Replacing adenoviral vector HVR1 with a malaria B cell epitope improves immunogenicity and circumvents preexisting immunity to adenovirus in mice
Takayuki Shiratsuchi, Urvashi Rai, Anja Krause, Stefan Worgall, Moriya Tsuji
Takayuki Shiratsuchi, Urvashi Rai, Anja Krause, Stefan Worgall, Moriya Tsuji
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Research Article Infectious disease

Replacing adenoviral vector HVR1 with a malaria B cell epitope improves immunogenicity and circumvents preexisting immunity to adenovirus in mice

Abstract

Although adenovirus (Ad) has been regarded as an excellent vaccine vector, there are 2 major drawbacks to using this platform: (a) Ad-based vaccines induce a relatively weak humoral response against encoded transgenes, and (b) preexisting immunity to Ad is highly prevalent among the general population. To overcome these obstacles, we constructed an Ad-based malaria vaccine by inserting a B cell epitope derived from a Plasmodium yoelii circumsporozoite (CS) protein (referred to as the PyCS-B epitope) into the capsid proteins of WT/CS-GFP, a recombinant Ad expressing P. yoelii CS protein and GFP as its transgene. Multiple vaccinations with the capsid-modified Ad induced a substantially increased level of protection against subsequent malaria challenge in mice when compared with that of unmodified WT/CS-GFP. Increased protection correlated with augmented antibody responses against the PyCS-B epitope expressed in the capsid. Furthermore, replacement of hypervariable region 1 (HVR1) of the Ad capsid proteins with the PyCS-B epitope circumvented neutralization of the modified Ad by preexisting Ad-specific antibody, both in vivo and in vitro. Importantly, the immunogenicity of the Ad-containing PyCS-B epitope in the HVR1 and a P. yoelii CS transgene was maintained. Overall, this study demonstrates that the HVR1-modifed Ad vastly improves upon Ad as a promising malaria vaccine platform candidate.

Authors

Takayuki Shiratsuchi, Urvashi Rai, Anja Krause, Stefan Worgall, Moriya Tsuji

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Figure 5

P. yoelii CS–specific immune responses after a single immunizing dose of capsid-modified rAd.

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P. yoelii CS–specific immune responses after a single immunizing dose o...
(A) Immunization regimen. Groups of naive BALB/c mice (5 per group) were immunized with 1 × 108, 1 × 109, or 1 × 1010 v.p. of various rAds intramuscularly, and P. yoelii CS–specific humoral and cell-mediated immune responses (CMI) were measured at 2 weeks after immunization. (B) Anti-(QGPGAP)3 and anti-(PPQQ)4 responses. Antibody titer was determined using an end point dilution titer by ELISA. Horizontal bars represent the geometric mean. (C) P. yoelii CS–specific CD8+ T cell response. P. yoelii CS–specific CD8+ T cell responses were determined using IFN-γ ELISPOT assay. Horizontal bars represent the mean.