2015. pathogens to protect against several diseases at once (multidisease or multipathogen vaccines). E protein (Is usually-98-STI)Between P/M genesMice (IFNAR?, CD46)1 104 or 1 106 TCID50 (wk 0, wk 4)?i.p., LD50 of WNV Is usually-98-ST1100% of animals protected89Mice (BALB/c)2 l pooled immune sera from IFNAR? CD46 mice?i.p., 10 LD50 of WNV Is usually-98-ST1100% of animals protectedMeasles, SARS295 to 394) and the ectodomain of the M protein (aa 1 to 40) from strain FGA/89 French Guiana for serotype DV1, Jamaica/N.1409 for DV2, DV3 H87, 63632/76 Burma for DV4Between P/M genesMice (IFNAR?, CD46)i.p., 1 105 TCID50 (wk 0, wk 4)?92Measles, chikungunya feverC, E3, E2, 6K, E1 (La Reunion strain 06-49)Mice (IFNAR?, CD46)i.p., 1 103, 1 104, or 1 105 TCID50 (wk 0, wk 4)?i.p., 1 102 PFU CHIKV 06-49 (= 33 occasions LD50)100% survival (immunized with 104 or 105 TCID50); 83% survival (immunized with 103 TCID50)**26, 27Modified vaccinia AnkaraInfluenza H5N1 strains*HA of A/Vietnam/1203/04, A/Indonesia/CDC669/06, and A/Anhui/01/05Deletion site IIIMice (BALB/c)i.m., 100 l 8 107 TCID50 (day 0, day 28)?i.n., 10 MLD50 of A/Vietnam/1203/04 or A/chicken/Shanxi/2/06100% of animals guarded61Varicella-zoster virusMumps, chickenpox/shinglesHN and F protein (or F protein with serine 195 replaced with tyrosine)Unique long domainGuinea pigss.c., 2 106 to 5 106 MRC-5 cells infected with VZV vOka-HN-F (day 0, day 14, day 28, day 42)?42 Open in a separate window aAn asterisk indicates a multivalent/polyvalent vaccine candidate. Two asterisks indicate a vaccine candidate that advanced to phase 1 clinical studies. bSARS, severe acute respiratory syndrome. cWNV, West Nile computer virus. dSARS-CoV, severe acute respiratory syndrome coronavirus. eaa, amino acid. fITR, inverted terminal repeat. gi.m., intramuscularly; i.p., intraperitoneally; s.c., subcutaneously; i.n., intranasally; CCID50, 50% cell culture infective dose; MID50, 50% median infective dose. MULTIVALENT AND MULTIPATHOGEN VACCINES FOR HUMAN APPLICATIONS A wide variety of viruses have been EC089 investigated as single-pathogen vector vaccines; amazingly fewer have been utilized for multivalent and multipathogen applications. Viruses have to meet several requirements to be considered suitable multipathogen or multivalent vectors. The viral vector has to be capable of taking up large fragments of immunogenic genes, together with regulatory elements (e.g., promoter, polymerase, terminator, etc.), or immunomodulators like cytokines, to enhance humoral and cellular immune responses (14,C16). These need to be expressed efficiently and stably, sometimes from different loci within the genome and preferably without the persistence of the recombinant computer virus in the host or its integration into the EC089 host genome. Other factors that have to be considered when choosing a vector platform are the lack of toxicity in the host, affordable large-scale production, or issues with preexisting vector immunity that may lead to a reduced immune response to the vector (15, 16). Table 2 compares the viral vectors discussed in this article with respect to their individual vector characteristics and suitability as multivalent/multipathogen viral vector candidates. TABLE 2 Comparison of the viral vectors discussed in this minireview based on specific vector characteristics with a single-stranded, negative-sense RNA genome. Several MV strains (e.g., the Moraten, Schwarz, or Edmonston measles computer virus vaccine strain) have been safely used as vaccines for many years; they exhibit strong immunogenic properties leading to lifelong protection. MV replication occurs purely in the cytoplasm of infected cells, which contributes to a consistent security profile because no viral DNA is usually integrated into the host’s genome (17). The ability to achieve the stable insertion of more than 5,000 nucleotides into the MV genome (unlike other RNA viruses), together with the efficient expression of transgenes and low production costs, makes MV a valuable potential vaccine delivery system (18, 19). In many multipathogen vaccine candidates based on measles computer virus vectors, the computer virus itself is used as an immunogen. One example is usually a MV vector (Moraten Berna measles vaccine strain sequence) human papillomavirus (HPV) vaccine candidate (rMVb2-HPV-L1), generated by Cantarella and colleagues (20), which proved to induce strong humoral immune responses against MV and HPV in Rabbit Polyclonal to MRPS36 transgenic interferon alpha receptor-deficient (IFNAR?/?) CD46 mice. Reverse genetics technology enabled the rescue of MV (an RNA computer virus) from cloned plasmid DNA, made up of MV antigenomes, in cell culture using the human helper cell collection 293-3-46. The structural L1 protein sequence from HPV16, found to be immunogenic in previous studies, was inserted between the M and P sequence of the MV, forming virus-like particles after expression (20,C22). The stability EC089 of the transgene expression, an important factor for a successful vaccine candidate, was tested over 10 passages in MRC-5 cells (human.