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For more than a century, the vast lands of Northern Ontario have been shared among the governments of Canada, Ontario, and the First Nations who signed Treaty No. 9 in 1905. For just as long, details about the signing of the constitutionally recognized agreement have been known only through the accounts of two of the commissioners appointed by the Government of Canada. Treaty No. 9 provides a truer perspective on the treaty by adding the neglected account of a third commissioner and tracing the treaty’s origins, negotiation, explanation, interpretation, signing, implementation, and recent commemoration.

The Peste des Petits Ruminants (PPR) live attenuated vaccines, the PPR virus (PPRV) Nigeria 75/1 strain (lineage II) and PPRV India Sungry 96 strain (lineage IV), currently used for control and eradication programme are very efficient vaccines as they provide the host, sheep and goats, a lifelong immunity after a single minimum recommended dose of 102.5 TCID50/mL. Unfortunately, both live attenuated vaccines are thermolabile and their use requires maintaining the cold chain from the manufactory premises to the field as most PPR-infected regions are facing of hot climate, with poor infrastructure, and the maintenance of an effective cold chain remains a challenge. To address this challenge, efforts have focused on developing thermotolerant (ThT) PPR vaccines using different stabilisers and improving the freeze-drying process. This study aimed to define the criteria for the evaluation of the stability of ThT PPR vaccines. A total of 37 batches of freeze-dried PPR vaccines using the PPRV Nigeria 75/1 strain, including eight (8) and twenty-nine (29) vaccines labelled as ThT and conventional formulations, respectively, were tested to evaluate the stability at temperatures of 40 °C to simulate the field conditions in some hot climate regions. All the vaccine batches included in this study initially showed acceptable levels of residual moisture, below 3%, and titres above the minimum WOAH standard requirement of 102.5 TCID50/mL. Following the incubation at 40 °C, 56.7% and 46% of the 37 vaccine batches tested retained titres above 102.5 TCID50/mL on day 3 and day 5, respectively. These vaccines use stabilisers such as skimmed milk, lactalbumin–sucrose, trehalose and one unnamed product (which may be protected for patent). The mean of titre loss among the PPR vaccines maintaining titres above 102.5 TCID50/mL was 0.78 log10 at day 3 and 0.99 log10 at day 5, suggesting a significant early degradation during the first 3 days. Based on these data, it is proposed that thermotolerant PPR vaccines should maintain a minimum titre of 102.5 TCID50/mL for vaccine dose on day 5 post-incubation at 40 °C with a titre loss below 1 log10 per mL. Preliminary immunogenicity test results showed that the PPR ThT vaccine meeting this criterion could be used in the field without maintaining a cold chain for up to 3 weeks, offering a practical solution for vaccination in remote areas.

Viral vectors are agents enabling gene transfer and genome editing and have widespread utility across the healthcare and biotechnology sectors. In January 2023, the International Bureau for Weights and Measures’ Consultative Committee for Amount of Substance (CCQM) held a workshop on Metrology for Viral systems as molecular tools. The workshop brought together international leaders from across regulatory, industry, government science, and metrology sectors to better understand key challenges for the community: Exploring current limitations in the measurement of virus-derived, virus-based, and virus-like systems in terms of quantification and characterisation; surveying the state-of-the-art in analytical methods and reference material provision for these entities; and initiating a dialog for the strategic development and implementation of suitable standardisation approaches for this sector. This article presents the workshop background and rationale, presentation summaries, conclusions, and recommendations.

ObjectiveTo analyze whether myelin oligodendrocyte glycoprotein antibody (MOG-Ab) titres at onset of the disease were different according to the clinical phenotype at presentation, and to investigate whether the titres were associated with risk of further relapses or predicted clinical outcome in adult patients. Finally, we assessed an alternative method to the classical measurement of MOG-Ab levels by serial dilutions.MethodsThis is a retrospective study including 79 MOG-Ab-positive adult patients, whose samples were obtained at first episode. MOG-Ab were tested by cell-based assay. HEK293 cells were transfected (tHEK293) with human-MOG plasmid. Non-tHEK293 cells were used as negative controls. Assessment of antibody titres was performed by serial dilution, and delta mean fluorescence intensity ratio signal (MOG-ratio ΔMFI) by flow cytometry. MOG-ratio ΔMFI was calculated as follows: (MFI tHEK293cells- MFI non-tHEK293cells)/MFI non-tHEK293cells. MOG-ratio ΔMFI was calculated from the first serum dilution at 1:320. The association between MOG-Ab titres and risk of relapse was analyzed by Cox regression. The association between MOG-Ab titres and visual or motor disability at last follow-up was performed by binary logistic regression. Poor visual outcome was defined when patients displayed some degree of visual disability (visual acuity [VA] < 20/20) and poor motor outcome when patients displayed some degree of motor disability (Disability Status Scale [DSS] > 1). We also investigated correlations between MOG-Ab titres and MOG-ratio ΔMFI.ResultsMOG-Ab titres were higher in Caucasians than in those with other ethnicities, and in patients with a more severe VA (VA ≤ 20/100) or motor disability (DSS ≥ 3.0) at onset (p = 0.006, 0.034, and 0.058, respectively). MOG-Ab titres were not associated with risk of relapses or with the final clinical outcome. MOG-ratio ΔMFI correlated with MOG-Ab titres in the whole cohort (ρ = 0.90; p < 0.001), and when stratified by initial clinical phenotype.ConclusionHigh MOG-Ab titres at onset are associated with a more severe presentation, but do not predict the future disease course. MOG-ratio ΔMFI is an alternative and straightforward method to determine MOG-Ab levels.

There are a myriad of vaccine schedules for rabies pre- (PrEP) and post-exposure prophylaxis (PEP) that differ in the number and timedoses, number of visits, length of schedule, and route of administration. The objective of this study was to systematically review the evidence and investigate how thedifferences in schedules influence titres over time. Four databaseswere searched from inception to January 2020 for rabies PrEP and PEP studies. Adose–response meta-analysis was utilised to pool geometric mean titres (GMT) over time. Subgroup analyses by route of administration, age group, and schedule were conducted. 80 studies met the inclusion criteria and contributed with 191 datasets and 12,413 participants. Both intradermal (ID) and intramuscular (IM) PrEP/PEP produce adequate GMTs. Significantly lower GMT levels were achieved in older (>50yrs) compared to younger (<50yrs) participants. Short 1-week schedules were as effective as longer schedules that can take between 3 and 12 weeks to complete. Several effective ID and IM schedules were identified, the selection of a schedule should take into account the patient’s needs, costs, availability to return for subsequent doses, and the time required to complete the schedule. Older individuals warrant special attention as they develop lower antibody response.

Bacillus Calmette-Guérin vaccine (BCG), one of the most widely used vaccines, does not only provide protection against tuberculosis and other mycobacterial infections, but also has non-specific (heterologous) immunomodulatory effects. In participants in a randomised trial, we investigated the effect of neonatal BCG immunisation on antibody responses to routine infant vaccines given in the first year of life. Antibodies against antigens in the diphtheria, tetanus, pertussis, polio, Haemophilus influenzae type b (Hib), and the 13-valent pneumococcal conjugate vaccines were measured in 91 (45 BCG-vaccinated, 46 BCG-naïve) infants one month after, and in 310 (169 BCG-vaccinated, 141 BCG-naïve) infants seven months after immunisation at 6 weeks, 4 and 6 months of age. In addition, antibodies against meningococcus C, Hib, measles, mumps, and rubella were measured in 147 (78 BCG-vaccinated, 69 BCG-naïve) infants one month after immunisation at 12 months of age. The seroprotection rates for each vaccine and the geometric mean concentrations (GMC) of antibodies were compared in BCG-vaccinated and BCG-naïve infants. At 7 months of age, seroprotection rates were high in both BCG-vaccinated and BCG-naïve infants. At 13 months of age, seroprotection rates were lower than at 7 months of age, particularly for pertussis and a number of pneumococcal antigens, with generally higher rates for the latter in BCG-vaccinated infants. Although not statistically significant, antibody responses in BCG-vaccinated infants were consistently higher against diphtheria, tetanus, and pneumococcal antigens at both 7 and 13 months of age, and against measles and mumps at 13 months of age, but were lower against Hib one month after immunisation at both 7 and 13 months of age. The immunomodulatory effect of BCG on antibody responses to heterologous vaccines adds to the evidence that BCG immunisation at birth has broad heterologous effects on the infant immune system.

N6 methylation of adenosine (m6A) was recently discovered to play a role in regulating the life cycle of various viruses by modifying viral and host RNAs. However, different studies on m6A effects on the same or different viruses have revealed contradictory roles for m6A in the viral life cycle. In this study, we sought to define the role of m6A on infection by rice black streaked dwarf virus (RBSDV), a double‐stranded RNA virus, of its vector small brown planthopper (SBPH). Infection by RBSDV decreased the level of m6A in midgut cells of SBPHs. We then cloned two genes (LsMETTL3 and LsMETTL14) that encode m6A RNA methyltransferase in SBPHs. After interference with expression of the two genes, the titre of RBSDV in the midgut cells of SBPHs increased significantly, suggesting that m6A levels were negatively correlated with virus replication. More importantly, our results revealed that m6A modification might be the epigenetic mechanism that regulates RBSDV replication in its insect vector and maintains a certain virus threshold required for persistent transmission. N6 methylation of adenosine modification might be the epigenetic mechanism that regulates rice black streaked dwarf virus replication in its insect vector and maintains a certain virus threshold for persistent transmission.

Purpose: Enzyme replacement therapy with rhGAA (Myozyme®) has lead to improved survival, which is largely attributable to improvements in cardiomyopathy and skeletal muscle function. However, crossreactive immunologic material-negative patients have a poor clinical response to enzyme replacement therapy secondary to high sustained antibody titers. Furthermore, although the majority of crossreactive immunologic material-positive patients tolerize or experience a downtrend in anti-rhGAA antibody titers, antibody response is variable with some crossreactive immunologic material-positive infants also mounting high sustained antibody titers. Methods: We retrospectively analyzed 34 infants with Pompe disease: 11 crossreactive immunologic material-negative patients, nine high-titer crossreactive immunologic material-positive patients, and 14 low-titer crossreactive immunologic material-positive patients. Clinical outcome measures were overall survival, ventilator-free survival, left ventricular mass index, Alberta Infant Motor Scale score, and urine Glc 4 levels. Results: Clinical outcomes in the high-titer crossreactive immunologic material-positive group were poor across all areas evaluated relative to the low-titer crossreactive immunologic material-positive group. For the crossreactive immunologic material-negative and high-titer crossreactive immunologic material-positive groups, no statistically significant differences were observed for any outcome measures, and both patient groups did poorly. Conclusions: Our data indicate that, irrespective of crossreactive immunologic material status, patients with infantile Pompe disease with high sustained antibody titer have an attenuated therapeutic response to enzyme replacement therapy. With the advent of immunomodulation therapies, identification of patients at risk for developing high sustained antibody titer is critical.

ObjectivesPatients with laboratory or clinical manifestations suggestive of antiphospholipid syndrome (APS) but not fulfilling the classification criteria constitute a clinical challenge. This study aims to compare non-criteria APS (NC-APS) with definite APS in terms of clinical manifestations, therapies, and outcomes.MethodsA systematic review of observational studies comparing definite and NC-APS was performed searching four electronic databases. Data on clinical manifestations, therapies and clinical outcomes was extracted.ResultsSixteen studies, assessing a total of 3,798 participants, were included. Seven out of 10 studies found no significant difference in the prevalence of arterial or venous thrombosis between definite and NC-APS, with two studies on seronegative APS also finding no difference in thrombosis recurrence. Seven out of 12 studies found no significant difference in the prevalence of obstetric manifestations between groups, with the remaining exhibiting conflicting results. In 9 studies comparing treatment frequency in obstetric patients, all but one described similar treatment frequency, with the percentage of NC-APS treated during pregnancy ranging from 26% to 100%. In 10 studies comparing pregnancy outcomes of NC-APS versus definite APS, 7 found similar successful pregnancies/live births. Additionally, 5 studies described improvement of live births in both groups with treatment, with three signalling aspirin monotherapy as efficacious as combination therapy in NC-APS.ConclusionThis review hints at an absence of marked differences in most evaluated parameters between definite and NC-APS, emphasizing the value of a more active follow-up of these patients. The low-quality available evidence highlights the need for well-defined NC-APS populations in future studies.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero, identifier CRD42020210674.

Human rabies is rare, though almost universally fatal. Rabies pre-exposure prophylaxis (PrEP) simplifies the post-exposure prophylaxis regimen and may offer some protection from unrecognized rabies exposures. Several different PrEP schedules are recommended by different jurisdictions. The objective of this review was to systematically analyze the impact of schedule and route of administration on immune responses to rabies vaccine in the short-term, long-term, and post-booster, specifically comparing one-, two-, and three-dose schedules, and intramuscular (IM) and 2-site intradermal (ID) routes of administration. An existing systematic review was leveraged, and an updated search was conducted in three databases from inception to January 15, 2024. Meta-analyses of seroconversion (≥0.5 IU/mL) and geometric mean titres (GMTs) from direct comparison studies, studies which allowed comparisons of schedules within the same participants/groups of participants, and pooled data across study arms were conducted. Fifty-four studies met the eligibility criteria. Short-term, most participants who received two or three doses achieved titres ≥0.5 IU/mL regardless of route of administration; seroconversion and GMTs were significantly lower with one-dose schedules. Titres fell over time for all schedules with lower maintenance of seroconversion for two-dose IM schedules than three-dose IM schedules. Following the administration of booster doses, all schedules boosted to GMTs higher than after the primary series resulting in almost 100 % seroconversion, with the lowest seroconversion (98.7 %) for those who received a one 2-site ID dose for their primary vaccination. When comparing IM to 2-site ID administration of rabies vaccine, generally, no significant differences in seroconversion and limited differences in GMTs were observed. Two- and three-dose schedules had similar seroconversion regardless of route of administration in the short-term and after the booster, but two doses given IM resulted in lower maintenance of seroconversion in the long-term than three doses IM. Seroconversion was significantly reduced with a one-dose schedule in the short- and long-term. Immune responses to all schedules decreased over time, but almost all participants seroconverted following a booster dose. Responses between 2-site ID and IM administration were generally similar with only a few differences observed.