Jean-Pierre Amorij

Needle-free influenza vaccination

Vaccination is the cornerstone of influenza control in epidemic and pandemic situations. Influenza vaccines are typically given by intramuscular injection. However, needle-free vaccinations could offer several distinct advantages over intramuscular injections: they are pain-free, easier to distribute, and easier to give to patients, and their use could reduce vaccination costs. Moreover, vaccine delivery via the respiratory tract, alimentary tract, or skin might elicit mucosal immune responses at the site of virus entry and better cellular immunity, thus improving effectiveness. Although various needle-free vaccination methods for influenza have shown preclinical promise, few have progressed to clinical trials-only live attenuated intranasal vaccines have received approval, and only in some countries. Further clinical investigation is needed to help realise the potential of needle-free vaccination for influenza.

Current and next generation influenza vaccines: Formulation and production strategies

Vaccination is the most effective method to prevent influenza infection. However, current influenza vaccines have several limitations. Relatively long production times, limited vaccine capacity, moderate efficacy in certain populations and lack of cross-reactivity are important issues that need to be addressed. We give an overview of the current status and novel developments in the landscape of influenza vaccines from an interdisciplinary point of view. The feasibility of novel vaccine concepts not only depends on immunological or clinical outcomes, but also depends on biotechnological aspects, such as formulation and production methods, which are frequently overlooked. Furthermore, the next generation of influenza vaccines is addressed, which hopefully will bring cross-reactive influenza vaccines. These developments indicate that an exciting future lies ahead in the influenza vaccine field.

Towards tailored vaccine delivery: Needs, challenges and perspectives

The ideal vaccine is a simple and stable formulation which can be conveniently administered and provides life-long immunity against a given pathogen. The development of such a vaccine, which should trigger broad and strong B-cell and T-cell responses against antigens of the pathogen in question, is highly dependent on tailored vaccine delivery approaches. This review addresses vaccine delivery in its broadest scope. We discuss the needs and challenges in the area of vaccine delivery, including restrictions posed by specific target populations, potentials of dedicated stable formulations and devices, and the use of adjuvants. Moreover, we address the current status and perspectives of vaccine delivery via several routes of administration, including non- or minimally invasive routes. Finally we suggest possible directions for future vaccine delivery research and development.

Buccal and sublingual vaccine delivery.

Abstract Because of their large surface area and immunological competence, mucosal tissues are attractive administration and target sites for vaccination. An important characteristic of mucosal vaccination is its ability to elicit local immune responses, which act against infection at the site of pathogen entry. However, mucosal surfaces are endowed with potent and sophisticated tolerance mechanisms to prevent the immune system from overreacting to the many environmental antigens. Hence, mucosal vaccination may suppress the immune system instead of induce a protective immune response. Therefore, mucosal adjuvants and/or special antigen delivery systems as well as appropriate dosage forms are required in order to develop potent mucosal vaccines. Whereas oral, nasal and pulmonary vaccine delivery strategies have been described extensively, the sublingual and buccal routes have received considerably less attention. In this review, the characteristics of and approaches for sublingual and buccal vaccine delivery are described and compared with other mucosal vaccine delivery sites. We discuss recent progress and highlight promising developments in the search for vaccine formulations, including adjuvants and suitable dosage forms, which are likely critical for designing a successful sublingual or buccal vaccine. Finally, we outline the challenges, hurdles to overcome and formulation issues relevant for sublingual or buccal vaccine delivery.

Bioneedles as alternative delivery system for hepatitis B vaccine

An alternative vaccine delivery system for needle injections is the Bioneedle. Hepatitis B surface antigen (HBsAg) was formulated with Bioneedles. Three formulations were used: plain antigen, HBsAg adjuvated with aluminum hydroxide and HBsAg with LPS-derived lpxL1. Bioneedles with HBsAg-lpxL1 were the most stable and the most immunogenic formulations. The conventional liquid alum adjuvated vaccine lost 40% of its antigenicity after 1week at 50°C whereas the HBsAg-lpxL1 Bioneedles showed no significant decrease after 3 weeks at 50°C. In vivo studies revealed that the HBsAg-lpxL1 Bioneedle formulations induced comparable IgG titers as conventional liquid formulations after 2 immunizations, but higher IgG2a titers were found already after 1 immunization. The in vivo and in vitro studies showed that the Bioneedle is an attractive alternative for needle injections of HBsAg vaccines.

Development of cross-protective influenza a vaccines based on cellular responses.

Seasonal influenza vaccines provide protection against matching influenza A virus (IAV) strains mainly through the induction of neutralizing serum IgG antibodies. However, these antibodies fail to confer a protective effect against mismatched IAV. This lack of efficacy against heterologous influenza strains has spurred the vaccine development community to look for other influenza vaccine concepts, which have the ability to elicit cross-protective immune responses. One of the concepts that is currently been worked on is that of influenza vaccines inducing influenza-specific T cell responses. T cells are able to lyse infected host cells, thereby clearing the virus. More interestingly, these T cells can recognize highly conserved epitopes of internal influenza proteins, making cellular responses less vulnerable to antigenic variability. T cells are therefore cross-reactive against many influenza strains, and thus are a promising concept for future influenza vaccines. Despite their potential, there are currently no T cell-based IAV vaccines on the market. Selection of the proper antigen, appropriate vaccine formulation and evaluation of the efficacy of T cell vaccines remains challenging, both in preclinical and clinical settings. In this review, we will discuss the current developments in influenza T cell vaccines, focusing on existing protein-based and novel peptide-based vaccine formulations. Furthermore, we will discuss the feasibility of influenza T cell vaccines and their possible use in the future.

Predicting the influence of liposomal lipid composition on liposome size, zeta potential and liposome-induced dendritic cell maturation using a design of experiments approach.

In this study, the effect of liposomal lipid composition on the physicochemical characteristics and adjuvanticity of liposomes was investigated. Using a design of experiments (DoE) approach, peptide-containing liposomes containing various lipids (EPC, DOPE, DOTAP and DC-Chol) and peptide concentrations were formulated. Liposome size and zeta potential were determined for each formulation. Moreover, the adjuvanticity of the liposomes was assessed in an in vitro dendritic cell (DC) model, by quantifying the expression of DC maturation markers CD40, CD80, CD83 and CD86. The acquired data of these liposome characteristics were successfully fitted with regression models, and response contour plots were generated for each response factor. These models were applied to predict a lipid composition that resulted in a liposome with a target zeta potential. Subsequently, the expression of the DC maturation factors for this lipid composition was predicted and tested in vitro; the acquired maturation responses corresponded well with the predicted ones. These results show that a DoE approach can be used to screen various lipids and lipid compositions, and to predict their impact on liposome size, charge and adjuvanticity. Using such an approach may accelerate the formulation development of liposomal vaccine adjuvants.

Pulmonary Vaccine Delivery: A Realistic Approach?

Pulmonary vaccine delivery has gained increasing attention during the last decade because this vaccination method combines potential advantages such as the fact that it omits the use of needles and may elicit immunity at the port of entry for many pathogens. In this review the current status of pulmonary vaccination, the potential advantages of pulmonary vaccine delivery, the hurdles to overcome in the future, and the overall perspectives of this vaccination strategy are described.

Alternative delivery of a thermostable inactivated polio vaccine

In the near future oral polio vaccine (OPV) will be replaced by inactivated polio vaccine (IPV) as part of the eradication program of polio. For that reason, there is a need for substantial amount of safe and more affordable IPV for low-income countries. Bioneedles, which are biodegradable mini-implants, have the potential to deliver vaccines outside the cold-chain and administer them without the use of needles and syringes. In the current study, Bioneedles were filled with IPV, subsequently lyophilized, and antigenic recoveries were determined both directly after IPV-Bioneedle preparation as well as after elevated stability testing. Further, we assessed the immunogenicity of IPV-Bioneedles in rats and the residence time at the site of administration. Trivalent IPV was formulated in Bioneedles with recoveries of 101±10%, 113±18%, and 92±15%, respectively for serotypes 1, 2 and 3. IPV in Bioneedles is more resistant to elevated temperatures than liquid IPV: liquid IPV retained less than half of its antigenicity after 1 day at 45°C and IPV in Bioneedles showed remaining recoveries of 80±10%, 85±4% and 63±4% for the three serotypes. In vivo imaging revealed that IPV administered via Bioneedles as well as subcutaneously injected liquid IPV showed a retention time of 3 days at the site of administration. Finally, an immunogenicity study showed that IPV-filled Bioneedles are able to induce virus-neutralizing antibody titers similar to those obtained by liquid intramuscular injection when administered in a booster regime. The addition of LPS-derivate PagL in IPV-filled Bioneedles did not increase immunogenicity compared to IPV-Bioneedles without adjuvant. The current study demonstrates the pre-clinical proof of concept of IPV-filled Bioneedles as a syringe-free alternative delivery system. Further pre-clinical and clinical studies will be required to assess the feasibility whether IPV-Bioneedles show sufficient safety and efficacy, and may contribute to the efforts to eradicate and prevent polio in the future.

Development of Thermostable Lyophilized Inactivated Polio Vaccine

PurposeThe aim of current study was to develop a dried inactivated polio vaccine (IPV) formulation with minimal loss during the drying process and improved stability when compared with the conventional liquid IPV.MethodsExtensive excipient screening was combined with the use of a Design of Experiment (DoE) approach in order to achieve optimal results with high probability.ResultsAlthough it was shown earlier that the lyophilization of a trivalent IPV while conserving its antigenicity is challenging, we were able to develop a formulation that showed minimal loss of potency during drying and subsequent storage at higher temperatures.ConclusionThis study showed the potential of a highly stable and safe lyophilized polio vaccine, which might be used in developing countries without the need of a cold-chain.