title: The effect of azithromycin on the immunogenicity of oral poliovirus vaccine: a double-blind randomised placebo-controlled trial in seronegative Indian infants.
abstract: Oral poliovirus vaccine is less immunogenic and effective in low-income countries than in high-income countries, similarly to other oral vaccines. The high prevalence of intestinal pathogens and associated environmental enteropathy has been proposed to explain this problem. Because administration of an antibiotic has the potential to resolve environmental enteropathy and clear bacterial pathogens, we aimed to assess whether antibiotics would improve oral poliovirus vaccine immunogenicity.
  
  
  
  We did a double-blind, randomised, placebo-controlled trial of the effect of azithromycin on the immunogenicity of serotype-3 monovalent oral poliovirus vaccine given to healthy infants living in 14 blocks of Vellore district, India. Infants were eligible to participate if they were 6-11 months old, available for the study duration, and lacked serum neutralising antibodies to serotype-3 poliovirus. Infants were randomly assigned (1:1) at enrolment to receive oral 10 mg/kg azithromycin or placebo once daily for 3 days, followed by serotype-3 monovalent oral poliovirus vaccine on day 14. The primary outcome was detection of serum neutralising antibodies to serotype-3 poliovirus at a dilution of one in eight or more on day 35 and was assessed in the per-protocol population (ie, all those who received azithromycin or placebo, oral poliovirus vaccine, and provided a blood sample according to the study protocol). Safety outcomes were assessed in all infants enrolled in the study. The trial is registered with the Clinical Trials Registry India, number CTRI/2014/05/004588.
  
  
  
  Between Aug 5, 2014, and March 21, 2015, 754 infants were randomly assigned: 376 to receive azithromycin and 378 to placebo. Of these, 348 (93%) of 376 in the azithromycin group and 357 (94%) of 378 infants in the placebo group completed the study per protocol. In the azithromycin group, 175 (50%) seroconverted to serotype-3 poliovirus compared with 192 (54%) in the placebo group (risk ratio 0·94, 95% CI 0·81-1·08; p=0·366). Azithromycin reduced faecal biomarkers of environmental enteropathy (calprotectin, myeloperoxidase, α1-antitrypsin) and the prevalence of bacterial but not viral or eukaryotic pathogens. Viral pathogens were associated with lower seroconversion. Three serious adverse events were reported (two in the azithromycin group and one in the placebo group), but none was considered related to the study interventions.
  
  
  
  Azithromycin did not improve the immunogenicity of oral poliovirus vaccine despite reducing biomarkers of environmental enteropathy and the prevalence of pathogenic intestinal bacteria. Viral interference and innate antiviral immune mechanisms might be more important determinants of the immunogenicity of live-virus oral vaccines.
  
  
  
  Bill & Melinda Gates Foundation.
authors.affiliation: Department of Infectious Disease Epidemiology, Imperial College London, London, UK; Christian Medical College, Vellore, Tamil Nadu, India. Electronic address: n.grassly@imperial.ac.uk.
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Grassly
authors.affiliation: Christian Medical College, Vellore, Tamil Nadu, India.
authors.forename: Ira
authors.initials: I
authors.lastname: Praharaj
authors.affiliation: Christian Medical College, Vellore, Tamil Nadu, India.
authors.forename: Sudhir
authors.initials: S
authors.lastname: Babji
authors.affiliation: Christian Medical College, Vellore, Tamil Nadu, India.
authors.forename: Saravanakumar Puthupalayam
authors.initials: SP
authors.lastname: Kaliappan
authors.affiliation: Christian Medical College, Vellore, Tamil Nadu, India.
authors.forename: Sidhartha
authors.initials: S
authors.lastname: Giri
authors.affiliation: Christian Medical College, Vellore, Tamil Nadu, India.
authors.forename: Srinivasan
authors.initials: S
authors.lastname: Venugopal
authors.affiliation: Department of Infectious Disease Epidemiology, Imperial College London, London, UK.
authors.forename: Edward P K
authors.initials: EP
authors.lastname: Parker
authors.affiliation: Christian Medical College, Vellore, Tamil Nadu, India.
authors.forename: Asha
authors.initials: A
authors.lastname: Abraham
authors.affiliation: Christian Medical College, Vellore, Tamil Nadu, India.
authors.forename: Jayaprakash
authors.initials: J
authors.lastname: Muliyil
authors.affiliation: Christian Medical College, Vellore, Tamil Nadu, India.
authors.forename: Sridhar
authors.initials: S
authors.lastname: Doss
authors.affiliation: Christian Medical College, Vellore, Tamil Nadu, India.
authors.forename: Uma
authors.initials: U
authors.lastname: Raman
authors.affiliation: Division of Infectious Diseases and International Health, University of Virginia School of Medicine, Charlottesville, VA, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.affiliation: Christian Medical College, Vellore, Tamil Nadu, India.
authors.forename: John Victor
authors.initials: JV
authors.lastname: Peter
authors.affiliation: Christian Medical College, Vellore, Tamil Nadu, India.
authors.forename: Meghana
authors.initials: M
authors.lastname: Paranjape
authors.affiliation: Christian Medical College, Vellore, Tamil Nadu, India.
authors.forename: Shalini
authors.initials: S
authors.lastname: Jeyapaul
authors.affiliation: Christian Medical College, Vellore, Tamil Nadu, India.
authors.forename: Shailaja
authors.initials: S
authors.lastname: Balakumar
authors.affiliation: Christian Medical College, Vellore, Tamil Nadu, India.
authors.forename: Jeniffer
authors.initials: J
authors.lastname: Ravikumar
authors.affiliation: Christian Medical College, Vellore, Tamil Nadu, India.
authors.forename: Rajan
authors.initials: R
authors.lastname: Srinivasan
authors.affiliation: WHO Regional Office for South-East Asia, New Delhi, India.
authors.forename: Sunil
authors.initials: S
authors.lastname: Bahl
authors.affiliation: Institute of Infection and Global Health, and NIHR Health Protection Research Unit in Gastrointestinal Infection, University of Liverpool, Liverpool, UK.
authors.forename: Miren
authors.initials: M
authors.lastname: Iturriza-Gómara
authors.affiliation: Translational Gastroenterology Unit, Nuffield Department of Medicine, and Department of Paediatrics, University of Oxford, Oxford, UK.
authors.forename: Holm H
authors.initials: HH
authors.lastname: Uhlig
authors.affiliation: Division of Infectious Diseases and International Health, University of Virginia School of Medicine, Charlottesville, VA, USA.
authors.forename: Eric R
authors.initials: ER
authors.lastname: Houpt
authors.affiliation: Christian Medical College, Vellore, Tamil Nadu, India.
authors.forename: Jacob
authors.initials: J
authors.lastname: John
authors.affiliation: Christian Medical College, Vellore, Tamil Nadu, India.
authors.forename: Gagandeep
authors.initials: G
authors.lastname: Kang
mesh_terms: D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D000914:Antibodies, Viral / Q000097:blood; D017963:Azithromycin / Q000627:therapeutic use*; D004311:Double-Blind Method; D006801:Humans; D007115:Immunization Schedule; D000071497:Immunogenicity, Vaccine; D007194:India; D007223:Infant; D011051:Poliomyelitis / Q000517:prevention & control; D017955:Poliovirus / Q000276:immunology; D011055:Poliovirus Vaccine, Oral / Q000008:administration & dosage* / Q000276:immunology; D014611:Vaccination / Q000379:methods
chemical_list: D000900:Anti-Bacterial Agents; D000914:Antibodies, Viral; D011055:Poliovirus Vaccine, Oral; D017963:Azithromycin