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•The immune response to vaccination is moderately heritable in dogs.•Many SNPs of low to high effect contribute to vaccine-induced immune response.•Genes involving the spliceosome may play a role in vaccine-induced immune response. Both genetic and non-genetic factors contribute to individual variation in the immune response to vaccination. Understanding how genetic background influences variation in both magnitude and persistence of vaccine-induced immunity is vital for improving vaccine development and identifying possible causes of vaccine failure. Dogs provide a relevant biomedical model for investigating mammalian vaccine genetics; canine breed structure and long linkage disequilibrium simplify genetic studies in this species compared to humans. The objective of this study was to estimate the heritability of the antibody response to vaccination against viral and bacterial pathogens, and to identify genes driving variation of the immune response to vaccination in Beagles. Sixty puppies were immunized following a standard vaccination schedule with an attenuated combination vaccine containing antigens for canine adenovirus type 2, canine distemper virus, canine parainfluenza virus, canine parvovirus, and four strains of Leptospira bacteria. Serum antibody measurements for each viral and bacterial component were measured at multiple time points. Heritability estimations and GWAS were conducted using SNP genotypes at 279,902 markers together with serum antibody titer phenotypes. The heritability estimates were: (1) to Leptospira antigens, ranging from 0.178 to 0.628; and (2) to viral antigens, ranging from 0.199 to 0.588. There was not a significant difference between overall heritability of vaccine-induced immune response to Leptospira antigens compared to viral antigens. Genetic architecture indicates that SNPs of low to high effect contribute to immune response to vaccination. GWAS identified two genetic markers associated with vaccine-induced immune response phenotypes. Collectively, these findings indicate that genetic regulation of the immune response to vaccination is antigen-specific and influenced by multiple genes of small effect.

Bordetella pertussis is the causative agent of whooping cough (pertussis), a severe respiratory disease that can be fatal, particularly in infants. Despite high vaccine coverage, pertussis remains a problem because the currently used DTaP and Tdap vaccines do not completely prevent infection or transmission. It is well established that the alum adjuvant is a potential weakness of the acellular vaccines because the immunity provided by it is short-term. We aimed to evaluate the potential of CpG 1018® adjuvant to improve antibody responses and enhance protection against B. pertussis challenge in a murine model. A titrated range of Tdap vaccine doses were evaluated in order to best identify the adjuvant capability of CpG 1018. Antibody responses to pertussis toxin (PT), filamentous hemagglutinin (FHA), or the whole bacterium were increased due to the inclusion of CpG 1018. In B. pertussis intranasal challenge studies, we observed improved protection and bacterial clearance from the lower respiratory tract due to adding CpG 1018 to 1/20th the human dose of Tdap. Further, we determined that Tdap and Tdap + CpG 1018 were both capable of facilitating clearance of strains that do not express pertactin (PRN-), which are rising in prevalence. Functional phenotyping of antibodies revealed that the inclusion of CpG 1018 induced more bacterial opsonization and antibodies of the Th1 phenotype (IgG2a and IgG2b). This study demonstrates the potential of adding CpG 1018 to Tdap to improve immunogenicity and protection against B. pertussis compared to the conventional, alum-only adjuvanted Tdap vaccine.

Background/Objectives: Spinocerebellar ataxia (SCA), or hereditary ataxia, is a progressive neurodegenerative disorder primarily affecting motor control and voluntary muscle coordination due to cerebellar or spinocerebellar dysfunction. While numerous genetic variants have been linked to SCA in both humans and dogs, some cases remain genetically unexplained. This study aimed to describe the clinical and pathological phenotype, and to identify the genetic basis, of an atypical form of SCA observed in a mixed-breed dog presenting with additional clinical signs beyond classic SCA. Methods: Clinical and postmortem examinations were performed to document neurological and systemic pathology. Whole-genome sequencing (WGS) was conducted on the affected dog, and variant filtering was carried out using a control cohort of over 700 unaffected dog genomes to identify candidate variants. Results: In addition to classical SCA features, the affected dog exhibited retinal and optic nerve degeneration and severe, non-regenerative anemia. WGS did not reveal any known SCA-associated variants. Variant filtering identified a novel homozygous 4-base-pair frameshift deletion in CLPX (caseinolytic mitochondrial matrix peptidase chaperone subunit X) [XM_038580726.1:c.1723_1726del; chr30:g.29943285_29943288del]. This variant is predicted to cause a frameshift and premature stop codon within 17 amino acids, truncating approximately 6.64% of the protein. Conclusions: This is the first report associating a CLPX variant with SCA in any species. Given the gene’s high evolutionary conservation and known role in mitochondrial protein homeostasis, this finding may have implications for understanding CLPX-related neurodegeneration and anemia in both veterinary and human medicine.

Spinocerebellar ataxia (SCA) or hereditary ataxia is a progressive neurodegenerative disorder primarily manifesting as cerebellar or spinocerebellar dysfunction, resulting in the loss of motor control and voluntary muscle coordination. SCAs are typically inherited conditions, with causative genetic variants identified in multiple genes in people and across various dog breeds. Recently, an atypical case of SCA was documented in a mixed breed dog. In addition to the classic clinical signs and spinocerebellar lesions of SCA, the dog had retinal and optic nerve degeneration and severe, non-regenerative anemia. Whole-genome sequence (WGS) of the affected dog did not reveal any previously identified canine SCA-associated variants. Subsequent variant filtering against a control cohort of over 700 unaffected dog genomes identified a homozygous 4-base-pair frameshift deletion in caseinolytic mitochondrial matrix peptidase chaperone subunit X (CLPX) [XM_038580726.1:c.1723_1726del]. CLPX encodes a subunit of the ATP-dependent ClpXP protease, a molecular chaperone involved in mitochondrial protein degradation. The variant is predicted to cause a frameshift and a premature stop codon within 17 amino acids, truncating approximately 6.64% of the protein. Our study is the first to explore the association of CLPX variants with SCA in any species. Given the high evolutionary conservation of CLPX, this report of a CLPX variant associated with SCA in a dog may have relevance for understanding CLPX-related neurodegeneration and/or anemia in other species. A young mixed-breed dog developed a gait abnormality that progressively worsened, together with vision loss, and severe anemia. Despite treatment, the dog’s condition deteriorated, and he was humanely euthanized. An autopsy revealed extensive abnormalities in the brain, spinal cord, eyes, and bone marrow. These histologic findings supported a diagnosis of spinocerebellar ataxia (SCA), also known as hereditary ataxia, which is a genetic neurological disorder that results in impaired movement and diminished coordination. Genetic analysis identified a previously unreported mutation in the CLPX gene. CLPX plays a key role in mitochondrial protein quality control by helping break down damaged or misfolded proteins within mitochondria—cell structures critical for energy production that are particularly crucial in high-demand tissues like the brain. This mutation likely disrupted normal CLPX protein function, leading to both nerve damage and impaired blood cell production. While related genes are known to cause similar conditions in humans, this is the first time a naturally occurring CLPX variant has been identified in an SCA case in any species. Because CLPX is highly conserved between dogs and humans, this finding may offer valuable insights into rare inherited neurological diseases in people.

Adoption of non-pharmaceutical interventions (NPIs) remains critical to curtail the spread of COVID-19. Using self-reported adherence to NPIs in Canada, assessed through a national cross-sectional survey of 4498 respondents, we aimed to identify and characterize non-adopters of NPIs, evaluating their attitudes and behaviours to understand barriers and facilitators of adoption. A cluster analysis was used to group adopters separately from non-adopters of NPIs. Associations with sociodemographic factors, attitudes towards COVID-19 and the public health response were assessed using logistic regression models comparing non-adopters to adopters. Of the 4498 respondents, 994 (22%) were clustered as non-adopters. Sociodemographic factors significantly associated with the non-adoption cluster were: (1) being male, (2) age 18–34 years, (3) Albertans, (4) lower education level and (5) higher conservative political leaning. Participants who expressed low concern for COVID-19 and distrust towards several institutions had greater odds of being non-adopters. This information characterizes individuals at greatest odds for non-adoption of NPIs to inform targeted marketing interventions.

There are concerns that vaccine hesitancy may impede COVID-19 vaccine rollout and prevent the achievement of herd immunity. Vaccine hesitancy is a delay in acceptance or refusal of vaccines despite their availability. We aimed to identify which people are more and less likely to take a COVID-19 vaccine and factors associated with vaccine hesitancy to inform public health messaging. A Canadian cross-sectional survey was conducted in Canada in October and November 2020, prior to the regulatory approval of the COVID-19 vaccines. Vaccine hesitancy was measured by respondents answering the question \"what would you do if a COVID-19 vaccine were available to you?\" Negative binomial regression was used to identify the factors associated with vaccine hesitancy. Cluster analysis was performed to identify distinct clusters based on intention to take a COVID-19 vaccine, beliefs about COVID-19 and COVID-19 vaccines, and adherence to nonpharmaceutical interventions. Of 4498 participants, 2876 (63.9%) reported COVID-19 vaccine hesitancy. Vaccine hesitancy was significantly associated with (1) younger age (18-39 years), (2) lower education, and (3) non-Liberal political leaning. Participants that reported vaccine hesitancy were less likely to believe that a COVID-19 vaccine would end the pandemic or that the benefits of a COVID-19 vaccine outweighed the risks. Individuals with vaccine hesitancy had higher prevalence of being concerned about vaccine side effects, lower prevalence of being influenced by peers or health care professionals, and lower prevalence of trust in government institutions. These findings can be used to inform targeted public health messaging to combat vaccine hesitancy as COVID-19 vaccine administration continues. Messaging related to preventing COVID among friends and family, highlighting the benefits, emphasizing safety and efficacy of COVID-19 vaccination, and ensuring that health care workers are knowledgeable and supported in their vaccination counselling may be effective for vaccine-hesitant populations.

Tenofovir gel is being evaluated for vaginal and rectal pre-exposure prophylaxis against HIV transmission. Because this is a new prevention strategy, we broadly assessed its effects on the mucosa. In MTN-007, a phase-1, randomized, double-blinded rectal microbicide trial, we used systems genomics/proteomics to determine the effect of tenofovir 1% gel, nonoxynol-9 2% gel, placebo gel or no treatment on rectal biopsies (15 subjects/arm). We also treated primary vaginal epithelial cells from four healthy women with tenofovir in vitro. After seven days of administration, tenofovir 1% gel had broad-ranging effects on the rectal mucosa, which were more pronounced than, but different from, those of the detergent nonoxynol-9. Tenofovir suppressed anti-inflammatory mediators, increased T cell densities, caused mitochondrial dysfunction, altered regulatory pathways of cell differentiation and survival, and stimulated epithelial cell proliferation. The breadth of mucosal changes induced by tenofovir indicates that its safety over longer-term topical use should be carefully monitored. Clinical trial registration: NCT01232803. Tenofovir is a drug that can stop some viruses—including HIV—from multiplying. It is commonly used in multidrug therapies to control HIV infection. Clinical trials are underway to find out whether using the drug in the form of a gel applied to the vagina or rectum could be an effective way to prevent HIV transmission during sex. Some of the clinical trials carried out so far have produced promising results. However, since the use of gels containing anti-viral drugs is a new strategy for HIV prevention, there are limited data available about the safety of these products. Previous studies have shown that the concentration of tenofovir in the vagina is much higher in individuals using the gel than in those taking the tablet form of the drug. These high concentrations could lead to unexpected effects on the health of the cells exposed to the gel. Here, Hladik, Burgener, Ballweber et al. used a systems biology approach to look at the broad effects of tenofovir gel on tissue from the rectum. Tissue samples taken from the rectums of 15 patients who used tenofovir gel for seven days were compared with tissue samples taken from individuals who used a control gel that did not contain the drug or who did not use any gel. Genes that regulate inflammation were suppressed in the rectal tissue from patients who used tenofovir, as were genes that help these tissues regenerate and produce energy. The tissue from these patients also contained more immune cells, suggesting that their local immune systems were more active. Additionally, Hladik, Burgener, Ballweber et al. observed changes that could potentially lead to the increased growth of cells. Similar differences were also observed in vaginal cells that had been treated with tenofovir in the laboratory. These findings suggest that tenofovir delivered directly to the vagina or rectum may have unintentional local side effects. However, it is important to acknowledge that tenofovir gel has been evaluated in multiple studies that have not observed overt clinical adverse effects. Therefore, the implication of these findings is currently unclear and warrants further study.

Muscosal effects for tenofovir 1% gel. eLife 4:e04525. doi: 10.7554/eLife.04525. Published 3 February 2015 During the production process the CONSORT checklist and CONSORT flow chart were not attached to the article and thus were omitted from the published version.

BACKGROUND Tenofovir gel is being evaluated for vaginal and rectal pre-exposure prophylaxis against sexual HIV transmission. Because this is a new prevention strategy targeting large numbers of healthy people, we broadly assessed its effects on the mucosa. METHODS AND FINDINGS In MTN-007, a phase 1, randomized, double-blinded rectal microbicide trial, we used systems genomics/proteomics to determine the effect of tenofovir 1% gel, nonoxynol-9 2% gel, placebo gel or no treatment on rectal biopsies taken at baseline, after one application or after seven daily applications (15 subjects/arm). Experiments were repeated using primary vaginal epithelial cells from four healthy women. After seven days of administration, tenofovir 1% gel had broad-ranging biological effects on the rectal mucosa, which were much more pronounced than but different from those caused by the detergent nonoxynol-9. Tenofovir profoundly suppressed anti-inflammatory mediators such as interleukin 10; increased T cell densities; caused mitochondrial dysfunction, possibly by blocking PNPT1 expression; and altered regulatory pathways of cell differentiation and survival. Except for leukocyte-derived factors, all these effects were replicated in primary vaginal epithelial cells, which also proliferated significantly faster in tenofovir s presence. CONCLUSIONS Tenofovir s suppression of anti-inflammatory activity could diminish its prophylactic efficacy over time. The breadth of mucosal changes, including mitochondrial dysfunction and epithelial proliferation, raises questions about its safety for long-term topical use. These findings suggest that a systems biology evaluation of mucosal effects may be beneficial before advancing to large-scale efficacy trials with topical HIV prevention agents that achieve high, long-lasting local drug concentrations.