In resource-poor countries, MeV vaccine is often given alone, but there is an effort for these countries to transition to delivery of combined measles and rubella (MR) vaccine (72). Not all children respond to the initial dose of MeV-containing vaccine given in infancy (85% at 9 months, 95% at 12 months) (179), so two doses are required to provide a second opportunity for response and achieve a population immunity of 92C95% required to eliminate endemic transmission (51). magnitude. Protective immunity is correlated with levels of neutralizing Ab, but the actual immunologic determinants of protection are not known. Because measles is highly transmissible, control requires high levels of population immunity. Delivery of the two doses of vaccine needed to achieve 90% immunity is accomplished by routine immunization of infants at 9C15 months of age followed by a second dose delivered before school entry or by periodic mass vaccination campaigns. Because delivery by injection creates hurdles to sustained high coverage, there are efforts to deliver MeV vaccine by inhalation. In addition, the safety record for the vaccine combined with advances in reverse genetics for negative strand viruses has expanded proposed uses for recombinant versions of measles vaccine as vectors for immunization against other infections and as oncolytic agents for a variety of tumors. to interfere with IFN induction (27,126,132) and with Stat1/2 to inhibit Rabbit Polyclonal to SFRS4 IFN signaling (19,140). The C protein downregulates viral RNA synthesis and production Arbutin (Uva, p-Arbutin) of defective interfering (DI) RNAs to decrease virus detection intracellularly (59,106,121,133). MeV is an antigenically monotypic virus, with 24 genotypes recognized based on the sequence of the C terminus of the N gene (148). MeV targets several types of cells (e.g., B and T lymphocytes, monocytes, and endothelial and epithelial cells) and uses multiple receptors in a virus strain and cell type-specific manner determined by the H protein. Three receptors have been identified: membrane cofactor protein or CD46, a complement regulatory protein present on all nucleated cells (35,109); signaling lymphocytic activation molecule (SLAM) or CD150, present on activated immune cells (177); and polio virus receptor related 4 or nectin 4, present on epithelial cells (101,114,158). The binding sites for these cellular receptors are overlapping on the lateral surface of the virulence has not been identified. Potential importance of H One potentially important biologic difference is the acquisition of efficient use of the CD46 receptor by vaccine strains (17,39,187). Tyr at position 481 of H (present in all vaccine strains) and Gly at 546 (present in Moraten, but not in EZ) are key determinants of the affinity of H for CD46 (9,161), but other residues also contribute to this interaction (88,147, 155,168). The mechanism by which gaining use of the CD46 receptor might lead to vaccine attenuation is not clear, unless the important consequence is loss of another interaction such as H binding to toll-like receptor (TLR) 2 (12). SLAM is expressed on immature thymocytes, activated lymphocytes, activated monocytes, and mature dendritic cells (DCs) (20,32) and is the most important receptor for MeV infection of lymphoid tissue (28,75). H residues important for binding SLAM are generally shared between MeV strains, and both vaccine and WT viruses use SLAM as a receptor (39,86C88,111,119,153,155,182,187). Evaluation in cynomolgus macaques of recombinant enhanced green fluorescent protein (eGFP)-expressing WT viruses with vaccine (Ed-tag) H instead of WT (IC-B) H showed attenuation without a change in tropism, suggesting that the important effect is on replication rather than on receptor binding (176). Viruses with WT Asn at H481 interact with SLAM, but not CD46, activate TLR2, and enter peripheral blood mononuclear cells (PBMCs) more efficiently than viruses with Tyr (confers CD46 binding) at this position (12,39,155), but the importance of changes in any of these parameters for attenuation is unclear. Potential Arbutin (Uva, p-Arbutin) importance of C and V Differences in induction of IFN have been proposed to explain the differences between WT (good blocking of IFN induction) and vaccine (poor blocking of IFN induction) strains of MeV in ability to cause disease (118). Multiple studies have compared type I IFN induction by vaccine and WT strains (110,132,163) of MeV. Some studies have shown more efficient induction of IFN by vaccine MeV, whereas others have not. However, interpretation has been complicated by use of vaccine virus stocks that contain viral particles with DI RNAs that Arbutin (Uva, p-Arbutin) efficiently induce IFN and are produced during MeV replication in tissue culture (68,163,165). The C and V sequences of vaccine and WT MeV strains are similar (44), but the literature on sequence-dependent effects on function has been complicated by the analysis of recombinant viruses that contain mutations (Y110H, C272R) present in the early MeV vaccine cDNA clone (EdTag) used for reverse genetics that are not present in vaccine strains (33,159,171). Analysis of validated C and V proteins from vaccine and WT strains shows no differences in ability to regulate the IFN response (44,105). There is little evidence of type I IFN induction in humans with.