Emulsion based vaccine adjuvants

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This is a very short and focused “book,” which is really a collection of three review articles covering oil-in-water emulsion adjuvants with a focus on their use in flu vaccines. The first chapter covers the most established emulsion adjuvant, MF59, which has been approved and used commercially since 1997, while the second chapter covers the AS03 emulsion adjuvant from GSK, which obtained first approval in 2009 to meet the challenges of the H1N1 pandemic. These are both brief but clear reviews, although they have a different emphasis, which probably reflects the primary interests of the authors. Neither of the reviews on the emulsion adjuvants included in licensed vaccines is from the commercial suppliers of the products, which has both advantages and disadvantages. Both of the chapters offer independent views on the science and clinical data for the adjuvants, but inevitably, since they are not “insiders” some of the finer details may not be fully accurate. Nevertheless, these chapters generally offer fresh and succinct views on the performance of these two distinct adjuvants, MF59 and AS03.

The MF59 chapter is brief and focused and offers a clear perspective in a well-written review, although there are some minor omissions. There is a significant discussion on how the adjuvant works, which has been extensively explored and summarized recently by the reviewers.¹ In this chapter the authors highlight the good safety and tolerability profile of MF59 adjuvanted vaccines in extended clinical use over many flu seasons, but also for the expanded pandemic use. However, notable absences from the review include the publication that demonstrated clinical effectiveness of the MF59 adjuvanted vaccine in adults over 65 y old, a population for which effective influenza vaccines are generally unavailable. This recent landmark report highlighted a 25% reduction in pneumonia and influenza hospitalizations in adjuvanted compared with unadjuvanted vaccine recipients across >170,000 person-seasons of observation.² Additional publications on the effectiveness of the vaccine during the pandemic, including the important finding that the adjuvanted vaccine administered to pregnant women was not only safe, but also reduced adverse outcomes such as pre-term birth and low birth weight perhaps were perhaps too recent for inclusion. As too was the recent review of all that we know on the mechanism of action of MF59 adjuvant.¹ Given the prominence in the following chapter on the potential association of the use of AS03 adjuvanted vaccines with narcolepsy, it might have been appropriate to highlight that MF59 adjuvanted vaccines have not shown any such association.³ However, the authors of the MF59 chapter could not perhaps appreciate that the potential narcolepsy link would have been given such prominence by the authors of the AS03 chapter. If we need to be critical of the MF59 chapter, we would highlight that it is it is our view that the increased breadth of response induced by the MF59 adjuvant is an important attribute, which we have highlighted,⁴ particularly for a pandemic vaccine. This is covered briefly but not given much prominence in the chapter.

The AS03 chapter is more focused on the clinical experience than the previous chapter on MF59 and discusses extensively the experience during the H1N1 pandemic, which represented the first wide spread clinical use for this adjuvant. Within the first page the authors highlight the restrictions placed on the use of the AS03 adjuvant by the EMA following an association, but not a proven link with an apparent increased incidence of narcolepsy in children in Scandinavian countries.⁵ Unfortunately, this story has continued to grow since the chapter was written and more countries have highlighted a potential association, most recently the UK⁶ Overall, this chapter gives a more significant focus on clinical effectiveness during the H1N1 pandemic, which was largely over looked in the MF59 chapter and highlights that the adjuvanted vaccine appeared to work very well while being reasonably well tolerated. However, they also highlight the increased reactogenicity seen with this adjuvanted vaccine, mainly involving increased local pain, but also with a higher than expected incidence of fever. The authors rightly feel compelled to highlight that it is important to differentiate the composition of MF59 from AS03, but also to highlight that they were used with different kinds of influenza vaccines during the H1N1 pandemic. The only oil component in MF59 is squalene, whereas AS03 contains a similar amount of squalene to MF59, in addition to the immune potentiator DL-α-tocopherol, in approximately a 1:1 (w/w) ratio as highlighted in Table 2.1 in Chapter 2. The published work on the mechanism of action of AS03 from the manufacturer GSK is summarized in Chapter 2 and specifically highlighted that AS03 (with α-tocopherol) was more potent than a squalene only o/w emulsion adjuvant. It was also reported that AS03 induced a non-specific activation signal in the local lymph node, while the squalene only emulsions did not.⁷ Chapter 2 authors also highlighted that for the H1N1 pandemic, the two different emulsion adjuvants (MF59 and AS03) were used with two different kinds of influenza vaccines, produced by different processes, a highly purified subunit vaccine (MF59 adjuvant) vs. a split vaccine (AS03).

Chapter 3 purports to represent “innovations in emulsion adjuvants” but is perhaps the least illuminating of the chapters. It is not clear what the authors are trying to communicate in this article, since they move rapidly from topic to topic that are not well connected. They give a cursory review of the history of emulsions, which is already very well-known and much has been written about, but no new insight is gained. Key points that perhaps could and should have been included are missing. For example, they highlight that emulsions have been around a long time, but what happened to allow them to be more successful and more widely used only recently. They present some of their own basic research data involving immunization of small animals with newer adjuvants, but it is not clear what are the advantages of the “new” emulsion adjuvants. The previous two chapters showed very clearly that the existing emulsion adjuvants are very effective for flu, so it is not clear what needs to be improved for this target. In addition, the authors appear to imply erroneously that squalene has inherent adjuvant activity, which we believe to be untrue. What they actually show in the data presented is that an emulsion prepared with squalene is more potent than emulsions prepared with alternative oils, but there are a number of alternative explanations for this data which are not explored. In fact, it has been shown previously that squalene alone is not an adjuvant and this was cited in the first chapter in this book.

Perhaps what is most disappointing and the biggest “gap” in Chapter 3 is any attempt to put emulsions into perspective in the adjuvant field. Alum based adjuvants were the first that became established, but emulsions were discovered soon after, why did they not become so widely used, what were the issues? More importantly, what are the current limitations of emulsion adjuvants, are they able to replace Alum, or should they only be used for new generation vaccines. Do emulsions have advantages over Alum, and if so what are these advantages vs. any potential disadvantages? Are emulsion adjuvants only good for flu vaccines, since that is the apparent focus of this book, or could they be used successfully for others, which ones? What about other adjuvants that have emerged more recently, including liposomes, microparticles, etc.; how do emulsions compare with these alternate approaches? None of this is covered and could easily have been by this team with good experience on a range of adjuvants. They focus on alternative sources of squalene as a possible way forward, but is this the extent of the evolution that they envisage in this field? They also highlight alternative routes of delivery for emulsions, but fail to note that the most established emulsion adjuvant MF59 progressed as far as a human clinical evaluation for intranasal application, but was shown to not enhance the immune response vs. a formulation with no adjuvant by the same route. If the most established emulsion adjuvant did not work by the IN route, why should any of the others? Unfortunately the reader is left with many questions regarding the outlook of emulsion adjuvants with very little perspective on the rest of the adjuvant field. Overall, perhaps this book is best suited for clinicians with a cursory knowledge of vaccinology looking to better educate themselves on the clinical aspects of the two oil-in-water emulsion adjuvants used commercially in flu vaccines. Unfortunately, the story around the use of AS03 and possible association with increased incidence of narcolepsy is evolving very quickly, with several key publications since the AS03 chapter was written. For those vaccinologists with an in-depth knowledge of vaccine adjuvants, including emulsions, and looking to get a sense of where the field is headed, they would be better served by looking elsewhere.

Disclosure of Potential Conflicts of Interest

All authors are employees and shareholders of Novartis Vaccines and Diagnostics.