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Exploration of the biologic basis for underperformance of oral polio and rotavirus vaccines. Progress to Date - Bangladesh. Oral polio and rotavirus vaccines are significantly less effective in children living in the developing world compared to peers in other countries.

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exploration of the biologic basis for underperformance of oral polio and rotavirus vaccines
Exploration of the biologic basis for underperformance of oral polio and rotavirus vaccines

Progress to Date - Bangladesh

Oral polio and rotavirus vaccines are significantly less effective in children

living in the developing world compared to peers in other countries.

Tropical enteropathy, which is associated with intestinal inflammation,

decreased absorption and increased permeability, may contribute substantially

to oral vaccine failure in developing country settings. The primary hypothesis

of this clinical trial is that tropical enteropathy decreases the effectiveness

of oral polio and rotavirus vaccines in infants by disrupting the enteric

immune system.

This single-blind study will enroll 1,070 healthy infants and their mothers

residing in urban slums in Dhaka, Bangladesh and Kolkata, India in two

prospective cohorts. The Bangladesh arm of the study, enrolling 700 infants from May 2011, will employ a 2x2 factorial study design, separately randomizing infants to receive oral rotavirus vaccine (Rotarix) and a boost of inactivated polio vaccine (IPV). The India arm of the study, enrolling 370 infants from early 2012, will randomize infants for a boost of IPV.

The trial will investigate other possible causes of oral vaccine underperformance,

including: malnutrition, interference with maternal or breast milk antibodies,

changes in gut microbiota, and genetic susceptibility.

Introduction

Research Objectives

Study Design

Acknowledgements

2 x 2 Factorial Study Design (Bangladesh)

Group A Rotarix + No IPV (175)

Group B Rotarix + with IPV boost (175)

Group C No Rotarix + No IPV (175)

Group D No Rotarix + with IPV boost (175)

This research is funded through the generous support of Bill and Melinda Gates Foundation.

Primary Objective

Determine whether decreased vaccine responsiveness to oral polio or rotavirus vaccines is associated with the presence of

tropical enteropathy.

Secondary Objectives

Determine the impact of an inactivated polio vaccine (IPV) boost on systemic (neutralizing antibodies) and mucosal immune

responses (shedding OPV vaccine virus) to polio vaccines following vaccination with oral polio vaccine (OPV).

Determine the efficacy of rotavirus vaccination to prevent rotavirus diarrhea.

Exploratory Objectives

Describe the impact on vaccine failure and tropical enteropathy due to:

  • Breast milk and maternal antibodies
  • Malnutrition
  • Genetics (pending funding)
  • Changes in gut microbiome (Jeff Gordon)
  • Enteric Infections (Houpt: multiplex PCR)

Devise novel cellular assays to explore immunologic phenotypes with vaccine failure and TE (Mark Davis, Stanford)

  • Phospho-flow (phosphorylation of STAT proteins)
  • Mass spec based flow cytometry (CyTOF)
  • Combinatorial tetramers with CyTOF
  • Gene expression

Evaluate modified immunogenicity assays and biomarkers

  • ALS vs. ELISPOT
  • Breast milk IgA
  • Fecal IgA
  • Novel markers or indices of tropical enteropathy (with MAL-ED)

Laboratory Progress

Conducted extractions for fecal IgAanalysis on:

Week 6 specimens 130

Week 17 specimens 19

Week 18 specimens 9

Shipped 252 stool specimens to the Bangladesh National Polio Lab for vaccine excretion analysis. Received preliminary results on 66 specimens.

Processed 156 Week 6 blood specimens and 35 Week 18 blood specimens.

Shipped 130 whole blood specimens to Children’s Hospital Oakland Research Institute for HLA analysis.

Completed initial processing of 150 whole blood specimens for Phosphoflow analysis and shipped to Stanford University.

Completed piloting of ALS assay for both rotavirus and polio.

Methods

Colgate ER, Kirkpatrick BD (University of Vermont); Haque R, Qadri F, Zaman K (ICDDR,B); Sur D (NICED); Czerkinsky C (IVI);

Davis M (Stanford University); Gordon J (Washington University); Mychaleckyj J, Petri WA (University of Virginia)

Clinical Progress since May 2011

Households surveilled 28,000+

Infants Screened 363

Infants Enrolled 215 (59% of screened)

Adverse Events 16

Serious Adverse Events 6

Early Withdrawals 33 (15% of enrolled)

Protocol Deviations 204

Specimen Collection

Infant blood 2ml – 5ml

Vaccine shedding stools

Study visit stools

Diarrheal stools

Infant urine

Mother blood

Mother breast milk

Clinic Procedures

Gestational age assessment

Anthropometry: child and mother

Biweekly diarrhea surveillance

Laboratory Assays

Vaccine Immunogenicity

  • ALS or Elispot (Polio and Rotavirus)
  • Polio Plasma Neutralizing Antibody
  • Rotavirus Plasma IgA
  • Fecal excretion of vaccine virus
  • Fecal IgA
  • Fecal cytokines
  • Mother breast milk IgA

Systemic Immunity

  • Tetanus IgG

Exploratory Immunology

  • Phosphorylation of STAT proteins
  • Tetramer-flow cytometry
  • CyTOF mass spec based cellular analysis
  • Gene expression

Tropical Enteropathy

  • Lactulose-Mannitol urine test
  • Plasma α-LPS and CRP

Nutritional Status

  • Retinol, Vitamin D, Zinc, Ferritin

HLA

Microbiome

Oral Polio Vaccine Efficacy2

Rotavirus Vaccine Efficacy1

Malnourished children (by HAZ) in Dhaka are more unresponsive to OPV.

1Parashar UD, Glass RI. Rotavirus vaccines--early success, remaining questions. N Engl J Med. Mar 12 2009;360(11):1063-1065.

2Petri, Snider, Pallansch, and Haque (unpublished)