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african-lineage zika virus replication dynamics and maternal-fetal interface infection in pregnant rhesus macaques.following the zika virus (zikv) outbreak in the americas, zikv was causally associated with microcephaly and a range of neurological and developmental symptoms, termed congenital zika syndrome (czs). the viruses responsible for this outbreak belonged to the asian lineage of zikv. however, in vitro and in vivo studies assessing the pathogenesis of african-lineage zikv demonstrated that african-lineage isolates often replicated to high titers and caused more-severe pathology than asian-lineage iso ...202134076485
early embryonic loss following intravaginal zika virus challenge in rhesus macaques.zika virus (zikv) is an arthropod-borne virus (arbovirus) and is primarily transmitted by aedes species mosquitoes; however, zikv can also be sexually transmitted. during the initial epidemic and in places where zikv is now considered endemic, it is difficult to disentangle the risks and contributions of sexual versus vector-borne transmission to adverse pregnancy outcomes. to examine the potential impact of sexual transmission of zikv on pregnancy outcome, we challenged three rhesus macaques (m ...202134079560
a human antibody of potent efficacy against sars-cov-2 in rhesus macaques showed strong blocking activity to b.1.351.severe acute respiratory syndrome coronavirus-2 (sars-cov-2), which causes coronavirus disease-2019 (covid-19), interacts with the host cell receptor angiotensin-converting enzyme 2 (hace2) via its spike 1 protein during infection. after the virus sequence was published, we identified two potent antibodies against the sars-cov-2 receptor binding domain (rbd) from antibody libraries using a phage-to-yeast (pty) display platform in only 10 days. our lead antibody jmb2002, now in a phase 1 clinical ...202134097570
distinct transcriptional responses to fatal ebola virus infection in cynomolgus and rhesus macaques suggest species-specific immune responses.ebola virus (ebov) is a negative single-stranded rna virus within the filoviridae family and the causative agent of ebola virus disease (evd). nonhuman primates (nhps), including cynomolgus and rhesus macaques, are considered the gold standard animal model to interrogate mechanisms of ebov pathogenesis. however, despite significant genetic similarity (>90%), nhp species display different clinical presentation following ebov infection, notably a ∼1-2 days delay in disease progression. consequentl ...202134112056
sars-cov-2 vaccines elicit durable immune responses in infant rhesus macaques.the inclusion of infants in the sars-cov-2 vaccine roll-out is important to prevent severe complications of pediatric sars-cov-2 infections and to limit transmission and could possibly be implemented via the global pediatric vaccine schedule. however, age-dependent differences in immune function require careful evaluation of novel vaccines in the pediatric population. toward this goal, we assessed the safety and immunogenicity of two sars-cov-2 vaccines. two groups of 8 infant rhesus macaques (r ...202134131024
low-dose ad26.cov2.s protection against sars-cov-2 challenge in rhesus macaques.we previously reported that a single immunization with an adenovirus serotype 26 (ad26)-vector-based vaccine expressing an optimized sars-cov-2 spike (ad26.cov2.s) protected rhesus macaques against sars-cov-2 challenge. to evaluate reduced doses of ad26.cov2.s, 30 rhesus macaques were immunized once with 1 × 1011, 5 × 1010, 1.125 × 1010, or 2 × 109 viral particles (vp) ad26.cov2.s or sham and were challenged with sars-cov-2. vaccine doses as low as 2 × 109 vp provided robust protection in bronch ...202134133941
viremia controls env-specific antibody-secreting cell responses in siv-infected macaques pre- and post-art.to investigate the kinetics of env (gp140)-specific antibody-secreting cells (ascs) during acute and early chronic simian immunodeficiency virus (siv) infection, and prior to and post-antiretroviral therapy (art) in rhesus macaques (rms).202134148985
identification and characterization of defective viral genomes in ebola virus-infected rhesus macaques.ebola virus (ebov), of the family filoviridae, is an rna virus that can cause a hemorrhagic fever with a high mortality rate. defective viral genomes (dvgs) are truncated genomes that have been observed during multiple rna virus infections, including in vitro ebov infection, and have previously been associated with viral persistence and immunostimulatory activity. as dvgs have been detected in cells persistently infected with ebov, we hypothesized that dvgs may also accumulate during viral repli ...202134160256
the fc-mediated effector functions of a potent sars-cov-2 neutralizing antibody, sc31, isolated from an early convalescent covid-19 patient, are essential for the optimal therapeutic efficacy of the antibody.although sars-cov-2-neutralizing antibodies are promising therapeutics against covid-19, little is known about their mechanism(s) of action or effective dosing windows. we report the generation and development of sc31, a potent sars-cov-2 neutralizing antibody, isolated from a convalescent patient. antibody-mediated neutralization occurs via an epitope within the receptor-binding domain of the sars-cov-2 spike protein. sc31 exhibited potent anti-sars-cov-2 activities in multiple animal models. i ...202134161386
protective efficacy of ad26.cov2.s against sars-cov-2 b.1.351 in macaques.the emergence of sars-cov-2 variants that partially evade neutralizing antibodies poses a threat to the efficacy of current covid-19 vaccines1,2. the ad26.cov2.s vaccine expresses a stabilized spike protein from the wa1/2020 strain of sars-cov-2, and has recently demonstrated protective efficacy against symptomatic covid-19 in humans in several geographical regions-including in south africa, where 95% of sequenced viruses in cases of covid-19 were the b.1.351 variant3. here we show that ad26.cov ...202134161961
a recombinant receptor-binding domain in trimeric form generates protective immunity against sars-cov-2 infection in nonhuman primates.a safe and effective vaccine is critical to combat the covid-19 pandemic. here, we developed a trimeric sars-cov-2 receptor-binding domain (rbd) subunit vaccine candidate that simulates the natural structure of the spike (s) trimer glycoprotein. immunization with the rbd trimer-induced robust humoral and cellular immune responses, and a high level of neutralizing antibodies was maintained for at least 4.5 months. moreover, the antibodies that were produced in response to the vaccine effectively ...202134179862
neutralizing antibody induction associated with a germline immunoglobulin gene polymorphism in neutralization-resistant sivsme543-3 infection.antibody responses are crucial for the control of virus infection. understanding of the mechanism of antibody induction is important for the development of a vaccine eliciting effective anti-virus antibodies. virus-specific b cell receptor (bcr)/antibody repertoires are different among individuals, but determinants for this difference remain largely unclear. we have recently reported that a germline bcr immunoglobulin (igg) gene polymorphism (vh3.33_et or vh3.33_vi) in rhesus macaques is the det ...202134205728
late-phase dominance of a single epitope-specific cd8+ t-cell response in passive neutralizing antibody-infused siv controllers.analysis of the quantity and quality of epitope-specific cd8+ t-cell responses is crucial for understanding the mechanism of hiv/simian immunodeficiency virus (siv) replication control. we have previously shown that acute-phase passive infusion of neutralizing antibodies (nabs) results in augmented broad t-cell responses and robust sivmac239 control in rhesus macaques. analyzing long-term dynamics of cd8+ t-cell responses in these siv controllers provides important insights into designing lastin ...202134224443
early treatment with a combination of two potent neutralizing antibodies improves clinical outcomes and reduces virus replication and lung inflammation in sars-cov-2 infected macaques.there is an urgent need for effective therapeutic interventions against sars-cov-2, including new variants that continue to arise. neutralizing monoclonal antibodies have shown promise in clinical studies. we investigated the therapeutic efficacy of a combination of two potent monoclonal antibodies, c135-ls and c144-ls that carry half-life extension mutations, in the rhesus macaque model of covid-19. twelve young adult macaques (three groups of four animals) were inoculated intranasally and intr ...202134228761
interleukin-15 response signature predicts rhcmv/siv vaccine efficacy.simian immunodeficiency virus (siv) challenge of rhesus macaques (rms) vaccinated with strain 68-1 rhesus cytomegalovirus (rhcmv) vectors expressing siv proteins (rhcmv/siv) results in a binary outcome: stringent control and subsequent clearance of highly pathogenic siv in ~55% of vaccinated rms with no protection in the remaining 45%. although previous work indicates that unconventionally restricted, siv-specific, effector-memory (em)-biased cd8+ t cell responses are necessary for efficacy, the ...202134228762
oral vaccination approaches for anti-shiv immunity.we modified a sabin oral poliovirus vaccine (opv) vector to permit secretion of the antigens of interest with the goal of improving anti-hiv env humoral responses in a shiv mucosal immunization composed of dna and recombinant opvs. we evaluated stimulation of systemic and mucosal cell-mediated and humoral immunity in rhesus macaques by two regimens, both involving a prime with a shivbg505 dna construct producing non-infectious particles formulated in lipid nanoparticles, administered in the oral ...202134234789
in vitro characterization of fitness and convalescent antibody neutralization of sars-cov-2 cluster 5 variant emerging in mink at danish farms.in addition to humans, severe acute respiratory syndrome coronavirus 2 (sars-cov-2) can transmit to animals that include hamsters, cats, dogs, mink, ferrets, tigers, lions, cynomolgus macaques, rhesus macaques, and treeshrew. among these, mink are particularly susceptible. indeed, 10 countries in europe and north america reported sars-cov-2 infection among mink on fur farms. in denmark, sars-cov-2 spread rapidly among mink farms and spilled-over back into humans, acquiring mutations/deletions wi ...202134248922
transmission of infectious viruses in the natural setting at human-animal interface.most viral pathogens causing epidemics and pandemics are zoonotic, emerging from wildlife reservoirs like sars cov2 causing the global covid-19 pandemic, although animal origin of this virus remains a mystery. cross-species transmission of pathogens from animals to humans is known as zoonosis. however, pathogens are also transmitted from humans to animals in regions where there is a close interaction between animals and humans by 'reverse transmission' (anthroponosis). molecular evidence for the ...202134250513
why remdesivir failed: preclinical assumptions overestimate the clinical efficacy of remdesivir for covid-19 and ebola.remdesivir is a nucleoside monophosphoramidate prodrug that has been fda-approved for covid-19. however, the clinical efficacy of remdesivir for covid-19 remains contentious, as several trials have not found statistically significant differences in either time to clinical improvement or mortality between remdesivir-treated and control groups. similarly, the inability for remdesivir to provide a clinically significant benefit above other investigational agents in patients with ebola contrasts wit ...202134252308
one or two dose regimen of the sars-cov-2 synthetic dna vaccine ino-4800 protects against respiratory tract disease burden in nonhuman primate challenge model.safe and effective vaccines will provide essential medical countermeasures to tackle the covid-19 pandemic. here, we assessed the safety, immunogenicity and efficacy of the intradermal delivery of ino-4800, a synthetic dna vaccine candidate encoding the sars-cov-2 spike protein in the rhesus macaque model. single and 2 dose vaccination regimens were evaluated. vaccination induced both binding and neutralizing antibodies, along with ifn-γ-producing t cells against sars-cov-2. upon administration ...202134253420
invaplex functions as an intranasal adjuvant for subunit and dna vaccines co-delivered in the nasal cavity of nonhuman primates.development of intranasal vaccines for hiv-1 and other mucosal pathogens has been hampered by the lack of adjuvants that can be given safely to humans. we have found that an intranasal shigella vaccine (invaplex) which is well tolerated in humans can also function as an adjuvant for intranasal protein and dna vaccines in mice. to determine whether invaplex could potentially adjuvant similar vaccines in humans, we simultaneously administered a simian immunodeficiency virus (siv) envelope (env) pr ...202134258576
high-resolution quantitative mapping of macaque cervicovaginal epithelial thickness: implications for mucosal vaccine delivery.vaginal mucosal surfaces naturally offer some protection against sexually transmitted infections (stis) including human immunodeficiency virus-1, however topical preventative medications or vaccine designed to boost local immune responses can further enhance this protection. we previously developed a novel mucosal vaccine strategy using viral vectors integrated into mouse dermal epithelium to induce virus-specific humoral and cellular immune responses at the site of exposure. since vaccine integ ...202134262561
single-dose immunization with a chimpanzee adenovirus-based vaccine induces sustained and protective immunity against sars-cov-2 infection.the development of a safe and effective vaccine against sars-cov-2, the causative agent of pandemic coronavirus disease-2019 (covid-19), is a global priority. here, we aim to develop novel sars-cov-2 vaccines based on a derivative of less commonly used rare adenovirus serotype adc68 vector. three vaccine candidates were constructed expressing either the full-length spike (adc68-19s) or receptor-binding domain (rbd) with two different signal sequences (adc68-19rbd and adc68-19rbds). single-dose i ...202134262569
interferon-armed rbd dimer enhances the immunogenicity of rbd for sterilizing immunity against sars-cov-2.severe acute respiratory syndrome coronavirus 2 (sars-cov-2) has caused a global crisis, urgently necessitating the development of safe, efficacious, convenient-to-store, and low-cost vaccine options. a major challenge is that the receptor-binding domain (rbd)-only vaccine fails to trigger long-lasting protective immunity if used alone for vaccination. to enhance antigen processing and cross-presentation in draining lymph nodes (dlns), we developed an interferon (ifn)-armed rbd dimerized by an i ...202134267349
vaccine nanodiscs plus polyiclc elicit robust cd8+ t cell responses in mice and non-human primates.conventional cancer vaccines based on soluble vaccines and traditional adjuvants have produced suboptimal therapeutic efficacy in clinical trials. thus, there is an urgent need for vaccine technologies that can generate potent t cell responses with strong anti-tumor efficacy. we have previously reported the development of synthetic high-density protein (shdl) nanodiscs for efficient lymph node (ln)-targeted co-delivery of antigen peptides and cpg oligonucleotides (a toll-like receptor-9 agonist) ...202134280415
monitoring immune activation with whole-body fluorodeoxyglucose-positron-emission tomography in simian immunodeficiency virus-infected rhesus macaques.this study aimed to assess immune activation in tissues by measuring glucose metabolism with 18f-fluorodeoxyglucose (fdg) and investigate the associations of various peripheral markers of disease progression with initiation and interruption of combination antiretroviral therapy in siv-infected rhesus macaques (macaca mulatta). mixed-effect linear models revealed a significant inverse association of peripheral blood cd4+ t cell counts (p < 0.01) and a direct association of plasma viral load (p < ...202134282030
myeloid cell interferon responses correlate with clearance of sars-cov-2.the emergence of mutant sars-cov-2 strains associated with an increased risk of covid-19-related death necessitates better understanding of the early viral dynamics, host responses and immunopathology. while studies have reported immune profiling using single cell rna sequencing in terminal human covid-19 patients, performing longitudinal immune cell dynamics in humans is challenging. macaques are a suitable model of sars-cov-2 infection. we performed longitudinal single-cell rna sequencing of b ...202134282414
previously published ethno-pharmacological reports reveal the potentiality of plants and plant-derived products used as traditional home remedies by bangladeshi covid-19 patients to combat sars-cov-2.several plants have traditionally been used since antiquity to treat various gastroenteritis and respiratory symptoms similar to covid-19 outcomes. the common symptoms of covid-19 include fever or chills, cold, cough, flu, headache, diarrhoea, tiredness/fatigue, sore throat, loss of taste or smell, asthma, shortness of breath, or difficulty breathing, etc. this study aims to find out the plants and plant-derived products which are being used by the covid-19 infected patients in bangladesh and ho ...202134305428
host- and species-dependent quasispecies divergence of severe acute respiratory syndrome coronavirus-2 in non-human primate models.recently, newly emerging variants of severe acute respiratory syndrome coronavirus 2 (sars-cov-2) have been continuously reported worldwide. however, the precise evaluation of sars-cov-2 microevolution in host is very limited because the exact genetic information of infected virus could not be acquired in human researches. in this report, we performed deep sequencing for seed virus and sars-cov-2 isolated in eight cynomolgus and rhesus macaques at 3 days postinoculation and evaluated single-nucl ...202134305860
recovery from acute sars-cov-2 infection and development of anamnestic immune responses in t cell-depleted rhesus macaques.severe coronavirus disease 2019 (covid-19) has been associated with t cell lymphopenia, but no causal effect of t cell deficiency on disease severity has been established. to investigate the specific role of t cells in recovery from severe acute respiratory syndrome coronavirus 2 (sars-cov-2) infections, we studied rhesus macaques that were depleted of either cd4+, cd8+, or both t cell subsets prior to infection. peak virus loads were similar in all groups, but the resolution of virus in the t c ...202134311582
intranasal chadox1 ncov-19/azd1222 vaccination reduces viral shedding after sars-cov-2 d614g challenge in preclinical models.chadox1 ncov-19/azd1222 is an approved adenovirus-based vaccine for severe acute respiratory syndrome coronavirus 2 (sars-cov-2) currently being deployed globally. previous studies in rhesus macaques revealed that intramuscular vaccination with chadox1 ncov-19/azd1222 provided protection against pneumonia but did not reduce shedding of sars-cov-2 from the upper respiratory tract. here, we investigated whether intranasally administered chadox1 ncov-19 reduces detection of virus in nasal swabs aft ...202134315826
previous exposure to dengue virus is associated with increased zika virus burden at the maternal-fetal interface in rhesus macaques.concerns have arisen that pre-existing immunity to dengue virus (denv) could enhance zika virus (zikv) disease, due to the homology between zikv and denv and the observation of antibody-dependent enhancement (ade) among denv serotypes. to date, no study has examined the impact of pre-existing denv immunity on zikv pathogenesis during pregnancy in a translational non-human primate model. here we show that macaques with a prior denv-2 exposure had a higher burden of zikv vrna in maternal-fetal int ...202134329306
neutralizing antibodies against epstein-barr virus infection of b cells can protect from oral viral challenge in the rhesus macaque animal model.epstein-barr virus (ebv) and related lymphocryptoviruses (lcvs) from nonhuman primates are transmitted through oral secretions, penetrate the mucosal epithelium, and establish persistent infection in b cells. to determine whether neutralizing antibodies against epithelial or b cell infection could block oral transmission and persistent lcv infection, we use rhesus macaques, the most accurate animal model for ebv infection by faithfully reproducing acute and persistent infection in humans. naive ...202134337567
bundibugyo ebolavirus survival is associated with early activation of adaptive immunity and reduced myeloid-derived suppressor cell signaling.ebolaviruses bundibugyo virus (bdbv) and ebola virus (ebov) cause fatal hemorrhagic disease in humans and nonhuman primates. while the host response to ebov is well characterized, less is known about bdbv infection. moreover, immune signatures that mediate natural protection against all ebolaviruses remain poorly defined. to explore these knowledge gaps, we transcriptionally profiled bdbv-infected rhesus macaques, a disease model that results in incomplete lethality. this approach enabled us to ...202134372693
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