A total of 4 years have elapsed since we asked Expert Review of Vaccines to provide a forum in a special issue for an update on vaccine adjuvants. The level of interest in this review was very high, with 21,730 full text downloads and 90,952 abstracts viewed. The pace of generation of new data and the recent increases in commercial and public health interest in adjuvant approaches suggested to us that we should again survey and review the field. This issue provides an opportunity to look back and measure progress, and some regress, over the past few years.
Highlights in progress include the approval of the first adjuvant comprising a traditional component (alum) in combination with a Toll-like receptor (TLR) agonist (MPL® [GlaxoSmithKline, GSK]), known as AS04, for a hepatitis B vaccine; further approvals for the MF59 adjuvant for use in a prepandemic influenza vaccine (Focetria® [Novartis Vaccines and Diagnostics Inc., MA, USA]); clinical progress for the complex combination adjuvant, known as AS02, which represents a breakthrough in the malaria vaccine field; and the first field efficacy trial for the travelers’ diarrhea vaccine using transcutaneous immunization. Regrettably, CpG oligonucleotides suffered a setback in a related use of immunopotentiating agents in cancer immunotherapy with the halting of two Phase II and two Phase III trials. In addition, the withdrawal from the market of a nasal influenza vaccine (Nasalflu™ [Berna Biotech Ltd, Berne, Switzerland]) due to its linkage with Bell’s palsy, has been a major setback for nasal and mucosal delivery of vaccines in combination with adjuvants. Nevertheless, recent commercial and public health interest in adjuvants has increased significantly, due to a recognition of the importance of adjuvants for new product development. The commercial entity that owned MPL, Corixa, was purchased by GSK, primarily to gain access to the adjuvant, and IC31 was recently licensed by large vaccine manufacturers, both actions creating interest in the commercial value of adjuvants.
Vaccinologists frequently complain that the public health benefit of vaccines is disappointingly underappreciated, a direct consequence of the success of vaccines, which has lowered the perception of threat from many important pathogens. However, when faced with one of the greatest potential modern catastrophes, an influenza pandemic, public health officials have necessarily turned to adjuvants as a means to expand the supply of vaccines beyond current limits, by enhancing their immunogenicity and allowing the use of lower doses of pandemic influenza vaccines. Moreover, clinical trials have firmly established that pandemic influenza vaccines will be ineffective in the absence of adjuvants to improve their potency. In the USA, major development contracts have encouraged and supported an unprecedented cooperative effort to extend the pandemic influenza supply through the use of adjuvants. European governments have made advance purchases of adjuvanted vaccines, with limited clinical data on the specific vaccine but, wisely in our view, using existing licensed or late-stage adjuvants. History will call this effort prescient or phobic, but adjuvants are clearly in the public spotlight as never before.
The range of adjuvant approaches covered here is necessarily limited, due to space limitations. We have prioritized vaccine adjuvants with human experience, including the well-established alum and MF59 approaches, we have reviewed the background science, particularly in relation to activation of innate immunity, and we have covered the European regulatory perspectives on adjuvants and included an interesting study in vaccine safety, which followed a public health emergency, relevant to the pandemic influenza effort. We have also chosen some approaches that appear promising and we thought would be of general interest, including some promising new concepts summarized here for the first time. We apologize in advance for missing topics that we should have included and hope to offer this opportunity again in a future issue. We thank the current authors for their contributions and cooperation, and remark that there was not one refusal to contribute to the request for a review. We hope that the readers will find the issue informative and that it will spur continued interest in the further development of adjuvant science. A significant advance in the last few years is a much greater depth of understanding of the mechanisms underlying how and why adjuvants work. In particular, there have been significant advances in recognition of various pathogen-recognition receptor systems (e.g., TLR, nuclear oligomerization domains and retinoic acid-inducible genes), their subcellular location and the agents that activate them. Moreover, the interplay of these various systems is beginning to be appreciated, although this work is in the early stages and much more effort is required. A current overview of the area is provided by Bali Pulendran, which, while very insightful, highlights how much we still need to learn. The world of adjuvant development, while very pragmatic, is finally moving beyond the empirical to a situation where optimal adjuvants may be designed to achieve particular purposes. To achieve this, various synthetic components are being combined to ensure selective activation of the desired responses, through specific delivery of activating signals to particular subcellular compartments, to allow interaction with key receptors for downstream signaling pathways. The coming years will see significant improvements in these areas but their true test will be in the clinic, where safety issues can only be addressed seriously for the first time. Historically, this has been the main area of failure for vaccine adjuvants. Many current and previously available adjuvant approaches are highly potent but have failed to gain approval in products owing to poor tolerability or the perception of a possible safety problem. Hence, an area of research requiring significant work is preclinical safety predictions for adjuvants, which needs to move beyond the current empirical approaches to allow more accurate predictions from preclinical studies. We trust readers will profit from the articles in this issue of Expert Review of Vaccines and thank all the contributors for their hard work to put this issue out in such short order. We also hope that they view their efforts to have been worthwhile.
Financial & competing interests disclosure
GM Glenn is Chief Scientific Officer, Iomai Corporation, MD, USA. D O’Hagan is Head of Vaccine Delivery Research, Novartis Vaccines and Diagnostics, Inc., MA, USA. 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.
No writing assistance was utilized in the production of this manuscript.