Different human vaccine adjuvants promote distinct antigen-independent immunological signatures tailored to different pathogens

Niels Peter H Knudsen,Peter Andersen,Ugo D´Oro,Alessandra Bonci,Else Marie Agger,Ali M Harandi,Andreas Meinke,Rino Rappuoli,Rhea N Coler,Cecilia Buonsanti,Anja Olsen,Christopher B Fox,Yuan Zhang,Frank Follmann,Ennio De Gregorio,Daniele Casini,Rolf Billeskov

doi:10.1038/srep19570

Abstract

The majority of vaccine candidates in clinical development are highly purified proteins and peptides relying on adjuvants to enhance and/or direct immune responses. Despite the acknowledged need for novel adjuvants, there are still very few adjuvants in licensed human vaccines. A vast number of adjuvants have been tested pre-clinically using different experimental conditions, rendering it impossible to directly compare their activity. We performed a head-to-head comparison of five different adjuvants Alum, MF59®, GLA-SE, IC31® and CAF01 in mice and combined these with antigens from M. tuberculosis, influenza, and chlamydia to test immune-profiles and efficacy in infection models using standardized protocols. Regardless of antigen, each adjuvant had a unique immunological signature suggesting that the adjuvants have potential for different disease targets. Alum increased antibody titers; MF59® induced strong antibody and IL-5 responses; GLA-SE induced antibodies and Th1; CAF01 showed a mixed Th1/Th17 profile and IC31® induced strong Th1 responses. MF59® and GLA-SE were strong inducers of influenza HI titers while CAF01, GLA-SE and IC31® enhanced protection to TB and chlamydia. Importantly, this is the first extensive attempt to categorize clinical-grade adjuvants based on their immune profiles and protective efficacy to inform a rational development of next generation vaccines for human use.

Highlights

® ® adjuvants Alum, MF59, GLA-stable emulsion (SE), IC31 and CAF01 in mice and combined these with antigens from
® ® peptide KLK combined with the TLR9-stimulatory oligodeoxynucleotide ODN1a (IC31 ), cationic liposomes formed of dimethyldioctadecylammonium (DDA) stabilized with synthetic mycobacterial cord factor signaling through the C-type lectin receptor Mincle (CAF01), and conventional Alum delivered in the form of a 500 μ g aluminum-content dose of diluted 2.0% Alhydrogel
® ® 3 times s.c. with H56, MOMP or HA formulated in Alum, MF59 CAF01, GLA-SE or IC31 with 3 week intervals (H56 with Alum was not tested in this assay)

Summary

Introduction

® ® adjuvants Alum, MF59 , GLA-SE, IC31 and CAF01 in mice and combined these with antigens from. MF59 and GLA-SE were ® strong inducers of influenza HI titers while CAF01, GLA-SE and IC31 enhanced protection to TB and chlamydia This is the first extensive attempt to categorize clinical-grade adjuvants based on their immune profiles and protective efficacy to inform a rational development of generation vaccines for human use. Many novel vaccines currently in development are based on proteins or peptides predicted by computer databases or by screening antigen libraries[1,2] These advances in the post-genomic era have enabled the design of highly pure, safe and simple vaccines, other challenges have emerged in parallel, including the inherent lack of immunostimulatory properties of proteins and peptides. The recent clinical testing of several novel exploratory adjuvants with the ability to generate CMI responses[8,9] clearly indicates that it is plausible to expand the range of adjuvants available for human use

Objectives

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Conclusion