Accelerated vaccine development against emerging infectious diseases

Abstract

Emerging and re-emerging infectious diseases represent a major challenge to vaccine development since it involves two seemingly contradictory requirements. Rapid and flexible vaccine generation while using technologies and processes that can facilitate accelerated regulatory review. Development in the “-omics” in combination with advances in vaccinology offer novel opportunities to meet these requirements. Here we describe how a consortium of five different organizations from academia and industry is addressing these challenges. This novel approach has the potential to become the new standard in vaccine development allowing timely deployment to avert potential pandemics.

Keywords: :

• emerging infectious diseases
• human artificial lymph node
• immunoinformatics
• immunomics
• immunopeptides
• immunostimulatory
• immunotoxicity
• metagenomics
• proteomics
• self-assembling vaccine

Infectious diseases remain a major source of global suffering and death. While significant progress has been made against many traditional pathogens, new threats to human health are posed by re-emergent and antibiotic-resistant agents along with the appearance of new and unanticipated forms of infectious diseases. While vaccines have historically been one of the most cost-effective health care tools for combating infectious diseases,¹ there are unique challenges to the process of developing vaccines for emerging and re-emerging infectious diseases (EIDs). One of these is that the growing exposure of human populations to reservoirs of infection in a world of dense urban centers integrated through a highly efficient global transport network of people and goods potentiates the sudden emergence and rapid global proliferation of some EIDs.² The rapid “evolution” of the genome that can occur in some infectious agents (e.g., influenza) also puts a premium on the accelerated development of effective vaccines for these pathogens.^3,4

In such cases, effective vaccine development involves two seemingly contradictory requirements. Vaccine generation, testing, and production must be rapid and flexible to accommodate the abrupt appearance, genomic diversity, and rapid dissemination that characterize these kinds of EIDs. At the same time the technologies and processes used to generate and produce vaccines against diverse targets must be consistent, highly standardized, and reproducible to facilitate accelerated regulatory review. A successful approach must address both requirements. Traditional vaccine development and production approaches that meet national regulatory requirements often result in a new vaccine arriving too late on the market to influence the spread of infections to the general population.^5,6

Advancements in the “-omics” (genomics, metagenomics, proteomics, immunomics, functional genomics, transcriptomics etc.) are ushering in a new era in the development of effective vaccines.^7,8 Development efforts no longer need to depend on the generation of attenuated pathogens or random target identification in order to produce novel vaccines. Being able to compare the host genome and pathogen’s genome offers a unique opportunity to fine-tune the immune system against specific targets while avoiding unwanted outcomes such as the development of autoimmunity, or toxic side-effects.⁷ Emerging in vitro and ex vivo approaches also permit assessment of potential efficacy and toxicity of vaccines well ahead of preclinical studies.

Vaxcelerate, a consortium of five independent organizations from academia and industry, was convened to develop a new, modular process of rapid vaccine generation and testing that leverages new vaccine generation technologies and features an interactive and integrated process among best-in-class collaborators. Each member contributes its expertise to enable the rapid development and testing of new vaccines. The work of the consortium is facilitated by a number of multiparty intellectual property agreements and supported by an experience management team.

The members of the consortium include: the Vaccine and Immunotherapy Center (VIC, Massachusetts General Hospital), charged with the overall management of the Program as well as providing a self-assembling vaccine construct; EpiVax, a company with an established expertise and effectiveness at in silico antigen generation;^9-11 ProBiogen, a contract research organization with ex vivo vaccine efficacy tools and assessment expertise to the group; Evaxion, a biotech company that applies in silico algorithms for assessing antigen efficacy and safety; and Dr David Baker’s group (University of Washington), which will provide expertise in the design of next-generation synthetic adjuvants and targeting molecules.

Taking Advantage of Technology to Generate Faster, Safer Vaccines

Vaxcelerate’s development efforts center on a vaccine platform composed of a constant adjuvanting framework that is capable of “self-assembling” with different immunopeptides that can be customized to target an immune response against a specific pathogen. In silico approaches are applied to generate the optimized peptide epitopes and ex vivo and in silico assessment tools are used for the rapid, early prediction of efficacy and safety.

The self-assembling component of the vaccine, which would represent a constant unit in all generated vaccines, can be screened in advance for safety, dosing, and best route of administration, making it possible to stockpile a framework that has already undergone regulatory review. The variable peptide epitopes of the vaccine can be rapidly identified through high throughput computing, immunoinformatics, and vaccine design algorithms,^7,8 and produced quickly. Resultant vaccines have a consistent design but target the immune system to a specific pathogen. The combined components are subjected to a consistent and rapid safety and efficacy screen consisting of the use of in silico tools for predicting potential adverse events and ex vivo and in vivo assessment of efficacy and safety in an artificial lymph node and in humanized mouse models.

Self-assembly (VIC)

VIC has successfully experimented with the use of Mycobacterium tuberculosis heat shock protein 70 (MTBHSP70)-avidin fusion proteins to stimulate innate and adaptive immune response. The MTBHSP70-avidin fusion is the adjuvanting and delivery component of the self-assembling complex. It can be manufactured under GMP conditions and tested in silico, ex vivo and in vivo for safety and its ability to stimulate the desired immune response. Incubation of the fusion with the biotinylated immunogenic component(s) yields a testable vaccine in short order. A perceived drawback of the self-assembled complex is its size; it forms a tetrameric structure greater than 360 K_d. The next generation of self-assembling molecules is being designed in collaboration with Dr David Baker’s group at the University of Washington. They are focusing their attention on identifying the specific MTBHSP70 domains that give the protein its immunostimulatory properties and which could be used to produce a smaller and potentially safer self-assembling molecule.

Identification of broadly immunogenic peptide epitopes (EpiVax)

Epivax has developed computational tools to mine infectious agents’ genomes to identify genes encoding proteins with promising vaccine antigen properties such as secretion, upregulated expression, and virulence. Immunoinformatics tools are then used to map protein sequences for short, linear putative T-cell epitopes. Sequences are synthesized as peptides and evaluated for human leukocyte antigen (HLA) binding and antigenicity in survivors of infection or vaccinees.

In silico/ex vivo/in vivo assessment tools for efficacy and safety (ProBiogen, EpiVax and Evaxion)

Taking advantage of the efficient identification of immunogenic peptides by EpiVax and the known sequences of the self-assembling components, the first steps consists of in silico safety assessment. For example, given the fact that an IgE response is associated with adverse vaccination outcomes, Evaxion has adapted its VacFinder bioinformatics tool to generate a learning data set from IgE -inducing proteins based on helminthic antigens, venom, bacterial toxins and major allergens known to be IgE class-switch inducers. Peptides with a high potential for contributing to an adverse reaction are eliminated from further assessment. The MTBHSP70-avidin fusion is similarly scrutinized with this tool.

Further safety evaluations are afforded by the use of humanized mice and the ProBiogen’s human artificial lymph node (HuALN) technology. The HuALN technology consists of a 3D matrix-based technology using primary cells emulating in vivo conditions and allowing the analyses of immunogenicity, immunofunction and immunotoxicity. It provides a tool to bridge the existing gap between animal-based pre-clinical testing and first-in-man application. Among its key advantages are: the availability of long-term culture; close recapitulation of in vivo human lymph node conditions; and the ease with which samples can be obtained to assess immunogenicity, immunofunction and immunotoxicity. Humanized mice of a specific HLA that can be matched with the HLA in the HuALN to facilitate the efficacy assessment of a newly developed vaccine.

The success of this rapid vaccine development approach depends on the close collaboration of all parties involved in the consortium. This means constant updates of the state of development of all the components making the vaccine and of the immune status of the animals and performance of the HuALN system. If successful, this novel approach will become a new standard in vaccine development, capable of rapid generation of new vaccines that can receive accelerated regulatory review and be available in time to avert potential pandemics.

Abbreviations:
EIDs	=	emerging infectious diseases
HLA	=	human leukocyte antigen
HuALN	=	human artificial lymph node
IgE	=	immunoglobulin E
Kd	=	kilodalton
MTBHSP70	=	Mycobacterium tuberculosis heat shock protein 70