Unravelling the Measles Paradox: a Disease Associated With Both Immune Suppression and Immune Activation

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.