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International Clinical Trials

Added Impetus

Since the early days of Edward Jenner’s smallpox vaccine, immunisation has become a staple of disease prevention. By stimulating the immune system with antigens from a disease-causing agent, it becomes primed to kill off those invading pathogens. Historically, vaccines were based on live, attenuated viruses or killed whole organisms, but they now rely more on recombinant and synthetic antigens.

However, these modern antigens tend to be less immunogenic than those used in older vaccines, as they typically comprise only fragments of the protein or RNA. They are safer, but at the expense of effectiveness – and this is why adjuvants are key components in so many vaccines in the development pipeline today.

An adjuvant is designed to improve vaccine efficacy by modulating, enhancing or extending the immune response or therapeutic action. There is an additional advantage: it reduces the amount of antigen that is required in each dose. Combining immunomodulators or adjuvants with modified delivery vehicles can also improve the quality of the immune response.

Role of Dendritic Cells

The immune response is complex, with many different types of cells involved, including dendritic cells, macrophages, mast cells, eosinophils, neutrophils, and both B and T lymphocytes. Dendritic cells operate early on in the immune ‘cascade’, and are the most effective of the antigen-presenting cells. Activated dendritic cells drain into the local lymph node, where they spring into action by presenting the antigen to – and directing the differentiation of – T helper (Th) cells.

Antigen peptides are presented by the dendritic cells as short strings of 10 to 80 amino acids in a peptide/major histocompatibility complex Class II protein complex. This binds to the T cell receptors on Th cells, thus activating the major biochemical pathways in these cells’ cytosol. A second, independent biochemical pathway is triggered via interaction between CD80 or CD86 on the dendritic cells, and CD28 on the Th cells. These two activations result in selfproliferation, via the release of the T cell growth factor and interleukin 2 (IL-2). Ultimately, after numerous generations, each Th cell will differentiate into one of three types of T helper cells: effector, memory or suppressor.

There are two major subtypes into which the Th cells differentiate: Th1 and Th2. The immune responses induced by vaccines usually rely on either Th1 or Th2 cells. A third type of Th cell, Th17, is also now recognised as having potential in vaccination.

Cytokine secretion by the dendritic cells is crucial in determining how they differentiate, and thus their activity. If they differentiate into Th1 cells, then interferon-gamma will be secreted, along with IL-2 and IL-12. Cytotoxic CD8+ T cells will proliferate and macrophages will be activated. This will lead to the production of tumour necrosis factors gamma and beta, as well as immunoglobulin G2a.

In contrast, if they differentiate into Th2 cells, interleukins 4, 5, 6, 10 and 13 will be secreted. B cells will proliferate, with antibodies produced. Typically, an initial phase of immunoglobulin M production will be followed by a more specific immunoglobulin G conversion a few days or weeks later. If they differentiate into Th17 cells, they produce two main members of the IL-17 family – IL-17A and IL-17F – in addition to IL-22. This results in the recruitment, activation and migration of neutrophils.

Adjuvants Old and New

The first adjuvanted vaccines relied on aluminium salts; these are still by far the most widely used adjuvants, being added to current hepatitis A and B, diphtheria, anthrax and rabies formulations. They are believed to act on the dendritic cells and via apoptosis, although their precise mechanism of action continues to be investigated.

Various factors influence the rate and capacity of antigen adsorption on the large surface area of the aluminium salts, including electrostatic attraction, ligand exchange, hydrophobic interactions and non-charge associated surface interactions. However, the relationship between the strength of adsorption and immunogenicity is not consistent, and aluminium salts have a tendency to aggregate on storage, which can impact immunogenicity. Antigen stability can also be affected when they are combined with aluminium salts.

Numerous challenges face those looking to develop novel adjuvants that will be able to replace or enhance aluminium salts, whose adjuvantation effect is often limited or selective. Perhaps most importantly, it is still not clear how adjuvants work, and elucidating the exact mechanism of adjuvantation is far from trivial. While aluminium salts have been used for many years, there remains a lack of long-term safety data for any of the possible alternatives. There is no guarantee that if an adjuvant is effective with one type of vaccine, it will be successful in another; and there is a huge need for comparative studies to be carried out to support adjuvant selection.

Alternative Options

Many alternative adjuvants have been studied, and it is still a fruitful field for invention. These include, for example, biologic molecules such as oligonucleotides, carrier proteins, lipids, lipopolysaccharides and polysaccharides, RNA-like compounds, peptides and proteins, plus a range of active biologics such as granulocyte-macrophage colony stimulating factor, cytokines and interleukins. Formulation ‘tricks’ like forming emulsions, liposomes, IscomatrixTM particle technology, polymeric solutions or particulates also have potential. Combinations of different adjuvants and techniques may prove particularly productive.

One technique that has garnered a good deal of attention is the use of lipid-based systems such as liposomes. These have been shown to up-regulate several chemokine genes in dendritic cells, facilitate the in vivo migration of antigens, and deliver antigen into the cytosol of antigen-presenting cells. They can induce greater cellular immune responses and work in a variety of different vaccine types, from viruses to parasites and even DNA vaccines. More complex cousins – for instance, proteoliposomes, cochleate structures and virosomes – are being explored too, with vesicle-based systems like these showing great promise as adjuvants.

Virus-like particles are also being widely studied. They have the key immunologic feature of virus-repetitive surfaces, and may be rapidly changed, displaying high-density, repetitive epitopes. These particles facilitate the presentation of both foreign antigens and haptens, and are especially effective as carriers for non-immunogenic haptens. While they are showing real potential as effective vaccine adjuvants, there are drawbacks, including low yield and purifi cation problems. In addition, their complexity adds major cost to vaccine manufacturing, which could prove limiting.

Future Combinations

Combining different adjuvant technologies could prove a successful strategy in enhancing and changing immune response. A variety of combinations have been attempted, such as using aluminium salts with either naloxone or CpG oligonucleotides, liposomes, or oil-in-water emulsions, with a variety of other adjuvants.

Some of these combinations have proved both potent and promising, but the effect can still be limited and, worse still, side-effects may be enhanced. This is one reason why it is important that the adjuvants are studied extremely carefully, both with and without the vaccine antigens, to establish their effect and – perhaps more importantly – their side-effects. Overall, however, it seems likely that the future of successful adjuvantation lies in combination.

To date, only a handful of products that include nonaluminium adjuvants have reached the market, and even a couple of these still have aluminium components. Three are flu vaccines: GlaxoSmithKline's (GSK's) pandemic flu vaccine, Pandemrix, is an oil-in-water emulsion, as is Fluad, from Novartis; while Crucell’s Inflexal V is a virosome formulation. Two further GSK products are adjuvanted with the combination of monophosphoryl lipid A and aluminium salts – human papilloma virus vaccine, Cervarix, and Fendrix for hepatitis B.

Study Approach

A recent Phase 1 study of a potential new vaccine for Haemophilus influenza highlights the sort of comparative trials that need to be carried out in the early development stages of an adjuvanted vaccine, to establish whether the adjuvant(s) improves its immunogenicity and effectiveness.

The early phase trial was a randomised, observer-blind, placebo-controlled, multi-centre, dose-escalation study to evaluate the safety, reactogenicity and immunogenicity of the vaccine in current and former smokers. Subjects were dosed with a non-typeable H. influenza vaccine – either adjuvanted using a liposome-based adjuvant system, or without adjuvants – via intramuscular injection on days 0, 60 and 180.

Comparative trials are needed to provide an additional layer of clinical investigation to explore the role of adjuvants in a new vaccine formulation. This is typically done via some form of randomised, placebo-controlled Phase 1 trial, where subjects are dosed with the vaccine, either with or without adjuvants. The effects of the two versions can then be compared to determine whether the adjuvantation is having the desired effect.

According to data from, in 464 of 2,481 studies on vaccines – almost a fifth – carried out between 2008 and September 2014, some form of adjuvant was included in the formulation. The proportion of studies using adjuvanted vaccines grew over that period from 16.5% to 23.4%. Of these, 232 were adjuvanted vaccines for infection, 169 therapeutic vaccines for neoplasms, and the remaining 63 other types of adjuvanted vaccine for indications such as Alzheimer’s disease.

Early-Phase Impact

The added complexity of identifying the best adjuvant, or adjuvant combination, for each individual vaccine project has greatly increased the importance of early-phase clinical development. With effects such as immunogenicity and reactogenicity, and the added safety issues related to the adjuvants and their interaction with antigens – all important to evaluate in human subjects – the intricacies of clinical trial design has deepened substantially.

There is no substitute for experience, and having conversations with the regulatory authorities at an early stage can be extremely helpful. They tend to be very open to discussion and, by working with their experts on the file even before submission, approval for an individual clinical trial is more likely to be achieved in a timely manner. This is particularly important if new mechanisms of adjuvants are involved.

A whole host of challenges face scientists and clinicians at all stages of vaccine R&D – not least the lower immunogenicity of modern synthetic or fragment antigens. Adjuvants will play a crucial role in vaccines going forward, because of their ability to tailor immune responses to maximise protection or therapeutic effect. They can also reduce the quantity and potential toxicity of target molecule or epitope required, which may have a significant impact on costs. Extensive research is under way into the development and application of adjuvants that will be required to make the safe and effective vaccines of tomorrow.

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Dr Robert Lins is Project Director, Vaccines and Senior Clinical Adviser for SGS Life Science Services. He is the former Managing Director of SGS, having led the company from 2007 until 2011. Robert received his Medical Degree from the University of Ghent, specialising in Nephrology and Hypertension. He also holds a Doctor of Philosophy degree in Medical Sciences from the University of Antwerp. Previously, he was Director of the Nephrology- Hypertension Department at Stuivenberg Hospital in Antwerp, eventually becoming a General Manager. Robert started a Phase 1 unit at the hospital in 1987, which was subsequently acquired by SGS.
Robert Lins
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