Publications by authors named "Kasi Russell-Lodrigue"

41 Publications

Adjuvanting a subunit COVID-19 vaccine to induce protective immunity.

Nature 2021 06 19;594(7862):253-258. Epub 2021 Apr 19.

Tulane National Primate Research Center, Covington, LA, USA.

The development of a portfolio of COVID-19 vaccines to vaccinate the global population remains an urgent public health imperative. Here we demonstrate the capacity of a subunit vaccine, comprising the SARS-CoV-2 spike protein receptor-binding domain displayed on an I53-50 protein nanoparticle scaffold (hereafter designated RBD-NP), to stimulate robust and durable neutralizing-antibody responses and protection against SARS-CoV-2 in rhesus macaques. We evaluated five adjuvants including Essai O/W 1849101, a squalene-in-water emulsion; AS03, an α-tocopherol-containing oil-in-water emulsion; AS37, a Toll-like receptor 7 (TLR7) agonist adsorbed to alum; CpG1018-alum, a TLR9 agonist formulated in alum; and alum. RBD-NP immunization with AS03, CpG1018-alum, AS37 or alum induced substantial neutralizing-antibody and CD4 T cell responses, and conferred protection against SARS-CoV-2 infection in the pharynges, nares and bronchoalveolar lavage. The neutralizing-antibody response to live virus was maintained up to 180 days after vaccination with RBD-NP in AS03 (RBD-NP-AS03), and correlated with protection from infection. RBD-NP immunization cross-neutralized the B.1.1.7 SARS-CoV-2 variant efficiently but showed a reduced response against the B.1.351 variant. RBD-NP-AS03 produced a 4.5-fold reduction in neutralization of B.1.351 whereas the group immunized with RBD-NP-AS37 produced a 16-fold reduction in neutralization of B.1.351, suggesting differences in the breadth of the neutralizing-antibody response induced by these adjuvants. Furthermore, RBD-NP-AS03 was as immunogenic as a prefusion-stabilized spike immunogen (HexaPro) with AS03 adjuvant. These data highlight the efficacy of the adjuvanted RBD-NP vaccine in promoting protective immunity against SARS-CoV-2 and have led to phase I/II clinical trials of this vaccine (NCT04742738 and NCT04750343).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41586-021-03530-2DOI Listing
June 2021

Adjuvanting a subunit SARS-CoV-2 nanoparticle vaccine to induce protective immunity in non-human primates.

bioRxiv 2021 Feb 11. Epub 2021 Feb 11.

The development of a portfolio of SARS-CoV-2 vaccines to vaccinate the global population remains an urgent public health imperative. Here, we demonstrate the capacity of a subunit vaccine under clinical development, comprising the SARS-CoV-2 Spike protein receptor-binding domain displayed on a two-component protein nanoparticle (RBD-NP), to stimulate robust and durable neutralizing antibody (nAb) responses and protection against SARS-CoV-2 in non-human primates. We evaluated five different adjuvants combined with RBD-NP including Essai O/W 1849101, a squalene-in-water emulsion; AS03, an alpha-tocopherol-containing squalene-based oil-in-water emulsion used in pandemic influenza vaccines; AS37, a TLR-7 agonist adsorbed to Alum; CpG 1018-Alum (CpG-Alum), a TLR-9 agonist formulated in Alum; or Alum, the most widely used adjuvant. All five adjuvants induced substantial nAb and CD4 T cell responses after two consecutive immunizations. Durable nAb responses were evaluated for RBD-NP/AS03 immunization and the live-virus nAb response was durably maintained up to 154 days post-vaccination. AS03, CpG-Alum, AS37 and Alum groups conferred significant protection against SARS-CoV-2 infection in the pharynges, nares and in the bronchoalveolar lavage. The nAb titers were highly correlated with protection against infection. Furthermore, RBD-NP when used in conjunction with AS03 was as potent as the prefusion stabilized Spike immunogen, HexaPro. Taken together, these data highlight the efficacy of the RBD-NP formulated with clinically relevant adjuvants in promoting robust immunity against SARS-CoV-2 in non-human primates.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/2021.02.10.430696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885918PMC
February 2021

Burkholderia pseudomallei OMVs derived from infection mimicking conditions elicit similar protection to a live-attenuated vaccine.

NPJ Vaccines 2021 Jan 29;6(1):18. Epub 2021 Jan 29.

Department of Microbiology and Immunology, School of Medicine, Tulane University, New Orleans, LA, USA.

Burkholderia pseudomallei is a Gram-negative, facultative intracellular bacillus that causes the disease melioidosis. B. pseudomallei expresses a number of proteins that contribute to its intracellular survival in the mammalian host. We previously demonstrated that immunization with OMVs derived from B. pseudomallei grown in nutrient-rich media protects mice against lethal disease. Here, we evaluated if OMVs derived from B. pseudomallei grown under macrophage-mimicking growth conditions could be enriched with intracellular-stage proteins in order to improve the vaccine. We show that OMVs produced in this manner (M9 OMVs) contain proteins associated with intracellular survival yet are non-toxic to living cells. Immunization of mice provides significant protection against pulmonary infection similar to that achieved with a live attenuated vaccine and is associated with increased IgG, CD4, and CD8 T cells. OMVs possess inherent adjuvanticity and drive DC activation and maturation. These results indicate that M9 OMVs constitute a new promising vaccine against melioidosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41541-021-00281-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846723PMC
January 2021

Increased Proviral DNA in Circulating Cells Correlates with Plasma Viral Rebound in Simian Immunodeficiency Virus-Infected Rhesus Macaques after Antiretroviral Therapy Interruption.

J Virol 2021 02 24;95(6). Epub 2021 Feb 24.

Tulane National Primate Research Center, Tulane University School of Medicine, Covington, Louisiana, USA

The human immunodeficiency virus (HIV) reservoir is responsible for persistent viral infection, and a small number of mosaic latent cellular reservoirs promote viral rebound upon antiretroviral therapy interruption, which is the major obstacle to a cure. However, markers that determine effective therapy and viral rebound posttreatment interruption remain unclear. In this study, we comprehensively and longitudinally tracked dynamic decay of cell-associated viral RNA/DNA in systemic and lymphoid tissues in simian immunodeficiency virus (SIV)-infected rhesus macaques on prolonged combined antiretroviral therapy (cART) and evaluated predictors of viral rebound after treatment cessation. The results showed that suppressive ART substantially reduced plasma SIV RNA, cell-associated unspliced, and multiply spliced SIV RNA to undetectable levels, yet viral DNA remained detectable in systemic tissues and lymphoid compartments throughout cART. Intriguingly, a rapid increase of integrated proviral DNA in peripheral mononuclear cells was detected once treatment was withdrawn, accompanied by the emergence of detectable plasma viral load. Notably, the increase of peripheral proviral DNA after treatment interruption correlated with the emergence and degree of viral rebound. These findings suggest that measuring total viral DNA in SIV infection may be a relatively simple surrogate marker of reservoir size and may predict viral rebound after treatment interruption and inform treatment strategies. Viral reservoirs are involved in persistent HIV infection, and a small number of mosaic latent cellular reservoirs promote viral rebound upon analytical treatment interruption, which is the major obstacle to a cure. However, early indicators that can predict resurgence of viremia after treatment interruption may aid treatment decisions in people living with HIV. Utilizing the rhesus macaque model, we demonstrated that increased proviral DNA in peripheral cells after treatment interruption, rather than levels of proviral DNA, was a useful marker to predict the emergence and degree of viral rebound after treatment interruption, providing a rapid approach for monitoring HIV rebound and informing decisions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/JVI.02064-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8094949PMC
February 2021

Effects of Social Housing Changes on Immunity and Vaccine-Specific Immune Responses in Adolescent Male Rhesus Macaques.

Front Immunol 2020 15;11:565746. Epub 2020 Oct 15.

Division of Veterinary Medicine, Tulane National Primate Research Center, Covington, LA, United States.

Nonhuman primates (NHPs) in research institutions may be housed in a variety of social settings, such as group housing, pair housing or single housing based on the needs of studies. Furthermore, housing may change over the course of studies. The effects of housing and changes in housing on cell activation and vaccine mediated immune responses are not well documented. We hypothesized that animals moved indoors from group to single housing (GH-SH) would experience more stress than those separated from groups into pair housing (GH-PH), or those placed briefly into pair housing and separated 5 weeks later into single housing (GH-PH-SH). We also compared the effects of separation from group to pair housing with the separation from pair to single housing. Eighteen male rhesus macaques were followed over the course of changes in housing condition over 10-14 weeks, as well as prior to and after primary vaccination with a commercially available measles vaccine. We identified two phenotypic biomarkers, namely total CD8 population and proliferating B cells, that differed significantly across treatment groups over time. At 10 weeks post-separation, levels of proliferating B cells were higher in GH-SH subjects compared to GH-PH subjects, and in the latter, levels were lower at 10 weeks than prior to removal from group housing. At 2 weeks post-separation from group to single housing, the frequency of CD8+ T cells was higher in GH-SH subjects compared to one week post separation from pair into single housing in the GH-PH-SH subjects. Comparing the same elapsed time since the most recent separation activated CD20 populations were persistently higher in the GH-SH animals than the GH-PH-SH animals. Housing configuration did not influence vaccine-mediated responses. Overall, our study found benefits of pair housing over single housing, suggesting that perturbations in immune function will be more severe following separation from group to single housing than from pair to single housing, and supporting the use of short-duration pair housing even when animals must subsequently be separated. These findings are useful for planning the housing configurations of research NHPs used for vaccine studies and other studies where immune response is being assessed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2020.565746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7593645PMC
May 2021

Acute Respiratory Distress in Aged, SARS-CoV-2-Infected African Green Monkeys but Not Rhesus Macaques.

Am J Pathol 2021 02 7;191(2):274-282. Epub 2020 Nov 7.

Tulane National Primate Research Center, Covington, Louisiana; Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, Louisiana.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces a wide range of disease severity, ranging from asymptomatic infection to a life-threating illness, particularly in the elderly population and individuals with comorbid conditions. Among individuals with serious coronavirus 2019 (COVID-19) disease, acute respiratory distress syndrome (ARDS) is a common and often fatal presentation. Animal models of SARS-CoV-2 infection that manifest severe disease are needed to investigate the pathogenesis of COVID-19-induced ARDS and evaluate therapeutic strategies. We report two cases of ARDS in two aged African green monkeys (AGMs) infected with SARS-CoV-2 that had pathological lesions and disease similar to severe COVID-19 in humans. We also report a comparatively mild COVID-19 phenotype characterized by minor clinical, radiographic, and histopathologic changes in the two surviving, aged AGMs and four rhesus macaques (RMs) infected with SARS-CoV-2. Notable increases in circulating cytokines were observed in three of four infected, aged AGMs but not in infected RMs. All the AGMs had increased levels of plasma IL-6 compared with baseline, a predictive marker and presumptive therapeutic target in humans infected with SARS-CoV-2. Together, our results indicate that both RMs and AGMs are capable of modeling SARS-CoV-2 infection and suggest that aged AGMs may be useful for modeling severe disease manifestations, including ARDS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajpath.2020.10.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648506PMC
February 2021

Lung Expression of Human Angiotensin-Converting Enzyme 2 Sensitizes the Mouse to SARS-CoV-2 Infection.

Am J Respir Cell Mol Biol 2021 01;64(1):79-88

Tulane National Primate Research Center, Covington, Louisiana; and.

Preclinical mouse models that recapitulate some characteristics of coronavirus disease (COVID-19) will facilitate focused study of pathogenesis and virus-host responses. Human agniotensin-converting enzyme 2 (hACE2) serves as an entry receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to infect people via binding to envelope spike proteins. Herein we report development and characterization of a rapidly deployable COVID-19 mouse model. C57BL/6J (B6) mice expressing hACE2 in the lung were transduced by oropharyngeal delivery of the recombinant human adenovirus type 5 that expresses hACE2 (Ad5-hACE2). Mice were infected with SARS-CoV-2 at Day 4 after transduction and developed interstitial pneumonia associated with perivascular inflammation, accompanied by significantly higher viral load in lungs at Days 3, 6, and 12 after infection compared with Ad5-empty control group. SARS-CoV-2 was detected in pneumocytes in alveolar septa. Transcriptomic analysis of lungs demonstrated that the infected Ad5-hACE mice had a significant increase in IFN-dependent chemokines and , and genes associated with effector T-cell populations including C. Pathway analysis showed that several Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were enriched in the data set, including cytokine-cytokine receptor interaction, the chemokine signaling pathway, the NOD-like receptor signaling pathway, the measles pathway, and the IL-17 signaling pathway. This response is correlative to clinical response in lungs of patients with COVID-19. These results demonstrate that expression of hACE2 via adenovirus delivery system sensitized the mouse to SARS-CoV-2 infection and resulted in the development of a mild COVID-19 phenotype, highlighting the immune and inflammatory host responses to SARS-CoV-2 infection. This rapidly deployable COVID-19 mouse model is useful for preclinical and pathogenesis studies of COVID-19.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1165/rcmb.2020-0354OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781002PMC
January 2021

Rationally Attenuated Vaccines for Venezuelan Equine Encephalitis Protect Against Epidemic Strains with a Single Dose.

Vaccines (Basel) 2020 Sep 2;8(3). Epub 2020 Sep 2.

World Reference Center for Emerging Viruses and Arboviruses, University of Texas Medical Branch, Galveston, TX 77555, USA.

Venezuelan equine encephalitis virus (VEEV) is a re-emerging virus of human, agriculture, and bioweapon threat importance. No FDA-approved treatment is available to combat Venezuelan equine encephalitis in humans, prompting the need to create a vaccine that is safe, efficacious, and cannot be replicated in the mosquito vector. Here we describe the use of a serotype ID VEEV (ZPC-738) vaccine with an internal ribosome entry site (IRES) to alter gene expression patterns. This ZPC/IRES vaccine was genetically engineered in two ways based on the position of the IRES insertion to create a vaccine that is safe and efficacious. After a single dose, both versions of the ZPC/IRES vaccine elicited neutralizing antibody responses in mice and non-human primates after a single dose, with more robust responses produced by version 2. Further, all mice and primates were protected from viremia following VEEV challenge. These vaccines were also safer in neonatal mice than the current investigational new drug vaccine, TC-83. These results show that IRES-based attenuation of alphavirus genomes consistently produce promising vaccine candidates, with VEEV/IRES version 2 showing promise for further development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/vaccines8030497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563393PMC
September 2020

Quantifying the contribution of Fc-mediated effector functions to the antiviral activity of anti-HIV-1 IgG1 antibodies in vivo.

Proc Natl Acad Sci U S A 2020 07 14;117(30):18002-18009. Epub 2020 Jul 14.

Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032;

In combating viral infections, the Fab portion of an antibody could mediate virus neutralization, whereas Fc engagement of Fc-γ receptors (FcγRs) could mediate an array of effector functions. Evidence abounds that effector functions are important in controlling infections by influenza, Ebola, or HIV-1 in animal models. However, the relative contribution of virus neutralization versus effector functions to the overall antiviral activity of an antibody remains unknown. To address this fundamental question in immunology, we utilized our knowledge of HIV-1 dynamics to compare the kinetics of the viral load decline (ΔVL) in infected animals given a wild-type (WT) anti-HIV-1 immunoglobulin G1 (IgG1) versus those given a Fc-Null variant of the same antibody. In three independent experiments in HIV-1-infected humanized mice and one pivotal experiment in simian-human immunodeficiency virus (SHIV)-infected rhesus macaques, an earlier and sharper decline in viral load was consistently detected for the WT antibody. Quantifications of the observed differences indicate that Fc-mediated effector functions accounted for 25-45% of the total antiviral activity in these separate experiments. In this study, Fc-mediated effector functions have been quantified in vivo relative to the contribution of virus neutralization mediated by the Fab.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.2008190117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7395461PMC
July 2020

Trio housing of adult male rhesus macaques (Macaca mulatta): Methodology and outcome predictors.

J Med Primatol 2020 08 13;49(4):188-201. Epub 2020 Apr 13.

Division of Veterinary Medicine, Tulane National Primate Research Center, Covington, LA, USA.

Background: This study evaluated the feasibility of trio housing caged adult male rhesus macaques and attempted to identify outcome predictors for trio housing formation and its intermediary introduction steps.

Methods: Subjects were familiarized consecutively to each potential group member via protected contact prior to introduction into the trio. Seven trios were attempted, involving 18 males, with three males attempted in two different trios.

Results: One group was deemed successful, with a tenure of 51 days. Five were disbanded within minutes, and one was deemed unsuccessful the following morning. Two males sustained wounds requiring veterinary care over the course of the study. Outcome of the protected contact phase was predicted by age and temperament disparities as well as initial behavior.

Conclusions: While outcomes were poor, it suggests that attempts can be made relatively safely, and alternative introduction strategies should be explored to increase the feasibility of trio housing for adult males.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jmp.12469DOI Listing
August 2020

Isoniazid and Rifapentine Treatment Eradicates Persistent in Macaques.

Am J Respir Crit Care Med 2020 02;201(4):469-477

Tulane National Primate Research Center, Tulane University School of Medicine, Covington, Louisiana.

The authors have informed the Journal that they have become aware that some of the data in this article may be unreliable. Therefore, we have added this expression of concern while the situation is being reviewed. Direct evidence for persistence of () during asymptomatic latent tuberculosis infection (LTBI) in humans is currently lacking. Moreover, although a 12-week regimen of once-weekly isoniazid and rifapentine (3HP) is currently recommended by the CDC as treatment for LTBI, experimental evidence for 3HP-mediated clearance of persistent infection in human lungs has not been established. Using a nonhuman primate (NHP) model of TB, we sought to assess 3HP treatment-mediated clearance of infection in latently infected macaques. Sixteen NHPs were infected via inhalation with ∼10 cfu of CDC1551, after which asymptomatic animals were either treated with 3HP or left untreated. Pharmacokinetics of the 3HP regimen were measured. Following treatment, animals were coinfected with simian immunodeficiency virus to assess reactivation of LTBI and development of active TB disease. Fourteen NHPs remained free of clinical signs or microbiological evidence of active TB following infection with and were subsequently either treated with 3HP ( = 7) or left untreated ( = 7). Untreated NHPs were asymptomatic for 7 months but harbored persistent infection, as shown by reactivation of latent infection following simian immunodeficiency virus coinfection. However, none of the treated animals developed TB reactivation disease, and they remained without clinical or microbiological evidence of persistent bacilli, suggesting treatment-mediated clearance of bacteria. can persist in asymptomatic macaques for at least 7 months. Furthermore, 3HP treatment effectively cleared bacteria and prevented reactivation of TB in latently infected macaques.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1164/rccm.201903-0646OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049922PMC
February 2020

Chemokine receptor CCR5 correlates with functional CD8 T cells in SIV-infected macaques and the potential effects of maraviroc on T-cell activation.

FASEB J 2019 08 29;33(8):8905-8912. Epub 2019 Apr 29.

Tulane National Primate Research Center, Tulane University School of Medicine, Covington, Louisiana, USA.

C-C chemokine receptor 5 (CCR5) plays an essential role in HIV pathogenesis as the major coreceptor on CD4 T cells used by HIV, yet the function of CCR5 on CD8 T cells is not well understood. Furthermore, the immunologic effects of the CCR5 inhibitor maraviroc (MVC), despite approval for clinical use, have not yet been well evaluated for their potential effects on cytotoxic T-cell responses. In this study, we characterized the development and function of CCR5CD8 T cells in rhesus macaques with or without Simian immunodeficiency virus (SIV) infection. We also investigated the effects of the CCR5 antagonist MVC on functional CCR5CD8 T-cell responses . The data show that CCR5CD8 T cells have an effector memory phenotype and increase with age in systemic and mucosal lymphoid tissues as a heterogeneous population of polyfunctional CD8 T cells. In addition, CCR5 is highly expressed on SIV gag-specific (CM9) CD8 T cells in SIV-infected macaques, yet CCR5CD8 T cells are significantly reduced in mucosal lymphoid tissues with disease progression. Furthermore, MVC treatment reduced activation and cytokine secretion of CD8 T cells a CCR5-independent pathway. These findings suggest that surface CCR5 protein plays an important role in differentiation and activation of CD8 T cells. Although MVC may be helpful in reducing chronic inflammation and activation, it may also inhibit virus-specific CD8 T-cell responses. Thus optimal use of CCR5 antagonists either alone or in combination with other drugs should be defined by further investigation.-Wang, X., Russell-Lodrigue, K. E., Ratterree, M. S., Veazey, R. S., Xu, H. Chemokine receptor CCR5 correlates with functional CD8 T cells in SIV-infected macaques and the potential effects of maraviroc on T-cell activation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1096/fj.201802703RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6662974PMC
August 2019

Adverse event following live attenuated chikungunya vaccine in a cynomolgus macaque with pre-existing chronic hydrocephalus.

J Med Primatol 2019 08 3;48(4):257-259. Epub 2019 Apr 3.

Tulane National Primate Research Center, Covington, Louisiana.

A cynomolgus macaque (Macaca fascicularis) with a pre-existing, undiagnosed, subclinical but severe cerebral hydrocephalus was enrolled in a study of long-term immunogenicity of the IRES/CHIK vaccine. The animal began showing signs of neurological dysfunction post-vaccination, which progressed and ultimately resulted in euthanasia. The underlying brain abnormality was revealed at necropsy and was subsequently investigated with gross and microscopic examination. This becomes the first reported case of an adverse event following administration of a live attenuated vaccine and suggests the possibility of an increased susceptibility risk of unwanted adverse outcome associated with vaccination in populations with pre-existing conditions such as hydrocephalus.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jmp.12414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7006034PMC
August 2019

Impaired Development and Expansion of Germinal Center Follicular Th Cells in Simian Immunodeficiency Virus-Infected Neonatal Macaques.

J Immunol 2018 10 13;201(7):1994-2003. Epub 2018 Aug 13.

Tulane National Primate Research Center, Tulane University School of Medicine, Covington, LA 70433

Germinal center (GC) CD4 follicular Th (Tfh) cells are critical for cognate B cell help in humoral immune responses to pathogenic infections. Although Tfh cells are expanded or depleted in HIV/SIV-infected adults, the effects of pediatric HIV/SIV infection on Tfh cells remain unclear. In this study, we examined changes in lymphoid follicle formation in lymph nodes focusing on GC Tfh cells, B cell development, and differentiation in SIV-infected neonatal rhesus macaques () compared with age-matched cohorts. Our data showed that follicles and GCs of normal infants rapidly formed in the first few weeks of age, in parallel with increasing GC Tfh cells in various lymphoid tissues. In contrast, GC development and GC Tfh cells were markedly impaired in SIV-infected infants. There was a very low frequency of GC Tfh cells throughout SIV infection in neonates and subsequent infants, accompanied by high viremia, reduction of B cell proliferation/resting memory B cells, and displayed proinflammatory unresponsiveness. These findings indicate neonatal HIV/SIV infection compromises the development of GC Tfh cells, likely contributing to ineffective Ab responses, high viremia, and eventually rapid disease progression to AIDS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4049/jimmunol.1800235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6245642PMC
October 2018

Hydrocephalus after Intrathecal Administration of Dextran to Rhesus Macaques ().

Comp Med 2018 06 18;68(3):227-232. Epub 2018 May 18.

Division of Immunology, Tulane National Primate Research Center, Covington, Louisiana, USA.

Dextrans have been used extensively as medical therapies and labeling agents in biomedical research to investigate the blood-brain barrier and CSF flow and absorption. Adverse effects from dextrans include anaphylactic reaction and dilation of the cerebral ventricles due to administration into the subarachnoid space. This retrospective study describes 51 rhesus macaques (Macaca mulatta) that received dextran intrathecally. The purpose of intrathecal administration was to enable detection of long-lived, dextran-labeled macrophages and to study monocyte-macrophage turnover in the CNS of SIV- or SHIV- infected and uninfected animals by using immunofluorescence. Of the 51 dextran-treated macaques, 8 that received dextran diluted in saline developed hydrocephalus; 6 of these 8 animals exhibited neurologic signs. In contrast, none of the macaques that received intrathecal dextran diluted in PBS developed hydrocephalus. These data suggest the use of saline diluent and the duration of dextran exposure as potential factors contributing to hydrocephalus after intrathecal dextran in rhesus macaques.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.30802/AALAS-CM-17-000096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6008720PMC
June 2018

Evaluation of a therapy for Idiopathic Chronic Enterocolitis in rhesus macaques () and linked microbial community correlates.

PeerJ 2018 11;6:e4612. Epub 2018 Apr 11.

Division of Veterinary Medicine, Tulane National Primate Research Center, Covington, LA, United States of America.

Idiopathic chronic enterocolitis (ICE) is one of the most commonly encountered and difficult to manage diseases of captive rhesus macaques (). The etiology is not well understood, but perturbations in gut microbial communities have been implicated. Here we evaluated the effects of a 14-day course of vancomycin, neomycin, and fluconazole on animals affected with ICE, comparing treated, untreated, and healthy animals. We performed microbiome analysis on duodenal and colonic mucosal samples and feces in order to probe bacterial and/or fungal taxa potentially associated with ICE. All treated animals showed a significant and long-lasting improvement in stool consistency over time when compared to untreated and healthy controls. Microbiome analysis revealed trends associating bacterial community composition with ICE, particularly lineages of the Lactobacillaceae family. Sequencing of DNA from macaque food biscuits revealed that fungal sequences recovered from stool were dominated by yeast-derived food additives; in contrast, bacteria in stool appeared to be authentic gut residents. In conclusion, while validation in larger cohorts is needed, the treatment described here was associated with significantly improved clinical signs; results suggested possible correlates of microbiome structure with disease, though no strong associations were detected between single microbes and ICE.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7717/peerj.4612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5899420PMC
April 2018

Pseudoaneurysm and Arteriovenous Fistula in a Rhesus Macaque ().

Comp Med 2018 02;68(1):74-79

Divisions of Comparative Pathology, Tulane National Primate Research Center, Covington, Louisiana.

An 8-y-old female rhesus macaque (Macaca mulatta) presented for swelling of the left lower limb distal to the inguinal region and associated with the femoral artery. Physical and ultrasound examinations suggested an arteriovenous fistula combined with a pseudoaneurysm. After review of possible treatment options, we determined that open surgical repair was the best course of action. The pseudoaneurysm and arteriovenous fistula were surgically resected, and the macaque recovered without complication.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5824142PMC
February 2018

In vivo inhibition of tryptophan catabolism reorganizes the tuberculoma and augments immune-mediated control of .

Proc Natl Acad Sci U S A 2018 01 18;115(1):E62-E71. Epub 2017 Dec 18.

Tulane National Primate Research Center, Tulane University School of Medicine, Covington, LA 70433;

continues to cause devastating levels of mortality due to tuberculosis (TB). The failure to control TB stems from an incomplete understanding of the highly specialized strategies that utilizes to modulate host immunity and thereby persist in host lungs. Here, we show that induced the expression of indoleamine 2,3-dioxygenase (IDO), an enzyme involved in tryptophan catabolism, in macrophages and in the lungs of animals (mice and macaque) with active disease. In a macaque model of inhalation TB, suppression of IDO activity reduced bacterial burden, pathology, and clinical signs of TB disease, leading to increased host survival. This increased protection was accompanied by increased lung T cell proliferation, induction of inducible bronchus-associated lymphoid tissue and correlates of bacterial killing, reduced checkpoint signaling, and the relocation of effector T cells to the center of the granulomata. The enhanced killing of in macrophages in vivo by CD4 T cells was also replicated in vitro, in cocultures of macaque macrophages and CD4 T cells. Collectively, these results suggest that there exists a potential for using IDO inhibition as an effective and clinically relevant host-directed therapy for TB.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1711373114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5776797PMC
January 2018

A Burkholderia pseudomallei Outer Membrane Vesicle Vaccine Provides Cross Protection against Inhalational Glanders in Mice and Non-Human Primates.

Vaccines (Basel) 2017 Dec 9;5(4). Epub 2017 Dec 9.

Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, LA 70112, USA.

is a Gram-negative, non-motile, facultative intracellular bacillus and the causative agent of glanders, a highly contagious zoonotic disease. is naturally resistant to multiple antibiotics and there is concern for its potential use as a bioweapon, making the development of a vaccine against of critical importance. We have previously demonstrated that immunization with multivalent outer membrane vesicles (OMV) derived from provide significant protection against pneumonic melioidosis. Given that many virulence determinants are highly conserved between the two species, we sought to determine if the OMV vaccine could cross-protect against . We immunized C57Bl/6 mice and rhesus macaques with OMVs and subsequently challenged animals with aerosolized . Immunization with OMVs significantly protected mice against and the protection observed was comparable to that achieved with a live attenuated vaccine. OMV immunization induced the production of specific serum IgG and a mixed Th1/Th17 CD4 and CD8 T cell response in mice. Additionally, immunization of rhesus macaques with OMVs provided protection against glanders and induced -specific serum IgG in non-human primates. These results demonstrate the ability of the multivalent OMV vaccine platform to elicit cross-protection against closely-related intracellular pathogens and to induce robust humoral and cellular immune responses against shared protective antigens.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/vaccines5040049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5748615PMC
December 2017

Nonpathologic Infection of Macaques by an Attenuated Mycobacterial Vaccine Is Not Reactivated in the Setting of HIV Co-Infection.

Am J Pathol 2017 Dec 19;187(12):2811-2820. Epub 2017 Sep 19.

Tulane National Primate Research Center, Covington, Louisiana; Center for Biomedical Research Excellence, Louisiana State University School of Veterinary Medicine, Baton Rouge, Louisiana; Department of Pathobiological Sciences, Louisiana State University School of Veterinary Medicine, Baton Rouge, Louisiana. Electronic address:

Failure to replace Bacille Calmette-Guerin vaccines with efficacious anti-tuberculosis (TB) vaccines have prompted outside-the-box thinking, including pulmonary vaccination to elicit local immunity. Inhalational MtbΔsigH, a stress-response-attenuated strain, protected against lethal TB in macaques. While live mycobacterial vaccines show promising efficacy, HIV co-infection and the resulting immunodeficiency prompts safety concerns about their use. We assessed the persistence and safety of MtbΔsigH, delivered directly to the lungs, in the setting of HIV co-infection. Macaques were aerosol-vaccinated with ΔsigH and subsequently challenged with SIVmac. Bronchoalveolar lavage and tissues were sampled for mycobacterial persistence, pathology, and immune correlates. Only 35% and 3.5% of lung samples were positive for live bacilli and granulomas, respectively. Our results therefore suggest that the nonpathologic infection of macaque lungs by ΔsigH was not reactivated by simian immunodeficiency virus, despite high viral levels and massive ablation of pulmonary CD4 T cells. Protective pulmonary responses were retained, including vaccine-induced bronchus-associated lymphoid tissue and CD8 effector memory T cells. Despite acute simian immunodeficiency virus infection, all animals remained asymptomatic of pulmonary TB. These findings highlight the efficacy of mucosal vaccination via this attenuated strain and will guide its further development to potentially combat TB in HIV-endemic areas. Our results also suggest that a lack of pulmonary pathology is a key correlate of the safety of live mycobacterial vaccines.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajpath.2017.08.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5718104PMC
December 2017

Mucosal bacterial dissemination in a rhesus macaque model of experimental brucellosis.

J Med Primatol 2018 02 2;47(1):75-77. Epub 2017 Jun 2.

Tulane National Primate Research Center, Covington, LA, USA.

Animals were experimentally infected with Brucella melitensis via aerosol. B. melitensis was cultured from the saliva and vaginal vault of infected animals, corresponding to bacterial dissemination in other target tissues. This is the first report of bacterial dissemination to these mucosal surfaces in a non-human primate model of brucellosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jmp.12282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5946315PMC
February 2018

Cabotegravir long acting injection protects macaques against intravenous challenge with SIVmac251.

AIDS 2017 02;31(4):461-467

aAaron Diamond AIDS Research Center, The Rockefeller University, New York City, New York bViiV Healthcare, Research Triangle Park, North Carolina cTulane National Primate Research Center, Covington, Louisiana dGlaxoSmithKline, Research Triangle Park, North Carolina, USA.

Objective: We evaluated the effectiveness of cabotegravir (CAB; GSK1265744 or GSK744) long acting as preexposure prophylaxis (PrEP) against intravenous simian immunodeficiency virus (SIV) challenge in a model that mimics blood transfusions based on the per-act probability of infection.

Design: CAB long acting is an integrase strand transfer inhibitor formulated as a 200 mg/ml injectable nanoparticle suspension that is an effective PrEP agent against rectal and vaginal simian/human immunodeficiency virus transmission in macaques.

Methods: Three groups of rhesus macaques (n = 8 per group) were injected intramuscularly with CAB long acting and challenged intravenously with 17 animal infectious dose 50% SIVmac251 on week 2. Group 1 was injected with 50 mg/kg on week 0 and 4 to evaluate the protective efficacy of the CAB long-acting dose used in macaque studies mimicking sexual transmission. Group 2 was injected with 50 mg/kg on week 0 to evaluate the necessity of the second injection of CAB long acting for protection against intravenous challenge. Group 3 was injected with 25 mg/kg on week 0 and 50 mg/kg on week 4 to correlate CAB plasma concentrations at the time of challenge with protection. Five additional macaques remained untreated as controls.

Results: CAB long acting was highly protective with 21 of the 24 CAB long-acting-treated macaques remaining aviremic, resulting in 88% protection. The plasma CAB concentration at the time of virus challenge appeared to be more important for protection than sustaining therapeutic plasma concentrations with the second CAB long acting injection.

Conclusion: These results support the clinical investigation of CAB long acting as PrEP in people who inject drugs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/QAD.0000000000001343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5263045PMC
February 2017

CD4+ T-cell-independent mechanisms suppress reactivation of latent tuberculosis in a macaque model of HIV coinfection.

Proc Natl Acad Sci U S A 2016 09 6;113(38):E5636-44. Epub 2016 Sep 6.

Tulane National Primate Research Center, Covington, LA 70471; Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, LA 70112;

The synergy between Mycobacterium tuberculosis (Mtb) and HIV in coinfected patients has profoundly impacted global mortality because of tuberculosis (TB) and AIDS. HIV significantly increases rates of reactivation of latent TB infection (LTBI) to active disease, with the decline in CD4(+) T cells believed to be the major causality. In this study, nonhuman primates were coinfected with Mtb and simian immunodeficiency virus (SIV), recapitulating human coinfection. A majority of animals exhibited rapid reactivation of Mtb replication, progressing to disseminated TB and increased SIV-associated pathology. Although a severe loss of pulmonary CD4(+) T cells was observed in all coinfected macaques, a subpopulation of the animals was still able to prevent reactivation and maintain LTBI. Investigation of pulmonary immune responses and pathology in this cohort demonstrated that increased CD8(+) memory T-cell proliferation, higher granzyme B production, and expanded B-cell follicles correlated with protection from reactivation. Our findings reveal mechanisms that control SIV- and TB-associated pathology. These CD4-independent protective immune responses warrant further studies in HIV coinfected humans able to control their TB infection. Moreover, these findings will provide insight into natural immunity to Mtb and will guide development of novel vaccine strategies and immunotherapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5035858PMC
http://dx.doi.org/10.1073/pnas.1611987113DOI Listing
September 2016

C5A Protects Macaques from Vaginal Simian-Human Immunodeficiency Virus Challenge.

Antimicrob Agents Chemother 2016 01 9;60(1):693-8. Epub 2015 Nov 9.

Department of Immunology & Microbial Science, The Scripps Research Institute, La Jolla, California, USA

A safe and effective vaginal microbicide could decrease human immunodeficiency virus (HIV) transmission in women. Here, we evaluated the safety and microbicidal efficacy of a short amphipathic peptide, C5A, in a rhesus macaque model. We found that a vaginal application of C5A protects 89% of the macaques from a simian-human immunodeficiency virus (SHIV-162P3) challenge. We observed no signs of lesions or inflammation in animals vaginally treated with repeated C5A applications. With its noncellular cytotoxic activity and rare mechanism of action, C5A represents an attractive microbicidal candidate.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/AAC.01925-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4704173PMC
January 2016

Mucosal vaccination with attenuated Mycobacterium tuberculosis induces strong central memory responses and protects against tuberculosis.

Nat Commun 2015 Oct 13;6:8533. Epub 2015 Oct 13.

Tulane National Primate Research Center, Covington, Louisiana 70433, USA.

Tuberculosis (TB) is a global pandaemic, partially due to the failure of vaccination approaches. Novel anti-TB vaccines are therefore urgently required. Here we show that aerosol immunization of macaques with the Mtb mutant in SigH (MtbΔsigH) results in significant recruitment of inducible bronchus-associated lymphoid tissue (iBALT) as well as CD4(+) and CD8(+) T cells expressing activation and proliferation markers to the lungs. Further, the findings indicate that pulmonary vaccination with MtbΔsigH elicited strong central memory CD4(+) and CD8(+) T-cell responses in the lung. Vaccination with MtbΔsigH results in significant protection against a lethal TB challenge, as evidenced by an approximately three log reduction in bacterial burdens, significantly diminished clinical manifestations and granulomatous pathology and characterized by the presence of profound iBALT. This highly protective response is virtually absent in unvaccinated and BCG-vaccinated animals after challenge. These results suggest that future TB vaccine candidates can be developed on the basis of MtbΔsigH.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ncomms9533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4608260PMC
October 2015

Neuropathogenesis of Chikungunya infection: astrogliosis and innate immune activation.

J Neurovirol 2016 Apr 29;22(2):140-8. Epub 2015 Sep 29.

Tulane National Primate Research Center, Tulane Medical School, Covington, LA, 70433, USA.

Chikungunya, "that which bends up" in the Makonde dialect, is an emerging global health threat, with increasing incidence of neurological complications. Until 2013, Chikungunya infection had been largely restricted to East Africa and the Indian Ocean, with cases within the USA reported to be from foreign travel. However, in 2014, over 1 million suspected cases were reported in the Americas, and a recently infected human could serve as an unwitting reservoir for the virus resulting in an epidemic in the continental USA. Chikungunya infection is increasingly being associated with neurological sequelae. In this study, we sought to understand the role of astrocytes in the neuropathogenesis of Chikungunya infection. Even after virus has been cleared form the circulation, astrocytes were activated with regard to TLR2 expression. In addition, white matter astrocytes were hypertrophic, with increased arbor volume in gray matter astrocytes. Combined, these would alter the number and distribution of synapses that each astrocyte would be capable of forming. These results provide the first evidence that Chikungunya infection induces morphometric and innate immune activation of astrocytes in vivo. Perturbed glia-neuron signaling could be a major driving factor in the development of Chikungunya-associated neuropathology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s13365-015-0378-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4783292PMC
April 2016

IRES-Containing VEEV Vaccine Protects Cynomolgus Macaques from IE Venezuelan Equine Encephalitis Virus Aerosol Challenge.

PLoS Negl Trop Dis 2015 May 28;9(5):e0003797. Epub 2015 May 28.

Divisions of Veterinary Medicine and Microbiology, Tulane National Primate Research Center, Covington, Louisiana, United States of America; Department of Microbiology and Immunology, Tulane School of Medicine, New Orleans, Louisiana, United States of America.

Venezuelan equine encephalitis virus (VEEV) is an arbovirus endemic to the Americas that is responsible for severe, sometimes fatal, disease in humans and horses. We previously described an IRES-based VEE vaccine candidate based up the IE serotype that offers complete protection against a lethal subtype IE VEEV challenge in mice. Here we demonstrate the IRES-based vaccine's ability to protect against febrile disease in cynomolgus macaques. Vaccination was well tolerated and elicited robust neutralizing antibody titers noticed as early as day 14. Moreover, complete protection from disease characterized by absence of viremia and characteristic fever following aerosolized IE VEEV challenge was observed in all vaccinees compared to control animals, which developed clinical disease. Together, these results highlight the safety and efficacy of IRES-based VEEV vaccine to protect against an endemic, pathogenic VEEV IE serotype.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pntd.0003797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4447396PMC
May 2015

The DosR Regulon Modulates Adaptive Immunity and Is Essential for Mycobacterium tuberculosis Persistence.

Am J Respir Crit Care Med 2015 May;191(10):1185-96

1 Division of Microbiology.

Rationale: Hypoxia promotes dormancy by causing physiologic changes to actively replicating Mycobacterium tuberculosis. DosR controls the response of M. tuberculosis to hypoxia.

Objectives: To understand DosR's contribution in the persistence of M. tuberculosis, we compared the phenotype of various DosR regulon mutants and a complemented strain to M. tuberculosis in macaques, which faithfully model M. tuberculosis infection.

Methods: We measured clinical and microbiologic correlates of infection with M. tuberculosis relative to mutant/complemented strains in the DosR regulon, studied lung pathology and hypoxia, and compared immune responses in lung using transcriptomics and flow cytometry.

Measurements And Main Results: Despite being able to replicate initially, mutants in DosR regulon failed to persist or cause disease. On the contrary, M. tuberculosis and a complemented strain were able to establish infection and tuberculosis. The attenuation of pathogenesis in animals infected with the mutants coincided with the appearance of a Th1 response and organization of hypoxic lesions wherein M. tuberculosis expressed dosR. The lungs of animals infected with the mutants (but not the complemented strain) exhibited early transcriptional signatures of T-cell recruitment, activation, and proliferation associated with an increase of T cells expressing homing and proliferation markers.

Conclusions: Delayed adaptive responses, a hallmark of M. tuberculosis infection, not only lead to persistence but also interfere with the development of effective antituberculosis vaccines. The DosR regulon therefore modulates both the magnitude and the timing of adaptive immune responses in response to hypoxia in vivo, resulting in persistent infection. Hence, DosR regulates key aspects of the M. tuberculosis life cycle and limits lung pathology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1164/rccm.201408-1502OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4451619PMC
May 2015

A long-acting integrase inhibitor protects female macaques from repeated high-dose intravaginal SHIV challenge.

Sci Transl Med 2015 Jan;7(270):270ra4

Aaron Diamond AIDS Research Center, The Rockefeller University, New York, NY 10016, USA.

Long-acting GSK1265744 (GSK744 LA) is a strand transfer inhibitor of the HIV/SIV (simian immunodeficiency virus) integrase and was shown to be an effective preexposure prophylaxis (PrEP) agent in a low-dose intrarectal SHIV (simian-human immunodeficiency virus) rhesus macaque challenge model. We examined the pharmacokinetics and efficacy of GSK744 LA as PrEP against repeat high-dose intravaginal SHIV challenge in female rhesus macaques treated with Depo-Provera (depot medroxyprogesterone acetate), which promotes viral transmission vaginally. When Depo-Provera-treated female rhesus macaques were dosed with GSK744 LA (50 mg/kg) monthly, systemic and tissue drug concentrations were lower than previously observed in male rhesus macaques. GSK744 concentrations were fivefold lower on average in cervical tissues than in rectal tissues. Eight female rhesus macaques were treated with GSK744 LA at week 0, and four female rhesus macaques served as controls. All animals received a high-dose challenge of SHIV162P3 at week 1. No infection was detected in GSK744 LA-treated rhesus macaques, whereas viremia was detected 1 to 2 weeks after SHIV challenge in all control animals. The GSK744 LA-treated rhesus macaques were given a second administration of drug at week 4 and further challenged at weeks 5 and 7. GSK744 LA treatment protected six of eight female rhesus macaques against three high-dose SHIV challenges, whereas all control animals became infected after the first challenge (P = 0.0003, log-rank test). These results support further clinical development of GSK744 LA for PrEP.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/scitranslmed.3010298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4449736PMC
January 2015

Immunologic characterization of a rhesus macaque H1N1 challenge model for candidate influenza virus vaccine assessment.

Clin Vaccine Immunol 2014 Dec 8;21(12):1668-80. Epub 2014 Oct 8.

Baylor Institute for Immunology Research, Dallas, Texas, USA

Despite the availability of annually formulated vaccines, influenza virus infection remains a worldwide public health burden. Therefore, it is important to develop preclinical challenge models that enable the evaluation of vaccine candidates while elucidating mechanisms of protection. Here, we report that naive rhesus macaques challenged with 2009 pandemic H1N1 (pH1N1) influenza virus do not develop observable clinical symptoms of disease but develop a subclinical biphasic fever on days 1 and 5 to 6 postchallenge. Whole blood microarray analysis further revealed that interferon activity was associated with fever. We then tested whether type I interferon activity in the blood is a correlate of vaccine efficacy. The animals immunized with candidate vaccines carrying hemagglutinin (HA) or nucleoprotein (NP) exhibited significantly reduced interferon activity on days 5 to 6 postchallenge. Supported by cellular and serological data, we conclude that blood interferon activity is a prominent marker that provides a convenient metric of influenza virus vaccine efficacy in the subclinical rhesus macaque model.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/CVI.00547-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4248778PMC
December 2014
-->