Modern Vaccine Adjuvant/Formulation—Session 9: Adjuvants

Abstract

The Session 9 of the Modern Vaccine Adjuvant/Formulation meeting pointed out the permanent need for vaccine improvement and for adjuvant development. Indeed, the increasing use of recombinant subunit vaccines for both parenteral and mucosal vaccination necessitates the development of improved adjuvants. This session dealt with strategies for the development of new vaccine adjuvants with respect to the availability of new molecules targeting specifically the receptors of the systemic or mucosal immune system.

Keywords: :

• formulation
• adjuvants
• mucosal immunity
• T-cell response

Biomarkers of experimental mucosal adjuvants

Because most infectious agents invade the body through the mucosal surface, the mucosal immune response functions as a first line of defense. Eliciting a local mucosal immune response is important for protection against diseases. Dr Ali Harandi from the Department of Microbiology and Immunology, Institute of Biomedicine, University of Gothenburg, Sweden, presented us an overview of current mucosal immunization strategies and mucosal adjuvants.¹ He highlighted the interest of mucosal vaccination approaches owing to the facts that 80% of the immune cells are located in the mucosa associate lymphoid tissues² and the immune response in the mucosal system is more tightly regulated than in any other tissue.

The mucosal vaccination started early in the Human history with the nasal administration of powdered smallpox vaccine in the 16^th century in China. However, despite the success of the oral polio vaccine over 50 years ago, currently only a few commercially available mucosal vaccines exist, based on live attenuated, non living whole cell or sub component vaccines. Against cholera: Dukoral (Crucell), Shanchol (Shantha Biotechnics) and Orochol (Crucell); against rotaviruses: RotaTeq (Merck), Rotarix (GlaxoSmithKline); against Poliovirus (many developers); against flu: Nasovac (Serum Institute of India) and FluMist (MedImmune).

Four reasons were put forward to explain the limited number of mucosal vaccines. Tradition was the first as vaccines are mainly given by parenteral routes. For some mucosal vaccines, safety concerns were observed such as Bell’s palsy or intussusception. Globally mucosal vaccination is poorly developed because of limited knowledge in mucosal immune response, and then because of the lack of mucosal adjuvants, vectors and of adapted delivery devices.

Parenteral vaccination may elicit a mucosal response in some instances, but usually a mucosal vaccination route is more effective for generating a protective immunity against mucosal pathogens. The development of mucosal vaccines will necessitate the development of safe and effective mucosal adjuvants and delivery systems. Over the past decade, a number of immunomodulatory agents where tested, including toxin based adjuvants such as cholera toxin (CT) and E. coli heat-labile toxin (LT), Toll like receptor (TLR) agonists and non TLR-targeting immunostimulators as well as delivery systems. A lot of efforts have been made to segregate adjuvanticity from toxicity associated with toxins,^3,4 but the design of an effective and safe mucosal adjuvant needs the understanding of the mode of action of the candidates, and the identification of biomarkers that predict their potency.^5,6

Complement as natural adjuvant

Presented by Dr Martin F Bachmann (University of Zurich; Zurich, Switzerland)

Various classes of soluble molecules from microbial or non microbial origin are recognized by immune cells receptors, like TLR, RIG, NOD or Dectin, harnessing the innate immunity to promote the adaptive immunity.⁷ TLR agonists activate the immune response against coadministered antigens and can be packaged into virus like particles (VLPs) in the aim of reducing their side effects and increasing their immune stimulating effect. VLPs exhibiting the appropriate particle size for phagocytosis and toll like receptor agonists activating APC have been shown capable of inducing T cell responses to the levels obtained with live vaccines.⁸ Additional studies demonstrated that cross presentation and cross-priming were independent. In these studies, VLPs were cross presented by DCs even in the absence of TLR signaling but they failed to induce a protective CD8⁺ response in the absence of an innate stimuli.⁹ This is in contrast with observations made on model soluble antigens where cross presentation was dependent on TLR signaling. In the case of VLPs, the repetitive structure of VLPs promoting multiple antibody binding and the activation of the complement cascade may be sufficient for cross presentation.

Other results presented, demonstrated that mice deficient for the third component of the complement (C3^−/− mice) are highly susceptible to influenza infection.¹⁰ The antiviral protection is mediated by CD4⁺ and CD8⁺ T cell response, enhanced by C3-degradation products. Additionally, C3d is described as an adjuvant¹¹ and polymeric nanoparticles are able to activate complement.¹²

The key message was that VLPs are optimal for B cell activation; they are efficiently transported to splenic follicular dendritic cells, which reduces the threshold of B cell activation.¹³ Repetitive motives in VLPs fix the complement. Nanosized vaccines such as VLPs are preferable to induce a T-cell response.¹⁴

A novel combination adjuvant for mucosal vaccination against respiratory syncytial virus

Presented by Dr Sylvia van Drunen Littel-van den Hurk (VIDO—Intervac and Viral Pathogenesis and Vaccine Development Group at University of Saskatchewan, Canada)

The respiratory syncytial virus (RSV) is the most common respiratory pathogen in infants and children. In some cases RSV infects the lower respiratory tract and causes severe pneumonia and/or bronchiolitis.¹⁵ Dr Sylvia van Drunen Littel showed preclinical data generated with a vaccine candidate based on a subunit recombinant antigen, using an adjuvant platform that is suitable for mucosal delivery and cross-presentation. This platform is based on the combination of three immune stimulators, namely a poly I:C, TLR3 agonist, and an innate defense regulator (IDR) peptide in polyphosphazene microparticles, and was used in a formulation with a truncated secreted version of the RSV fusion (F) protein. Preclinical studies suggested that TLR activation was crucial for designing a RSV vaccine, and that the formulation must elicit a balanced response with neutralizing antibodies and CD8⁺ T cell response.¹⁶ This vaccine candidate induced in mice both systemic and local immunity, including virus neutralizing antibodies, CD4⁺ and CD8⁺ IFN-γ-secreting T cells as well as RSV specific CD8⁺ T cells in the lung. Protective immunity was also demonstrated in the RSV cotton rat model.¹⁷ In order to evaluate the potential of the vaccine for neonatal immunization, a newborn lambs model was establish for bovine and human RSV.¹⁸

Novel vaccine adjuvant for cellular and humoral immunity

Dr Sandrine Grabé from Wittycell presented a new adjuvant, analog of iGB3, which is a natural ligand for the Natural Killer T Cells, naturally presented by Cd1d molecules expressed at the surface of the Antigen Presenting Cells, including Dendritic Cells

One of the advantages of this agonist is that the stimulation pathway that conducts to NKT cells activation is complex and is regulated by a negative feed back loop system, limiting the pro inflammatory reaction.

The WTCc adjuvant is fully documented. The adjuvant information package comprises information on its Immunomodulatory properties, the development of regulatory package including scale up, GMP batch production, toxicity profile, and stability data. The adjuvant is currently tested in a phase I/IIa clinical trial with HBV surface antigen.¹⁹

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

10.4161/hv.26074