Are we entering a new age for human vaccine adjuvants?

Abstract

Major advances in adjuvant development for human vaccines have been reported recently for a range of indications, including malaria, influenza and varicella zoster virus. Furthermore, there is an increased understanding of adjuvant mechanisms of action and a greater emphasis on the importance of formulation and characterization. This progress may signify a new golden age of vaccine adjuvant discovery and development.

Keywords:

• formulation
• MF59
• MPL
• QS21
• vaccine adjuvant

In retrospect, perhaps the late 1980's can be considered as a ‘golden’ age for the identification and advancement of vaccine adjuvants for human vaccines, since many new approaches were originally described and moved into development at this time [1]. This followed on from the revolution in recombinant DNA technology that occurred at the beginning of the decade, which was rapidly applied to the expression of vaccine antigens by the founders of Chiron Corporation [2]. Remarkably, this resulted in licensure of the first recombinant vaccine (for hepatitis B) only 4 years later. However, the ability to easily express many new antigens resulted in an overly optimistic interpretation that many new vaccines would soon follow. Although this approach was rapidly applied to several additional pathogens (including herpes simplex virus, cytomegalovirus, hepatitis C virus, malaria and HIV), it soon became apparent that highly purified recombinant antigens were lacking in potency. They were inherently less immunogenic than more traditional vaccines, which typically comprised whole bacteria or viruses, or inactivated antigens extracted from the native organisms. Hence, the existing vaccines often contained additional components from the pathogens, which were able to activate a more potent immune response. Therefore, it became increasingly clear that new and more potent adjuvants would be needed to enable the recombinant vaccines to succeed. This realization was the driving force behind the expanded effort in the late 1980s to identify more potent adjuvants than the long established insoluble aluminum salts, which had been included in childhood vaccines for many decades. The need to develop improved vaccine adjuvants was particularly driven by the emerging threat posed by HIV at this time. Several of the currently prominent adjuvant technologies, including squalene-based emulsions (MF59), purified saponins (QS21) and purified bacterial components (MPL) first emerged and moved into clinical testing as HIV vaccine candidates [3].

In the early years of the development of these adjuvants in the 1990s, they were perceived as key and attractive technological assets. However, this perception shifted somewhat as it became clear that product development was much more difficult than originally thought and that the timelines were very long. Perhaps the early and rapid success with hepatitis B virus (HBV) encouraged an unrealistic expectation for subsequent products. Nevertheless, some very important lessons were learned as these adjuvants moved through the arduous vaccine development pathways. It is now clear that even with very safe recombinant antigens, vaccine development in non-emergency situations is a decades-long endeavor, particularly when a new technology is involved. This is particularly true if the vaccine under development is to be licensed for use in young children, which is often the case. Overall, perhaps one unavoidable conclusion that has emerged is that it is now likely that only large established vaccine companies have the necessary capabilities and resources in place to successfully develop new vaccines, particularly those including novel adjuvants.

The key message we would like to propose here is that several recent advances for adjuvanted vaccines suggest that we are now entering a new age for adjuvants. This new age might be considered to have started in 2009 with the approval by the US FDA of the HPV vaccine Cervarix, which at the time was the only vaccine approved for human use in the USA that contained an adjuvant component (MPL) other than aluminum salts. In the same year, this was followed by the widespread use of squalene-based oil-in-water emulsions in influenza vaccines due to the H1N1 pandemic, bringing the total doses administered of this class of adjuvant to ∼ 200 M [4]. Finally, in 2013, the FDA approved for the first time a pandemic influenza vaccine (Q-Pan) containing an oil-in-water emulsion adjuvant [5]. In addition to these advances, there are some more recent groundbreaking developments in the adjuvant field, including:

1. The efficacy data generated for an adjuvanted recombinant malaria vaccine (Malaria Phase III) and the subsequent submission for licensure [6].

2. The recent licensure of the use of an MF59 adjuvanted flu vaccine in young children in Canada [7].

3. The recently reported 97% reduction in incidence of shingles in elderly subjects (> 50 years old) for an adjuvanted recombinant protein vaccine from varicella zoster virus (VZV) in a large (37,000 subjects) Phase III trial [8].

Each of these advances represents an important vaccine success story, using adjuvant technologies that first emerged in the late 1980s [1]. The AS01 adjuvant used by GlaxoSmithKline in the development of the first effective malaria vaccine comprises a liposome formulation of both QS21 and MPL [9]. The vaccine emerged from a long and rigorous development program in which different adjuvant technologies were competitively evaluated in human challenge studies to determine which was the most effective [9]. Subsequently, the lead candidate was evaluated in large efficacy trials in endemic areas in young children [10]. The second example represents the first approval of an adjuvanted seasonal influenza vaccine in young children, after it was shown that the MF59 adjuvant improved efficacy from 42 to 89% [11]. Moreover, the safety profile of MF59 in this population was supported by extensive use during the H1N1 pandemic [12]. The third example represents a remarkable success story for a recombinant vaccine in combination with the AS01 adjuvant, which showed a 97% reduction in recurrence in elderly subjects. Although it is broadly accepted that adjuvanted vaccines are unlikely to prime CD8⁺ T-cell responses in man (vectors or nucleic acid vaccines may be needed to trigger this response), the clinical outcome for the VZV vaccine may indicate that adjuvanted vaccines can boost a CD8⁺ T-cell response, if it has been primed by prior infection. However, this is a speculation and must await the data to emerge, since the remarkable efficacy could also be due to antibody responses alone.

While many adjuvants originally emerged in the 1980s, the intervening years have seen a huge expansion in knowledge of how they work. This knowledge has included the discovery of the immune activation signaling pathways, including the Toll-like receptor families and others [13]. Subsequently, this information has enabled a new ‘golden’ age of adjuvant discovery, in which many new potential adjuvants have been identified. For example, we recently described the discovery and development of a new class of adjuvants called small molecule immune potentiators that were identified by high-throughput screening of traditional ‘drug-like’ molecules [14]. It is to be hoped that some of the lessons we have learned since the 1990s may offer insights to accelerate the development of these new adjuvants. Certainly, a fuller understanding of their mechanism is already a significant step forward from where we were two decades ago. Nevertheless, the development of vaccines containing new adjuvants will continue to be a challenging area, as highlighted by some recent setbacks. Hopefully, the field in general can learn some important lessons from the efforts to develop an improved HBV vaccine in the USA by Dynavax, which has required multiple Phase III clinical trials (ongoing) [15]; and by the unfortunate association of Pandemrix, an adjuvanted H1N1 influenza vaccine, with an increased incidence of narcolepsy in Europe [16], although recent evidence indicates that this may be mainly attributable to antigen manufacturing differences rather than the inclusion of an adjuvant [17]. However, even in the face of these setbacks, there are additional adjuvanted vaccines that are making significant progress, including ISCOM-like adjuvants, which have entered Phase II trials as an adjuvanted pandemic flu vaccine [18], and GLA-SE (an oil-in-water formulation of a synthetic Toll-like receptor 4 ligand), which has also entered Phase II testing for pandemic flu [19].

Importantly, beyond a much improved mechanistic understanding of adjuvants, there is also a realization that adjuvants in vaccines need to represent well-characterized formulations, like any other pharmaceutical product [20]. Newly emerging adjuvant technologies are designed to achieve optimal impact from immune-activating components, while minimizing any safety concerns, by ensuring co-delivery of the antigens with the immune potentiators. Moreover, in recent years, there has also been a significant expansion in the technologies available to fully characterize vaccine adjuvants, although further developments are welcome in this area. The development of rationally designed, fully characterized and manufacturable vaccine adjuvant formulations with established mechanisms of action will help to ensure that the new age of adjuvants continues to result in successful vaccines that will fill unmet needs.

Financial & competing interests disclosure

DT O’Hagan is an employee of Novartis, which has developed the MF59 adjuvant. CB Fox is an employee of IDRI, which has developed the GLA-SE adjuvant. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.