Patients receive standardized treatment, consisting of Oseltamivir and Azithromycin

Patients receive intravenous infusion of 1x10^6 unit of umbilical-cord derived mesenchymal stem cells (UC-MSCs)/kgBW in 100 cc of 0.9% NaCl for 1 hour, in addition to standardized treatment

COVID

Pulmonary Infection

Sars-CoV2

Current standardized treatment for Covid-19

Oseltamivir

Azithromycin

Adjuvant therapy on top of current standardized treatment (Oseltamivir + Azithromycin)

Umbilical Cord Mesenchymal Stem Cells

Cipto Mangunkusumo General Hospital

Persahabatan General Hospital

Sulianti Saroso Center for Infectious Disease

Universitas Indonesia Hospital

Administration of Allogenic UC-MSCs as Adjuvant Therapy for Critically-Ill COVID-19 Patients

Application of Umbilical Cord Mesenchymal Stem Cells as Adjuvant Therapy for Critically-Ill COVID-19 Patients

Assessing whether the patients still have dyspnea, one of cardinal symptoms of Covid-19, assessed from the respiratory rate

Assessing whether the patients still have productive cough, one of cardinal symptoms of Covid-19, assessed from lung auscultation

Assessing the presence of fever from measurement of body temperature checking, assessed on daily basis

Assessing whether the patients still require ventilation, one of cardinal symptoms of ARDS in Covid-19, assessed from patients' ability during ventilation weaning phase

Assessing the patients' blood pressure on daily basis

Assessing the patients' heart rate on daily basis

Assessing the patients' respiratory rate on daily basis

Assessing the patients' oxygen saturation on daily basis

Assessing the changes in total leukocyte upon MSCs administration, assessed prior to and 1st day after implantation, then once every 3 days post implantation

Assessing the changes in lymphocytes level upon MSCs administration, assessed prior to and 1st day after implantation, then once every 3 days post implantation

Assessing the changes in blood pH level upon MSCs administration, assessed prior to and 1st day after implantation, then once every 3 days post implantation

Assessing the changes in blood base excess level upon MSCs administration, assessed prior to and 1st day after implantation, then once every 3 days post implantation

Assessing the changes in blood oxygen partial pressure upon MSCs administration, assessed prior to and 1st day after implantation, then once every 3 days post implantation

Assessing the changes in blood level of HCO3 upon MSCs administration, assessed prior to and 1st day after implantation, then once every 3 days post implantation

Assessing the changes in blood level of O2 saturation upon MSCs administration, assessed prior to and 1st day after implantation, then once every 3 days post implantation

Assessing the changes in level of CRP, assessed prior to and 1st day after implantation, then once every 3 days post implantation

Assessing the changes in laboratory parameter, consist of SGOT/SGPT (AST/ALT) level, assessed prior to and 1st day after implantation, then once every 3 days post implantation

Assessing the changes in laboratory parameter, consist of ureum/creatinine level, assessed prior to and 1st day after implantation, then once every 3 days post implantation

Assessing the changes in laboratory parameter, consist of eGFR, assessed prior to and 1st day after implantation, then once every 3 days post implantation

Assessing the changes in level of sodium, assessed prior to and 1st day after implantation, then once every 3 days post implantation

Assessing the changes in level of potassium, assessed prior to and 1st day after implantation, then once every 3 days post implantation

Assessing the changes in level of chloride, assessed prior to and 1st day after implantation, then once every 3 days post implantation

Assessing the changes in procalcitonin level to assess the anti-inflammatory properties of MSCs, assessed prior to and 1st day after implantation, then once every 3 days post implantation

Assessing the changes in albumin level, assessed prior to and 1st day after implantation, then once every 3 days post implantation

Assessing the changes in total bilirubin level, assessed prior to and 1st day after implantation, then once every 3 days post implantation

Assessing the changes in D-Dimer to assess the anti-inflammatory properties of MSCs, assessed prior to and 1st day after implantation, then once every 3 days post implantation

Assessing the changes in fibrinogen to assess the anti-inflammatory properties of MSCs, assessed prior to and 1st day after implantation, then once every 3 days post implantation

Assessing the changes in troponin level to assess the anti-inflammatory properties of MSCs and their effect in cardiac remodelling, assessed prior to and 1st day after implantation, then once every 3 days post implantation

Assessing the changes in NT proBNP to assess the anti-inflammatory properties of MSCs and their effect in cardiac remodelling, assessed prior to and 1st day after implantation, then once every 3 days post implantation

Assessing the changes in leukemia inhibiting factor (LIF) to assess the anti-inflammatory properties of MSCs, assessed prior to implantation and on the 7th day post-implantation

Assessing the changes in level of IL-6 to assess the anti-inflammatory properties of MSCs, assessed prior to implantation and on the 7th day post-implantation

Assessing the changes in level of IL-10 to assess the anti-inflammatory properties of MSCs, assessed prior to implantation and on the 7th day post-implantation

Assessing the changes in vascular endothelial growth factor (VEGF) to assess the effect of growth factors in the MSCs, assessed prior to implantation and on the 7th day post-implantation

Assessing the changes in level of ferritin to assess the anti-inflammatory properties of MSCs, assessed prior to implantation and on the 7th day post-implantation

Assessing the changes in level of CXCR3 to assess the anti-inflammatory properties of MSCs, assessed prior to implantation and on the 7th day post-implantation

Assessing the changes in level of CD4 to assess the anti-inflammatory properties of MSCs, assessed prior to implantation and on the 7th day post-implantation

Assessing the changes in level of CD8 to assess the anti-inflammatory properties of MSCs, assessed prior to implantation and on the 7th day post-implantation

Assessing the changes in CD56 to assess the anti-inflammatory properties of MSCs, assessed prior to implantation and on the 7th day post-implantation

Assessing the changes in radiology examination (Chest X-Ray/CT Scan) for any increased in lung infiltration or ground glass opacity, assessed prior to implantation and once every 3 days post-implantation

Ismail Hadisoebroto Dilogo

Principal Investigator

Indonesia University

1,200 pregnant women (600 HIV+ mothers and 600 HIV-controls) in their third trimester were enrolled from January 2016 to June 2019. Participants are being followed as mother-baby pairs at birth, within 10 days of life 6, 10, 14 24, 48, 72 and 96 weeks of age. At each visit clinical examinations are being used to assess health and the impact of environmental factors. In addition, questionnaires are administered and bio-samples for laboratory tests. The design of the study is non-interventional cohort but participants are being offered advice regarding health and hygiene.

maternal urine, stool, plasma, milk, cord blood, amniotic fluid, placenta, infant serum/plasma, dried blood spots and stool

HIV Infections

Immune Activation

Cormobidities

The University of Zimbabwe College of Health Science (UZ-CHS) BIRTH COHORT Study

HIV Exposure, Disease Acquisition and Progression Among Children: Role of Maternal Immunogenetics, Viral Genetic Diversity, HAART Exposure, Co-morbidities and Psycho-Social Status: (UZ-CHS Birth Cohort)

Comparison of morbidity of HEU vs. HUU infants, defined as impaired growth, immune- and neuro-development and/ or frequent clinically relevant infections

To determine any association of maternal HIV infection, HAART exposure.

To determine any association with maternal HIV and HAART exposure.

To determine any association of HAART exposure in utero and during breast feeding with pregnancy outcome, infant (HUU, HEU, HEI) growth and immune- and neuro-development.

To determine vertical transmission rates for HIV at birth and within the first 2 years of life and assess risk factors for transmission

HIV incidence rate among mother sero-negative at enrollment

To determine the association between maternal baseline and delivery HAART levels in different compartments and the relation of those to infant HIV transmission, mortality and morbidity.

To determine the association between antenatal immune dysregulation and infant death, growth and immune responses to vaccines.

To determine HIV drug resistance profiles in mother and infants unresponsive to HAART

To determine how CMV DNA is influenced by HIV infection, HAART use and as single infection or combined infections in HIV+ and HIV- women and determine the impact on pregnancy outcome and infant cmv vertical transmission

To determine how HBV infection infections in HIV+ and HIV- women and determine the impact on pregnancy outcome, infant vertical transmission

To determine HCV infections proportion in HIV positives and negatives and HIV+ and HIV- women and determine the impact on pregnancy outcome, infant incidence of congenital cmv infection

To determine syphilis infections proportion in HIV positives and negatives and the impact on pregnancy outcome, infant incidence of congenital syphilis infection

To determine the prevalence of helminthes infection using 18s sequencing and correlate with infant development of atopic dermatitis.

To determine the prevalence of maternal under and overnutrition using BMI and MUAC impact on pregnancy outcomes, infant mortality and morbidity.

To assess abnormalities in HIV + and HIV- including lipid profiles, bone, haematological (anemia) and hepatic toxicities associated with exposure to HAART among mothers and infants.

To determine infant non-infectious comorbidities (e.g. anaemia, atopic dermatitis, congenital infections and other conditions) and their impact on mortality and morbidity.

To assess delayed neuro-cognitive development using the Denver II tool in HUU, HEU and HEI infants and correlated with socio economic status and infectious diseases.

To determine humoural immune responses to EPI vaccines including antibody levels against measles, tetanus, diphtheria, pertussis, polio and rotavirus) in HUU, HEU and HEI infants.

To determine immune activation and systemic inflammatory biomarkers in HUU, HEU and HEI infants

To determine biomarkers for endothelial dysfunction including microbial translocation in HUU, HEU and HEI infants and association with household hygiene at delivery, 6, 48 and 96 weeks of age.

To determine antenatal reference ranges for MUAC, haemoglobin from FBC analyses, and biochemistry (kidney function, liver function tests, bone, lipid profiles) in mothers with a favourable outcome of pregnancy

To determine maternal- infant microbiota16S sequencing in pregnancy and relate it to infant immune development and atopy (anti-inflammatory (IL-4, -5, -13) and regulatory cytokines (IL-10, TGF-β) at delivery, 6 weeks 48 and 96 weeks of age.

Bacterial full genome metagenomics shotgun sequencing to identify the microbiota metabolic potential (i.e. bacterial genes present will be done) and mass spectrometry will be performed for analysis of small intestinal content (metabolome).

Wide range of nutritional profiles and HAART levels spectrometry will be performed for analysis of at least 700 metabolites including amino acids and lipids will be performed in plasma, breast milk and stool samples

To characterize pathogen genetic diversity including HIV, HBV, HCV, CMV subtypes, prevalent in our study population at time of infection

To determine host genetic markers for infectious disease susceptibility including human leukocyte antigen (HLA) and killer immunoglobulin like receptor (KIR) gene variants and their association with infection rates of HIV and co-infections in mothers and their infants.

Only anonymous data will be stored at local sites and transferred between sites for collaborative research efforts. All original data will be stored locally at the UZ-CHS for at least 10 years on suitable electronic devices. Data transfer with collaborating partners will be encrypted. using EGAcryptor. With our European partners we will follow the current European General Data Protection Regulation effective May 25, 2018.

Kerina Duri

Associate Professor

University of Zimbabwe

University Hospital Inselspital, Berne

University of Hamburg

University of Oxford

Wellcome Trust

University of Yaounde

University of Cape Town

Midlands State University, Zimbabwe

National Institute of Health Research, Zimbabwe

Pediatric participants received ProQuad® Dose 1 at 9 months of age and ProQuad® Dose 2 at 12 months of age.

Pediatric participants received ProQuad® Dose 1 at 11 months of age and ProQuad® Dose 2 at 14 months of age.

Pediatric participants received ProQuad® Dose 1 at 12 months of age and ProQuad® Dose 2 at 15 months of age.

Pediatric participants received ProQuad® Dose 1 at 9 months of age and ProQuad® Dose 2 90 days later at 12 months of age.

Arm 1: ProQuad® at 9 and 12 Months

Pediatric participants received ProQuad® Dose 1 at 11 months of age and ProQuad® Dose 2 90 days later at 14 months of age.

Arm 2: ProQuad® at 11 and 14 Months

Pediatric participants received ProQuad® Dose 1 at 12 months of age and ProQuad® Dose 2 90 days later at 15 months of age.

Arm 3: ProQuad® at 12 and 15 Months

Total

Sex: Female, Male

Immunogenicity response rates were compared in participants with baseline seronegativity from Arm 2 (received ProQuad® Dose 1 at 11 months) and Arm 3 (received ProQuad® Dose 1 at 12 months). Measles, mumps and rubella antibody levels were determined using enzyme-linked immunosorbent assay (ELISA) and varicella antibody levels were determined with glycoprotein-based ELISA (gpELISA). Response and baseline seronegativity criteria were as follows: measles antibody titre ≥255 mIU/mL in participants with baseline titre <255 mIU/mL; mumps antibody titre ≥10 ELISA Ab units/mL in participants with baseline titre <10 ELISA Ab units mL; rubella antibody titre ≥10 IU/mL in participants with baseline titre <10 IU/mL; varicella antibody titre ≥5 gpELISA units/mL in participants with baseline titre <1.25 gpELISA units/mL.

Percentage of Participants in Arm 2 and Arm 3 Meeting Antibody Immunogenicity Response Criteria Following ProQuad® Dose 2

Immunogenicity response rates were compared in participants with baseline seronegativity from Arm 1 (received ProQuad® Dose 1 at 9 months) and Arm 3 (received ProQuad® Dose 1 at 12 months). Measles, mumps and rubella antibody levels were determined using ELISA and varicella antibody levels were determined with gpELISA. Response and baseline seronegativity criteria were as follows: measles antibody titre ≥255 mIU/mL in participants with baseline titre <255 mIU/mL; mumps antibody titre ≥10 ELISA Ab units/mL in participants with baseline titre <10 ELISA Ab units mL; rubella antibody titre ≥10 IU/mL in participants with baseline titre <10 IU/mL; varicella antibody titre ≥5 gpELISA units/mL in participants with baseline titre <1.25 gpELISA units/mL.

Percentage of Participants in Arm 1 and Arm 3 Meeting Antibody Immunogenicity Response Criteria Following ProQuad® Dose 2

The solicited injection-site AEs erythema, swelling, and pain were monitored for 4 days after administration of ProQuad® Dose 1.

Percentage of Participants With Solicited Injection-site Adverse Reactions

The percentage of participants with unsolicited injection-site reactions after ProQuad® Dose 1 was determined.

Percentage of Participants Experiencing Unsolicited Injection-site Adverse Reactions

The percentage of participants with systemic adverse events after ProQuad® Dose 1 was determined.

Percentage of Participants Experiencing a Systemic Adverse Event After ProQuad® Dose 1

The percentage of participants with a rectal (or rectal equivalent) temperature ≥ 39.4°C after ProQuad® Dose 1 was determined.

Percentage of Participants With Rectal (or Rectal Equivalent) Temperature ≥ 39.4°C

Antibody titres (GMT) to measles, mumps, rubella, and varicella were determined after the first ProQuad® dose in participants with seronegative baseline values. Baseline seronegativity criteria were as follows: measles antibody titre <255 mIU/mL; mumps antibody titre <10 ELISA Ab units mL; rubella antibody titre <10 IU/mL; and varicella antibody titre <1.25 gpELISA units/mL.

Geometric Mean Titres (GMT) to Measles, Mumps, Rubella, and Varicella After ProQuad® Dose 1

Antibody titres (GMT) to measles, mumps, rubella, and varicella were determined after the second ProQuad® dose in participants with seronegative baseline values. Baseline seronegativity criteria were as follows: measles antibody titre <255 mIU/mL; mumps antibody titre <10 ELISA Ab units mL; rubella antibody titre <10 IU/mL; and varicella antibody titre <1.25 gpELISA units/mL.

GMT to Measles, Mumps, Rubella, and Varicella After ProQuad® Dose 2

The percentage of participants with varicella antibody titre ≥ 1.25 gpELISA units/mL 6 weeks after each ProQuad® dose was determined.

Percentage of Participants With Varicella Antibody Titre ≥ 1.25 gpELISA Units/mL

The percentage of baseline seronegative participants meeting measles, mumps, rubella, and varicella antibody response criteria after the first ProQuad® dose was determined. Measles, mumps and rubella antibody levels were determined using ELISA and varicella antibody levels were determined with gpELISA. Response and baseline seronegativity criteria were as follows: measles antibody titre ≥255 mIU/mL in participants with baseline titre <255 mIU/mL; mumps antibody titre ≥10 ELISA Ab units/mL in participants with baseline titre <10 ELISA Ab units mL; rubella antibody titre ≥10 IU/mL in participants with baseline titre <10 IU/mL; varicella antibody titre ≥5 gpELISA units/mL in participants with baseline titre <1.25 gpELISA units/mL.

Percentage of Baseline Seronegative Participants Meeting Antibody Immunogenicity Response Criteria After ProQuad® Dose 1

The percentage of participants with rashes of interest after ProQuad® Dose 1 was determined. Rashes of interest consisted of measles-like rash, rubella-like rash, varicella-like rash, zoster-like rash, and mumps-like rash.

Percentage of Participants With Non-injection Site Rashes of Interest Following ProQuad® Dose 1

The percentage of participants with rashes of interest after receiving ProQuad® Dose 2 was determined. Rashes of interest consisted of measles-like rash, rubella-like rash, varicella-like rash, zoster-like rash, and mumps-like rash.

Percentage of Participants With Non-injection Site Rashes of Interest Following ProQuad® Dose 2

Overall Study

Senior Vice President, Global Clinical Development

Measles

Mumps

Rubella

Varicella

A 2-dose regimen of ProQuad® (0.5 mL per dose) given via subcutaneous injection into the deltoid muscle at a 3-month interval. Each dose contains measles virus Enders' Edmonston strain (live attenuated), mumps virus Jeryl Lynn™ (Level B) strain (live attenuated), rubella virus Wistar RA 27 or 3 strain (live attenuated), and varicella virus Oka or Merck strain (live attenuated).

ProQuad® manufactured with recombinant Human Albumin (rHA)

Comparative Study of Immunogenicity and Safety of a 2-dose Regimen of ProQuad® Manufactured With rHA (V221-038)

An Open-label, Randomised, Comparative, Multi-centre Study of the Immunogenicity and Safety of a 2-dose Regimen of ProQuad® Manufactured With rHA Administered to Healthy Children From 9 Months of Age

Merck Sharp & Dohme Corp.

V205C, measles, mumps, and rubella virus vaccine live

Comparator: Measles, Mumps, and Rubella Virus Vaccine Live

A Measles, Mumps, and Rubella Investigational Vaccine Trial (V205C-010)(COMPLETED)

A Comparison of the Safety, Tolerability, and Immunogenicity of V205C Manufactured From the 2003 Measles Stock Seed With Recombinant Human Albumin (rHA) Versus Currently Licensed V205C Manufactured From the 1967 Measles Stock Seed With Human Serum Albumin (HSA) in Healthy Children 12 to 18 Months of Age

measles, mumps, and rubella virus vaccine live

Safety, Tolerability, and Immunogenicity of an Investigational Vaccine With Recombinant Human Albumin (rHA) in Children 12 to 18 Months of Age (V205C-009)(COMPLETED)

A Comparison of the Safety, Tolerability, and Immunogenicity of V205C Manufactured With Recombinant Human Albumin (rHA) Versus V205C Manufactured With Pooled-Donor Human Serum Albumin (HSA) in Healthy Children 12 to 18 Months of Age

rubella/albumin

Administration of Allogenic UC-MSCs as Adjuvant Therapy for Critically-Ill COVID-19 Patients

The University of Zimbabwe College of Health Science (UZ-CHS) BIRTH COHORT Study

Comparative Study of Immunogenicity and Safety of a 2-dose Regimen of ProQuad® Manufactured With rHA (V221-038)

A Measles, Mumps, and Rubella Investigational Vaccine Trial (V205C-010)(COMPLETED)

Safety, Tolerability, and Immunogenicity of an Investigational Vaccine With Recombinant Human Albumin (rHA) in Children 12 to 18 Months of Age (V205C-009)(COMPLETED)

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