Outer membrane vesicles: moving within the intricate labyrinth of assays that can predict risks of reactogenicity in humans

ABSTRACT

Outer membrane vesicles (OMV) are exosomes naturally released from the surface of Gram-negative bacteria. Since the ’80s, OMVs have been proposed as powerful vaccine platforms due to their intrinsic self-adjuvanticity and ability to present multiple antigens in natural conformation. However, the presence of several pathogen-associated molecular patterns (PAMPs), especially lipid A, has raised concerns about potential systemic reactogenicity in humans. Recently, chemical and genetic approaches allowed to efficiently modulate the balance between reactogenicity and immunogenicity for the use of OMV in humans. Several assays (monocyte activation test, rabbit pyrogenicity test, limulus amebocyte lysate, human transfectant cells, and toxicology studies) were developed to test, with highly predictive potential, the risk of reactogenicity in humans before moving to clinical use. In this review, we provide a historical perspective on how different assays were and can be used to successfully evaluate systemic reactogenicity during clinical development and after licensure.

KEYWORDS:

• GMMA
• outer membrane vesicle (OMV)
• endotoxin
• vaccine
• TLR
• rabbit pyrogenicity test (RPT)
• fever
• human
• reactogenicity
• monocyte activation test (MAT)

Acknowledgments

We thank Dr Allan Saul, Dr Rino Rappuoli, and Dr Francesca Micoli for suggestions and critical revision of the review.

Disclosure of potential conflicts of interest

This work was undertaken at the request of and sponsored by GlaxoSmithKline Biologicals SA. GSK Vaccines Institute for Global Health Srl is an affiliate of GlaxoSmithKline Biologicals SA.

The authors have the following conflict of interest to declare: all authors were, at the time in which the study was conducted, employee of the GSK Vaccines Institute for Global Health, part of the GSK group of companies. This does not alter the authors’ adherence to all Journal policies on data and material sharing.

Ethics

All animal studies were ethically reviewed and carried out in accordance with European Directive 2010/63/EEC and the GSK policy on the Care, Welfare and Treatment of Animals.

Additional information

Funding

This work was supported by the GlaxoSmithKline Biologicals SA.