Neutropenia as an Adverse Event following Vaccination: Results from Randomized Clinical Trials in Healthy Adults and Systematic Review

PLoS One. 2016 Aug 4;11(8):e0157385. doi: 10.1371/journal.pone.0157385. eCollection 2016.

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.

Methodology: 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.

Principal findings: 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.

Trial registration: ClinicalTrials.gov NCT02017899, NCT02034500, NCT01771367, NCT01765413, NCT02523287.

Publication types

  • Review
  • Systematic Review

MeSH terms

  • Databases, Factual
  • Dysentery, Bacillary / prevention & control
  • Hematologic Tests
  • Humans
  • Neutropenia / etiology*
  • Neutropenia / pathology
  • Randomized Controlled Trials as Topic
  • Severity of Illness Index
  • Shigella Vaccines / adverse effects
  • Shigella Vaccines / immunology
  • Shigella sonnei / immunology
  • Vaccines / adverse effects*

Substances

  • Shigella Vaccines
  • Vaccines

Associated data

  • ClinicalTrials.gov/NCT01765413
  • ClinicalTrials.gov/NCT02034500
  • ClinicalTrials.gov/NCT02523287
  • ClinicalTrials.gov/NCT01771367
  • ClinicalTrials.gov/NCT02017899

Grant support

This work was supported by EUROPEAN COMMISSION - Grant 261472 (STOPENTERICS) (http://stopenterics.bio-med.ch/cms/default.aspx) to OL, PL, A. Anemona, AS, and AP; EUROPEAN COMMISSION - Grant 280873 (ADITEC) (http://www.aditecproject.eu/) to DL, A. Anemona, AS, and AP; Innovative Medicines Initiative Joint Undertaking. Grant 115308 (http://www.biovacsafe.eu/) to DL, GLR, and A. Aerssens. These funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Additionally, A. Anemona, NG, AS and AP were employed by Novartis at the time these studies were conducted and are currently employed by GSK. VMK was a medical intern in Novartis at the time these studies were conducted and is currently employed by GSK. The company provided support in the form of salaries for these authors, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.