• Open Access

Optimizing rational vaccine design


Vaccines are the most cost-efficient tool to prevent infectious diseases, and their therapeutic use, against both infectious and non-infectious (e.g. cancer, autoimmunity) diseases, is gaining considerable interest. However, despite major advances in the fields of microbial pathogenesis, immunology and vaccinology, there are still many diseases for which vaccines are not available or the available vaccines are inadequate in terms of efficacy and/or safety. This is particularly true for chronic or persisting infections. In the post genomic era all potential antigens, which are coming into consideration for inclusion into a vaccine formulation, are well known. This knowledge has been exploited in the context of reverse vaccinology-driven approaches, which in combination with comparative genomics enabled to select the most highly conserved and promising antigens for vaccine design. However, the advent of new vaccines against diseases such as AIDS, chronic hepatitis or malaria, as well as improved vaccines against ‘old diseases’, such as tuberculosis, is well overdue. It is obvious that extremely optimistic end-points for vaccination against these agents, such as the stimulation of sterilizing immunity, should be replaced by more realistic goals, like the stimulation of immune responses able to delay disease onset or progression. However, this is not the key issue. Where then lay the most critical roadblocks preventing the development of effective immune interventions against the agents causing these diseases?

The first roadblock is that our knowledge on the effector mechanisms responsible for the clearance of these pathogens is by and large fragmentary. In-depth studies of natural infections represent the best strategy to access this knowledge. There are individuals who are refractory to infection (e.g. multiple exposed uninfected individuals for HIV) or develop slow progressing forms of disease (e.g. long-term non-progressors for HIV, chronically infected patients without liver cirrhosis for hepatitis). Well-defined patient cohorts with different forms of disease were established in recent years, which are being characterized in terms of their genetic, microbiological and immunological profiles. This is expected to lead to biomarkers and molecular/phenotypic signatures associated with better prognosis, as well as to the identification of the effector mechanisms responsible for microbial clearance. This knowledge base will considerably facilitate and accelerate rational vaccine design.

Let us consider for an instant an ideal scenario in which the first roadblock has been overcome. It is exactly known which antigens need to be included in the formulation and which kind of effector mechanism should be stimulated to confer protection. Considering the present state of the art, a subunit vaccine will probably be the strategy of choice, as the replacement of whole cell vaccines or semi-crude antigen preparations by well-defined antigens has dramatically improved their safety profile. At this point we will face the second roadblock; namely the availability of tools enabling the stimulation of predictable immune responses of the adequate quality following vaccination. In fact, highly purified antigens are often less immunogenic than more complex preparations, rendering essential their co-administration with potent adjuvants. These compounds also have immune modulatory properties, which allow to fine tune the responses elicited. This is critical issue since the stimulation of a wrong response pattern may even lead to more severe forms of disease. However, despite the fact that there are several adjuvants under development, the sad truth is that only a handful of them have been licensed for human use (i.e. Alum, MF59 and MPL; Tagliabue and Rappuoli (2008). This is far worse if compounds exhibiting activity when administered by mucosal route are considered, from which only a few candidates are in the development pipeline (Rharbaoui and Guzmán, 2005; Ebensen and Guzmán, 2008). Hence, there is a critical need for novel adjuvants, particularly those exerting their biological activities when administered by mucosal route. This is very important, as most pathogens enter the host via the mucosal tissues. Thus, the stimulation of an effective local response would also enable to block infectious agents at their portal of entry, thereby reducing their capacity to colonize and be further transmitted to other susceptible hosts. It is expected that in the coming years we will see a new generation of well-defined and highly efficient adjuvants coming in the market. This will facilitate the development of a new generation of more effective vaccines, as the availability of adjuvants exhibiting different biological properties will allow efficient fine-tuning of the immune responses elicited according to specific clinical needs.

The third roadblock is related to the need to bridge the translational gap, as well as to current stringent regulations for vaccine testing (e.g. requirement of GMP grade material for phase I studies), which have in turn led to an explosive increase in clinical development costs. To accelerate translation novel strategies are needed for a rapid and cost-efficient screening, selection and prioritization of the most promising candidates. For certain pathogens the most widely accepted animal model are primates (e.g. HIV, HCV). However, one of the most significant issues associated with these animal models is that they do not completely reproduce the pathophysiology of human diseases. Reproducibility is also an issue, as they suffer greatly by the small number of animals that can be studied at any time and by inter-individual variability, which limit their statistical power. Furthermore, primate models are often too expensive and fraught with ethical constraints. Thus, none of the existing models adequately address the needs of the vaccine developer. Hence, there is a clear need for cost-efficient small animal models to address these limitations.

In this context, mice are ideally suited to perform the initial validation of vaccine candidates in a cost-efficient manner. However, the results obtained in mouse-based systems cannot always be extrapolated to humans. A very promising alternative strategy consists in the engraftment of components of the human immune system into immune compromised mice (Shultz et al., 2007; Legrand et al., 2008). When these animals are engrafted with liver or cord blood derived stem cells, proper development of NK cells, B cells, dendritic cells and different T-cell subsets (e.g. CD4+, CD8+, Treg) is obtained. While still experiencing some limitations, these human/mouse chimeras are permissive to infection by different infectious agents, including the HIV (Baenziger et al., 2006; An et al., 2007). However, there is still margin for further development, such as the improvement of adaptive cellular responses. It is also critical to ensure that they fulfil with the key features of good animal models, namely ensure their reproducibility and an adequate high throughput, perform thoroughly validation with known human vaccines, and made them available at an acceptable cost respect to their benefit. Nevertheless, these aspects will be fully addressed in the coming years, thereby enabling their routine application for vaccine preclinical validation. It is expected that the use of these advanced animal models for vaccine testing will result in increased predictability for their performance in humans, thereby enabling a rapid and efficient selection of the best candidates to be transferred into the clinical development pipeline.