adjuvants: progress, regress and pandemic preparedness
TRANSCRIPT
Editorial
10.1586/14760584.6.5.651 © 2007 Future Drugs Ltd ISSN 1476-0584 651
Adjuvants: progress, regress and pandemic preparedness‘This issue provides an opportunity to look back and measure progress, and some regress, over the past few years.’
Gregory M Glenn† and Derek T O’Hagan†Author for correspondenceIomai Corporation, 20 Firstfield Road, Suite 250, Gaithersburg, MD 20878, USATel.: +1 301 556 4500Fax: +1 301 556 [email protected]
Expert Rev. Vaccines 6(5), 651–652 (2007)
A total of 4 years have elapsed since we askedExpert Review of Vaccines to provide a forum ina special issue for an update on vaccine adju-vants. The level of interest in this review wasvery high, with 21,730 full text downloads and90,952 abstracts viewed. The pace of genera-tion of new data and the recent increases incommercial and public health interest in adju-vant approaches suggested to us that we shouldagain survey and review the field. This issueprovides an opportunity to look back andmeasure progress, and some regress, over thepast few years.
Highlights in progress include the approvalof the first adjuvant comprising a traditionalcomponent (alum) in combination with aToll-like receptor (TLR) agonist (MPL®
[GlaxoSmithKline, GSK]),known as AS04, for a hepa-titis B vaccine; furtherapprovals for the MF59adjuvant for use in a pre-pandemic influenza vaccine(Focetria® [Novartis Vac-cines and Diagnostics Inc.,MA, USA]); clinical progress for the complexcombination adjuvant, known as AS02,which represents a breakthrough in themalaria vaccine field; and the first field effi-cacy trial for the travelers’ diarrhea vaccineusing transcutaneous immunization. Regret-tably, CpG oligonucleotides suffered a set-back in a related use of immunopotentiatingagents in cancer immunotherapy with thehalting of two Phase II and two Phase III tri-als. In addition, the withdrawal from themarket of a nasal influenza vaccine(Nasalflu™ [Berna Biotech Ltd, Berne,
Switzerland]) due to its linkage with Bell’spalsy, has been a major setback for nasal andmucosal delivery of vaccines in combinationwith adjuvants. Nevertheless, recent commer-cial and public health interest in adjuvantshas increased significantly, due to a recogni-tion of the importance of adjuvants for newproduct development. The commercial entitythat owned MPL, Corixa, was purchased byGSK, primarily to gain access to the adju-vant, and IC31 was recently licensed by largevaccine manufacturers, both actions creatinginterest in the commercial value of adjuvants.
Vaccinologists frequently complain that thepublic health benefit of vaccines is disappoint-ingly underappreciated, a direct consequenceof the success of vaccines, which has lowered
the perception of threatfrom many important path-ogens. However, when facedwith one of the greatestpotential modern catastro-phes, an influenza pan-demic, public health offi-cials have necessarily turned
to adjuvants as a means to expand the supplyof vaccines beyond current limits, by enhanc-ing their immunogenicity and allowing the useof lower doses of pandemic influenza vaccines.Moreover, clinical trials have firmly establishedthat pandemic influenza vaccines will be inef-fective in the absence of adjuvants to improvetheir potency. In the USA, major developmentcontracts have encouraged and supported anunprecedented cooperative effort to extend thepandemic influenza supply through the use ofadjuvants. European governments have madeadvance purchases of adjuvanted vaccines,
‘…clinical trials have firmly established that pandemic influenza
vaccines will be ineffective in the
absence of adjuvants to improve their potency.’
Glenn & O’Hagan
652 Expert Rev. Vaccines 6(5), (2007)
with limited clinical data on the specific vaccine but, wisely inour view, using existing licensed or late-stage adjuvants. Historywill call this effort prescient or phobic, but adjuvants are clearlyin the public spotlight as never before.
The range of adjuvant approaches covered here is necessarilylimited, due to space limitations. We have prioritized vaccineadjuvants with human experience, including the well-estab-lished alum and MF59 approaches, we have reviewed thebackground science, particularly in relation to activation ofinnate immunity, and we have covered the European regula-tory perspectives on adjuvants and included an interestingstudy in vaccine safety, which followed a public health emer-gency, relevant to the pandemic influenza effort. We have alsochosen some approaches that appear promising and wethought would be of general interest, including some promis-ing new concepts summarized here for the first time. We apol-ogize in advance for missing topics that we should haveincluded and hope to offer this opportunity again in a futureissue. We thank the current authors for their contributionsand cooperation, and remark that there was not one refusal tocontribute to the request for a review. We hope that the read-ers will find the issue informative and that it will spur contin-ued interest in the further development of adjuvant science. Asignificant advance in the last few years is a much greaterdepth of understanding of the mechanisms underlying howand why adjuvants work. In particular, there have been signif-icant advances in recognition of various pathogen-recognitionreceptor systems (e.g., TLR, nuclear oligomerization domainsand retinoic acid-inducible genes), their subcellular locationand the agents that activate them. Moreover, the interplay ofthese various systems is beginning to be appreciated, althoughthis work is in the early stages and much more effort isrequired. A current overview of the area is provided by BaliPulendran, 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 empiricalto a situation where optimal adjuvants may be designed toachieve particular purposes. To achieve this, various syntheticcomponents are being combined to ensure selective activationof the desired responses, through specific delivery of activatingsignals to particular subcellular compartments, to allow inter-action with key receptors for downstream signaling pathways.The coming years will see significant improvements in theseareas but their true test will be in the clinic, where safety issuescan 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 approachesare highly potent but have failed to gain approval in productsowing to poor tolerability or the perception of a possiblesafety problem. Hence, an area of research requiring signifi-cant work is preclinical safety predictions for adjuvants, whichneeds to move beyond the current empirical approaches toallow more accurate predictions from preclinical studies. Wetrust readers will profit from the articles in this issue of ExpertReview of Vaccines and thank all the contributors for their hardwork to put this issue out in such short order. We also hopethat they view their efforts to have been worthwhile.
Financial & competing interests disclosureGM Glenn is Chief Scientific Officer, Iomai Corporation, MD,USA. D O’Hagan is Head of Vaccine Delivery Research, NovartisVaccines and Diagnostics, Inc., MA, USA. The authors have noother relevant affiliations or financial involvement with anyorganization or entity with a financial interest in or financialconflict with the subject matter or materials discussed in themanuscript apart from those disclosed.
No writing assistance was utilized in the production of thismanuscript.
Affiliations
• Gregory M GlennChief Scientific Officer, Iomai Corporation, 20 Firstfield Road, Suite 250, Gaithersburg, MD 20878, USATel.: +1 301 556 4500Fax: +1 301 556 [email protected]
• Derek T O’HaganHead of Vaccine Delivery Research, Novartis Vaccines and Diagnostics,Via Fiorentina 1, 53100 Siena, ItalyTel.: +39 577 245 265Fax: +39 577 243 [email protected]