Current Topics in Medicinal Chemistry - Volume 13, Issue 20, 2013

Most bacterial pathogens are decorated with surface glycans called capsular polysaccharides (CPSs). Each CPS has a unique structure that is distinctively recognized by our immune cells. These polysaccharides are important vaccine candidates given that they are located on the surface of pathogens, are easily accessible by the immune system, and often result in formation of protective antibodies. To induce CPS specific adaptive immune response (i.e., T cell-mediated B cell response), CPSs are conjugated with carrier proteins, and the conjugation products are called glycoconjugate vaccines. Immunization with glycoconjugate vaccines has had significant health benefits in controlling infections caused by Haemophilus influenzae, Streptococcus pneumoniae and Neisseria meningitidis. However, owing to insufficient understanding of their immune activation mechanisms, glycoconjugate vaccines have been designed and synthesized empirically. In recent years, we have witnessed important advancements in the glycoconjugate vaccine field: the discovery of the mechanism of action for glycoconjugate vaccines, a novel in vivo conjugation strategy, and progress in the use of novel carriers. These studies will be reviewed in detail herein.

Vaccines are powerful public health tools that have been of tremendous benefit in protecting vulnerable populations worldwide from many pathogens. However, vaccine- preventable diseases still remain a considerable burden and this is particularly true among aging and aged populations in industrialized countries. The predicted demographic shift in the population landscape towards an ever-increasing aging population and the evidence suggesting that older individuals mount less-than optimal immune response to vaccination have raised the question of improving vaccine responses in older individuals. This review presents recent progress in the understanding at the cellular and molecular levels of age related immune decline and strategies to translate current knowledge into the development of immunization strategies to promote healthy aging, keeping older members of our society autonomous and independent.

This review is aimed to focus on NSCLC as an emerging and promising model for active immunotherapy and the challenges for its inclusion in the current clinical scenario. Cancer vaccines for NSCLC have been focused as a therapeutic option based on the identification of a tumor hallmark and the active immunization with the related molecules that triggers cellular and/or humoral responses that consequently destroy or delay the rate of malignant progression. This therapeutic intervention in an established disease state has been aimed to impact into prolonging patient´s survival with ethically accepted quality of life. Understanding of relationship between structure and function in cancer vaccines is essential to interpret their opportunities to impact into prolonging survival and increasing quality of life in cancer patients. It is widely accepted that the failure of the cancer vaccines in the NSCLC scenario is related with its introduction in the advanced disease stages and poor performance status of the patients due to the combination of the tumor induced immunosuppression with the immune senescence. Despite first, second and emerging third line of onco-specific treatments the life expectancy for NSCLC patients diagnosed at advanced stages is surrounding the 12 months of median survival and in facts the today real circumstances are extremely demanding for the success inclusion of cancer vaccines as therapeutic choice in the clinical scenario. The kinetics of the active immunizations encompasses a sequential cascade of clinical endpoints: starting by the activation of the immune system, followed by the antitumor response and finalizing with the consequential impact on patients’ overall survival. Today this cascade of clinical endpoints is the backbone for active immunization assessment and moreover the concept of cancer vaccines, applied in the NSCLC setting, is just evolving as a complex therapeutic strategy, in which the opportunities for cancer vaccines start from the selection of the target cancer hallmark, followed by the vaccine formulation and its platforms for immune potentiating, also cover the successful insertion in the standard of care, the chronic administration beyond progression disease, the personalization based on predictors of response and the potential combination with other targeted therapies.

Vaccines represent the most efficient tool for preventing diseases caused by infectious pathogens. During the last century significant progress has been made in vaccine development, resulting in the eradication or control of several diseases. However, the emergence of new pathogens and the inadequate protection conferred by some existing vaccines render necessary new vaccination strategies. Newly arising immunization approaches, such as subunit vaccines and mucosal administration, make the use of novel adjuvants essential. However, only a limited number of adjuvants are available on the market. The present review is focused on vaccine adjuvants approved for human vaccines and promising candidates which are currently under development. In this regard, emerging immune stimulators and combinations are discussed, together with their strengths, limitations and regulatory framework.

Bordetella pertussis is the causative agent of whooping cough (pertussis) which is a worldwide vaccine preventable acute respiratory illness that predominantly involves infants. The reactogenicity of whole-cell (Pw) vaccines and the difficulty of their consistent production have led to the development of acellular pertussis (Pa) vaccines. However, despite high vaccination coverage using either Pw or Pa and introduction of adolescent and adult vaccines with reduced antigen content, there are still reports about the circulation of the microorganism in populations, morbidity in infants and increasing incidence of pertussis among adolescent and adults who transmit the infection to yet unimmunized infants. Waning vaccine-induced immunity and antigenic divergence in circulating strains seem to be the major problems accounting for resurgence of pertussis. Considering the need for new vaccination strategies, improvement of current Pa vaccines by including new virulence factors would probably be the most rationale strategy. Recent advances in B. pertussis proteomics, subproteomics and immunoproteomics greatly aided in identifying novel antigens of the pathogen. Future studies involving quantitative transcriptomic and proteomic profiling of host-B. pertussis interactions, studying gene expression in vivo and reverse vaccinology will also be very promising approaches and tools to develop pertussis vaccines inducing long term immunity.

The use of vaccines has led to tremendous decreases in disease burdens across the world. Many challenges remain in expanding vaccine coverage to new pathogens, however, a struggle further hampered by a lack of understanding into many of the fundamental processes through which vaccines elicit robust immunity. In this review we cover recent advances in the field of innate immunity and vaccinology that offer new insights into the reasons some vaccines may succeed or fail. We begin with the secreted cytokines that can influence the nature of the adaptive immune response, and how these may be tuned with the use of particular adjuvants. From there we cover dendritic cells, perhaps the key cell at the interface between innate and adaptive immunity. We discuss mechanisms for targeting specific subsets of dendritic cells, and the effects of this targeting. We further discuss additional modifications of the vaccine formulation to enhance interactions with innate immunity, including phagocytocis and antigen presentation. Finally, we step back to review recent advances in systems biology, and the ability of these new tools to provide deeper understanding of innate immune functions. We hope that this review will provide researchers with access to a breadth and depth of recent work that will allow for the rational design of novel vaccines to combat the most serious infectious diseases of today and tomorrow.

Mucosal vaccinology is a relatively young but rapidly expanding discipline. At present the vast majority of vaccines are administered by injection, including vaccines that protect against mucosally acquired pathogens such as influenza virus and human papilloma virus. However, mucosal immune responses are most efficiently induced by the administration of vaccines onto mucosal surfaces. The small number of currently licensed mucosal vaccines have reduced the burden of disease and mortality caused by enteric pathogens including rotavirus, V. cholerae and S. typhi, or those that spread to affect distal organs such as poliovirus. Expanding knowledge about the special features of the mucosal immune system promises to accelerate development of mucosal vaccines that could contribute significantly to protection against pathogens that colonize or invade via mucosal surfaces including HIV, Shigella, ETEC, Campylobacter jejuni, Helicobacter pylori and many others.

The Structural Vaccinology (SV) approach is the logical evolution of Reverse Vaccinology: a genome-based approach combined with structural biology, with the idea that protective determinants can be used to selectively engineer the antigens that can be re-designed and simplified for inclusion in vaccine combinations. The final objectives of the rational structure-based antigen optimization are the facilitation of industrial-scale production of the antigens combination, obtain a greater immunogenicity and a greater safety profile and finally expand the breadth of protection. Structural Vaccinology is particularly powerful in case of antigenic variation between closely related strains and species. Several examples are available in literature of how SV has already been applied successfully to several bacterial and viral projects. The examples of structure-based antigens optimization reviewed here describe different template procedures that can be followed to develop improved vaccines against other pathogens and potentially help resolve challenges in manufacturing or efficacy.

Vaccination is one of the safest and most cost-effective public health interventions, which save millions of lives annually. Thanks to all the genius pioneers of the field, we have already developed many effective vaccines. On the other hand, there are still many pathogens for which we do not yet have an effective or optimal vaccine, including malaria, HIV, and tuberculosis. In the 21st century, biological sciences are at the edge of a growing and fruitful genomics era, which provide many opportunities for vaccine research to have a better understanding of host-pathogen interactions, immune responses, targets and thus allow the scientists to design better vaccines. After the publication of the first bacterial genome of a pathogen, Haemophilus influenza, genomics technology revolutionized the field and created novel vaccine discovery approaches like reverse vaccinology, antigenome technology, surfome analysis, immunoproteomics, and genetics vaccinology to discover novel immunogenic antigens. This review is an attempt to briefly explain these methodologies and the history of their development since the beginning of the century.