University of Groningen
Improving influenza prevention
van Doorn, Eva
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Publication date: 2018
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van Doorn, E. (2018). Improving influenza prevention: Why universal influenza vaccines are needed. Rijksuniversiteit Groningen.
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CHAPTER 9
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187 In the first part of this thesis we reported on the effectiveness of conventional influenza vaccines that have been used in the Netherlands over the past decade as assessed by the test-negative case control study design. Modifying virological factors such as the effect of vaccine match status and circulating influenza virus (sub)types/lineages (Chapter 2) as well as methodological factors as the definition of the control group (Chapter 3) were evaluated. In the second part of this thesis, the safety and tolerability of vaccine adjuvants that are used in formulations in pre-marketing influenza vaccine trials were evaluated (Chapters 4 and 5). In the final part of this thesis, we presented an overview on guidelines for ethical and competent authority approval for a pre-registration vaccine trial in different European countries (Chapter 6). In addition, the clinical evaluation of a novel influenza vaccine concept in a pre-registration phase two trial was presented (Chapters 7 and 8).
Influenza vaccine effectiveness in the Netherlands
The effectiveness of currently marketed influenza vaccines is particularly low when the vaccine strains do not match the circulating viruses and when A(H3N2) is the dominant influenza virus (Chapter 2). A vaccine mismatch has occurred in more than half of the past influenza seasons in the Netherlands (seven out of the 11 seasons from 2003/2004 until 2013/2014).
Low vaccine effectiveness for the A(H3N2) influenza virus subtype has been found in other studies [1,2]. The low effectiveness might be explained by virological and epidemiological differences between influenza viruses. The influenza A(H3N2) virus has shown to have a higher mutation rate compared to the A(H1N1) and B viruses, and it is associated with more (severe) infections [3-5]. This could result in a different number of cases in each influenza season, and consequently affect the influenza vaccine effectiveness (IVE).
For several seasons, there was an inconsistency between the vaccine match status and the A(H3N2) IVE, i.e., an absence of effect was found despite a vaccine match. One of the speculations is that vaccination in a prior year influences the effects of influenza vaccination in the current season [6]. It has been hypothesized that repeated vaccination might negatively interfere with the effectiveness of a current vaccine. The immunologic mechanism is not exactly known, but it may be explained by the phenomenon that antibodies of persons who are vaccinated against influenza in a previous season will cross-react with the vaccine antigen given in a current season [7,8]. As a consequence, the effectiveness of a current vaccine may be reduced [8]. This effect is postulated to be greater when the antigenic distance between the vaccines is small and especially when the previous vaccine does not match the circulating strains [6,8]. Several papers did not find any evidence for such a negative interference while others did [7,9-11]. Recent studies show that, when such a detrimental effect was detected, this was especially pertaining to the influenza A(H3N2) virus subtype [6,7,11,12]. Hence, this phenomenon might also, in part, be an explanation for the low IVE estimates for A(H3N2) found in Chapter 2. Such an effect could, unfortunately, not be addressed in our studies since no information on prior vaccinations was present. Another explanation for low vaccine effectiveness pertains to the growing of the vaccines in eggs. For example, in the 2012/2013
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season, the low vaccine effectiveness was not caused by an antigenic drift but by mutations in the egg-adapted A(H3N2) vaccine strain [13,14].
From a methodological point of view, the definition of the control group may also influence IVE estimates in test-negative case control design studies (Chapter 3). In Chapter 3, we concluded that controls who tested negative for influenza and other respiratory viruses (pan-negative controls) seem less valid as a control group since a high proportion of patients in this group likely visits the general practitioner because of a non-infectious cause of an influenza-like illness (ILI). In this control group compared to the other control groups, patients were, on average, older and had a higher prevalence of chronic diseases. When using controls that were positive for another respiratory virus (non-influenza positive controls), the IVE estimates were more consistent with previous effectiveness studies and clinical trial data. According to several other researchers, the non-influenza virus positive control group is also the best control group to use since the presence of differential misclassification is highly unlikely because there is a confirmed infectious cause of ILI in both cases and controls [15-17]. A recent meta-analysis from Feng et al. including our study and eleven other studies which also estimated the IVE with three control groups (all influenza negative, non-influenza virus positive and pan-negative) did not find any difference in the IVE estimates based on the control group that was used. According to the investigators, influenza-negative controls are likely to produce vaccine effectiveness results that are just as reliable as the other control groups due to the absence of virus interference [18].
The test-negative design is commonly applied since, compared to other observational studies, it introduces less confounding and misclassification errors because cases and controls are selected from the same source population, and the influenza infection status is known of all of the patients [19,20]. However, the study design is still vulnerable to confounding, selection bias, and limited applicability. For example, the elderly and the patients with a chronic disease could be more frequently selected for influenza virus infection detection since they are at a higher risk of developing severe influenza complications, and might be more susceptible to health care-seeking behavior. The influenza vaccination coverage in such at-risk patient groups is also higher. Moreover, selected patients are not a representative sample of patients in the population since most persons with ILI will not visit their general practitioner; therefore, the vaccine effectiveness from the test-negative design cannot be interpreted as vaccine effectiveness against infection in the total targeted population [19]. Also, the specificity and sensitivity of the laboratory test used to detect influenza virus infection, and thereby the classification of cases and controls, influences the ‘true’ estimation of the vaccine effectiveness [19,21].
Future studies using the test-negative design should take into account these confounding factors and uncertainties by adjusting for potential confounders (e.g., age, presence of chronic medical conditions, previous vaccination status). Further exploration of effect modification on the IVE estimates against (different) virus subtypes is needed.
189 Safety and tolerability evaluation of vaccine adjuvants
A strategy to improve the immune response to vaccine antigens is the incorporation of an adjuvant into a vaccine formulation. The inclusion of an adjuvant has several advantages such as the enhancement of the immunogenicity of antigens and a reduction of the amount of antigen. However, the adjuvant should have an acceptable balance between the beneficial effects on the immune response and the risk of local and systemic adverse events [22]. In
Chapters 4 and 5 we evaluated the safety and tolerability of adjuvants that are currently under
investigation in pre-marketing influenza vaccine clinical trials. Based on the evaluated limited number of studies, we found no specific concern for the evaluated adjuvants Montanide ISA 51TM (ISA 51), QS-21, and ISCOMATRIX, but we advise caution especially when using ISA 51.
Safety concerns with respect to the use of adjuvants in vaccines have been raised over a long period of time, and many adjuvants have been developed in the past but were never accepted for routine vaccination due to these concerns [22]. Safety concerns have also been raised for licensed adjuvants, such as during the 2009 influenza pandemic for an AS03-adjuvanted H1N1 pandemic vaccine (Pandemrix ®). The administration of Pandemrix® was associated with an increase in narcolepsy cases in children and adolescents, and it was hypothesized that this was caused by the oil-in-water adjuvant AS03.
In both Sweden and Finland, an increase in childhood narcolepsy cases was reported in the months after introduction of the vaccine [23,24]. Other studies conducted in Ireland, England, Norway, and France also found increased narcolepsy incidences in young children and adolescents (until the age of 20 years) associated with Pandemrix ® [25-29]. In Canada, where another AS03-adjuvanted pandemic vaccine (Arepanrix ®) was used, fewer incidences of narcolepsy cases were reported than in Europe [30].
In contrast, to date, no subject who received an MF59-adjuvanted pandemic vaccine (Focetria ®) was reported as having narcolepsy [31]. Another important finding during the pandemic in China where there was a significant increase in narcolepsy cases independent of the A(H1N1)pdm09 vaccination implies that vaccine-associated narcolepsy may not only have been caused by the AS03 adjuvant alone [32,33]. The causal relationship with narcolepsy may be explained by the differences in the amounts of nucleoprotein in the vaccines; a conserved epitope of the nucleoprotein might have triggered a cross-reactive immune response to receptors in the brain which are associated with the development of narcolepsy. Pandremix ® had the highest nucleoprotein quantity compared to Arepranix ® and Focetria ®. The adjuvant could have boosted the immune response, generating higher amounts of antibodies cross-reacting with the specific receptors in the brain and thereby accelerating the time to develop narcolepsy [29].
The European Medicine’s Agency’s Committee for Medicinal Products for Human Use (CHMP) concluded in 2012 that an increased risk of narcolepsy was seen in several countries and that this cannot be ruled out for other countries [34]. The uncertainties about the safety of AS03 in the pandemic vaccine highlights our findings in Chapters 4 and 5 where we concluded that an appropriate trial design including at least a large enough active control group with only the adjuvant under study is desired for future trials that evaluate adjuvanted-vaccines.
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Ethical and competent authority approval of clinical trials
Before any clinical trial can start, ethical and competent authority approval needs to be obtained. The European Union (EU) Directive 2001/20/EC was implemented in 2001 with the aim to harmonize the national procedures for the ethical approval of clinical trials in EU Member States (Chapter 7). However, the directive has been implemented differently in the national laws of Member States since directives are only binding to the result that has to be achieved. In Chapter 7, we have illustrated these differences in the ethical and competent authority review procedures in five EU countries for a vaccine trial. We found differences among the countries in the documents that have to be submitted for the review procedures, the submission procedures, language requirements, organization of the ethics committees (e.g., national, regional, institutional), and the role of the competent authority in the approval procedure. Especially for multicenter trials, it is difficult and expensive to carry out cross-border trials since a single opinion is required from each Member State that will participate.
In 2014, the EU adopted a new clinical trial regulation which is directly applicable for EU Member States and will repeal Directive 2001/20/EC if the regulation is implemented [35]. It is now forecasted that the implementation will occur in 2019 [36]. The aim of this regulation is to harmonize the national ethical approval procedures by, e.g., an installment of an EU portal for the application procedure and a harmonized procedure for the assessment of clinical trial applications [37]. For multinational trials, this still means that the ethical approval is carried out by each concerned Member State. One part of the application (e.g., relevance of the trial, investigator’s brochure, requirements concerning the manufacturing, labelling) will be assessed by a reporting Member State, and the assessment report drafted by the reporting Member State should be reviewed by all concerned Member States. The reporting Member States shall take into account all considerations of the concerned Member States before sending the assessment report to the sponsor of a trial. In addition, all concerned Member States should evaluate country specific documents (e.g., informed consent, rewarding and compensation of subjects, insurance) [38].
The new regulation will have several important consequences for the Member States such as the dual approval by an ethics committee and the competent authority. For example, in the Netherlands, the competent authority will no longer have a role in the assessment of a clinical trial, as this will only be done by the Central Committee on Research Involving Human Subjects (CCMO) or a medical research committee. The CCMO will have an important coordinating role in assigning a study to a medical research committee or the CCMO and in the communication with other Member States in the case of a multinational trial [36]. Also, the ambitious shorter timelines for the evaluation process and the collaboration between different Member States for multinational trials are interesting new challenges which have to be dealt with by all Member States when the regulation comes into force in 2019 [36]. Time has to show if this regulation will indeed harmonize the procedures of the Member States without having any consequences on the number of trial applications and delay in the launching of a trial.
191 Clinical evaluation of broad-spectrum influenza vaccine
Finally, as described in Chapter 2, a mismatch between the circulating virus strains and vaccine strains occurs frequently resulting in a suboptimal IVE. In addition to other limitations of currently marketed influenza vaccines (e.g., yearly update, selection of vaccine strains based on HAI assays with ferret anti-sera, egg-based production), there is a quest for influenza vaccines that give the target population broad protection against multiple influenza virus strains. The protocol of a multicenter, randomized, double-blind, and placebo-controlled phase IIb trial to evaluate the immunogenicity and safety of such a vaccine is described in Chapter 7. Healthy volunteers aged 18-60 years were randomized 1:1:1 to receive two administrations of Multimeric-001 (M-001) at a low (0.5 mg) or high dose (1.0 mg) or saline as a placebo. All of the subjects received an investigational aluminum phosphate gel (AlPO4) adjuvanted pre-pandemic H5N1 influenza vaccine as a third administration. M-001’s potential as a standalone vaccine and to act as a primer for the investigational H5N1 vaccine was assessed. M-001 was proven to be safe and was able to increase CD4+ T-cells with both doses of 0.5 mg and 1.0 mg (Chapter 8).
M-001 was able to increase CD4+ IFN-γ +, IL-2+ and TNF-a+ cells which implies a T-helper 1 (Th1) cell response. These cytokines promote different mechanisms such as the production of antibodies via the activation of B-cells and they activate cytotoxic T lymphocytes [39]. Moreover, studies show that CD4+ T-cells might also act as antiviral cytotoxic T-cells themselves and, therefore, may have a direct effect [40,41]. In contrast to previous studies with M-001, we found no appreciable difference between the treatment groups in the induction of CD8+ T-cells, that are important for the direct killing of influenza virus-infected cells [42,43]. Though there appeared to be a small increase in antibody titers for the drifted H5N1 A/Turkey/ Turkey/1/2005 strain in individuals primed with M-001, no appreciable priming effect for the H5N1 investigational vaccine was observed. This low response might be explained by the low dose of hemagglutinin (3 µg instead of 6 µg in the marketed vaccine) in the investigational H5N1 vaccine. This may have resulted in insufficient induction of an immune response in the absence of memory responses to avian influenza strains.
Vaccines such as M-001 that induce a cellular immune response by targeting conserved internal influenza proteins may have the potential to mediate an immune response against several virus strains. Hence, such vaccines will not prevent an influenza infection but can play an important role in viral clearance and, therefore, in the reduction of influenza disease severity. Studies have shown that pre-existing virus-specific CD8+ T-cells in humans were correlated with less severe illness during the 2009 pandemic in the absence of cross reactive neutralizing antibodies [44]. Another study showed that CD4+ T-cells and not CD8+ T-cells activated by an earlier infection were associated with lower virus shedding and less severe illness in the absence of any detectable neutralizing antibodies [45]. This points out the ability of vaccines that target T-cells to protect against new seasonal and even future pandemic virus strains [46]. The induction of a Th1 response is especially important for elderly people since, with aging, a decline in Th1 relative to Th2 cytokine production occurs [47,48]. This
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shift is considered to be related with a decrease in the recruitment of cytotoxic T-cells and, consequently, an increased risk of influenza illness [39,47]. The stimulation of a Th1 response could, therefore, provide a more effective protection in older adults [47,48].
Future perspectives
In order for M-001 to be marketed as a broadly reactive (or universal) influenza vaccine further work has to be carried out. It should be proven that M-001 is able to reduce the incidences of influenza infections (clinical efficacy) and that the vaccine is able to induce a more durable, long-term, immune response [46]. In addition, its safety and immunogenicity among the target group for influenza vaccination should be proven. Moreover, in general, other issues still have to be clarified regarding the breadth of protection that has to be afforded by a ‘universal’ influenza vaccine, the regulatory pathway to licensure, and the evaluation methods of the immunogenicity and the clinical efficacy. Evaluation methods other than the HAI assay should be developed to assess immunogenicity since influenza vaccines that target conserved epitopes other than the HA globular head region of the influenza virus do not have any hemagglutination capacity. Furthermore, for the evaluation of the novel vaccines that mainly target the cellular immune response, new assays should be developed, and new correlates of protection need to be identified and validated.
The inclusion of an adjuvant in a universal influenza vaccine should be considered with caution. Novel vaccines which are currently being evaluated might need an adjuvant to enhance the immune response, however, our studies and the Pandremix® affair shows that a good safety evaluation is needed before such a vaccine can be marketed. The underlying mechanism of adverse events caused by adjuvanted vaccines is very complex.
When a ‘universal’ vaccine that can give the population broad protection against multiple influenza strains can be marketed, this will mean a breakthrough in influenza vaccine research and public health. The yearly prediction of circulating influenza strains for vaccine formulations and the yearly vaccination campaigns could belong to the past. Also, the time-dependent egg-production will no longer be needed since the egg-production of novel vaccines that are currently in the development pipeline are not egg-dependent [49]. For the pharmaceutical industry that produces the current registered influenza vaccines, this will mean that the production and sale strategies need to be changed. As some companies are already investigating, the development and/or production of universal influenza vaccines should be high on the priority list. The government should have an important role by stimulating the pharmaceutical industry to switch gears or to fund small and medium enterprises that produce universal influenza vaccines.
Most importantly, when a universal influenza vaccine can be marketed, it can further reduce the mortality and morbidity rates from influenza. Such a vaccine has the potential to substantially reduce the social and economic impact of influenza virus infections since it might protect the general population against both seasonal and pandemic influenza. However, to be able for a universal influenza vaccine to truly have this unprecedented large beneficial effect,
193 efforts should be continued to increase the influenza vaccination coverage. For example, in the Netherlands, vaccination coverage has been dropping by a few percent each year since the 2009 pandemic until even 50% in 2015 among the total target group for influenza vaccination [50]. The population should be accurately informed about the working mechanism of such a universal vaccine and the importance of vaccination (e.g., reduced risk of severe illness, complications, protection of vulnerable patients).
Current research on other administration routes of the influenza vaccine could also contribute to the increase in the vaccination coverage. Currently licensed vaccines and vaccines under development are mainly administered by the parenteral route (intramuscular, subcutaneous, or intradermal). Parenteral administration has several disadvantages, especially for third world countries, such as the need of trained healthcare workers, limited acceptance due to needle phobia, and the need for clean disinfected water for reconstruction of the vaccine [51-53]. The pulmonary delivery of an antigen might, for example, have several advantages over parenteral administration. The administration is non-invasive and it may induce, in contrast to parenteral administered vaccines, both local (mucosal) and systemic immune responses since the antigen is directly delivered at the ‘porte d’entrée’ of the pathogen. Therefore, the pulmonary delivery could best mimic the induction of the immune response in the respiratory tract after a natural infection by a pathogen [52,54]. Moreover, for influenza, the mucosal immune response may give broader protection rather than only inducing systemic immune response since mucosal antibodies are more cross reactive [55,56]. Therefore, for example, a universal influenza vaccine delivered by a dry powder inhaler that is cheap to manufacture and easy to use would be the ideal influenza vaccine; such an administration is currently under investigation [51]. A dry powder vaccine also does not need a cold-chain since dry powder formulations have increased stability and longer shelf life compared to liquid formulations. Most of the currently available influenza vaccines should be stored at 2 to 8 oC. However, when
the temperature is too high or too low, the vaccine might lose its potency due to damage to the vaccine content. Therefore, a cold chain should be organized to make sure that the vaccine is stored at the correct temperature from the manufacture until the point of vaccination [57,58]. However, this is especially a challenge in third world countries. When an influenza vaccine that does not need a cold chain can be marketed, this could contribute to the increase in the vaccination coverage and health equity [58].
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CONCLUSION
Both virological and methodological factors influence influenza vaccine effectiveness estimates when using the test-negative case-control study. These factors should be taken into account when estimating vaccine effectiveness and interpreting the estimates. The effectiveness of currently marketed influenza vaccines in the Netherlands is low, especially for the A(H3N2) influenza virus. Adjuvants could be used to increase efficacy, however, the inclusion of an adjuvant should be considered with caution because of the associated adverse events. To accurately address the safety of vaccine adjuvants and adjuvanted vaccines, appropriate trial designs including a large enough active control group and a standardized reporting system for adverse events are required. The frequent mismatch between the vaccine and circulating virus strains over the past decade in the Netherlands highlights the need for influenza vaccines that protect the target population against a broader spectrum of influenza virus strains. A universal influenza vaccine could make sure that the uncertainties in the process of the yearly prediction of the circulating strains, the selection of the vaccine strains, and egg-dependent production belong to the past. M-001 has the potential to mediate an immune response against several influenza viruses and, therefore, to cause a breakthrough in the influenza vaccine market and public health. However, further research is needed to assess M-001’s potential such as its clinical efficacy and the ability to induce a durable, long-lasting immune response.
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45. Wilkinson TM, Li CK, Chui CS, Huang AK, Perkins M, Liebner JC, et al. Preexisting influenza-specific CD4+ T cells correlate with disease protection against influenza challenge in humans. Nat Med 2012;18(2):274-280.
46. Kelso A. CD4+ T cells limit the damage in influenza. Nat Med 2012;18(2):200-202.
47. McElhaney JE. Influenza vaccine responses in older adults. Ageing Res Rev 2011;10(3):379-388.
48. Merani S, Pawelec G, Kuchel GA, McElhaney JE. Impact of Aging and Cytomegalovirus on Immunological Response to Influenza Vaccination and Infection. Front Immunol 2017;8:784.
49. Berlanda Scorza F, Tsvetnitsky V, Donnelly JJ. Universal influenza vaccines: Shifting to better vaccines. Vaccine 2016;34(26):2926-2933.
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50. Heins M, Hooiveld M, ten Veen P, Korevaar J. Vaccine coverage Dutch National Influenza Prevention Program2015: Brief monitor. Available at: http://www.rivm.nl/dsresource?objectid=ffce256d-9a2b-4c33-a7e8-f41150bc2b2c&type=PDF. Accessed September 1, 2017.
51. Sou T, Meeusen EN, de Veer M, Morton DA, Kaminskas LM, McIntosh MP. New developments in dry powder pulmonary vaccine delivery. Trends Biotechnol 2011;29(4):191-198.
52. Tonnis WF, Lexmond AJ, Frijlink HW, de Boer AH, Hinrichs WL. Devices and formulations for pulmonary vaccination. Expert Opin Drug Deliv 2013;10(10):1383-1397.
53. Giudice EL, Campbell JD. Needle-free vaccine delivery. Adv Drug Deliv Rev 2006;58(1):68-89. 54. Lu D, Hickey AJ. Pulmonary vaccine delivery. Expert Rev Vaccines 2007;6(2):213-226.
55. Tumpey TM, Renshaw M, Clements JD, Katz JM. Mucosal delivery of inactivated influenza vaccine induces B-cell-dependent heterosubtypic cross-protection against lethal influenza A H5N1 virus infection. J Virol 2001;75(11):5141-5150.
56. Asahi-Ozaki Y, Yoshikawa T, Iwakura Y, Suzuki Y, Tamura S, Kurata T, et al. Secretory IgA antibodies provide cross-protection against infection with different strains of influenza B virus. J Med Virol 2004;74(2):328-335.
57. WHO. How to monitor temperatures in the vaccine supply chain. July 2015; Available at: http://apps.who.int/iris/ bitstream/10665/183583/1/WHO_IVB_15.04_eng.pdf. Accessed September 1, 2017.
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SUMMARY
Vaccination is the most effective way to prevent influenza virus infections and related diseases. Currently, the influenza vaccine has to be updated annually due to antigenic drift of the virus. Despite the yearly update, the influenza vaccine effectiveness varies per season, per country, and even per influenza (sub)type/lineage. Efforts are being made to develop influenza vaccines that give the population broad protection against multiple influenza virus strains (a ‘universal’ influenza vaccine).
In Chapter 2, we estimated the influenza vaccine effectiveness over 11 seasons in the Netherlands using the test-negative design (TND) case-control study and investigated the effect of vaccine match status and circulating influenza virus (sub)types/lineages. In seven out of the 11 influenza seasons, the vaccine strains did not match the circulating strains. In general, the vaccine showed the highest protective effect when the vaccine strains matched with the circulating viruses and was particularly low when the vaccine did not match with the circulating viruses and when influenza A(H3N2) was the dominant virus subtype. Also, the control group used in the TND case-control study influences the influenza vaccine effectiveness estimate. In Chapter 3, we estimated the influenza vaccine effectiveness using all influenza negative patients (all patients tested negative for influenza virus infection), non-influenza virus positive patients (patients tested negative for influenza virus but positive for another respiratory virus), and pan-negative patients (negative for influenza and other respiratory viruses). We concluded that pan-negative patients seem less valid as a control group since a high proportion of patients in this group likely visits the general practitioner because of a non-infectious cause of influenza-like illness. Patients in this group were, on average, older and the prevalence of any chronic disease was higher compared to the cases and other control groups. The influenza vaccine effectiveness estimates when using non-influenza positive controls were more consistent with previous effectiveness studies and clinical trial data likely due to limiting controls without an infectious cause of a respiratory disease.
A strategy to increase the efficacy of an influenza vaccine is the incorporation of an adjuvant. However, the inclusion of an adjuvant should be justified and should have an acceptable balance between the beneficial effects on the immune response and the risk of local and systemic adverse events. In Chapters 4 and 5, we assessed the safety and tolerability of adjuvants that are currently being tested in pre-registration clinical trials for (universal) influenza vaccines. Based on the evaluated limited number of studies, we found no specific concern for the adjuvants Montanide ISA 51 TM (ISA 51), QS-21, and ISCOMATRIX, but we
advise caution especially when using ISA 51. This is based on the reported serious adverse events and premature termination of two controlled trials with healthy subjects using ISA 51. Studies have shown that the adverse events might be preventable to a certain extent with the proper mixing of the antigen with ISA 51 to a stable emulsion by using two-syringe mixing instead of vortex-mixing. We advised in both chapters that future studies evaluating adjuvanted-vaccines should include an active control group (only antigen or antigen with a licensed adjuvant) and that a standard coding system for adverse events should be used. This
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is recommended in order to accurately address the safety and tolerability of a vaccine adjuvant and to be able to present a complete overview of the occurrence and frequency of adverse events experienced by trial subjects.
Before a clinical trial can start, ethical and competent authority approval needs to be obtained. In Chapter 6, we assessed the differences in the ethical approval and competent authority authorization procedure for a vaccine trial under EU Directive 2001/20/EC in five European countries. We found differences among the countries in the documents that have to be submitted for the review procedures, the submission procedures themselves (e.g., digital, on paper, web-portal), language requirements of the documents, the organization of the ethics committee (e.g., national, regional, institutional), and the role of the competent authority in the approval procedure (marginal review vs. complete review). Especially for multicenter trials, it is difficult and expensive to carry out cross-border trials since a positive opinion is required from each Member State where a trial will be conducted. A more harmonized procedure, therefore, is desirable. Time has to show if the new clinical trial regulation will indeed harmonize these procedures among EU Member States.
Finally, Chapter 7 describes the protocol of a multicenter, randomized, double blind, and controlled phase IIb trial to evaluate the immunogenicity and safety of a universal influenza vaccine (Multimeric-001, M-001) both as a standalone vaccine and as a pandemic primer. Healthy volunteers aged 18-60 years were randomized 1:1:1 to receive two administrations of M-001 at a low (0.5 mg) or high dose (1.0 mg) or saline as a placebo. All of the subjects received an investigational aluminum phosphate gel adjuvanted H5N1 pre-pandemic influenza vaccine as a third administration. In Chapter 8, we showed that the vaccine was proven to be safe and able to increase CD4+ IFN-γ +, IL2+ and TNF-α+ cells after stimulation with influenza peptides. Such an elevation implies an influenza-specific T-helper 1 (Th1) cell response. In contrast to previous studies with M-001, no appreciable difference was found among the treatment groups in the CD8+ T-cell response. Though there appeared to be a small increase in antibody titers for a drifted H5N1 strain, no priming effect for the H5N1 investigational strain was found. The elevation in CD4+ T-cells indicate M-001’s potential to serve as a broad spectrum influenza vaccine since such an elevation is associated with lower virus shedding and less severe illness. Additional trials are needed to further assess M-001’s potential. Future studies should especially assess its ability to reduce the incidence of influenza infections.
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NEDERLANDSE SAMENVATTING
Vaccinatie is de meest effectieve manier om een influenzavirusinfectie en gerelateerde ziekten te voorkomen. Het influenzavaccin dient jaarlijks te worden aangepast doordat het virus continue verandert middels antigene drift. Ondanks de jaarlijkse aanpassingen, varieert de influenzavaccin effectiviteit per seizoen, per land en zelfs per influenza (sub)type/lijn. Er worden inspanningen verricht om influenzavaccins te ontwikkelen die de bevolking een bredere bescherming tegen een variatie aan influenzavirusstammen kunnen bieden (een universeel influenzavaccin).
In Hoofdstuk 2 hebben we de influenzavaccin effectiviteit over elf seizoenen in Nederland bepaald met behulp van het test-negatief patiënt-controle onderzoek. We hebben hierbij het effect van de vaccinmatch status en circulerende influenzavirus (sub)types/lijnen onderzocht. In zeven van de elf influenzaseizoenen was er sprake van een mismatch tussen het vaccin en het circulerende virustype. Over het algemeen liet het vaccin het beste beschermende effect zien als er sprake was van een vaccinmatch en was de effectiviteit met name laag wanneer er sprake was van een vaccinmismatch en wanneer influenza A(H3N2) het dominante influenzavirussubtype was. De controlegroep die wordt gebruikt in het test-negatief patiënt-controle onderzoek, beïnvloedt ook de influenzavaccin effectiviteit. In Hoofdstuk 3 hebben we de influenzavaccin effectiviteit bepaald met alle influenza-negatieve patiënten (alle patiënten met een negatief monster voor een influenzavirus infectie), niet-influenza virus positieve patiënten (patiënten met een negatief monster voor influenza maar positief voor een andere respiratoir virus) en pan-negatieve patiënten (patiënten met een negatief monster voor zowel influenza als andere respiratoire virussen). We concludeerden dat pan-negatieve patiënten minder geschikt zijn als controlegroep. Dit omdat een groot gedeelte van deze patiënten de huisarts waarschijnlijk bezoeken voor een niet-infectieuze oorzaak van een influenza-achtig ziektebeeld. De patiënten in deze controlegroep waren ouder en het aantal patiënten met een chronische ziekte was hoger in vergelijking met de cases en andere controlegroepen. De influenzavaccin effectiviteit schattingen zijn meer in lijn met eerdere effectiviteitstudies en klinische trialdata wanneer gebruik wordt gemaakt van niet-influenza positieve patiënten, waarschijnlijk door het beperken van controles zonder een infectieuze oorzaak van een respiratoire ziekte.
Een strategie om de werkzaamheid van een influenzavaccin te verhogen is het toevoegen van een adjuvant. Echter, de inclusie van een adjuvant dient te worden gerechtvaardigd en er dient sprake te zijn van een acceptabele balans tussen het gunstige effect op de immuunrespons en de lokale en systemische bijwerkingen. In Hoofdstukken 4 en 5 hebben we de veiligheid en verdraagbaarheid onderzocht van adjuvants die momenteel in klinische pre-registratie studies met (universele) influenzavaccins worden gebruikt. Op basis van het beperkte aantal geëvalueerde studies hebben we geen specifieke zorgen gevonden voor de geëvalueerde adjuvants Montanide ISA 51 (ISA 51), QS-21, en ISCOMATRIX maar we adviseren voorzichtigheid met name bij het gebruik van ISA 51. Dit vanwege de gerapporteerde serieuze bijwerkingen en de vroegtijdige beëindiging van twee gecontroleerde studies met gezonde vrijwilligers waarin
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ISA 51 werd gebruikt. Studies laten zien dat de bijwerkingen mogelijk te voorkomen zijn door het op een juiste manier mengen van het antigeen met ISA 51 tot een stabiele emulsie door het mengen met behulp van twee injectiespuiten in plaats van het mengen met behulp van een vortex. We adviseren in beide hoofdstukken dat toekomstige studies die geadjuveerde vaccins evalueren een actieve controlegroep dienen te includeren (alleen antigen of antigen met een adjuvant dat is opgenomen in een vaccin dat op de markt is) en een standaard coderingssysteem voor bijwerkingen dienen te gebruiken. Dit wordt aangeraden om op een correcte manier de veiligheid en verdraagbaarheid van een vaccin adjuvant te kunnen evalueren en om een compleet overzicht te kunnen presenteren van bijwerkingen die zijn opgetreden tijdens klinische studies en de frequentie daarvan.
Voordat een klinisch geneesmiddelenonderzoek uitgevoerd mag worden dient deze te worden goedgekeurd door een ethische commissie en de bevoegde instantie. In Hoofdstuk 6 hebben we de verschillen in de ethische goedkeuringsprocedure en autorisatieprocedure door de bevoegde instantie onderzocht voor een vaccinstudie onder de EU Richtlijn 2001/20/EC in vijf Europese landen. We hebben verschillen gevonden tussen de landen in de documenten die moeten worden ingediend voor de review procedures, de indieningsprocedure (digitaal, op paper, web-portaal), taalvereisten voor de documenten, de organisatie van de ethische commissie (nationaal, regionaal, institutionele), en de rol van de bevoegde instantie in de review procedure (marginale review vs. complete review). Met name voor multinationale studies is het lastig en duur om studies uit te voeren omdat een positief oordeel van elk land verkregen moet worden waar de klinische studie uitgevoerd zal worden. Een meer geharmoniseerd systeem is daarom wenselijk. De tijd zal het leren of de nieuwe klinische studie verordening daadwerkelijk de procedures in de EU-lidstaten zal harmoniseren.
Tot slot wordt in Hoofdstuk 7 een protocol beschreven voor een multicenter, gerandomiseerd, dubbelblind en gecontroleerd fase IIb onderzoek om de immunogeniciteit en veiligheid van een universeel griepvaccin (Multimeric-001, M-001) te evalueren als een alleenstaand vaccin en als een pandemische primer. Gezonde vrijwilligers van 18-60 jaar oud werden 1:1:1 gerandomiseerd om twee toedieningen van M-001 in een lage (0.5 mg) of hoge dosering (1.0 mg) te ontvangen, of zoutoplossing als placebo. Alle deelnemers ontvingen een aluminiumfosfaat gel geadjuveerd H5N1 pre-pandemisch influenzavaccin als derde toediening. In Hoofstuk 8 laten we zien dat het vaccin veilig is en in staat om is om CD4+ IFN-γ+, IL2+ en TNF-α+ cellen te laten toenemen na stimulatie met influenzapeptiden. Een dergelijke toename impliceert een T-helper 1 (Th1) cel respons. In tegenstelling tot eerdere studies met M-001 werd er geen duidelijk verschil gevonden tussen de studiegroepen in de CD8+ T-cel respons. Ondanks een kleine verhoging in de antilichaam titer voor een gedrifte H5N1 stam, werd er geen priming effect gezien voor de H5N1 studievaccinstam. De verhoging van CD4+ T-cellen laten de potentie van M-001 zien om als breedspectrum influenzavaccin te dienen omdat een dergelijke verhoging geassocieerd is met een lagere virus shedding en minder ernstige ziekte. Meer klinische studies zijn nodig om de potentie van M-001 verder te evalueren. Toekomstige studies dienen met name de mogelijkheid te onderzoeken of M-001 de incidentie van influenza infecties kan verlagen.
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DANKWOORD
Dit proefschrift is met hulp van velen tot stand gekomen. Allen die direct, indirect of zelfs onbewust hebben bijgedragen: Bedankt!
In het bijzonder:
Allereerst mijn promotoren prof. Hak en prof. Huckriede.
Prof. Hak, beste Eelko, bedankt voor de kans die je mij gegeven hebt om dit promotieonderzoek te mogen uitvoeren. Bedankt voor de dagelijkse begeleiding, je input en alle mogelijkheden die je mij tijdens het gehele promotietraject geboden hebt.
Prof. Huckriede, beste Anke, bedankt voor je waardevolle input waar ik altijd op kon rekenen. Prof. Wilffert, beste Bob, als begeleider van mijn masterthesis begon de start van mijn promotietraject bij jou. Bedankt voor je begeleiding, je oprechte interesse en dat je deur altijd open stond.
All members of the UNISEC-consortium for their input and nice informative meetings. All other partners of WP6 thatwere involved in the conduct of the clinical trials.
Marcy, thank you for our collaboration in the preparation of the clinical trials and other projects. Thanks a lot for your tips on writing scientific publications.
Atique, thanks for the statistical support in the last months.
Dr. Ben-Yedidia, dear Tammy, thanks a lot for the always pleasant collaboration, your patience and your trust in me to be a small part of the development of your product.
Denise, ik kon altijd bij je terecht voor vragen omtrent het reilen en zeilen van de klinische studies, om te brainstormen en om andere zaken te bespreken. Door jou heb ik onwijs veel geleerd over de verschillende aspecten van het klinisch onderzoek. Bedankt.
Prof. Frijlink, beste Erik, bedankt voor al je input als leider van het consortium en de kans die je mij hebt gegeven om mee te werken aan de first-in-man trial van de Twincer-Flu. Ik vind het jammer dat de studie uiteindelijk niet is doorgegaan, ik hoop dat dit in de toekomst nog gaat gebeuren (bel mij). Bedankt voor onze gesprekken en je altijd eerlijke en leerzame adviezen. Philip, veel mooie momenten hebben wij samen gehad bij de diverse congressen en meetings. Uiteraard ook op de universiteit waar wij alles bespraken in de koffiepauzes. Bedankt voor dit alles en veel succes met het afronden van jouw PhD.
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Alle coauteurs buiten het UNISEC-consortium: Dr. Adam Meijer, Emilia Bigaeva, Frederika Dijkstra, Dr. Gé Donker, Laura Cadenau, Dr. Maarten Bijlsma, Marit de Lange, Dr. Maryam Darvishian en Pieter Overduin. Bedankt voor de samenwerking en de bijdragen aan de artikelen in dit proefschrift.
Prof. van der Werf, beste Tjip, bedankt voor de plezierige samenwerking en de ‘klinische lessen’ die ik van je gekregen heb als ik bij je langskwam voor overleg over de Twincer-Flu. Ik heb dit altijd zeer gewaardeerd. Erg fijn dat je alle tijd nam om deze studie met mij voor te bereiden voor de kliniek.
Feikje en Marjan, bedankt voor de fijne samenwerking. Hopelijk volgt de publicatie.
Collega’s van de afdeling FarmacoTherapie, -Epidemiologie & -Economie, bedankt voor de plezierige werksfeer, weird food festivals, afdelingsuitjes, acteersessies bij GIMMICS, etc. Pepijn, bedankt voor je quotes, filmpjes, politieke verhalen en perikelen, inzichten en brainstormsessies. Je tips en trucs over het uitvoeren van onderzoek, artikelen schrijven en de omgang met collega’s. Niet te vergeten de chocoladekoeken en je eigen gebakken taarten. Dit alles was altijd een zeer welkome afleiding tijdens de onderzoeksdagen en heb ik zeer gewaardeerd.
Jurjen, we hebben samen een mooie tijd op de afdeling gehad. In het bijzonder de laatste maanden toen we in dezelfde kamer werkten aan het laatste deel van onze onderzoeken. Bedankt voor het samen brainstormen, je luisterend oor met regelmatig wijze raad en ook voor je gezelligheid, de mooie trip in Ierland, de (vrijdagmiddag) borrels en dat je mij appelcider hebt leren maken.
Thea, we hebben kort met elkaar op de kamer gewerkt en gelukkig zat je daarna niet ver weg. Bedankt voor je blijvende interesse in mijn onderzoek en alles daarbuiten.
Lisette, jammer dat de tijd samen op de afdeling kort was. Bedankt voor alle leuke momenten op de afdeling en ook voor het windsurfen, de feestjes en alle andere momenten.
Christiaan, dankzij jou mag ik mij ook een “R-pro” noemen. Bedankt voor je technische hulp, de borrels, de boevengym, het hardlopen, je afleiding en praatjes.
Annemiek en Ryanne, bedankt voor jullie vriendschap en dat jullie tijdens mijn verdediging naast mij staan.
207 Merel en Bob, bedankt voor het relativeren en het in perspectief zetten van “mijn stage”. Ondanks dat jullie het niet helemaal begrepen waar ik de afgelopen jaren mee bezig was, bedankt voor de moeite die jullie hebben genomen om het te begrijpen.
Merel, bedankt voor alle input over hoe dit proefschrift er nu uiteindelijk uitziet.
Pap en mam, voor jullie was het ook niet altijd precies duidelijk wat ik deed tijdens mijn onderzoek. Bedankt voor alle moeite die jullie gedaan hebben het te begrijpen. Pap, bedankt voor het doorlezen van alle stukken in de loop der jaren. Bedankt dat jullie altijd achter mij staan, voor jullie onvoorwaardelijke support en blijk van trots.
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CURRICULUM VITAE
Eva van Doorn (1990) was born in the Noordoostpolder, the Netherlands. After finishing secondary education and studying Dutch law for a year she started to study Pharmacy at the University of Groningen in 2009. She obtained her master’s degree in Pharmacy in 2016 with honors. The last year of her Master’s degree she combined with a research position at the Department of PharmacoTherapy, -Epidemiology & - Economics. The research was conducted within the European Union funded Universal Influenza Vaccines Secured (UNISEC) project that aimed at the development and evaluation of different universal influenza vaccine concepts. The focus of her research was the clinical evaluation of two universal influenza vaccine concepts and the evaluation of the effectiveness of currently available influenza vaccines.
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LIST OF PUBLICATIONS
2017
[Effectiveness of influenza vaccine in the Netherlands: predominant circulating virus type and vaccine match are important conditions]. E. van Doorn, M. Darvishian, F. Dijkstra, M.J. Bijlsma, G.A. Donker, M.M.A. de Lange, L.M. Cadeau, E. Hak, A. Meijer. Ned Tijdschr
Geneeskd. 2017; 161:D1648.
Influenza vaccine effectiveness estimates in the Dutch population from 2003 to 2014: The test-negative design case-control study with different control groups. E. van Doorn, M. Darvishian, F. Dijkstra, G.A. Donker, P. Overduin, A. Meijer, E. Hak. Vaccine. 2017; 35(21):2831-2839. Evaluation of the immunogenicity and safety of different doses and formulations of a broad spectrum influenza vaccine (FLU-v) developed by SEEK: study protocol for a single-center, randomized, double-blind and placebo-controlled clinical phase IIb trial. E. van Doorn, O. Pleguezuelos, H. Liu, A. Fernandez, R. Bannister, G. Stoloff, F. Oftung, S. Norley, A. Huckriede, H.W. Frijlink, E. Hak. BMC Infect Dis. 2017; 17(1): 241.
Evaluating the immunogenicity and safety of a BiondVax-developed universal influenza vaccine (Mulitmeric-001) either as a standalone vaccine or as a primer to H5N1 influenza vaccine: Phase IIb study protocol. E. van Doorn, H. Liu, T. Ben-Yedidia, S. Hassin, I. Visontai, S. Norley, H.W. Frijlink, E. Hak. Medicine. 2017; 96(11):e6339.
Influenza Vaccine Effectiveness in the Netherlands from 2003/2004 through 2013/2014: The Importance of Circulating Influenza Virus Types and Subtypes. M. Darvishian, F. Dijkstra, E.
van Doorn, M.J. Bijlsma, G.A. Donker, M.M. de Lange, L.M. Cadenau, E. Hak, A. Meijer. PLoS
One. 2017; 12(1):e0169528.
2016
Influenza Vaccine Research funded by the European Commission FP7-Health-2013-Innovation-1 project. H. Liu, H.W. Frijlink, A. Huckriede, E. van Doorn, E. Schmidt, O. Leroy, G. Rimmelzwaan, K. McCullough, M. Whelan, E. Hak. Vaccine. 2016; 34(48):5845-5854. Safety and tolerability of evaluation of the use of Montanide ISATM 51 as vaccine adjuvant: A
systematic review. E. van Doorn, H. Liu, A. Huckriede, E. Hak. Hum Vaccin Immunother. 2016; 12(1): 159-169.
Meta-Analysis on Randomized Controlled Trials of Vaccines with QS-21 or ISCOMATRIX Adjuvant: Safety and Tolerability. E. Bigaeva, E. van Doorn, H. Liu, E. Hak. PLoS One. 2016; 11(5):e0154757.
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2015
National Differences in Requirements for Ethica land Competent Authority Approval for a Multinational Vaccine Trial under the EU Directive 2001/20/EC. E. van Doorn, E. Hak, B. Wilffert. Vaccines. 2015; 3(2): 263-292.
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RESEARCH INSTITUTE SHARE
This thesis is published within the Research Institute SHARE (Science in Healthy Ageing and healthcaRE) of the University Medical Center Groningen / University of Groningen. Further information regarding the institute and its research can be obtained from our internetsite: http://www.share.umcg.nl/
More recent theses can be found in the list below. ((co-) supervisors are between brackets)
2017
Most PJ van der
Development of bioinformatic tools and application of novel statistical methods in genome-wide analysis
(prof H Snieder, Prof P van der Harst, dr IM Nolte)
Fleurke-Rozema H
Impact of the 20-week scan
(prof CM Bilardo, prof E Pajkrt, dr RJM Snijders)
Schripsema NR
Medical students selection; effects of different admissions processes
(prof J Cohen-Schotanus, prof JCC Borleffs, dr AM van Trigt)
Ven HA van de
Shift your work; towards sustainable employability by implementing new shift systems
(prof JJL van der Klink, prof MP de Looze, prof U Bültmann, prof S Brouwer)
Hoekstra F
ReSpAct: Rehabilitation, sports and active lifestyle
(prof LHV van der Woude, prof CP van der Schans, dr R Dekker, dr FJ Hettinga)
De Carvalho Honorato T
Diminished ovarian reserve and adverse reproductive outcomes
214
Olthof M
Patient characteristics related to health care consumption; towards a differentiated capitation model
(prof SK Bulstra, prof MY Berger, dr I van den Akker-Scheek, dr M Stevens)
Bessem B
The young athlete’s heart; an electrocardiographic challenge
(prof J Zwerver, prof MP van den Berg, dr W Nieuwland)
Husarova D
Barriers to active participation of school-aged children
(prof SA Reijneveld, prof A Madarasova-Geckova, dr JP van Dijk)
Schenk HM
Affect and physical health; studies on the link between affect and physiologiocal processes
(prof JGM Rosmalen, prof P de Jonge, prof JPJ Slaets)
Wilk AD van der
Patient centered development and clinical evaluation of an ankle foot orthosis
(prof GJ Verkerke, prof K Postema, dr JM Hijmans)
Koorevaar R
Psychological symptoms and clinical outcome after shoulder surgery
(prof SK Bulstra)
Beijersbergen CMI
Effects of lower extremity power training on gait biomechanics in old adults; the Potsdam Gait Study (POGS)
(prof T Hortobagyi, prof P DeVita, prof U Granacher)
Islam Md A
Statistical approaches to explore clinical heterogeneity in psychosis
(prof ER van den Heuvel, dr R Bruggeman, dr BZ Alizadeh)
Dallinga JM
Injury prevention in team sport athletes
215
Geboers BJM
Understanding the role of health literacy in self-management and health behaviors among older adults
(prof SA Reijneveld, prof CJM Jansen, dr AF de Winter)
Zult TD
Inter-limb mechanisms and clinical relevance of cross-education in humans
(prof T Hortobagyi, prof G Howatson, dr CAT Zijdewind, dr JP Farthing)
