The best form of protection against influenza is vaccination, in terms of efficacy to protect individuals and reduction of the social impact of epidemics on our human societies. Chapter 1 of this... Show moreThe best form of protection against influenza is vaccination, in terms of efficacy to protect individuals and reduction of the social impact of epidemics on our human societies. Chapter 1 of this thesis details the current influenza vaccines available and their lack of efficacy, and the current need for new adjuvanted influenza formulations. Pathogens are often particles and formulating antigens into nanoparticles (NP) results in systems that resemble the pathogens in terms of size, and notably can promote antigen uptake by dendritic cells (DC). The principal aim of the research in this thesis was to investigate how NP systems can act as an adjuvant for subunit influenza vaccine Show less
Eby, J.M.; Barse, L.; Henning, S.W.; Rabelink, M.J.W.E.; Klarquist, J.; Gilbert, E.R.; ... ; Poole, I.C. le 2017
To maintain momentum towards improved malaria control and elimination, a vaccine would be a key addition to the intervention toolkit. Two approaches are recommended: (1) promote the development and... Show moreTo maintain momentum towards improved malaria control and elimination, a vaccine would be a key addition to the intervention toolkit. Two approaches are recommended: (1) promote the development and short to medium term deployment of first generation vaccine candidates and (2) support innovation and discovery to identify and develop highly effective, long-lasting and affordable next generation malaria vaccines. Show less
Rosalia, R.A.; Cruz, L.J.; Duikeren, S. van; Tromp, A.T.; Silva, A.L.; Jiskoot, W.; ... ; Ossendorp, F. 2015
Schistosomiasis is a tropical disease affecting over 230 million people worldwide. Although effective drug treatment is available, reinfections are common, and development of immunity is slow. Most... Show moreSchistosomiasis is a tropical disease affecting over 230 million people worldwide. Although effective drug treatment is available, reinfections are common, and development of immunity is slow. Most antibodies raised during schistosome infection are directed against glycans, some of which are thought to be protective. Developing schistosomula are considered most vulnerable to immune attack, and better understanding of local antibody responses raised against glycans expressed by this life stage might reveal possible glycan vaccine candidates for future vaccine research. In this tehsis we adressed the spatial and temporal expression of glycans expressed during the critical larval stages of schistosome development and we studied the (protective) antibody responses against these glycans in animals and infected human populations. Together these studies thereby contribute to an important basis for the understanding of the anti-glycan antibody responses towards Schistosoma in general and towards the vulnerable schistosomulum in particular. Show less
using the Prevenar-13 vaccine. Twenty-four healthy male volunteers were vaccinated with Prevenar-13, either three times, twice or once in a double-blind, placebo-controlled, randomized single... Show moreusing the Prevenar-13 vaccine. Twenty-four healthy male volunteers were vaccinated with Prevenar-13, either three times, twice or once in a double-blind, placebo-controlled, randomized single center clinical study. Anti-pneumococcal wall, oxLDL and phosphorycholine antibody levels were measured at a fixed serum dilution, as well as circulating lipid levels over the course of 68 weeks. A significant increase in anti-oxLDL IgG and IgM was seen in the group receiving two doses six months apart compared to the placebo. However, these differences were not observed in the groups receiving a single dose, two doses one month apart, or three doses. This study shows that vaccination with Prevenar-13 does not result in robust anti-oxLDL IgM levels in humans. Further research would be required to test alternative pneumococcal-based vaccines, vaccination regimens or study populations, such as cardiovascular disease patients. Show less
Every day Tuberculosis (TB) kills approximately three thousand people, a number that is on the rise due to the impact of the current COVID-19 pandemic on essential TB services. The causative agent... Show moreEvery day Tuberculosis (TB) kills approximately three thousand people, a number that is on the rise due to the impact of the current COVID-19 pandemic on essential TB services. The causative agent of TB, Mycobacterium tuberculosis (Mtb), is an ancient pathogen that through its evolution developed complex mechanisms to evade immune surveillance and acquired the ability to establish persistent infection in its hosts. To achieve TB eradication, the discovery of Mtb antigens that effectively correlate with the human response to infection, with the curative host response following TB treatment, and with natural as well as vaccine induced protection is critical. This thesis contributes to this ambitious aim through several findings. First, it uncovers multiple new in vivo expressed Mtb (IVE-TB) antigens by combining Mtb-transcriptomic data with advanced bioinformatics tools and medium throughput cytokine screening. Second, it deepens our understanding of the cellular and humoral immunity to Mtb antigens in latently Mtb infected donors (LTBIs) and TB patients as well as in animal models. Lastly, it demonstrates the feasibility of combining and integrating pre-clinical research of multiple mycobacterial diseases, which are endemic in the same areas and against which vaccines could induce cross-disease protection (i.e., TB and leprosy). Show less
The COVID-19 pandemic has galvanized the global response towards the development of new vaccines based on novel technologies at an unprecedented pace. Since the widespread implementation of... Show moreThe COVID-19 pandemic has galvanized the global response towards the development of new vaccines based on novel technologies at an unprecedented pace. Since the widespread implementation of vaccination campaigns, case reports on vaccines' systemic side effects, including ocular manifestations, have emerged. Since administered vaccines are generally not able to cause the disease in the recipient, or induce an immune response against the pathogen, we hypothesize that the development of ocular phenomena post-COVID-19 vaccination may occur via an immune response elicited by the vaccine. Of many, the most common ocular adverse events include facial nerve palsy, central venous sinus thrombosis and acute anterior uveitis. These COVID-19 vaccine-induced ocular (CVIO) adverse events could resemble the ocular findings in some of the COVID-19 patients. This review will provide a comprehensive overview of published ocular side effects potentially associated with COVID-19 vaccination and serve as a springboard for further research into CVIO adverse events. Show less
Currently, only one tuberculosis (TB) vaccine is available: Mycobacterium bovis Bacille Calmette-Gu_rin (BCG). This vaccine induces highly variable protection against pulmonary TB, the most common... Show moreCurrently, only one tuberculosis (TB) vaccine is available: Mycobacterium bovis Bacille Calmette-Gu_rin (BCG). This vaccine induces highly variable protection against pulmonary TB, the most common and contagious form of TB. There is an urgent need for an effective TB vaccine which is safe also in the immunocompromised host. The main focus of this thesis was to identify Mycobacterium tuberculosis (Mtb) infection phase related antigens and to evaluate these as potential antigens for TB vaccines. The studies presented in this thesis describe: (i) the immunogenic potential of two previously described sets of antigens; resuscitation promoting factor (Rpf) and dormancy regulon encoded (DosR) antigens, (ii) the identification and immunogenicity of a third set of antigens known as in vivo expressed Mtb (IVE-TB) antigens, (iii) the protective value of IVE-TB antigen Rv2034 and (iv) the analysis of Rv2034-specific T cell r esponses at the clonal level. Together, these data illustrate the vaccine potential of infection phase related antigens. Show less
Current seasonal influenza vaccines rely on the induction of antibodies to neutralize the virus. However, influenza viruses frequently undergo genetic mutations due to antigenic drift and shift,... Show moreCurrent seasonal influenza vaccines rely on the induction of antibodies to neutralize the virus. However, influenza viruses frequently undergo genetic mutations due to antigenic drift and shift, altering the surface proteins hemagglutinin and neuraminidase to which antibodies usually bind. This could render vaccine-induced antibody responses ineffective, resulting in an ineffective influenza vaccine. Influenza vaccines based on the induction of T cell responses might be cross-reactive, since they target conserved influenza epitopes that do not tend to mutate. However, the peptide antigens that are able to induce such T cell responses are often poorly immunogenic. In this thesis, several formulation strategies are described that could improve the immunogenicity of influenza T cell peptide antigens. Using combinations of delivery systems and immunostimulators, the peptide antigens were able to induce influenza-specific T cell responses in mice. Furthermore, a model was developed that could predict the in vitro adjuvanticity of liposomes according to the liposomal lipid composition. In addition, the recent advances in influenza vaccine development are discussed. Finally, an alternative delivery system, the Bioneedle, was evaluated for the delivery of several influenza vaccines. Show less
Despite intense efforts over the past 50 years to develop a vaccine, there is currently no licensed malaria vaccine available. The limited success in inducing sufficient protection against malaria... Show moreDespite intense efforts over the past 50 years to develop a vaccine, there is currently no licensed malaria vaccine available. The limited success in inducing sufficient protection against malaria with subunit-vaccines has renewed an interest in whole-parasite vaccination strategies. While live-vaccines are hard to formulate and administer, they have been shown to confer long-lasting sterile immunity in humans. The aim of the work described in this thesis was to genetically engineer and characterize growth- and virulence-attenuated blood stage parasites (GAPBS) in the rodent malaria model, P. berghei. Specifically, the identification of GAPBS that produce only short-lived, low-level infections that can provoke strong and long-lasting protective immunity. The thesis describes improved methods to produce and screen potential GAPBS, specifically transfection methods to generate GAPBS and methods to analyze their blood stage growth-characteristics. In addition, we report the generation and characterization of a number of novel GAPBS that are virulence-attenuated and produce self-resolving infections in mice. These GAPBS are useful tools to better understand the induction of protective immunity against Plasmodium blood stages and may help to create an effective and broad acting antimalarial vaccine. Show less
General significance: Histo-blood group glycans have a unique linking position in the complex network of genes, oncodevelopmental biological processes, and disease mechanisms. Thus, they are highly... Show moreGeneral significance: Histo-blood group glycans have a unique linking position in the complex network of genes, oncodevelopmental biological processes, and disease mechanisms. Thus, they are highly promising targets for novel approaches in the field of personalized medicine. This article is part of a Special Issue entitled "Glycans in personalised medicine" Guest Editor: Professor Gordan Lauc. (C) 2015 Elsevier B.V. All rights reserved. Show less
Reigadas, E.; Prehn, J. van; Falcone, M.; Fitzpatrick, F.; Vehreschild, M.J.G.T.; Kuijper, E.J.; ... ; Study Grp Host Microbiota Interact 2021
Background: Clostridioides difficile infection (CDI) remains the leading cause of healthcare-associated diarrhoea, despite existing guidelines for infection control measures and antimicrobial... Show moreBackground: Clostridioides difficile infection (CDI) remains the leading cause of healthcare-associated diarrhoea, despite existing guidelines for infection control measures and antimicrobial stewardship. The high associated health and economic burden of CDI calls for novel strategies to prevent the development and spread of CDI in susceptible patients. Objectives: We aim to review CDI prophylactic treatment strategies and their implementation in clinical practice. Sources: We searched PubMed, Embase, Emcare, Web of Science, and the COCHRANE Library databases to identify prophylactic interventions aimed at prevention of CDI. The search was restricted to articles published in English since 2012. Content: A toxin-based vaccine candidate is currently being investigated in a phase III clinical trial. However, a recent attempt to develop a toxin-based vaccine has failed. Conventional probiotics have not yet proved to be an effective strategy for prevention of CDI. New promising microbiota-based interventions that bind and inactivate concomitantly administered antibiotics, such as ribaxamase and DAV-132, have been developed. Prophylaxis of CDI with C. difficile antibiotics should not be performed routinely and should be considered only for secondary prophylaxis in very selected patients who are at the highest imminent risk for recurrent CDI (R-CDI) after a thorough evaluation. Faecal microbiota transplantation (FMT) has proved to be a very effective treatment for patients with multiple recurrences. Bezlotoxumab provides protection against R-CDI, mainly in patients with primary episodes and a high risk of relapse. Implications: There are no proven effective, evidenced-based prophylaxis options for primary CDI. As for secondary prevention, FMT is considered the option of choice in patients with multiple recurrences. Bezlotoxumab can be added to standard treatment for patients at high risk for R-CDI. The most promising strategies are those aimed at reducing changes in intestinal microbiota and development of a new effective non-toxin-based vaccine. Elena Reigadas, Clin Microbiol Infect 2021;27:1777 (c) 2021 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved. Show less
Kasteren, P.B. van; Knaap, R.C.M.; Elzen, P. van den; Snijder, E.J.; Balasuriya, U.B.R.; Born, E. van den; Kikkert, M. 2015
The impact of respiratory virus infections on the health of children and adults can be very significant. Yet, in contrast to most other childhood infections as well as other viral and bacterial... Show moreThe impact of respiratory virus infections on the health of children and adults can be very significant. Yet, in contrast to most other childhood infections as well as other viral and bacterial diseases, prophylactic vaccines or effective antiviral treatments against viral respiratory infections are either still not available, or provide only limited protection. Given the widespread prevalence, a general lack of natural sterilizing immunity, and/or high morbidity and lethality rates of diseases caused by influenza, respiratory syncytial virus, coronaviruses, and rhinoviruses, this difficult situation is a genuine societal challenge. A thorough understanding of the virus-host interactions during these respiratory infections will most probably be pivotal to ultimately meet these challenges. This review attempts to provide a comparative overview of the knowledge about an important part of the interaction between respiratory viruses and their host: the arms race between host innate immunity and viral innate immune evasion. Many, if not all, viruses, including the respiratory viruses listed above, suppress innate immune responses to gain a window of opportunity for efficient virus replication and setting-up of the infection. The consequences for the host's immune response are that it is often incomplete, delayed or diminished, or displays overly strong induction (after the delay) that may cause tissue damage. The affected innate immune response also impacts subsequent adaptive responses, and therefore viral innate immune evasion often undermines fully protective immunity. In this review, innate immune responses relevant for respiratory viruses with an RNA genome will briefly be summarized, and viral innate immune evasion based on shielding viral RNA species away from cellular innate immune sensors will be discussed from different angles. Subsequently, viral enzymatic activities that suppress innate immune responses will be discussed, including activities causing host shut-off and manipulation of stress granule formation. Furthermore, viral protease-mediated immune evasion and viral manipulation of the ubiquitin system will be addressed. Finally, perspectives for use of the reviewed knowledge for the development of novel antiviral strategies will be sketched. Show less
In summary, the collective results described in this thesis show that nanoparticulate vaccines can be delivered intradermally by coated and hollow microneedles and evoke antigen-specific immune... Show moreIn summary, the collective results described in this thesis show that nanoparticulate vaccines can be delivered intradermally by coated and hollow microneedles and evoke antigen-specific immune responses. The choice of both the nanoparticles and the microneedle(s) could have important influences on the immune responses. Microneedle arrays coated with antigen loaded and lipid bilayer fused mesoporous silica nanoparticles (MSNs) could be a promising system for convenient and fast intradermal delivery of protein antigen, although our results indicate that the system needs to be improved in order to obtain optimal immune responses. Moreover, antigen and adjuvant loaded nanoparticles can increase IgG2a (Th1) and CD8+ responses after intradermal delivery by hollow microneedles. This effect depends on the type and the physicochemical characteristics of the nanoparticles, in which smaller size and controlled release properties of antigen and adjuvant were found to correlate with the stronger effect. Finally, the combination of separate antigen loaded and adjuvant loaded nanoparticles may be as efficient as the antigen and adjuvant co-encapsulated nanoparticles for modification of the immune responses following intradermal immunization. Show less
Background: COVID-19 is associated with increased morbidity and mortality in patients with chronic kidney disease (CKD) stages G4-G5, on dialysis or after kidney transplantation (kidney replacement... Show moreBackground: COVID-19 is associated with increased morbidity and mortality in patients with chronic kidney disease (CKD) stages G4-G5, on dialysis or after kidney transplantation (kidney replacement therapy, KRT). SARS-CoV-2 vaccine trials do not elucidate if SARS-CoV-2 vaccination is effective in these patients. Vaccination against other viruses is known to be less effective in kidney patients. Our objective is to assess the efficacy and safety of various types of SARS-CoV-2 vaccinations in patients with CKD stages G4-G5 or on KRT. Methods: In this national prospective observational cohort study we will follow patients with CKD stages G4-G5 or on KRT (n = 12,000) after SARS-CoV-2 vaccination according to the Dutch vaccination program. Blood will be drawn for antibody response measurements at day 28 and month 6 after completion of vaccination. Patient characteristics and outcomes will be extracted from registration data and questionnaires during 2 years of follow-up. Results will be compared with a control group of non-vaccinated patients. The level of antibody response to vaccination will be assessed in subgroups to predict protection against COVID-19 breakthrough infection. Results: The primary endpoint is efficacy of SARS-CoV-2 vaccination determined as the incidence of COVID-19 after vaccination. Secondary endpoints are the antibody based immune response at 28 days after vaccination, the durability of this response at 6 months after vaccination, mortality and (serious) adverse events. Conclusion: This study will fulfil the lack of knowledge on efficacy and safety of SARS-CoV-2 vaccination in patients with CKD stages G4-G5 or on KRT. Current knowledge about this subject. COVID-19 has devastating impact on patients with CKD stages G4-G5, on dialysis or after kidney transplantation.. Effective SARS-CoV-2 vaccination is very important in these vulnerable patient groups.. Recent studies on vaccination in these patient groups are small short-term studies with surrogate endpoints. Contribution of this study. Assessment of incidence and course of COVID-19 after various types of SARS-CoV-2 vaccination during a twoyear follow-up period in not only patients on dialysis or kidney transplant recipients, but also in patients with CKD stages G4-G5.. Quantitative analysis of antibody response after SARS-CoV-2 vaccination and its relationship with incidence and course of COVID-19 in patients with CKD stages G4-G5, on dialysis or after kidney transplantation compared with a control group.. Monitoring of (serious) adverse events and development of anti-HLA antibodies. Impact on practice or policy. Publication of the study design contributes to harmonization of SARS-CoV-2 vaccine study methodology in kidney patients at high-risk for severe COVID-19.. Data on efficacy of SARS-CoV-2 vaccination in patients with CKD will provide guidance for future vaccination policy. Show less
Replication of positive-stranded RNA viruses requires the activity of proteases that cleave the viral replicase polyproteins. For Middle East respiratory coronavirus (MERS-CoV), the virus-encoded... Show moreReplication of positive-stranded RNA viruses requires the activity of proteases that cleave the viral replicase polyproteins. For Middle East respiratory coronavirus (MERS-CoV), the virus-encoded papain-like protease (PLpro) is one of such proteases. This protease also functions as a deubiquitinating enzyme (DUB) that removes ubiquitin from substrates, most likely to suppress the ubiquitin-dependent activation of the innate immune response. The work described in this thesis provides novel insights in the interaction between PLpro and ubiquitin. The crystal structure of the PLpro-ubiquitin complex facilitated the design of substitutions in PLpro that selectively disrupted its DUB activity. DUB-negative MERS-CoV induced enhanced immune responses compared to wild-type virus, while showing similar replication in infected cells. Relative to wild-type virus, the virulence of DUB-negative MERS-CoV was reduced in mice and earlier, better-regulated immune responses were measured in their lungs. In the search for novel antivirals, ubiquitin sequence variants were selected that bound with very high affinity to MERS-CoV PLpro. Expression of those ubiquitin variants affected the activity of PLpro and concomitantly inhibited virus replication resulting in severely less virus progeny. Collectively, the gained knowledge can be used to design novel coronavirus vaccines or further develop ubiquitin variants as antiviral agents against viruses that encode DUBs. Show less
