Abstract
Adenoviral vectored vaccines have shown considerable promise but could be improved by molecular adjuvants. Ligands in the TNF superfamily (TNFSF) are potential adjuvants for adenoviral vector (Ad5) vaccines based on their central role in adaptive immunity. Many TNFSF ligands require aggregation beyond the trimeric state (multi-trimerization) for optimal biological function. Here we describe Ad5 vaccines for HIV-1 Gag antigen (Ad5-Gag) adjuvanted with the TNFSF ligands 4-1BBL, BAFF, GITRL and CD27L constructed as soluble multi-trimeric proteins via fusion to Surfactant Protein D (SP-D) as a multimerization scaffold. Mice were vaccinated with Ad5-Gag combined with Ad5 expressing one of the SP-D-TNFSF constructs or single-chain IL-12p70 as adjuvant. To evaluate vaccine-induced protection, mice were challenged with vaccinia virus expressing Gag (vaccinia-Gag) which is known to target the female genital tract, a major route of sexually acquired HIV-1 infection. In this system, SP-D-4-1BBL or SP-D-BAFF led to significantly reduced vaccinia-Gag replication when compared to Ad5-Gag alone. In contrast, IL-12p70, SP-D-CD27L and SP-D-GITRL were not protective. Histological examination following vaccinia-Gag challenge showed a dramatic lymphocytic infiltration into the uterus and ovaries of SP-D-4-1BBL and SP-D-BAFF-treated animals. By day 5 post challenge, proinflammatory cytokines in the tissue were reduced, consistent with the enhanced control over viral replication. Splenocytes had no specific immune markers that correlated with protection induced by SP-D-4-1BBL and SP-D-BAFF versus other groups. IL-12p70, despite lack of anti-viral efficacy, increased the total numbers of splenic dextramer positive CD8+ T cells, effector memory T cells, and effector Gag-specific CD8+ T cells, suggesting that these markers are poor predictors of anti-viral immunity in this model. In conclusion, soluble multi-trimeric 4-1BBL and BAFF adjuvants led to strong protection from vaccinia-Gag challenge, but the protection was independent of standard immune markers. Soluble multi-trimeric SP-D-4-1BBL and SP-D-BAFF provide a novel technology to enhance adenoviral vector vaccines against HIV-1.
Highlights
The HIV pandemic continues to be a major concern worldwide and novel strategies are being investigated to develop effective HIV-1 prophylactic vaccines
We propose that the activity of BAFF as a DNA vaccine adjuvant may be mediated by the expression of BAFF receptor (BAFF-R) on T cells
In this report we investigated the ability of soluble multi-trimers of TNF superfamily ligands 4-1BBL, BAFF, GITRL and CD27L to enhance Ad5 viral vector vaccines
Summary
The HIV pandemic continues to be a major concern worldwide and novel strategies are being investigated to develop effective HIV-1 prophylactic vaccines. Despite disappointing results from the Step clinical trial and related animal trials [1,2,3,4,5] adenoviral vectors continue to be evaluated as a component of HIV-1 vaccines, including prime/boost vaccine strategies [6,7,8]. Despite encouraging results in animal models, a Phase II clinical trial of DNA prime/Ad5 boost vaccination was recently discontinued due to failure to protect against infection [17]. These data suggest that novel methods are required to alter the immune response generated by adenoviral vectors, potentially through the use of novel molecular adjuvants
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