Netherlands Vaccine Institute

Bilthoven, Netherlands

Netherlands Vaccine Institute

Bilthoven, Netherlands

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Thomassen Y.E.,Netherlands Vaccine Institute | Van Sprang E.N.M.,Toegepaste Industriele Procesbeheersing | Van Der Pol L.A.,Netherlands Vaccine Institute | Bakker W.A.M.,Netherlands Vaccine Institute
Biotechnology and Bioengineering | Year: 2010

Historical manufacturing data can potentially harbor a wealth of information for process optimization and enhancement of efficiency and robustness. To extract useful data multivariate data analysis (MVDA) using projection methods is often applied. In this contribution, the results obtained from applying MVDA on data from inactivated polio vaccine (IPV) production runs are described. Data fromover 50 batches at two different production scales (700-L and 1,500-L) were available. The explorative analysis performed on single unit operations indicated consistent manufacturing. Known outliers (e.g., rejected batches) were identified using principal component analysis (PCA). The source of operational variation was pinpointed to variation of input such as media. Other relevant process parameters were in control and, using this manufacturing data, could not be correlated to product quality attributes. The gained knowledge of the IPV production process, not only from the MVDA, but also from digitalizing the available historical data, has proven to be useful for troubleshooting, understanding limitations of available data and seeing the opportunity for improvements. © 2010 Wiley Periodicals, Inc.


Amorij J.-P.,University of Groningen | Amorij J.-P.,Netherlands Vaccine Institute | Hinrichs W.L.J.,University of Groningen | Frijlink H.W.,University of Groningen | And 2 more authors.
The Lancet Infectious Diseases | Year: 2010

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. © 2010 Elsevier Ltd.


Biesbroek G.,University Utrecht | Biesbroek G.,TNO | Wang X.,University Utrecht | Keijser B.J.F.,TNO | And 6 more authors.
Emerging Infectious Diseases | Year: 2014

Seven-valent pneumococcal conjugate vaccine (PCV- 7) is effective against vaccine serotype disease and carriage. Nevertheless, shifts in colonization and disease toward nonvaccine serotypes and other potential pathogens have been described. To understand the extent of these shifts, we analyzed nasopharyngeal microbial profiles of 97 PCV-7-vaccinated infants and 103 control infants participating in a randomized controlled trial in the Netherlands. PCV-7 immunization resulted in a temporary shift in microbial community composition and increased bacterial diversity. Immunization also resulted in decreased presence of the pneumococcal vaccine serotype and an increase in the relative abundance and presence of nonpneumococcal streptococci and anaerobic bacteria. Furthermore, the abundance of Haemophilus and Staphylococcus bacteria in vaccinees was increased over that in controls. This study illustrates the much broader effect of vaccination with PCV- 7 on the microbial community than currently assumed, and highlights the need for careful monitoring when implementing vaccines directed against common colonizers.


Kaaijk P.,National Institute for Public Health and the Environment RIVM | Van Straaten I.,Netherlands Vaccine Institute | Van De Waterbeemd B.,National Institute for Public Health and the Environment RIVM | Boot E.P.J.,Netherlands Vaccine Institute | And 4 more authors.
Vaccine | Year: 2013

Background: An improved nonavalent PorA native outer membrane vesicle vaccine was developed with intrinsic adjuvating activity due to presence of less-toxic (lpxL1) LPS. In the present study, the safety and immunogenicity of this next-generation NonaMen vaccine were evaluated following repeated vaccination in rabbits and mice. Methods: A repeated-dose toxicology study was performed in rabbits. Immunogenicity of next-generation NonaMen was evaluated by determining the serum bactericidal antibody (SBA) titers against meningococcal serogroup B strains containing several PorA subtypes. Release of the pro-inflammatory cytokine, interleukin-6 (IL-6), by the human monocytic cell line (MM6) was measured to estimate pyrogenic activity. Results: No toxicologically relevant findings were noted in vaccinated rabbits receiving plain next-generation NonaMen. In agreement, next-generation NonaMen induced reduced amounts of the pro-inflammatory cytokine, IL-6, released by human monocyte cell line. In both rabbits and mice, next-generation NonaMen induced high SBA titers against all tested MenB strains regardless of whether or not aluminium phosphate adjuvant is used. Conclusions: The data suggest that next-generation NonaMen is a safe vaccine with the potential to develop a broadly protective immune response and encourage the start of the first clinical studies. © 2012 Elsevier Ltd.


Soonawala D.,Leiden University | Verdijk P.,Vaccinology Unit | Wijmenga-Monsuur A.J.,Vaccinology Unit | Boog C.J.,Vaccinology Unit | And 3 more authors.
Vaccine | Year: 2013

For global eradication of poliomyelitis, inactivated poliovirus vaccine (IPV) needs to become available in all countries. Using fractional-doses (reduced-doses) may impact affordability and optimize the utilization of the production capacity. Intradermal administration has the potential to lower the dose without reducing immunogenicity. A needle-free jet injector may be a reliable way to administer vaccines intradermally. The primary objective of this randomized controlled trial was to compare the immunogenicity and tolerability of fractional-dose intradermal IPV (Netherlands Vaccine Institute, NVI) booster vaccination administered with a jet injector (PharmaJet) to full-dose and fractional-dose intramuscular vaccination with a needle and syringe. Immunogenicity was assessed by comparing the differences in the post-vaccination log2 geometric mean concentrations of neutralizing antibodies (GMC) between the study groups. A total of 125 Dutch adult volunteers with a well-documented vaccination history were randomized to one of four groups: full-dose intramuscular needle (IM-NS-0.5), full-dose intramuscular jet injector (IM-JI-0.5), 1/5th dose intramuscular needle (IM-NS-0.1), 1/5th dose intradermal jet injector (ID-JI-0.1). Vaccination with the JI was less painful (87% no pain) than vaccination with a NS (60% no pain), but caused more transient erythema (JI 85%, NS 24%) and swelling (JI 50%, NS 5%). Intradermal vaccination caused less vaccination site soreness (ID 16%, IM 52%). At baseline all subjects had seroprotective antibody concentrations. After 28 days, GMC were slightly lower in the ID-JI-0.1 group than in the reference group (IM-NS-0.5). The differences were not statistically significant, but the stringent non-inferiority criterion (i.e. a difference of 1 serum dilution in the microneutralization assay) was not met. After one year, differences in GMC were no longer apparent. In contrast, intramuscular vaccination with a fractional dose administered with a needle (IM-NS-0.1) was statistically inferior to full-dose intramuscular vaccination. This shows that intradermal but not intramuscular delivery of fractional-dose IPV may be sufficient for routine polio vaccination. © 2013 Elsevier Ltd.


Bal S.M.,Leiden University | Ding Z.,Leiden University | Kersten G.F.A.,Netherlands Vaccine Institute | Jiskoot W.,Leiden University | Bouwstra J.A.,Leiden University
Pharmaceutical Research | Year: 2010

Purpose: The purpose of this study was to gain insight into the delivery and immunogenicity of N-trimethyl chitosan (TMC) adjuvanted diphtheria toxoid (DT) formulations applied transcutaneously with microneedles. Methods: Mice were vaccinated with DT-loaded TMC nanoparticles, a solution of TMC and DT (TMC/DT) or DT alone. The formulations were applied onto the skin before or after microneedle treatment with two different 300-μm-long microneedle arrays and also injected intradermally (ID). As a positive control, alum-adjuvanted DT (DT-alum) was injected subcutaneously (SC). Ex vivo confocal microscopy studies were performed with rhodamine-labelled TMC. Results: Independent of the microneedle array used and the sequence of microneedle treatment and vaccine application, transcutaneous immunisation with the TMC/DT mixture elicited 8-fold higher IgG titres compared to the TMC nanoparticles or DT solution. The toxin-neutralising antibody titres from this group were similar to those elicited by SC DT-alum. After ID immunisation, both TMC-containing formulations induced enhanced titres compared to a DT solution. Confocal microscopy studies revealed that transport of the TMC nanoparticles across the microneedle conduits was limited compared to a TMC solution. Conclusions: In conclusion, TMC has an adjuvant function in transcutaneous immunisation with microneedles, but only if applied in a solution. © 2010 The Author(s).


BACKGROUND: Respiratory syncytial virus (RSV) is a primary cause of serious lower respiratory tract illness for which there is still no safe and effective vaccine available. Using reverse genetics, recombinant (r)RSV and an rRSV lacking the G gene (DeltaG) were constructed based on a clinical RSV isolate (strain 98-25147-X). RESULTS: Growth of both recombinant viruses was equivalent to that of wild type virus in Vero cells, but was reduced in human epithelial cells like Hep-2. Replication in cotton rat lungs could not be detected for DeltaG, while rRSV was 100-fold attenuated compared to wild type virus. Upon single dose intranasal administration in cotton rats, both recombinant viruses developed high levels of neutralizing antibodies and conferred comparable long-lasting protection against RSV challenge; protection against replication in the lungs lasted at least 147 days and protection against pulmonary inflammation lasted at least 75 days. CONCLUSION: Collectively, the data indicate that a single dose immunization with the highly attenuated DeltaG as well as the attenuated rRSV conferred long term protection in the cotton rat against subsequent RSV challenge, without inducing vaccine enhanced pathology. Since DeltaG is not likely to revert to a less attenuated phenotype, we plan to evaluate this deletion mutant further and to investigate its potential as a vaccine candidate against RSV infection.


Van Mourik A.,University Utrecht | Steeghs L.,University Utrecht | Van Laar J.,University Utrecht | Meiring H.D.,Netherlands Vaccine Institute | And 3 more authors.
Journal of Biological Chemistry | Year: 2010

Modification of the lipid A moiety of bacterial lipopolysaccharide influences cell wall properties, endotoxic activity, and bacterial resistance to antimicrobial peptides. Known modifications are variation in the number or length of acyl chains and/or attached phosphoryl groups. Here we identified two genes (gnnA and gnnB) in the major foodborne pathogen Campylobacter jejuni that enable the synthesis of a GlcN3N precursor UDP 2-acetamido-3-amino-2,3-dideoxy- α-D-glucopyranose (UDP-GlcNAc3N) in the lipid A backbone. Mass spectrometry of purified lipooligosaccharide verified that the gene products facilitate the formation of a 2,3-diamino-2,3-dideoxy-D-glucose (GlcN3N) disaccharide lipid A backbone when compared with the β-1′-6-linked D-glucosamine (GlcN) disaccharide observed in Escherichia coli lipid A. Functional assays showed that inactivation of the gnnA or gnnB gene enhanced the TLR4-MD2-mediated NF-κB activation. The mutants also displayed increased susceptibility to killing by the antimicrobial peptides polymyxin B, colistin and the chicken cathelicidin-1. The gnnA and gnnB genes are organized in one operon with hemH, encoding a ferrochelatase catalyzing the last step in heme biosynthesis. These results indicate that lipid A modification resulting in amide-linked acyl chains in the lipid A is an effective mechanism to evade activation of the innate host defense and killing by antimicrobial peptides. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.


Venhuis B.J.,National Institute for Public Health and the Environment | Zomer G.,Netherlands Vaccine Institute | Hamzink M.,Netherlands Vaccine Institute | Meiring H.D.,Netherlands Vaccine Institute | And 2 more authors.
Journal of Pharmaceutical and Biomedical Analysis | Year: 2011

A new unapproved analogue of sildenafil was detected in capsules of a herbal dietary supplement promoted as a libido enhancing product. Using LC-DAD-MS, MS-MS, HRMS, IR and NMR the analogue was shown to be a derivative of the PDE-5 inhibitor aildenafil with a nitrosamine moiety. A hydrolysis experiment showed that the new analogue was a prodrug of aildenafil and was therefore named nitroso-prodenafil. A capsule contained 108 mg of nitroso-prodenafil which is equivalent to 84 mg of aildenafil and 5.1 mg of nitrogen monoxide (NO). Although it is unknown how much NO can be usefully generated there is 3-fold more NO present than in a 10 mg isorbide nitrate tablet. Both PDE-5 inhibitors and nitrosamines cause vasodilatation by increasing levels of NO. To their coincidental use is warned against because it may cause a fatal drop in blood pressure. In addition, nitrosamines are known carcinogens. This is the first time a PDE-5 inhibitor and a potential NO donor were identified in one molecule. The findings indicate the dangerous level of advancement in medicinal chemistry by producers of unapproved drugs. © 2010 Elsevier B.V.


Venhuis B.J.,National Institute for Public Health and the Environment | Zomer G.,Netherlands Vaccine Institute | Vredenbregt M.J.,National Institute for Public Health and the Environment | de Kaste D.,National Institute for Public Health and the Environment
Journal of Pharmaceutical and Biomedical Analysis | Year: 2010

Four blisters with suspect Cialis® (tadalafil) 20 mg tablets were screened for authenticity using near infrared spectroscopy (NIRS) and for the presence of phosphodiesterase 5 (PDE-5) inhibitors using LC-DAD-MS. All samples were identified as counterfeit Cialis® and contained sildenafil or a combination of tadalafil and sildenafil. Although the tablets contained efficacious amounts of PDE-5 inhibitors, neither the active ingredient nor the dosage corresponded to the description on the blister. This is the first reported case of a diastereomeric mixture of tadalafil and trans-tadalafil (3:1) being identified in a counterfeit medicine. The LC-DAD-CD revealed that both diastereomers had a high optical purity. The optical rotation of the diastereomeric mixture was measured indicating the presence of (-)-trans-tadalafil, which is the only other stereoisomer with some PDE-5 inhibitory activity. As no safety profiles are known for the stereoisomers of tadalafil, there is a potential health risk. In addition, the optical purity of tadalafil needs to be taken into account when calculating the dosage in illegal medicines. © 2009.

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