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FEATURE
Rational Design for the Next Generation of Vaccines
John E. Connolly & Ping Zhong

Capitalizing on Advances in Immunology

Vaccines represent one of the most important medical advances in the history of human health, second only to sanitation in their impact on overall mortality. Nowhere is this better demonstrated than in the eradication of smallpox. From the early 1960s to the late 1970s, the burden of smallpox was reduced from more than 2 million cases per year to zero through a proactive vaccination campaign. Despite their success, most vaccines contain attenuated or killed pathogens and were developed empirically, with very little understanding of the immunological mechanisms by which they induce protective immunity. An improved understanding of our immune system is ushering in a new era of modern, rationally designed vaccine.

Investment in Prevention

For most people in the world death from infectious diseases remains a tangible threat. The inevitability of global pandemics and the mortality from endemic diseases continues to pose an enormous challenge in the foreseeable future. Overall, infectious diseases are the leading cause of human morbidity and are responsible for one quarter of all deaths annually. In addition, the number of people afflicted with nonfatal infectious diseases also represents significant global healthcare and economic burden. Vaccination represents one of the most consequential and cost effective preventative measures for both the population and the individual. While difficult to calculate precisely, the global vaccine market is roughly $25 billion, and is predicted to reach $57 billion by 2017. The relationship between health and economic growth is a cornerstone of economic development worldwide, making continued investment in vaccines a priority.

New Vaccines to Address Emerging Needs

The field of vaccine development faces a number of daunting challenges moving forward. Emerging infectious diseases such as pandemic influenza strains represent a major difficulty for vaccinologists and public health specialists. The frequency of epidemics caused by newly emerging pathogens and the likelihood of rapid global spread have increased in recent decades, as illustrated by the emergence of panzootic H5N1 avian influenza in 1997, Nipah encephalitis in 1999 and severe acute respiratory syndrome (SARS) in 2003. Mounting an effective response to these emerging threats requires the mobilization of a rapid, flexible and scalable vaccine platform which fulfils the stringent regulatory requirements of safety and efficacy in at risk populations. The importance for such a strategy was apparent during the H1N1 influenza pandemic in 2009 when the rate of viral dissemination far outpaced the global availability of vaccine. Meanwhile, chronic infections pose their own difficulties. The development of vaccines which are effective against chronic infections, such as HIV, hepatitis C virus (HCV), and human papillomavirus (HPV) will require new approaches to improve immunogenicity and long lasting protection. This is due in large part to a complex antigenic profile and immune evasion strategies utilized by these viruses to circumvent the development of natural immunity.

Immune Mechanisms of Protection: a Systems-Based Approach

To date, characterization of human responses to vaccination has mainly relied on measuring antibody titers or cellular responses from peripheral blood samples. This approach does not permit a comprehensive analysis of the integrated cellular players or the underlying pathways stimulated during the development of a protective response. Efforts are being made therefore to deconvolute the immune response to pathogenic challenge in order to identify key regulatory systems which drive the protection. These systems-based cohort studies take a multimodal approach to look into the functional, genotypic and phenotypic immune parameters in time following vaccination which correlate with protective immunization. Systems impacting the duration of the protective response and the breadth of the cross-protection to similar pathogens are also important factors that could benefit from these studies.

Directing the Immune Response Against a Defined Target

Novel subunit vaccines are based on a restricted number of individual pathogen specific components which are able to confer protective immunity. The advantage is an improved product consistency and an enhanced safety profile, as demonstrated in an increasing number of modern vaccines. The shift in focus has yielded a better understanding of the specific requirements of an effective vaccine antigen (the key molecule for an effective vaccine) with special emphasis on epitope identification (the key molecular motif that triggers immune protection) within a given component. Advances in proteomics and molecular modelling have accelerated the development of these structurally specific component vaccines which would overcome many technical drawbacks of current technology based on purification of pathogen or pathogen ingredients.

In addition to identification of antigenic epitopes and structures, the context in which these antigens are presented to the immune system is important in determining the magnitude of response. Immunogenic pathogen components, such as viral envelope proteins that are recognized by the immune system and drive the production of protecting antibodies, are often found in tandem repeats in the microbe. These structured repeats allow the antigen to efficiently communicate with B-cells, the antibody producing immune cells, by providing a more potent signal for activation. Additionally, the microenvironment where these events take place provides important influences on the specific types of antibody made. This microenvironment is often the product of T-cells, immune cells that are also capable of recognizing antigenic epitopes and assist B-cells in generation of protective antibodies. Therefore, an optimal component vaccine should embody those epitopes that can interact with T-cells in high affinity as well as epitopes that are structurally defined and can be presented in regular repeats to B-cells, thus increasing the likelihood of a protective antibody response.

Dictating the Quality of the Immune Response

Progress in the generation of component vaccines from defined antigens has led to products with an improved consistency and safety profile. In the absence of other microbial compounds however these purified antigen components alone are usually poorly immunostimulatory; the use of a companion adjuvant compound is essential. The origin of the word 'adjuvant' is from the Latin 'adjuvare', which means 'to help'. Adjuvants have been used to increase the immunogenicity of vaccines for decades. Despite this, only a few have been licensed for human use, leaving the options extremely limited. Thus, the expanded use of existing adjuvants and development of new adjuvants capable of promoting broad and sustained immune responses are needed. The current obstacle is in part due to the lack of understanding of the molecular mechanism underlying the immune boosting efficacy of these adjuvants. Recent advances in our knowledge of the immune system have facilitated the identification of novel immune stimulators and have begun to reveal basic molecular and cellular action of an effective adjuvant.

Pioneering studies into the fundamental mechanism of immune recognition have led to the discovery of pathogen associated molecular patterns (PAMPs) that are specific to a given microbe. Recognition of these PAMPs is the mechanism by which our immune system identifies and initiates a response to an invading organism. By developing potent agonists which mimic these PAMPs, we can elicit qualitatively different immune responses. The example of compound R-848 has been demonstrated mimic aspects of viral genomes and elicit potent antiviral responses, functioning as an effective adjuvant in a vaccine. Studies investigating how the immune system initiates and responds to infection serve as the basis by which we may use combinations of these agents to selectively enhance vaccine response to complex pathogens in at-risk and immunocompromised populations such as children or the elderly.

Dendritic Cells, the Target of Next Generation Rationally Designed Vaccines

Dendritic cells (DCs) are antigen-presenting cells (APCs), the immune cells that process antigenic components and present them to the B-cells and T-Cells; thus they are the key to initiate and control adaptive immune responses. Proper dendritic cell function is the foundation of any successful vaccine response. These cells express a broad array of molecular antenna which permits them to senses microbial invasion, to diagnose the nature of the invading pathogen (i.e., viral, fungal, bacterial) and to direct the proper polarization of the downstream immune response. In the past decade clinical studies have exploited DCs as a means to improve vaccine efficiency. In these autologous, cell based vaccine has been developed, for example, a vaccine, that consists of DCs that were prepared outside the human body and were loaded with desired antigens, was administered to patients. Though this strategy has demonstrated some level of efficacy in the therapeutic setting, as a vaccine it is highly invasive, labour intensive and costly, unsuitable for large scale immunization.

Given their central role in determining both the magnitude and quality of the antigen-specific immunity, an ideal vaccine would be capable of targeting an optimized antigen and adjuvant combination directly to DCs. The development of affinity reagents which target these cells has significantly accelerated the progress of these rationally designed vaccines. One of such idea is to utilize recombinant monoclonal antibodies specific to certain specific proteins of these dendritic cell. Antigens linked to such antibodies are thereby specifically delivered to dendritic cells in order to elicit an immune response. Recombinant, chimeric vaccines consisting of such a monoclonal antibody specific for dendritic cells fused to an optimized set of antigens are demonstrating clinical efficacy in trials in recent years. The ability to rapidly produce these recombinant molecules and flexibility to change their associated antigens make them the potential candidates for pandemic response vaccines.

Another method of directed delivery antigens to dendritic cells is through the use of engineered nanoparticles. Particle-based vaccines, such as, gold-NPs, self-assembling polymers, lipid immunostimulatory cages (ISCOMs) and exosomes are a promising avenue for future vaccine development. One of the greatest benefits of particle-based antigen delivery systems is the capability of these targeting platforms for a proper structural presentation of antigenic components for effective immune activation. Additionally, these vaccines are also often able to carry cargo such as immune stimulatory agents either through chemical conjugation or through direct incorporation into the structure. It is intriguing to speculate that the systematic reverse engineering of a pathogen to create a synthetic construct capable of delivering highly specific activating signals in conjunction with optimized antigens may constitute an effective platform for personalized vaccines.

Perspectives and Challenges

Vaccine development has played a critical role in human health. Despite our many successes, there is an ever increasing need for new vaccines. Some of the greatest hurdles we face in the coming decade are not scientific but rather societal. Progress is often hindered by a lack of regulatory approved adjuvants and delivery systems to induce the effective immune responses. In addition, the financial commitment required to take a new vaccine forward is significant, and the most commercially lucrative markets are often not those with the greatest need. A mechanistic understanding of the immune responses required specifically for protection, coupled with modern molecular and computational technologies promises to lower the barrier for new vaccine development. Biologically relevant immune correlates of protection will reduce the need of massive population based studies to demonstrate efficacy. By capitalizing on the recent advances in immunology we can bring the right vaccine at the right time to the right population in an equitable and sustainable manner.

About the Author

Dr. Connolly is a Senior Principal Investigator and Director for Translational Immunology at the Institute of Molecular and Cellular Biology (IMCB). Additionally, Dr. Connolly serves as Program Director for the A*Star Program in Translational Research in Infectious Disease, a multi-disciplinary center focused on target discovery and vaccine development. His research interests focus on rational vaccine design. He is an Adjunct Associate Professor of Immunology at Baylor University. Dr. Connolly received his Ph.D. in Immunology from Dartmouth Medical School and studied human dendritic cell biology under Dr. Michael Fanger. During this time he was involved in the development of immunotherapeutic preclinical models and clinical trials for Glioblastoma multiforme (GBM). He moved to the Baylor Institute for Immunology Research, a fully translational research institute dedicated to rationally designed vaccines against cancer and infectious disease. Dr. Connolly served as the Director of Research Initiatives for the Baylor Research Institute, leading a large integrated translational research resource and multi-institutional programs that involved a number of international sites. During his tenure at Baylor, Dr. Connolly was the central core facility director of the NIAID Centers for Translational Research on Human Immunology and Biodefense, an NIH funded consortium of basic, translational research and clinical trials focused on vaccine design. Dr. Connolly is the past President of the Board of Directors of The American Cancer Society in N. Texas.

Following his medical training in China, Dr. Zhong received his Ph.D. in pharmacology at Georgetown University, USA and later received his postdoctoral training at Stanford University. Since then he had made his career in the biotech/pharmaceutical industries. He first joined in the assay development and biochemistry department of Neurex Corporation in Silicon Valley of California, which later became part of Elan Pharmaceuticals. In 2000, he co-founded Abmaxis Inc., a biotech startup of state-of-art antibody and protein engineering technology that aimed to integrate computation biology with molecular engineering technology in protein design, where he served as founding board member, Chief Operating Officer, Director of Display Technology, VP of Molecular Biology, and VP of Biology. In mid-2006, after the acquisition of Abmaxis Inc. by Merck, Dr. Zhong became Senior Investigator of Merck Biologics Research Department, and continued his leadership in antibody and protein engineering technology and biologic drug development. Dr. Zhong is currently a Senior Principal Investigator of Singapore Immunology Network (SIgN) of Biomedical Sciences Institutes (BMSI) under Agency for Science, Technology and Research (A*Star).

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