Mice were challenged 7 weeks after the last immunization with 106PFU of CHIKV in the feet. epitope mapping revealed differences in the qualitative immune responses induced by the different vaccine candidates and immunization strategies. Rabbit polyclonal to ACE2 Most vaccine modalities resulted in complete protection against wild-type CHIKV contamination; however, we did identify circumstances under which certain immunization regimens may lead to enhancement of inflammation upon challenge. These results should help Istradefylline (KW-6002) guideline the design of CHIKV vaccine studies and will form the basis for further preclinical and clinical evaluation of these vaccine candidates. IMPORTANCEAs of today, there is no licensed vaccine to prevent CHIKV contamination. In considering potential new vaccine candidates, a vaccine that could raise long-term protective immunity after a single immunization would be preferable. While humoral immunity seems to be central for protection against CHIKV contamination, we do not yet fully understand the correlates of protection. Therefore, in the absence of a functional vaccine, there is a need to evaluate a number of different candidates, assessing their merits when they are used either in a single immunization or in a homologous or heterologous prime-boost modality. Here we show that while single immunization with numerous vaccine candidates results in potent responses, combined methods significantly enhance responses, suggesting that such methods need to be considered in the further development of an efficacious CHIKV vaccine. == INTRODUCTION == Chikungunya computer virus (CHIKV) is an alphavirus of the familyTogaviridaethat is usually transmitted via bites ofAedesmosquitoes and causes debilitating polyarthralgia in humans (1). During the past decade, CHIKV has reemerged and caused large epidemics, predominantly in Africa and Asia, Istradefylline (KW-6002) but occasionally on other continents, including Europe and North America (2). The quick spread of CHIKV is Istradefylline (KW-6002) usually exemplified by the recent outbreaks in several of the Caribbean Islands, with an imminent risk of further spread in the surrounding countries with nave populations (3). Thus, CHIKV has now been listed as a Category C Priority Pathogen by the National Institute of Allergy and Infectious Diseases (NIAID) in the United States and is considered a global health problem. Chikungunya is usually a Makonde word that means which bends up and refers to the stooped posture of infected individuals caused by incapacitating arthralgia, the hallmark of CHIKV contamination (4,5). Other symptoms of CHIKV contamination include a quick onset of high fever, headache, skin rash, and myalgia. Most of the symptoms normally resolve in weeks but can develop into chronic joint problems and, in rare cases, even mortality (68). There is currently no CHIKV-specific treatment and no licensed vaccine that can prevent CHIKV contamination (9). Several CHIKV vaccine candidates are under development (9), including attenuated (1016) or inactivated (1719) CHIKV, alphavirus chimeras (2022), and subunit (2327) and genetic (21,2831) vaccines. Moreover, we have reported previously around the construction and preclinical evaluation of novel CHIKV Istradefylline (KW-6002) vaccine candidates, based on attenuated CHIKV (12) or recombinant altered vaccinia computer virus Ankara (MVA) expressing CHIKV antigens (MVA-CHIKV) (29), that were able to induce strong immunogenicity and efficacy in a mouse model. Both these and other CHIKV vaccine candidates have been evaluated in separate studies as single vaccine modalities, administered by single or multiple immunizations. In this study, in addition to the previously explained attenuated 5nsp3 (12) and recombinant MVA-CHIKV (29) vaccine candidates, novel p62-E1 protein- and DNA replicon (DREP)-based CHIKV vaccines were compared. We evaluated immunogenicity and efficacy in mice immunized with several homologous and heterologous prime-boost immunization protocols using unique CHIKV vaccine candidates representing different antigens and vaccine modalities. The DREP platform differs from standard DNA plasmids in that it encodes the alphavirus (CHIKV) replicase, which drives the production of the subgenomic RNA and thus the expression of the encoded CHIKV antigen. Moreover, DREPs also possess intrinsic adjuvant properties, since the replicase and RNA intermediates stimulate the production of type 1 interferons (IFNs) and apoptosis (3234). Promising results have been reported for DNA replicons generated from other alphaviruses, including Istradefylline (KW-6002) Semliki Forest computer virus (3537), Sindbis computer virus (38,39), and Venezuelan equine encephalitis computer virus (40), when they are used for priming immunizations prior to boosting with other vaccine modalities (36). The heterologous prime-boost approach takes advantage of the unique immune profiles induced by the different vaccine platforms. For example, both attenuated and genetic vaccines are produced endogenously and thus can give rise to T-cell-mediated immune responses. In contrast, protein antigens generally lack the ability to elicit cytotoxic T cell responses and are thus limited to the induction of humoral responses. Combining different vaccine strategies in heterologous prime-boost immunizations should.
