Replacing adenoviral vector HVR1 with a malaria B cell epitope improves immunogenicity and circumvents preexisting immunity to adenovirus in mice
Takayuki Shiratsuchi, … , Stefan Worgall, Moriya Tsuji
Takayuki Shiratsuchi, … , Stefan Worgall, Moriya Tsuji
Published September 1, 2010
Citation Information: J Clin Invest. 2010;120(10):3688-3701. https://doi.org/10.1172/JCI39812.
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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 1

Structure of capsid-modified rAd.

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Structure of capsid-modified rAd. An immunodominant B cell epitope of P....
An immunodominant B cell epitope of P. yoelii CS protein (QGPGAP)3 was inserted in the hexon and/or in the fiber of WT/CS-GFP, which has optimized P. yoelii CS and GFP coding sequences as transgenes. P. yoelii CS protein contains 2 tandem repeats of (QGPGAP)19 and (PPQQ)7 in the central domain.