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Safety and immunogenicity of influenza whole inactivated virus vaccines: A phase I randomized clinical trial a

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b

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Renée A.J. Van Boxtel , Pauline Verdijk , Otto J. De Boer , Elly Van Riet , Tjeert T. c

Mensinga & Willem Luytjes

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Centre for Infectious Diseases Control; National Institute for Public Health and the Environment (RIVM); P.O. Box 1, 3720 BA Bilthoven, the Netherlands, , b

Institute for Translational Vaccinology (Intravacc), P.O. Box 450, 3720 AL Bilthoven, the Netherlands, , , c

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QPS, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands, Accepted author version posted online: 09 Mar 2015.

To cite this article: Renée A.J. Van Boxtel, Pauline Verdijk, Otto J. De Boer, Elly Van Riet, Tjeert T. Mensinga & Willem Luytjes (2015): Safety and immunogenicity of influenza whole inactivated virus vaccines: A phase I randomized clinical trial, Human Vaccines & Immunotherapeutics To link to this article: http://dx.doi.org/10.1080/21645515.2015.1012004

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Short title:

Phase I trial with Influenza whole inactivated virus vaccines

Safety and Immunogenicity of Influenza Whole Inactivated Virus Vaccines: A Phase I Randomised Clinical Trial

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Renée A.J. van Boxtel1, Pauline Verdijk2, Otto J. de Boer2*, Elly van Riet2, Tjeert T. Mensinga3, Willem Luytjes1

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Centre for Infectious Diseases Control; National Institute for Public Health and the

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Environment (RIVM); P.O. Box 1, 3720 BA Bilthoven, the Netherlands, [email protected], [email protected]

Institute for Translational Vaccinology (Intravacc), P.O. Box 450, 3720 AL

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Bilthoven, the Netherlands, [email protected], [email protected]

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[email protected]

QPS, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands,

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[email protected]

Corresponding author: Otto de Boer, Institute for Translational Vaccinology P.O.

Box

450,

3720

AL

Bilthoven,

The

Netherlands,

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(Intravacc),

[email protected], Ph: +31 30 274 2923

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The authors have no conflict of interest. 1.

Abstract

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BACKGROUND: Influenza vaccine production capacity is still insufficient to meet global demand in case of a pandemic. To expand worldwide influenza vaccine production capacity, a solid and transferable egg-based influenza vaccine production process was established that is suitable for upscaling and technology transfer to vaccine manufacturers in low- and middle-income countries. As a proof-of concept,

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the safety and immunogenicity of a pandemic whole inactivated virus (WIV) vaccine (H5N1) and a monovalent seasonal WIV vaccine (H3N2) were evaluated in a phase I clinical trial in adults. METHODS: Subjects were vaccinated with two doses of pandemic WIV vaccine (pWIV), or one dose of either seasonal WIV vaccine (sWIV)

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or a commercially available trivalent comparator followed by a placebo dose. Haemagglutination inhibiting antibody titres against the influenza strains were

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severity of adverse reactions were comparable between groups. No serious adverse

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events were reported. After a single dose of sWIV the seroconversion rate was 91%

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(Committee for Proprietary Medicinal Products (CPMP) criterion >40%), the seroprotection rate was 100% (CPMP criterion >70%), and the mean geometric mean

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titre (GMT) increase was 24.9 (CPMP criterion >2.5). After two doses of pWIV, seroconversion rate and seroprotection rate were both 71%, and the mean GMT

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increase was 7.8. CONCLUSIONS: Both pWIV and sWIV were equally welltolerated as the comparator vaccine, and both vaccines complied with all three CPMP

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criteria. EudraCT 2006-003448-40. Netherlands National Trial Register 2695. Keywords: Influenza, whole inactivated virus vaccine, pandemic, seasonal, safety,

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immunogenicity, phase I trial

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determined before and 21 days after each vaccination. RESULTS: The frequency and

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2.

INTRODUCTION

Influenza seasonal epidemics continue to be a major cause of high morbidity and mortality worldwide1-3. Currently, vaccination against influenza remains the most effective measure for reducing the impact of influenza virus infection2-5. In addition,

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the 2009 influenza H1N1 pandemic has shown that with modern levels of global travel as well as urbanization, and overcrowded conditions, a new influenza virus is

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The threat of an imminent influenza pandemic has been felt closely, since in 1997 a highly pathogenic avian influenza A (H5N1) virus became infectious in humans. It

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triggered World Health Organization (WHO) to evaluate pandemic preparedness, eventually resulting in the Global Pandemic Influenza Action Plan (GAP) initiated by

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WHO in 20067. At that time, estimated worldwide vaccine production capacity for influenza vaccines was 350 million doses per year8. Currently, influenza vaccine

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production capacity is still insufficient to meet global demand in case of a pandemic. Major influenza vaccine producers operate and supply largely in Europe and North

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America. During a pandemic, unavailability of a vaccine would put the majority of

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the population in low- and middle-income countries, mostly in Africa, Middle-East and Asia, seriously at risk of a high death toll and morbidity burden. WHO currently estimates worldwide production capacity for pandemic vaccines at 3 billion doses per

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able to quickly take hold around the world6.

year9, which will be quite inadequate to cover a world population of 6.8 billion people in which virtually everyone is susceptible to infection by a new and readily contagious virus. The main objective of GAP is to increase the supply of pandemic influenza vaccine, and thereby reduce the current gap between demand and supply that is anticipated during an influenza pandemic5,

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. One of the approaches is to

expand worldwide influenza vaccine production capacity by transfer of influenza 3

vaccine production technology to low- and middle-income countries. Netherlands Vaccine Institute1 (NVI), now Intravacc, has been selected by WHO in 2007 to establish an expertise centre (“hub”) for technology transfer of all aspects of production and quality control of influenza vaccines within an International

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Technology Platform for Influenza Vaccines (ITPIV)11. Primary objective of the ITPIV project is to increase availability and affordability of

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technology that is needed to establish their own production facilities. As it is not economically feasible for manufacturers to focus only on production of vaccines that

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are needed in the occasional event of an influenza pandemic, the technology to be transferred should also be applicable for production of seasonal influenza vaccines. A

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solid and transferable egg-based influenza vaccine production process was established, that is suitable for upscaling, and technology transfer to vaccine

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manufacturers in low- and middle-income countries meeting WHO defined quality/viability criteria, and in compliance with WHO guidelines, as outlined in the

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recommendations for the production and control of influenza vaccine12, and the standards published in the European Pharmacopoeia (5th Edition, 01/2005). The use of

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the egg-based production method was chosen at the request of WHO, for which the reasons as well as the possible limitations and logistic aspects have been described and discussed elsewhere11.

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(pandemic) influenza vaccines for low- and middle-income countries by transferring

Although most vaccine manufacturers nowadays produce split virus or subunit influenza vaccines, in this study a whole inactivated virus (WIV) vaccine was

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In 2011 and 2012, the research and development department of NVI was part of the National Institute of Public Health and the Environment (Dutch acronym: RIVM). Since the 1st of January 2013 this part of the RIVM formed a new Institute for Translational Vaccinology (Intravacc). 4

developed instead. This decision was guided by the main purpose of the ITPIV project to set up an affordable and robust production process for a potent influenza vaccine, being less complicated to produce and without the need for addition of adjuvants. A production process without splitting, further purification and adjuvation procedures

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has a number of beneficial consequences including a decrease in number of production steps and corresponding analytical tests required and thus a shorter

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did not differ between split and WIV vaccines when produced at pilot scale. Besides

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the benefits of a simpler and shorter production process, evidence exists that immunogenicity induced by WIV vaccines is superior to split virus or subunit

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and viral RNA16,

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. In addition, virus

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nature of whole virus particles16,

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vaccines, especially in the naive human population13-15, likely due to the adjuvating

inactivation was performed with beta-propiolactone (BPL) instead of formalin to

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preserve the fusion activity of the virus which is associated with immunogenicity in the mouse model21. Using the production process developed in the technology transfer

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project, two WIV vaccines were produced, one with a prototype pandemic influenza strain and one with a seasonal influenza strain. In the phase I study presented here the

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safety and immunogenicity of these WIV vaccines were investigated to establish proof-of-concept and to explore whether the criteria for acceptance of influenza vaccines according to the European Agency for the Evaluation of Medicinal Products

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production time and lower production costs. In our laboratory, product consistency

were met.

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RESULTS 3.1.

Subject disposition

In total, 170 subjects were screened, of which 120 subjects fulfilled all inclusion criteria and were randomized either to pWIV (30 subjects), sWIV (60 subjects) or

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seasonal split comparator vaccine (30 subjects) (Fig. 1). All eligible subjects received the first vaccination and were included in the safety evaluation. Because of two drop-

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58 subjects in the sWIV group, and 28 subjects in the pWIV group (Fig. 1). No subjects discontinued the study due to an adverse event. No major differences in age,

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gender or Body Mass Index (BMI) were observed between the different treatment

3.2.

Safety

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groups (Table 1).

Solicited local and systemic adverse events during the first five days following each

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vaccination are shown in Table 2. In the pWIV group, occurrence of at least one

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solicited local reaction was reported by 24 subjects (80%) after the first, and by 13 subjects (46%) after the second vaccination. In the sWIV group and the comparator

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vaccine group, at least one local reaction occurred in 47 subjects (78%) and 21 subjects (70%), respectively. After placebo injection the occurrence of at least one local reaction was significantly lower: 4 subjects (13%) in the comparator group and

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outs in each WIV group, immunogenicity evaluation was performed with data from

10 subjects (17%) in the sWIV group respectively (Table 2). In all groups the most frequent reported local reaction was pain at injection site, followed by reduced movement of the injected arm. Almost all local adverse events were of mild or moderate intensity. Of five subjects reporting induration, one also reported swelling of severe intensity (≥ 5cm) after sWIV vaccine administration, which had completely 6

resolved on day 2 in both cases. The majority of local reactions in all groups resolved within 3 days. Injection site swelling and erythema were less often reported in sWIV and pWIV groups than in the comparator vaccine group (p-values

Safety and immunogenicity of influenza whole inactivated virus vaccines: A phase I randomized clinical trial.

Influenza vaccine production capacity is still insufficient to meet global demand in case of a pandemic. To expand worldwide influenza vaccine product...
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