Elsevier

Vaccine

Volume 30, Issue 29, 19 June 2012, Pages 4341-4348
Vaccine

Review
The mechanism of action of MF59 – An innately attractive adjuvant formulation

https://doi.org/10.1016/j.vaccine.2011.09.061Get rights and content

Abstract

MF59 is a safe and effective vaccine adjuvant which was originally approved to be included in a licensed influenza vaccine to be used in the elderly in Europe in 1997. The MF59 adjuvanted influenza vaccine (Fluad™) is now licensed in more than 20 countries worldwide and more than 85 million doses have been administered. More recently the vaccine adjuvant has also been shown to be safe and effective in young children and resulted in a significant increase in influenza vaccine efficacy in a controlled clinical trial in Europe. Since the early days of its discovery we have explored the mechanism of action of MF59, using a variety of available techniques. In recent years we have explored more thoroughly the mechanism of action using new and more sophisticated techniques. It is remarkable how consistent the data has been, using a variety of different approaches both in several small animal models and also using human immune cells in vitro. Here we present a summary of all the work performed to date on the mechanism of action of MF59 and we present a unified theory based on the accumulated data of how it exerts its adjuvant effects. A key element of the mechanism of action appears to be the creation of a transient ‘immunocompetent’ local environment at the injection site, resulting in the recruitment of key immune cells, which are able to take up antigen and adjuvant and transport them to the local lymph nodes, where the immune response is induced. This recruitment appears to be triggered by the induction of a chemokine driven gradient by the impact of MF59 on local cells, which are activated to secrete further chemokines, which are recruitment factors for more immune cells.

Highlights

MF59 is a safe and well established vaccine adjuvant. ► The mechanism of action of adjuvants is often poorly defined. ► A key component of the mechanism of action of MF59 is cellular recruitment to the injection site. ► MF59 creates a local immunocompetent environment at the injection site.

Section snippets

Introduction – the current status of MF59 adjuvant

MF59 is a well established, safe and potent emulsion-based vaccine adjuvant that has been licensed in more than 20 countries for more than 14 years, for use in an improved influenza vaccine focused mainly on elderly subjects (Fluad®). The overall safety profile of MF59 has been established clinically with a large safety database [1] and through an extensive pharmacovigilance evaluation of the greater than 85 million doses that have been distributed commercially (data from 27 million subjects

The importance of the mechanism of action of vaccine adjuvants

Over the years, we have undertaken extensive evaluations designed to gain insights into the mechanism of action of MF59. We believed that this was important, although as the mechanism of action of adjuvants has been generally understudied for a long time and the importance has been under much appreciated.

In the literature, vaccine adjuvants are frequently classified into two broad groups, called delivery systems, like Alum or MF59, and immune potentiators, like monophosphoryl lipid A (MPL) or

The early origins of the MF59 adjuvant

The MF59 emulsion was originally developed to facilitate the co-delivery of antigen with N-acetyl-l-alanyl-d-isoglutanimyl-l-alanine-2-(1,2-dipalmitoyl) (abbreviated to MTP-PE), which is a synthetic version of muramyl dipeptide (MDP), a naturally occurring bacterial cell wall component known to activate innate immunity. MTP-PE is an immune potentiator and was initially added to the emulsion to improve the potency of the adjuvant. In pre-clinical studies in guinea pigs, the combination adjuvant

The detailed mechanism of action of MF59 – what do we know about how it works?

The first studies undertaken to determine the mechanism of action for MF59 adjuvant were performed in Emeryville, CA in the early 1990s, where the adjuvant was first developed at Chiron Vaccines. These studies focused on the simple questions that could be readily addressed using the techniques available at the time. Subsequently in the mid 1990s, and more recently, we have re visited the mechanism of action and gained important insights. However, it is notable that many of the early

Conclusion – summarizing the overall mechanism of action

Over the years, we have tried to adopt a comprehensive approach to determine the mechanism of action of MF59, combining available knowledge in vaccinology and state-of-the-art techniques. Through the recent application of advanced cellular immunology, gene array studies and cell tracing techniques, we have dissected the mechanism in great detail, using human immune cells in vitro and mouse immunization models in vivo. Our combined studies have consistently asked the following questions: which

Acknowledgments

“We are grateful to Giorgio Corsi for artwork and Kristine Karklins for formatting and submission”.

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