Publications by authors named "Lisa H Tostanoski"

36 Publications

A modular protein subunit vaccine candidate produced in yeast confers protection against SARS-CoV-2 in non-human primates.

bioRxiv 2021 Jul 14. Epub 2021 Jul 14.

Vaccines against SARS-CoV-2 have been distributed at massive scale in developed countries, and have been effective at preventing COVID-19. Access to vaccines is limited, however, in low- and middle-income countries (LMICs) due to insufficient supply, high costs, and cold storage requirements. New vaccines that can be produced in existing manufacturing facilities in LMICs, can be manufactured at low cost, and use widely available, proven, safe adjuvants like alum, would improve global immunity against SARS-CoV-2. One such protein subunit vaccine is produced by the Serum Institute of India Pvt. Ltd. and is currently in clinical testing. Two protein components, the SARS-CoV-2 receptor binding domain (RBD) and hepatitis B surface antigen virus-like particles (VLPs), are each produced in yeast, which would enable a low-cost, high-volume manufacturing process. Here, we describe the design and preclinical testing of the RBD-VLP vaccine in cynomolgus macaques. We observed titers of neutralizing antibodies (>10 ) above the range of protection for other licensed vaccines in non-human primates. Interestingly, addition of a second adjuvant (CpG1018) appeared to improve the cellular response while reducing the humoral response. We challenged animals with SARS-CoV-2, and observed a ~3.4 and ~2.9 log reduction in median viral loads in bronchoalveolar lavage and nasal mucosa, respectively, compared to sham controls. These results inform the design and formulation of current clinical COVID-19 vaccine candidates like the one described here, and future designs of RBD-based vaccines against variants of SARS-CoV-2 or other betacoronaviruses.
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http://dx.doi.org/10.1101/2021.07.13.452251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8288147PMC
July 2021

Protective efficacy of Ad26.COV2.S against SARS-CoV-2 B.1.351 in macaques.

Nature 2021 Jun 23. Epub 2021 Jun 23.

Bioqual, Rockville, MD, USA.

The emergence of SARS-CoV-2 variants that partially evade neutralizing antibodies poses a threat to the efficacy of current COVID-19 vaccines. 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 variant. Here we show that Ad26.COV2.S elicits humoral and cellular immune responses that cross-react with the B.1.351 variant and protects against B.1.351 challenge in rhesus macaques. Ad26.COV2.S induced lower binding and neutralizing antibodies against B.1.351 as compared to WA1/2020, but elicited comparable CD8 and CD4 T cell responses against the WA1/2020, B.1.351, B.1.1.7, P.1 and CAL.20C variants. B.1.351 infection of control rhesus macaques resulted in higher levels of virus replication in bronchoalveolar lavage and nasal swabs than did WA1/2020 infection. Ad26.COV2.S provided robust protection against both WA1/2020 and B.1.351, although we observed higher levels of virus in vaccinated macaques after B.1.351 challenge. These data demonstrate that Ad26.COV2.S provided robust protection against B.1.351 challenge in rhesus macaques. Our findings have important implications for vaccine control of SARS-CoV-2 variants of concern.
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http://dx.doi.org/10.1038/s41586-021-03732-8DOI Listing
June 2021

Protective efficacy of rhesus adenovirus COVID-19 vaccines against mouse-adapted SARS-CoV-2.

bioRxiv 2021 Jun 15. Epub 2021 Jun 15.

The global COVID-19 pandemic has sparked intense interest in the rapid development of vaccines as well as animal models to evaluate vaccine candidates and to define immune correlates of protection. We recently reported a mouse-adapted SARS-CoV-2 virus strain (MA10) with the potential to infect wild-type laboratory mice, driving high levels of viral replication in respiratory tract tissues as well as severe clinical and respiratory symptoms, aspects of COVID-19 disease in humans that are important to capture in model systems. We evaluated the immunogenicity and protective efficacy of novel rhesus adenovirus serotype 52 (RhAd52) vaccines against MA10 challenge in mice. Baseline seroprevalence is lower for rhesus adenovirus vectors than for human or chimpanzee adenovirus vectors, making these vectors attractive candidates for vaccine development. We observed that RhAd52 vaccines elicited robust binding and neutralizing antibody titers, which inversely correlated with viral replication after challenge. These data support the development of RhAd52 vaccines and the use of the MA10 challenge virus to screen novel vaccine candidates and to study the immunologic mechanisms that underscore protection from SARS-CoV-2 challenge in wild-type mice.

Importance: We have developed a series of SARS-CoV-2 vaccines using rhesus adenovirus serotype 52 (RhAd52) vectors, which exhibits a lower seroprevalence than human and chimpanzee vectors, supporting their development as novel vaccine vectors or as an alternative Ad vector for boosting. We sought to test these vaccines using a recently reported mouse-adapted SARS-CoV-2 (MA10) virus to i) evaluate the protective efficacy of RhAd52 vaccines and ii) further characterize this mouse-adapted challenge model and probe immune correlates of protection. We demonstrate RhAd52 vaccines elicit robust SARS-CoV-2-specific antibody responses and protect against clinical disease and viral replication in the lungs. Further, binding and neutralizing antibody titers correlated with protective efficacy. These data validate the MA10 mouse model as a useful tool to screen and study novel vaccine candidates, as well as the development of RhAd52 vaccines for COVID-19.
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http://dx.doi.org/10.1101/2021.06.14.448461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8219099PMC
June 2021

Low-dose Ad26.COV2.S protection against SARS-CoV-2 challenge in rhesus macaques.

Cell 2021 06 1;184(13):3467-3473.e11. Epub 2021 Jun 1.

Bioqual, Rockville, MD 20852, USA.

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 × 10, 5 × 10, 1.125 × 10, or 2 × 10 viral particles (vp) Ad26.COV2.S or sham and were challenged with SARS-CoV-2. Vaccine doses as low as 2 × 10 vp provided robust protection in bronchoalveolar lavage, whereas doses of 1.125 × 10 vp were required for protection in nasal swabs. Activated memory B cells and binding or neutralizing antibody titers following vaccination correlated with protective efficacy. At suboptimal vaccine doses, viral breakthrough was observed but did not show enhancement of disease. These data demonstrate that a single immunization with relatively low dose of Ad26.COV2.S effectively protected against SARS-CoV-2 challenge in rhesus macaques, although a higher vaccine dose may be required for protection in the upper respiratory tract.
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http://dx.doi.org/10.1016/j.cell.2021.05.040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8166510PMC
June 2021

Immunogenicity of Ad26.COV2.S vaccine against SARS-CoV-2 variants in humans.

Nature 2021 Jun 9. Epub 2021 Jun 9.

Janssen Vaccines & Prevention, Leiden, The Netherlands.

The Ad26.COV2.S vaccine has demonstrated clinical efficacy against symptomatic COVID-19, including against the B.1.351 variant that is partially resistant to neutralizing antibodies. However, the immunogenicity of this vaccine in humans against SARS-CoV-2 variants of concern remains unclear. Here we report humoral and cellular immune responses from 20 Ad26.COV2.S vaccinated individuals from the COV1001 phase I-IIa clinical trial against the original SARS-CoV-2 strain WA1/2020 as well as against the B.1.1.7, CAL.20C, P.1 and B.1.351 variants of concern. Ad26.COV2.S induced median pseudovirus neutralizing antibody titres that were 5.0-fold and 3.3-fold lower against the B.1.351 and P.1 variants, respectively, as compared with WA1/2020 on day 71 after vaccination. Median binding antibody titres were 2.9-fold and 2.7-fold lower against the B.1.351 and P.1 variants, respectively, as compared with WA1/2020. Antibody-dependent cellular phagocytosis, complement deposition and natural killer cell activation responses were largely preserved against the B.1.351 variant. CD8 and CD4 T cell responses, including central and effector memory responses, were comparable among the WA1/2020, B.1.1.7, B.1.351, P.1 and CAL.20C variants. These data show that neutralizing antibody responses induced by Ad26.COV2.S were reduced against the B.1.351 and P.1 variants, but functional non-neutralizing antibody responses and T cell responses were largely preserved against SARS-CoV-2 variants. These findings have implications for vaccine protection against SARS-CoV-2 variants of concern.
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http://dx.doi.org/10.1038/s41586-021-03681-2DOI Listing
June 2021

Immunogenicity of COVID-19 mRNA Vaccines in Pregnant and Lactating Women.

JAMA 2021 06;325(23):2370-2380

Harvard Medical School, Boston, Massachusetts.

Importance: Pregnant women are at increased risk of morbidity and mortality from COVID-19 but have been excluded from the phase 3 COVID-19 vaccine trials. Data on vaccine safety and immunogenicity in these populations are therefore limited.

Objective: To evaluate the immunogenicity of COVID-19 messenger RNA (mRNA) vaccines in pregnant and lactating women, including against emerging SARS-CoV-2 variants of concern.

Design, Setting, And Participants: An exploratory, descriptive, prospective cohort study enrolled 103 women who received a COVID-19 vaccine from December 2020 through March 2021 and 28 women who had confirmed SARS-CoV-2 infection from April 2020 through March 2021 (the last follow-up date was March 26, 2021). This study enrolled 30 pregnant, 16 lactating, and 57 neither pregnant nor lactating women who received either the mRNA-1273 (Moderna) or BNT162b2 (Pfizer-BioNTech) COVID-19 vaccines and 22 pregnant and 6 nonpregnant unvaccinated women with SARS-CoV-2 infection.

Main Outcomes And Measures: SARS-CoV-2 receptor binding domain binding, neutralizing, and functional nonneutralizing antibody responses from pregnant, lactating, and nonpregnant women were assessed following vaccination. Spike-specific T-cell responses were evaluated using IFN-γ enzyme-linked immunospot and multiparameter intracellular cytokine-staining assays. Humoral and cellular immune responses were determined against the original SARS-CoV-2 USA-WA1/2020 strain as well as against the B.1.1.7 and B.1.351 variants.

Results: This study enrolled 103 women aged 18 to 45 years (66% non-Hispanic White) who received a COVID-19 mRNA vaccine. After the second vaccine dose, fever was reported in 4 pregnant women (14%; SD, 6%), 7 lactating women (44%; SD, 12%), and 27 nonpregnant women (52%; SD, 7%). Binding, neutralizing, and functional nonneutralizing antibody responses as well as CD4 and CD8 T-cell responses were present in pregnant, lactating, and nonpregnant women following vaccination. Binding and neutralizing antibodies were also observed in infant cord blood and breast milk. Binding and neutralizing antibody titers against the SARS-CoV-2 B.1.1.7 and B.1.351 variants of concern were reduced, but T-cell responses were preserved against viral variants.

Conclusion And Relevance: In this exploratory analysis of a convenience sample, receipt of a COVID-19 mRNA vaccine was immunogenic in pregnant women, and vaccine-elicited antibodies were transported to infant cord blood and breast milk. Pregnant and nonpregnant women who were vaccinated developed cross-reactive antibody responses and T-cell responses against SARS-CoV-2 variants of concern.
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http://dx.doi.org/10.1001/jama.2021.7563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120446PMC
June 2021

Correlates of Neutralization against SARS-CoV-2 Variants of Concern by Early Pandemic Sera.

J Virol 2021 06 24;95(14):e0040421. Epub 2021 Jun 24.

Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.

Emerging SARS-CoV-2 variants of concern that overcome natural and vaccine-induced immunity threaten to exacerbate the COVID-19 pandemic. Increasing evidence suggests that neutralizing antibody (NAb) responses are a primary mechanism of protection against infection. However, little is known about the extent and mechanisms by which natural immunity acquired during the early COVID-19 pandemic confers cross-neutralization of emerging variants. In this study, we investigated cross-neutralization of the B.1.1.7 and B.1.351 SARS-CoV-2 variants in a well-characterized cohort of early pandemic convalescent subjects. We observed modestly decreased cross-neutralization of B.1.1.7 but a substantial 4.8-fold reduction in cross-neutralization of B.1.351. Correlates of cross-neutralization included receptor binding domain (RBD) and N-terminal domain (NTD) binding antibodies, homologous NAb titers, and membrane-directed T cell responses. These data shed light on the cross-neutralization of emerging variants by early pandemic convalescent immune responses. Widespread immunity to SARS-CoV-2 will be necessary to end the COVID-19 pandemic. NAb responses are a critical component of immunity that can be stimulated by natural infection as well as vaccines. However, SARS-CoV-2 variants are emerging that contain mutations in the spike gene that promote evasion from NAb responses. These variants may therefore delay control of the COVID-19 pandemic. We studied whether NAb responses from early COVID-19 convalescent patients are effective against the two SARS-CoV-2 variants, B.1.1.7 and B.1.351. We observed that the B.1.351 variant demonstrates significantly reduced susceptibility to early pandemic NAb responses. We additionally characterized virological, immunological, and clinical features that correlate with cross-neutralization. These studies increase our understanding of emerging SARS-CoV-2 variants.
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http://dx.doi.org/10.1128/JVI.00404-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223959PMC
June 2021

Novel approaches for vaccine development.

Cell 2021 03;184(6):1589-1603

Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Massachusetts Consortium on Pathogen Readiness, Boston, MA, USA. Electronic address:

Vaccines are critical tools for maintaining global health. Traditional vaccine technologies have been used across a wide range of bacterial and viral pathogens, yet there are a number of examples where they have not been successful, such as for persistent infections, rapidly evolving pathogens with high sequence variability, complex viral antigens, and emerging pathogens. Novel technologies such as nucleic acid and viral vector vaccines offer the potential to revolutionize vaccine development as they are well-suited to address existing technology limitations. In this review, we discuss the current state of RNA vaccines, recombinant adenovirus vector-based vaccines, and advances from biomaterials and engineering that address these important public health challenges.
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http://dx.doi.org/10.1016/j.cell.2021.02.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049514PMC
March 2021

Immunogenicity of the Ad26.COV2.S Vaccine for COVID-19.

JAMA 2021 04;325(15):1535-1544

Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts.

Importance: Control of the global COVID-19 pandemic will require the development and deployment of safe and effective vaccines.

Objective: To evaluate the immunogenicity of the Ad26.COV2.S vaccine (Janssen/Johnson & Johnson) in humans, including the kinetics, magnitude, and phenotype of SARS-CoV-2 spike-specific humoral and cellular immune responses.

Design, Setting, And Participants: Twenty-five participants were enrolled from July 29, 2020, to August 7, 2020, and the follow-up for this day 71 interim analysis was completed on October 3, 2020; follow-up to assess durability will continue for 2 years. This study was conducted at a single clinical site in Boston, Massachusetts, as part of a randomized, double-blind, placebo-controlled phase 1 clinical trial of Ad26.COV2.S.

Interventions: Participants were randomized to receive 1 or 2 intramuscular injections with 5 × 1010 viral particles or 1 × 1011 viral particles of Ad26.COV2.S vaccine or placebo administered on day 1 and day 57 (5 participants in each group).

Main Outcomes And Measures: Humoral immune responses included binding and neutralizing antibody responses at multiple time points following immunization. Cellular immune responses included immunospot-based and intracellular cytokine staining assays to measure T-cell responses.

Results: Twenty-five participants were randomized (median age, 42; age range, 22-52; 52% women, 44% male, 4% undifferentiated), and all completed the trial through the day 71 interim end point. Binding and neutralizing antibodies emerged rapidly by day 8 after initial immunization in 90% and 25% of vaccine recipients, respectively. By day 57, binding and neutralizing antibodies were detected in 100% of vaccine recipients after a single immunization. On day 71, the geometric mean titers of spike-specific binding antibodies were 2432 to 5729 and the geometric mean titers of neutralizing antibodies were 242 to 449 in the vaccinated groups. A variety of antibody subclasses, Fc receptor binding properties, and antiviral functions were induced. CD4+ and CD8+ T-cell responses were induced.

Conclusion And Relevance: In this phase 1 study, a single immunization with Ad26.COV2.S induced rapid binding and neutralization antibody responses as well as cellular immune responses. Two phase 3 clinical trials are currently underway to determine the efficacy of the Ad26.COV2.S vaccine.

Trial Registration: ClinicalTrials.gov Identifier: NCT04436276.
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http://dx.doi.org/10.1001/jama.2021.3645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953339PMC
April 2021

Engineered SARS-CoV-2 receptor binding domain improves immunogenicity in mice and elicits protective immunity in hamsters.

bioRxiv 2021 Mar 4. Epub 2021 Mar 4.

Global containment of COVID-19 still requires accessible and affordable vaccines for low- and middle-income countries (LMICs). Recently approved vaccines provide needed interventions, albeit at prices that may limit their global access. Subunit vaccines based on recombinant proteins are suited for large-volume microbial manufacturing to yield billions of doses annually, minimizing their manufacturing costs. These types of vaccines are well-established, proven interventions with multiple safe and efficacious commercial examples. Many vaccine candidates of this type for SARS-CoV-2 rely on sequences containing the receptor-binding domain (RBD), which mediates viral entry to cells via ACE2. Here we report an engineered sequence variant of RBD that exhibits high-yield manufacturability, high-affinity binding to ACE2, and enhanced immunogenicity after a single dose in mice compared to the Wuhan-Hu-1 variant used in current vaccines. Antibodies raised against the engineered protein exhibited heterotypic binding to the RBD from two recently reported SARS-CoV-2 variants of concern (501Y.V1/V2). Presentation of the engineered RBD on a designed virus-like particle (VLP) also reduced weight loss in hamsters upon viral challenge.
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http://dx.doi.org/10.1101/2021.03.03.433558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7941618PMC
March 2021

Exploiting Rational Assembly to Map Distinct Roles of Regulatory Cues during Autoimmune Therapy.

ACS Nano 2021 03 1;15(3):4305-4320. Epub 2021 Mar 1.

Fischell Department of Bioengineering, University of Maryland, 3102 A. James Clark Hall, 8278 Paint Branch Drive, College Park, Maryland 20742, United States.

Autoimmune diseases like multiple sclerosis (MS), type 1 diabetes, and lupus occur when the immune system attacks host tissue. Immunotherapies that promote selective tolerance without suppressing normal immune function are of tremendous interest. Here, nanotechnology was used for rational assembly of peptides and modulatory immune cues into immune complexes. Complexes containing self-peptides and regulatory nucleic acids reverse established paralysis in a preclinical MS model. Importantly, mice responding to immunotherapy maintain healthy, antigen-specific B and T cell responses during a foreign antigen challenge. A therapeutic library isolating specific components reveals that regulatory nucleic acids suppress inflammatory genes in innate immune cells, while disease-matched peptide sequences control specificity of tolerance. Distinct gene expression profiles in cells and animals are associated with the immune signals administered in particulate and soluble forms, highlighting the impact of biophysical presentation of signals. This work provides insight into the rational manipulation of immune signaling to drive tolerance.
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http://dx.doi.org/10.1021/acsnano.0c07440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116774PMC
March 2021

Low-Dose Ad26.COV2.S Protection Against SARS-CoV-2 Challenge in Rhesus Macaques.

bioRxiv 2021 Jan 27. Epub 2021 Jan 27.

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. In this study, we evaluated the immunogenicity and protective efficacy of reduced doses of Ad26.COV2.S. 30 rhesus macaques were immunized once with 1×10 , 5×10 , 1.125×10 , or 2×10 vp Ad26.COV2.S or sham and were challenged with SARS-CoV-2 by the intranasal and intratracheal routes. Vaccine doses as low as 2×10 vp provided robust protection in bronchoalveolar lavage, whereas doses of 1.125×10 vp were required for protection in nasal swabs. Activated memory B cells as well as binding and neutralizing antibody titers following vaccination correlated with protective efficacy. At suboptimal vaccine doses, viral breakthrough was observed but did not show evidence of virologic, immunologic, histopathologic, or clinical enhancement of disease compared with sham controls. These data demonstrate that a single immunization with a relatively low dose of Ad26.COV2.S effectively protected against SARS-CoV-2 challenge in rhesus macaques. Moreover, our findings show that a higher vaccine dose may be required for protection in the upper respiratory tract compared with the lower respiratory tract.
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http://dx.doi.org/10.1101/2021.01.27.428380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852276PMC
January 2021

Correlates of protection against SARS-CoV-2 in rhesus macaques.

Nature 2021 02 4;590(7847):630-634. Epub 2020 Dec 4.

Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.

Recent studies have reported the protective efficacy of both natural and vaccine-induced immunity against challenge with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in rhesus macaques. However, the importance of humoral and cellular immunity for protection against infection with SARS-CoV-2 remains to be determined. Here we show that the adoptive transfer of purified IgG from convalescent rhesus macaques (Macaca mulatta) protects naive recipient macaques against challenge with SARS-CoV-2 in a dose-dependent fashion. Depletion of CD8 T cells in convalescent macaques partially abrogated the protective efficacy of natural immunity against rechallenge with SARS-CoV-2, which suggests a role for cellular immunity in the context of waning or subprotective antibody titres. These data demonstrate that relatively low antibody titres are sufficient for protection against SARS-CoV-2 in rhesus macaques, and that cellular immune responses may contribute to protection if antibody responses are suboptimal. We also show that higher antibody titres are required for treatment of SARS-CoV-2 infection in macaques. These findings have implications for the development of SARS-CoV-2 vaccines and immune-based therapeutic agents.
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http://dx.doi.org/10.1038/s41586-020-03041-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906955PMC
February 2021

Ad26 vaccine protects against SARS-CoV-2 severe clinical disease in hamsters.

Nat Med 2020 11 3;26(11):1694-1700. Epub 2020 Sep 3.

Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.

Coronavirus disease 2019 (COVID-19) in humans is often a clinically mild illness, but some individuals develop severe pneumonia, respiratory failure and death. Studies of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in hamsters and nonhuman primates have generally reported mild clinical disease, and preclinical SARS-CoV-2 vaccine studies have demonstrated reduction of viral replication in the upper and lower respiratory tracts in nonhuman primates. Here we show that high-dose intranasal SARS-CoV-2 infection in hamsters results in severe clinical disease, including high levels of virus replication in tissues, extensive pneumonia, weight loss and mortality in a subset of animals. A single immunization with an adenovirus serotype 26 vector-based vaccine expressing a stabilized SARS-CoV-2 spike protein elicited binding and neutralizing antibody responses and protected against SARS-CoV-2-induced weight loss, pneumonia and mortality. These data demonstrate vaccine protection against SARS-CoV-2 clinical disease. This model should prove useful for preclinical studies of SARS-CoV-2 vaccines, therapeutics and pathogenesis.
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http://dx.doi.org/10.1038/s41591-020-1070-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7671939PMC
November 2020

Single-shot Ad26 vaccine protects against SARS-CoV-2 in rhesus macaques.

Nature 2020 10 30;586(7830):583-588. Epub 2020 Jul 30.

Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.

A safe and effective vaccine for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may be required to end the coronavirus disease 2019 (COVID-19) pandemic. For global deployment and pandemic control, a vaccine that requires only a single immunization would be optimal. Here we show the immunogenicity and protective efficacy of a single dose of adenovirus serotype 26 (Ad26) vector-based vaccines expressing the SARS-CoV-2 spike (S) protein in non-human primates. Fifty-two rhesus macaques (Macaca mulatta) were immunized with Ad26 vectors that encoded S variants or sham control, and then challenged with SARS-CoV-2 by the intranasal and intratracheal routes. The optimal Ad26 vaccine induced robust neutralizing antibody responses and provided complete or near-complete protection in bronchoalveolar lavage and nasal swabs after SARS-CoV-2 challenge. Titres of vaccine-elicited neutralizing antibodies correlated with protective efficacy, suggesting an immune correlate of protection. These data demonstrate robust single-shot vaccine protection against SARS-CoV-2 in non-human primates. The optimal Ad26 vector-based vaccine for SARS-CoV-2, termed Ad26.COV2.S, is currently being evaluated in clinical trials.
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http://dx.doi.org/10.1038/s41586-020-2607-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581548PMC
October 2020

SARS-CoV-2 infection protects against rechallenge in rhesus macaques.

Science 2020 08 20;369(6505):812-817. Epub 2020 May 20.

Janssen Vaccines & Prevention BV, Leiden, Netherlands.

An understanding of protective immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical for vaccine and public health strategies aimed at ending the global coronavirus disease 2019 (COVID-19) pandemic. A key unanswered question is whether infection with SARS-CoV-2 results in protective immunity against reexposure. We developed a rhesus macaque model of SARS-CoV-2 infection and observed that macaques had high viral loads in the upper and lower respiratory tract, humoral and cellular immune responses, and pathologic evidence of viral pneumonia. After the initial viral clearance, animals were rechallenged with SARS-CoV-2 and showed 5 log reductions in median viral loads in bronchoalveolar lavage and nasal mucosa compared with after the primary infection. Anamnestic immune responses after rechallenge suggested that protection was mediated by immunologic control. These data show that SARS-CoV-2 infection induced protective immunity against reexposure in nonhuman primates.
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http://dx.doi.org/10.1126/science.abc4776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7243369PMC
August 2020

DNA vaccine protection against SARS-CoV-2 in rhesus macaques.

Science 2020 08 20;369(6505):806-811. Epub 2020 May 20.

Bioqual, Rockville, MD 20852, USA.

The global coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has made the development of a vaccine a top biomedical priority. In this study, we developed a series of DNA vaccine candidates expressing different forms of the SARS-CoV-2 spike (S) protein and evaluated them in 35 rhesus macaques. Vaccinated animals developed humoral and cellular immune responses, including neutralizing antibody titers at levels comparable to those found in convalescent humans and macaques infected with SARS-CoV-2. After vaccination, all animals were challenged with SARS-CoV-2, and the vaccine encoding the full-length S protein resulted in >3.1 and >3.7 log reductions in median viral loads in bronchoalveolar lavage and nasal mucosa, respectively, as compared with viral loads in sham controls. Vaccine-elicited neutralizing antibody titers correlated with protective efficacy, suggesting an immune correlate of protection. These data demonstrate vaccine protection against SARS-CoV-2 in nonhuman primates.
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http://dx.doi.org/10.1126/science.abc6284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7243363PMC
August 2020

Differential Regulation of T-cell Immunity and Tolerance by Stromal Laminin Expressed in the Lymph Node.

Transplantation 2019 10;103(10):2075-2089

Department of Surgery, University of Maryland School of Medicine, Baltimore, MD.

Background: Stromal laminins α4 and α5 are differentially regulated in transplant tolerance and immunity, respectively, resulting in altered T-cell trafficking. We hypothesized that laminins directly regulated T-cell activation and polarization.

Methods: Human and mouse CD4 T cells were activated in Th1, Th2, Th17, or regulatory T cell (Treg) environments with/without laminin α4 and/or α5. Laminin α5 receptors were blocked with anti-α6 integrin or anti-α-dystroglycan (αDG) monoclonal antibodies, and T-cell polarization was determined. T-cell receptor transgenic TEa CD4 cells that recognized donor alloantigen were transferred into C57BL/6 mice that received alloantigen or cardiac allografts. Laminin receptors were blocked, and TEa T-cell migration and differentiation were assessed. Laminin expression was measured in several models of immunity and tolerance.

Results: In diverse models, laminins α4 and α5 were differentially regulated. Immunity was associated with decreased laminin α4:α5 ratio, while tolerance was associated with an increased ratio. Laminin α4 inhibited CD4+ T-cell proliferation and Th1, Th2, and Th17 polarization but favored Treg induction. Laminin α5 favored T-cell activation and Th1, Th2, and Th17 polarization and inhibited Treg. Laminin α5 was recognized by T cell integrin α6 and is important for activation and inhibition of Treg. Laminin α5 was also recognized by T cell α-DG and required for Th17 differentiation. Anti-α6 integrin or anti-DG prolonged allograft survival.

Conclusions: Laminins α4 and α5 are coinhibitory and costimulatory ligands for human and mouse CD4 T cells, respectively. Laminins and their receptors modulate immune responses by acting as one of the molecular switches for immunity or suppression.
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http://dx.doi.org/10.1097/TP.0000000000002774DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6768765PMC
October 2019

Engineering release kinetics with polyelectrolyte multilayers to modulate TLR signaling and promote immune tolerance.

Biomater Sci 2019 Feb;7(3):798-808

Fischell Department of Bioengineering, A. James Clark Hall, Room 5110, 8278 Paint Branch Drive, College Park, Maryland 20742, USA.

Autoimmune disorders, such as multiple sclerosis and type 1 diabetes, occur when immune cells fail to recognize "self" molecules. Recently, studies have revealed aberrant inflammatory signaling through pathogen sensing pathways, such as toll-like receptors (TLRs), during autoimmune disease. Therapeutic inhibition of these pathways might attenuate disease development, skewing disease-causing inflammatory cells towards cell types that promote tolerance. Delivering antagonistic ligands to a TLR upstream of an inflammatory signaling cascade, TLR9, has demonstrated exciting potential in a mouse model of MS; however, strategies that enable sustained delivery could reduce the need for repeated administration or enhance therapeutic efficacy. We hypothesized that GpG - an oligonucleotide TLR9 antagonist - which is inherently anionic, could be self-assembled into polyelectrolyte multilayers (PEMs) with a cationic, degradable poly(β-amino ester) (Poly1). We hypothesized that degradable Poly1/GpG PEMs could promote sustained release of GpG and modulate inflammatory immune cell functions. Here we demonstrate layer-by-layer assembly of degradable PEMs, as well as subsequent degradation and release of GpG. Following assembly and release, GpG maintains the ability to reduce dendritic cell activation and inflammatory cytokine secretion, restrain TLR9 signaling, and polarize myelin specific T cells towards regulatory phenotypes and functions in primarily immune cells. These results indicate that degradable PEMs may be able to promote tolerogenic immune function in the context of autoimmunity.
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http://dx.doi.org/10.1039/c8bm01572dDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391195PMC
February 2019

Engineering Immunological Tolerance Using Quantum Dots to Tune the Density of Self-Antigen Display.

Adv Funct Mater 2017 Jun 3;27(22). Epub 2017 Apr 3.

Fischell Department of Bioengineering, University of Maryland, 8228 Paint Branch Drive, College Park, MD 20742, USA.

Treatments for autoimmunity - diseases where the immune system mistakenly attacks self-molecules - are not curative and leave patients immunocompromised. New studies aimed at more specific treatments reveal development of inflammation or tolerance is influenced by the form self-antigens are presented. Using a mouse model of multiple sclerosis (MS), we show for the first time that quantum dots (QDs) can be used to generate immunological tolerance by controlling the density of self-antigen on QDs. These assemblies display dense arrangements of myelin self-peptide associated with disease in MS, are uniform in size (<20 nm), and allow direct visualization in immune tissues. Peptide-QDs rapidly concentrate in draining lymph nodes, co-localizing with macrophages expressing scavenger receptors involved in tolerance. Treatment with peptide-QDs reduces disease incidence 10-fold. Strikingly, the degree of tolerance - and the underlying expansion of regulatory T cells - correlates with the density of myelin molecules presented on QDs. A key discovery is that higher numbers of tolerogenic particles displaying lower levels of self-peptide are more effective for inducing tolerance than fewer particles each displaying higher densities of peptide. QDs conjugated with self-antigens could serve as a new platform to induce tolerance, while visualizing QD therapeutics in tolerogenic tissue domains.
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http://dx.doi.org/10.1002/adfm.201700290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5828250PMC
June 2017

Advanced manufacturing of microdisk vaccines for uniform control of material properties and immune cell function.

Biomater Sci 2017 Dec;6(1):115-124

Fischell Department of Bioengineering, University of Maryland, 2212 Jeong H. Kim Engineering Building, 8228 Paint Branch Drive, College Park, Maryland 20742, USA.

The continued challenges facing vaccines in infectious disease and cancer highlight a need for better control over the features of vaccines and the responses they generate. Biomaterials offer unique advantages to achieve this goal through features such as controlled release and co-delivery of antigens and adjuvants. However, many synthesis strategies lead to particles with heterogeneity in diameter, shape, loading level, or other properties. In contrast, advanced manufacturing techniques allow precision control of material properties at the micro- and nano-scale. These capabilities in vaccines and immunotherapies could allow more rational design to speed efficient design and clinical translation. Here we employed soft lithography to generate polymer microdisk vaccines with uniform structures and tunable compositions of vaccine antigens and toll like receptor agonists (TLRas) that serve as molecular adjuvants. Compared to conventional PLGA particles formed by emulsion, microdisks provided a dramatic improvement in the consistency of properties such as diameter. During culture with primary dendritic cells (DCs) from mice, microdisks were internalized by the cells without toxicity, while promoting co-delivery of antigen and TLRa to the same cell. Analysis of DC surface activation markers by flow cytometry revealed microdisk vaccines activated dendritic cells in a manner that depended on the level of TLRa, while antigen processing and presentation depended on the amount of antigen in the microdisks. Together, this work demonstrates the use of advanced manufacturing techniques to produce uniform vaccines that direct DC function depending on the composition in the disks.
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http://dx.doi.org/10.1039/c7bm00520bDOI Listing
December 2017

Controlled Release of Second Generation mTOR Inhibitors to Restrain Inflammation in Primary Immune Cells.

AAPS J 2017 07 8;19(4):1175-1185. Epub 2017 May 8.

Fischell Department of Bioengineering, University of Maryland, 2212 Jeong H. Kim Engineering Building, 8228 Paint Branch Drive, College Park, Maryland, 20742, USA.

Autoimmune disease occurs when the immune system incorrectly targets the body's own tissue. Inflammatory CD4 T cell phenotypes, such as T1 and T17, are key drivers of this attack. Recent studies demonstrate treatment with rapamycin-a key inhibitor of the mTOR pathway-can skew T cell development, moving T cell responses away from inflammatory phenotypes and toward regulatory T cells (T). T are important in inducing and maintaining tolerance to self-antigens, creating new potential to treat autoimmune diseases more effectively and specifically. Next generation analogs of rapamycin, such as everolimus and temsirolimus, confer increased potency with reduced toxicity, but are understudied in the context of autoimmunity. Further, these drugs are still broadly-acting and require frequent treatment due to short half-lives. Thus, there is strong interest in harnessing the unique properties of biomaterials-controlled drug release and targeting, for example, to improve autoimmune therapies. Using second generation mTOR inhibitors and rapamycin, we prepared sets of degradable polymer particles from poly(lactide-co-glycolide). We then used these materials to assess physicochemical properties and the ability to control autoimmune inflammation in a primary cell co-culture model. Treatment with particle formulations resulted in significant dose-dependent decreases in dendritic cell activation, T cell proliferation, inflammatory cytokines, and frequencies of inflammatory T1 phenotypes. Considering the current limitations of rapamycin, and the potential of next-generation analogs, this work provides a screening platform for biomaterials and sets the stage for in vivo evaluation, where delivery kinetics, stability, and targeting could improve autoimmune therapies through biomaterial-enabled delivery.
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http://dx.doi.org/10.1208/s12248-017-0089-1DOI Listing
July 2017

Engineering self-assembled materials to study and direct immune function.

Adv Drug Deliv Rev 2017 05 6;114:60-78. Epub 2017 Apr 6.

Fischell Department of Bioengineering, University of Maryland, 8228 Paint Branch Drive, College Park, MD 20742, USA; Department of Microbiology and Immunology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA; Marlene and Stewart Greenebaum Cancer Center, 22 S. Greene St., Baltimore, MD 21201, USA; United States Department of Veterans Affairs, 10 North Greene Street, Baltimore, MD 21201, USA. Electronic address:

The immune system is an awe-inspiring control structure that maintains a delicate and constantly changing balance between pro-immune functions that fight infection and cancer, regulatory or suppressive functions involved in immune tolerance, and homeostatic resting states. These activities are determined by integrating signals in space and time; thus, improving control over the densities, combinations, and durations with which immune signals are delivered is a central goal to better combat infectious disease, cancer, and autoimmunity. Self-assembly presents a unique opportunity to synthesize materials with well-defined compositions and controlled physical arrangement of molecular building blocks. This review highlights strategies exploiting these capabilities to improve the understanding of how precisely-displayed cues interact with immune cells and tissues. We present work centered on fundamental properties that regulate the nature and magnitude of immune response, highlight pre-clinical and clinical applications of self-assembled technologies in vaccines, cancer, and autoimmunity, and describe some of the key manufacturing and regulatory hurdles facing these areas.
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http://dx.doi.org/10.1016/j.addr.2017.03.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6262758PMC
May 2017

Expansion of Melanoma-Specific T Cells Using Microneedle Arrays Coated with Immune-Polyelectrolyte Multilayers.

ACS Biomater Sci Eng 2017 Feb 1;3(2):195-205. Epub 2016 Sep 1.

Fischell Department of Bioengineering, University of Maryland, College Park, 8228 Paint Branch Drive, 2212 Jeong H. Kim Building, College Park, Maryland 20742, United States; Department of Microbiology and Immunology, University of Maryland Medical School, 685 West Baltimore Street, HSF-I Suite 380, Baltimore, Maryland 21201, United States; Marlene and Stewart Greenebaum Cancer Center, 22 S. Greene Street, Suite N9E17, Baltimore, Maryland 21201, United States.

Microneedles (MNs) are micron-scale polymeric or metallic structures that offer distinct advantages for vaccines by efficiently targeting skin-resident immune cells, eliminating injection-associated pain, and improving patient compliance. These advantages, along with recent studies showing therapeutic benefits achieved using traditional intradermal injections in human cancer patients, suggest MN delivery might enhance cancer vaccines and immunotherapies. We recently developed a new class of polyelectrolyte multilayers based on the self-assembly of model peptide antigens and molecular toll-like receptor agonists (TLRa) into ultrathin, conformal coatings. Here, we reasoned that these immune polyelectrolyte multilayers (iPEMs) might be a useful platform for assembling cancer vaccine components on MN arrays for intradermal delivery from these substrates. Using conserved human melanoma antigens and a potent TLRa vaccine adjuvant, CpG, we show that iPEMs can be assembled on MNs in an automated fashion. These films, prepared with up to 128 layers, are approximately 200 nm thick but provide cancer vaccine cargo loading >225 μg/cm. In cell culture, iPEM cargo released from MNs is internalized by primary dendritic cells, promotes activation of these cells, and expands T cells during coculture. In mice, application of iPEM-coated MNs results in the codelivery of tumor antigen and CpG through the skin, expanding tumor-specific T cells during initial MN applications and resulting in larger memory recall responses during a subsequent booster MN application. This study support MNs coated with PEMs built from tumor vaccine components as a well-defined, modular system for generating tumor-specific immune responses, enabling new approaches that can be explored in combination with checkpoint blockade or other combination cancer therapies.
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http://dx.doi.org/10.1021/acsbiomaterials.6b00414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5338335PMC
February 2017

Low-dose controlled release of mTOR inhibitors maintains T cell plasticity and promotes central memory T cells.

J Control Release 2017 Oct 28;263:151-161. Epub 2017 Feb 28.

Fischell Department of Bioengineering, University of Maryland, College Park, MD, United States; Department of Microbiology and Immunology, University of Maryland Medical School, Baltimore, MD, United States; Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD, United States; United States Department of Veterans Affairs, Baltimore, MD, United States. Electronic address:

An important goal for improving vaccine and immunotherapy technologies is the ability to provide further control over the specific phenotypes of T cells arising from these agents. Along these lines, frequent administration of rapamycin (Rapa), a small molecule inhibitor of the mammalian target of rapamycin (mTOR), exhibits a striking ability to polarize T cells toward central memory phenotypes (T), or to suppress immune function, depending on the concentrations and other signals present during administration. T exhibit greater plasticity and proliferative capacity than effector memory T cells (T) and, therefore, polarizing vaccine-induced T cells toward T is an intriguing strategy to enhance T cell expansion and function against pathogens or tumors. Here we combined biodegradable microparticles encapsulating Rapa (Rapa MPs) with vaccines composed of soluble peptide antigens and molecular adjuvants to test if this approach allows polarization of differentiating T cells toward T. We show Rapa MPs modulate DC function, enhancing secretion of inflammatory cytokines at very low doses, and suppressing function at high doses. While Rapa MP treatment reduced - but did not stop - T cell proliferation in both CD4 and CD8 transgenic T cell co-cultures, the expanding CD8 T cells differentiated to higher frequencies of T at low doses of MP Rapa MPs. Lastly, we show in mice that local delivery of Rapa MPs to lymph nodes during vaccination either suppresses or enhances T cell function in response to melanoma antigens, depending on the dose of drug in the depots. In particular, at low Rapa MP doses, vaccines increased antigen-specific T, resulting in enhanced T cell expansion measured during subsequent booster injections over at least 100days.
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http://dx.doi.org/10.1016/j.jconrel.2017.02.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5573661PMC
October 2017

Polyplexes assembled from self-peptides and regulatory nucleic acids blunt toll-like receptor signaling to combat autoimmunity.

Biomaterials 2017 02 30;118:51-62. Epub 2016 Nov 30.

Fischell Department of Bioengineering, University of Maryland, 8228 Paint Branch Drive, College Park, MD 20742, USA; Department of Microbiology and Immunology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA; Marlene and Stewart Greenebaum Cancer Center, 22 S. Greene Street, Baltimore, MD 21201, USA; United States Department of Veterans Affairs, 10 North Greene Street, Baltimore, Maryland 21201, USA. Electronic address:

Autoimmune diseases occur when the immune system incorrectly recognizes self-molecules as foreign; in the case of multiple sclerosis (MS), myelin is attacked. Intriguingly, new studies reveal toll-like receptors (TLRs), pathways usually involved in generating immune responses against pathogens, play a significant role in driving autoimmune disease in both humans and animal models. We reasoned polyplexes formed from myelin self-antigen and regulatory TLR antagonists might limit TLR signaling during differentiation of myelin-specific T cells, inducing tolerance by biasing T cells away from inflammatory phenotypes. Complexes were formed by modifying myelin peptide with cationic amino acids to create peptides able to condense the anionic nucleic-acid based TLR antagonist. These immunological polyplexes eliminate synthetic polymers commonly used to condense polyplexes and do not rely on gene expression; however, the complexes mimic key features of traditional polyplexes such as tunable loading and co-delivery. Using these materials and classic polyplex analysis techniques, we demonstrate condensation of both immune signals, protection from enzymatic degradation, and tunable physicochemical properties. We show polyplexes reduce TLR signaling, and in primary dendritic cell and T cell co-culture, reduce myelin-driven inflammation. During mouse models of MS, these tolerogenic polyplexes improve the progression, severity, and incidence of disease.
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http://dx.doi.org/10.1016/j.biomaterials.2016.11.052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5189983PMC
February 2017

Reprogramming the Local Lymph Node Microenvironment Promotes Tolerance that Is Systemic and Antigen Specific.

Cell Rep 2016 09;16(11):2940-2952

Fischell Department of Bioengineering, University of Maryland, 8228 Paint Branch Drive, College Park, MD 20742, USA; Department of Microbiology and Immunology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA; Marlene and Stewart Greenebaum Cancer Center, 22 South Greene Street, Baltimore, MD 21201, USA; United States Department of Veteran Affairs, 10 North Greene Street, Baltimore, MD 21201, USA. Electronic address:

Many experimental therapies for autoimmune diseases, such as multiple sclerosis (MS), aim to bias T cells toward tolerogenic phenotypes without broad suppression. However, the link between local signal integration in lymph nodes (LNs) and the specificity of systemic tolerance is not well understood. We used intra-LN injection of polymer particles to study tolerance as a function of signals in the LN microenvironment. In a mouse MS model, intra-LN introduction of encapsulated myelin self-antigen and a regulatory signal (rapamycin) permanently reversed paralysis after one treatment during peak disease. Therapeutic effects were myelin specific, required antigen encapsulation, and were less potent without rapamycin. This efficacy was accompanied by local LN reorganization, reduced inflammation, systemic expansion of regulatory T cells, and reduced T cell infiltration to the CNS. Our findings suggest that local control over signaling in distinct LNs can promote cell types and functions that drive tolerance that is systemic but antigen specific.
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http://dx.doi.org/10.1016/j.celrep.2016.08.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5024722PMC
September 2016

Design of Polyelectrolyte Multilayers to Promote Immunological Tolerance.

ACS Nano 2016 Oct 7;10(10):9334-9345. Epub 2016 Sep 7.

Fischell Department of Bioengineering, University of Maryland , 8228 Paint Branch Drive, College Park, Maryland 20742, United States.

Recent studies demonstrate that excess signaling through inflammatory pathways (e.g., toll-like receptors, TLRs) contributes to the pathogenesis of human autoimmune diseases, including lupus, diabetes, and multiple sclerosis (MS). We hypothesized that codelivery of a regulatory ligand of TLR9, GpG oligonucleotide, along with myelin-the "self" molecule attacked in MS-might restrain the pro-inflammatory signaling typically present during myelin presentation, redirecting T cell differentiation away from inflammatory populations and toward tolerogenic phenotypes such as regulatory T cells. Here we show that myelin peptide and GpG can be used as modular building blocks for co-assembly into immune polyelectrolyte multilayers (iPEMs). These nanostructured capsules mimic attractive features of biomaterials, including tunable cargo loading and codelivery, but eliminate all carriers and synthetic polymers, components that often exhibit intrinsic inflammatory properties that could exacerbate autoimmune disease. In vitro, iPEMs assembled from myelin and GpG oligonucleotide, but not myelin and a control oligonucleotide, restrain TLR9 signaling, reduce dendritic cell activation, and polarize myelin-specific T cells toward tolerogenic phenotype and function. In mice, iPEMs blunt myelin-triggered inflammatory responses, expand regulatory T cells, and eliminate disease in a common model of MS. Finally, in samples from human MS patients, iPEMs bias myelin-triggered immune cell function toward tolerance. This work represents a unique opportunity to use PEMs to regulate immune function and promote tolerance, supporting iPEMs as a carrier-free platform to alter TLR function to reduce inflammation and combat autoimmunity.
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http://dx.doi.org/10.1021/acsnano.6b04001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6291352PMC
October 2016

Targeted Programming of the Lymph Node Environment Causes Evolution of Local and Systemic Immunity.

Cell Mol Bioeng 2016 27;9:418-432. Epub 2016 Jun 27.

Fischell Department of Bioengineering, University of Maryland, 8228 Paint Branch Drive, College Park, MD 20742 USA.

Biomaterial vaccines offer cargo protection, targeting, and co-delivery of signals to immune organs such as lymph nodes (LNs), tissues that coordinate adaptive immunity. Understanding how individual vaccine components impact immune response has been difficult owing to the systemic nature of delivery. Direct intra-lymph node () injection offers a unique opportunity to dissect how the doses, kinetics, and combinations of signals reaching LNs influence the LN environment. Here, injection was used as a tool to study the local and systemic responses to vaccines comprised of soluble antigen and degradable polymer particles encapsulating toll-like receptor agonists as adjuvants. Microparticle vaccines increased antigen presenting cells and lymphocytes in LNs, enhancing activation of these cells. Enumeration of antigen-specific CD8 T cells in blood revealed expansion over 7 days, followed by a contraction period over 1 month as memory developed. Extending this strategy to conserved mouse and human tumor antigens resulted in tumor antigen-specific primary and recall responses by CD8 T cells. During challenge with an aggressive metastatic melanoma model, . delivery of depots slowed tumor growth more than a potent human vaccine adjuvant, demonstrating local treatment of a target immunological site can promote responses that are potent, systemic, and antigen-specific.
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http://dx.doi.org/10.1007/s12195-016-0455-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4978773PMC
June 2016
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