Vaccine Adjuvants: Scientific Challenges and Strategic Initiatives

Ali M. Harandi; Gwyn Davies; Ole F. Olesen

Disclosures

Expert Rev Vaccines. 2009;8(3):293-298. 

In This Article

Recent Advances & Future Scientific Challenges

Several decades after the introduction of alum, four new adjuvants have now been incorporated into vaccines that are licensed for human use, and this has led to the recognition of adjuvants other than alum. One of these is MF59, an oil-in-water emulsion adjuvant developed by ex-Chiron, now Novartis Vaccines. While MF59 demonstrated satisfactory adjuvant effect with the influenza vaccine Fluad®,[4] it had a limited beneficial effect when used in conjunction with recombinant herpes simplex virus (HSV) type 2 protein for induction of protection against genital herpes in a human vaccine trial.[5] The second new adjuvant is the immunopotentiating reconstituted influenza virosomes, used in the hepatitis A vaccine Epaxal® (Berna Biotech/Crucell).[6] The other two adjuvants have been developed by GlaxoSmithKline (GSK) Biologicals; AS04 is a component of the hepatitis B virus (HBV) vaccine Fendrix® and of the human papillomavirus (HPV) vaccine Cervarix®, and AS03 is a component of the prepandemic influenza vaccine Prepandrix®.[7,8]

Recent developments in immunology, including the discovery of Toll-like receptors (TLRs) and other innate immune receptors with the capacity to bridge innate and adaptive immunity, have offered new opportunities for the development of immunostimulatory adjuvants.[9,10] Advances in the design of efficient adjuvants based on the use of TLR agonists have been promising (although it should be noted that some of these were in development before the role of TLRs was identified) and some of these have reached advanced human trials and even registration. Monophosphoryl lipid A (MPL), a TLR4 agonist, is included as a component in AS04, the adjuvant system used in Fendrix and Cervarix developed by GSK.[7] This molecule is derived from the lipid A portion of Salmonella minnesota Re595 lipopolysaccharide (LPS), considered too toxic itself for use in human vaccines, by removal of a phosphate group and one of its acyl chains. Mode-of-action studies demonstrated that TLR4 signaling for the closely-related molecule MPLA (removal of the phosphate group but not the acyl chain) is biased towards the adaptor molecule Toll/IL-1 receptor domain containing adaptor protein-inducing IFN-γ (TRIF), compared with its parent LPS that signals through the inflammatory adaptor protein myeloid differentiation factor 88 (MyD88), as well as TRIF.[11] The TRIF pathway generates no overt inflammation/toxicity in the host and this TRIF bias could, at least in part, be responsible for the reduced toxicity. Since the parent S. minnesota LPS itself has been reported to have a TRIF-biased signaling pathway compared with Escherichia coli LPS,[12] it is possible that the MPL adjuvant in Fendrix and Cervarix has similar properties and this could, in part, explain its reduced toxicity. As a word of caution, in spite of the major recent successes with TLR agonists as vaccine adjuvants, it is noteworthy that a recent experimental study demonstrated that, at least under some circumstances, TLR signaling is dispensable for induction of antibody responses by several standard adjuvants.[13]

The use of immunostimulatory molecules as immunopotentiators/vaccine adjuvants raises theoretical safety concerns, owing to the possibility that some might induce overproduction of inflammatory molecules, leading to overt inflammatory reactions or induction of autoimmunity. Recently, human trials with Heplisav™ (developed by Dynavax), which combines hepatitis B antigen with a CpG sequence (ISS 1018), a TLR9 agonist, were halted in response to a serious adverse effect report from a Phase III trial. After receiving two doses of Heplisav, one of the vaccinees was preliminarily diagnosed with Wegener's granulomatosis, an autoimmune disease involving production of antibodies against neutrophils leading to inflammation of the vasculature.[14] By contrast, a recent large integrated analysis of 68,000 participants who received AS04-adjuvanted GSK vaccines, including hepatitis B vaccine as well as HPV-16/18 and HSV vaccines, concluded that participants who received AS04-adjuvanted vaccines or controls demonstrated a low rate of autoimmune disorders, without evidence of an increase in relative risk associated with AS04-adjuvanted vaccines.[15] In conclusion, TLR agonists have a high potential as vaccine adjuvants but the safety of each adjuvant-antigen combination will have to be carefully evaluated. Based on the rapid evolution of this field, it is likely that a new generation of immunomodulatory adjuvants devoid of, or at least with minimal, systemic adverse reactions and local reactogenicity will be forthcoming.

The vast majority of pathogens invade the body through or establish infection in the mucosal tissues, but most vaccines for human use are administered parenterally. Mucosal immunization has recently attracted much interest as a means of generating protective immunity against mucosally transmitted pathogens. Mucosal immunization offers potential advantages over the parenteral vaccination, including reduced risk of transmission of certain types of infectious agents, for example HIV and HBV, and enhanced patient compliance due to ease of administration. However, our understanding of mucosal immunity and the development of mucosal vaccines remains largely incomplete. This is, in part, because it has often proven difficult to induce potent mucosal immunity by mucosal administration of protein antigens and that recovery and functional testing of antibodies present in the mucosal secretions, as well as mucosal T cells, are labor intensive and technically challenging.[16] In fact, only very few mucosal vaccines are presently approved for human use, including oral polio vaccine, oral live-attenuated typhoid vaccine Vivotif® (Berna Biotech/Crucell), oral cholera vaccines Dukoral® (SBL Vaccines/Crucell) and Orochol® (Berna Biotech/Crucell),[17] oral live-attenuated rotavirus vaccines RotaRix® (GSK) and RotaTeq® (Merck),[18] as well as nasal live-attenuated influenza vaccine FluMist® (MedImmune Vaccines, Inc.).[19] It is becoming increasingly clear, however, that the development of a broader range of mucosal vaccines will require the development of safe and effective mucosal adjuvants. Bacterial toxins, such as cholera toxin (CT) and the closely analogous heat-labile enterotoxin (LT) and their derivatives, are commonly used as potent mucosal adjuvants in experimental models. However, their toxicity, associated with an ADP-ribosylating enzymatic activity, has limited their use for human vaccination. In addition, intranasal administration of toxin-based adjuvants is linked to an elevated risk of adverse reactions, such as Bell's palsy, in humans.[20] In spite of this, and underlining the critical effect of the route of administration for safety as well as for efficacy, LT is being developed for transcutaneous immunization against traveller's diarrhea.[21] To circumvent toxicity, new generations of LT and CT mutants have been developed with reduced or no ADP-ribosylating enzymatic activity and, hence, possessing reduced toxicity but significant adjuvanticity,[22] among which LTK63 developed by Novartis Vaccines has reached advanced human trials.[23] Whether this modification will impact on the risk of Bell's palsy remains to be determined. Therefore, the development of safe yet potent mucosal adjuvants for human use remains a priority with high potential impact.

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