Single-injection prime-boost vaccines based on biodegradable polymers

Many vaccines require multiple doses for optimal protection against the pathogen. Currently, these vaccines are administered by means of multiple injections, which often leads to a lower vaccination coverage. Such a vaccination schedule, also referred to as a prime-boost schedule, consists of the administration of a first dose (primer) followed by a second and sometimes even a third or fourth dose (booster) several weeks, months or years later. Vaccination coverage for the abovementioned vaccines could be improved by developing an alternative vaccine formulation that includes both the primer and the booster doses, so that a single injection is sufficient. The antigen must be released from the formulation in a controlled manner, for example by encapsulating the antigen in a matrix of a biodegradable polymer. In the research of Renée van der Kooij, different formulations were developed with both a pulsatile and a sustained release profile. Two different prototypes of a pulsatile-release implant were found to be suitable for the (biphasic) pulsatile release of a vaccine. However, the prototypes were too large for clinical application, so injectable microspheres were developed. Microspheres with a core-shell structure exhibited a delayed (pulsatile) release of a model antigen, where the lag time could be varied. Monolithic microspheres exhibited a sustained release, where the total release duration could be varied. These microspheres induced a strong antibody response in mice, similar to the immune response after a primer-booster injection of the model antigen. However, further research with a clinically relevant antigen and optimization of the developed formulations and associated release profiles is required

An overview of the production methods for core-shell microspheres for parenteral controlled drug delivery

Core-shell microspheres hold great promise as a drug delivery system because they offer several benefits over monolithic microspheres in terms of release kinetics, for instance a reduced initial burst release, the possibility of delayed (pulsatile) release, and the possibility of dual-drug release. Also, the encapsulation efficiency can significantly be improved. Various methods have proven to be successful in producing these core-shell microspheres, both the conventional bulk emulsion solvent evaporation method and methods in which the microspheres are produced drop by drop. The latter have become increasingly popular because they provide improved control over the particle characteristics. This review assesses various production methods for core-shell microspheres and summarizes the characteristics of formulations prepared by the different methods, with a focus on their release kinetics

Microfluidic Production of Polymeric Core-Shell Microspheres for the Delayed Pulsatile Release of Bovine Serum Albumin as a Model Antigen

For many vaccines, multiple injections are required to confer protective immunity against targeted pathogens. These injections often consist of a primer administration followed by a booster administration of the vaccine a few weeks or months later. A single-injection vaccine formulation that provides for both administrations could greatly improve the convenience and vaccinee’s compliance. In this study, we developed parenterally injectable core-shell microspheres with a delayed pulsatile release profile that could serve as the booster in such a vaccine formulation. These microspheres contained bovine serum albumin (BSA) as the model antigen and poly(DL-lactide-co-glycolide) (PLGA) with various DL-lactide:glycolide monomer ratios as the shell material. Highly monodisperse particles with different particle characteristics were obtained using a microfluidic setup. All formulations exhibited a pulsatile in vitro release of BSA after an adjustable lag time. This lag time increased with the increasing lactide content of the polymer and ranged from 3 to 7 weeks. Shell thickness and bovine serum albumin loading had no effect on the release behavior, which could be ascribed to the degradation mechanism of the polymer, with bulk degradation being the main pathway. Co-injection of the core-shell microspheres together with a solution of the antigen that serves as the primer would allow for the desired biphasic release profile. Altogether, these findings show that injectable core-shell microspheres combined with a primer are a promising alternative for the current multiple-injection vaccines

The mechanism behind the biphasic pulsatile drug release from physically mixed poly(DL-lactic(-co-glycolic) acid)-based compacts

Successful immunization often requires a primer, and after a certain lag time, a booster administration of the antigen. To improve the vaccinees' comfort and compliance, a single-injection vaccine formulation with a biphasic pulsatile release would be preferable. Previous work has shown that such a release profile can be obtained with compacts prepared from physical mixtures of various poly(DL-lactic(-co-glycolic) acid) types (Murakami et al., 2000). However, the mechanism behind this release profile is not fully understood. In the present study, the mechanism that leads to this biphasic pulsatile release was investigated by studying the effect of the glass transition temperature (Tg) of the polymer, the temperature of compaction, the compression force, the temperature of the release medium, and the molecular weight of the incorporated drug on the release behavior. Compaction resulted in a porous compact. Once immersed into release medium with a temperature above the Tg of the polymer, the drug was released by diffusion through the pores. Simultaneously, the polymer underwent a transition from the glassy state into the rubbery state. The pores were gradually closed by viscous flow of the polymer and further release was inhibited. After a certain period of time, the polymer matrix ruptured, possibly due to a build-up in osmotic pressure, resulting in a pulsatile release of the remaining amount of drug. The compression force and the molecular weight of the incorporated drug did not influence the release profile. Understanding this mechanism could contribute to further develop single-injection vaccines

Meditation or Medication? Mindfulness training versus medication in the treatment of childhood ADHD: a randomized controlled trial

Background Attention-Deficit-Hyperactivity-Disorder (ADHD) is, with a prevalence of 5 %, a highly common childhood disorder, and has severe impact on the lives of youngsters and their families. Medication is often the treatment of choice, as it currently is most effective. However, medication has only short-term effects, treatment adherence is often low and most importantly; medication has serious side effects. Therefore, there is a need for other interventions for youngsters with ADHD. Mindfulness training is emerging as a potentially effective training for children and adolescents with ADHD. The aim of this study is to compare the (cost) effectiveness of mindfulness training to the (cost) effectiveness of methylphenidate in children with ADHD on measures of attention and hyperactivity/impulsivity. Methods/design A multicenter randomized controlled trial with 2 follow-up measurements will be used to measure the effects of mindfulness training versus the effects of methylphenidate. Participants will be youngsters (aged 9 to 18) of both sexes diagnosed with ADHD, referred to urban and rural mental healthcare centers. We aim to include 120 families. The mindfulness training, using the MYmind protocol, will be conducted in small groups, and consists of 8 weekly 1.5-h sessions. Youngsters learn to focus and enhance their attention, awareness, and self-control by doing mindfulness exercises. Parents will follow a parallel mindful parenting training in which they learn to be fully present in the here and now with their child in a non-judgmental way, to take care of themselves, and to respond rather than react to difficult behavior of their child. Short-acting methylphenidate will be administered individually and monitored by a child psychiatrist. Assessments will take place at pre-test, post-test, and at follow-up 1 and 2 (respectively 4 and 10 months after the start of treatment). Informants are parents, children, teachers, and researchers. Discussion This study will inform mental health care professionals and health insurance companies about the clinical and cost effectiveness of mindfulness training for children and adolescents with ADHD and their parents compared to the effectiveness of methylphenidate. Limitations and several types of bias that are anticipated for this study are discussed

A Single Injection with Sustained-Release Microspheres and a Prime-Boost Injection of Bovine Serum Albumin Elicit the Same IgG Antibody Response in Mice

Although vaccination is still considered to be the cornerstone of public health care, the increase in vaccination coverage has stagnated for many diseases. Most of these vaccines require two or three doses to be administered across several months or years. Single-injection vaccine formulations are an effective method to overcome the logistical barrier to immunization that is posed by these multiple-injection schedules. Here, we developed subcutaneously (s.c.) injectable microspheres with a sustained release of the model antigen bovine serum albumin (BSA). The microspheres were composed of blends of two novel biodegradable multi-block copolymers consisting of amorphous, hydrophilic poly(ε-caprolactone)-poly(ethylene glycol)-poly(ε-caprolactone) (PCL-PEG-PCL) blocks and semi-crystalline poly(dioxanone) (PDO) blocks of different block sizes. In vitro studies demonstrated that the release of BSA could be tailored over a period of approximately four to nine weeks by changing the blend ratio of both polymers. Moreover, it was found that BSA remained structurally intact during release. Microspheres exhibiting sustained release of BSA for six weeks were selected for the in vivo study in mice. The induced BSA-specific IgG antibody titers increased up to four weeks after administration and were of the same magnitude as found in mice that received a priming and a booster dose of BSA in phosphate-buffered saline (PBS). Determination of the BSA concentration in plasma showed that in vivo release probably took place up to at least four weeks, although plasma concentrations peaked already one week after administration. The sustained-release microspheres might be a viable alternative to the conventional prime-boost immunization schedule, but a clinically relevant antigen should be incorporated to assess the full potential of these microspheres in practice