Healthcare on the brink: navigating the challenges of an aging society in the United States.

The US healthcare system is at a crossroads. With an aging population requiring more care and a strained system facing workforce shortages, capacity issues, and fragmentation, innovative solutions and policy reforms are needed. This paper aims to spark dialogue and collaboration among healthcare stakeholders and inspire action to meet the needs of the aging population. Through a comprehensive analysis of the impact of an aging society, this work highlights the urgency of addressing this issue and the importance of restructuring the healthcare system to be more efficient, equitable, and responsive.

Exploring the future adult vaccine landscape-crowded schedules and new dynamics.

Amidst the backdrop of the COVID-19 pandemic, vaccine innovation has garnered significant attention, but this field was already on the cusp of a groundbreaking renaissance. Propelling these advancements are scientific and technological breakthroughs, alongside a growing understanding of the societal and economic boons vaccines offer, particularly for non-pediatric populations like adults and the immunocompromised. In a departure from previous decades where vaccine launches could be seamlessly integrated into existing processes, we anticipate potentially than 100 novel, risk-adjusted product launches over the next 10 years in the adult vaccine market, primarily addressing new indications. However, this segment is infamous for its challenges: low uptake, funding shortfalls, and operational hurdles linked to delivery and administration. To unlock the societal benefits of this burgeoning expansion, we need to adopt a fresh perspective to steer through the dynamics sparked by the rapid growth of the global adult vaccine market. This article aims to provide that fresh perspective, offering a detailed analysis of the anticipated number of adult vaccine approvals by category and exploring how our understanding of barriers to adult vaccine uptake might evolve. We incorporated pertinent insights from external stakeholder interviews, spotlighting shifting preferences, perceptions, priorities, and decision-making criteria. Consequently, this article aspires to serve as a pivotal starting point for industry participants, equipping them with the knowledge to skillfully navigate the anticipated surge in both volume and complexity.

Transforming drug development with synthetic biology and AI.

The COVID-19 pandemic has thrust RNA as a platform for drug development into the spotlight. However, identifying promising drug candidates is challenging. With advances in synthetic biology and artificial intelligence (AI) models, we can overcome this hurdle, transforming drug development and ushering in a new era in the pharmaceutical industry.

Breaking the mold with RNA-a "RNAissance" of life science.

In the past decade, RNA therapeutics have gone from being a promising concept to one of the most exciting frontiers in healthcare and pharmaceuticals. The field is now entering what many call a renaissance or "RNAissance" which is being fueled by advances in genetic engineering and delivery systems to take on more ambitious development efforts. However, this renaissance is occurring at an unprecedented pace, which will require a different way of thinking if the field is to live up to its full potential. Recognizing this need, this article will provide a forward-looking perspective on the field of RNA medical products and the potential long-term innovations and policy shifts enabled by this revolutionary and game-changing technological platform.

Outlook of pandemic preparedness in a post-COVID-19 world.

The COVID-19 pandemic was met with rapid, unprecedented global collaboration and action. Even still, the public health, societal, and economic impact may be felt for years to come. The risk of another pandemic occurring in the next few decades is ever-present and potentially increasing due to trends such as urbanization and climate change. While it is difficult to predict the next pandemic pathogen threat, making reasonable assumptions today and evaluating prior efforts to plan for and respond to disease outbreaks and pandemics may enable a more proactive, effective response in the future. Lessons from the COVID-19 response and pandemic influenza preparedness underscore the importance of strengthening surveillance systems, investing in early-stage research on pandemic pathogens and development of platform technologies, and diversifying response plans across a range of tactics to enable earlier access to safe and effective interventions in the next pandemic. Further, sustaining the robust vaccine manufacturing capacity built because of COVID-19 will keep it ready for rapid response in the future. These actions will not be successful without improved global coordination and collaboration. Everyone, including the biopharmaceutical industry, has a role to play in pandemic preparedness, and working together will ensure that the most lives are saved in the next pandemic.

Harnessing synthetic biology for advancing RNA therapeutics and vaccine design.

Recent global events have drawn into focus the diversity of options for combatting disease across a spectrum of prophylactic and therapeutic approaches. The recent success of the mRNA-based COVID-19 vaccines has paved the way for RNA-based treatments to revolutionize the pharmaceutical industry. However, historical treatment options are continuously updated and reimagined in the context of novel technical developments, such as those facilitated through the application of synthetic biology. When it comes to the development of genetic forms of therapies and vaccines, synthetic biology offers diverse tools and approaches to influence the content, dosage, and breadth of treatment with the prospect of economic advantage provided in time and cost benefits. This can be achieved by utilizing the broad tools within this discipline to enhance the functionality and efficacy of pharmaceutical agent sequences. This review will describe how synthetic biology principles can augment RNA-based treatments through optimizing not only the vaccine antigen, therapeutic construct, therapeutic activity, and delivery vector. The enhancement of RNA vaccine technology through implementing synthetic biology has the potential to shape the next generation of vaccines and therapeutics.

Antigen delivery format variation and formulation stability through use of a hybrid vector.

A hybrid biological-biomaterial antigen delivery vector comprised of a polymeric shell encapsulating an Escherichia coli core was previously developed for in situ antigen production and subsequent delivery. Due to the engineering capacity of the bacterial core, the hybrid vector provides unique opportunities for immunogenicity optimization through varying cellular localization (cytoplasm, periplasm, cellular surface) and type (protein or DNA) of antigen. In this work, three protein-based hybrid vector formats were compared in which the pneumococcal surface protein A (PspA) was localized to the cytoplasm, surface, and periplasmic space of the bacterial core for vaccination against pneumococcal disease. Furthermore, we tested the hybrid vector's capacity as a DNA vaccine against Streptococcus pneumoniae by introducing a plasmid into the bacterial core to facilitate PspA expression in antigen presenting cells (APCs). Through testing these various formulations, we determined that cytoplasmic accumulation of PspA elicited the strongest immune response (antibody production and protection against bacterial challenge) and enabled complete protection at substantially lower doses when compared to vaccination with PspA + adjuvant. We also improved the storage stability of the hybrid vector to retain complete activity after 1 month at 4 °C using an approach in which hybrid vectors suspended in a microbial freeze drying buffer were desiccated. These results demonstrate the flexibility and robustness of the hybrid vector formulation, which has the potential to be a potent vaccine against S. pneumoniae.

Engineering a Next-Generation Glycoconjugate-Like Streptococcus pneumoniae Vaccine.

We detail the development of a next-generation Streptococcus pneumoniae liposomal encapsulation of polysaccharides (LEPS) vaccine, with design characteristics geared toward best-in-class efficacy. The first generation LEPS vaccine, which contained 20 encapsulated pneumococcal capsular polysaccharides (CPSs) and two surface-displayed virulence-associated proteins (GlpO and PncO), enabling prophylactic potency against 70+ serotypes of Streptococcus pneumoniae (the causative agent of pneumococcal disease), was rationally redesigned for advanced clinical readiness and best-in-class coverage. In doing so, the virulent-specific GlpO protein antigen was removed from the final formulation due to off-target immunogenicity toward bacterial species within the human microbiome, while directed protection was maintained by increasing the dose of PncO from 17 to 68 µg. LEPS formulation parameters also readily facilitated an increase in CPS valency (to a total of 24) and systematic variation in protein-liposome attachment mechanisms in anticipation of clinical translation. An additional safety assessment study demonstrated that LEPS does not exhibit appreciable toxicological effects even when administered at ten times the effective dose. In summary, this new design offers the broadest, safest, and most-complete protection while maintaining desirable glycoconjugate-like features, positioning the LEPS vaccine platform for clinical success and a global health impact.

Phenotypic Variation during Biofilm Formation: Implications for Anti-Biofilm Therapeutic Design.

Various bacterial species cycle between growth phases and biofilm formation, of which the latter facilitates persistence in inhospitable environments. These phases can be generally characterized by one or more cellular phenotype(s), each with distinct virulence factor functionality. In addition, a variety of phenotypes can often be observed within the phases themselves, which can be dependent on host conditions or the presence of nutrient and oxygen gradients within the biofilm itself (i.e., microenvironments). Currently, most anti-biofilm strategies have targeted a single phenotype; this approach has driven effective, yet incomplete, protection due to the lack of consideration of gene expression dynamics throughout the bacteria’s pathogenesis. As such, this article provides an overview of the distinct phenotypes found within each biofilm development phase and demonstrates the unique anti-biofilm solutions each phase offers. However, we conclude that a combinatorial approach must be taken to provide complete protection against biofilm forming bacterial and their resulting diseases.

Comprehensive vaccine design for commensal disease progression.

Commensal organisms with the potential to cause disease pose a challenge in developing treatment options. Using the example featured in this study, pneumococcal disease begins with Streptococcus pneumoniae colonization, followed by triggering events that prompt the release of a virulent subpopulation of bacteria. Current vaccines focus on colonization prevention, which poses unintended consequences of serotype niche replacement. In this study, noncovalent colocalization of two classes of complementary antigens, one to prevent the colonization of the most aggressive S. pneumoniae serotypes and another to restrict virulence transition, provides complete vaccine effectiveness in animal subjects and the most comprehensive coverage of disease reported to date. As a result, the proposed vaccine formulation offers universal pneumococcal disease prevention with the prospect of effectively managing a disease that afflicts tens to hundreds of millions globally. The approach more generally puts forth a balanced prophylactic treatment strategy in response to complex commensal-host dynamics.

Pressing diseases that represent promising targets for gene therapy.

Over time, there has been a growing interest in the application of gene therapy within the healthcare industry as demonstrated by the nearly 3,000 clinical trials associated with gene therapy that are listed in clinicaltrials.gov. However, there are various difficulties associated with gene therapy that have limited the realization of licensed gene therapies to only a handful of treatments. Furthermore, efforts to develop gene therapeutics have been narrowly focused and most clinical trials have sought to develop treatments for cancer (64.6%), monogenic diseases (10.5%), infectious diseases (7.4%), and cardiovascular diseases (7.4%). In addition, nearly 70% of clinical trials have utilized viral-based delivery systems, despite various concerns associated with this strategy. Each of these factors highlights the lack of diversity in the development of gene therapeutics that should be addressed. In recent years, developments in gene manipulation and delivery such as CRISPR and non-viral vectors (e.g., liposomes) demonstrate promise for improving outcomes for gene therapy. The increased fidelity and capacity afforded by these technologies provide the potential to improve upon contemporary gene therapy approaches and enable the development of treatments for less-emphasized disorders. In this review, we provide a summary of gene delivery technology and discuss various developments in gene therapy technology. We conclude by proposing several genetic conditions that represent promising targets for gene therapy given recent developments in gene delivery and manipulation.

In situ pneumococcal vaccine production and delivery through a hybrid biological-biomaterial vector.

The type and potency of an immune response provoked during vaccination will determine ultimate success in disease prevention. The basis for this response will be the design and implementation of antigen presentation to the immune system. Whereas direct antigen administration will elicit some form of immunological response, a more sophisticated approach would couple the antigen of interest to a vector capable of broad delivery formats and designed for heightened response. New antigens associated with pneumococcal disease virulence were used to test the delivery and adjuvant capabilities of a hybrid biological-biomaterial vector consisting of a bacterial core electrostatically coated with a cationic polymer. The hybrid design provides (i) passive and active targeting of antigen-presenting cells, (ii) natural and multicomponent adjuvant properties, (iii) dual intracellular delivery mechanisms, and (iv) a simple formulation mechanism. In addition, the hybrid format enables device-specific, or in situ, antigen production and consolidation via localization within the bacterial component of the vector. This capability eliminates the need for dedicated antigen production and purification before vaccination efforts while leveraging the aforementioned features of the overall delivery device. We present the first disease-specific utilization of the vector toward pneumococcal disease highlighted by improved immune responses and protective capabilities when tested against traditional vaccine formulations and a range of clinically relevant Streptococcus pneumoniae strains. More broadly, the results point to similar levels of success with other diseases that would benefit from the production, delivery, and efficacy capabilities offered by the hybrid vector.

Directed vaccination against pneumococcal disease.

Immunization strategies against commensal bacterial pathogens have long focused on eradicating asymptomatic carriage as well as disease, resulting in changes in the colonizing microflora with unknown future consequences. Additionally, current vaccines are not easily adaptable to sequence diversity and immune evasion. Here, we present a "smart" vaccine that leverages our current understanding of disease transition from bacterial carriage to infection with the pneumococcus serving as a model organism. Using conserved surface proteins highly expressed during virulent transition, the vaccine mounts an immune response specifically against disease-causing bacterial populations without affecting carriage. Aided by a delivery technology capable of multivalent surface display, which can be adapted easily to a changing clinical picture, results include complete protection against the development of pneumonia and sepsis during animal challenge experiments with multiple, highly variable, and clinically relevant pneumococcal isolates. The approach thus offers a unique and dynamic treatment option readily adaptable to other commensal pathogens.

Improving global vaccine accessibility.

Although the beneficial impact of vaccination is well established, developing countries often rely upon humanitarian support to obtain access to routine immunization schedules. Furthermore, philanthropic funders require that vaccines be supplied at prices that are drastically lower than that charged in developed nations. This pricing requirement arises due to both the massive volume of vaccines needed and the logistics necessary to ensure their integrity (i.e. the cold chain). Cost-prohibitive vaccine formulation strategies, especially for newer vaccines, along with the lack of infrastructure in developing nations can further complicate this process. Extensive research is being conducted to develop novel technological platforms that overcome each of these accessibility impediments. This review provides an overview of the humanitarian organizations and technological developments that are dedicated to improving global healthcare by increasing vaccine accessibility.

Overcoming Gene-Delivery Hurdles: Physiological Considerations for Nonviral Vectors.

With the use of contemporary tools and techniques, it has become possible to more precisely tune the biochemical mechanisms associated with using nonviral vectors for gene delivery. Consequently, nonviral vectors can incorporate numerous vector compositions and types of genetic cargo to develop diverse genetic therapies. Despite these advantages, gene-delivery strategies using nonviral vectors have poorly translated into clinical success due to preclinical experimental design considerations that inadequately predict therapeutic efficacy. Furthermore, the manufacturing and distribution processes are critical considerations for clinical application that should be considered when developing therapeutic platforms. In this review, we evaluate potential avenues towards improving the transition of gene-delivery technologies from in vitro assessment to human clinical therapy.

Contemporary approaches for nonviral gene therapy.

Gene therapy is the manipulation of gene expression patterns in specific cells to treat genetic and pathological diseases. This manipulation is accomplished by the controlled introduction of exogenous nucleic acids into target cells. Given the size and negative charge of these biomacromolecules, the delivery process is driven by the carrier vector, of which the usage of viral vectors dominates. Taking into account the limitations of viral vectors, nonviral alternatives have gained significant attention due to their flexible design, low cytotoxicity and immunogenicity, and their gene delivery efficacy. That stated, the field of nonviral vectors has been dominated by research dedicated to overcoming barriers in gene transfer. Unfortunately, these traditional nonviral vectors have failed to completely overcome the barriers required for clinical translation and thus, have failed to match the delivery outcomes of viral vector. This has consequently encouraged the development of new, more radical approaches that have the potential for higher clinical translation. In this review, we discuss recent advances in vector technology and nucleic acid chemistry that have challenged the current understanding of nonviral systems. The diversity of these approaches highlights the numerous alternative avenues for overcoming innate and technical barriers associated with gene delivery.

Influence of molecular weight upon mannosylated bio-synthetic hybrids for targeted antigen presenting cell gene delivery.

Given the rise of antibiotic resistant microbes, genetic vaccination is a promising prophylactic strategy that enables rapid design and manufacture. Facilitating this process is the choice of vector, which is often situationally-specific and limited in engineering capacity. Furthermore, these shortcomings are usually tied to an incomplete understanding of the structure-function relationships driving vector-mediated gene delivery. Building upon our initial report of a hybrid bacterial-biomaterial gene delivery vector, a comprehensive structure-function assessment was completed using a class of mannosylated poly(beta-amino esters). Through a top-down screening methodology, an ideal polymer was selected on the basis of gene delivery efficacy and then used for the synthesis of a stratified molecular weight polymer library. By eliminating contributions of polymer chemical background, we were able to complete an in-depth assessment of gene delivery as a function of (1) polymer molecular weight, (2) relative mannose content, (3) polymer-membrane biophysical properties, (4) APC uptake specificity, and (5) serum inhibition. In summary, the flexibility and potential of the hybrid design featured in this work highlights the ability to systematically probe vector-associated properties for the development of translational gene delivery candidates.