Evaluation of an inactivated Ross River virus vaccine in active and passive mouse immunization models and establishment of a correlate of protection

Holzer, Georg W.; Coulibaly, Sogue; Aichinger, Gerald; Savidis-Dacho, Helga; Mayrhofer, Josef; Brunner, Susanne M.; Schmid, Karl; Kistner, Otfried; Aaskov, John; Falkner, Falko G.; Ehrlich, Hartmut J.; Barrett, Perry; Kreil, Thomas R.

doi:10.1016/j.vaccine.2011.03.089

Cited by 35 publications

(36 citation statements)

References 39 publications

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“…Since vaccines against RRV are expected to also protect from CHIKV infection (57,63), it is of interest to look at possible CoP in this model. Indeed, while the mouse models used in our studies differ significantly both in the mouse strains used (wild-type strain and IFN-␣ knockout) and in the challenge dose, total IgG titers around 10 4 or slightly below also seem to be protective against RRV (62). Furthermore, levels of neutralizing antibodies correlated linearly with IgG titers, where neutralizing antibody titers of about 15 to 20 were protective.…”

Section: Discussionmentioning

confidence: 79%

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Prime-Boost Immunization Strategies against Chikungunya Virus

Holzmann

Lum

Kümmerer

et al. 2014

J Virol

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Chikungunya virus (CHIKV) is a reemerging mosquito-borne alphavirus that causes debilitating arthralgia in humans. Here we describe the development and testing of novel DNA replicon and protein CHIKV vaccine candidates and evaluate their abilities to induce antigen-specific immune responses against CHIKV. We also describe homologous and heterologous prime-boost immunization strategies using novel and previously developed CHIKV vaccine candidates. Immunogenicity and efficacy were studied in a mouse model of CHIKV infection and showed that the DNA replicon and protein antigen were potent vaccine candidates, particularly when used for priming and boosting, respectively. Several prime-boost immunization strategies eliciting unmatched humoral and cellular immune responses were identified. Further characterization by antibody epitope mapping revealed differences in the qualitative immune responses induced by the different vaccine candidates and immunization strategies. Most vaccine modalities resulted in complete protection against wild-type CHIKV infection; however, we did identify circumstances under which certain immunization regimens may lead to enhancement of inflammation upon challenge. These results should help guide the design of CHIKV vaccine studies and will form the basis for further preclinical and clinical evaluation of these vaccine candidates. IMPORTANCE As of today, there is no licensed vaccine to prevent CHIKV infection. In considering potential new vaccine candidates, a vaccinethat could raise long-term protective immunity after a single immunization would be preferable. While humoral immunity seems to be central for protection against CHIKV infection, 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 various vaccine candidates results in potent responses, combined approaches significantly enhance responses, suggesting that such approaches need to be considered in the further development of an efficacious CHIKV vaccine.

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Section: Discussionmentioning

confidence: 79%

“…Inactivated vaccine candidates against the closely related alphavirus Ross River virus (RRV) have also been evaluated in a mouse model (62). Since vaccines against RRV are expected to also protect from CHIKV infection (57,63), it is of interest to look at possible CoP in this model.…”

Section: Discussionmentioning

confidence: 99%

Prime-Boost Immunization Strategies against Chikungunya Virus

Holzmann

Lum

Kümmerer

et al. 2014

J Virol

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“…In addition, natural antibodies present in the sera of uninfected C57BL/6 mice were able to partially inhibit CHIKV (75). Furthermore, therapies based on passively transferred anti-CHIKV neutralizing antibodies conferred protection to A129 mice (42,44,45,70,71,73,(76)(77)(78) and nonhuman primates (37) against CHIKV and protection to mice against more distantly related arthrogenic alphaviruses (43,93,96), establishing the key role of humoral immunity in the control of CHIKV replication. Interestingly, complete protection from CHIKV challenge can be obtained using adoptive transfer of antibodies induced by immunization with a CHIKV/IRES vaccine candidate and occurs in the absence of CD4 ϩ /CD8 ϩ T cells (42); a titer of 35 for neutralizing antibodies was sufficient to protect mice from a challenge with 100 PFU of CHIKV (42).…”

Section: Discussionmentioning

confidence: 98%

A Novel Poxvirus-Based Vaccine, MVA-CHIKV, Is Highly Immunogenic and Protects Mice against Chikungunya Infection

García-Arriaza

Cepeda

Holzmann

et al. 2014

J Virol

106

127

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There is a need to develop a single and highly effective vaccine against the emerging chikungunya virus (CHIKV), which causes a severe disease in humans. Here, we have generated and characterized the immunogenicity profile and the efficacy of a novel CHIKV vaccine candidate based on the highly attenuated poxvirus vector modified vaccinia virus Ankara (MVA) expressing the CHIKV C, E3, E2, 6K, and E1 structural genes (termed MVA-CHIKV). MVA-CHIKV was stable in cell culture, expressed the CHIKV structural proteins, and triggered the cytoplasmic accumulation of Golgi apparatus-derived membranes in infected human cells. Furthermore, MVA-CHIKV elicited robust innate immune responses in human macrophages and monocyte-derived dendritic cells, with production of beta interferon (IFN-␤), proinflammatory cytokines, and chemokines. After immunization of C57BL/6 mice with a homologous protocol (MVA-CHIKV/MVA-CHIKV), strong, broad, polyfunctional, and durable CHIKVspecific CD8؉ T cell responses were elicited. The CHIKV-specific CD8 ؉ T cells were preferentially directed against E1 and E2 proteins and, to a lesser extent, against C protein. CHIKV-specific CD8؉ memory T cells of a mainly effector memory phenotype were also induced. The humoral arm of the immune system was significantly induced, as MVA-CHIKV elicited high titers of neutralizing antibodies against CHIKV. Remarkably, a single dose of MVA-CHIKV protected all mice after a high-dose challenge with CHIKV. In summary, MVA-CHIKV is an effective vaccine against chikungunya virus infection that induced strong, broad, highly polyfunctional, and long-lasting CHIKV-specific CD8 ؉ T cell responses, together with neutralizing antibodies against CHIKV. These results support the consideration of MVA-CHIKV as a potential vaccine candidate against CHIKV. IMPORTANCEWe have developed a novel vaccine candidate against chikungunya virus (CHIKV) based on the highly attenuated poxvirus vector modified vaccinia virus Ankara (MVA) expressing the CHIKV C, E3, E2, 6K, and E1 structural genes (termed MVA-CHIKV). Our findings revealed that MVA-CHIKV is a highly effective vaccine against chikungunya virus, with a single dose of the vaccine protecting all mice after a high-dose challenge with CHIKV. Furthermore, MVA-CHIKV is highly immunogenic, inducing strong innate responses: high, broad, polyfunctional, and long-lasting CHIKV-specific CD8 ؉ T cell responses, together with neutralizing antibodies against CHIKV. This work provides a potential vaccine candidate against CHIKV.

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“…We have developed a Vero cell culture-derived whole-virus inactivated RRV vaccine which is highly protective in animal models of viremia and disease (10,11). In a phase 1/2 dose-finding study, the whole-virus RRV vaccine was safe and well-tolerated in healthy adults, and a 2.5-g alum-adjuvanted dose was demonstrated to be best tolerated and to induce the highest RRV-specific total IgG and RRV-neutralizing antibody responses.…”

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confidence: 99%

“…In a phase 1/2 dose-finding study, the whole-virus RRV vaccine was safe and well-tolerated in healthy adults, and a 2.5-g alum-adjuvanted dose was demonstrated to be best tolerated and to induce the highest RRV-specific total IgG and RRV-neutralizing antibody responses. In passive transfer studies (10), administration of human vaccinee sera from the phase 1/2 study protected RRV-challenged mice from viremia and development of arthritic symptoms. Based on the good correlation between neutralizing antibody titers and total IgG antibody titers in human sera and protection of animals, a conservative correlate of protection was defined as a neutralizing antibody titer of Ն1:10.…”

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confidence: 99%