Clinical trial NCT06923631: Unravelling the Measles Paradox in Children
Official title: Unravelling the Measles Paradox in Children: a Disease Associated With Both Immune Suppression and Immune Activation
Study type: OBSERVATIONAL
Overall status: NOT_YET_RECRUITING
Conditions: MEASLES DISEASE
Keywords: measles
immune response
Lead sponsor: Erasmus Medical Center
Sponsor class: OTHER
First posted: 2025-04-11
Enrollment: 100
Sex: ALL
Minimum age (years): 4
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: yes
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Children in group A will be from 4 up to and including 17 years of age and include children who are not protected against measles. Families willing to participate will self-identify them to the researchers, with the help of schools, Municipal Health Services and regional general practitioners.

Children in group B will be from 4 up to and including 17 years of age and have received one or two MMR vaccinations, depending on their age. The children will be recruited from the same geographical regions with low vaccine coverage as the children in group A, for example classmates.

Brief summary: Measles is caused by measles virus (MeV). The disease is associated with lymphopenia and immune suppression, which is an important cause of measles-associated morbidity and mortality. Measles-induced immune suppression can last several years, whereas measles lymphopenia is usually resolved within two weeks. At the same time, measles induces lifelong immunity. This apparent contradiction, known as the 'measles paradox', was partially solved when investigators demonstrated that MeV infects and depletes pre-existing memory cells, thereby causing 'immune amnesia'. This model is supported by observations in animal models and clinical studies, but several questions remain to be addressed, like the duration of measles-induced amnesia and changes in the immune repertoire after measles. to address the immunological questions regarding MeV infection.

Detailed description: Measles is caused by measles virus (MeV). The disease is associated with lymphopenia and immune suppression, which is an important cause of measles-associated morbidity and mortality. Measles-induced immune suppression can last several years, whereas measles lymphopenia is usually resolved within two weeks. At the same time, measles induces lifelong immunity. This apparent contradiction, known as the 'measles paradox', was partially solved when investigators demonstrated that MeV infects and depletes pre-existing memory cells, thereby causing 'immune amnesia'. This model is supported by observations in animal models and clinical studies, but several questions remain to be addressed, like the duration of measles-induced amnesia and changes in the immune repertoire after measles. Recently, investigators have acquired permission to address these remaining questions in 18-25 years old adults (MEC-2024-0230). However, investigators have reservations about the feasibility of including enough participants between 18 and 25 years old that have not been vaccinated against or infected with MeV; it is possible that investigators will not reach sufficient inclusions to address the immunological questions regarding MeV infection in that protocol. Therefore, investigators propose to additionally study these questions in children in the age of 4 up to and including 17.

Eligibility criteria: Inclusion Criteria:

Group A

* Aged 4 - 17 years old
* Susceptible to measles
* No pre-existing immunity against measles (vaccination or earlier infection)

Group B

* Aged 4 - 17 years old
* Protected against measles due to vaccination or earlier infection

Exclusion Criteria:

A potential subject who meets any of the following criteria will be excluded from participation in this study:

* Diagnosed chronic disease that lasted over 3 months
* Immune suppression (due to medication or underlying disease)
* Group A; Detectable MeV-antibodies in the T1 blood sample

Primary outcomes:
measure: Compare measles-induced loss of pathogen-specific antibodies
timeFrame: 36 months
measure: Compare measles-induced loss of pathogen-specific T-cells
timeFrame: 36 months
Secondary outcomes:
Other outcomes:
Locations:
Study officials:
References:
citation: van Velzen E, de Coster E, van Binnendijk R, Hahne S. Measles outbreak in an anthroposophic community in The Hague, The Netherlands, June-July 2008. Euro Surveill. 2008 Jul 31;13(31):18945. No abstract available.
citation: Mollema L, Harmsen IA, Broekhuizen E, Clijnk R, De Melker H, Paulussen T, Kok G, Ruiter R, Das E. Disease detection or public opinion reflection? Content analysis of tweets, other social media, and online newspapers during the measles outbreak in The Netherlands in 2013. J Med Internet Res. 2015 May 26;17(5):e128. doi: 10.2196/jmir.3863.
citation: Laksono BM, de Vries RD, Verburgh RJ, Visser EG, de Jong A, Fraaij PLA, Ruijs WLM, Nieuwenhuijse DF, van den Ham HJ, Koopmans MPG, van Zelm MC, Osterhaus ADME, de Swart RL. Studies into the mechanism of measles-associated immune suppression during a measles outbreak in the Netherlands. Nat Commun. 2018 Nov 23;9(1):4944. doi: 10.1038/s41467-018-07515-0.
citation: Knol M, Urbanus A, Swart E, Mollema L, Ruijs W, van Binnendijk R, Te Wierik M, de Melker H, Timen A, Hahne S. Large ongoing measles outbreak in a religious community in the Netherlands since May 2013. Euro Surveill. 2013 Sep 5;18(36):pii=20580. doi: 10.2807/1560-7917.es2013.18.36.20580.
citation: Van Den Hof S, Smit C, Van Steenbergen JE, De Melker HE. Hospitalizations during a measles epidemic in the Netherlands, 1999 to 2000. Pediatr Infect Dis J. 2002 Dec;21(12):1146-50. doi: 10.1097/00006454-200212000-00012.
citation: Mina MJ, Kula T, Leng Y, Li M, de Vries RD, Knip M, Siljander H, Rewers M, Choy DF, Wilson MS, Larman HB, Nelson AN, Griffin DE, de Swart RL, Elledge SJ. Measles virus infection diminishes preexisting antibodies that offer protection from other pathogens. Science. 2019 Nov 1;366(6465):599-606. doi: 10.1126/science.aay6485.
citation: Rennick LJ, de Vries RD, Carsillo TJ, Lemon K, van Amerongen G, Ludlow M, Nguyen DT, Yuksel S, Verburgh RJ, Haddock P, McQuaid S, Duprex WP, de Swart RL. Live-attenuated measles virus vaccine targets dendritic cells and macrophages in muscle of nonhuman primates. J Virol. 2015 Feb;89(4):2192-200. doi: 10.1128/JVI.02924-14. Epub 2014 Dec 3.
citation: de Vries RD, Lemon K, Ludlow M, McQuaid S, Yuksel S, van Amerongen G, Rennick LJ, Rima BK, Osterhaus AD, de Swart RL, Duprex WP. In vivo tropism of attenuated and pathogenic measles virus expressing green fluorescent protein in macaques. J Virol. 2010 May;84(9):4714-24. doi: 10.1128/JVI.02633-09. Epub 2010 Feb 24.
citation: Aaby P, Bukh J, Lisse IM, Smits AJ. Measles vaccination and reduction in child mortality: a community study from Guinea-Bissau. J Infect. 1984 Jan;8(1):13-21. doi: 10.1016/s0163-4453(84)93192-x.
citation: Sato R, Haraguchi M. Effect of measles prevalence and vaccination coverage on other disease burden: evidence of measles immune amnesia in 46 African countries. Hum Vaccin Immunother. 2021 Dec 2;17(12):5361-5366. doi: 10.1080/21645515.2021.2013078. Epub 2021 Dec 29.
citation: Petrova VN, Sawatsky B, Han AX, Laksono BM, Walz L, Parker E, Pieper K, Anderson CA, de Vries RD, Lanzavecchia A, Kellam P, von Messling V, de Swart RL, Russell CA. Incomplete genetic reconstitution of B cell pools contributes to prolonged immunosuppression after measles. Sci Immunol. 2019 Nov 1;4(41):eaay6125. doi: 10.1126/sciimmunol.aay6125.
citation: Cox RM, Wolf JD, Lieberman NA, Lieber CM, Kang HJ, Sticher ZM, Yoon JJ, Andrews MK, Govindarajan M, Krueger RE, Sobolik EB, Natchus MG, Gewirtz AT, deSwart RL, Kolykhalov AA, Hekmatyar K, Sakamoto K, Greninger AL, Plemper RK. Therapeutic mitigation of measles-like immune amnesia and exacerbated disease after prior respiratory virus infections in ferrets. Nat Commun. 2024 Feb 8;15(1):1189. doi: 10.1038/s41467-024-45418-5.
citation: Laksono BM, Roelofs D, Comvalius AD, Schmitz KS, Rijsbergen LC, Geers D, Nambulli S, van Run P, Duprex WP, van den Brand JMA, de Vries RD, de Swart RL. Infection of ferrets with wild type-based recombinant canine distemper virus overwhelms the immune system and causes fatal systemic disease. mSphere. 2023 Aug 24;8(4):e0008223. doi: 10.1128/msphere.00082-23. Epub 2023 Jun 28.
citation: Ward BJ, Johnson RT, Vaisberg A, Jauregui E, Griffin DE. Cytokine production in vitro and the lymphoproliferative defect of natural measles virus infection. Clin Immunol Immunopathol. 1991 Nov;61(2 Pt 1):236-48. doi: 10.1016/s0090-1229(05)80027-3.
citation: Hirsch RL, Griffin DE, Johnson RT, Cooper SJ, Lindo de Soriano I, Roedenbeck S, Vaisberg A. Cellular immune responses during complicated and uncomplicated measles virus infections of man. Clin Immunol Immunopathol. 1984 Apr;31(1):1-12. doi: 10.1016/0090-1229(84)90184-3.
citation: Tamashiro VG, Perez HH, Griffin DE. Prospective study of the magnitude and duration of changes in tuberculin reactivity during uncomplicated and complicated measles. Pediatr Infect Dis J. 1987 May;6(5):451-4. doi: 10.1097/00006454-198705000-00007.
citation: de Vries RD, McQuaid S, van Amerongen G, Yuksel S, Verburgh RJ, Osterhaus AD, Duprex WP, de Swart RL. Measles immune suppression: lessons from the macaque model. PLoS Pathog. 2012;8(8):e1002885. doi: 10.1371/journal.ppat.1002885. Epub 2012 Aug 30.
citation: de Swart RL, Ludlow M, de Witte L, Yanagi Y, van Amerongen G, McQuaid S, Yuksel S, Geijtenbeek TB, Duprex WP, Osterhaus AD. Predominant infection of CD150+ lymphocytes and dendritic cells during measles virus infection of macaques. PLoS Pathog. 2007 Nov;3(11):e178. doi: 10.1371/journal.ppat.0030178.
citation: Mina MJ, Metcalf CJ, de Swart RL, Osterhaus AD, Grenfell BT. Long-term measles-induced immunomodulation increases overall childhood infectious disease mortality. Science. 2015 May 8;348(6235):694-9. doi: 10.1126/science.aaa3662. Epub 2015 May 7.
citation: Ludlow M, Lemon K, de Vries RD, McQuaid S, Millar EL, van Amerongen G, Yuksel S, Verburgh RJ, Osterhaus AD, de Swart RL, Duprex WP. Measles virus infection of epithelial cells in the macaque upper respiratory tract is mediated by subepithelial immune cells. J Virol. 2013 Apr;87(7):4033-42. doi: 10.1128/JVI.03258-12. Epub 2013 Jan 30.
citation: Ludlow M, de Vries RD, Lemon K, McQuaid S, Millar E, van Amerongen G, Yuksel S, Verburgh RJ, Osterhaus ADME, de Swart RL, Duprex WP. Infection of lymphoid tissues in the macaque upper respiratory tract contributes to the emergence of transmissible measles virus. J Gen Virol. 2013 Sep;94(Pt 9):1933-1944. doi: 10.1099/vir.0.054650-0. Epub 2013 Jun 19.
citation: Lemon K, de Vries RD, Mesman AW, McQuaid S, van Amerongen G, Yuksel S, Ludlow M, Rennick LJ, Kuiken T, Rima BK, Geijtenbeek TB, Osterhaus AD, Duprex WP, de Swart RL. Early target cells of measles virus after aerosol infection of non-human primates. PLoS Pathog. 2011 Jan 27;7(1):e1001263. doi: 10.1371/journal.ppat.1001263.
citation: Laksono BM, de Vries RD, McQuaid S, Duprex WP, de Swart RL. Measles Virus Host Invasion and Pathogenesis. Viruses. 2016 Jul 28;8(8):210. doi: 10.3390/v8080210.
citation: Laksono BM, de Vries RD, Duprex WP, de Swart RL. Measles pathogenesis, immune suppression and animal models. Curr Opin Virol. 2020 Apr;41:31-37. doi: 10.1016/j.coviro.2020.03.002. Epub 2020 Apr 24.
citation: de Vries RD, de Swart RL. Measles immune suppression: functional impairment or numbers game? PLoS Pathog. 2014 Dec 18;10(12):e1004482. doi: 10.1371/journal.ppat.1004482. eCollection 2014 Dec. No abstract available.