Immune response analysis to Measles virus in subjects vaccinated with MMR vaccine and naturally infected subjects.

Measles virus belongs to the Morbillivirus genus, Paramixoviridae family. It is the causative agent of a highly contagious acute infective disease, typical of infancy, characterized by fever, skin rash, cough and conjunctivitis, and a generalized immune suppression (Griffin, 2013). The virus is transmitted through the respiratory tract, multiplicates in its upper part and in regional lymph nodes, thus resulting in lymphatic and hematic dissemination with appearance of first clinical signs after 9-19 days (de Vries et al., 2015). In 30% of the cases, complications in the lower respiratory tract or the central nervous system (CNS) can occur. The first sign of infection is represented by an early immune depression, due to the loss of B and T immune memory cells (Mina et al., 2015), resulting in an increased susceptibility to opportunistic infections and to life-threatening complications such as pneumonia and/or gastro-intestinal disease (de Vries et al., 2015). However, this type of disease is paradoxically associated with the induction of a strong and specific immune response to the virus, which is usually permanent (Laksono et al., 2016). There is no specific treatment against measles, and this is the reason why vaccination is considered the best strategy against the virus. Furthermore, the monotypic nature of the virus and the lack of an animal reservoir, make measles a considerable candidate for eradication (Rota et al., 2016). Although a combined vaccine, called MMR (measles, mumps and rubella) is used in routinely vaccination schedule, measles remains a significative cause of morbidity and mortality, particularly during infancy (Moss & Griffin, 2012; Wolfson et al., 2009; Nandy et al., 2003). MMR live attenuated vaccine is very efficacious in protecting people against measles, mumps, and rubella, and preventing the complications caused by these diseases. The measles virus contained in the vaccine is represented by the live attenuated Edmoston B strain. The World Health Organization recommends two doses of vaccine for all children and adults; the first dose should be given at 13-15 months of age. The second dose is often done at 5 - 6 years, in Italy. About 3 out of 100 people who get two doses of MMR vaccine will get measles if exposed to the virus. However, they are more likely to have a milder illness, and are also less likely to spread the disease to other people (Centers for Disease Control and Prevention, 2018). Epidemiologic studies have shown that the level of neutralizing antibodies at the time of exposure to wild type (WT) virus in the community is a good indicator of protection from infection, with higher titers necessary to prevent infection than to prevent disease (rash) (Chen et al., 1990). High avidity antibodies are required to neutralize CD150-mediated WT MeV infection of lymphoid cells (Polack et al., 2003). However, levels of circulating anti-measles neutralizing antibody tend to reduce or even to fade during lifetime, especially among vaccinated subjects (Kennedy et al., 2019; Davidkin et al., 2008; Carryn et al., 2019; Seagle et al., 2018; Gonçalves et al., 2015; Le Baron et al., 2007). Because CD4+ T cell help is required for isotype and affinity maturation of antibody-secreting cells, B cell memory and maturation of CD8+ T cell memory, cellular immune response is also important for the induction of protective immunity (Laksono et al., 2018). All these things highlight the necessity to invest on studies focused on the correlates of protection against Measles virus. Recent evaluation systems for vaccines point towards the measurement of Tcell quality with regards to cytokine secretion as a protective correlate in addition to antibody titers in serum during the course of an immune response. Although the generation of immune memory supports the concept of vaccine efficacy, direct assessment of immune memory cells and their precursors has not yet been established as a correlate of protection. With the growing knowledge on the phenotype, function and localization of the immune memory cells in the body, researchers think that these cells may provide a novel correlate of protection for evaluation of more efficacious vaccines. Finally, transcriptome-level characterization (mRNA-Seq data) of responses to measles virus stimulation in antibody responders (either vaccinated or naturally infected) and those who have not responded to the vaccine, could help to identify plausible regulators (genes/pathways) that drive the observed differences among these subjects. Such study may help to develop a panel of biomarkers to monitor, besides the antibody response, the immune response to measles vaccine with the aim to protect, in case of outbreaks, not only the fragile subjects, but also the vaccinated subjects who eventually become seronegative along the time, with a booster composed of specific, immunogenic MeV proteins.