Overcoming formulation challenges for the next generation of vaccines

KEYWORDS:

• Vaccine
• drug delivery
• protein
• formulation
• stabilization

1. Overcoming formulation challenges for the next generation of vaccines

When you have worked for a long time at something with only limited success, you must begin to ask yourself the reason you have not met your goals. Is it because your goals are unrealistic, the presence of a fundamental flaw in your assumptions and approach, or perhaps unexpected obstacles? This situation appears to be facing the drug delivery field for vaccines, which we reviewed in 2008 [1]. The goal that has yet to be reached is a major contribution of the many novel technologies that have been created in the last 30 or so years to the development of new vaccines.

Advances in modern drug delivery technologies, including devices, at the experimental level have truly been spectacular [2–5]. Ranging from aerosols and oral routes to microneedles, jet injectors, and micro/nanoparticles, the degree of sophistication and preclinical success of these myriad approaches have been quite remarkable [6]. Drug delivery approaches have attempted to improve vaccinations by changing the route of administration, by extending residence time on mucosal surfaces, promoting accumulation in secondary lymphoid tissue, or by modifying the rate of protein and/or adjuvant release. Many of these methods include some degree of active or passive targeting and have demonstrated efficacy in animal models. Ultimate success, however, has only been demonstrated in a few cases such as with aerosols (intranasal influenza vaccine) and oral delivery (rotavirus and adenovirus) as well as in the use of a few new adjuvants. ‘Nanoparticles’ in the form of virus-like particles (e.g. hepatitis B and human papilloma virus vaccines) have been particularly impressive although based on a tendency of viral surface proteins to self-organize into particulate antigens mimicking native viral structure. But in the context of the efforts over the last 30 years, this is a modest output indeed. So what is the problem? Why have we seen so little of this extensive research turned into new vaccine products?

There are a number of reasons which we will consider later that may have impeded the translation of vaccine drug delivery systems to the clinic. In the case of nanoparticles and micro-particles, large-scale manufacturing and both in vitro and in vivo stability are critical issues that are often inadequately addressed and may lead to a failure in development. Creating even the simplest vaccine formulations at an industrial scale is already a monumental task. Implementing manufacturing steps to create nanoparticles or to encapsulate or even conjugate purified proteins only adds complexity. Stability issues associated with the resulting formulation may be addressable but may reflect an intrinsic, deleterious property of the delivery system.

As with traditional vaccines, preclinical development represents another major hurdle for vaccine delivery systems. The use of rodent animal models rarely provides a representative picture of the behavior of vaccines in humans. For example, a recent meta-analysis of publications focused on preclinical studies of anticancer nanoparticles indicated ‘there are serious problems for the translation of cancer targeting nanoparticles for human use’ [7]. Furthermore, simple proteins such as the serum albumins or lysozyme are poor surrogates for actual vaccines. It is important to remember that even adjuvanted recombinant proteins are infrequently effective as human vaccines with the exception of virus-like particles. While the use of adjuvants can aid in the solution of this problem, even our increased understanding of the innate immune system has yet to yield universally effective adjuvants in humans. Despite these barriers, it does seem possible but is by no means certain that the current plethora of new delivery systems has the potential to contribute to vaccines. But, there are several more difficult problems that have yet to significantly occupy the concerns of drug delivery technologists.

First, do we really need new delivery technology? Perceived problems of pain, convenience, potency, and toxicity have not been convincingly documented. While a child may cry when a vaccine is injected through a needle, this has not stopped vaccines from being effective worldwide. Problems with the delivery of vaccines in the developing world are often more a problem of effort than one of real barriers. There are certainly many vaccines that we lack which are urgently needed in various environments (malaria, tuberculosis, pandemic viruses, etc.), but it is unclear what novel drug delivery technologies have to contribute to these efforts. The latest new vaccines (flu, meningococcal disease, shigella, etc.) are all delivered by conventional means. Could drug delivery really improve access, compliance, or even efficacy while maintaining current standards of safety? This question certainly deserves more attention given the current extensive effort devoted to the novel methods of vaccine delivery.

A second issue too little discussed is the view of the small number of global vaccine producers on the importance and direct relevance of new delivery technology to their current and future vaccines. One issue here is cost. There is an obvious need to keep vaccine costs as low as possible. It is highly probable that any new delivery method is likely to raise rather than to lower such costs. Furthermore, especially with current vaccines, no company is likely to compete with themselves, even internally. For example, the measles vaccine is delivered by injection, often as part of a combination vaccine. New technologies have been developed which effectively deliver the live attenuated measles vaccine (e.g. aerosols) have been available for some time but have yet to become commercially available. Despite their lack of associated pain and effectiveness, there is little driving force for their final development. This is no doubt for the reasons given above including cost, self-competition, and driving need.

But what about our recent advances in our understanding of the biology of the immune response? For example, the development of bioconjugates of antigens and adjuvants and targeting to lymph nodes? [8] To our mind, this probably includes the most exciting recent work with the potential to enhance vaccine developments. While prognostication is always hazardous, it seems likely the results of this work will encounter many if not all of the obstacles described earlier. Thus, work such as this will have to be performed in the light of these concerns.

2. Expert opinion

So what can one suggest to enhance the development of vaccines using new delivery approaches? We feel the main question that should be addressed is need. Does a drug delivery technology attack a well-defined problem in a realistic manner in terms of cost and medical need and does it possess a feasible path forward in terms of pharmaceutical development and manufacturing? [9,10] Issues such as stability and evidence of efficacy in animals other than rodent models need to be addressed early in feasibility studies when possible. In particular, researchers should carefully characterize formulations to validate the properties of exactly what is being injected. New techniques such as intravital microscopy and analytical equipment capable of simulating an injection site will help illuminate what is happening to vaccine components after administration. Improving the stability or maintaining association of antigen and adjuvant in vivo may be a real opportunity for drug delivery technologists [2,6,11].

The preliminary success of novel technologies has led to the training of a large number of drug delivery scientists. We must be cautious that this does not result in an internal perpetuation of a field. It may be that the scientific creativity manifested here has somewhat obscured the research community’s understanding of hurdles associated with manufacturing a vaccine product. New technologies have led to an emphasis on the technologies themselves. Whenever possible, any new delivery method should be coupled to a vaccine of immediate medical interest and not be a ‘me too’ vaccine unless addressing a well-rationalized issue with safety or compliance. If one cannot find an industrial partner or at least a funding source with interest in one’s vaccine, this may be a message that need is less than that required and temper enthusiasm for a particular technology.

There is little doubt that our enhanced understanding of the immune system will help in the creation of physiological models that better represent the human situation. An improved understanding of human immunity will provide guiding principles for designing vaccine delivery systems that can then be tested in a relevant manner. Even carefully reviewing seminal discoveries throughout the rich history of vaccine development in light of our current understanding of human immunity would help hone modern drug delivery approaches. A critical consideration of the issues we raise should help increase the probability novel delivery technologies will contribute to the development of new and more effective vaccines.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded.