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. Recently, a new approach has been taken in an attempt to augment Ad-induced humoral response by inserting a B epitope in Ad capsid proteins, such as hexon, fiber, penton, and pIX (13-16). Also, in an effort to circumvent preexisting immunity to Ad5, other Ad serotypes with lower seroprevalence, such as Ad11, Ad35, Ad26, Ad48, Ad49, and Ad50, have been evaluated as alternative Ad vaccine platforms. These other Ad serotypes have been shown to induce immune response to a transgene, despite of the presence of anti-Ad5 immunity Substitution of Ad5 hexon, which among capsid proteins is the main target of neutralizing antibodies, with that of other serotypes has also been constructed in order to escape preexisting anti-Ad5 immunity For this study, in an attempt to enhance humoral response to the P. yoelii CS protein and circumvent preexisting immunity to Ad5, we have constructed and analyzed what we believe to be several novel recombinant Ads (rAds), which express a B epitope of the P. yoelii CS protein of malaria parasites, in hexon and/or fiber, in addition to containing the P. yoelii CS transgene.