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Intradermal (ID) vaccination can be highly immunogenic due to the density of antigen-presenting cells in the skin, but reliable ID delivery remains technically challenging. We evaluated a programmable microneedle-array intradermal injector, InocuJect, designed to distribute vaccine micro-deposits across a defined dermal area. In female Hartley guinea pigs, we compared vaccination with the automated ID device to conventional Mantoux intradermal injection followed by electroporation (ID+EP) using two vaccine platforms: a DNA vaccine encoding SARS-CoV-2 spike (pIDV-II-SARS-CoV-2) and the licensed virus-like particle vaccine GARDASIL®9. For the DNA vaccine, both methods induced spike-specific and pseudovirus-neutralizing responses by day 56, with similar neutralizing titers between groups. For GARDASIL®9, both delivery methods generated comparable HPV16 L1-specific IgG at the final time points. In contrast, the automated ID device induced stronger antigen-specific cellular responses, as reflected by increased IFN-γ RNA and protein levels following peptide stimulation. These findings suggest that spatially distributed dermal delivery using a microneedle-array-based intradermal injector is associated with enhanced IFN-γ-based cellular immune readouts, while maintaining robust humoral responses across distinct vaccine platforms.

The development of safe and effective vaccines to prevent SARS-CoV-2 infections remains an urgent priority worldwide. We have used a recombinant vesicular stomatitis virus (rVSV)-based prime-boost immunization strategy to develop an effective COVID-19 vaccine candidate. We have constructed VSV genomes carrying exogenous genes resulting in the production of avirulent rVSV carrying the full-length spike protein (S F ), the S1 subunit, or the receptor-binding domain (RBD) plus envelope (E) protein of SARS-CoV-2. Adding the honeybee melittin signal peptide (msp) to the N-terminus enhanced the protein expression, and adding the VSV G protein transmembrane domain and the cytoplasmic tail (Gtc) enhanced protein incorporation into pseudotype VSV. All rVSVs expressed three different forms of SARS-CoV-2 spike proteins, but chimeras with VSV-Gtc demonstrated the highest rVSV-associated expression. In immunized mice, rVSV with chimeric S protein-Gtc derivatives induced the highest level of potent neutralizing antibodies and T cell responses, and rVSV harboring the full-length msp-S F -Gtc proved to be the superior immunogen. More importantly, rVSV-msp-S F -Gtc vaccinated animals were completely protected from a subsequent SARS-CoV-2 challenge. Overall, we have developed an efficient strategy to induce a protective response in SARS-CoV-2 challenged immunized mice. Vaccination with our rVSV-based vector may be an effective solution in the global fight against COVID-19.

[This corrects the article DOI: 10.1371/journal.ppat.1010092.].

Background The gut microbiota (GM) has proven to be essential for both physical health and mental wellbeing, yet the forces that ultimately shape its composition remain opaque. One critical force known to affect the GM is the social environment. Prior work in humans and free-ranging non-human primates has shown that cohabitation and frequent social interaction can lead to changes in GM composition. However, it is difficult to assess the direction of causation in these studies, and interpretations are complicated by the influence of uncontrolled but correlated factors, such as shared diet. Results We performed a 15-month longitudinal investigation wherein we disentangled the impacts of diet and social living conditions on GM composition in a captive cohort of 13 male cynomolgus macaques. The animals were in single housing for the first 3 months of the study initially with a variable diet. After baseline data collection they were placed on a controlled diet for the remainder of the study. Following this diet shift the animals were moved to paired housing for 6 months, enabling enhanced social interaction, and then subsequently returned to single housing at the end of our study. This structured sequencing of diet and housing changes allowed us to assess their distinct impacts on GM composition. We found that the early dietary adjustments led to GM changes in both alpha and beta diversity, whereas changes in social living conditions only altered beta diversity. With respect to the latter, we found that two particular bacterial families — Lactobacillaceae and Clostridiaceae — demonstrated significant shifts in abundance during the transition from single housing to paired housing, which was distinct from the shifts we observed based on a change in diet. Conversely, we found that other bacteria previously associated with sociality were not altered based on changes in social living conditions but rather only by changes in diet. Conclusions Together, these findings decouple the influences that diet and social living have on GM composition and reconcile previous observations in the human and animal literatures. Moreover, the results indicate biological alterations of the gut that may, in part, mediate the relationship between sociality and wellbeing.

Monkeys are becoming important translational models of neurodegenerative disease. To facilitate model development, we measured cerebrospinal fluid (CSF) concentrations of key biomarkers in healthy male and female cynomolgus and rhesus macaques. Amyloid beta (Aβ40, Aβ42), tau (total tau [t‐tau], phosphorylated tau [pThr181]), and neurofilament light (NfL) concentrations were measured in CSF of 82 laboratory‐housed, experimentally naïve cynomolgus (n = 33) and rhesus (n = 49) macaques. Aβ40 and Aβ42 were significantly higher in rhesus, and female rhesus were higher than males. NfL and t‐tau were higher in males, and NfL was higher in rhesus macaques. p‐tau was not affected by species or sex. We also examined whether sample location (lumbar or cisterna puncture) affected concentrations. Sample acquisition site only affected NfL, which was higher in CSF from lumbar puncture compared to cisterna magna puncture. Establishing normative biomarker values for laboratory‐housed macaque monkeys provides an important resource by which to compare to monkey models of neurodegenerative diseases.

Introduction Neurofilament light (NFL) in cerebrospinal fluid (CSF) is elevated in neurodegenerative disease patients, and may track disease progression and treatment. Macaque monkeys are emerging as important translational models of neurodegeneration, and NFL may be a useful biomarker. Methods To determine the influence of a previous lumbar puncture (LP) on NFL, we collected CSF at multiple time points in macaque monkeys via LP or cisterna magna puncture. NFL, amyloid beta (Aβ40, Aβ42), and tau (tTau, pTau) in CSF were measured by standard enzyme‐linked immunosorbent assay and multiplex. Results NFL was significantly elevated at 14 to 23 days after an LP (median increase: 162%). Aβ and tau biomarkers remained stable. NFL peaked and decayed over 1 to 2 months after LP. NFL was not elevated after cisterna magna puncture. Discussion Results suggest damage of the cauda equina during LP may increase NFL. Caution should be taken in interpreting NFL concentration in studies in which repeat LPs are performed.

Poly-arginine peptide-18 (R18) is neuroprotective in different rodent middle cerebral artery occlusion (MCAO) stroke models. In this study, we examined whether R18 treatment could reduce ischemic brain injury and improve functional outcome in a nonhuman primate (NHP) stroke model. A stroke was induced in male cynomolgus macaques by MCAO distal to the orbitofrontal branch of the MCA through a right pterional craniotomy, using a 5-mm titanium aneurysm clip for 90 min. R18 (1000 nmol/kg) or saline vehicle was administered intravenously 60 min after the onset of MCAO. Magnetic resonance imaging (MRI; perfusion-weighted imaging, diffusion-weighted imaging, or T2-weighted imaging) of the brain was performed 15 min, 24 h, and 28 days post-MCAO, and neurological outcome was assessed using the NHP stroke scale (NHPSS). Experimental endpoint was 28 days post-MCAO, treatments were randomized, and all procedures were performed blinded to treatment status. R18 treatment reduced infarct lesion volume by up to 65.2% and 69.7% at 24 h and 28 days poststroke, respectively. Based on NHPSS scores, R18-treated animals displayed reduced functional deficits. This study confirms the effectiveness of R18 in reducing the severity of ischemic brain injury and improving functional outcomes after stroke in a NHP model, and provides further support for its clinical development as a stroke neuroprotective therapeutic.

Maternal ethanol consumption during pregnancy can produce a range of teratogenic outcomes in offspring. The mechanism of ethanol teratogenicity is multi-faceted, but may involve alterations in insulin and insulin-like growth factor (IGF) signaling pathways. These pathways are not only important for metabolism, but are also critically involved in neuronal survival and plasticity, and they can be altered by chronic prenatal ethanol exposure (CPEE). The objective of this study was to test the hypothesis that CPEE alters expression of insulin and IGF signaling molecules in the prefrontal cortex and liver of adult guinea pig offspring. Pregnant Dunkin-Hartley-strain guinea pigs received ethanol (4 g/kg maternal body weight/day) or isocaloric-sucrose/pair-feeding (nutritional control) throughout gestation. Fasting blood glucose concentration was measured in male and female offspring at postnatal day 150–200, followed by euthanasia, collection of prefrontal cortex and liver, and RNA extraction. IGF-1, IGF-1 receptor (IGF-1R), IGF-2, IGF-2 receptor (IGF-2R), insulin receptor substrate (IRS)-1, IRS-2, and insulin receptor (INSR) mRNA expression levels were measured in tissues using quantitative real-time PCR. The mean maternal blood ethanol concentration was 281 ± 15 mg/dL at 1 h after the second divided dose of ethanol on GD 57. CPEE resulted in increased liver weight in adult offspring, but produced no difference in fasting blood glucose concentration compared with nutritional control. In the liver, CPEE decreased mRNA expression of IGF-1, IGF-1R, and IGF-2, and increased IRS-2 mRNA expression in male offspring only compared with nutritional control. Female CPEE offspring had decreased INSR hepatic mRNA expression compared with male CPEE offspring. In the prefrontal cortex, IRS-2 mRNA expression was increased in CPEE offspring compared with nutritional control. The data demonstrate that CPEE alters both central and peripheral expression of insulin and IGF signaling molecules at the mRNA level, which may be related to metabolic dysregulation in adult offspring. Furthermore, altered insulin and IGF signaling may be a mechanism of ethanol neurobehavioral teratogenicity.

Structured Abstract INTRODUCTION Non-human primates are important translational models of neurodegenerative disease. We characterized how species, sex, age, and site of sampling affected concentrations of key biomarkers of neurodegeneration. METHODS Amyloid-beta (Aβ40, Aβ42), tau (tTau, pTau), and neurofilament light (NFL) in CSF were measured in 82 laboratory-housed naïve cynomolgus and rhesus macaques of both sexes. RESULTS Aβ40, Aβ42, and NFL were significantly higher in rhesus compared with cynomolgus macaques. tTau and NFL were higher in males. pTau was not affected by species or sex. Site of acquisition only affected NFL, with NFL being higher in CSF acquired from lumbar compared with cisterna magna puncture. DISCUSSION Normative values for key neurodegeneration biomarkers were established for laboratory housed cynomolgus and rhesus macaque monkeys. Differences were observed as a function of species, sex and site of CSF acquisition that should be considered when employing primate models. Research In Context 1. Systematic review: We reviewed reports characterizing CSF biomarkers of neurodegenerative diseases in non-human primates – an increasingly important model of disease - revealing that studies with laboratory housed macaque monkeys were of small sample size, with a paucity of data about how biomarkers varied as a function of species, sex, age, and site of acquisition. 2. Interpretation: To address this gap, we collected CSF from 82 naïve laboratory housed male and female macaques of two species and measured Aβ40, Aβ42, tTau, pTau, and NFL. In addition to providing normative statistics for concentrations of these biomarkers, we revealed various species and sex differences. 3. Future directions: Establishing normative values of biomarkers is an important step to the efficient development of cynomolgus and rhesus macaques as models of neurodegenerative disorders such as Alzheimer’s disease. Reference values reduce the need for large control groups by which to compare with disease model animals. Competing Interest Statement The authors have declared no competing interest. Footnotes * Financial Disclosures: No financial disclosures declared by any authors.