The role of airway mucus and diseased pulmonary epithelium on the absorption of inhaled antibodies.

Inhaled antibody therapy for the treatment of respiratory diseases is a promising strategy to maximize pulmonary exposure and reduce side effects associated with parenteral administration. However, the development of inhaled antibodies is often challenging due to a poor understanding of key mechanisms governing antibody absorption and clearance in healthy and diseased pulmonary epithelium. Here, we utilize well established Human Bronchial Epithelial Cell (HBEC) models grown at air-liquid interface to study the absorption process of antibodies and antibody fragments. With these cellular models, we recapitulate the morphology and function of healthy and diseased pulmonary epithelium, and incorporate the mucosal barrier to enable the investigation of both cellular permeability as well as mucodiffusion. We studied the saturation of antibody transport across the HBEC barriers and estimated the impact of disease-like epithelial barriers on antibody paracellular transport. Additionally, we identified a potential role of neonatal Fc receptor (FcRn)-independent and target-mediated transcytosis in the transport of Fragment antigen-binding (Fab) and F(ab)2 antibody fragments. Lastly, our models were able to pinpoint an impaired antibody diffusion across mucus gels. These mechanistic cellular models are promising in vitro tools to inform Physiologically-based Pharmacokinetic (PBPK) computational models for dose prediction toward de-risking the development of inhaled biologics

Risk of adverse outcomes in offspring with RT-PCR confirmed prenatal Zika virus exposure: an individual participant data meta-analysis of 13 cohorts in the Zika Brazilian Cohorts

The Zika Brazilian Cohorts Consortium was supported by the National Council for Scientific and Technological Development (Conselho Nacional de Desenvolvimento Científico e Tecnológico – CNPq) (grant number 404861/2018-0). The individual studies participating in the ZBC-Consortium were funded by: Wellcome Trust and the United Kingdom’s Department for International Development (grant numbers: 205377/Z/16/Z; 201870/Z/16/Z). European Union’s Horizon 2020 research and innovation programme under ZikaPLAN (grant number 734584). Wellcome Trust - Research Enrichment in Epidemic Situation (grant number 107779/Z/15/Z; with ER1505 & ER1601). Medical Research Council on behalf of the Newton Fund and Wellcome Trust (grant number MC_PC_15088). National Institutes of Health/National Institute of Allergy and Infectious Diseases (grant number RO1/ AI140718). Fondation Christophe et Rodolphe Mérieux. National Council for Scientific and Technological Development (Conselho Nacional de Desenvolvimento Científico e Tecnológico – CNPq) (grant numbers 443875/2018-9; 440573/2016-5; 441098/2016-9; 305090/2016-0; 307282/2017-1; 304476/2018-8; 465549/2014-4; 440763/2016-9; 309722/2017-9; 306708/2014-0; 440577/2016-0). Coordination for the improvement of Higher Education Personnel (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Capes) (grant numbers 88881.130813/2016-01; 88887.116627/2016-01; 88887.136366/2017-00). Ministry of Health of Brazil - Emergency Response in Public Health - Zika virus and Microcephaly (Ministério da Saúde de Brasil - Resposta à Emergência em Saúde Pública – Zika vírus e Microcefalia) (grant number 837058/2016). Department of Science and Technology (Departamento de Ciência e Tecnologia - DECIT) (grant numbers 25000.072811/2016-19; 440839/2016-5). Foundation of Research Support of the State of São Paulo (Fundação de Amparo à Pesquisa do Estado de São Paulo – FAPESP) (grant numbers 2016/08578-0; 2017/21688-1; 2013/21719-3; 2016/ 15021-1; 2015/12295-0; 2016/05115-9). Foundation of Research Support of the State of Rio de Janeiro (Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro – FAPERJ) (grant numbers E-26/201.351/2016; E-18/ 2015TXB; E-26/202.862/2018; E 26/010.002477/2016). Foundation of Support for Research and Scientific and Technological Development of Maranhão (Fundação de Amparo à Pesquisa e ao Desenvolvimento Científico e Tecnológico do Maranhão – FAPEMA) (grant number 008/2016). Brazilian Ministry of Health (Ministério da Saúde – MS) (grant number 929698560001160-02). Evandro Chagas Institute/Brazilian Ministry of Health (Instituto Evandro Chagas/Ministério da Saúde). Foundation of Research Support of the State of Goiás (Fundação de Amparo à Pesquisa do Estado de Goiás – FAPEG) (number grant 2017/10267000531). Foundation of Research Support of the State of Rio Grande do Sul (Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul – FAPERGS) (grant number 17/2551-0000521-0). Foundation to Support Teaching, Research and Assistance at Hospital das Clínicas, Faculty of Medicine of Ribeirão Preto (Fundação de Apoio ao Ensino, Pesquisa e Assistência do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto) and São Paulo State Department of Health (Secretaria de Saúde do Estado de São Paulo). Support Foundation of Pernambuco Science and Technology (Fundação de Amparo à Ciência e Tecnologia de Pernambuco – FACEPE) (grant numbers APQ-0172-4.01/16; APQ-0192-4.01/17; APQ0793-4.01/17).Federal University of Pernambuco. Postgraduate Program in Tropical Medicine. Recife, PE, Brazil / University of Pernambuco. Post-Graduation in Health Sciences. Recife, PE, Brazil.University of Pernambuco. Post-Graduation in Health Sciences. Recife, PE, Brazil.London School of Hygiene & Tropical Medicine. Department of Infectious Disease Epidemiology. London, UK.Federal University of Pernambuco. Postgraduate Program in Collective Health. Recife, PE, Brazil.University of Pernambuco. Post-Graduation in Health Sciences. Recife, PE, Brazil.University of Amazonas State. Postgraduate Program in Tropical Medicine. Manaus, AM, Brazil / Doctor Heitor Vieira Dourado Tropical Medicine Foundation. Postgraduate Program in Tropical Medicine. Manaus, AM, Brazil.Ribeirão Preto Medical School. Department of Pediatrics. Ribeirão Preto, SP, Brazil.Ribeirão Preto Medical School. Department of Gynecology and Obstetrics. Ribeirão Preto, SP, Brazil.Ribeirão Preto Medical School. Department of Gynecology and Obstetrics. Ribeirão Preto, SP, Brazil.Ribeirão Preto Medical School. Department of Pediatrics. Ribeirão Preto, SP, Brazil.University of Amazonas State. Postgraduate Program in Tropical Medicine. Manaus, AM, Brazil / Doctor Heitor Vieira Dourado Tropical Medicine Foundation. Postgraduate Program in Tropical Medicine. Manaus, AM, Brazil.University of Amazonas State. Postgraduate Program in Tropical Medicine. Manaus, AM, Brazil / Doctor Heitor Vieira Dourado Tropical Medicine Foundation. Postgraduate Program in Tropical Medicine. Manaus, AM, Brazil.Instituto Fernandes Figueira. Clinical Research Unit. Rio de Janeiro, RJ, Brazil.Oswaldo Cruz Foundation. Instituto Fernandes Figueira. Clinical Research Unit. Rio de Janeiro, RJ, Brazil.Oswaldo Cruz Foundation. Instituto Fernandes Figueira. Obstretics. Rio de Janeiro, RJ, Brazil.University of California. David Geffen School of Medicine. Department of Pediatrics. Los Angeles, CA, Estados Unidos.Oswaldo Cruz Foundation. Research Center Aggeu Magalhães. Recife, PE, Brazil.London School of Hygiene & Tropical Medicine. Department of Infectious Disease Epidemiology. London, UK.Oswaldo Cruz Foundation. Research Center Aggeu Magalhães. Recife, PE, Brazil.Altino Ventura Foundation. Department of Ophthalmology. Recife, PE, Brazil / Pernambuco Eyes Hospital. Recife, PE, Brazil.Ministério da Saúde. Secretaria de Vigilância em Saúde e Ambiente. Instituto Evandro Chagas. Ananindeua, PA, Brasil.Ministério da Saúde. Secretaria de Vigilância em Saúde e Ambiente. Instituto Evandro Chagas. Ananindeua, PA, Brasil.Ministério da Saúde. Secretaria de Vigilância em Saúde e Ambiente. Instituto Evandro Chagas. Ananindeua, PA, Brasil.Ministério da Saúde. Secretaria de Vigilância em Saúde e Ambiente. Instituto Evandro Chagas. Ananindeua, PA, Brasil.Medicine School of São José do Rio Preto. Department of Infectious Disease. São José do Rio Preto, SP, Brazil.Medicine School of São José do Rio Preto. Department of Infectious Disease. São José do Rio Preto, SP, Brazil.Medicine School of São José do Rio Preto. Department of Gynecology and Obstetrics. São José do Rio Preto, SP, Brazil.Medicine School of Jundiaí. Infectious Pediatric Laboratory. Jundiaí, SP, Brazil.Federal University of São Paulo. Department of Fetal Medicine. São Paulo, SP, Brazil.Father Anchieta University Center. Nursing School. Jundiaí, SP, Brazil.Federal University of São Paulo. Paulista School of Medicine. Departament of Obstetrics. São Paulo, SP, Brazil.Federal University of Goiás. Institute of Tropical Pathology and Public Health. Goiânia, GO, Brazil.Health Secretariat of Goiás State. Maternal and Child Hospital. Goiânia, GO, Brazil.Federal University of São Paulo. Paulista School of Medicine. Departament of Obstetrics. São Paulo, SP, Brazil.Health Secretariat of Goiás State. Maternal and Child Hospital. Goiânia, GO, Brazil.Universidade Federal do Rio Grande do Sul. Hospital das Clinicas de Porto Alegre. Departamento de Genética. Porto Alegre, RS, Brazil.City Hall of Tangará da Serra, Municipal Health Department, Tangará da Serra, MT, Brazil.Federal University of Campina Grande. Medical Academic Unit. Campina Grande, PB, Brazil.Federal University of Campina Grande. Medical Academic Unit. Campina Grande, PB, Brazil.Federal University of Rio de Janeiro. Department of Pediatrics. Rio de Janeiro, RJ, Brazil.D’Or Institute for Research & Education. Department of Pediatrics. Rio de Janeiro, RJ, Brazil.Departmentiversity of Rio de Janeiro Maternity School. Department of Obstectrics. Rio de Janeiro, RJ, Brazil.Departmentiversity of Rio de Janeiro Maternity School. Department of Obstectrics. Rio de Janeiro, RJ, Brazil.Reference Maternity Prof. José Maria de Magalhães Netto. Bahia Health Department, Salvador, BA, Brazil.Oswaldo Cruz Foundation. Gonçalo Moniz Institute. Salvador, BA, Brazil.Oswaldo Cruz Foundation. Gonçalo Moniz Institute. Salvador, BA, Brazil.Federal University of Rio de Janeiro. Department of Infecitous Diseases. Rio de Janeiro, RJ, Brazil.Federal University of Rio de Janeiro. Department of Infecitous Diseases. Rio de Janeiro, RJ, Brazil.Oswaldo Cruz Foundation. Gonçalo Moniz Institute. Salvador, BA, Brazil.Oswaldo Cruz Foundation. Leonidas and Maria Deane Institute. Manaus, AM, Brazil.University of Amazonas State. Postgraduate Program in Tropical Medicine. Manaus, AM, Brazil / Doctor Heitor Vieira Dourado Tropical Medicine Foundation. Postgraduate Program in Tropical Medicine. Manaus, AM, Brazil / Oswaldo Cruz Foundation. Leonidas and Maria Deane Institute. Manaus, AM, Brazil.Oswaldo Cruz Foundation. Instituto Nacional de Infectologia Evandro Chagas. Rio de Janeiro, RJ, Brazil.Background: Knowledge regarding the risks associated with Zika virus (ZIKV) infections in pregnancy has relied on individual studies with relatively small sample sizes and variable risk estimates of adverse outcomes, or on surveillance or routinely collected data. Using data from the Zika Brazilian Cohorts Consortium, this study aims, to estimate the risk of adverse outcomes among offspring of women with RT-PCR-confirmed ZIKV infection during pregnancy and to explore heterogeneity between studies. Methods: We performed an individual participant data meta-analysis of the offspring of 1548 pregnant women from 13 studies, using one and two-stage meta-analyses to estimate the absolute risks. Findings: Of the 1548 ZIKV-exposed pregnancies, the risk of miscarriage was 0.9%, while the risk of stillbirth was 0.3%. Among the pregnancies with liveborn children, the risk of prematurity was 10,5%, the risk of low birth weight was 7.7, and the risk of small for gestational age (SGA) was 16.2%. For other abnormalities, the absolute risks were: 2.6% for microcephaly at birth or first evaluation, 4.0% for microcephaly at any time during follow-up, 7.9% for neuroimaging abnormalities, 18.7% for functional neurological abnormalities, 4.0% for ophthalmic abnormalities, 6.4% for auditory abnormalities, 0.6% for arthrogryposis, and 1.5% for dysphagia. This risk was similar in all sites studied and in different socioeconomic conditions, indicating that there are not likely to be other factors modifying this association. Interpretation: This study based on prospectively collected data generates the most robust evidence to date on the risks of congenital ZIKV infections over the early life course. Overall, approximately one-third of liveborn children with prenatal ZIKV exposure presented with at least one abnormality compatible with congenital infection, while the risk to present with at least two abnormalities in combination was less than 1.0%

Risk of adverse outcomes in offspring with RT-PCR confirmed prenatal Zika virus exposure: an individual participant data meta-analysis of 13 cohorts in the Zika Brazilian Cohorts ConsortiumResearch in context

Summary: Background: Knowledge regarding the risks associated with Zika virus (ZIKV) infections in pregnancy has relied on individual studies with relatively small sample sizes and variable risk estimates of adverse outcomes, or on surveillance or routinely collected data. Using data from the Zika Brazilian Cohorts Consortium, this study aims, to estimate the risk of adverse outcomes among offspring of women with RT-PCR-confirmed ZIKV infection during pregnancy and to explore heterogeneity between studies. Methods: We performed an individual participant data meta-analysis of the offspring of 1548 pregnant women from 13 studies, using one and two-stage meta-analyses to estimate the absolute risks. Findings: Of the 1548 ZIKV-exposed pregnancies, the risk of miscarriage was 0.9%, while the risk of stillbirth was 0.3%. Among the pregnancies with liveborn children, the risk of prematurity was 10,5%, the risk of low birth weight was 7.7, and the risk of small for gestational age (SGA) was 16.2%. For other abnormalities, the absolute risks were: 2.6% for microcephaly at birth or first evaluation, 4.0% for microcephaly at any time during follow-up, 7.9% for neuroimaging abnormalities, 18.7% for functional neurological abnormalities, 4.0% for ophthalmic abnormalities, 6.4% for auditory abnormalities, 0.6% for arthrogryposis, and 1.5% for dysphagia. This risk was similar in all sites studied and in different socioeconomic conditions, indicating that there are not likely to be other factors modifying this association. Interpretation: This study based on prospectively collected data generates the most robust evidence to date on the risks of congenital ZIKV infections over the early life course. Overall, approximately one-third of liveborn children with prenatal ZIKV exposure presented with at least one abnormality compatible with congenital infection, while the risk to present with at least two abnormalities in combination was less than 1.0%. Funding: National Council for Scientific and Technological Development - Brazil (Conselho Nacional de Desenvolvimento Científico e Tecnológico – CNPq); Wellcome Trust and the United Kingdom's Department for International Development; European Union's Horizon 2020 research and innovation program; Medical Research Council on behalf of the Newton Fund and Wellcome Trust; National Institutes of Health/National Institute of Allergy and Infectious Diseases; Foundation Christophe et Rodolphe Mérieux; Coordination for the improvement of Higher Education Personnel (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Capes); Ministry of Health of Brazil; Brazilian Department of Science and Technology; Foundation of Research Support of the State of São Paulo (Fundação de Amparo à Pesquisa do Estado de São Paulo – FAPESP); Foundation of Research Support of the State of Rio de Janeiro (Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro – FAPERJ); Foundation of Support for Research and Scientific and Technological Development of Maranhão; Evandro Chagas Institute/Brazilian Ministry of Health (Instituto Evandro Chagas/Ministério da Saúde); Foundation of Research Support of the State of Goiás (Fundação de Amparo à Pesquisa do Estado de Goiás – FAPEG); Foundation of Research Support of the State of Rio Grande do Sul (Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul – FAPERGS); Foundation to Support Teaching, Research and Assistance at Hospital das Clínicas, Faculty of Medicine of Ribeirão Preto (Fundação de Apoio ao Ensino, Pesquisa e Assistência do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto); São Paulo State Department of Health (Secretaria de Saúde do Estado de São Paulo); Support Foundation of Pernambuco Science and Technology (Fundação de Amparo à Ciência e Tecnologia de Pernambuco – FACEPE)