de Pijper-Reus, C.A.

English

In this thesis, two viral diseases are discussed in two separate parts, namely Zika and rabies virus. Both diseases are of military importance to prevent losing strength of manpower. As the title implies: Quis custodiet ipsos custodes? (Who guards the guardians?), if we can protect our military personnel, then they will protect us. The general introduction starts with a history of military losses, 75% of which are caused by disease and non-battle injuries, where preventive measures can be applied to lower their number. In this thesis, for both diseases, measures are available to prevent contracting the disease. Apart from research on preventing infection by both viruses, clinical aspects are also topic of this thesis. So, we reviewed severe thrombocytopenia as a rare, but very serious complication of ZIKV infection, and, we reported two fatal cases of clinical rabies virus infected patients in our center, who deceased despite all treatment efforts, including the intravenous and intrathecal administration of monoclonal antibodies. A lot of attention is paid to preventive measures in military training and pre-deployment lessons. To avoid mosquito bites, the Ministry of Defense provides impregnated clothing, mosquito nets, and insect repellent. Military personnel are vaccinated against rabies before deployment in endemic areas, and known what actions to take after a bite. If we, medical doctors, take good care of our soldiers, they will take good care of us, as reflected in the title of this thesis: Quis costodiet ipsos custodes?, which can be freely translated from Latin into: “Who protects our protectors?

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UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl)UvA-DARE (Digital Academic Repository)Quis custodiet ipsos custodes?Who guards our guardians?de Pijper-Reus, C.A.Publication date2022Link to publicationCitation for published version (APA):de Pijper-Reus, C. A. (2022). Quis custodiet ipsos custodes? Who guards our guardians?[Thesis, fully internal, Universiteit van Amsterdam].General rightsIt is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s)and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an opencontent license (like Creative Commons).Disclaimer/Complaints regulationsIf you believe that digital publication of certain material infringes any of your rights or (privacy) interests, pleaselet the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the materialinaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letterto: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. Youwill be contacted as soon as possible.Download date:14 Apr 2023Antibody response in Dutch marines to a single intramuscular rabies booster immunization 1–2.5 years after an intradermal pre-exposure schedule: An observational studyCHAPTER 7Cornelis A. De Pijper, Sanne Terryn, Steven Van Gucht, Martin P. Grobusch, Abraham Goorhuis, Cornelis StijnisTravel Medicine and Infectious Disease 38 (2020) 101907https://doi.org/10.1016/j.tmaid.2020.101907Background.Prompt administration of post-exposure rabies prophylaxis (PEP) is lifesaving. We measured the anamnestic rabies antibody response to a single intramuscular booster immunization, administered 1 - 2.5 years after intradermal pre-exposure prophylaxis (PrEP).Methods. This observational study is a follow-up of the MARINE-study in which the immunogenicity of three-visit-one-dose intradermal PrEP among Dutch military personnel was assessed. In this study, we measured antibody titers before, and on days 7 and 14 after a single intramuscular booster immunization for personnel deployed to rabies-endemic areas. Results.Among all 24 subjects, had adequate titers on day 7 (geometric mean titer: 18.58 IU/mL). The study had to be terminated before completion (125 planned subjects), in compliance with an updated Dutch military guideline (based on the WHO rabies update), precluding the indication for booster immunization in this group. Conclusion. The study shows that anamnestic immune responses (“boostability”) were excellent after one and 2/2.5 years after intradermal PrEP administration.AbstractMaraboo study: boostability after intradermal PrEP   |   147 71. INTRODUCTIONDear Editor, in 2018, we published our article on immunogenicity data after two intradermal (ID) rabies immunizations [1]. We followed this cohort for their planned booster immunization. The aim of this follow-up study was to assess the rabies booster response (‘boostability’) measured one year after the three-visit-one-dose ID pre-exposure prophylaxis (PrEP)-schedule.Later in 2018, Soentjens et al. published a study that showed that the booster immunization one to three years after a three-visit-one-dose and an alternative two-visit-two-dose ID PrEP-schedule led to excellent booster responses 7 days after re-immunization [2]. Partly based on these data, a new WHO guideline was issued in 2018, followed by a similar adaptation of Dutch national and military guidelines, in which standard booster immunization after PrEP was no longer advised [3]. This led to premature termination of our study, before completion of the planned enrollment of 125 study subjects. More about the background and change of policy in the Dutch Ministry of Defense (MOD) during the study can be found in the Supplementary Materials file.2. MATERIAL AND METHODSThis observational study is a follow-up of the MARINE-study in which the immunogenicity of three-visit-one-dose intradermal PrEP among Dutch military personnel was assessed. In this study, we measured antibody titers before, and on days 7 and 14 after a single intramuscular (IM) booster immunization for personnel deployed to rabies-endemic areas. An extensive Materials and Method section can be consulted in the Supplementary Materials file.148   |   Chapter 73. RESULTSIn total, we included 24 military participants for a booster after 1 and 2/2.5 years after PrEP, namely 17 and seven subjects, respectively. Two subjects left the study before day 7, and six subjects before day 14, due to operational deployment. The results of the latter six subjects could still be used for day 7 data analysis. No AE or SAE were reported. Baseline characteristics are depicted in the Table provided as Supplementary Materials. Before booster immunization, all subjects with a 1-year interval had antibody titers above 0.5 IU/mL, in contrast to the subjects with an interval of 2/2.5 years, of which only 42.9% had adequate level of antibodies. All subjects had adequate rabies antibodies (≥0.5 IU/mL) on day 7 after booster immunization, with a GMT of 18.58 IU/mL and 95% CI of 12.44–28.02 IU/mL. The GMT on day 7 was 25.50 IU/mL for those with a 1-year interval between initial PrEP and booster immunization, and 9.43 IU/mL for those with a 2/2.5-year interval. After 14 days, titers increased in all subjects to levels above 10 IU/mL, with a GMT of 86.46 IU/mL. All immunogenicity data are shown in Table 1. A Figure is included in the Supplementary Materials visualizing the data.Table 1. Rabies immunogenicity data per point-in-time.Interval (years) Day N≥0.5 IU/mLa N GMTb 95% CIb Rangeb ≥3.0 IU/mL≥10.0 IU/mLPooled 0 24 83.3 20 2.73 1.77–4.21 0.52–31.04 37.5% 4.2%1 17 100 17 2.79 1.67–4.65 0.52–31.042/2.5 7 42.9 3 2.41 0.80–7.21 1.47–3.45Pooled 7 22 100 22 18.58 12.33–28.02 1.87–116.06 95.5% 81.8%1 15 100 15 25.50 15.95–40.77 3.73–116.062/2.5 7 100 7 9.43 4.79–18.60 1.87–14.13Pooled 14 16 100 16 86.46 54.03–138.36 18.04–381.57 100% 100%1 11 100 11 129.18 78.78–211.79 31.73–381.572/2.5 5 100 5 35.74 22.20–57.53 18.04–44.38Abbreviations: CI = confidence interval; GMT = geometric mean titer; IU/mL = international units per milliliter.a Adequate titers in percent.b In subjects with adequate titers (≥0.5 IU/mL) in international units per milliliter.Maraboo study: boostability after intradermal PrEP   |   149 74. DISCUSSIONThe results of this prematurely terminated study show that within seven days after the rabies booster immunization, the anamnestic rabies antibody response (boostability) resulted in adequate titers of all participants, with a high GMT of 18.58 IU/mL. Our results, with small numbers, are in accordance with boostability data in Belgian military personnel published in 2018. In that study, a different ID PrEP-schedule (two-visit-two-dose) resulted in 100% adequate antibody response 1–3 years after administration of 0.1 mL ID booster immunization [2].In our study, adequate pre-booster antibody titers were present in all participants with a 1-year interval between PrEP and booster immunization, whereas this was the case in only 3/7 (43%) of those with a 2/2.5-year interval. In the meta-analysis of Langedijk et al., similar prebooster results were seen in the included ID PrEP studies [4]. However, this finding did not impact significantly on the strength of the booster response, as all seroconverted to adequate levels within a week, regardless of route of administration, as was seen in our study. One case-report has been published in which a previously vaccinated individual did not receive PEP after exposure and died [5]. This reflects the need for PEP booster immunization in all exposed individuals that previously received PrEP.Whilst this cohort is very small due to early study termination, data are in support of previously published results. In the Netherlands, PEP consists of two IM immunizations on days 0 and 3 in previously vaccinated persons, instead of the one IM booster administered in our study. Therefore, even higher titers may be expected in individuals that receive a two-dose PEP according to WHO, national and military guidelines [3]. In this study, Verorab® vaccine was used in the initial PrEP, while Rabipur® was used as booster immunization due to availability of vaccines at the time of the study in the MOD. This interchangeability is in accordance with WHO recommendations regarding the use of different brands of rabies vaccine within a single PrEP or PEP administration [3].5. CONCLUSSIONIn conclusion, the immunogenicity data of all participants show an anamnestic individual response (“boostability”) within seven days after one and 2/2.5 years after a three-visit-one-dose intradermal injection. Our results are consistent with similar studies on boostability after two-visit-two- dose ID PrEP [2]. Thus, different intradermal PrEP-schedules appear to be a safe alternative to intramuscular PrEP. ID immunization is valuable when less vaccine antigen is available, and costs can be reduced to one third compared to IM. Hopefully, this will lead to a higher number of PrEP immunizations in travelers. As no rabies immune globulin (RIG) is indicated in PEP-treatment after previous PrEP, travelers can be treated easily at their destination once bitten, and less RIG will be required on a national level.150   |   Chapter 7Author contributionThe study was designed by CADP, CS, AG and MPG; CADP conducted the study. The RFFIT was performed by ST and SVG; CADP drafted the first version of the manuscript; all authors critically revised the draft and approved the final version of the manuscript for submission.FundingThis work was approved by the Ministry of Defense, The Netherlands. The National Reference Center of Rabies is partially supported by the Belgian Ministry of Social Affairs through a fund from the Health Insurance System (https://nrchm.wiv-isp.be/default.aspx).Ethics approval and consent to participateThe study protocol was approved by the local Medical Research Ethics Committee of the Academic Medical Center (AMC, Amsterdam, The Netherlands) under NL59466.018.16 2016_276 and Dutch MOD under DGO111116010. All participants provided a written informed consent before enrollment.Declaration of competing interestThe authors declare no conflict of interest.AcknowledgmentsThe authors acknowledge the Ministry of Defense of his approval, the military nurses for their help with patient enrollment, and all military participants for their commitment to the study. We thank the AMC methodology and AMC statistical unit for their consultation.Supplementary dataSupplementary data to this article can be found online at https://doi.org/10.1016/j.tmaid.2020.101907.NoteMaraboo study: boostability after intradermal PrEP   |   151 7REFERENCES 1.  De Pijper CA, Boersma J, Terryn S, Van Gucht S, Goorhuis A, Grobusch MP, Stijnis C. Rabies antibody response after two intradermal pre-exposure prophylaxis immunizations: an observational cohort study. Trav Med Infect Dis 2018;22:36–9. https://doi.org/10.1016/j.tmaid.2018.03.006.2.  Soentjens P, Andries P, Aerssens A, Tsoumanis A, Ravinetto R, Heuninckx W, Van Loen H, Brochier B, Van Gucht S, Van Damme P, Van Herrewege Y, Bottieau E. Preexposure intradermal rabies vaccination: a noninferiority trial in healthy adults on shortening the vaccination schedule from 28 to 7 days. Clin Infect Dis 2019;68 (4):607–14. https://doi.org/10.1093/cid/ciy513.3.  World Health Organization. WHO expert consultation on rabies: third report: WHO Technical Report Series No. 1012. https://www.who.int/publications-detail/WHOTRS- 1012; 2018.4. Langedijk AC, De Pijper CA, Spijker R, Holman R, Grobusch MP, Stijnis C. Rabies antibody response after booster immunization: a systematic review and meta-analysis. Clin Infect Dis 2018;67:1932–47. https://doi.org/10.1093/cid/ciy420.5.  Bernard KW, Fishbein DB, Miller KD, et al. Pre-exposure rabies immunization with human diploid cell vaccine: decreased antibody responses in persons immunized in developing countries. Am J Trop Med Hyg 1985;34:633–47. https://doi.org/10.4269/ajtmh.1985.34.633.152   |   Chapter 7SUPPLEMENTARY DATABackground: Change MOD: Change of policy during the study timeExtended Materials en Methods sectionTable: S1: Study population demographics and characteristics at baselineFigure: S1: Individual titers of all participants and Geometric Mean Titer in subjects with adequate titer per point-in-time.1. BACKGROUND CHANGE MOD CHANGE OF POLICY DURING THE STUDY TIME Rabies is an important topic in the disease prevention program of the Dutch Ministry of Defense (MOD). Rabies pre-exposure prophylaxis (PrEP) is routinely administered to military personnel deployed to endemic regions, and at start of this study consisted of three immunizations (administered on days 0, 7, and between days 21 and 28. A booster immunization was preferably administered at one-year post-PrEP, to extend the presumed interval of protection. When this routine booster had been missed, it was administered later, before the next deployment to a rabies-endemic region. The only MOD-approved route of administration (ROA) of rabies vaccine administration was the intramuscular (IM) route.In 2015, a nationwide vaccine shortage occurred, leading the MOD to approve intradermal (ID) ROA in a group of 430 Dutch Marines, on the condition that all individuals would be tested for seroconversion. By that time, WHO already considered both the IM and the ID ROA as equivalent and defined seroconversion after rabies PrEP as a post-immunization titer of least 0.5 IU/mL [1, 2].The immunogenicity data on the seroconversion rate (SCR) in this group that received 0.1 mL ID on days 0, 7 and 21-28, showed an excellent immunogenicity after two ID vaccine doses (serologic response was measured prior to the administration of the third vaccine dose), and were published in 2018 [3].The Dutch MOD guideline was changed during the study, in which standard booster immunization after PrEP was no longer advised. This led to a premature termination of our study.Maraboo study: boostability after intradermal PrEP   |   153 72. MATERIALS AND METHODS2.1 Study populationIn April 2018, we published the immunogenicity data of the two-visit-one-dose ID rabies PrEP schedule, among 430 Dutch Marines [3]. In order to complete the then recommended immunization schedule (administration on day 0, 7 and 21-28), all received a third single dose of 0.1 mL ID of Verorab® 0.5 mL (1/5 partial dose) rabies vaccine on day 21 or 28. All participants of that study were eligible to partake in the current study, if booster immunization was required according MOD regulations, ≥1 year after completion of the ID PrEP schedule. Immunocompromised persons had previously been excluded, as well as persons with an allergy to active/adjuvants components of the rabies vaccine, and persons using mefloquine as malaria chemoprophylaxis because this was presumed to influence the antibody response.Note: Recent data showed that this presumption for exclusion mefloquine is unfounded.2.2 Study designThis prospective observational cohort study was conducted in the sickbay of the Marine base in Doorn, The Netherlands, from December 2016 to May 2018. Registered military nurses administered the vaccine and took blood samples prior to booster immunization and on days 7 and 14 after immunization. Adverse events (AEs) and serious AEs were recorded until 14 days after immunization.2.3 VaccineAll participants received 1 mL inactivated rabies vaccine, Rabipur® (PL 16033/0010 GSK) intramuscularly, ≥1 year after completion of a three-visit-one-dose ID rabies PrEP schedule.2.4 Rabies antibody titer measurementAll blood samples were shipped within one week after collection to Sciensano, the national reference center for rabies in Brussels, Belgium. For rabies antibody determination, we used the rapid fluorescent focus inhibition test (RFFIT), which is considered as gold standard by WHO. All results were expressed in International Units per milliliter (IU/mL) [2].2.5 Statistical analysisThe initial sample size was calculated at 125 study subjects and was based on describing the percentage of titers ≥0.5 IU/mL with a sufficiently narrow two-sided 95% confidence interval (CI). We transformed all titers with a base-10 log for calculation. In line with the WHO Technical Report we report the immunogenicity data of rabies including percentage of titers ≥0.5 IU/mL, and geometric mean titer (GMT), with a 95% CI, and range of antibody titers [4].154   |   Chapter 7Initially, we planned univariable linear regression to examine the association between log transformed titers and age (5-year sub groups), sex, BMI, smoking (never vs stopped vs yes), and alcohol consumption. We abandoned this analysis, due to the small numbers of subjects per category. 3. REFERENCES1.  World Health Organization (WHO). Rabies vaccines: WHO position paper, April 2018, Weekly epidemiological record, No. 16; 2018. p. 93, 201–2202.  World Health Organization. WHO expert consultation on rabies: third report: WHO Technical Report Series No. 1012. 2018. https://www.who.int/publications-detail/WHO-TRS-10123. De Pijper CA, Boersma J, Terryn S, Van Gucht S, Goorhuis A, Grobusch MP, Stijnis C. Rabies antibody response after two intradermal pre-exposure prophylaxis immunizations: an observational cohort study. Trav Med Infect Dis 2018;22:36–9. https://doi.org/10.1016/j.tmaid.2018.03.0064.  World Health Organ Tech Rep Ser WHO Expert Committee on biological standardization. 2007. 1–340, back coverTable: S1. Study population demographics and characteristics at baselineCohort characteristics Pooled 1 year 2/2.5 year No of subjects 24 17 7 Age (years) [median, range] 24 [20-47] 23 [20-47] 26 [22-31] Sex     Male 22 (91.7%) 15 (88.2%) 7 (100%)      Female 2 (8.3%) 2 (11.8%) 0 BMI [mean, range] 24.8 [21.4-28.9] 24.5 [21.4-28.93] 25.9 [24.3-28.9] Smoking     Never 12 (50%) 6 (35.3%) 6 (85.7%)      Stopped 3 (12.5%) 3 (17.6%) 0      Yes 9 (37.5%) 8 (47.1%) 1 (14.3%) Alcohol consumption     0 units per week 1 (4.2%) 1 (5.9%) 0      1-3 units per week 6 (25%) 3 (17.6%) 3 (42.8%)      4-9 units per week 12 (50%) 10 (58.8%) 2 (28.6%)      10 or more units per week 5 (20.8%) 3 (17.6%) 2 (28.6%) Maraboo study: boostability after intradermal PrEP   |   155 710.112481632641282560.10.112481632641282560.10.53100.5310day 0day 0day 0day 7day 7day 7day 14day 14day 14pooledyear 1year 2/2.5year 1 + 2/2.5Figure S1. Individual titers of all participants and Geometric Mean Titer in subjects with adequate titer per point-in-time.Geometric Mean Titer (GMT) displayed with line before (day 0) and after boostering (day 7 and 14) with one intramuscular rabies immunization after a three-visit-one-dose ID schedule. The cutoff value of 0.5, 3 and 10 is depicted as a dotted line.

Quis custodiet ipsos custodes?:Who guards our guardians?

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Quis custodiet ipsos custodes?:Who guards our guardians?

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