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Posted: 6 Jun 2013
2013 Adjuvants in Vaccination Symposium - Meeting Report

"Adjuvants in Vaccination Symposium"
 Ragon Institute and Harvard CFAR
21 May, 2013
Meeting Report

This one day meeting brought together experts from academia and industry to discuss the effect of adjuvants on immune responses elicited by vaccination, their mechanisms of action and efforts to discover new and improved adjuvants.

Below are some of the highlights from the presentations and discussions.

Danilo Casimiro (Merck)

Danilo introduced the concept of adjuvants and said that vaccine developers use these enhancers of immune responses for a number of reasons, including improvement of responses in elder and immunocompromised populations, to increase the rapidity of responses, to makie responses more durable, to modify the quality of T cell responses, to focus immune responses on mucosal sites, and for dose sparing. Only a small number of adjuvants are included in vaccines licensed for human use: Alum, AS04 (3D-MPL on Alum), and oil-in-water emulsions AS03, AF03, and MF59. However, a wide variety of novel adjuvants are being developed, many of which aim to stimulate innate responses via Toll-like Receptors (TLRs). At the same time, industry is exploring ways to bypass the use of adjuvants by incorporating immunostimulatory agents directly into antigens, for example by conjugating an antigen of choice to a carrier protein such as OMPC.

While acute adverse events associated with vaccines are readily tractable and quantifiable, detecting long-term safety and very rare events is extremely challenging. In addition to the need to do long-term follow-up, it is complicated by the fact that animal models are not available and in some cases the prevalence of a condition is not well known in a target population. Moreover, in order to understand the causes of such events, pre-vaccination samples need to be available and banking such samples on a very large scale is impractical. Merck is working on approaches that would allow down-selection of candidate vaccines based on in vitro assays, such as by monitoring production of cytokines by cell lines in response to a vaccine. They are also working on primate models that would allow correlating adverse events with biomarkers and they already have a potential classification algorithm based on RNA signatures of proteins from several antiviral/chemokine/cytokine/signaling pathways.

Nicholas Valiante (Novartis)

Nicholas presented the work of the Novartis adjuvant-discovery group, which is engineering small molecules as minimal essential adjuvants. The focus of the program is on striking the balance between immunopathology due to innate responses activated by adjuvants, and immunoprotection, which requires these innate responses to stimulate adaptive immunity. It is driven by the hypothesis that a large part of the inflammatory responses elicited by adjuvants is not necessary for engaging adaptive responses and, therefore, is wasted. Hoping that this unneeded inflammation can be avoided via rationally-designed approaches; the group is trying to develop a toolbox of small molecules that target different molecular pathways involved in immunity.

They started by screening a large library of compounds to identify those that activate specific pathways, for example a TLR7, which recognizes single-stranded RNA. Then using combinatorial chemistry, the group identified a specific charge pattern on the nucleoside that appears to be responsible for that recognition. Using that knowledge and additional compounds based on the original molecule, the researchers were able to identify molecules that induce innate responses of smaller magnitude and of more focused impact, but which produce antibody titers comparable or higher than the starting compound, supporting the “wasted inflammation” hypothesis. While this provides the proof of principle, the identified compounds have poor solubility and have weeks-long retention at the injection site. Additional analogues have been screened and new compounds are now moving into studies in humans.

Bali Pulendran (Emory University)

Bali described some of the work currently being done at the Emory NHP B cell consortium to study the effect of adjuvants on magnitude and durability of antibody responses. Immunizing 10 monkeys per group, they are comparing antibody responses to either SIV VLPs (containing Env and Gag) or a mixture of gp140 and gag p55 recombinant proteins. Two types of adjuvants are used in both cases: Alum alone was compared to PLGA-based nanoparticles containing MPL (activator of TLR4) and R484 (activator of TLR7/8). From the four groups, the group that received recombinant proteins adjuvanted with nanoparticles showed the best antibody responses, while VLP+Alum had the lowest responses. This was true for serum and mucosal IgG and IgA, as well as for the number of plasmablasts. The difference was especially striking for the number of long-lived plasma cells in the bone marrow, where the numbers differed by more than 10-fold. The efficacy of these responses will be tested in the near future by challenging animals with a low-dose repeated SIVsmE660 virus.

Switching from humoral responses to CD8 responses, Bali recalled that when his groups looked for gene signatures for potency of the yellow fever vaccine, they identified a protein kinase, EIF2AK4, which is responsible for integrated stress response. By phosphorylating eIF2a (also known as GCN2), EIF2AK4 blocks translation and leads to sequestration of all mRNAs in stress granules. Trying to understand the role of this protein in CD8 responses, Bali’s group looked at GCN2 -/- knockout mice and found that they have reduced CD8 responses to the yellow fever vaccine. After vaccination in these mice, the cytokines levels are normal, as well as the antigen uptake. The hypothesis proposed by the Pulendran lab for the involvement of GCN2 in immune responses is based on the observation that infection with yellow fever (as well as with other viruses) leads to reduced levels of aminoacids and activation of autophagy. The defect of GCN2 blocks this pathway and reduces antigen presentation by infected professional APCs, such as DCs.

Julie McElrath (Fred Hutchinson Cancer Research Center)

Julie presented results of assays looking at innate immune responses in samples from a number of clinical trials including DNA vaccines, Ad5-based vaccines, RV144, and GSK HIV-002. She noted that they haven’t observed more than 2-3-fold increases of effects of new adjuvants when compared to the classical adjuvant Alum. This, however, can be misleading because in some cases binding antibody levels remain fairly stable, while the neutralization titers are dropping off quickly after immunization. She stressed the importance of clinical data, as neither safety nor immunogenicity can be reliably assessed in non-human primates. Comparative adjuvant studies done with same antigens are needed. However, multiple challenges exist on the path to such studies: formal agreements need to be established, IP issues addressed, data sharing discussed and agreed upon, and formulation needs to be consistent across studies.