Advanced human mucosal tissue models are needed to improve preclinical testing of vaccines

ABSTRACT Definition of the key parameters mediating effective antibody blocking of HIV-1 acquisition within mucosal tissue may prove critical to effective vaccine development and the prophylactic use of monoclonal antibodies. Although direct antibody-mediated neutralization is highly effective against cell-free virus, antibodies targeting different sites of envelope vulnerability may display differential activity against mucosal infection. Nonneutralizing antibodies (nnAbs) may also impact mucosal transmission events through Fc-gamma receptor (FcγR)-mediated inhibition. In this study, a panel of broadly neutralizing antibodies (bnAbs) and nnAbs, including those associated with protection in the RV144 vaccine trial, were screened for the ability to block HIV-1 acquisition and replication across a range of cellular and mucosal tissue models. Neutralization potency, as determined by the TZM-bl infection assay, did not fully predict activity in mucosal tissue. CD4-binding site (CD4bs)-specific bnAbs, in particular VRC01, were consistent in blocking HIV-1 infection across all cellular and tissue models. Membrane-proximal external region (MPER) (2F5) and outer domain glycan (2G12) bnAbs were also efficient in preventing infection of mucosal tissues, while the protective efficacy of bnAbs targeting V1-V2 glycans (PG9 and PG16) was more variable. In contrast, nnAbs alone and in combinations, while active in a range of cellular assays, were poorly protective against HIV-1 infection of mucosal tissues. These data suggest that tissue resident effector cell numbers and low FcγR expression may limit the potential of nnAbs to prevent establishment of the initial foci of infection. The solid protection provided by specific bnAbs clearly demonstrates their superior potential over that of nonneutralizing antibodies for preventing HIV-1 infection at the mucosal portals of infection. IMPORTANCE Key parameters mediating effective antibody blocking of HIV-1 acquisition within mucosal tissue have not been defined. While bnAbs are highly effective against cell-free virus, they are not induced by current vaccine candidates. However, nnAbs, readily induced by vaccines, can trigger antibody-dependent cellular effector functions, through engagement of their Fc-gamma receptors. Fc-mediated antiviral activity has been implicated as a secondary correlate of decreased HIV-1 risk in the RV144 vaccine efficacy trial, suggesting that protection might be mediated in the absence of classical neutralization. To aid vaccine design and selection of antibodies for use in passive protection strategies, we assessed a range of bnAbs and nnAbs for their potential to block ex vivo challenge of mucosal tissues. Our data clearly indicate the superior efficacy of neutralizing antibodies in preventing mucosal acquisition of infection. These results underscore the importance of maintaining the central focus of HIV-1 vaccine research on the induction of potently neutralizing antibodies.

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Incoming Flow Lamination Increases the Efficiency of Aerosolized Medication Delivery to 3D Oral Mucosal Tissue Models

International Journal of Dentistry and Oral Health ◽

10.16966/2378-7090.372 ◽

2021 ◽

Vol 7 (5) ◽

Author(s):

Haroutunian GG ◽

Tsagikian A ◽

Fedorova E ◽

Zheng H ◽

Gusella GL ◽

...

Keyword(s):

Oral Health ◽

Side Effects ◽

Turbulent Flow ◽

Complex Interaction ◽

Incoming Flow ◽

Mucosal Tissue ◽

Negative Effects ◽

Medication Delivery ◽

Oropharyngeal Cavity ◽

Tissue Models

Background: Inhalable medication devices on the market deliver aerosolized drugs in a turbulent flow, which in complex interaction with oropharyngeal geometry causes the major portion of the drug to deposit locally, while creating significant obstacles for reaching the lower lungs. The unintended deposition of aerosolized medications in the oropharynx is known to have negative effects on oral health. The emergence of numerous new aerosolized medications on the market is very likely to add significantly to the list of side effects. We hypothesized that lamination of the outflow by sequentially subdividing the aerosol flow within the spacer into smaller sub-flows using internal septi of different lengths will improve the delivery of the aerosol to distant targets while reducing its deposition in anterior aspects of the airways, especially in oropharyngeal cavity.

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Denture-associated biofilm infection in three-dimensional oral mucosal tissue models

Journal of Medical Microbiology ◽

10.1099/jmm.0.000677 ◽

2018 ◽

Vol 67 (3) ◽

pp. 364-375 ◽

Cited By ~ 7

Author(s):

Daniel J. Morse ◽

Melanie J. Wilson ◽

Xiaoqing Wei ◽

Michael A. O. Lewis ◽

David J. Bradshaw ◽

...

Keyword(s):

Three Dimensional ◽

Mucosal Tissue ◽

Tissue Models ◽

Biofilm Infection

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The Pediatric Brain Tumor Preclinical Testing Program: an update on the current status

Klinische Pädiatrie ◽

10.1055/s-0032-1320178 ◽

2012 ◽

Vol 224 (06) ◽

Author(s):

T Milde ◽

M Zucknick ◽

M Kool ◽

A Korshunov ◽

H Witt ◽

...

Keyword(s):

Brain Tumor ◽

Pediatric Brain Tumor ◽

Current Status ◽

Preclinical Testing ◽

Testing Program ◽

Pediatric Brain

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Faculty Opinions recommendation of Initial testing (stage 1) of the PARP inhibitor BMN 673 by the pediatric preclinical testing program: PALB2 mutation predicts exceptional in vivo response to BMN 673.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718892387.793522092 ◽

2016 ◽

Author(s):

Stephen Lessnick

Keyword(s):

Parp Inhibitor ◽

Preclinical Testing ◽

Testing Program ◽

Initial Testing ◽

Testing Stage ◽

Palb2 Mutation ◽

Stage 1

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Clinical Drug Development for the Treatment of Pulmonary Arterial Hypertension: Collaboration With the Pharmaceutical Industry and Regulatory Agencies

Advances in Pulmonary Hypertension ◽

10.21693/1933-088x-9.4.214 ◽

2010 ◽

Vol 9 (4) ◽

pp. 214-219

Author(s):

Robyn J. Barst

Keyword(s):

Clinical Trials ◽

Pulmonary Arterial Hypertension ◽

Drug Development ◽

Phase 1 ◽

Preclinical Studies ◽

Phase 2 ◽

Phase 3 ◽

Preclinical Testing ◽

New Drug ◽

Pulmonary Arterial

Drug development is the entire process of introducing a new drug to the market. It involves drug discovery, screening, preclinical testing, an Investigational New Drug (IND) application in the US or a Clinical Trial Application (CTA) in the EU, phase 1–3 clinical trials, a New Drug Application (NDA), Food and Drug Administration (FDA) review and approval, and postapproval studies required for continuing safety evaluation. Preclinical testing assesses safety and biologic activity, phase 1 determines safety and dosage, phase 2 evaluates efficacy and side effects, and phase 3 confirms efficacy and monitors adverse effects in a larger number of patients. Postapproval studies provide additional postmarketing data. On average, it takes 15 years from preclinical studies to regulatory approval by the FDA: about 3.5–6.5 years for preclinical, 1–1.5 years for phase 1, 2 years for phase 2, 3–3.5 years for phase 3, and 1.5–2.5 years for filing the NDA and completing the FDA review process. Of approximately 5000 compounds evaluated in preclinical studies, about 5 compounds enter clinical trials, and 1 compound is approved (Tufts Center for the Study of Drug Development, 2011). Most drug development programs include approximately 35–40 phase 1 studies, 15 phase 2 studies, and 3–5 pivotal trials with more than 5000 patients enrolled. Thus, to produce safe and effective drugs in a regulated environment is a highly complex process. Against this backdrop, what is the best way to develop drugs for pulmonary arterial hypertension (PAH), an orphan disease often rapidly fatal within several years of diagnosis and in which spontaneous regression does not occur?

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