Pharmaceutical companies such as Novartis and GlaxoSmithKline have staked out a large share of the adjuvant market with their proprietary emulsion-based compounds and adjuvant systems, respectively. Currently, large-scale vaccine manufacturers appear to be content with existing options, such as the traditional first-generation alum adjuvants, but the public opinion of adjuvant use might be improving.
Vaccine manufacturers are adopting more sophisticated methods of introducing adjuvanting properties into their vaccine formulations through complex combinatorial formulations, which achieve immunoenhancing activity in addition to antigen delivery. Most of these innovations, driven by newer regulatory incentives, are currently in the early phases of R&D among growing biotech companies, which are not only positioned as key acquisition or in-licensing opportunities, but also underscore the stagnant state of adjuvant discovery within bigger pharmaceutical companies.
The level of clinical unmet need in vaccinology remains the ultimate driving force behind more recent R&D efforts with adjuvants. The need for higher efficacy and stronger safety profiles is likely to remain the main focus of vaccine manufacturers for the foreseeable future.
The ability to provide a longer-lasting immune response with a single dose is considered an ideal feature for any new vaccine launching today; however, given the overall sub-optimal effect of adjuvants in current vaccine formulations, more research is required to determine which mechanisms will be best used to exploit the host immune system and deliver a robust, long-lasting immune response.
Other unmet needs in this space are improving public opinion and the perception of adjuvants in vaccines. Due to strong media campaigns and certain adverse effects, such as adjuvant-related narcolepsy, adjuvants have suffered from a tainted perception among end-consumers, such that patients are wary of adjuvants present in vaccines. It is crucial to overcome these misconceptions in order to achieve larger adoption within all patient groups.
On the market
GlaxoSmithKline’s (GSK) adjuvant system, AS04, was the first novel adjuvant to receive FDA approval. The adjuvant was approved as part of the formulation of Cervarix, GSK’s vaccine that was designed to prevent infection from two strains of the human papillomavirus (HPV), 16 and 18.
This bivalent vaccine displayed an acceptable safety profile and comparable efficacy in providing protection against the two strains of HPV when compared with its main competitor, Merck’s tetravalent vaccine Gardasil, which is adjuvanted with traditional aluminium salts.
Novartis has also received favourable responses to Fluad, its adjuvanted seasonal influenza vaccine, as a vaccine that primarily targets the elderly population and is adjuvanted with the company’s novel MF59 adjuvant.
Novel adjuvants have the potential to answer concerns that have long plagued the vaccines, and these recent approvals suggest that adjuvants are likely to enjoy increasing market demand in the US, much like in the EU.
The US gives these vaccine manufacturers access to a very rich pharmaceutical market, where physician and patient preferences tend to be bigger factors in determining market share. The US market, in addition to those in Europe, can also help provide these companies with the resources to improve on R&D for vaccines needed in developing countries.
Vaccine adjuvants are synthetic or recombinant protein products that are used in the vaccine formulation to elicit a stronger immune response, often at the site of infection. While there are many adjuvants that have been tested, the majority of today’s vaccines still rely on the use of aluminium salts to provide the desired immunological boost within the host.
These adjuvants can work in different ways to increase the immune response; however, the three main methods by which adjuvants augment the activity of the antigen within the host are:
- increasing the half-life of the vaccine antigen to promote the activation of the host’s innate immune system (depot effect)
- increasing the likelihood of antigenic uptake with the development of new vehicles for antigen delivery
- modulation of innate immune response to provide appropriate signalling cascade, such as the production of specific cytokines or chemokines (Buonaguro et al, 2011; Knipe et al, 2007).
The overall unmet needs in the adjuvant market mirror those of global infectious disease vaccines, because of the inherently symbiotic nature of both components. Key opinion leaders observed that, in practice, adjuvants use is not indicative of the true gains made in immunological research today.
To give some perspective to the discussion of unmet needs, it is imperative to understand some of the general drivers and barriers that affect the current vaccine market. These environmental factors dictate the acceptance and approval of the novel adjuvants as used in newer vaccines, and are also likely to outline overarching problems that vaccine manufacturers encounter.
The key drivers and barriers that influence the size of the vaccine market and the subsequent uptake of vaccine adjuvants are indicated in Table 1. While most companies are able to mitigate the risks associated with being a part of the vaccine industry, the factors listed overlook the relatively high barriers to entry, which stands as the primary limitation to new innovation and companies entering the market.
The overall level of unmet need in the adjuvants and vaccine market is moderate. This can be described as a need for increased clinical safety, adjuvants that can be recognised specifically by dendritic cells (DC), appropriate toll-like receptor (TLR) targeting and activation, and better formulations and dosing offerings.
Table 2 lists the prominent unmet needs present in the vaccine adjuvant market, along with a numerical value to depict the level of attainment of these needs in different markets (1 – low attainment, 5 – high attainment). The table also ranks the relative importance of each of the unmet needs on a scale of low, moderate or high.
Adjuvant safety
The clinical safety associated with the use of adjuvants is a factor detrimental to their use in vaccines. Many or most adjuvants are associated with inducing mild-to-moderate injection-site adverse reactions, such as swelling, redness and soreness, as a result of a strong inflammatory response by the immune system.
While the use of adjuvants in most infectious disease vaccines is considered key to eliciting the desired immune response, a poor safety profile is likely to limit the approval of the vaccine.
To cite a recent case, Dynavax’s vaccine against hepatitis B was denied FDA approval for its Biologics License Application based on its poor safety performance in trials. Achieving a high enough level of adjuvanting efficacy with a low adverse effect profile will prove to be tricky for vaccine manufacturers to overcome. Vaccine adjuvant options currently provide temperamental results in enhancing the immune response, often in a dose-dependent manner.
DC recognition
DC recognition is critical in stimulating the immune response. These antigen-preventing cells (APCs) are the primary target for all vaccines, and adjuvants are expected to function as an antigen depot in order to provide the DCs with adequate time to recognise the antigen and stimulate the immune response.
Although most vaccines use the first-generation adjuvant, alum, creating an effective antigen-depot effect is not always achieved. This effect is likely to be enhanced by the delivery of an adjuvant that is stable and yet able to create a strong enough bond with the antigen that the process is gradual. Research studies have shown that too much antigen can cause the opposite effect among participating DCs and prevent the uptake of the appropriate antigen.
Therefore, further research is needed to provide an efficient alternative that maintains the antigen-depot effect to sustain the immune response.
Appropriate TLR activation
In achieving a strong immune response, researchers have identified that TLRs are a strong target option; however, literature has shown that not all TLR responses are accurate for the purposes of eliciting an immune response or the appropriate immune response.
As more adjuvants are being developed with increasingly rational design methods, careful thought to mechanism downstream of the initial TLR target is required in order to achieve the appropriate type and magnitude of the immune response; for example, knowing that lipopolysaccharides are capable of stimulating TLR4 provides a basis for the in vitro analysis of the presumed immune response.
This type of preclinical study design can help to identify the appropriate markers to quantify the immune response after vaccination. This also bolsters the understanding of preclinical models (such as mice) and allows researchers to better extrapolate this data into the expected effects in a human.
Formulation and dosing
The formulation and dosing regimen of vaccines today is largely a result of historical norms and poor clinical efficacy. Most of the vaccines on the market are administered intramuscularly, which can result in poor efficacy profiles due to the low concentration of DCs present in the muscle as opposed to the dermis.
As more vaccine manufacturers begin to develop vaccines with novel ROAs, there remains a disconnection between the types of adjuvants that can be used in these new formulations and those that are used.
Adjuvant-driven research in preclinical models has shown that certain adjuvants are better suited to stimulate a stronger immune response in specific tissues, such as the ability of CpG oligodeoxynucleotides (CpG ODNs) to elicit a strong response in mucosal surfaces. Furthermore, there is an increasing number of vaccine manufacturers involved in creating new devices that eliminate the use of a needle and use newer technology, such as mini needles, transcutaneous patches, aerosols and even needle-free injector systems (Moingeon et al, 2002).
Dosing also poses an unmet need for vaccines on the market. Many childhood immunisations require the use of multiple booster doses in order to achieve longer immunity protection.
Adjuvants can be considered the answer to this concern; however, current adjuvants are not the solution. Further research is required to develop stronger adjuvants that are able to lengthen the antigen-depot effect and provide the host with desired long-lasting immunity.
Clinical trial design
Adjuvants used in vaccines against infectious disease subscribe to the same type of regulatory procedure rigour as unadjuvanted vaccines. Clinical trials with vaccines are set up under two distinct safety evaluation segments – the non-clinical safety evaluation and the clinical safety evaluation.
The non-clinical safety evaluation lays the foundation for the clinical safety evaluation, where researchers and clinicians are required to pay attention to the specific safety parameters in their assigned preclinical models to ensure minimal adverse effects during clinical testing in humans. These two evaluation segments, combined with the analysis of the adjuvant’s mechanism of action (MOA), form the three tiers of adjuvant safety evaluation as a part of R&D of a new vaccine (Garçon et al, 2011).
Non-clinical evaluation
The non-clinical evaluation process of vaccines and their related components deals with basic preclinical toxicology studies. These studies are also augmented by specific hypersensitivity and autoimmunity tests and assays (Garçon, 2011). These assays, conducted in animal models, are set to test the local tolerance and maximum tolerated dose of the vaccine. The major findings of these studies are often simply to test for and assess any potential systemic or local adverse events that may occur as a result of the vaccine’s administration.
The potential for adverse effects that harm the reproductive capability of a woman are also tested at this phase. Manufacturers are also expected to provide a full assessment of the effects of the vaccine on a variety of tissues, as listed out by the WHO (Gruber, 2012; WHO, 2003).
The appropriate extrapolation of data from these preclinical studies is a strong point of contention among clinicians and researchers alike. Nevertheless, the structure of these non-clinical studies offers a window of insight into the parameters that are required for the scaling-up of the vaccine to be tested in humans.
Adjuvant MOA evaluation
The MOA for an adjuvant is often difficult to pinpoint. In the case of alum or aluminium salts, scientists are still unable to elucidate the exact MOA that determines its efficacy as a strong adjuvant.
With second-generation adjuvants, however, the regulatory bodies require manufacturers to provide documentation on the presumed MOA of the adjuvant, by indicating the duration of the immunostimulatory effect post-vaccination. This data is also expected to highlight an understanding of the signalling pathways employed by the adjuvant to help promote the immune-boosting effect (Garçon, 2011).
Clinical safety evaluation
The clinical safety evaluation, as with all other drugs and therapies, includes the three phases. In addition, unlike unadjuvanted vaccines, adjuvanted vaccines are subject to post-licensure studies to provide long-term safety data against the adjuvant included in the vaccine formulation.
Phase I and early phase II trials are set up to help the manufacturer identify the ideal dose strength and determine the appropriate dosing regimen to ensure immunoprotection.
These studies are performed on a small number of patients (between 20 and 80 patients, depending on the indication) and serve a primary function as identifying potential adverse safety effects (Garçon, 2011; Gruber, 2012).
The later phases of clinical development (phases II and III) are used to determine not only the safety of the administered vaccine, but also the efficacy and related immunogenicity-inducing capability of the vaccine.
Due to the impact of these studies, they often involve a large number of subjects (up to tens of thousands) to provide the analysis to show the breadth of coverage among a varied group of patients. This data is expected to be collected from double-blind randomised studies, which intrinsically impose the ‘burden of proof’ requirement on the data accrued (Gruber, 2012). The last phase of regulatory assessment for an adjuvanted vaccine comes from the post-licensure testing that takes place after the product is released onto the market. This includes an assessment of the safety parameters of the vaccine up to 12 months after the administration of the vaccine into the test subject.
These studies test for any type of new adverse event, in addition to providing follow-up analysis of any primary adverse events highlighted during clinical trials. They also analyse any precursor signs to autoimmune or inflammatory responses that could be indicative of an adverse effect to the presence of the adjuvant in the vaccine.
Regulatory strategy
The regulatory pathway for adjuvanted vaccines is a combination of guidelines set by regulatory bodies, such as the US FDA, the WHO and the European Medicines Agency (EMA).
The WHO has had a strong influence on the development of the guidelines used throughout the different countries. Due to the nature of vaccines as a weapon in the fight against many preventable diseases, the development of vaccines has a great impact on the standard of care across many developing countries as well.
According to key opinion leaders in the fields of vaccinology and immunology, there is a need for a streamlined regulatory process for adjuvanted vaccines, or perhaps even for vaccines in general.
In addition, clinicians are currently unable to outline a specific path that would increase the likelihood of approval, primarily due to the limitations imposed by the ‘burden of proof’, where researchers are required to offer enough clinical and research evidence to confirm a vaccine’s proposed health benefits.
The development of vaccines requires strong commercial and research expertise. This can act as a strong barrier to entry for newcomer companies that are unable to generate the revenue required not only to conduct the clinical research, but also to eventually achieve licensure and bring the vaccine to the market.
