Vaccine adjuvants

I am pleased to be helping with this special focus issue on adjuvants, which contains a variety of articles reviewing recent developments in several aspects of adjuvant development, including classes of adjuvant molecules that have extensive clinical experience [1–4], and discussions of adjuvant formulations and their application in addressing unmet needs in vaccinology [5–9]. Excellent insights in the form of interviews by vaccine experts are also included [10–12]. Adjuvants have been the subject of much research and much controversy, and interesting examples of these topics are included in this edition.

Why are adjuvants needed, and why are new adjuvants needed? When asked for adjuvant recommendations by individuals with candidates on a clinical development path, I tell people to keep it simple. If an adjuvant is needed, and alum meets the need, use it. However, several applications, actual and potential, demand progress in adjuvant research and development. New vaccine candidates, such as those comprising poorly immunogenic antigens of HIV, or vaccines targets such as tuberculosis, which require effective T-cell responses, will require adjuvants that enable these responses. Vaccines targeting antigenically-diverse pathogens can benefit from adjuvants that enhance immune response broadening, enabling vaccines to induce immunity to antigenic variations of a particular pathogen. A new generation of adjuvants will be needed to achieve rapid response to vaccines, such as in the case of bio-threats where single shot vaccines may be desirable, and which may induce immunity even in a post exposure setting. Finally, this issue also covers emerging areas including immune senescence, which is critical to aging but otherwise healthy populations for which adjuvanted vaccines may play a role in boosting protective immune responses. Another of these emerging areas is the exciting field of therapeutic vaccines, both for cancer and infectious diseases, which will require adjuvants to enhance and direct effective immune responses.

The unmet needs are there, and product development solutions lie within our grasp in many, or perhaps all, of these areas. Development of products containing new adjuvants to address and solve these unmet needs will require close coordination between vaccine developers and regulators who may share common goals, albeit for different reasons. In general, adjuvants are not approved alone, but rather vaccines that contain adjuvants are approved (or not) as products, with safety and efficacy of the combination product considered as a whole. However, when an adverse event occurs in a clinical trial involving an adjuvanted vaccine, it is often the safety of the adjuvant, not the product, that is called into question. Adjuvant safety is unquestionably the most critical, and often the most difficult, issue to address, and vaccine developers must be as thorough as possible to provide a comprehensive safety package to regulators. The issue of adjuvant safety is also covered in this issue [13].

If a new adjuvant is needed, it may lower development hurdles to utilize, as far as possible, adjuvant and formulation platforms with which there is the most clinical experience. One way of building upon proven formulation platforms, including alum, liposomes (and virosomes), and emulsions, is by adding small amounts of defined innate immune response modifiers, such as Toll-like receptor (TLR) ligands, which are present in nature and abundantly present in widely used first generation vaccines. This approach is represented by AS04, a combination of alum and MPL, in the licensed HPV vaccine, Cervarix (GSK). The approval of this vaccine by the US FDA in 2009, following earlier approvals in the EU and elsewhere, represented a milestone in adjuvant development. Monophosphoryl lipid A, which activates via TLR4, remains the only defined TLR ligand in an approved vaccine.

Finally, the critical role of adjuvant formulation, now well recognized in industry but poorly understood in most academic laboratories, can help avoid past situations in which very large amounts of TLR ligands were administered in animal studies or clinical trials without consideration of formulation aspects that can greatly enhance cellular uptake and dramatically decrease the amount of ligand needed for induction of effective immune responses. Addressing such critical details early in the development process can lead to adjuvants as useful products for human and veterinary vaccines, as opposed to only immune stimulants demonstrating activity in animal models, an important distinction. The articles and discussions presented in this volume will provide insight into critical issues in adjuvant development.

Financial & competing interests disclosure

SG Reed has stock ownership and holdings in Immune Design Corporation. The author has 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.