Modern Vaccines/Adjuvants Formulation—Session 2 (Plenary II)

Abstract

On the 15–17th May 2013, the Fourth International Conference on Modern Vaccines/Adjuvants Formulation was organized in Lausanne, Switzerland, and gathered stakeholders from academics and from the industry to discuss several challenges, advances and promises in the field of vaccine adjuvants. Plenary session 2 of the meeting was composed of four different presentations covering: (1) the recent set-up of an adjuvant technology transfer and training platform in Switzerland, (2) the proposition to revisit existing paradigms of modern vaccinology, (3) the properties of polyethyleneimine as potential new vaccine adjuvant, and (4) the progresses in the design of HIV vaccine candidates able to induce broadly neutralizing antibodies.

Keywords: :

• vaccine adjuvant
• technology transfer
• HIV vaccine
• cationic polymer
• formulation

Addressing the Challenge of Access to Adjuvants

The field of modern vaccinology is evolving rapidly and this has been accompanied by a growing need for accessing know-how on adjuvants and vaccine formulation. Nicolas Collin, from the University of Lausanne, Epalinges, Switzerland, presented some key activities of the Vaccine Formulation Laboratory, a platform established in 2010 under the auspices of the World Health Organization, with the mission of facilitating access to adjuvants and vaccine formulation know-how for the vaccine community.

An example of a recent adjuvant technology transfer project was presented. Funded by US-HHS BARDA and the German Society for International Cooperation (GIZ), this project aimed to transfer the equipment and expertise to manufacture an oil-in-water emulsion to Bio Farma, a Developing Countries Vaccine Manufacturer based in Indonesia.¹ Bio Farma staff is now able to manufacture autonomously the oil-in-water emulsion at pilot-scale and the transferred adjuvant was demonstrated to be suitable for formulation with (and for dose-sparing of) pandemic influenza vaccine candidates, based on stability and immunogenicity data of oil-in-water adjuvanted H5N1 antigens.

As accessing know-how in parallel to acquiring adjuvant systems and methods is of paramount importance, the establishment of a Vaccine Formulation training center in Lausanne was also presented. This has involved the implementation of tailored training courses in order to disseminate adjuvant and vaccine formulation knowledge. Some examples of training courses held at the Lausanne training center were presented, including the adjuvant training courses organized by the European Commission FP7-funded TRANSVAC and ADITEC consortia.

Moving From Empiricism and Alchemy To Rational Vaccine Design: A Badly Needed (R)evolution in Vaccinology?

As most of the Th-dependent epitopes used in contemporary vaccines are subject to variability or immune restriction, this makes them potentially prone to a lack of immune recognition or to immune escape. Geert Van den Bossche from UNIVAC llc., Seattle, Washington, USA shared his views on how the field of vaccinology could benefit from new insights in this area.

Classically, addressing immune restriction can be achieved by including adjuvants (TLR agonists, aluminum salts, etc.) in the vaccine preparation and/or by working on vaccine formulation (particulate antigens, virus-like particles, etc.). This is done with the goal of inducing a desired Th1 or Th2 bias. Dr Van den Bossche highlighted the current limitations of these approaches and suggested that the use of invariable and/or conserved T-cell epitopes, and co-localized broadly cross-reactive Th peptides could be a way to overcome antigen variability and immune restriction. He further reminded that there is currently no known adjuvant approach enabling vaccine antigens to actively induce broadly cross-neutralizing antibodies and multi-epitopic CTL.

Finally, turning conserved/invariant antigens that pathogens universally use to subvert the host immune system into immune protective antigens was presented as a multidisciplinary and rational approach, but one which should always remain product-oriented.

Adjuvant Properties of Polyethyleneimine

Polyethyleimine (PEI) is an organic cationic polymer often used in paint and paper manufacture, and as transfection reagents in biology. Quentin Sattentau from the Sir William Dunn School of Pathology, University of Oxford, United Kingdom, presented recent experimental data on the potential use of this polymer as a vaccine adjuvant.²

PEI properties as mucosal adjuvant were evaluated using three different recombinant antigens: HIV gp140, Influenza purified HA trimer and HSV-2 gD glycoprotein. Following intranasal administration in mice and rats, PEI-adjuvanted HIV gp140 elicited stronger antibody responses than with gp140 antigen alone. Moreover, immunization with PEI-adjuvanted influenza HA trimer and PEI-adjuvanted HSV gD improved protection of mice against lethal challenge with influenza and HSV respectively. Dr Sattentau presented data exploring the mode of action of PEI as mucosal adjuvant. PEI does not activate directly the antigen-presenting cells via PRRs (independent of MyD88 and TRIF pathways). Instead PEI triggers DAMPs, likely through the release of intracellular DNA which further leads to the activation of Irf3 and to the inflammasome cascade. PEI also associates physically with gp140 antigen, forming nanoscale complexes and therefore acts as a delivery vehicle.

Next, the systemic adjuvant effects of PEI were tested. Mice and rabbits were immunized through the subcutaneous route with HIV gp140 adjuvanted with PEI or aluminum salts. Higher IgG titers were generated with PEI than with aluminum salts. In the context of systemic administration, the TRIF pathway was involved for PEI activity as demonstrated by experiments using TRIF knockout mice.

Overall, PEI merits further investigation as a vaccine adjuvant for human use. Its mode of action was shown to be dependent upon the route of administration and several questions still need to be addressed to better understand its adjuvant properties.

Adjuvanted HIV Envelope Vaccines: The Challenge of Eliciting HIV Broadly Neutralizing Antibodies

One of the major hurdles impairing the development of efficacious HIV vaccines lies with the extreme genetic variability of the pathogen. When designing HIV vaccines, two main goals are targeted: to induce the generation of neutralizing antibodies that could prevent infection of virtually any HIV strain (broadly neutralizing antibodies, or bnAb), and to induce the establishment of a cell-mediated immunity robust enough to control infection by any HIV strain. Hansi Dean, Director of New Alliances at the International AIDS Vaccine Initiative (IAVI), University of Wisconsin, USA, presented the current challenges behind the development of HIV vaccine candidates designed to generate broadly neutralizing antibodies.

None of the clinical trials completed to date identified immunogens eliciting bnAb. Dr Dean highlighted the progress in identification of vaccine targets on the HIV envelope and its glycans through identification of bnAb. The functional envelope protein is a trimer of gp140. A soluble, stabilized gp140 foldon trimer was designed as a vaccine candidate in order to mimic the structure of a native env trimer. The antigen was derived from JR-FL primary R5 HIV-1 isolate, altered in gp120/gp41 proteolytic cleavage sites, further stabilized with trimerization domain from bacteriophage T4 fibritin and produced in human cells for preserving a native glycosylation. In non-human primates, a prime/boost regimen composed of immunization with JR-FL env plasmid DNA followed by immunization with Adjuplex^TM-adjuvanted JR-FL gp140-foldon induced antibodies that were able to broadly neutralize in vitro tier 1 and tier 2 HIV strains.

Appropriate adjuvant formulation and immunization schedule are considered essential to increase the magnitude and breadth of neutralizing antibody response. However, even an optimized HIV antigen/adjuvant formulation may not be sufficient to drive a desired extensive antibody somatic mutation. To illustrate this, a recent clinical trial with gp120 + NefTat fusion protein adjuvanted with AS01_B showed that autologous neutralizing antibody responses were generated, but with only a low level of affinity maturation despite a four-immunization schedule.

In conclusion, progress is being made but significant challenges remain to focus immune responses on vulnerable regions, drive somatic mutation and elicit broadly neutralizing antibody responses to HIV-1.

Summary

This session was composed of four different presentations which highlighted some major bottlenecks in the adjuvant field, and proposed some solutions which could be implemented to tackle them. Facilitating access to vaccine formulation and adjuvant know-how, revisiting existing paradigms of vaccine design, dissecting further the mode of action of adjuvants to rationalize their use, and working on molecular characterizations, formulations and regimens to design effective modern vaccines are all topics of critical importance whose implementation will benefit the whole vaccine field and community.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.