title: Neutropenia as an Adverse Event following Vaccination: Results from Randomized Clinical Trials in Healthy Adults and Systematic Review.
abstract: BACKGROUND
  In the context of early vaccine trials aimed at evaluating the safety profile of novel vaccines, abnormal haematological values, such as neutropenia, are often reported. It is therefore important to evaluate how these trials should be planned not to miss potentially important safety signals, but also to understand the implications and the clinical relevance.
  
  
  METHODS
  We report and discuss the results from five clinical trials (two with a new Shigella vaccine in the early stage of clinical development and three with licensed vaccines) where the absolute neutrophil counts (ANC) were evaluated before and after vaccination. Additionally, we have performed a systematic review of the literature on cases of neutropenia reported during vaccine trials to discuss our results in a more general context.
  
  
  RESULTS
  Both in our clinical trials and in the literature review, several cases of neutropenia have been reported, in the first two weeks after vaccination. However, neutropenia was generally transient and had a benign clinical outcome, after vaccination with either multiple novel candidates or well-known licensed vaccines. Additionally, the vaccine recipients with neutropenia frequently had lower baseline ANC than non-neutropenic vaccinees. In many instances neutropenia occurred in subjects of African descent, known to have lower ANC compared to western populations.
  
  
  CONCLUSIONS
  It is important to include ANC and other haematological tests in early vaccine trials to identify potential safety signals. Post-vaccination neutropenia is not uncommon, generally transient and clinically benign, but many vaccine trials do not have a sampling schedule that allows its detection. Given ethnic variability in the level of circulating neutrophils, normal ranges taking into account ethnicity should be used for determination of trial inclusion/exclusion criteria and classification of neutropenia related adverse events.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT02017899, NCT02034500, NCT01771367, NCT01765413, NCT02523287.
authors.affiliation: Novartis Vaccines Institute for Global Health, Siena, Italy.
authors.forename: Vincent
authors.initials: V
authors.lastname: Muturi-Kioi
authors.affiliation: Surrey Clinical Research Centre, University of Surrey, Guildford, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Lewis
authors.affiliation: Université Paris Descartes, Sorbonne Paris cité, and Inserm CIC 1417, F-CRIN I-Reivac, Assistance Publique Hôpitaux de Paris, CIC Cochin-Pasteur, Paris, France.
authors.forename: Odile
authors.initials: O
authors.lastname: Launay
authors.affiliation: Ghent University and University Hospital, Gent, Belgium.
authors.forename: Geert
authors.initials: G
authors.lastname: Leroux-Roels
authors.affiliation: Novartis Vaccines Institute for Global Health, Siena, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Anemona
authors.affiliation: Université Paris Descartes, Sorbonne Paris cité, and Inserm CIC 1417, F-CRIN I-Reivac, Assistance Publique Hôpitaux de Paris, CIC Cochin-Pasteur, Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Loulergue
authors.affiliation: Surrey Clinical Research Centre, University of Surrey, Guildford, United Kingdom.
authors.forename: Caroline L
authors.initials: CL
authors.lastname: Bodinham
authors.affiliation: Ghent University and University Hospital, Gent, Belgium.
authors.forename: Annelies
authors.initials: A
authors.lastname: Aerssens
authors.affiliation: Novartis Vaccines & Diagnostics, Siena, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Groth
authors.affiliation: Novartis Vaccines Institute for Global Health, Siena, Italy.
authors.forename: Allan
authors.initials: A
authors.lastname: Saul
authors.affiliation: Novartis Vaccines Institute for Global Health, Siena, Italy.
authors.forename: Audino
authors.initials: A
authors.lastname: Podda
mesh_terms: D016208:Databases, Factual; D004405:Dysentery, Bacillary / Q000517:prevention & control; D006403:Hematologic Tests; D006801:Humans; D009503:Neutropenia / Q000209:etiology* / Q000473:pathology; D016032:Randomized Controlled Trials as Topic; D012720:Severity of Illness Index; D022281:Shigella Vaccines / Q000009:adverse effects / Q000276:immunology; D012764:Shigella sonnei / Q000276:immunology; D014612:Vaccines / Q000009:adverse effects*
chemical_list: D022281:Shigella Vaccines; D014612:Vaccines