Unravelling the Measles Paradox (MISIA)

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:

1. The Orthodox Protestant community: The outbreak in 1999-2000 involved 3,381 reported cases and led to 106 hospitalizations, including 3 deaths. The 2012-2013 outbreak involved 2,668 reported cases and 164 hospitalizations, leading to 1 acute and 3 long-term deaths. Since outbreaks occur at an interval of 10-12 years, the time needed to build a large enough group of individuals susceptible to measles, a new outbreak is anticipated.
2. Immigrant population in Rotterdam: Vaccination coverage in Rotterdam is monitored by The Rotterdam Outbreak Surveillance Team' (ROST), a collaboration between the Erasmus MC department of Viroscience, the GGD Rotterdam, and the Erasmus MC Pandemic and Disaster Preparedness Center. Coverage of the two-dose vaccination schedule in Rotterdam is estimated at 76%; however, in some neighbourhoods and schools it has apparently dropped below 45%. Outbreaks in these clusters of low vaccination coverage are a realistic possibility.

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.