Our R&D Programs

Our R&D Programs

Based on a long-standing historic track-record, we have state-of-the-art and readily available vaccine platform technologies and development capabilities. In recent years, we further developed these scale-able platform technologies that can be applied to quickly develop vaccines.

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In our state-of-the-art facilities, our experienced R&D institute takes your discovery up to Phase I/II clinical trials. Furthermore, we share and transfer our knowledge and technologies to public and private partners worldwide and work on collaborative R&D. 

  • Laboratory area 3500 m² BSL2, BSL3 & GMP facilities;
  • Animal Research Center;
  • Lab- & pilot-scale production capabilities (using glass, stainless steel, and disposable bioreactor technologies);
  • Upstream Processing (USP) and Downstream Processing (DSP);
  • Experience in bio safety (BSL2) and containment;
  • Advanced analytical capabilities (including: MS, NMR, HPLC, FACS, Biacore, etc.);
  • Design-of-Experiments (DoE) expertise, including scale-up and scale-down models for all unit operations;
  • Mathematical model development & cost-of-goods calculations.

 

Global Health

Global Health

Our aim is worldwide equity in access to affordable vaccines. Achieving our aim requires a wide range of expertises in the field of vaccinology and intense interdisciplinary collaboration. 

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Intravacc provides the know-how and tools to support the development of innovative ideas from universities and start-ups into concept products that are interesting for pharmaceutical companies who are able to bring vaccines to the market. These crucial development phases from research up to clinical phase I/II studies ask for highly professional expertise and infrastructure.

Through co-development and by transferring vaccine technologies and knowledge, we partner with vaccine manufacturers worldwide to develop or improve their vaccine production processes and analytical assays, thereby enhancing both the quality and the quantity of global vaccine manufacturing.

Our programs and projects are supported by the Netherlands Government, the European Union, the World Health organization (WHO) and the Bill and Melinda Gates Foundation.

To contribute to global health, among others we collaborate with:

  • Developing Countries Vaccine Manufacturing Network (DCVMN) and its members
  • European Vaccine Initiative (EVI)
  • EU IMI (Innovative Medicines Initiative)

UN Millennium Goals

Bacterial and Viral vaccines

Bacterial and Viral vaccines

We develop bacterial and viral vaccines from discovery up to phase I/II clinical trials. We developed advanced technologies and use these, as well as established technologies, such as Outer Membrane Vesicles (OMV), conjugation and regulatory approved Vero cells.

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Bacterial vaccines

For bacterial vaccines, we focus on the research and development of two technologies.

Conjugate vaccine technology

  • Hib vaccine
  • Shigella

OMV technology 

A novel approach for bacterial vaccines is the use of Outer Membrane Vesicles or Bacterial Like Particles. OMV technology is defined as a platform technology for bacterial vaccines, eg:

  • Pertussis
  • MenB
  • Lyme
  • TB

Our key assets on OMV technology are:

  • Native conformation of virulence factors
  • Dedicated genetic engineering to optimize antigen composition
  • State of the art analytical methods to characterize vaccines
  • Multi-reactor and downstream systems at laboratory and pilot scale for design of experiments approach
  • Specific expertise and IP portfolio to engineer LPS and thus modulate the required immune response
  • Track record, expertise and GMP facilities to develop an OMV vaccine from the laboratory bench to the first trials in men.

Viral vaccines

Verocell platform technology is the basis for:

  • Sabin Inactivated Polio Vaccine (sIPV) development; including process optimization, scale-up to industrial scale, and clinical production, and technology transfer to vaccine manufacturers in emerging markets in collaboration with WHO;
  • New Oral Polio Vaccine type 2 (nOPV2); Master- and Working virus seed lots production under cGMP (based on synthetically developed attenuated virus strains) for the Bill & Melinda Gates Foundation;
  • Respiratory Syncytial Virus (RSV) vaccine concept development;
  • Rotavirus vaccine concept development;
  • Enterovirus (EV71) vaccine concept development.

Key assets:

  • Qualified Vero cell line (established MCB and WCB available);
  • Legacy micro-carriers technology;
  • Animal Component Free cell- and virus culture media;
  • Multi-bioreactor vessels for parallel up-stream processing development;
  • High-throughput down-stream processing (including clarification, concentration, purification & inactivation) technologies;
  • Virus vector technology (including: vaccine seed strain development, transfection, plaque purification & genome sequencing);
  • WHO endorsed Technology Transfer infrastructure, proven track-record & ongoing partnerships.
Polio Expertise Center

Polio Expertise Center

With our Polio Expertise Center, we contribute to the eradication of polio worldwide. We use our proven platform technologies to swiftly develop an affordable, high quality polio vaccine in accordance with EMA and WHO requirements.

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Polio Expertise Center

Polio is a severe disease and once infected, there is no cure. Prevention is the key word, and fortunately there are effective vaccines against polio. To prevent future outbreaks, vaccination will remain necessary, even after eradication. To increase polio vaccine availability and accessibility, on assignment by the World Health Organization, we developed a new inactivated polio vaccine.

Intravacc serves as an expert center to improve your polio vaccine by:

  • Performing polio vaccine specific analytical assays
  • Optimizing production processes
  • Trouble shooting
  • Technology Transfer to set up your own Sabin-IPV manufacturing process, or improve your process
  • Production of Sabin-IPV vaccine for R&D, and for clinical studies
  • Evaluation of alternative poliovirus seed strains, and seed lots production

We use a science-based quality by design (QbD) approach following ICH Q8 and ICH Q11 guidelines for low cost-of-goods virus vaccines based on an available scale-down process for inactivated polio vaccines.

Sabin-strain based inactivated polio vaccine

By using the weakened and less transmissible Sabin polioviruses in production, the risk of facility related outbreaks can be reduced significantly. Therefore, our technology allows manufacturers to securely produce Sabin-IPV (Inactivated Polio Vaccine), and in this way also actively contribute to the GPEI goals for polio eradication.

In recent clinical studies the new Sabin-IPV was successfully shown to be safe and immunogenic in both adults and infants.

Genetically modified poliovirus strains

The implementation of post-eradication containment requirements (GAPIII) may influence the activities in future polio virus vaccine research, and in production facilities. Therefore, alternative poliovirus strains and methods are actively being developed that could reduce the risk of facility-associated transmission and may require lower levels of containment. For example, new Oral Polio Vaccine type 2 (nOPV2) strains are being developed as commissioned by the Bill and Melinda Gates Foundation. Currently, based on our established platform technologies, Intravacc is producing the polio virus nOPV2 Master- and Working seed lots in this project under cGMP.  

Technology Transfer

We have longstanding historic track record in transferring knowledge and technology, for example regarding Hib conjugate vaccine, and influenza vaccine (WHO program). Currently, our Sabin-IPV production technology, including the product specific assays, is actively being transferred by hands-on training to local vaccine manufacturers in emerging economies. For example, in this way China, South Korea and India are enabled to safely produce the Sabin-IPV vaccine to vaccinate their local population and for international supply to UNICEF. We are open for new collaborations, and licensure of our unique Sabin-IPV technology.

In parallel, continued process optimization and modernization is ongoing. This will contribute to increase the affordable Sabin-IPV quantities available for the post-eradication era.

Platform technologies 

The Sabin-IPV vaccine is developed on our proven Vero cell platform technology. These platform technologies can also be applied to quickly develop several other viral vaccines to control emergency outbreaks. 

Animal models and 3R Research

Animal models and 3R Research

The use of laboratory animals often remains a necessity in biomedical research. Intravacc acknowledges that laboratory animals are sentient beings and as such, have an intrinsic value. Therefore we have an active research program on Replacing, Reducing and Refining animal use; the so-called 3Rs.

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3R Research

It is our ambition to replace the use of animals for routine lot release testing of (classical) vaccines by innovative animal-free techniques and to improve the scientific substantiation of these methods.

To achieve this, Intravacc is developing several methods based on the 3R’s (reduction, refinement & replacement) of which some have already been adopted by the European Pharmacopoeia. In addition, we are a front runner in the development and distribution of a new paradigm in vaccine lot release testing, known as the consistency approach. To promote the implementation of this strategy, we participate in a IMI-funded European consortium on consistency testing.
We have a profound interest to cooperate within both public and industrial partnerships to improve the 3R research, that currently focusses on:

  • Development of assays for use in consistency testing to assess vaccine potency (cell-based in vitro models, physico-chemical techniques and immunochemical assays).
  • Development of in vitro assays as alternatives to vaccine safety tests in animals.
  • Implementation of a transgenic mouse model for neurovirulence testing of OPV or Sabin-IPV lots as an alternative to the classical monkey test.

Animal models

Intravacc acknowledges that laboratory animals are sentient beings and as such, have an intrinsic value. Therefore, we use use high quality and welfare standards for animal experimentation. 

We have a long standing track record in the performance of animal experiments. We are specialized in animal model infectiology and vaccinology. Our Animal Research Center has three state-of-the-art animal laboratory facilities for housing different species of experimental animals, e.g. (transgenic) mice, rats, cotton rats, ferrets, guinea pigs, rabbits etc.

All species can be housed in accommodations with different containment restrictions and biosafety levels. The flexibility of the animal facilities (i.e various closed compartments and 65 stainless steel isolators) offers the possibility to create tailor-made conditions for each animal species under the optimal housing restrictions and biosafety level BSL-2/DM-II and BSL-3/DM-III.

We pay specific attention to guarantee the microbiological status of the animals during the study. With ISO 9002 and ISO 14001, GMP and GLP quality requirements we can ensure that animal experiments are carried out at a very high quality level. All animal experiments are performed in accordance with the Dutch Law of animal experiments (Wod) and the European Directive 2010/63/EU. The ethical permissibility of the experiment is assessed before the start of each study and during the experiments the animal welfare is monitored by experts according the Wod.

Innovative Concepts, Formulation and Delivery

Innovative Concepts, Formulation and Delivery

To ensure state of the art expertise and knowledge, we offer innovative research and have several development programs on vaccine delivery and formulation.

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Innovative Concepts

We are continuously working to optimize vaccine design and monitoring strategies. The pillars to support translational vaccinology comprise of:
KNOWLEDGE - What should a certain vaccine ideally look like and why?
TOOLS & ASSAYS - How to optimize and monitor vaccine development?

The way this is accomplished by Intravacc varies from collaboration with research institutes/universities/companies to a customer service, examples include:

  • Design of novel adjuvants including LPS derivatives and alum formulations.
  • State-of-the-art mass spectrometry, for full characterization of vaccine formulations and immunoproteomics.
  • Development of ‘omics’ tools to monitor immune responses induced by new vaccine formulations or alternative delivery routes in comparison to existing vaccines and/or natural infection.
  • Design of conformational peptide conjugate vaccines against neurodegenerative diseases.
  • Click chemistry as a tool to reduce process development costs and increase flexibility in vaccine design.

Vaccine Delivery

The ideal vaccine is highly efficacious, easy to administer, thermostable and capable of providing life-long immunity against a given pathogen. Unfortunately, not all vaccines are ideal.

We aim to optimize the efficacy of existing and future vaccines. In addition, optimization of the administration of vaccines can lead to thermostable, pain free and affordable vaccination. Using its proven track record, Intravacc focuses amongst others on improved and innovative techniques for subcutaneous, intramuscular, dermal and mucosal vaccination. By combining innovation and knowledge into a product-oriented approach Intravacc contributes to improved vaccine delivery worldwide.

The Intravacc Vaccine Delivery Platform focuses with its partners on

  • Mucosal vaccination, specifically using intranasal, sublingual and buccal delivery systems.
  • Dermal/transcutaneous vaccination, utilizing microneedles
  • Subcutaneous and intramuscular vaccination using injectables and jet injectors.

Formulation

Our experienced team is working on the stabilization of vaccines and diagnostics by delivering an appropriate formulation suitable for storage in either a liquid or a dried presentation. We offer various drying methods such as spray-drying, freeze-drying, vacuum-drying or foam-drying depending on your needs. We will execute the work in an ML-II environment and are experienced in formulating and drying of genetically modified microorganisms.
We have a broad arrange of equipment, amongst which are:

  • Two pilot scale freeze-dryers for R&D
  • One pilot scale freeze-dryer for GMP purposes
  • One lab-scale freeze-dryer suitable for both vials and ampoules
  • A lab-scale spray dryer and a glove box (N2 atmosphere).

Intravacc strives for an efficient optimization of drying processes with a minimal risk for failure to guarantee product excellence. Therefore, we offer the following services:

  • Acquiring a GMO license (including a tailored risk analysis)
  • Formulation development
  • Drying process optimization (a tailored drying process can be offered)
  • Up-scaling of the freeze-drying process (from pilot to production scale)
  • Quality by Design (QbD) to study for example process robustness
  • Design of Experiment (DoE) Analytics (e.g. Residual water content, Differential scanning calorimetry, Freeze-drying microscopy, Near infrared spectroscopy, Various methods for determining the endpoint of primary drying, availability of a sample thief to remove vials during the freeze-drying process for analysis. Container closure test by spark testing)
  • Freeze-drying under a GMP quality regime including all required documents, aseptic manual filling in a down-flow booth and freeze-drying in a dedicated freeze-dryer.
  • Troubleshooting

 

Meet Intravacc

Meet Intravacc

Intravacc is an experienced, not-for-profit R&D organization. We optimize vaccines, vaccine processes and vaccine technologies. Our aim is to substantially reduce development risks and costs of new vaccines in order to contribute to global health and equity in access to vaccines worldwide.   

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We achieve our aim by developing and improving vaccine design, production processes, analytics and technologies. In our state-of-the-art facilities, our experienced R&D institute takes your discovery up to Phase I/II clinical trials. Furthermore, we share and transfer our knowledge and technologies to public and private partners worldwide and work on collaborative R&D. 

Our client base:

  • Biotech
  • Big pharma
  • Universities worldwide
  • Public health institutes
  • Government

Our institute in short:

  • A team of 150 professionals
  • Originating from the former Netherlands Vaccine Institute (NVI) and the Dutch National Institute for Public Health and the Environment (RIVM)
  • Currently operating under the Dutch Ministry of Public Health, Welfare and Sport
  • Located at Science Park Bilthoven (SPB) in The Netherlands

 

 

 

FActsheet vaccine

Factsheets

News

Bordetella pertussis infection and pertussis vaccination unraveled

News | 16-09-2016
Bordetella pertussis infection and pertussis vaccination unraveled

Recently, the PhD thesis of René Raeven appeared entitled ’Systems vaccinology – Molecular signatures of immunity to Bordetella pertussis’. In this thesis, the immune responses following Bordetella pertussis infection and immunization with different pertussis vaccines have been investigated and described in detail. This knowledge is essential for the development of improved pertussis vaccines and optimization of the vaccination strategy.

The research has been performed at the Institute for Translational Vaccinology (Intravacc) in close collaboration with the National Institute for Public Health and Environment (RIVM) and the Leiden Academic Center for Drug Research (LACDR).

Pertussis, a severe respiratory infectious disease that is especially dangerous for babies, is still endemic despite high vaccination coverage. It is therefore present in the top 10 of vaccine-preventable diseases that still circulate. The worldwide resurgence of Bordetella pertussis infections is associated with pathogen adaptation and suboptimal immunity induced by the current vaccines. Therefore, improved vaccines are required.

In this research, an experimental outer membrane vesicle pertussis vaccine, developed at Intravacc, has been compared in detail with current marketed vaccines; the acellular vaccine, containing purified pertussis proteins, and the classic whole-cell vaccine, that contains the complete inactive bacteria. The results indicate that immunization with outer membrane vesicles provides excellent protection in mice against a Bordetella pertussis infection. The immune responses are directed against much more antigens compared to the acellular vaccine. This is of great importance as a broader response may provide protection against different Bordetella pertussis strains. Moreover, the outer membrane vesicles induce less pro-inflammatory cytokines that are associated with reactogenic side effects compared to the classic whole-cell vaccine.

The researchers additionally investigated the immune responses following a Bordetella pertussis infection itself that infects through nose and lungs. Whereas the infection-induced immunity does also not provide life-long protection, the duration of protection is better compared to that induce by current pertussis vaccines. This improved protection is mainly attributed to the induction of specific responses in the lung itself. Such local response at the site of infection are not induced by the vaccines that are injected into the system. Immunization of the outer membrane vesicles directly into the lungs demonstrated that this induces the similar superior responses as induced by Bordetella pertussis infection even though the vesicles are not capable of infecting the lungs. This pinpoints the importance for the route of immunization as a valuable parameter for improving pertussis vaccines.

The application of systems vaccinology demonstrates that a comprehensive insight into the immune responses following immunization can contribute to optimizing the safety, efficacy and application of vaccines. In addition, it enables to compare the responses between vaccines.

The defense of the PhD thesis will take place on September 22, 15.00 at the University of Leiden.

EVI 2015 Annual Report

News | 15-09-2016
EVI 2015 Annual Report

The European Vaccine Initiative (EVI) is leading European efforts to develop effective, accessible and affordable vaccines against diseases of poverty. Intravacc is represented in the board of EVI. Please follow link for the annual report of 2015.

Winners of TU Delft student competition ‘Low-cost design and production of MenB vaccine’ announced at Intravacc in Bilthoven

News | 15-08-2016
Winners of TU Delft student competition ‘Low-cost design and production of MenB vaccine’ announced at Intravacc in Bilthoven

On the 30th of June, the finals of the yearly Design competition, part of the master programme in Life Science & Technology at the TU Delft, took place at Intravacc. Five teams, of five students each, worked independently towards a complete design of a cost-effective MenB (meningococcal B) vaccine. The main objective of this Design competition was to evaluate the actual NonaMen process developed by Intravacc and propose the best option for a MenB  vaccine process to be implemented at commercial scale, taking into account the market dynamics and product potential. The competition was organized in cooperation with Intravacc, TU Delft and BE-Basic Foundation. The winning team presented a complete process and business design and had proposed optimizations of the current Intravacc process leading to a lower production cost. They were awarded with a prize of €400. To read the full press release, follow this link.

VAC2VAC, a new project funded by the Innovative Medicines Initiative (IMI2)

News | 30-06-2016
VAC2VAC, a new project funded by the Innovative Medicines Initiative (IMI2)

European public and private organisations, including Intravacc, are collaborating in VAC2VAC, a new project funded by the Innovative Medicines Initiative (IMI2) to develop and validate quality testing approaches for both human and veterinary vaccines using non-animal methods.

For more information and full press release, follow link.

Technology transfer of Haemophilus influenzae type B (Hib) to local vaccine manufacturers in emerging countries.

News | 24-05-2016
Technology transfer of Haemophilus influenzae type B (Hib) to local vaccine manufacturers in emerging countries.

One of Intravacc’s senior scientists, Ahd Hamidi, recently submitted her doctoral thesis on the development and technology transfer of a low-cost, high quality Hib vaccine to local vaccine manufacturers in emerging countries like China, India and Indonesia. On March 3rd at TU Delft she defended successfully her thesis. In relation to her PhD graduation, the independent student newspaper of TU Delft, ‘Delta’, interviewed Dr. Hamidi about her general motives and methods. If you’re interested in reading the full interview (in Dutch), please follow this link.

Intravacc teams up with the Viral Pseudotype Unit to fight Ebola

News | 11-04-2016
Intravacc teams up with the Viral Pseudotype Unit to fight Ebola

Pseudo viruses (PVs) are non-infectious particles with the 'core' of one virus and the envelope glycoprotein of the study virus. PVs can be used as a fast, safe and effective screening tool for the prevalence of viruses in suspected infectees (www.viralpseudotypeunit.info). Intravacc supports a recent grant application from Dr Simon Scott, Dr Nigel Temperton (University of Kent) and Dr Edward Wright (University of Westminster) to develop a lyophilized, Ebola Pseudovirus- based Antibody neutralization kit for commercial use. By contributing to the project with its lyophilization and scale-up knowledge, Intravacc aims to contribute to the fight against Ebola, a disease featured on the current WHO priority disease list.

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Visiting address | Antonie van Leeuwenhoeklaan 9 | 3721 MA | Bilthoven | The Netherlands
Postal Address | Antonie van Leeuwenhoeklaan 9 | P.O. Box 450 | 3720 AL | Bilthoven | The Netherlands
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