Adenovirus vectored vaccines are a highly effective strategy to induce cellular immune responses which are particularly effective against intracellular pathogens. Recombinant simian adenovirus ...vectors were developed to circumvent the limitations imposed by the use of human adenoviruses due to widespread seroprevalence of neutralising antibodies. We have constructed a replication deficient simian adenovirus-vectored vaccine (ChAdOx2) expressing 4 genes from the
subspecies
(
,
,
and
). Safety and T-cell immunogenicity results of the first clinical use of the ChAdOx2 vector are presented here. The trial was conducted using a 'three-plus-three' dose escalation study design. We demonstrate the vaccine is safe, well tolerated and immunogenic.
Glucose-6-phosphate dehydrogenase deficiency (G6PDd), haemoglobin C (HbC) and S (HbS) are inherited blood disorders (IBD) common in populations in malaria endemic areas. All are associated to some ...degree with protection against clinical malaria whilst additionally G6PDd is associated with haemolysis following treatment with 8-aminoquinolines. Measuring the prevalence of these inherited blood disorders in affected populations can improve understanding of disease epidemiology. Current methodologies in epidemiological studies commonly rely on individual target amplification and visualization; here a method is presented to simultaneously detect the polymorphisms and that can be expanded to include other single nucleotide polymorphisms (SNPs) of interest.
Human DNA from whole blood samples was amplified in a novel, multiplex PCR reaction and extended with SNP-specific probes in an allele specific primer extension (ASPE) to simultaneously detect four epidemiologically important human markers including G6PD SNPs (G202A and A376G) and common haemoglobin mutations (HbS and HbC). The products were hybridized to magnetic beads and the median fluorescence intensity (MFI) was read on MAGPIX
(Luminex corp.). Genotyping data was compared to phenotypical data generated by flow cytometry and to established genotyping methods.
Seventy-five samples from Burkina Faso (n = 75/78, 96.2%) and 58 samples from The Gambia (n = 58/61, 95.1%) had a G6PD and a HBB genotype successfully assigned by the bead-based assay. Flow cytometry data available for n = 61 samples further supported the concordance between % G6PD normal/deficient cells and genotype.
The bead based assay compares well to alternative measures of genotyping and phenotyping for G6PD. The screening is high throughput, adaptable to inclusion of multiple targets of interest and easily standardized.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background: Pre-existing T cell responses to influenza have been correlated with improved clinical outcomes in natural history and human challenge studies. We aimed to determine the efficacy, safety ...and immunogenicity of a T-cell directed vaccine in older people. Methods: This was a multicentre, participant- and safety assessor-blinded, randomised, placebo-controlled trial of the co-administration of Modified Vaccinia Ankara encoding nucleoprotein and matrix protein 1 (MVA-NP+M1) and annual influenza vaccine in participants ≥ 65. The primary outcome was the number of days with moderate or severe influenza-like symptoms (ILS) during the influenza season. Results: 846 of a planned 2030 participants were recruited in the UK prior to, and throughout, the 2017/18 flu season. There was no evidence of a difference in the reported rates of days of moderate or severe ILS during influenza-like illness episodes (unadjusted OR = 0.95, 95% CI: 0.54–1.69; adjusted OR = 0.91, 95% CI: 0.51–1.65). The trial was stopped after one season due to a change in the recommended annual flu vaccine, for which safety of the new combination had not been established. More participants in the MVA-NP+M1 group had transient moderate or severe pain, redness, and systemic responses in the first seven days. Conclusion: The MVA-NP+M1 vaccine is well tolerated in those aged 65 years and over. Larger trials would be needed to determine potential efficacy.
Seasonal influenza infections have a significant global impact leading to increased health and economic burden. The efficacy of currently available seasonal influenza vaccines targeting polymorphic ...surface antigens has historically been suboptimal. Cellular immune responses against highly conserved Influenza A virus antigens, such as nucleoprotein (NP) and matrix protein-1 (M1), have previously been shown to be associated with protection from disease, whilst viral-vectored vaccines are an effective strategy to boost cell-mediated immunity. We have previously demonstrated that MVA encoding NP and M1 can induce potent and persistent T cell responses against influenza. In this Phase I study, we evaluated the safety and immunogenicity of MVA-NP+M1, which was newly manufactured on an immortalized cell line, in six healthy adult participants. The vaccine was well-tolerated with only mild to moderate adverse events that resolved spontaneously and were comparable to previous studies with the same vaccine manufactured in chick embryo fibroblasts. A significant increase in vaccine-specific T cell responses was detected seven days after immunization and was directed against both antigens in the vector insert. This small Phase I study supports progression of this vaccine to a Phase IIb study to assess immunogenicity and additional protective efficacy in older adults receiving licensed seasonal influenza vaccines.
Cases of Middle East respiratory syndrome coronavirus (MERS-CoV) infection continue to rise in the Arabian Peninsula 7 years after it was first described in Saudi Arabia. MERS-CoV poses a significant ...risk to public health security because of an absence of currently available effective countermeasures. We aimed to assess the safety and immunogenicity of the candidate simian adenovirus-vectored vaccine expressing the full-length spike surface glycoprotein, ChAdOx1 MERS, in humans.
This dose-escalation, open-label, non-randomised, uncontrolled, phase 1 trial was done at the Centre for Clinical Vaccinology and Tropical Medicine (Oxford, UK) and included healthy people aged 18–50 years with negative pre-vaccination tests for HIV antibodies, hepatitis B surface antigen, and hepatitis C antibodies (and a negative urinary pregnancy test for women). Participants received a single intramuscular injection of ChAdOx1 MERS at three different doses: the low-dose group received 5 × 109 viral particles, the intermediate-dose group received 2·5 × 1010 viral particles, and the high-dose group received 5 × 1010 viral particles. The primary objective was to assess safety and tolerability of ChAdOx1 MERS, measured by the occurrence of solicited, unsolicited, and serious adverse events after vaccination. The secondary objective was to assess the cellular and humoral immunogenicity of ChAdOx1 MERS, measured by interferon-γ-linked enzyme-linked immunospot, ELISA, and virus neutralising assays after vaccination. Participants were followed up for up to 12 months. This study is registered with ClinicalTrials.gov, NCT03399578.
Between March 14 and Aug 15, 2018, 24 participants were enrolled: six were assigned to the low-dose group, nine to the intermediate-dose group, and nine to the high-dose group. All participants were available for follow-up at 6 months, but five (one in the low-dose group, one in the intermediate-dose group, and three in the high-dose group) were lost to follow-up at 12 months. A single dose of ChAdOx1 MERS was safe at doses up to 5 × 1010 viral particles with no vaccine-related serious adverse events reported by 12 months. One serious adverse event reported was deemed to be not related to ChAdOx1 MERS. 92 (74% 95% CI 66–81) of 124 solicited adverse events were mild, 31 (25% 18–33) were moderate, and all were self-limiting. Unsolicited adverse events in the 28 days following vaccination considered to be possibly, probably, or definitely related to ChAdOx1 MERS were predominantly mild in nature and resolved within the follow-up period of 12 months. The proportion of moderate and severe adverse events was significantly higher in the high-dose group than in the intermediate-dose group (relative risk 5·83 95% CI 2·11–17·42, p<0·0001) Laboratory adverse events considered to be at least possibly related to the study intervention were self-limiting and predominantly mild in severity. A significant increase from baseline in T-cell (p<0·003) and IgG (p<0·0001) responses to the MERS-CoV spike antigen was observed at all doses. Neutralising antibodies against live MERS-CoV were observed in four (44% 95% CI 19–73) of nine participants in the high-dose group 28 days after vaccination, and 19 (79% 58–93) of 24 participants had antibodies capable of neutralisation in a pseudotyped virus neutralisation assay.
ChAdOx1 MERS was safe and well tolerated at all tested doses. A single dose was able to elicit both humoral and cellular responses against MERS-CoV. The results of this first-in-human clinical trial support clinical development progression into field phase 1b and 2 trials.
UK Department of Health and Social Care, using UK Aid funding, managed by the UK National Institute for Health Research.
CMV is associated with immunosenescence and reduced vaccine responses in the elderly (>70 yr). However, the impact of CMV in young adults is less clear. In this study, healthy UK and Senegalese ...adults aged 18-50 yr (average, 29 yr) were vaccinated with the Ebola vaccine candidate chimpanzee adenovirus type 3-vectored Ebola Zaire vaccine (ChAd3-EBO-Z) and boosted with modified vaccinia Ankara Ebola Zaire-vectored (MVA-EBO-Z) vaccine. CMV carriage was associated with an expansion of phenotypically senescent CD4+ and CD8+ T cells expressing CD57 and killer cell lectin-like receptor G1 (KLRG1), which was negatively associated with vaccine responses in both cohorts. Ebola-specific T cell responses induced by vaccination also contained significantly increased frequencies of terminally differentiated CD57+KLRG1+ cells in CMV seropositive (CMV+) individuals. This study suggests that CMV can also affect vaccine responses in younger adults and may have a particularly marked impact in many developing countries where CMV seroprevalence is almost universal.
Recombinant fusion proteins consisting of the extracellular domain of immunoregulatory proteins and the constant domain of immunoglobulin G (IgG) are a novel class of human therapeutics. IgG isofors ...exert different levels of immune effector functions, such as complement lysis and antibody‐dependent cell cytotoxicity (ADCC). Several OX40‐Ig fusion proteins were generated and compared in their potency to inhibit immune reactions. OX40‐IgG fusion proteins act as decoys and inhibit T cell costimulation and extravasation induced by OX40 ligand‐expressing antigen‐presenting cells (APC) and vascular endothelial cells, respectively. In addition, OX40‐IgG1 protein induces ADCC and complement lysis in OX40 ligand‐expressing cells. Replacement of the IgG1 by the IgG4 domain (OX40‐IgG4) eliminated complement lysis and reduced ADCC by half. Mutation of Leu235 to Glu in IgG4 eliminated the remaining ADCC activity and generated a protein devoid of immune effector functions (OX40‐IgG4mut). In vitro, OX40‐IgG1 was more potent in inhibiting proliferation and cytokine release by peripheral blood mononuclear cells than OX40‐IgG4mut, as OX40‐IgG1 induced cell death in APC. However, both proteins reduced T cell‐mediated colitis in mice to the same extent, indicating that in vivo neutralization of OX40L is sufficient. This study also demonstrates that effector functions of antibodies are retained and can be rationally designed in receptor‐IgG fusion proteins.
PDF
