Human cytomegalovirus vaccination: progress and perspectives of recombinant gB

A vaccine for Human cytomegalovirus (HCMV) remains a high priority as complications following infection are observed in immunocompromised individuals and in congenitally infected neonates. Numerous preclinical and clinical studies have investigated vaccine strategies ranging from live attenuated preparations, nucleic acid-based approaches and recombinant delivery systems to subunit vaccines. These have defined the importance of both cell-mediated and humoral immunity to viral gB in the control of HCMV infection. This review will cover clinical trials investigating vaccine approaches that have incorporated gB and discuss the future perspectives of the recombinant gB subunit vaccine for HCMV

Echocardiography allows for analysis of pulmonary arterial flow in mice with congenital diaphragmatic hernia

BACKGROUND: Congenital diaphragmatic hernia (CDH) is a structural birth defect associated with pulmonary hypoplasia and pulmonary arterial hypertension (PAH). We hypothesize that echocardiography provides a method to assess real-time right ventricle (RV) function, remodeling, and pulmonary artery (PA) flow. MATERIALS AND METHODS: Slit3 wild-type (WT) (n = 6) and knockout (KO) (n = 5) mice were analyzed at 2-3 months of age. Mice were anesthetized using isoflurane. Echocardiography was performed to analyze left and right ventricular wall thickness, internal diameter (ID), and function. Color Doppler was used to analyze flow in the PA and across the tricuspid valve. RESULTS: There was significant RV dilation in the KO mice versus WT, with an average RVID of 1.99 mm versus 1.26 mm, respectively (P = 0.007). Flow in the PA of KO mice was altered compared to WT, with elevated PA velocity time indices, 30.68 mm versus 22.13 mm (P = 0.012), elevated PA peak velocities, 952.61 mm/s versus 628.73 mm/s (P = 0.003), and decreased pulmonary acceleration times, 8.94 ms versus 16.18 ms (P = 0.002), respectively. Pulmonary vascular resistance, calculated by measuring tricuspid regurgitation peak velocity and right ventricular outflow tract velocity time index, was increased in KO versus WT mice, 17.61 mm2/s versus 8.91 mm2/s (P = 0.003), respectively. CONCLUSIONS: Slit3 KO mice with CDH show evidence of PAH and resultant RV dilation. Using direct cardiac puncture, elevated RV systolic pressures have been demonstrated in KO mice as evidence of PAH. Echocardiography allows direct analysis of the PA and real-time RV function without sacrifice of the mouse. This mode of evaluation allows longitudinal study in mice with PAH and CDH

Mechanisms of rhinovirus neutralisation by antibodies

Antibodies are a critical immune correlate of protection for rhinoviruses, particularly those antibodies found in the secretory compartment. For nonenveloped viruses such as rhinoviruses, antibody binding to regions of the icosahedral capsid can neutralise infections by a number of different mechanisms. The purpose of this review is to address the neutralising mechanisms of antibodies to rhinoviruses that would help progress vaccine development. At least five mechanisms of antibody neutralisation have been identified which depend to some extent on the antibody binding footprints upon the capsid. The most studied mechanisms are virion aggregation, inhibition of attachment to cells, and stabilisation or destabilisation of the capsid structure. Newer mechanisms of degradation inside the cell through cytoplasmic antibody detection or outside by phagocytosis rely on what might have been previously considered as non-neutralising antibodies. We discuss these various approaches of antibody interference of rhinoviruses and offer suggestions as to how these could influence vaccine design

SARS-Cov-2 variants: biological and mathematical considerations for nomenclature

Coronavirus(CoV) is one of the most widely used words during the past two years. If it were announced that Delta CoV only affects animals such as pigs and wigeons while Omicron CoV does not even exist, surely people would be offended and question the credibility of whoever stated this. But both statements are true, scientifically. Ofnote, it was stated Delta CoV and Omicron CoV, not Delta variant or Omicron variant of SARS-CoV-2. Such potentially confusing naming of a globally important virus therefore warrants further analyses. At the subfamily level, CoVs are divided into four genera (Alpha, Beta, Gamma, Delta) and only viruses of the Alpha and Beta branch infect humans. Now that the Omicron variant of SARS-CoV-2 have taken over from the Delta variant globally, the issue of the double use of genus labels (Alpha, Beta, Gamma, Delta) for variant naming is mitigated. However, we can still pause and ponder whether the Greek symbols alone are indeed ideal for labeling waves of SARS-CoV-2 variants. Here we propose additional criteria for naming of variants that considers specific biological and molecular characteristics of the virus-cell interaction. Our aim is to define a biological and structurally defined metric that can be used to distinguish SARS-CoV-2 variants interactions with host cells. This metric could find utility with numerous human viruses and provide an additional parameter for improved naming of viruses

Interactive digital interventions to promote self-management in adults with asthma : systematic review and meta-analysis

This paper presents independent research funded by the National Institute for Health Research (NIHR) under its Programme Grants for Applied Research Programme (Grant Reference Number (RP-PG- 1211–20001).Background: To identify, summarise and synthesise the evidence for using interactive digital interventions to support patient self-management of asthma, and determine their impact. Methods: Systematic review with meta-analysis. We searched MEDLINE, EMBASE, CINAHL, PsycINFO, ERIC, Cochrane Library, DoPHER, TROPHI, Social Science Citation Index and Science Citation Index. The selection criteria requirement was studies of adults (16 years and over) with asthma, interventions that were interactive digital interventions and the comparator was usual care. Outcomes were change in clinical outcomes, cost effectiveness and patient-reported measures of wellbeing or quality of life. Only Randomised Controlled Trials published in peer-reviewed journals in English were eligible. Potential studies were screened and study characteristics and outcomes were extracted from eligible papers independently by two researchers. Where data allowed, meta-analysis was performed using a random effects model. Results: Eight papers describing 5 trials with 593 participants were included, but only three studies were eligible for inclusion for meta-analysis. Of these, two aimed to improve asthma control and the third aimed to reduce the total dose of oral prednisolone without worsening control. Analyses with data from all three studies showed no significant differences and extremely high heterogeneity for both Asthma Quality of Life (AQLQ) (Standardised Mean Difference (SMD) 0.05; 95 % Confidence Interval (CI) 0.32 to -0.22: I2 96.8) and asthma control (SMD 0.21; 95 % CI -0.05 to .42; I2 = 87.4). The removal of the third study reduced heterogeneity and indicated significant improvement for both AQLQ (SMD 0.45; 95 % CI 0.13 to 0.77: I2 = 0.34) and asthma control (SMD 0.54; 95 % CI 0.22 to 0.86: I2 = 0.11). No evidence of harm was identified. Conclusion: Digital self-management interventions for adults with asthma show promise, with some evidence of small beneficial effects on asthma control. Overall, the evidence base remains weak due to the lack of large, robust trials.Publisher PDFPeer reviewe

Rapid quantification of SARS-CoV-2 neutralising antibodies using time- resolved fluorescence immunoassay

The quantification of neutralising antibodies (NAb) for SARS-CoV-2 has become an important tool for monitoring protective immunity following infection or immunisation. In this study, we evaluated using World Health Organisation standard immunoglobulin preparations, a novel point-of-care test that quantitates NAb by time-resolved fluorescent immunoassay. The assay provided robust data of binding antibody units (BAU) in 15 minutes that was well correlated to NAb values obtained by traditional in vitro neutralisation assay. It also correlated well to spike receptor binding domain binding antibodies over a broad range of plasma dilutions. The assay was extremely sensitive, able to detect positive samples after dilution 1:10000 and over a wide range of BAU. Assay specificity was estimated at 96% using Pre-COVID serum samples, when applying a cut-off value of 47 BAU/ml although readings up to 100 BAU/ml could be considered borderline. This point-of-care diagnostic test is useful for rapid population screening, includes the use of capillary blood samples, and provides results for SARS-CoV-2 NAb in 15 minutes that can inform immediate decisions regarding protective immunity levels and the need for continued COVID immunisations

Essential role for proteinase-activated receptor-2 in arthritis

Using physiological, pharmacological, and gene disruption approaches, we demonstrate that proteinase-activated receptor-2 (PAR-2) plays a pivotal role in mediating chronic inflammation. Using an adjuvant monoarthritis model of chronic inflammation, joint swelling was substantially inhibited in PAR-2-deficient mice, being reduced by more than fourfold compared with wild-type mice, with virtually no histological evidence of joint damage. Mice heterozygous for PAR-2 gene disruption showed an intermediate phenotype. PAR-2 expression, normally limited to endothelial cells in small arterioles, was substantially upregulated 2 weeks after induction of inflammation, both in synovium and in other periarticular tissues. PAR-2 agonists showed potent proinflammatory effects as intra-articular injection of ASKH95, a novel synthetic PAR-2 agonist, induced prolonged joint swelling and synovial hyperemia. Given the absence of the chronic inflammatory response in the PAR-2-deficient mice, our findings demonstrate a key role for PAR-2 in mediating chronic inflammation, thereby identifying a novel and important therapeutic target for the management of chronic inflammatory diseases such as rheumatoid arthritis

Epitope mapping of antibodies induced with a conserved rhinovirus protein generating protective anti-rhinovirus immunity

Human rhinovirus (RV) infections are the principle cause of common colds and precipitate asthma and chronic obstructive pulmonary disease (COPD) exacerbations. Currently there is no vaccine for RV which is largely due to the existence of ~160 serotypes/strains. We demonstrated previously that immunising mice with highly conserved VP4 and VP2 regions of the RV polyprotein (RV-A16 VP0) generated cross-reactive immunity to RV in vivo. The current study investigated and mapped the epitopes of RV-A16 VP0 that are targets for antibodies in serum samples from VP0 immunisation and RV challenge studies in mice. Recombinant capsid proteins, peptide pools and individual peptides spanning the immunogen sequence (RV-A16 VP0) were assessed for IgG binding sites to identify epitopes. We found that peptide pools covering the C-terminus of VP4, the N-terminus of VP2 and the neutralising NIm-II site within VP2 were bound by serum IgG from immunised mice. The NIm-II site peptide pool blocked IgG binding to the immunogen RV-A16 VP0 and individual peptides within the pool binding IgG were further mapped. Thus, we have identified immunodominant epitopes of RV vaccine candidate RV-A16 VP0, noting that strong IgG binding antibodies were observed that target a key neutralising epitope that is highly variable amongst RV serotypes

Identification of similar epitopes between SARS-CoV-2 and Bacillus Calmette-Guérin: potential for cross-reactive adaptive immunity

Objectives: Bacillus Calmette–Guérin (BCG) vaccination has been implicated in protection against SARS-CoV-2 and as a non-specific immunization method against the virus. We therefore decided to investigate T cell and B cell epitopes within the BCG Pasteur strain proteome for similarity to immunogenic peptides of SARS-CoV-2. Methods: We used a bioinformatic approach and analyzed the BCG-Pasteur proteome to identify similar peptides to established and novel SARS-CoV-2 T cell and B cell epitopes. Results: We found 112 BCG MHC-I restricted T cell epitopes similar to MHC-I restricted T cell SARS-CoV-2 epitopes and 690 BCG B cell epitopes similar to SARS-CoV-2 B cell epitopes. The SARS-CoV-2 T cell epitopes represented 16 SARS-CoV-2 proteins, the SARS-CoV-2 B cell epitopes represented 5 SARS-CoV-2 proteins, including the receptor binding domain of the spike glycoprotein. Conclusion: Altogether our results provide a mechanistic basis for the potential cross-reactive adaptive immunity that may exists between the two microorganisms

Epitope-specific humoral responses to human cytomegalovirus glycoprotein-B vaccine with MF59: Anti-AD2 levels correlate with protection from viremia

The human cytomegalovirus (HCMV) virion envelope protein glycoprotein B (gB) is essential for viral entry and represents a major target for humoral responses following infection. Previously, a phase-2 placebo-controlled clinical trial conducted in solid organ transplant candidates demonstrated that vaccination with gB plus MF59 adjuvant significantly increased gB ELISA antibody levels whose titer correlated directly with protection against post-transplant viremia. The aim of the current study was to investigate in more detail this protective humoral response in vaccinated seropositive transplant recipients. We focussed on four key antigenic domains (AD) of gB; AD1, AD2, AD4 and AD5 measuring antibody levels in patient sera and correlating these with post-transplant HCMV viremia. Vaccination of seropositive patients significantly boosted pre-existing antibody levels against the immunodominant region AD1 as well as against AD2, AD4 and AD5. A decreased incidence of viremia correlated with higher antibody titers against AD2 but not with antibody titers against the other three ADs. Overall, these data support the hypothesis that antibodies against AD2 are a major component of the immune protection of seropositives seen following vaccination with gB/MF59 vaccine and identify a correlate of protective immunity in allograft patients