Alphavirus-Based Vaccines

Lundstrom, Kenneth

In a combined vaccine approach, SFV DNA vectors and recombinant adenovirus expressing the classical swine fever virus (CSFV) E2 glycoprotein elicited higher titers of neutralizing antibodies in pigs [26] . After challenges with the virulent CSFV Shimen strain, no symptoms of viremia were observed, for the combined vaccine, whereas vaccination with adenovirus alone resulted in viremia in one pig of five. Furthermore, sequential immunization with SIN and VEE replicon particles expressing the type 1 HIV gp140 envelope (Env) and trimeric Env protein in MF59 adjuvant provided partial protection in macaques against intravenous challenges with high doses of simian-human immunodeficiency virus (SHIV) [61] . The administration could be further extended to intramuscular and mucosal delivery [62] . Different degrees of protection were observed against challenges with SHIV after mucosal administration. In contrast, intramuscular vaccination rendered macaques to be completely resistant to SHIV. In cotton rats, SIN DNA vectors carrying the hemagglutinin (pMSIN-H) and fusion proteins (pMSINH-FdU) elicited neutralizing antibodies, mucosal and systemic antibody-secreting cells, memory B-cells and IFNɤ secreting T-cells [47] . Priming with pMSIN-H provided 100% protection against challenges with pulmonary measles. However, pMSINH-FdU priming was observed only after a boost with live measles virus vaccine. In another study, chimeric VEE/SIN replicon particles were applied for the expression of measles virus hemagglutinin (H) and fusion (F) proteins, which elicited high-titer neutralizing antibody and IFNɤ-producing T-cells in macaques after intradermal vaccination [48] . Protection from rash and viremia was obtained after challenges with wild-type measles virus 12-17 months after vaccination. Alphaviruses have also been subjected to the development of smallpox vaccines by the introduction of A33R, B5R, A27L and L1R genes into VEE particles [59] . Vaccinated mice showed protective immunity. Furthermore, vaccination of macaques elicited strong antibody responses and was capable of neutralizing and inhibiting the spread of vaccinia and monkey pox viruses. SIN-based DNA vaccines have been developed against rabies [51] . In comparison to a conventional rabies DNA vaccine, the SIN DNA vaccine induced better humoral and cell-mediated immune responses in immunized mice and showed complete protection against challenge with the CVS rabies strain.