OVX033, a nucleocapsid-based vaccine candidate, provides broad-spectrum protection against SARS-CoV-2 variants in a hamster challenge model.

Spike-based COVID-19 vaccines induce potent neutralizing antibodies but their efficacy against SARS-CoV-2 variants decreases. OVX033 is a recombinant protein composed of the full-length nucleocapsid (N) protein of SARS-CoV-2 genetically fused to oligoDOM®, a self-assembling domain which improves antigen immunogenicity. OVX033 including N as an antigenic target is proposed as new vaccine candidate providing broad-spectrum protection against sarbecoviruses. OVX033 demonstrated its ability to trigger cross-reactive T cell responses and cross-protection against three variants of SARS-CoV-2 (B.1 Europe, Delta B.1.617.2, and Omicron B.1.1.529) in a hamster challenge model, as evidenced by lower weight loss, lower lung viral loads, and reduced lung histopathological lesions.

Immunogenicity, safety, and preliminary efficacy evaluation of OVX836, a nucleoprotein-based universal influenza A vaccine candidate: a randomised, double-blind, placebo-controlled, phase 2a trial.

BACKGROUND: OVX836, a recombinant vaccine containing the nucleoprotein of the influenza A virus A/WSN/1933 (H1N1) and the oligomerisation domain OVX313, has displayed a good safety profile and elicited dose-dependent humoral and cellular immune responses at 90 µg or 180 µg (intramuscularly) in previous clinical trials. The aim of this study was to explore higher doses, since no maximum tolerated dose had been reached. METHODS: In this phase 2a, randomised, double-blind, placebo-controlled study, we recruited 137 healthy adults aged 18-55 years in a single centre in Belgium. Participants were randomly assigned (interactive web response system; block size=4) using SAS (version 9.4) to receive one single intramuscular administration of OVX836 influenza vaccine at three doses (180 µg [n=33], 300 µg [n=35], and 480 µg [n=36]) or placebo (n=33). The two primary endpoints were the safety and the cell-mediated immune response to OVX836 at the three doses in terms of change of nucleoprotein-specific IFNγ spot forming cell (SFC) frequencies in the peripheral blood mononuclear cell (PBMC) population, measured by IFNγ ELISpot, at day 8 versus pre-injection baseline (day 1). The population used for the safety analysis is the modified intention-to-treat cohort. The population used for the immunogenicity analysis is the per-protocol cohort. This trial is registered with ClinicalTrials.gov, NCT05060887, and EudraCT, 2021-002535-39. FINDINGS: Participants were recruited between Nov 15, 2021, and Feb 1, 2022. OVX836 had a favourable safety profile up to 480 µg without reaching the maximum tolerated dose, and showed a good safety profile at all doses with mild local and systemic reactogenicity. 7 days after vaccination, although no significant differences were observed between the doses, OVX836 increased the frequency of nucleoprotein-specific IFNγ SFCs per million PBMCs from days 1 to 8 (primary endpoint): by 124 SFCs per 106 PMBCs (95% CI 67 to 180; p=0·002) at 180 µg; by 202 SFCs per 106 PMBCs (95% CI 138 to 267; p<0·0001) at 300 µg; by 223 SFCs per 106 PMBCs (95% CI 147 to 299; p<0·0001) at 480 µg; and decreased by 1 SFCs per 106 PMBCs (95% CI -24 to 22] in the placebo group (Kruskal-Wallis test p<0·0001 followed by Mann-Whitney's tests; per-protocol cohort). Dose-dependent and polyfunctional nucleoprotein-specific CD4 T-cell responses were observed, and CD8 T-cell responses were elicited at 300 µg and 480 µg (secondary endpoints). INTERPRETATION: OVX836 appears to be a safe and well tolerated candidate vaccine that elicits humoral and cellular nucleoprotein-specific immune responses (including CD8 T cells at the highest dose levels) and showed a preliminary signal of protection against influenza. Therefore, OVX836 is a promising vaccine candidate for universal influenza A prevention, that warrants further trials. FUNDING: OSIVAX, Bpifrance, Wallonia Region, and the EUs Horizon 2020 Research and Innovation Program.

Association of preoperative Enzian score with postoperative fertility in patients with deep pelvic endometriosis.

INTRODUCTION: Endometriosis is a chronic inflammatory disease with a negative impact on fertility. The Enzian classification provides a precise description of deep pelvic endometriotic lesions, especially in the retroperitoneal area, from preoperative pelvic MRI scans. However, it is not known if it is correlated with postoperative fertility. STUDY OBJECTIVE: To determine if there is an association between the preoperative Enzian score and postoperative fertility after deep pelvic endometriosis surgery. DESIGN: We conducted a descriptive, retrospective study using information from the ENDOREN database. SETTING: This was a retrospective study at the Department of Obstetrics and Gynecology at Rennes University Hospital (France) from January 2013 to May 2019 PATIENTS AND INTERVENTIONS: We used information from the ENDOREN database that included all women who underwent surgery for deep endometriosis and wish to conceive. This surgery was intended in a view to achieve a complete removal of endometriosis. MEASUREMENTS: The Enzian score was calculated from preoperative MRI scans, and total, spontaneous, and after In Vitro fertilization (IVF) live births and pregnancies outcomes were collected from the patients'computerized medical records. Univariate and multivariate analysis was performed. RESULTS: Sixty-eight patients were included. The live-birth rate was 35% (24/68). According to the Enzian classification, 25 patients (35%) were classified in compartment A, 64 patients (94%) in compartment B, and 27 (40%) in compartment C. In multivariate analysis, positive predictor of live birth was single Enzian B score (OR=4.7[1.21; 18.81], p = 0.03), negative predictors were uterine adenomyosis and a history of endometriosis surgery. In multivariate analysis, positive predictor of spontaneous live birth was EFI score ≥7 (OR =22.434; CI [1.138; 442.190]). In multivariate analysis, positive predictor was Enzian A score (OR=15.9[2.2; 114.7], p = 0.006), and negative predictors was uterine adenomyosis and Enzian B score (OR=0.01[0; 0.495], p = 0.02) for live birth after IVF. CONCLUSION: The present retrospective study cannot strongly conclude about fertility and correlation with Enzian score because the groups are too small. However, it seems that when solely the compartment B is involved by endometriosis, complete full removal of endometriosis leads to better post-operative live births results. Other studies must be done to determine if Enzian classification based on preoperative pelvic MRI could be clinical value in the decision-making strategy for managing infertile patients with deep pelvic endometriosis.

Randomized, Double-Blind, Reference-Controlled, Phase 2a Study Evaluating the Immunogenicity and Safety of OVX836, A Nucleoprotein-Based Influenza Vaccine.

OVX836 is a recombinant protein-based vaccine targeting the highly conserved influenza nucleoprotein (NP), which aims to confer a broad-spectrum protection against influenza. In a Phase 1 study, OVX836, administered intramuscularly, has been found safe and immunogenic. The 90µg and 180µg dose levels were selected to be further evaluated in this randomized, monocenter, reference-controlled (Influvac Tetra™: quadrivalent seasonal influenza subunit vaccine), parallel group, double-blind, Phase 2a study in 300 healthy volunteers, aged 18-65 years, during the 2019/2020 flu season. Safety, influenza-like illness episodes (ILI; based on the Flu-PRO® questionnaire) and immunogenicity were assessed up to 180 days post-vaccination. OVX836 was safe and presented a reactogenicity profile similar to Influvac Tetra. It induced a significant increase in terms of NP-specific interferon-gamma (IFNγ) spot forming cells (SFCs), NP-specific CD4+ T-cells (essentially polyfunctional cells) and anti-NP IgG responses. OVX836 was superior to Influvac Tetra for all immunological parameters related to NP, and the 180µg dose was significantly superior to the 90µg dose for SFCs and CD4+ T-cells expressing IFNγ. Both the CD4+ T-cell and the anti-NP IgG responses persisted up to Day 180. An efficacy signal was observed with OVX836 at 180µg through reduction of ILI episodes occurring during the flu season as of 14 days post-vaccination. In conclusion, these results encourage further clinical evaluation of OVX836 in order to confirm the signal of efficacy on ILIs and/or laboratory-confirmed influenza cases. NCT04192500 (https://clinicaltrials.gov/ct2/show/study/NCT04192500).

Phase 1 Randomized, Placebo-Controlled, Dose-Escalating Study to Evaluate OVX836, a Nucleoprotein-Based Influenza Vaccine: Intramuscular Results.

BACKGROUND: OVX836 is a recombinant protein vaccine targeting the highly conserved influenza nucleoprotein (NP), which could confer broad-spectrum protection against this disease. METHODS: A randomized, placebo-controlled, double-blind, dose-escalating, single- center, first-in-human study was conducted in 36 healthy adults aged 18-49 years. Twelve subjects per cohort (9 vaccine and 3 placebo) received 2 OVX836 intramuscular administrations on days 1 and 28 at the dose level of 30 µg, 90 µg, or 180 µg. Safety and immunogenicity were assessed after each vaccination and for 150 days in total. RESULTS: OVX836 was safe and well tolerated at all dose levels, with no difference in solicited local and systemic symptoms, and unsolicited adverse events between the first and second administration, or between dose levels. All subjects presented pre-existing NP-specific immunity at baseline. OVX836 induced a significant increase in NP-specific interferon-gamma T cells and anti-NP immunoglobulin G at all dose levels after the first vaccination. The second vaccination did not further increase the response. There was a trend for a dose effect in the immune response. CONCLUSIONS: The safety and reactogenicity profile, as well as the humoral and cellular immune responses, encourage further evaluation of OVX836 in a larger Phase 2a study.

OVX836 Heptameric Nucleoprotein Vaccine Generates Lung Tissue-Resident Memory CD8+ T-Cells for Cross-Protection Against Influenza.

Tissue-resident memory (TRM) CD8+ T-cells play a crucial role in the protection against influenza infection but remain difficult to elicit using recombinant protein vaccines. OVX836 is a recombinant protein vaccine, obtained by the fusion of the DNA sequence of the influenza A nucleoprotein (NP) to the DNA sequence of the OVX313 heptamerization domain. We previously demonstrated that OVX836 provides broad-spectrum protection against influenza viruses. Here, we show that OVX836 intramuscular (IM) immunization induces higher numbers of NP-specific IFNγ-producing CD8+ T-cells in the lung, compared to mutant NP (NPm) and wild-type NP (NPwt), which form monomeric and trimeric structures, respectively. OVX836 induces cytotoxic CD8+ T-cells and high frequencies of lung TRM CD8+ T-cells, while inducing solid protection against lethal influenza virus challenges for at least 90 days. Adoptive transfer experiments demonstrated that protection against diverse influenza subtypes is mediated by NP-specific CD8+ T-cells isolated from the lung and spleen following OVX836 vaccination. OVX836 induces a high number of NP-specific lung CD8+ TRM-cells for long-term protection against influenza viruses.

OVX836 a recombinant nucleoprotein vaccine inducing cellular responses and protective efficacy against multiple influenza A subtypes.

Inactivated influenza vaccines (IIVs) lack broad efficacy. Cellular immunity to a conserved internal antigen, the nucleoprotein (NP), has been correlated to protection against pandemic and seasonal influenza and thus could have the potential to broaden vaccine efficacy. We developed OVX836, a recombinant protein vaccine based on an oligomerized NP, which shows increased uptake by dendritic cells and immunogenicity compared with NP. Intramuscular immunization in mice with OVX836 induced strong NP-specific CD4+ and CD8+ T-cell systemic responses and established CD8+ tissue memory T cells in the lung parenchyma. Strikingly, OVX836 protected mice against viral challenge with three different influenza A subtypes, isolated several decades apart and induced a reduction in viral load. When co-administered with IIV, OVX836 was even more effective in reducing lung viral load.

Ultrasound evaluation of cervical regeneration after LLETZ for cervical intraepithelial neoplasia: a prospective observational study.

OBJECTIVES: To assess cervical regeneration after large loop excision of the transformation zone (LLETZ) by ultrasound (US) measurements of cervical length (CL) before conization as well as in the postoperative short- and long-term and to identify factors affecting regeneration. PATIENTS AND METHODS: This was a prospective observational study including patients under 45 years of age treated by LLETZ for Cervical Intraepithelial Neoplasia (CIN) with repeated measurements of CL by transvaginal US before and just after LLETZ, at 1 and 6 months postoperatively. RESULTS: A total of 83 patients were enrolled, out of which 53 were included in the study. The mean CL was 28.6 mm (±5.7) preoperatively versus 18.3 mm (±4.2) after surgery; 21.8 mm (±4.4) at 1 month and 25.5 mm (±4.9) at 6 months. The mean cone length estimated by US was 10.3 mm (±3.4). The differences in CL before/after conization and CL after conization/at 6 months were statistically significant (p<0.0001). Cervical regeneration at 6 months was 71% (±20), statistically greater than regeneration at 1 month (32%, ±16) (p<0.0001). DISCUSSION: Post-conization cervical tissue regeneration occurred with almost three quarters of the initial cervical length restored at 6 months. Further studies evaluating obstetric outcomes after LLETZ according to cervical regeneration might subsequently be used in clinical practice to identify high-risk pregnancies by pre- and postoperative US measurements of the cervical length. A rigorous assessment of CIN treatment risks and benefits remains essential when considering treating patients of childbearing age given a potential obstetric risk from conization.

Incineration of municipal and assimilated wastes in France: assessment of latest energy and material recovery performances.

Incineration has an important place in waste management in France. In 2003, around 130 incineration plants have treated 12.6 Mt of non-dangerous waste, mainly composed of household waste (10.8 Mt), non-dangerous waste from industry, business, services (1.0 Mt), sewage sludge (0.2 Mt) or clinical waste (0.1 Mt). The incineration of these wastes generated 3.0 Mt of bottom ash of which 2.3 Mt were used for roads construction and 0.2 Mt of ferrous and non-ferrous metal were recycled. It also produced 2,900,000 MWh of electricity, of which 2,200,000 MWh were sold to Electricité de France (EDF) and 9,100,000 MWh of heat, of which 7,200,000 MWh were sold to private or public users. These French incinerators of non-hazardous waste are currently being thoroughly modernized, thus making possible the consolidation and the enhancement of their environmental and energy performance. This process is related to the implementation of the European Directive 2000/76/CE whose expiration date is 28 December 2005. Upon request of ADEME, the engineering company GIRUS has realised the first technical and economical evaluation of works necessary to bring incinerators into compliance. The financial estimations, carried out in 30 June 2003, show that the investments to be devoted could reach 750 million euros. This assessment shed new light on the situation of non-hazardous waste incinerators, including an identification and a rank ordering for each incinerator of the most frequent and the most complex non-conformities to be solved in term of cost and delay. At last, this assessment gives the solutions for each non-compliance.

Continuous epidural block versus continuous popliteal nerve block for postoperative pain relief after major podiatric surgery in children: a prospective, comparative randomized study.

Foot and ankle surgery in children is very painful postoperatively. Adverse effects from opioids and continuous epidural block (CEB) limit their use in children. Continuous popliteal nerve blocks (CPNB) have not been studied for this indication in children. In this prospective, randomized study we evaluated the effectiveness and adverse events of CPNB or CEB in children after podiatric surgery. Fifty-two children scheduled for foot surgery were separated into four groups by age and analgesia technique. After general anesthesia, 0.5 to 1 mL/kg of an equal-volume mixture of 0.25% bupivacaine and 1% lidocaine with 1:200000 epinephrine was injected via epidural or popliteal catheters. In the postoperative period, 0.1 mL x kg(-1) x h(-1) (group CPNB) or 0.2 mL x kg(-1) x h(-1) (group CEB) of 0.2% ropivacaine was administered for 48 h. Niflumic acid was routinely used. Adverse events were noted in each treatment group. Postoperative pain during motion was evaluated at 1, 6, 12, 18, 24, 36, and 48 h. Requirement for rescue analgesia (first-line propacetamol 30 mg/kg 4 times daily or second-line 0.2 mg/kg IV nalbuphine), and motor blockade were recorded. Parental satisfaction was noted at 48 h. Twenty-seven patients were included in the CEB groups and 25 in CPNB groups. There were 32 children 1 to 6 yr of age (CPNB = 15; CEB = 17) and 20 children 7 to 12 yr of age (CPNB = 10; CEB = 10). The demographic data were comparable among groups. Postoperative analgesia was excellent for the two continuous block techniques and in the two age groups. Motor block intensity was equal between techniques. Adverse events (postoperative nausea or vomiting, urinary retention, and premature discontinuation of local anesthetic infusion in the 1- to 6-yr-old group) were significantly more frequent in the CEB group (P < 0.05). Eighty-six percent of the parents in the CEB groups and 100% in the CPNB groups were satisfied. We conclude that although both CEB and CPNB resulted in excellent postoperative analgesia in this study, CPNB was associated with less urinary retention and nausea and vomiting. Therefore, we recommend CPNB as the ideal form of postoperative analgesia after major podiatric surgery in 1- to 12-yr-old children.