Granulomas Following Subcutaneous Injection With Aluminum Adjuvant-Containing Products in Sheep

Vet Pathol. 2019 May;56(3):418-428. doi: 10.1177/0300985818809142. Epub 2018 Oct 31.


The use of vaccines including aluminum (Al)-based adjuvants is widespread among small ruminants and other animals. They are associated with the appearance of transient injection site nodules corresponding to granulomas. This study aims to characterize the morphology of these granulomas, to understand the role of the Al adjuvant in their genesis, and to establish the presence of the metal in regional lymph nodes. A total of 84 male neutered lambs were selected and divided into 3 treatment groups of 28 animals each: (1) vaccine (containing Al-based adjuvant), (2) adjuvant-only, and (3) control. A total of 19 subcutaneous injections were performed in a time frame of 15 months. Granulomas and regional lymph nodes were evaluated by clinicopathological means. All of the vaccine and 92.3% of the adjuvant-only lambs presented injection-site granulomas; the granulomas were more numerous in the group administered the vaccine. Bacterial culture in granulomas was always negative. Histologically, granulomas in the vaccine group presented a higher degree of severity. Al was specifically identified by lumogallion staining in granulomas and lymph nodes. Al median content was significantly higher ( P < .001) in the lymph nodes of the vaccine group (82.65 μg/g) compared with both adjuvant-only (2.53 μg/g) and control groups (0.96 μg/g). Scanning transmission electron microscopy demonstrated aggregates of Al within macrophages in vaccine and adjuvant-only groups. In these two groups, Al-based adjuvants induce persistent, sterile, subcutaneous granulomas with macrophage-driven translocation of Al to regional lymph nodes. Local translocation of Al may induce further accumulation in distant tissues and be related to the appearance of systemic signs.

Keywords: aluminum-based adjuvants; granuloma; lymph node; macrophage; sheep; vaccine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adjuvants, Immunologic / administration & dosage
  • Adjuvants, Immunologic / adverse effects*
  • Aluminum / administration & dosage
  • Aluminum / adverse effects*
  • Animals
  • Granuloma / chemically induced
  • Granuloma / pathology
  • Granuloma / veterinary*
  • Injection Site Reaction / etiology
  • Injection Site Reaction / pathology
  • Injection Site Reaction / veterinary*
  • Injections, Subcutaneous / adverse effects
  • Injections, Subcutaneous / veterinary
  • Lymph Nodes / pathology
  • Male
  • Sheep
  • Sheep Diseases / chemically induced*
  • Sheep Diseases / pathology


  • Adjuvants, Immunologic
  • Aluminum