting shared, conserved neutralizing epitopes in a variable background may focus broadly neutralizing antibody responses to these targets.IMPORTANCE Despite being the focus of extensive research, we still do not know how to reproducibly elicit cross-neutralizing antibodies against variable pathogens by vaccination. Here, we characterize the antibody responses in people coinfected with more than one HIV variant, providing insights into how the use of antigen “cocktails” might affect the breadth of the elicited neutralizing antibody response and how the relatedness of the antigens may shape this.

Enrofloxacin Induces Intestinal Microbiota-Mediated Immunosuppression in Zebrafish.

The immunosuppressive effects of antibiotics and the potential associations with the intestinal microbiota of the host have been increasingly recognized in recent years. However, the detailed underlying mechanisms of immune interference of antibiotics in environmental organisms remain unclear, particularly at the early life stage of high sensitivity. To better understand the gut microbiome and immune function interactions, the vertebrate model, zebrafish, was treated with environmentally relevant concentrations of a frequently detected antibiotic, enrofloxacin (ENR), ranging from 0.01 to 100 μg/L. 16S ribosomal RNA sequencing indicated diminished diversity, richness, and evenness of intestinal flora following ENR treatment. Twenty-two taxa of gut bacteria including Rickettsiales, Pseudomonadales, and Flavobacteriales were significantly correlated with immunosuppressive biomarkers, including a significant decrease in the abundance of macrophages and neutrophils. To validate the immunomodulatory effects due to altered intestinal microbial populations, zebrafish reared under sterile and non-sterile husbandry conditions were compared after ENR treatment. A significant inhibitory effect was induced by ENR treatment under non-sterile conditions, while the number of macrophages and neutrophils, as well as biomarkers of immunosuppressive effects, were significantly salved in zebrafish under sterile conditions, confirming for the first time that immunosuppression by ENR was closely mediated through alterations of the intestinal microbiome in fish.

Response to Comment on "Oxidative Stress, Endocrine Disturbance, and Immune Interference in Humans Showed Relationships to Serum Bisphenol Concentrations in a Dense Industrial Area".

Response to Comment on "Oxidative Stress, Endocrine Disturbance, and Immune Interference in Humans Showed Relationships to Serum Bisphenol Concentrations in a Dense Industrial Area".

Comment on "Oxidative Stress, Endocrine Disturbance and Immune Interference in Humans Showed Relationships to Serum Bisphenol Concentrations in a Dense Industrial Area": Importance and Influence of Gender.

Comment on "Oxidative Stress, Endocrine Disturbance and Immune Interference in Humans Showed Relationships to Serum Bisphenol Concentrations in a Dense Industrial Area": Importance and Influence of Gender.

Emerging Potential of Exosomal Non-coding RNA in Parkinson's Disease: A Review.

Exosomes are extracellular vesicles that are released by cells and circulate freely in body fluids. Under physiological and pathological conditions, they serve as cargo for various biological substances such as nucleotides (DNA, RNA, ncRNA), lipids, and proteins. Recently, exosomes have been revealed to have an important role in the pathophysiology of several neurodegenerative illnesses, including Parkinson’s disease (PD). When secreted from damaged neurons, these exosomes are enriched in non-coding RNAs (e.g., miRNAs, lncRNAs, and circRNAs) and display wide distribution characteristics in the brain and periphery, bridging the gap between normal neuronal function and disease pathology. However, the current status of ncRNAs carried in exosomes regulating neuroprotection and PD pathogenesis lacks a systematic summary. Therefore, this review discussed the significance of ncRNAs exosomes in maintaining the normal neuron function and their pathogenic role in PD progression. Additionally, we have emphasized the importance of ncRNAs exosomes as potential non-invasive diagnostic and screening agents for the early detection of PD. Moreover, bioengineered exosomes are proposed to be used as drug carriers for targeted delivery of RNA interference molecules across the blood-brain barrier without immune system interference. Overall, this review highlighted the diverse characteristics of ncRNA exosomes, which may aid researchers in characterizing future exosome-based biomarkers for early PD diagnosis and tailored PD medicines.

Safety and immunogenicity of a high-dose quadrivalent influenza vaccine administered concomitantly with a third dose of the mRNA-1273 SARS-CoV-2 vaccine in adults aged ≥65 years: a phase 2, randomised, open-label study

BackgroundConcomitant seasonal influenza vaccination with a COVID-19 vaccine booster could help to minimise potential disruption to the seasonal influenza vaccination campaign and maximise protection against both diseases among individuals at risk of severe disease and hospitalisation. This study aimed to assess the safety and immunogenicity of concomitant administration of high-dose quadrivalent influenza vaccine (QIV-HD) and a mRNA-1273 vaccine booster dose in older adults.MethodsThis study is an ongoing, phase 2, multicentre, open-label, descriptive trial at six clinical research sites in the USA. We describe the interim results up to 21 days after vaccination (July–August, 2021). Community-dwelling adults aged 65 years and older, who were previously vaccinated with a two-dose primary schedule of the mRNA-1273 SARS-CoV-2 vaccine, were eligible for inclusion. The second dose of the primary mRNA-1273 vaccination series was required to have been received at least 5 months before enrolment in the study. Participants were randomly assigned (1:1:1) using a permuted block method stratified by site and by age group (<75 years vs ≥75 years), to receive concomitant administration of QIV-HD and mRNA-1273 vaccine, QIV-HD alone, or mRNA-1273 vaccine alone. Randomisation lists, generated by Sanofi Pasteur biostatistics platform, were provided to study investigators for study group allocation. Unsolicited adverse events occurring immediately, solicited local and systemic reactions up to day 8, and unsolicited adverse events, serious adverse events, adverse events of special interest, and medically attended adverse events up to day 22 were reported. Haemagglutination inhibition antibody responses to influenza A/H1N1, A/H3N2, B/Yamagata, and B/Victoria strains and SARS CoV-2 binding antibody responses (SARS-CoV-2 pre-spike IgG ELISA) were assessed at day 1 and day 22. All analyses were descriptive. The study is registered with ClinicalTrials.gov, NCT04969276.FindingsBetween July 16 and Aug 31, 2021, 306 participants were enrolled and randomly assigned, of whom 296 received at least one vaccine dose (100 in the coadministration group, 92 in the QIV-HD, and 104 in the mRNA-1273 group). Reactogenicity profiles were similar between the coadministration and mRNA-1273 groups, with lower reactogenicity rates in the QIV-HD group (frequency of solicited injection site reactions 86·0% [95% CI 77·6–92·1], 91·3% [84·2–96·0], and 61·8% [50·9–71·9]; frequency of solicited systemic reactions 80·0%, [70·8–87·3], 83·7% [75·1–90·2], and 49·4% [38·7–60·2], respectively). Up to day 22, unsolicited adverse events were reported for 17·0% (95% CI 10·2–25·8) of participants in the coadministration group and 14·4% (8·3–22·7) of participants in the mRNA-1273 group, and tended to be reported at a slightly lower rate (10·9% [5·3–19·1]) in participants in the QIV-HD group. Seven participants each reported one medically attended adverse event (three in the coadministration group, one in the QIV-HD group, and three in the mRNA-1273 group). There were no serious adverse events, adverse events of special interest, or deaths. Haemagglutination inhibition antibody geometric mean titres increased from day 1 to day 22 to similar levels in the coadministration and QIV-HD groups, for each influenza strain (A/H1N1: 363 [95% CI 276–476] vs 366 [272–491]; A/H3N2: 286 [233–352] vs 315 [257–386]; B/Yamagata: 429 [350–525] vs 471 [378–588]; B/Victoria: 377 [325–438] vs 390 [327–465] for the coadministration and QIV-HD groups, respectively). SARS-CoV-2 binding antibody geometric mean concentrations also increased to similar levels in the coadministration and mRNA-1273 groups at day 22 (7634 [95% CI 6445–9042] and 7904 [6883–9077], respectively).InterpretationNo safety concerns or immune interference were observed for concomitant administration of QIV-HD with mRNA-1273 booster in adults aged 65 years and older, supporting co-administration recommendations.FundingSanofi Pasteur.

Immune interference revisited: Impact of live-attenuated influenza vaccine prior to yellow fever vaccination

BackgroundDuring routine mass live-attenuated influenza vaccination (LAIV) for military personnel, emergent deployment for Ebola humanitarian assistance (OUA) required mass yellow fever vaccination (YF17D), often < 4-weeks recommended timing post-LAIV—triggering concerns for immune interference. We compared YF17D seroconversion rates in personnel who received YF17D as recommended (vaccinated by guidelines [VBG]) to those who received the vaccine outside the recommended timing following LAIV (not vaccinated by guidelines [NVBG]). MethodsOUA deploying personnel who received LAIV simultaneously or before YF17D and had pre- and post-vaccination archived serum were included. VBG was defined as YF17D given concurrently or ≥ 30 days post-LAIV and NVBG as YF17D given 1–29 days post-LAIV. YF17D seroresponse was determined by screening ELISA confirmed with plaque reduction neutralization testing (PRNT) on positive ELISA samples. Exclusion criteria were prior YF17D and pre-vaccination YF17D positive PRNT. ResultsOf the 660 personnel included, 507 were VBG and 153 were NVBG. Median age was 25 years for both groups. Men accounted for 84% of those VBG and 79% NVBG (p = 0.194). Seroconversion rates were 97.8% for VBG and 95.4% for NVBG (p = 0.15). Multivariate logistic regression revealed that YF17D on days 7–21 post-LAIV (adjusted odds ratio [aOR] 0.304, p = 0.017; confidence interval [CI] 0.114–0.810) and female sex (aOR 0.330, p = 0.026; CI 0.124–0.879) were associated with decreased seroresponse. ConclusionsIn this healthy, young adult military population, there was high seroconversion following YF17D when administered simultaneously and at various time points after LAIV. Slight decreases in seroresponse were seen in women and those receiving YF17D 7–21 days following LAIV.

ACIP issues recommendations for zoster, pneumococcal vaccines

At a recent meeting of CDC’s Advisory Committee of Immunization Practices (ACIP), the group recommended recombinant zoster vaccine (RZV) for adults 19 years and older who are immunodeficient or immunosuppressed as well as the routine use of select pneumococcal vaccines in adults 65 years and older and those aged 19 to 64 years with certain underlying medical conditions or other risk factors. The pneumococcal vaccine recommendation only applies to those who have not yet received a pneumococcal conjugate vaccine or those whose vaccination history is unknown. Data presented at the ACIP meeting on October 20, 2021, revealed the complications of herpes zoster (e.g., post-herpetic neuralgia, hospitalizations), and how the risk of zoster infection is heightened for those who are immunocompromised. The ACIP group recommended that adults (19 years and older) who are immunodeficient or immunosuppressed due to disease or therapy receive 2 doses of RZV for the prevention of herpes zoster and its complications. Clinicians may be challenged, however, in identifying those who are immunodeficient or immunosuppressed, as conditions in this group of patients might not appear as straightforward as those who have cancer or a transplant. “I don’t think a Medrol Dose Pack is immunosuppressive, but dispensing software may flag it as such—so the pharmacist needs to be able to work through that decision-making,” said Adam Welch, PharmD, MBA, FAPhA, associate dean for assessment and academic affairs at East Tennessee State University’s Bill Gatton College of Pharmacy. “Pharmacists should review guidance from ACIP on altered immunocompetence to help them.” This guidance can be found on CDC’s website at apha.us/ACIPrecs Another consideration is the timing and spacing of the 2 doses. “It’s best to give RZV prior to the next cycle/dose of an immunosuppressive drug if it can’t be given in anticipation of immunosuppression,” said Welch. Additionally, the second dose can be given 1 to 2 months after the first dose (minimum of a 4-week spacing period) for immunocompromised adults, whereas those who are immunocompetent can continue to receive the 2 doses 2 to 6 months apart. Welch also noted that RZV has been studied concomitantly with other vaccines (e.g., Fluarix, PPSV23, and Boostrix) with no evidence of immune response interference or safety concerns and it can be administered with COVID-19 vaccines. The new ACIP recommendations state that eligible patients should receive a pneumococcal conjugate vaccine, either the PCV20 (20-valent pneumococcal conjugate vaccine) or PCV15 (15-valent pneumococcal conjugate vaccine). If PCV15 is used, this should be followed by a dose of PPSV23 (23-valent pneumococcal polysaccharide vaccine). Based on these new recommendations, PCV13 is no longer recommended for use in adults. This is the first time any pneumococcal conjugate vaccine has been routinely recommended for certain risk populations ages 19 to 64, such as those with diabetes and asthma. The table below lists certain medical conditions and other risk factors for those 19 to 64 years. “Based on this new recommendation it’s important to note that if a patient already received PCV13, it looks like they wouldn’t need PCV15/PPSV23 or PCV20,” said Welch. “Also, clear documentation is essential, using the correct abbreviations.” He said it will be important for clinicians to not call it pneumococcal vaccine, since that is now too vague. It should be identified more specifically as either PPSV23, PCV15, or PCV20. The ACIP recommendations are not final until they receive approval from CDC and HHS. Underlying medical conditions or other risk factors▪Alcohol use disorder▪Chronic heart/liver/lung disease▪Cigarette smoking▪Diabetes mellitus▪Chronic renal failure▪Nephrotic syndrome▪Immunodeficiency▪Iatrogenic immunosuppression▪Generalized malignancy▪HIV▪Hodgkin disease, leukemia, lymphoma, multiple myeloma▪Solid organ transplants▪Congenital or acquired asplenia▪Sickle cell disease or other hemoglobinopathies▪CSF leak or cochlear implant ▪Alcohol use disorder▪Chronic heart/liver/lung disease▪Cigarette smoking▪Diabetes mellitus▪Chronic renal failure▪Nephrotic syndrome▪Immunodeficiency▪Iatrogenic immunosuppression▪Generalized malignancy▪HIV▪Hodgkin disease, leukemia, lymphoma, multiple myeloma▪Solid organ transplants▪Congenital or acquired asplenia▪Sickle cell disease or other hemoglobinopathies▪CSF leak or cochlear implant

Cancer attrition immunotherapy

Cancer is a deadly disease wherein the immune system is inefficient, resulting in malignant tumors that metastasize. An active and robust immune system is the body’s natural defense. Research efforts continue exploring alternative immunotherapies to fight cancer. This communication proposes non-infectious vaccines and hyper-allergenic skin creams to starve malignant tumors through immune metabolic interference.

Immune dysregulation and immunopathology induced by SARS-CoV-2 and related coronaviruses - are we our own worst enemy?

Human coronaviruses cause a wide spectrum of disease, ranging from mild common colds to acute respiratory distress syndrome and death. Three highly pathogenic human coronaviruses — severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus and SARS-CoV-2 — have illustrated the epidemic and pandemic potential of human coronaviruses, and a better understanding of their disease-causing mechanisms is urgently needed for the rational design of therapeutics. Analyses of patients have revealed marked dysregulation of the immune system in severe cases of human coronavirus infection, and there is ample evidence that aberrant immune responses to human coronaviruses are typified by impaired induction of interferons, exuberant inflammatory responses and delayed adaptive immune responses. In addition, various viral proteins have been shown to impair interferon induction and signalling and to induce inflammasome activation. This suggests that severe disease associated with human coronaviruses is mediated by both dysregulated host immune responses and active viral interference. Here we discuss our current understanding of the mechanisms involved in each of these scenarios.

Vaccine efficacy and immune interference: co-administering COVID-19 and influenza vaccines

As we head towards the second anniversary of the COVID-19 pandemic, attention widens to encompass the array of unforeseen health-care consequences of these unprecedented times and measures. In this context, efforts have been made to analyse data and predict how the winter months will look in terms of the interplay between infections by SARS-CoV-2 and other common respiratory viruses, influenza, and respiratory syncytial virus. To an extent, there is still no consensus in the scientific and medical communities as to the risk and impact of concomitant respiratory infections: on the one hand, lockdown and other mitigations that have limited the spread of COVID-19 would be predicted to have limited influenza and respiratory syncytial virus too.

Distributed fiber optic radiation sensors

Abstract. The international research efforts focused on the development of radiation sensors based on optic fibers have their origins in the 1970s (Evans et al., 1978). Generally, the lightweight fiber optic sensors are immune to electromagnetic field interference and high voltages making them deployable in harsh environments at hard to reach areas where conventional sensors usually will not work at all. A further advantage of such radiation sensors is the possibility of remote and real-time monitoring (Huston et al., 2001). In this work, we present our results achieved in several research activities for development of fiber optic dosimeters. The findings show that both the measurement of the radiation-induced attenuation (RIA) along the entire sensing fiber and the accompanying change in the refractive index of the fiber core can be used for distributed radiation monitoring in the kGy and MGy range, respectively. Depending on the fiber type and material the RIA shows varying response to dose rates, environmental temperatures and the wavelength of the laser source used. Thereby, an operation with visible laser light provides most favorable performance in terms of high radiation sensitivity. Operating at these wavelengths, RIA monitoring could yield high-sensitivity dose measurement with sub-gray resolution and accuracy (Stajanca and Krebber, 2017b); however, conventional optical time-domain reflectometry (OTDR) systems for RIA measurements operating in the visible range suffer from low-spatial resolution, long measurement times and poor signal-to-noise (SNR) ratio. The limitations of the OTDR performance can be overcome by the incoherent optical frequency domain reflectometry (I-OFDR) developed by the Federal Institute of Materials Research and Testing (BAM, Liehr et al., 2009) with potential for dynamic real-time measurement. Over the years, several highly radiation sensitive fibers, such as perfluorinated polymer optical fibers (PF-POF, Stajanca and Krebber, 2017a), phosphorous-doped silica optical fibers (SOF, Paul et al., 2009), aluminium-doped SOF (Faustov et al., 2013) and erbium-doped SOF (Wosniok et al., 2016) have been identified and are commercially available. As mentioned before, the radiation-induced RIA increase is associated with an increase in the refractive index leading also to material compaction in the fiber core. The latter two effects can be used for measuring radiation distribution based on Brillouin scattering in the range of high radiation doses of several MGy (Phéron et al., 2012; Wosniok et al., 2016). When using fiber optic sensors for radiation monitoring, the existing post-irradiation annealing behavior of the optical fiber sensors must also be considered.

Stress associated proteins coordinate the activation of comprehensive antiviral immunity in Phalaenopsis orchids.

Viruses cause severe damage on crops, and identification of key gene(s) that can comprehensively activate antiviral immunity will provide insights for designing effective antiviral strategies. Salicylic acid (SA)-mediated antiviral immunity and RNA interference (RNAi) are two independently discovered antiviral pathways. Previously, we identified the orchid stress-associated protein (SAP), Pha13, which serves as a hub in SA-mediated antiviral immunity. As SAPs exist as a protein family, whether duplicated SAPs have redundant or distinctive functions in antiviral immunity remains elusive. We performed functional assays on orchid Pha21, a homolog of Pha13, using transient and transgenic approaches on orchid, Arabidopsis and Nicotiana benthamiana to overexpress and/or silence Pha21. The SA treatment induced the expression of both Pha13 and Pha21, whereas Pha21 was found to play a key role in the initiation of the RNAi pathway in Phalaenopsis orchids. We demonstrated that Pha21-mediated antiviral immunity and enhancement of the RNAi pathway is conserved between dicotyledons and monocotyledons. We provide new insight that orchid SAPs confer distinctive functions to coordinate both SA-signaling and RNAi for comprehensive activation of antiviral immunity, and this information will help us develop antiviral strategies on crops.

Attenuated Salmonella carrying plasmid co-expressing HPV16 L1 and siRNA-E6 for cervical cancer therapy

Human papillomavirus (HPV) infection is the major etiological factor for cervical cancer. HPV prophylactic vaccines based on L1 virus-like particles have been considered as an effective prevention method. However, existing recombination vaccines are too expensive for developing countries. DNA vaccines might be a lower-cost and effective alternative. In this study, a plasmid (pcDNA3.1-HPV16-L1) and a co-expressing plasmid (pcDNA3.1-HPV16-L1-siE6) carried by attenuated Salmonella were constructed and their prevention and treatment effect on cervical cancer were observed, respectively. The results showed that pcDNA3.1-HPV16-L1 carried by attenuated Salmonella could induce the production of HPV16-L1 antibodies, IL-2 and INF-γ in mice serum, which presented its prevention effect on HPV. Subsequently, E6 and E7 gene silencing by pCG-siE6 inhibited the growth of cervical cancer both in vitro and in vivo. Furthermore, L1 up-regulation and E6/E7 down-regulation caused by co-expressing plasmid (pcDNA3.1-HPV16-L1-siE6) contributed to a significant anti-tumor effect on the mice. This study suggests that pcDNA3.1-HPV16-L1-siE6 carried by attenuated Salmonella has a synergistic effect of immune regulation and RNA interference in cervical cancer treatment.

Glucose inhibits haemostasis and accelerates diet-induced hyperlipidaemia in zebrafish larvae

Hyperglycaemia damages the microvasculature in part through the reduced recruitment of immune cells and interference with platelet signalling, leading to poor wound healing and accelerated lipid deposition in mammals. We investigated the utility of zebrafish larvae to model the effect of exogenous glucose on neutrophil and macrophage recruitment to a tail wound, wound-induced haemostasis, and chicken egg yolk feed challenge-induced hyperlipidaemia by supplementing larvae with exogenous glucose by immersion or injection. Neither method of glucose supplementation affected the recruitment of neutrophils and macrophages following tail transection. Glucose injection reduced thrombocyte retention and fibrin plug formation while only thrombocyte retention was reduced by glucose immersion following tail transection. We observed accelerated lipid accumulation in glucose-injected larvae challenged with high fat chicken egg yolk feeding. Our study identifies conserved and divergent effects of high glucose on inflammation, haemostasis, and hyperlipidaemia in zebrafish larvae compared to mammals.

PD-1/PD-L1 inhibitors-based treatment for advanced renal cell carcinoma: Mechanisms affecting efficacy and combination therapies.

With the widespread use of PD‐1/PD‐L1 monoclonal antibodies (mAbs) in the treatment of multiple malignant tumors, they were also gradually applied to advanced renal cell carcinoma (aRCC). Nowadays, multiple PD‐1/PD‐L1 mAbs, such as nivolumab, avelumab, and pembrolizumab, have achieved considerable efficacy in clinical trials. However, due to the primary, adaptive, and acquired resistance to these mAbs, the efficacy of this immunotherapy is not satisfactory. Theories also vary as to why the difference in efficacy occurs. The alterations of PD‐L1 expression and the interference of cellular immunity may affect the efficacy. These mechanisms demand to be revealed to achieve a sustained and complete objective response in patients with aRCC. Tyrosine kinase inhibitors have been proven to have synergistic mechanisms with PD‐1/PD‐L1 mAb in the treatment of aRCC, and CTLA‐4 mAb has been shown to have a non‐redundant effect with PD‐1/PD‐L1 mAb to enhance efficacy. Although combinations with targeted agents or other checkpoint mAbs have yielded enhanced clinical outcomes in multiple clinical trials nowadays, the potential of PD‐1/PD‐L1 mAbs still has a large development space. More potential mechanisms that affect the efficacy demand to be developed and transformed into the clinical treatment of aRCC to search for possible combination regimens. We elucidate these mechanisms in RCC and present existing combination therapies applied in clinical trials. This may help physicians’ select treatment options for patients with refractory kidney cancer.

Fusobacterium nucleatum and alteration of the oral microbiome: from pregnancy to SARS-COV-2 infection.

The human being has evolved in close symbiosis with its own ecological community of commensal, symbiotic and pathogenic bacteria. After the intestinal microbiome, that of the oral cavity is the largest and most diversified. Its importance is reflected not only in local and systemic diseases, but also in pregnancy since it would seem to influence the placental microbiome. This is a literature review of articles published in PubMed about Fusobacterium Nucleatum and both its implications with systemic and oral health, adverse pregnancy outcomes, flavors perception and its interference in the oral-nasal mucosal immunity. It is in maintaining the microbiome's homeostasis that the Fusobacterium nucleatum, an opportunistic periodontal pathogen of the oral cavity, plays a crucial role both as a bridge microorganism of the tongue biofilm, and in maintaining the balance between the different species in the oral-nasal mucosal immunity also by taste receptors interaction. It is also involved in the flavor perception and its detection in the oral microbiome of children from the first days of life suggests a possible physiological role. However, the dysbiosis can determine its pathogenicity with local and systemic consequences, including the pathogenesis of respiratory infections. It is interesting to evaluate its possible correlation with Sars-CoV-2 and the consequences on the microflora of the oral cavity, both to promote a possible broad-spectrum preventive action, in favor of all subjects for whom, by promoting the eubiosis of the oral microbiome, a defensive action could be envisaged by the commensals themselves but, above all, for patients with specific comorbidities and therefore already prone to oral dysbiosis.

Neisseria meningitidis Factor H Binding Protein Surface Exposure on Salmonella Typhimurium GMMA Is Critical to Induce an Effective Immune Response against Both Diseases.

GMMA, outer membrane vesicles resulting from hyperblebbing mutated bacterial strains, are a versatile vaccine platform for displaying both homologous and heterologous antigens. Periplasmic expression is a popular technique for protein expression in the lumen of the blebs. However, the ability of internalized antigens to induce antibody responses has not been extensively investigated. Herein, the Neisseria meningitidis factor H binding protein (fHbp) was heterologously expressed in the lumen of O-antigen positive (OAg+) and O-antigen negative (OAg−) Salmonella Typhimurium GMMA. Only the OAg− GMMA induced an anti-fHbp IgG response in mice if formulated on Alum, although it was weak and much lower compared to the recombinant fHbp. The OAg− GMMA on Alum showed partial instability, with possible exposure of fHbp to the immune system. When we chemically conjugated fHbp to the surface of both OAg+ and OAg− GMMA, these constructs induced a stronger functional response compared to the fHbp immunization alone. Moreover, the OAg+ GMMA construct elicited a strong response against both the target antigens (fHbp and OAg), with no immune interference observed. This result suggests that antigen localization on GMMA surface can play a critical role in the induction of an effective immune response and can encourage the development of GMMA based vaccines delivering key protective antigens on their surface.