Nanovaccine Delivery Approaches and Advanced Delivery Systems for the Prevention of Viral Infections: From Development to Clinical Application

Viral infections causing pandemics and chronic diseases are the main culprits implicated in devastating global clinical and socioeconomic impacts, as clearly manifested during the current COVID-19 pandemic. Immunoprophylaxis via mass immunisation with vaccines has been shown to be an efficient strategy to control such viral infections, with the successful and recently accelerated development of different types of vaccines, thanks to the advanced biotechnological techniques involved in the upstream and downstream processing of these products. However, there is still much work to be done for the improvement of efficacy and safety when it comes to the choice of delivery systems, formulations, dosage form and route of administration, which are not only crucial for immunisation effectiveness, but also for vaccine stability, dose frequency, patient convenience and logistics for mass immunisation. In this review, we discuss the main vaccine delivery systems and associated challenges, as well as the recent success in developing nanomaterials-based and advanced delivery systems to tackle these challenges. Manufacturing and regulatory requirements for the development of these systems for successful clinical and marketing authorisation were also considered. Here, we comprehensively review nanovaccines from development to clinical application, which will be relevant to vaccine developers, regulators, and clinicians.

Meeting Report: Vaccine Stability Considerations to Enable Rapid Development and Deployment

The Stability Community of the American Association of Pharmaceutical Scientists (AAPS) held a virtual workshop on “Vaccine Stability Considerations to Enable Rapid Development and Deployment”, on March 24-25, 2021. The workshop included distinguished speakers and panelists from across the industry, academia, regulatory agencies, as well as health care leaders. This paper presents a review of the topics covered. Specifically the challenges in accelerating vaccine development and analytical characterization techniques to establish shelf-life were covered. Additionally, vaccine stability modeling using prior knowledge stability models and advanced kinetic analysis played a key in the EUA approaches discussed during the workshop. Finally, the role of stability studies in addressing the challenges of vaccine distribution and deployment during the pandemic were a focus of presentations and panel discussions.Although the workshop did not have any presentation topics directly dedicated to the mRNA vaccines, the techniques discussed are generally applicable. The mRNA vaccine developers were represented in the panel discussions, where experts involved in the EUA approval/deployment stages for this vaccine type could discuss the challenges as applied to their vaccines.

The Same Combined Adjuvant NE+Rg1 Shows Different Immune Effects on Different Pathogen Antigens

Background New recombinant protein vaccines with high purity, clear ingredients and good safety are gradually replacing attenuated and inactivated vaccines in clinical practice. However, one of the main issues with use of these new vaccines is the need for adjuvants to enhance their immune effect. Aluminium salts (hydroxide and phosphate) were the first approved adjuvants used in human vaccines, but these salts have some limitations, such as their induction of primarily humoural immunity with weaker induction of cell-mediated immunity and the failure to clear intracellular viral infections. Therefore, there is a growing need for novel adjuvants. Combined adjuvants or adjuvant systems are increasingly being used to meet the need for adjuvant development for vaccines. Different pathogen antigens also need specific adjuvants to enhance the immune response and protection. Methods The present study evaluated the synergistic immunological effect of a combined nano emulsion (NE) with Ginsenoside Rg1, i.e. NE+Rg1, for the hepatitis B surface antigen (HBsAg) or H1N1 haemagglutinin (HA) of an inactivated influenza vaccine (split virion) in mice and the vaccine stability and safety. Non-parametric tests (Mann-Whitney test) and one-way analysis of variance (ANOVA) were used for statistical analyses. Tests were considered significant when P < 0.05.ResultsThe combined adjuvant NE+Rg1 showed high stability, a mean diameter of 168.1 nm, and a zeta potential of -22.8 mV. When combined with HBsAg, it produced a similar or higher anti-HB and IgG1/IgG2a titre and elevated IL-2 and IFN-γ expression in spot forming cells (SFCs) compared with NE alone and higher IFN-γ and IL-2 expression in CD8+ T cells than aluminium hydroxide. However, when combined with HA, HA+NE+Rg1 resulted in a comparable haemagglutination inhibition (HAI) titre as HA+NE compared to that in mice immunized with HA alone or HA+Rg1 and an even lower protection rate than HA+NE after PR/8/34 virus strain challenge in mice. Conclusions This research demonstrated that the same combined adjuvant NE+Rg1 had different immune effects on different antigens and suggests that the research and development of adjuvants must consider specific pathogens and should be studied on a case-by-case basis.

Live Vaccinia Virus-Coated Microneedle Array Patches for Smallpox Vaccination and Stockpiling

Although smallpox has been eradicated globally, the potential use of the smallpox virus in bioterrorism indicates the importance of stockpiling smallpox vaccines. Considering the advantages of microneedle-based vaccination over conventional needle injections, in this study, we examined the feasibility of microneedle-based smallpox vaccination as an alternative approach for stockpiling smallpox vaccines. We prepared polylactic acid (PLA) microneedle array patches by micromolding and loaded a second-generation smallpox vaccine on the microneedle tips via dip coating. We evaluated the effect of excipients and drying conditions on vaccine stability in vitro and examined immune responses in female BALB/c mice by measuring neutralizing antibodies and interferon (IFN)-γ-secreting cells. Approximately 40% of the virus titer was reduced during the vaccine-coating process, with or without excipients. At −20 °C, the smallpox vaccine coated on the microneedles was stable up to 6 months. Compared to natural evaporation, vacuum drying was more efficient in improving the smallpox vaccine stability. Microneedle-based vaccination of the mice elicited neutralizing antibodies beginning 3 weeks after immunization; the levels were maintained for 12 weeks. It significantly increased IFN-γ-secreting cells 12 weeks after priming, indicating the induction of cellular immune responses. The smallpox-vaccine-coated microneedles could serve as an alternative delivery system for vaccination and stockpiling.

The Effect of Adjuvants of Different Groups on the Immunogenicity of Vaccines against Hemorrhagic Fever with Renal Syndrome

Effects of different classes of adjuvants (aluminum hydroxide, spherical protein particles, thermolabile В protein, low-endotoxic pyrogen-free lipopolysaccharide) have been studied in order to enhance the immunogenicity of inactivated vaccines against hemorrhagic fever with renal syndrome. The Puumala virus-based monovaccine and multivalent vaccine based on Puumala, Hantaan and Sochi viruses were analyzed, and BALB/c mice were used as an animal model. It was shown that low-endotoxic pyrogen-free lipopolysaccharide stimulated the production of virus-neutralizing antibodies and increased the vaccine stability during storage, which allows to reduce the antigenic load of the vaccine. Aluminum hydroxide slightly increased the production of T-cells immune response mediators and did not affect the neutralizing antibodies induction and vaccine stability. Despite the adjuvant effect, it was shown that spherical protein particles and thermolabile В protein were unacceptable for vaccines administered to humans due to the high protein load and toxic effects, respectively. hantavirases, hemorrhagic fever with renal syndrome, inactivated vaccines, adjuvants, immune response The authors are grateful to Dr. O.V. Karpova (Department of Virology, Moscow State University) for providing the preparation of spherical particles, and to Dr. A.N. Noskov (Gamaleya Research Institute of Epidemiology and Microbiology, Moscow) for providing the preparation of the thermolabile enterotoxin B-subunit.

Microneedle Mediated Vaccine Delivery: A Comprehensive Review

Microneedles can be representative for paradigm shift of drug delivery from patient non-compliant parenteral injections to patient compliant drug delivery system, which can be utilized for administration of vaccines particularly along with macromolecular/micromolecular drugs. The concept of microneedles came into existence many decades ago but the use of microneedles to achieve efficient delivery of drugs into the skin became subject of research from mid of 1990’s. Various types of microneedles were utilized to enhance delivery of drugs and vaccines including solid microneedles for pre-treatment of skin to enhance drug permeability, dissolvable polymeric microneedles encapsulating drugs, microneedles coated with drugs and hollow microneedles for infusion of drugs through the skin. Microneedles have shown promisingdelivery of vaccines through skin in literature. But the successful utilization of this system for vaccine drug delivery mainly depends on design of device to facilitate microneedle infusion, vaccine stability and storage in system, recovery of skin on removal of microneedle and improved patient compliance. This article reviews the conventional and advanced methods of vaccine drug deliver, microneedles for drug delivery, types of microneedles, advantages of microneedles and potential of microneedles for vaccine drug delivery.