Search Results (93)

Background/Objectives: Western and Mediterranean diets have divergent effects on the brain. The gut microbiome may mediate diet effects, and specific microbes may be particularly significant contributors to these processes. Oscillospira, a genus of gut-dwelling bacteria, has been implicated as a key microbial target. Other peripheral contributors may include short-chain fatty acids (SCFAs), branched-chain amino acids (BCAAs), insulin resistance, and microbial translocation. Methods: We determined the effects of long-term (31 months, ~9 human years) consumption of a Mediterranean or Western-type diet on Oscillospira abundance, fecal SCFAs, plasma BCAAs, soluble CD14 (sCD14), and insulin responses in a randomized trial of 38 middle-aged female cynomolgus macaques (Macaca fascicularis). We determined diet effects and associations between dependent variables. For variables that were affected by diet composition and significantly associated with Oscillospira, we tested whether Oscillospira abundance mediated the effects of diet. Results: The Mediterranean diet resulted in higher Oscillospira (p = 0.004) and SCFAs (acetate p = 0.002; propionate p = 0.049) and lower BCAAs (isoleucine p = 0.035; leucine p = 0.007; valine p < 0.001). The Western diet increased insulin resistance (p = 0.040) and WM loss (p = 0.011). Oscillospira abundance was negatively associated with BCAAs (leucine p = 0.007; valine p = 0.005) and insulin resistance (insulin AUC: p = 0.024; increase in insulin AUC from pretreatment: p = 0.020), with trends for isoleucine (p = 0.066) and sCD14 (p = 0.103). Oscillospira abundance was positively associated with acetate (p = 0.032) and WM volume changes (p = 0.012). Oscillospira abundance significantly mediated the effects of diet on white matter volume changes (p = 0.020) and on insulin resistance (insulin AUC: p = 0.012 at study end; increase in insulin AUC during study: p = 0.020), presenting potential pathways through which diet may influence the brain. Conclusions: These findings suggest that diet-driven differences in Oscillospira are linked to metabolic regulation and white matter integrity, and Oscillospira may mediate the relationships. The results highlight a potential role for diet–microbiome interactions in shaping metabolic and brain aging trajectories. Full article

A novel HIV-1 vaccine candidate under development targeting the highly conserved protease cleavage regions reduced viral acquisition and delayed disease progression in a macaque SIV-challenge model. Breakthrough virus isolated from vaccinees and control animals were sequenced in the regions surrounding the SIV protease cleavages. We identified unique viral mutations that were associated with alterations in viral load and maintenance of CD4+ T cell counts in vaccinees. To evaluate whether the vaccine-elicited mutations were detrimental to virus fitness, we produced 11 mutant constructs and transfection-derived viral stocks harboring mutations in both PCS2 (in CA/p2) and PCS12 (in Nef) that had emerged at high frequency during breakthrough viremia. Virus preparations harboring mutations displayed impaired proteolytic Gag processing, reduced viral RNA incorporation and p27-CA content. These mutants were also compromised in their ability to replicate in primary cells and cell lines. Interestingly, we observed only partial compensation of these PCS2 defects by downstream mutation at PCS12. In sum, we demonstrate that vaccine-elicited immunity directed to viral protease cleavage regions impair viral escape, and breakthrough virus cannot easily restore replicative fitness. Full article

Background: Pneumococcal diseases remain a global threat due to the serotype-specific limitations of polysaccharide vaccines. This study evaluated a recombinant protein-based pneumococcal vaccine (PBPV) combining three PspA variants (PRX1/Family1Clade2, P3296/Family2/Clade3, P5668/Family2/Clade4) and detoxified pneumolysin (PlyLD). PspA targets conserved surface epitopes to block immune evasion and achieve broad coverage, while PlyLD neutralizes pore-forming toxins and enhances adaptive immunity. Methods: We evaluated the safety and immunogenicity of the PBPV in animal models. Acute toxicity studies were conducted by administering a single intramuscular injection to ICR mice, whereas chronic toxicity and immunogenicity studies were performed in cynomolgus monkeys via repeated intramuscular injections, with an equal number of male and female animals in both groups. Immune responses were assessed using ELISA, multiplexed opsonophagocytic killing assays (MOPAs), and neutralizing antibody assays. Results: Acute toxicity studies in ICR mice showed no signs of abnormal toxicity or irritation at one-dose levels. In the chronic toxicity study, cynomolgus monkeys received repeated intramuscular injections once every 3 weeks for a total of four administrations, at doses of one dose/monkey and five doses/monkey, followed by a 4-week recovery period. No significant systemic toxic reactions were observed, and the safe dose was determined to be five doses/monkey. In the immunogenicity study of monkey serum, both low-dose and high-dose groups demonstrated significant increases in antigen-specific IgG titers against each component; opsonophagocytic killing activity against pneumococcal strains from Clades 2, 3, and 4 from PspA Families 1 and 2; and neutralization antibody titers against pneumolysin post-vaccination. Conclusions: The recombinant protein-based pneumococcal vaccine exhibited a favorable safety profile and potent immunogenicity in animal models, indicating promise for broad protection against pneumococcal disease. These findings support the further development of PBPVs as a viable alternative to conventional polysaccharide-based vaccines. Full article

Background: Immune aging is a complex process involving various cellular changes, such as a myeloid bias, decreased functional activity of immune cells, accumulation of senescent cells, and alterations in serum levels of bactericidal humoral factors. As believed, these changes contribute to increased susceptibility of older adults to infectious diseases. Myeloid cells are considered the first line of defense against bacterial invasion. However, it remains unclear whether the protective functions of myeloid cells diminish in active older adults and whether potential age-related changes are evolutionarily conserved across primates. Methods: In this study, myeloid cell populations from peripheral blood and bone marrow of cynomolgus macaques and human peripheral blood were analyzed across a broad age range for phenotypic and functional characteristics, e.g., E. coli phagocytosis, secretion of proinflammatory factors, genetic instability, and signs of cellular aging. Results: Despite minor interspecies phenotypic differences in granulocyte populations, both the quantity and functions of myeloid cells were remarkably stable during aging in both species. Myeloid cells maintained genetic stability, and high SA-β-Gal activity was observed, likely reflecting metabolic traits rather than age-related changes. Importantly, a predominant and age-independent role of humoral factors, rather than cellular mechanisms, was identified in the initial control of bacterial infection. Conclusions: These findings suggest that innate immune functions remain stable for a long time during aging in both species. Full article

Background/Objectives: Varicella-zoster virus (VZV) causes herpes zoster (HZ/shingles), particularly in older adults with weakened cell-mediated immunity (CMI), which is essential for controlling VZV reactivation and reducing HZ severity. Currently vaccines, like recombinant subunit or live-attenuated vaccine, showed shortcomings in eliciting CD8⁺ T-cell responses. Addressing this, we utilized the novel replication-defective chimpanzee adenovirus vector ChAdOx1 to construct the ChAdOx1-VZV (CVE) vaccine, using full-length glycoprotein E (gE) as antigen. This study evaluated the immunogenicity of a heterologous intramuscular (IM) prime/intranasal (IN) boost regimen with the aim of developing a novel VZV vaccine candidate. Methods: BALB/c mice were immunized with CVE using homologous or heterologous prime-boost regimens via IM or IN. And cynomolgus macaques were immunized intramuscularly with three doses of CVE. Cellular responses were assessed by intracellular cytokine staining (ICS) and IFN-γ ELISpot using splenocytes and PBMCs. Humoral responses were evaluated by serum gE-IgG ELISA and bone-marrow LLPC ELISpot. Memory subsets and tissue-resident T cells were analyzed by flow cytometry. Results: Heterologous IM prime/IN boost CVE regimen markedly enhanced both cellular and humoral responses, especially CD8⁺ T-cell responses. The induced LLPC and memory T cell responses indicate the potential for long-term protection against herpes zoster. In cynomolgus macaques, CVE induced robust serum gE-specific IgG responses and strong IFN-γ secreting T-cell activity, supporting the immunogenicity of CVE in a genetically distinct primate model and enhancing its clinical translational potential. Conclusions: CVE induces potent cellular and humoral immunogenicity, with IM prime/IN boost vaccination. Cross species immunogenicity observed in nonhuman primates further strengthens the translational relevance of this platform. These findings support CVE as a promising herpes zoster vaccine candidate and provide a rationale for continued evaluation in human-relevant systems. Full article

Emesis is one of the most common side effects of ketamine sedation; however, predictors like species and sex have not been studied in macaques. This study aimed to determine the incidence and predictors of emesis in macaques undergoing ketamine sedation and to assess the efficacy of orally administered antiemetics in preventing emesis. A retrospective analysis was performed using medical records from rhesus and cynomolgus macaques who received ketamine sedation for veterinary examination events from August 2023 to April 2024. Among the 70 sedations performed using IM ketamine, the overall incidence of emesis was 26%. Cynomolgus macaques had a significantly higher risk of emesis (odds ratio (OR) 46.14, 95% confidence interval (CI): 7.08–493.9; p < 0.0001), with an emesis incidence of 55%. Females showed a higher incidence of emesis (75%) with an odds ratio of 3.72 (95% CI: 0.55–17.91; p = 0.24), though this difference was not statistically significant. In a prospective, randomized study, we compared the prophylactic use of oral maropitant citrate at a dose of 2 mg/kg or oral ondansetron at a dose of 1 mg/kg versus placebo for the prevention of emesis in cynomolgus macaques undergoing veterinary examination. Emesis was reduced from 58% in the control group to 50% in the maropitant group and 33% in the ondansetron group. However, the reduction in relative risk with either treatment did not reach statistical significance. Prophylactic oral administration of maropitant appears ineffective in preventing emesis in cynomolgus macaques. In contrast, prophylactic oral ondansetron is a more effective alternative in preventing emesis in these animals. Full article

Since the emergence of Junín virus in 1953, pathogenic New World arenaviruses have remained a public health concern. These viruses, which also include Machupo virus, Guanarito virus, Sabiá virus, and Chapare virus, cause acute viral hemorrhagic fever and neurological complications, resulting in significant morbidity and mortality. Given the dearth of licensed therapeutics or vaccines against these pathogens, animal models of infection that recapitulate human manifestations of disease remain critically important to the development of efficacious medical countermeasures. Rodents and non-human primates have been successfully used to model human New World arenaviral infections, with guinea pigs, rhesus macaques, and cynomolgus macaques being the most successful models of infection for most major pathogenic New World arenaviruses. Here, we provide a highly comprehensive review of publicly reported animal models of pathogenic New World arenavirus infections, with a discussion of advantages and disadvantages for each model. Full article

Background: Behavioral, social, and physical characteristics are posited to distinguish the sexes, yet research on transcription-level sexual differences in the brain is limited. Here, we investigated sexually divergent brain transcriptomics in pre-pubertal cynomolgus macaques, a commonly used surrogate species to humans. Methods: A transcriptomic profile using RNA sequencing was generated for the temporal lobe, ventral midbrain, and cerebellum of three female and three male cynomolgus macaques previously treated with an adeno-associated virus vector mix. Statistical analyses to determine differentially expressed protein-coding genes in all three lobes were conducted using DeSeq2 with a false-discovery-rate-corrected p-value of 0.05. Results: We identified target genes in the temporal lobe, ventral midbrain, and cerebellum with functions in translation, immunity, behavior, and neurological disorders that exhibited statistically significant sexually divergent expression. Conclusions: We provide potential mechanistic insights into the epidemiological differences observed between the sexes with regard to mental health and infectious diseases, such as COVID-19. Our results provide pre-pubertal information on sexual differences in non-human primate brain transcriptomics and may provide insight into health disparities between the biological sexes in humans. Full article

Chikungunya virus (CHIKV) is an alphavirus transmitted by mosquitos that poses a threat to global public health and for which there is an urgent need for widespread access to globally licensed vaccines. Here, we demonstrate that an inactivated CHIKV vaccine (BBV87) protects against systemic infection with CHIKV in a non-human primate (NHP) challenge model. Groups of five cynomolgus macaques received two doses of 20 µg BBV87 vaccine or saline alone (28 days apart). Twenty-eight days after the second immunisation, all animals were challenged with CHIKV. All controls were productively infected with detectable viremia and pathological responses following challenge, including altered thermoregulation, haematological and cytokine changes. Critically, the histopathological analysis of finger joints identified areas of inflammation in the synovium. By contrast vaccinated macaques had no detectable viremia and none of the pathological changes were reported in control animals. This study demonstrates that a 20 µg dose of BBV87 vaccine confers robust protection in vivo, both on the acquisition of infection and pathology. Full article

The recombinant vesicular stomatitis virus-Zaire Ebolavirus envelope glycoprotein vaccine (rVSVΔG-ZEBOV-GP) was highly effective against Ebola virus disease in a ring vaccination trial conducted during the 2014–2016 outbreak in Guinea and is licensed by regulatory agencies including US FDA, EMA, and prequalified by WHO. Vaccination studies in a nonhuman primate (NHP) model guided initial dose selection for clinical trial evaluation. We summarize two dose-ranging studies with the clinical-grade rVSVΔG-ZEBOV-GP vaccine candidate to assess the impact of dose level on immune responses and efficacy in an NHP Ebola virus (EBOV) challenge model. Forty-six cynomolgus macaques were vaccinated with a wide range of rVSVΔG-ZEBOV-GP doses and challenged 42 days later intramuscularly with 1000 pfu EBOV. Vaccination with rVSVΔG-ZEBOV-GP induced relatively high levels of EBOV-specific IgG and neutralizing antibodies, measured using the same validated assays as used in rVSVΔG-ZEBOV-GP clinical trials. Similar responses were observed across dose groups from 1 × 10⁸ to 1 × 10² pfu. A single vaccination conferred 98% protection from lethal intramuscular EBOV challenge across all dose groups. These results demonstrate that robust antibody titers are induced in NHPs across a wide range of rVSVΔG-ZEBOV-GP vaccine doses, correlating with high levels of protection against death from EBOV challenge. Full article

The rVSVΔG-ZEBOV-GP vaccine demonstrated efficacy in preventing Ebola virus (EBOV) disease in a ring vaccination clinical trial conducted during the 2014–2016 West Africa outbreak and is licensed by regulatory agencies, including the US FDA and the EMA. Here, we present two studies that evaluated the durability of immunogenicity and protection from an EBOV challenge up to ~12 months following vaccination with rVSVΔG-ZEBOV-GP in nonhuman primates (NHPs). Cynomolgus macaques were vaccinated with either one or two doses of rVSVΔG-ZEBOV-GP or a saline control and were challenged intramuscularly with EBOV at a target dose of 1000 pfu at ~4 months (Study 1) or ~8 or ~12 months (Study 2) after the last vaccination. All vaccinated animals developed robust ZEBOV-GP-specific IgG and neutralizing antibody titers, which were sustained until the last time point tested prior to the challenge. The majority of animals (88–93%) challenged with EBOV at ~4 or ~8 months post-vaccination survived, whereas the survival rate was lower (53%) in animals challenged ~12 months post-vaccination. These results demonstrate that both one-dose and two-dose regimens of the rVSVΔG-ZEBOV-GP vaccine induced durable ZEBOV-GP-specific antibody titers in NHPs and provided high levels of protection against a lethal EBOV challenge up to ~8 months post-vaccination. In this stringent challenge model, decreased protection was observed at ~12 months post-vaccination despite sustained antibody levels. Full article

Background/Objectives: In preparation for a potential pandemic caused by the H5N1 highly pathogenic avian influenza (HPAI) virus, pre-pandemic vaccines against several viral clades have been developed and stocked worldwide. Although these vaccines are well tolerated, their immunogenicity and cross-reactivity with viruses of different clades can be improved. Methods: To address this aspect, we generated recombinant influenza vaccines against H5-subtype viruses using two different strains of highly attenuated vaccinia virus (VACV) vectors. Results: rLC16m8-mcl2.2 hemagglutinin (HA) and rLC16m8-mcl2.3.4 HA consisted of a recombinant LC16m8 vector encoding the HA protein from clade 2.2 or clade 2.3.4 viruses (respectively); rDIs-mcl2.2 HA consisted of a recombinant DIs vector encoding the HA protein from clade 2.2. A single dose of rLC16m8-mcl2.2 HA showed rapid (1 week after vaccination) and long-term protection (20 months post-vaccination) in mice against the HPAI H5N1 virus. Moreover, cynomolgus macaques immunized with rLC16m8-mcl2.2 HA exhibited long-term protection when challenged with a heterologous clade of the HPAI H5N1 virus. Although the DIs strain is unable to grow in most mammalian cells, rDIs-mcl2.2 HA also showed rapid and long-lasting effects against HPAI H5N1 virus infection. Notably, the protective efficacy of rDIs-mcl2.2 HA was comparable to that of rLC16m8-mcl2.2 HA. Furthermore, these vaccines protected animals previously immunized with VACVs from a lethal challenge with the HPAI H5N1 virus. Conclusions: These results suggest that both rLC16m8-mcl2.2 HA and rDIs-mcl2.2 HA are effective in preventing HPAI H5N1 virus infection, and rDIs-mcl2.2 HA is a promising vaccine candidate against H5 HA-subtype viruses. Full article

Social housing changes are likely stressful and can be associated with diarrhea, the most common health problem noted in captive macaque populations. Diarrhea may reflect a negative shift in the gut flora (“gut dysbiosis”). This study reported on changes in the gut microbiome composition of juvenile primates (Macaca fascicularis) that experienced a change in social housing and exhibited diarrhea. A matched-case–control design was utilized to compare fecal samples from gut-unhealthy animals to healthy counterparts (n = 61). Baseline samples from recently imported animals were collected during routine sedation events. When an animal experienced a housing change, the entire cohort was monitored for diarrhea. Post-relocation samples were collected from animals that exhibited diarrhea and from their matched controls. Samples were assessed via 16S rRNA next-generation sequencing for a microbiome analysis and by ELISA for cortisol levels. Fecal cortisol levels did not differ between groups or across time points. Alpha diversity increased after relocation and differed by sex with males demonstrating a greater change in alpha diversity (p < 0.01). Although exhibiting diarrhea did not affect alpha diversity levels, it was associated with increased beta diversity (p < 0.05). Understanding how the microbiome may be affected by relocation will help guide prevention strategies such as the use of specific probiotics to reduce the incidence of diarrhea. Full article

Lymphocryptoviruses (LCVs) are ubiquitous gamma-herpesviruses that establish life-long infections in both humans and non-human primates (NHPs). In immunocompromised hosts, LCV infections are commonly associated with B cell disorders and malignancies such as lymphoma. In this study, we evaluated simian LCV-encoded small microRNAs (miRNAs) present in lymphoblastoid cell lines (LCLs) derived from a Mauritian cynomolgus macaque (Macaca fascicularis) with cyLCV-associated post-transplant lymphoproliferative disease (PTLD) as well as the viral miRNAs expressed in a baboon (Papio hamadryas) LCL that harbors CeHV12. Via sequence comparisons, we further predicted viral miRNAs encoded by LCVs that infect two additional NHP species: stump-tailed macaques (Macaca arctoides) and bonobos (Pan paniscus). Together, these species represent two arms of the primate phylogeny: Hominoids (Pan) and Old-World monkeys (Macaca, Papio). Through our analysis, we defined sequences for >95 viral miRNAs encoded by these four NHP LCVs. Our study provides the most comprehensive annotation of NHP LCV miRNAs to date, yielding a resource for developing sequence-specific reagents to detect these molecules. Importantly, we further demonstrate that cyLCV miRNAs can be detected in circulation in vivo and have biomarker potential for LCV-related PTLD. Full article

Background: Cervical cancer is associated with persistent infection of high-risk human papillomaviruses (HPVs). Prophylactic HPV vaccines have been recommended and have significant efficacy in preventing cervical cancer. Multivalent HPV vaccines have a better preventative effect on HPV-related diseases. However, there is currently only one nine-valent HPV vaccine on the market: Gardasil^® 9. The development of new HPV vaccines is still urgent in order to achieve the goal of eliminating cervical cancer as proposed by the WHO. Methods: In this study, we developed a nine-valent recombinant HPV virus-like particle (VLP) vaccine (HPV-9 vaccine) containing HPV type 6, 11, 16, 18, 31, 33, 45, 52, and 58 antigens, with an adjuvant of aluminum phosphate (AlPO₄). The type-specific L1 proteins were recombinantly expressed using Pichia pastoris, followed by self-assembly into VLPs. Immunogenicity studies of the HPV-9 vaccine were performed using rodents (mice and rats) and non-human primates (macaques) as animal models. Results: Immunogenicity studies showed that the HPV-9 vaccine is able to elicit a robust and long-lasting neutralizing antibody response in rodents (mice and rats) and non-human primates (cynomolgus macaque) models. The HPV-9 vaccine shows immunogenicity comparable to that of Walrinvax^® and Gardasil^® 9. Conclusions: In summary, this study provides a comprehensive investigation of the immunogenicity of the HPV-9 vaccine, including its immune persistence. These findings, derived from using models of diverse animal species, contribute valuable insights into the potential efficacy of the vaccine candidate in clinical settings. Full article