An observational study in MEASLES DISEASE, sponsored by Erasmus Medical Center. Recruiting at 1 site in Netherlands. Open to participants aged 18 Years and older, including healthy volunteers. Per ClinicalTrials.gov, last updated 2025-12-05.
Sponsored by Erasmus Medical Center · Observational
The measles (MeV) paradox refers to an apparent contradiction: natural measles causes a transient but profound immune suppression putting patients at risk for opportunistic infections for years, while at the same time MeV infection induces robust immune activation leading to lifelong protection against measles. In this protocol, we test our hypothesis that natural measles causes immune amnesia by altering the composition of circulating immune memory cells. In comparison to the prior studies performed during the 2013 outbreak, we will specifically determine [1] to what extent pre-existing immunity is reduced, [2] for how long this functional immune suppression can be detected, and [3] to what extent MeV-specific immune cells expand.
Recently, the WHO reported a 30-fold increase of the number of measles cases in the European Region in 2023 and the ECDC has published a threat assessment brief on increase of the number of cases and considerations for public health response. Combined with the reported drop in vaccination coverage, and several clusters of cases, we anticipate that we are at the verge of a new measles outbreak in the Netherlands
The measles paradox refers to an apparent contradiction: natural measles causes a transient but profound immune suppression putting patients at risk for opportunistic infections for years, while at the same time MeV infection induces robust immune activation leading to lifelong protection against measles. In this protocol, we test our hypothesis that natural measles causes immune amnesia by altering the composition of circulating immune memory cells. In comparison to the prior studies performed during the 2013 outbreak, we will specifically determine [1] to what extent pre-existing immunity is reduced, [2] for how long this functional immune suppression can be detected, and [3] to what extent MeV-specific immune cells expand.
Measles Measles is caused by infection with measles virus (MeV), which is the most contagious human virus known. It is transmitted via aerosols or direct contact with contaminated respiratory secretions and causes systemic disease with clinical signs that appear within two weeks after infection and include fever, rash, cough, coryza and conjunctivitis. Despite significant progress in global measles control programs, every year measles results in the death of more than 100,000 children. Most fatal cases occur in low-income countries, where case-fatality rates often exceed 1% but can be as high as 25% in refugee camps. Case-fatality rates are usually lower than 0.1% in high-income countries; during the Dutch 2013 outbreak, 2,700 cases were reported (real case numbers were likely around 30,000 based on estimated levels of under-reporting), and 1 fatal case was reported in the acute phase of the outbreak. Long-term neurological complications after measles caused two deaths.
Primary infections MeV is often referred to as a respiratory virus, but mainly infects cells of the immune system. Our studies in non-human primates demonstrated how the virus enters the host by infecting alveolar macrophages and dendritic cells in the lungs. After local replication and expansion in the lungs and local lymphoid tissues, MeV disseminated to all peripheral lymphoid tissues. This lymphoid phase was followed by spread to non-lymphoid tissues, including the gingiva, tongue, buccal mucosa, trachea, nose, and skin. Individuals are infectious before the rash appears, and host-to-host transmission is mediated by MeV particles produced by infected epithelial cells in the nose, or MeV-infected lymphocytes in the tonsils and adenoids. Damage to the epithelium of the trachea induces coughing, leading to both cell-free and cell-associated MeV being expelled into the air, which can be inhaled by a next susceptible host. Without complications, patients rapidly recover from measles and are protected for the rest of their life. However, measles transiently suppresses the immune system, leaving patients susceptible to opportunistic infections, like bacterial pneumonia or gastro-intestinal disease.
Lymphopenia and immune amnesia CD150 is the main cellular entry receptor for MeV, which is predominantly present on cells of the immune system. Our previous studies have shown that MeV preferentially infects CD150+ B-cells and central and effector memory T-cells in non-human primates and humans, which are responsible for immunological recall responses. MeV infection and subsequent depletion of B- and memory T-cells explains the measles-induced immune suppression. However, the number of lymphocytes in blood is restored within weeks, so this does not directly explain how immune suppression can last up to years after resolution of measles. We hypothesized that pre-existing immune memory is replaced by measles-specific memory, thus causing immune amnesia. This means that the numbers of antigen-specific lymphocytes are similar before and after measles, but that the repertoire is completely different. This model not only explains the measles paradox, but also why introduction of measles vaccine programs reached further than protection from measles alone.
Functionally, immune amnesia was confirmed by demonstrating disappearance of pre-existing Mantoux responses and impaired responses to prior vaccinations after natural measles. Recently, in vivo studies with canine distemper virus (CDV), a virus closely related to MeV that is used as a model to study immune suppression in ferrets, demonstrated a loss of influenza vaccine responses after CDV infection. Real-world data from African countries showed that the overall disease burden from diarrhoea, lower respiratory infection, malaria, meningitis, and tuberculosis is inversely proportional to measles prevalence. Additionally, the introduction of measles vaccination programs coincided with a drastic decrease in child morbidity and mortality, which could not be explained by the prevention measles alone.
Live attenuated vaccine A safe and effective live-attenuated measles vaccine is available and part of the Dutch national immunization program since 1976. In the Netherlands, the measles vaccine is administered as a trivalent vaccination with mumps and rubella (MMR). The MMR vaccine contains a live attenuated MeV strain that is highly immunogenic in healthy subjects, with measles neutralizing antibodies developing in 90% of individuals after the first dose and 99% after two doses. We have demonstrated in non-human primates that the vaccine virus replicates at a low level in the myeloid cells at the site of injection. It is generally accepted that the measles vaccine does not have an immune suppressive effect and vaccination does not result in lymphopenia, while still inducing lifelong immunity. Given the real-world evidence it is unlikely that the attenuated vaccine strain depletes pre-existing memory cells; yet small changes may go unnoticed as they seem clinically irrelevant. Therefore, subtle changes in the composition of the pre-existing immune repertoire, or the or magnitude of recall responses cannot be excluded.
Duration of measles induced immune suppression In our previous work during the 2013 outbreak, we mainly focused on the short-term effects of natural measles and demonstrated the infection and depletion of circulating immune memory cells. However, post measles blood samples were collected relatively short after recovery. No studies have been conducted yet to fully analyse long-term phenotypical and functional changes in the composition of circulating immune memory cells. Inclusion of controls (vaccinated and uninfected) is crucial for the success of this study.
Trend towards decreasing vaccine uptake and increased measles incidence
In the Dutch national immunization program, the first MMR vaccination is offered at the age of 14 months and the second when the child is 9 years old. Before the introduction of the measles vaccine nearly everyone experienced measles during their childhood, but since the introduction of measles vaccination usually only ±10 cases per year are reported, usually related to import from endemic countries. Although the exact MMR vaccination coverage in the Netherlands cannot be determined by the RIVM because of the implementation of an informed consent for data exchange in January 2022, the current registered percentage of full MMR vaccination is below the 95% needed to prevent transmission chains, and much lower in some regions. The vaccination coverage in the Netherlands shows large regional differences. Vaccine refusal in the Netherlands not only occurs in the Orthodox Protestant community, but also in people with an anthroposophical lifestyle and in certain immigrant populations. Combined, this leads to clusters of low vaccination coverage. For this protocol, we will predominantly (but not exclusively) recruit participants in two communities with low vaccination coverage:
On the verge of an outbreak Recently, the WHO reported a 30-fold increase of the number of measles cases in the European Region in 2023 and the ECDC has published a threat assessment brief on increase of the number of cases and considerations for public health response. Combined with the reported drop in vaccination coverage, and several clusters of cases, we anticipate that we are at the verge of a new measles outbreak in the Netherlands.
134 studies on the registry are indexed under Measles; 17 are open to participants now.
This study's planned enrollment of 300 is close to the median of 282 across 26 observational studies indexed under Measles.
Browse Measles studies →Erasmus Medical Center is the lead sponsor of 478 studies on the registry; 183 are open to participants now.
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The participants in this study are 18 years or older and will be recruited in areas with low vaccination coverage. Recruitment will occur through contacting orthodox protestant student associations, GPs with a large orthodox protestant patient base, orthodox protestant newspapers, and first year medical students at the Erasmus MC. The study does not include an intervention.
Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
Cohort A
Cohort B
Cohort C
Cohort D
Cohort E
Exclusion Criteria:
A potential participant who meets any of the following criteria will be excluded from the study:
Additionally for subjects recruited to Cohort A:
Participant who never had measles vaccine and are recently vaccinated against measles before the upcoming outbreak.
Participants who never had measles vaccine and decline recent offer for measles vaccine and get infected with measles during the upcoming outbreak.
Participants who never had measles vaccine and decline recent offer for measles vaccine and remain free from measles infection.
Participants who never had measles vaccine and had a history of measles infection.
Participants who have received measles vaccine about 10 years ago.
Compare measles-induced loss of pathogen-specific antibodies
The investigators will measure changes in the immune repertoire using longitudinal samples obtained from participants who are infected with MeV. To this end, they will measure pathogen-specific antibody responses (titers) pre- and post-measles and compare these to determine whether measles led to a loss of pathogen-specific antibodies.
Time frame: 36 months
Compare measles-induced loss of pathogen-specific T-cells
The investigators will measure changes in the immune repertoire using longitudinal samples obtained from participants who are infected with MeV. To this end, they will measure pathogen-specific T-cell responses (frequencies) pre- and post-measles and compare these to determine whether measles led to a loss of pathogen-specific T-cells.
Time frame: 36 months
Plan to share: Undecided
Started Jul 2025 (actual). Primary completion is estimated for Jul 2028, 36 months after the start.
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