Publications by authors named "Nita Patel"

78 Publications

Collaboration between the Fab and Fc contribute to maximal protection against SARS-CoV-2 following NVX-CoV2373 subunit vaccine with Matrix-M™ vaccination.

Res Sq 2021 Feb 15. Epub 2021 Feb 15.

Recently approved vaccines have already shown remarkable protection in limiting SARS-CoV-2 associated disease. However, immunologic mechanism(s) of protection, as well as how boosting alters immunity to wildtype and newly emerging strains, remain incompletely understood. Here we deeply profiled the humoral immune response in a cohort of non-human primates immunized with a stable recombinant full-length SARS-CoV-2 spike (S) glycoprotein (NVX-CoV2373) at two dose levels, administered as a single or two-dose regimen with a saponin-based adjuvant Matrix-M™. While antigen dose had some effect on Fc-effector profiles, both antigen dose and boosting significantly altered overall titers, neutralization and Fc-effector profiles, driving unique vaccine-induced antibody fingerprints. Combined differences in antibody effector functions and neutralization were strongly associated with distinct levels of protection in the upper and lower respiratory tract, pointing to the presence of combined, but distinct, compartment-specific neutralization and Fc-mechanisms as key determinants of protective immunity against infection. Moreover, NVX-CoV2373 elicited antibodies functionally target emerging SARS-CoV-2 variants, collectively pointing to the critical collaborative role for Fab and Fc in driving maximal protection against SARS-CoV-2. Collectively, the data presented here suggest that a single dose may prevent disease, but that two doses may be essential to block further transmission of SARS-CoV-2 and emerging variants.
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http://dx.doi.org/10.21203/rs.3.rs-200342/v1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7899467PMC
February 2021

Collaboration between the Fab and Fc contribute to maximal protection against SARS-CoV-2 in nonhuman primates following NVX-CoV2373 subunit vaccine with Matrix-M™ vaccination.

bioRxiv 2021 Feb 5. Epub 2021 Feb 5.

Recently approved vaccines have already shown remarkable protection in limiting SARS-CoV-2 associated disease. However, immunologic mechanism(s) of protection, as well as how boosting alters immunity to wildtype and newly emerging strains, remain incompletely understood. Here we deeply profiled the humoral immune response in a cohort of non-human primates immunized with a stable recombinant full-length SARS-CoV-2 spike (S) glycoprotein (NVX-CoV2373) at two dose levels, administered as a single or two-dose regimen with a saponin-based adjuvant Matrix-M™. While antigen dose had some effect on Fc-effector profiles, both antigen dose and boosting significantly altered overall titers, neutralization and Fc-effector profiles, driving unique vaccine-induced antibody fingerprints. Combined differences in antibody effector functions and neutralization were strongly associated with distinct levels of protection in the upper and lower respiratory tract, pointing to the presence of combined, but distinct, compartment-specific neutralization and Fc-mechanisms as key determinants of protective immunity against infection. Moreover, NVX-CoV2373 elicited antibodies functionally target emerging SARS-CoV-2 variants, collectively pointing to the critical collaborative role for Fab and Fc in driving maximal protection against SARS-CoV-2. Collectively, the data presented here suggest that a single dose may prevent disease, but that two doses may be essential to block further transmission of SARS-CoV-2 and emerging variants.

Highlights: NVX-CoV2373 subunit vaccine elicits receptor blocking, virus neutralizing antibodies, and Fc-effector functional antibodies.The vaccine protects against respiratory tract infection and virus shedding in non-human primates (NHPs).Both neutralizing and Fc-effector functions contribute to protection, potentially through different mechanisms in the upper and lower respiratory tract.Both macaque and human vaccine-induced antibodies exhibit altered Fc-receptor binding to emerging mutants.
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http://dx.doi.org/10.1101/2021.02.05.429759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872351PMC
February 2021

SARS-CoV-2 spike glycoprotein vaccine candidate NVX-CoV2373 immunogenicity in baboons and protection in mice.

Nat Commun 2021 01 14;12(1):372. Epub 2021 Jan 14.

Novavax, Inc., 21 Firstfield Road, Gaithersburg, MD, 20878, USA.

The COVID-19 pandemic continues to spread throughout the world with an urgent need for a safe and protective vaccine to effectuate herd protection and control the spread of SARS-CoV-2. Here, we report the development of a SARS-CoV-2 subunit vaccine (NVX-CoV2373) from the full-length spike (S) protein that is stable in the prefusion conformation. NVX-CoV2373 S form 27.2-nm nanoparticles that are thermostable and bind with high affinity to the human angiotensin-converting enzyme 2 (hACE2) receptor. In mice, low-dose NVX-CoV2373 with saponin-based Matrix-M adjuvant elicit high titer anti-S IgG that blocks hACE2 receptor binding, neutralize virus, and protects against SARS-CoV-2 challenge with no evidence of vaccine-associated enhanced respiratory disease. NVX-CoV2373 also elicits multifunctional CD4 and CD8 T cells, CD4 follicular helper T cells (Tfh), and antigen-specific germinal center (GC) B cells in the spleen. In baboons, low-dose levels of NVX-CoV2373 with Matrix-M was also highly immunogenic and elicited high titer anti-S antibodies and functional antibodies that block S-protein binding to hACE2 and neutralize virus infection and antigen-specific T cells. These results support the ongoing phase 1/2 clinical evaluation of the safety and immunogenicity of NVX-CoV2373 with Matrix-M (NCT04368988).
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http://dx.doi.org/10.1038/s41467-020-20653-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7809486PMC
January 2021

Induction of Cross-reactive Hemagglutination Inhibiting Antibody and Polyfunctional CD4+ T-cell Responses by a Recombinant Matrix-M-Adjuvanted Hemagglutinin Nanoparticle Influenza Vaccine.

Clin Infect Dis 2020 Nov 4. Epub 2020 Nov 4.

Novavax, Inc., Gaithersburg, MD, USA.

Background: Recurrent reports of suboptimal influenza vaccine effectiveness have renewed calls to develop improved, broadly cross-protective influenza vaccines. Here, we evaluated the safety and immunogenicity of a novel, saponin (Matrix-M)-adjuvanted, recombinant hemagglutinin (HA) quadrivalent nanoparticle influenza vaccine (qNIV).

Methods: We conducted a randomized, observer-blind, comparator-controlled (trivalent high-dose inactivated influenza vaccine [IIV3-HD], or quadrivalent recombinant influenza vaccine [RIV4]), safety and immunogenicity trial of qNIV (in 5 different doses/formulations) in healthy adults aged ≥65 years. Vaccine immunogenicity was measured by hemagglutination-inhibition assays using reagents expressing wild-type HA sequences (wt-HAI) and cell-mediated immune (CMI) responses.

Results: A total of 1375 participants were randomized, immunized, and followed for safety and immunogenicity. Matrix-M-adjuvanted qNIV induced superior wt-HAI antibody responses against 5 of 6 homologous or drifted strains evaluated compared to unadjuvanted qNIV. Adjuvanted qNIV induced post-vaccination wt-HAI antibody responses at Day 28 that were: statistically higher than IIV3-HD against a panel of homologous or drifted A/H3N2 strains; similar to IIV3-HD against homologous A/H1N1 and B (Victoria) strains; and similar to RIV4 against all homologous and drifted strains evaluated. The qNIV formulation with 75 µg Matrix-M adjuvant induced substantially higher post-vaccination geometric mean fold-increases of influenza HA-specific polyfunctional CD4+ T-cells compared to IIV3-HD or RIV4. Overall, similar frequencies of solicited and unsolicited adverse events (AEs) were reported in all treatment groups.

Conclusions: qNIV with 75 µg Matrix-M adjuvant was well tolerated and induced robust antibody and cellular responses, notably against both homologous and drifted A/H3N2 viruses. Further investigation in a pivotal phase 3 trial is underway.
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http://dx.doi.org/10.1093/cid/ciaa1673DOI Listing
November 2020

NVX-CoV2373 vaccine protects cynomolgus macaque upper and lower airways against SARS-CoV-2 challenge.

Vaccine 2020 11 23;38(50):7892-7896. Epub 2020 Oct 23.

Novavax, Inc., 21 Firstfield Road, Gaithersburg, MD 20878, USA. Electronic address:

There is an urgent need for a safe and protective vaccine to control the global spread of SARS-CoV-2 and prevent COVID-19. Here, we report the immunogenicity and protective efficacy of a SARS-CoV-2 subunit vaccine (NVX-CoV2373) produced from the full-length SARS-CoV-2 spike (S) glycoprotein stabilized in the prefusion conformation. Cynomolgus macaques (Macaca fascicularis) immunized with NVX-CoV2373 and the saponin-based Matrix-M™ adjuvant induced anti-S antibody that was neutralizing and blocked binding to the human angiotensin-converting enzyme 2 (hACE2) receptor. Following intranasal and intratracheal challenge with SARS-CoV-2, immunized macaques were protected against upper and lower infection and pulmonary disease. These results support ongoing phase 1/2 clinical studies of the safety and immunogenicity of NVX-CoV2327 vaccine (NCT04368988).
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http://dx.doi.org/10.1016/j.vaccine.2020.10.064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7584426PMC
November 2020

Structural analysis of full-length SARS-CoV-2 spike protein from an advanced vaccine candidate.

Science 2020 11 20;370(6520):1089-1094. Epub 2020 Oct 20.

Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.

Vaccine efforts to combat the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is responsible for the current coronavirus disease 2019 (COVID-19) pandemic, are focused on SARS-CoV-2 spike glycoprotein, the primary target for neutralizing antibodies. We performed cryo-election microscopy and site-specific glycan analysis of one of the leading subunit vaccine candidates from Novavax, which is based on a full-length spike protein formulated in polysorbate 80 detergent. Our studies reveal a stable prefusion conformation of the spike immunogen with slight differences in the S1 subunit compared with published spike ectodomain structures. We also observed interactions between the spike trimers, allowing formation of higher-order spike complexes. This study confirms the structural integrity of the full-length spike protein immunogen and provides a basis for interpreting immune responses to this multivalent nanoparticle immunogen.
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http://dx.doi.org/10.1126/science.abe1502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857404PMC
November 2020

Flexible RSV Prefusogenic Fusion Glycoprotein Exposes Multiple Neutralizing Epitopes that May Collectively Contribute to Protective Immunity.

Vaccines (Basel) 2020 Oct 14;8(4). Epub 2020 Oct 14.

Novavax, Inc. 21 Firstfield Road, Gaithersburg, MD 20878, USA.

Human respiratory syncytial virus (RSV) is a cause of lower respiratory tract infection in infants, young children, and older adults. There is no licensed vaccine and prophylactic treatment options are limited. The RSV fusion (F) glycoprotein is a target of host immunity and thus a focus for vaccine development. F-trimers are metastable and undergo significant rearrangements from the prefusion to a stable postfusion structure with neutralizing epitopes on intermediate structures. We hypothesize that vaccine strategies that recapitulate the breathable F quaternary structure, and provide accessibility of B-cells to epitopes on intermediate conformations, may collectively contribute to protective immunity, while rigid prefusion F structures restrict access to key protective epitopes. To test this hypothesis, we used the near full-length prefusogenic F as a backbone to construct three prefusion F variants with substitutions in the hydrophobic head cavity: (1) disulfide bond mutant (DS), (2) space filling hydrophobic amino acid substitutions (Cav1), and (3) DS, Cav1 double mutant (DS-Cav1). In this study, we compared the immunogenicity of prefusogenic F to prefusion F variants in two animal models. Native prefusogenic F was significantly more immunogenic, producing high titer antibodies to prefusogenic, prefusion, and postfusion F structures, while animals immunized with DS or DS-Cav1 produced antibodies to prefusion F. Importantly, prefusogenic F elicited antibodies that target neutralizing epitopes including prefusion-specific site zero (Ø) and V and conformation-independent neutralizing sites II and IV. Immunization with DS or DS-Cav1 elicited antibodies primarily to prefusion-specific sites Ø and V with little or no antibodies to other key neutralizing sites. Animals immunized with prefusogenic F also had significantly higher levels of antibodies that cross-neutralized RSV A and B subtypes, while immunization with DS or DS-Cav1 produced antibodies primarily to the A subtype. We conclude that breathable trimeric vaccines that closely mimic the native F-structure, and incorporate strategies for B-cell accessibility to protective epitopes, are important considerations for vaccine design. F structures locked in a single conformation restrict access to neutralizing epitopes that may collectively contribute to destabilizing F-trimers important for broad protection. These results also have implications for vaccine strategies targeting other type 1 integral membrane proteins.
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http://dx.doi.org/10.3390/vaccines8040607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7711572PMC
October 2020

Phase 1-2 Trial of a SARS-CoV-2 Recombinant Spike Protein Nanoparticle Vaccine.

N Engl J Med 2020 12 2;383(24):2320-2332. Epub 2020 Sep 2.

From Novavax, Gaithersburg, MD (C.K., G.A., I.C., A.R., P.R., S.N., J.S.P., M.Z., S.C.-C., H.Z., G.S., N.P., C.D., K.C., M.L., P.P.-A., N.F., V.S., L.F., B.W., G.M.G.), and the University of Maryland School of Medicine, Baltimore (M.B.F., R.E.H., J.L., M.M.G., S.W.); Baylor College of Medicine, Houston (P.A.P.); and Nucleus Network, Melbourne, VIC (J.D.L.), and Q-Pharm, Herston, QLD (P.G.) - both in Australia.

Background: NVX-CoV2373 is a recombinant severe acute respiratory syndrome coronavirus 2 (rSARS-CoV-2) nanoparticle vaccine composed of trimeric full-length SARS-CoV-2 spike glycoproteins and Matrix-M1 adjuvant.

Methods: We initiated a randomized, placebo-controlled, phase 1-2 trial to evaluate the safety and immunogenicity of the rSARS-CoV-2 vaccine (in 5-μg and 25-μg doses, with or without Matrix-M1 adjuvant, and with observers unaware of trial-group assignments) in 131 healthy adults. In phase 1, vaccination comprised two intramuscular injections, 21 days apart. The primary outcomes were reactogenicity; laboratory values (serum chemistry and hematology), according to Food and Drug Administration toxicity scoring, to assess safety; and IgG anti-spike protein response (in enzyme-linked immunosorbent assay [ELISA] units). Secondary outcomes included unsolicited adverse events, wild-type virus neutralization (microneutralization assay), and T-cell responses (cytokine staining). IgG and microneutralization assay results were compared with 32 (IgG) and 29 (neutralization) convalescent serum samples from patients with Covid-19, most of whom were symptomatic. We performed a primary analysis at day 35.

Results: After randomization, 83 participants were assigned to receive the vaccine with adjuvant and 25 without adjuvant, and 23 participants were assigned to receive placebo. No serious adverse events were noted. Reactogenicity was absent or mild in the majority of participants, more common with adjuvant, and of short duration (mean, ≤2 days). One participant had mild fever that lasted 1 day. Unsolicited adverse events were mild in most participants; there were no severe adverse events. The addition of adjuvant resulted in enhanced immune responses, was antigen dose-sparing, and induced a T helper 1 (Th1) response. The two-dose 5-μg adjuvanted regimen induced geometric mean anti-spike IgG (63,160 ELISA units) and neutralization (3906) responses that exceeded geometric mean responses in convalescent serum from mostly symptomatic Covid-19 patients (8344 and 983, respectively).

Conclusions: At 35 days, NVX-CoV2373 appeared to be safe, and it elicited immune responses that exceeded levels in Covid-19 convalescent serum. The Matrix-M1 adjuvant induced CD4+ T-cell responses that were biased toward a Th1 phenotype. (Funded by the Coalition for Epidemic Preparedness Innovations; ClinicalTrials.gov number, NCT04368988).
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http://dx.doi.org/10.1056/NEJMoa2026920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7494251PMC
December 2020

Structural analysis of full-length SARS-CoV-2 spike protein from an advanced vaccine candidate.

bioRxiv 2020 Aug 6. Epub 2020 Aug 6.

Dept. of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, 92037, USA.

Vaccine efforts against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) responsible for the current COVID-19 pandemic are focused on SARS-CoV-2 spike glycoprotein, the primary target for neutralizing antibodies. Here, we performed cryo-EM and site-specific glycan analysis of one of the leading subunit vaccine candidates from Novavax based on a full-length spike protein formulated in polysorbate 80 (PS 80) detergent. Our studies reveal a stable prefusion conformation of the spike immunogen with slight differences in the S1 subunit compared to published spike ectodomain structures. Interestingly, we also observed novel interactions between the spike trimers allowing formation of higher order spike complexes. This study confirms the structural integrity of the full-length spike protein immunogen and provides a basis for interpreting immune responses to this multivalent nanoparticle immunogen.
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http://dx.doi.org/10.1101/2020.08.06.234674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418715PMC
August 2020

Influenza Hemagglutinin Nanoparticle Vaccine Elicits Broadly Neutralizing Antibodies against Structurally Distinct Domains of H3N2 HA.

Vaccines (Basel) 2020 Feb 22;8(1). Epub 2020 Feb 22.

Novavax, Inc. Gaithersburg, MD 20878, USA.

Influenza vaccine effectiveness varies annually due to the fast evolving seasonal influenza A(H3N2) strain and egg-derived mutations-both of which can cause a mismatch between the vaccine and circulating strains. To address these limitations, we have developed a hemagglutinin (HA)-based protein-detergent nanoparticle influenza vaccine (NIV) with a saponin-based Matrix-M™ adjuvant. In a phase 1 clinical trial of older adults, the vaccine demonstrated broadly cross-reactive A(H3N2) HA antibody responses. Two broadly neutralizing monoclonal antibodies derived from NIV-immunized mice were characterized by transmission electron microscopy (TEM), antibody competition assays, fluorescence-activated cell sorting (FACS) analysis, and protein-protein docking. These antibodies recognize two conserved regions of the head domain, namely the receptor binding site and the vestigial esterase subdomain, thus demonstrating the potential for an HA subunit vaccine to elicit antibodies targeting structurally and antigenically distinct but conserved sites. Antibody competition studies with sera from the phase 1 trial in older adults confirmed that humans also make antibodies to these two head domains and against the highly conserved stem domain. This data supports the potential of an adjuvanted recombinant HA nanoparticle vaccine to induce broadly protective immunity and improved vaccine efficacy.
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http://dx.doi.org/10.3390/vaccines8010099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7157642PMC
February 2020

The challenges of living with and managing epidermolysis bullosa: insights from patients and caregivers.

Orphanet J Rare Dis 2020 01 3;15(1). Epub 2020 Jan 3.

St. George-Hospital, University of Sydney, NSW, 2052, Australia.

Background: Little information is available regarding the burden of living with and managing epidermolysis bullosa, including the distinct challenges faced by patients with different disease types/subtypes.

Methods: A 90-question/item survey was developed to collect demographics, diagnostic data, management practices, and burden of illness information for patients with epidermolysis bullosa living in the United States. Recruitment was conducted via email and social media in partnership with epidermolysis bullosa patient advocacy organizations in the United States, and the survey was conducted via telephone interview by a third-party health research firm. Respondents aged ≥ 18 years with a confirmed diagnosis of epidermolysis bullosa or caring for a patient with a confirmed diagnosis of epidermolysis bullosa were eligible to participate in the survey.

Results: In total, 156 responses were received from patients (n = 63) and caregivers (n = 93) representing the epidermolysis bullosa types of simplex, junctional, and dystrophic (subtypes: dominant and recessive). A large proportion of patients (21%) and caregivers (32%) reported that the condition was severe or very severe, and 19% of patients and 26% of caregivers reported a visit to an emergency department in the 12 months prior to the survey. Among the types/subtypes represented, recessive dystrophic epidermolysis bullosa results in the greatest wound burden, with approximately 60% of patients and caregivers reporting wounds covering > 30% of total body area. Wound care is time consuming and commonly requires significant caregiver assistance. Therapeutic options are urgently needed and reducing the number and severity of wounds was generally ranked as the most important treatment factor.

Conclusions: Survey responses demonstrate that epidermolysis bullosa places a considerable burden on patients, their caregivers, and their families. The limitations caused by epidermolysis bullosa mean that both patients and caregivers must make difficult choices and compromises regarding education, career, and home life. Finally, survey results indicate that epidermolysis bullosa negatively impacts quality of life and causes financial burden to patients and their families.
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http://dx.doi.org/10.1186/s13023-019-1279-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6942340PMC
January 2020

Respiratory syncytial virus prefusogenic fusion (F) protein nanoparticle vaccine: Structure, antigenic profile, immunogenicity, and protection.

Vaccine 2019 09 12;37(41):6112-6124. Epub 2019 Aug 12.

Novavax, Inc., Gaithersburg, MD, United States. Electronic address:

Respiratory syncytial virus (RSV) is a major cause of severe respiratory disease in the very young, elderly, and immunocompromised for which there is no vaccine. The surface exposed RSV fusion (F) glycoprotein is required for membrane fusion and infection and is a desirable vaccine candidate. RSV F glycoprotein structure is dynamic and undergoes significant rearrangements during virus assembly, fusion, and infection. We have previously described an RSV fusion-inactive prefusogenic F with a mutation of one of two furin cleavage sites resulting in the p27 region on the N-terminus of F1 with a truncated fusion peptide covalently linked to F2. A processing intermediate RSV prefusogenic F has been reported in infected cells, purified F, budded virus, and elicited a strong immune response against p27 in RSV infected young children. In this report, we demonstrate that prefusogenic F, when expressed on the cell surface of Sf9 insect and human 293T cells, binds monoclonal antibodies (mAbs) that target prefusion-specific antigenic sites Ø and VIII, and mAbs targeting epitopes common to pre- and postfusion F sites II and IV. Purified prefusogenic F bound prefusion F specific mAbs to antigenic sites Ø and VIII and mAbs targeting pre- and postfusion sites II, IV, and p27. Mice immunized with prefusogenic F antigen produced significantly higher levels of anti-F IgG and RSV neutralizing antibodies than prefusion or postfusion F antigens and induced antibodies competitive with mAbs to sites Ø, VIII, II, and IV. RSV prefusogenic F neutralization antibody responses were enhanced with aluminum phosphate adjuvant and significantly higher than prefusion F. Prefusogenic F vaccine protected cotton rats against upper and lower respiratory tract infection by RSV/A. For the first time, we present the structure, antigenic profile, immunogenicity, and protective efficacy of RSV prefusogenic F nanoparticle vaccine.
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http://dx.doi.org/10.1016/j.vaccine.2019.07.089DOI Listing
September 2019

Safety and Immunogenicity of a Respiratory Syncytial Virus Fusion (F) Protein Nanoparticle Vaccine in Healthy Third-Trimester Pregnant Women and Their Infants.

J Infect Dis 2019 10;220(11):1802-1815

Novavax, Inc., Gaithersburg, Maryland.

Background: Respiratory syncytial virus (RSV) is the leading cause of infant lower respiratory tract disease and hospitalization worldwide.

Methods: Safety and immunogenicity of RSV fusion (F) protein nanoparticle vaccine or placebo were evaluated in 50 healthy third-trimester pregnant women. Assessments included vaccine tolerability and safety in women and infants, and RSV-specific antibody measures in women before and after vaccination, at delivery and post partum.

Results: The vaccine was well tolerated; no meaningful differences in pregnancy or infant outcomes were observed between study groups. RSV-specific antibody levels increased significantly among vaccine recipients, including responses competitive with well-described monoclonal antibodies specific for multiple RSV neutralizing epitopes. No significant antibody increase was seen among placebo recipients, although a shallow upward trend across the RSV season was noted. Transplacental antibody transfer was 90%-120% across assays for infants of vaccinated women. Women with an interval of ≥30 days between vaccination and delivery demonstrated higher placental antibody transfer rates than women with an interval <30 days. Half-lives of RSV-specific antibodies in infants approximated 40 days. There was no evidence of severe RSV disease in infants of vaccinated mothers.

Conclusions: Data from this phase 2 study support a maternal immunization strategy to protect infants from RSV disease.

Clinical Trials Registration: NCT02247726.
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http://dx.doi.org/10.1093/infdis/jiz390DOI Listing
October 2019

Regulatory strategies for rare diseases under current global regulatory statutes: a discussion with stakeholders.

Orphanet J Rare Dis 2019 02 8;14(1):36. Epub 2019 Feb 8.

Amicus Therapeutics, Inc., 1 Cedar Brook Drive, Cranbury, NJ, 08512, USA.

Rare or orphan diseases often are inherited and overwhelmingly affect children. Many of these diseases have no treatments, are incurable, and have a devastating impact on patients and their families. Regulatory standards for drug approval for rare diseases must ensure that patients receive safe and efficacious treatments. However, regulatory bodies have shown flexibility in applying these standards to drug development in rare diseases, given the unique challenges that hinder efficient and effective traditional clinical trials, including low patient numbers, limited understanding of disease pathology and progression, variability in disease presentation, and a lack of established endpoints.To take steps toward improving rare disease clinical development strategies under current global regulatory statutes, Amicus Therapeutics, Inc. and BioNJ convened a 1-day meeting that included representatives from the Food and Drug Administration (FDA), biopharmaceutical industry, and not-for-profit agencies. The meeting focused on orphan diseases in pediatric and adult patients and was intended to identify potential strategies to overcome regulatory hurdles through open collaboration.During this meeting, several strategies were identified to minimize the limitations associated with low patient numbers in rare diseases, including the use of natural history to generate historical control data in comparisons, simulations, and identifying inclusion/exclusion criteria and appropriate endpoints. Novel approaches to clinical trial design were discussed to minimize patient exposure to placebo and to reduce the numbers of patients and clinical trials needed for providing substantial evidence. Novel statistical analysis approaches were also discussed to address the inherent challenges of small patient numbers. Areas of urgent unmet need were identified, including the need to develop registries that protect patient identities, to establish close collaboration and communication between the sponsor and regulatory bodies to address methodological and statistical challenges, to collaborate in pre-competitive opportunities within multiple sponsors and in conjunction with academia and disease-specific patient advocacy groups for optimal data sharing, and to develop harmonized guidelines for data extrapolation from source to target pediatric populations. Ultimately, these innovations will help in solving many regulatory challenges in rare disease drug development and encourage the availability of new treatments for patients with rare diseases.
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http://dx.doi.org/10.1186/s13023-019-1017-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6368795PMC
February 2019

Structure basis of neutralization by a novel site II/IV antibody against respiratory syncytial virus fusion protein.

PLoS One 2019 7;14(2):e0210749. Epub 2019 Feb 7.

Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas, United States of America.

Globally, human respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infections in newborns, young children, and the elderly for which there is no vaccine. The RSV fusion (F) glycoprotein is a major target for vaccine development. Here, we describe a novel monoclonal antibody (designated as R4.C6) that recognizes both pre-fusion and post-fusion RSV F, and binds with nanomole affinity to a unique neutralizing site comprised of antigenic sites II and IV on the globular head. A 3.9 Å-resolution structure of RSV F-R4.C6 Fab complex was obtained by single particle cryo-electron microscopy and 3D reconstruction. The structure unraveled detailed interactions of R4.C6 with antigenic site II on one protomer and site IV on a neighboring protomer of post-fusion RSV F protein. These findings significantly further our understanding of the antigenic complexity of the F protein and provide new insights into RSV vaccine design.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0210749PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6366758PMC
October 2019

Respiratory syncytial virus fusion nanoparticle vaccine immune responses target multiple neutralizing epitopes that contribute to protection against wild-type and palivizumab-resistant mutant virus challenge.

Vaccine 2018 12 30;36(52):8069-8078. Epub 2018 Oct 30.

Novavax, Inc., Gaithersburg, MD, USA. Electronic address:

Human respiratory syncytial virus (RSV) is the leading cause of severe lower respiratory tract infections in newborns, young children, elderly, and immune-compromised. The RSV fusion (F) glycoprotein is a major focus of vaccine development and the target of palivizumab (Synagis®) which is licensed as an immuno-prophylactic for use in newborn children at high risk of infection. However, clinical use of a narrowly targeted monoclonal antibodies leads to the generation of escape mutant strains that are fully resistant to neutralization by the antibody. Herein, we evaluated the RSV F nanoparticle vaccine (RSV F vaccine), produced as near-full-length, pre-fusogenic F trimers that form stable protein-detergent nanoparticles. The RSV F vaccine induces polyclonal antibodies that bind to antigenic site II as well as other epitopes known to be broadly neutralizing. Cotton rats immunized with the RSV F vaccine produced antibodies that were both neutralizing and protected against wild-type RSV infection, as well as against a palivizumab-resistant mutant virus. Use of aluminum phosphate adjuvant with the RSV F vaccine increased site II antibody avidity 100 to 1000-fold, which correlated with enhanced protection against challenge. The breadth of the vaccine-induced antibody response was demonstrated using competitive binding with monoclonal antibodies targeting antigenic sites Ø, II, IV, and VIII found on pre-fusion and post-fusion conformations of RSV F. In summary, we found the RSV F vaccine induced antibodies that bind to conserved epitopes including those defined as pre-fusion F specific; that use of adjuvant increased antibody avidity that correlated with enhanced protection in the cotton rat challenge model; and the polyclonal, high-avidity antibodies neutralized and protected against both wild-type and palivizumab-resistant mutant virus. These data support the ongoing clinical development of the aluminum phosphate adjuvanted RSV F nanoparticle vaccine.
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http://dx.doi.org/10.1016/j.vaccine.2018.10.073DOI Listing
December 2018

Correction to: A Semi-Physiologically Based Pharmacokinetic Model Describing the Altered Metabolism of Midazolam Due to Inflammation in Mice.

Pharm Res 2018 07 25;35(9):180. Epub 2018 Jul 25.

Department of Pharmaceutical Chemistry, The University of Kansas, 2095 Constant Ave, Lawrence, Kansas, 66047, USA.

One of the authors has his name incorrectly indexed in PubMed and SpringerLink as "Laird Forrest M" (last name "Laird Forrest"). His name should index as "Forrest M. Laird" with last name as "Forrest".
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http://dx.doi.org/10.1007/s11095-018-2463-9DOI Listing
July 2018

A Semi-Physiologically Based Pharmacokinetic Model Describing the Altered Metabolism of Midazolam Due to Inflammation in Mice.

Pharm Res 2018 06 21;35(8):162. Epub 2018 Jun 21.

Department of Pharmaceutical Chemistry, The University of Kansas, 2095 Constant Ave, Lawrence, Kansas, 66047, USA.

Purpose: To investigate influence of inflammation on metabolism and pharmacokinetics (PK) of midazolam (MDZ) and construct a semi-physiologically based pharmacokinetic (PBPK) model to predict PK in mice with inflammatory disease.

Methods: Glucose-6-phosphate isomerase (GPI)-mediated inflammation was used as a preclinical model of arthritis in DBA/1 mice. CYP3A substrate MDZ was selected to study changes in metabolism and PK during the inflammation. The semi-PBPK model was constructed using mouse physiological parameters, liver microsome metabolism, and healthy animal PK data. In addition, serum cytokine, and liver-CYP (cytochrome P450 enzymes) mRNA levels were examined.

Results: The in vitro metabolite formation rate was suppressed in liver microsomes prepared from the GPI-treated mice as compared to the healthy mice. Further, clearance of MDZ was reduced during inflammation as compared to the healthy group. Finally, the semi-PBPK model was used to predict PK of MDZ after GPI-mediated inflammation. IL-6 and TNF-α levels were elevated and liver-cyp3a11 mRNA was reduced after GPI treatment.

Conclusion: The semi-PBPK model successfully predicted PK parameters of MDZ in the disease state. The model may be applied to predict PK of other drugs under disease conditions using healthy animal PK and liver microsomal data as inputs.
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http://dx.doi.org/10.1007/s11095-018-2447-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6690355PMC
June 2018

Bone Marrow Harvest in Pediatric Sibling Donors: Role of Granulocyte Colony-Stimulating Factor Priming and CD34 Cell Dose.

Biol Blood Marrow Transplant 2018 02 23;24(2):324-329. Epub 2017 Oct 23.

Department of Pediatrics, Columbia University, New York, New York. Electronic address:

To ensure optimal clinical outcomes for patients while retaining adequate protection for donors, the National Marrow Donor Program developed guidelines specifying that up to 20 mL/kg of bone marrow can be harvested from donors. These guidelines, originally developed for unrelated adult donors, are followed in children as well. We studied the impact of granulocyte colony-stimulating factor (G-CSF) priming on the cellular composition of harvested bone marrow, sought to develop an algorithm to optimize bone marrow harvest volume from pediatric matched sibling donors, and studied the impact of CD34 cell dose on clinical outcomes. We analyzed data from 92 bone marrow harvests and clinical outcomes for 69 sibling recipient-donor duos, The mean age of recipients was 9.85 ± 5.90 years, and that of donors was 11.85 ± 6.36 years. G-CSF priming was not associated with higher yield of CD34 cells/µL. The median CD34 cell count obtained from donors was 700 cells/µL (range, 400-1700 cells/µL) in donors age <6 years, 360 cells/µL (range, 100-1100 cells/µL) in donors age 6 to 12 years, and 300 cells/µL (range, 80-800 cells/µL) in donors age >12 years (P < .001). The number of CD34 cells infused had no impact on traditional clinical outcomes; however, it was significantly related to graft-versus-host disease/relapse/rejection-free survival. Our investigation revealed that ultimately, a CD34 cell count of approximately 3 to 5 × 10/kg was a threshold beyond which increasing CD34 cell dose did not impact outcome. In this study, we addressed the broad question of whether harvesting up to 20 mL/kg of bone marrow from a child donor is truly necessary for optimal outcomes in every pediatric case.
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http://dx.doi.org/10.1016/j.bbmt.2017.10.031DOI Listing
February 2018

Safety of hematopoietic cell infusion in children with malignant and non-malignant diseases.

Pediatr Transplant 2017 Nov 28;21(7). Epub 2017 Aug 28.

Department of Pediatrics, Columbia University, New York, NY, USA.

HPC infusions have been associated with a variety of adverse events related to either patient or HPC product-related factors. Studies documenting infusion-related AEs in children are limited. We reviewed HPC infusion records in 354 children. Infusion-related adverse events were classified as follows: grade 0-absent, grade I-mild, grade II-moderate, grade III-severe, grade IV-life-threatening, and grade V-death. The percentage of patients with grade 0, I, and II-IV AEs was as follows: 0 = 67%, I = 23.4%, and II-V = 9.6% (one patient had fatal anaphylactic reaction to dimethyl sulfoxide). The incidence of grade II-IV hypertension was 7.1%. There was a higher incidence of AEs with infusion of allogeneic bone marrow versus allogeneic PBSCs (47.4% vs 25.3%, P = .001). Cryopreserved products had a lower incidence of infusion-associated AEs compared with fresh HPC products (24% vs 39.4%, P = .003). Allogeneic HPC infusion volume (>100 mL) was a significant risk factor for infusion-associated AEs (P < .001). Patients >10 years who received autologous HPC infusions had higher risk of AEs when compared to patients <10 years (P = .01). Our study demonstrated that despite a high incidence of infusion-associated hypertension, HPC infusion is relatively safe in children. Investigating strategies to optimize management of hypertension in the setting of HPC infusion is warranted.
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http://dx.doi.org/10.1111/petr.13038DOI Listing
November 2017

Novel hemagglutinin nanoparticle influenza vaccine with Matrix-M™ adjuvant induces hemagglutination inhibition, neutralizing, and protective responses in ferrets against homologous and drifted A(H3N2) subtypes.

Vaccine 2017 09 22;35(40):5366-5372. Epub 2017 Aug 22.

Novavax, Inc., 20 Firstfield Road, Gaithersburg, MD 20878, USA. Electronic address:

Influenza viruses frequently acquire mutations undergoing antigenic drift necessitating annual evaluation of vaccine strains. Highly conserved epitopes have been identified in the hemagglutinin (HA) head and stem regions, however, current influenza vaccines induce only limited responses to these conserved sites. Here, we describe a novel seasonal recombinant HA nanoparticle influenza vaccine (NIV) formulated with a saponin-based adjuvant, Matrix-M™. NIV induced hemagglutination inhibition (HAI) and microneutralizing (MN) antibodies against a broad range of influenza A(H3N2) subtypes. In a comparison of NIV against standard-dose and high-dose inactivated influenza vaccines (IIV and IIV-HD, respectively) in ferrets NIV elicited HAI and MN responses exceeding those induced by IIV-HD against homologous A(H3N2) by 7 fold, A(H1N1) by 26 fold, and B strain viruses by 2 fold. NIV also induced MN responses against all historic A/H3N2 strains tested, spanning more than a decade of viral evolution from the 2000-2017 influenza seasons whereas IIV and IIV-HD induced HAI and MN responses were largely directed against the homologous A(H3N2), A(H1N1), and B virus strains. NIV induced superior protection compared to IIV and IIV-HD in ferrets challenged with a homologous or 10-year drifted influenza A(H3N2) strain. HAI positive and HAI negative neutralizing monoclonal antibodies derived from mice immunized with NIV were active against homologous and drifted influenza A(H3N2) strains. Taken together these observations suggest that NIV can induce responses to one or more highly conserved HA head and stem epitopes and result in highly neutralizing antibodies against both homologous and drift strains.
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http://dx.doi.org/10.1016/j.vaccine.2017.08.021DOI Listing
September 2017

A highly potent extended half-life antibody as a potential RSV vaccine surrogate for all infants.

Sci Transl Med 2017 05;9(388)

Department of Infectious Disease, MedImmune LLC, One MedImmune Way, Gaithersburg, MD 20878, USA.

Prevention of respiratory syncytial virus (RSV) illness in all infants is a major public health priority. However, no vaccine is currently available to protect this vulnerable population. Palivizumab, the only approved agent for RSV prophylaxis, is limited to high-risk infants, and the cost associated with the requirement for dosing throughout the RSV season makes its use impractical for all infants. We describe the development of a monoclonal antibody as potential RSV prophylaxis for all infants with a single intramuscular dose. MEDI8897*, a highly potent human antibody, was optimized from antibody D25, which targets the prefusion conformation of the RSV fusion (F) protein. Crystallographic analysis of Fab in complex with RSV F from subtypes A and B reveals that MEDI8897* binds a highly conserved epitope. MEDI8897* neutralizes a diverse panel of RSV A and B strains with >50-fold higher activity than palivizumab. At similar serum concentrations, prophylactic administration of MEDI8897* was ninefold more potent than palivizumab at reducing pulmonary viral loads by >3 logs in cotton rats infected with either RSV A or B subtypes. MEDI8897 was generated by the introduction of triple amino acid substitutions (YTE) into the Fc domain of MEDI8897*, which led to more than threefold increased half-life in cynomolgus monkeys compared to non-YTE antibody. Considering the pharmacokinetics of palivizumab in infants, which necessitates five monthly doses for protection during an RSV season, the high potency and extended half-life of MEDI8897 support its development as a cost-effective option to protect all infants from RSV disease with once-per-RSV-season dosing in the clinic.
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http://dx.doi.org/10.1126/scitranslmed.aaj1928DOI Listing
May 2017

Evaluation and Optimization of Blood Micro-Sampling Methods: Serial Sampling in a Cross-Over Design from an Individual Mouse.

J Pharm Pharm Sci 2016 Oct - Dec;19(4):496-510

Drug Disposition Eli Lilly and Company, Indianapolis, USA.

Purpose: Current practices applied to mouse pharmacokinetic (PK) studies often use large numbers of animals with sporadic or composite sampling that inadequately describe PK profiles.  The purpose of this work was to evaluate and optimize blood microsampling techniques coupled with dried blood spot (DBS) and LC-MS/MS analysis to generate reliable PK data in mice.  In addition, the feasibility of cross-over designs was assessed and recommendations are presented.

Methods: The work describes a comprehensive evaluation of five blood microsampling techniques (tail clip, tail vein with needle hub, submandibular, retro-orbital, and saphenous bleeding) in CD-1 mice.  The feasibility of blood sampling was evaluated based on animal observations, ease of bleeding, and ability to collect serial samples.  Methotrexate, gemfibrozil and glipizide were used as test compounds and were dosed either orally or intravenously, followed by DBS collection and LC-MS/MS analysis to compare PK with various bleeding methods.

Results: Submandibular and retro-orbital methods that required non-serial blood collections did not allow for inter-animal variability assessments and resulted in poorly described absorption and distribution kinetics.  The submandibular and tail vein with needle-hub methods were the least favorable from a technical feasibility perspective.  Serial bleeding was possible with cannulated animals or saphenous bleeding in non-cannulated animals.

Conclusions:   Of the methods that allowed serial sampling, the saphenous method when executed as described in this report, was most practical, reproducible and provided for assessment of inter-animal variability.  It enabled the collection of complete exposure profiles from a single mouse and the conduct of an intravenous/oral cross-over study design.  This methodology can be used routinely, it promotes the 3Rs principles by achieving reductions in the number of animals used, decreased restraints and animal stress, and improved the quality of data obtained in mouse PK studies. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.
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http://dx.doi.org/10.18433/J3NK60DOI Listing
November 2017

Eye Care Quality and Accessibility Improvement in the Community (EQUALITY): impact of an eye health education program on patient knowledge about glaucoma and attitudes about eye care.

Patient Relat Outcome Meas 2016 19;7:37-48. Epub 2016 May 19.

Department of Ophthalmology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.

Purpose: To assess the impact of the education program of the Eye Care Quality and Accessibility Improvement in the Community (EQUALITY) telemedicine program on at-risk patients' knowledge about glaucoma and attitudes about eye care as well as to assess patient satisfaction with EQUALITY.

Patients And Methods: New or existing patients presenting for a comprehensive eye exam (CEE) at one of two retail-based primary eye clinics were enrolled based on ≥1 of the following at-risk criteria for glaucoma: African Americans ≥40 years of age, Whites ≥50 years of age, diabetes, family history of glaucoma, and/or preexisting diagnosis of glaucoma. A total of 651 patients were enrolled. A questionnaire was administered prior to the patients' CEE and prior to the patients receiving any of the evidence-based eye health education program; a follow-up questionnaire was administered 2-4 weeks later by phone. Baseline and follow-up patient responses regarding knowledge about glaucoma and attitudes about eye care were compared using McNemar's test. Logistic regression models were used to assess the association of patient-level characteristics with improvement in knowledge and attitudes. Overall patient satisfaction was summarized.

Results: At follow-up, all patient responses in the knowledge and attitude domains significantly improved from baseline (P≤0.01 for all questions). Those who were unemployed (odds ratio =0.63, 95% confidence interval =0.42-0.95, P=0.026) or had lower education (odds ratio =0.55, 95% confidence interval =0.29-1.02, P=0.058) were less likely to improve their knowledge after adjusting for age, sex, race, and prior glaucoma diagnosis. This association was attenuated after further adjustment for other patient-level characteristics. Ninety-eight percent (n=501) of patients reported being likely to have a CEE within the next 2 years, whereas 63% (n=326) had a CEE in the previous 2 years. Patient satisfaction with EQUALITY was high (99%).

Conclusion: Improved knowledge about glaucoma and a high intent to pursue eye care may lead to improved detection of early disease, thus lowering the risk of blindness.
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http://dx.doi.org/10.2147/PROM.S98686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4877018PMC
June 2016

2-Chloro-4-[[(1R,2R)-2-hydroxy-2-methyl-cyclopentyl]amino]-3-methyl-benzonitrile: A Transdermal Selective Androgen Receptor Modulator (SARM) for Muscle Atrophy.

J Med Chem 2016 Jan 7;59(2):750-5. Epub 2016 Jan 7.

Lilly Research Laboratories, Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States.

A transdermal SARM has a potential to have therapeutic benefit through anabolic activity in muscle while sparing undesired effects of benign prostate hyperplasia (BPH) and liver-mediated decrease in HDL-C. 2-Chloro-4-[(2-hydroxy-2-methyl-cyclopentyl)amino]-3-methyl-benzonitrile 6 showed the desired muscle and prostate effects in a preclinical ORX rat model. Compound 6 had minimal effect on HDL-C levels in cynomolgus monkeys and showed human cadaver skin permeability, thus making it an effective tool for proof-of-concept studies in a clinical setting.
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http://dx.doi.org/10.1021/acs.jmedchem.5b01168DOI Listing
January 2016

Eye Care Quality and Accessibility Improvement in the Community (EQUALITY) for adults at risk for glaucoma: study rationale and design.

Int J Equity Health 2015 Nov 18;14:135. Epub 2015 Nov 18.

Department of Ophthalmology, School of Medicine, University of Alabama at Birmingham, 700 S. 18th St, Birmingham, AL, 35294-0009, USA.

Background: Primary open angle glaucoma is a chronic, progressive eye disease that is the leading cause of blindness among African Americans. Glaucoma progresses more rapidly and appears about 10 years earlier in African Americans as compared to whites. African Americans are also less likely to receive comprehensive eye care when glaucoma could be detected before irreversible blindness. Screening and follow-up protocols for managing glaucoma recommended by eye-care professional organizations are often not followed by primary eye-care providers, both ophthalmologists and optometrists. There is a pressing need to improve both the accessibility and quality of glaucoma care for African Americans. Telemedicine may be an effective solution for improving management and diagnosis of glaucoma because it depends on ocular imaging and tests that can be electronically transmitted to remote reading centers where tertiary care specialists can examine the results. We describe the Eye Care Quality and Accessibility Improvement in the Community project (EQUALITY), set to evaluate a teleglaucoma program deployed in retail-based primary eye care practices serving communities with a large percentage of African Americans.

Methods/design: We conducted an observational, 1-year prospective study based in two Walmart Vision Centers in Alabama staffed by primary care optometrists. EQUALITY focuses on new or existing adult patients who are at-risk for glaucoma or already diagnosed with glaucoma. Patients receive dilated comprehensive examinations and diagnostic testing for glaucoma, followed by the optometrist's diagnosis and a preliminary management plan. Results are transmitted to a glaucoma reading center where ophthalmologists who completed fellowship training in glaucoma review results and provide feedback to the optometrist, who manages the care of the patient. Patients also receive eye health education about glaucoma and comprehensive eye care. Research questions include diagnostic and management agreement between providers, the impact of eye health education on patients' knowledge and adherence to follow-up and medication, patient satisfaction, program cost-effectiveness, and EQUALITY's impact on Walmart pharmacy prescription rates.

Discussion: As eye-care delivery systems in the US strive to improve quality while reducing costs, telemedicine programs including teleglaucoma initiatives such as EQUALITY could contribute toward reaching this goal, particularly among underserved populations at-risk for chronic blinding diseases.
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http://dx.doi.org/10.1186/s12939-015-0213-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4652429PMC
November 2015

Characterization of a Prefusion-Specific Antibody That Recognizes a Quaternary, Cleavage-Dependent Epitope on the RSV Fusion Glycoprotein.

PLoS Pathog 2015 Jul 10;11(7):e1005035. Epub 2015 Jul 10.

Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, United States of America.

Prevention efforts for respiratory syncytial virus (RSV) have been advanced due to the recent isolation and characterization of antibodies that specifically recognize the prefusion conformation of the RSV fusion (F) glycoprotein. These potently neutralizing antibodies are in clinical development for passive prophylaxis and have also aided the design of vaccine antigens that display prefusion-specific epitopes. To date, prefusion-specific antibodies have been shown to target two antigenic sites on RSV F, but both of these sites are also present on monomeric forms of F. Here we present a structural and functional characterization of human antibody AM14, which potently neutralized laboratory strains and clinical isolates of RSV from both A and B subtypes. The crystal structure and location of escape mutations revealed that AM14 recognizes a quaternary epitope that spans two protomers and includes a region that undergoes extensive conformational changes in the pre- to postfusion F transition. Binding assays demonstrated that AM14 is unique in its specific recognition of trimeric furin-cleaved prefusion F, which is the mature form of F on infectious virions. These results demonstrate that the prefusion F trimer contains potent neutralizing epitopes not present on monomers and that AM14 should be particularly useful for characterizing the conformational state of RSV F-based vaccine antigens.
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http://dx.doi.org/10.1371/journal.ppat.1005035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4498696PMC
July 2015

Do children with specific language impairment and autism spectrum disorders benefit from the presence of orthography when learning new spoken words?

J Exp Child Psychol 2015 Jun 19;134:43-61. Epub 2015 Mar 19.

Centre for Educational Development, Appraisal and Research (CEDAR), University of Warwick, Coventry CV4 7AL, UK.

This experiment investigated whether children with specific language impairment (SLI), children with autism spectrum disorders (ASD), and typically developing children benefit from the incidental presence of orthography when learning new oral vocabulary items. Children with SLI, children with ASD, and typically developing children (n=27 per group) between 8 and 13 years of age were matched in triplets for age and nonverbal reasoning. Participants were taught 12 mappings between novel phonological strings and referents; half of these mappings were trained with orthography present and half were trained with orthography absent. Groups did not differ on the ability to learn new oral vocabulary, although there was some indication that children with ASD were slower than controls to identify newly learned items. During training, the ASD, SLI, and typically developing groups benefited from orthography to the same extent. In supplementary analyses, children with SLI were matched in pairs to an additional control group of younger typically developing children for nonword reading. Compared with younger controls, children with SLI showed equivalent oral vocabulary acquisition and benefit from orthography during training. Our findings are consistent with current theoretical accounts of how lexical entries are acquired and replicate previous studies that have shown orthographic facilitation for vocabulary acquisition in typically developing children and children with ASD. We demonstrate this effect in SLI for the first time. The study provides evidence that the presence of orthographic cues can support oral vocabulary acquisition, motivating intervention approaches (as well as standard classroom teaching) that emphasize the orthographic form.
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http://dx.doi.org/10.1016/j.jecp.2015.01.015DOI Listing
June 2015

Discovery and Development of LX7101, a Dual LIM-Kinase and ROCK Inhibitor for the Treatment of Glaucoma.

ACS Med Chem Lett 2015 Jan 24;6(1):84-8. Epub 2014 Nov 24.

Department of Medicinal Chemistry, Lexicon Pharmaceuticals , 350 Carter Road, Princeton, New Jersey 08540, United States.

The structure of LX7101, a dual LIM-kinase and ROCK inhibitor for the treatment of ocular hypertension and associated glaucoma, is disclosed. Previously reported LIM kinase inhibitors suffered from poor aqueous stability due to solvolysis of the central urea. Replacement of the urea with a hindered amide resulted in aqueous stable compounds, and addition of solubilizing groups resulted in a set of compounds with good properties for topical dosing in the eye and good efficacy in a mouse model of ocular hypertension. LX7101 was selected as a clinical candidate from this group based on superior efficacy in lowering intraocular pressure and a good safety profile. LX7101 completed IND enabling studies and was tested in a Phase 1 clinical trial in glaucoma patients, where it showed efficacy in lowering intraocular pressure.
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http://dx.doi.org/10.1021/ml500367gDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4291717PMC
January 2015