Immunology

Immune Responses to Measles

Host antiviral responses are activated as soon as the virus enters the cells. Several cellular proteins act as primary intracellular sensor of virus-specific RNAs, but the most important measles morbillivirus (MeV) RNA sensor is retinoic acid-inducible gene I protein (RIG‑I). The binding of RIG-I to viral RNA triggers a signaling cascade which activates production of interferons (IFNs), which are secreted from the infected cell and act as a signal for neighboring cells to begin production of antiviral proteins. In addition, natural killer cells, activated by Interferons (IFN) signaling among other mechanisms, comprise an important part of the early host immune response.

Notwithstanding the early (innate) immune response, efficient clearance of MeV, clinical recovery from measles, and the establishment of long-term immunity all depend on the adaptive immune system. The importance of humoral immunity in preventing reinfection is illustrated by the efficacy of exogenous antibodies used in post-exposure prophylaxis (PEP) in measles prevention. The initial humoral response involves immunoglobulin M (IgM) antibodies (the purple line in Figure 1-2), which may persist up to two months after disease onset. The IgM response is characteristic of the initial infection (or vaccination) and is normally absent in reinfection (or revaccination). A few days after the IgM response, immunoglobulin G (IgG) antibodies become dominant (the pink line in Figure 1-2); these antibodies (i.e., the B-cell clones that produce them) persist for a lifetime, contributing to lifelong immunity to measles. As important as humoral immunity is, cellular immunity appears even more critical, as illustrated by the fact that patients with a congenital deficiency in antibody production can fully recover from measles, while those with T-cell defects often have severe or fatal outcomes. Both T helper (T_h) cells (i.e., CD4+ cells, shown in orange in Figure 1-2) and cytotoxic T cells (i.e., CD8+ cells, shown in blue in Figure 1-2) play important roles in recovery from measles. The T helper cell response is initially characterized by T_h1 cells and IFN-γ production, which promotes viral clearance. This later switches to the T_h2 response and interleukin 4 production, which promotes production of anti-MeV antibodies. Like MeV-specific IgG antibodies, populations of MeV-specific CD4+ and CD8+ T cells persist for a lifetime.

The measles vaccine (see Prevention and Control) is a live attenuated vaccine, allowing for just enough replication of the vaccine virus in the host to elicit robust lifelong immunity, like a wild-type MeV infection would, but without enough replication to cause anything but minor symptoms in a minority of vaccinees. This contrasts with the generally shorter-term immunity conferred by non-live whole organism and subunit vaccines. The trade-off is that a small percent of vaccinated individuals may develop mild measles-like symptoms (rash and fever in approximately 5% and 15%, respectively, of vaccinated children, respectively).

In addition to the strong immune reaction and lifelong MeV-specific immunity, measles also causes a temporary suppression of adaptive immune capacity and an erasure of prior immune memory of other pathogens (“immune amnesia”). While this typically lasts for several weeks or months, it can extend for years, as evidenced both by common infectious complications of measles (see Presentation and Diagnosis) and a close coupling of mortality from infectious disease and measles incidence over a period of 2-3 years. Current evidence suggests immune amnesia occurs as a result of the tropism MeV exhibits for CD150+ expressing memory T- and B-cells, which then undergo apoptosis. A study of 77 unvaccinated children revealed that measles leads to a median loss of 30% (range 12-73%) of preexisting pathogen-specific antibodies in children with mild measles and 40% (range 11-63%) in children with severe measles. Notably, measles vaccination does not lead to a diminishment of the antibody repertoire.

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