Hexon-chimaeric adenovirus serotype 5 vectors circumvent pre-existing anti-vector immunity

Abstract

A common viral immune evasion strategy involves mutating viral surface proteins in order to evade host neutralizing antibodies. Such immune evasion tactics have not previously been intentionally applied to the development of novel viral gene delivery vectors that overcome the critical problem of anti-vector immunity. Recombinant, replication-incompetent adenovirus serotype 5 (rAd5) vector-based vaccines for human immunodeficiency virus type 1 and other pathogens have proved highly immunogenic in preclinical studies but will probably be limited by the high prevalence of pre-existing anti-Ad5 immunity in human populations, particularly in the developing world. Here we show that rAd5 vectors can be engineered to circumvent anti-Ad5 immunity. We constructed novel chimaeric rAd5 vectors in which the seven short hypervariable regions (HVRs) on the surface of the Ad5 hexon protein were replaced with the corresponding HVRs from the rare adenovirus serotype Ad48. These HVR-chimaeric rAd5 vectors were produced at high titres and were stable through serial passages in vitro. HVR-chimaeric rAd5 vectors expressing simian immunodeficiency virus Gag proved comparably immunogenic to parental rAd5 vectors in naive mice and rhesus monkeys. In the presence of high levels of pre-existing anti-Ad5 immunity, the immunogenicity of HVR-chimaeric rAd5 vectors was not detectably suppressed, whereas the immunogenicity of parental rAd5 vectors was abrogated. These data demonstrate that functionally relevant Ad5-specific neutralizing antibodies are focused on epitopes located within the hexon HVRs. Moreover, these studies show that recombinant viral vectors can be engineered to circumvent pre-existing anti-vector immunity by removing key neutralizing epitopes on the surface of viral capsid proteins. Such chimaeric viral vectors may have important practical implications for vaccination and gene therapy.

Wild-type adenoviruses from groups A–F evoke unique innate immune responses, of which HAd3 and SAd23 are partially complement dependent

“…25 In most cases, alternative serotype Ads are not cross-neutralized by antibodies directed against another serotype. 26,27 Furthermore, the incidence rate of seroconversion to many alternative serotype HAds in many cases are significantly lower than the seroconversion rates noted for HAd5. 28 These facts have justified multiple investigations into the use of alternative serotype Ads for potential use in numerous human gene transfer applications.…”

Changing the adenovirus fiber for retaining gene delivery efficacy in the presence of neutralizing antibodies

“…34,35 A hexon-switch experiment would help understand whether anti-fiber NAbs are unique with regard to sero-switching for efficacy, or whether the same might be true for any anti-capsid NAb. 36 Moreover, completely non-Ad5 serotypes might be useful, 13,28,37,38 if the appealing attributes of Ad5 (for example, high gene expression, in vivo stability, easy production, safety) can be retained. This should not be taken for granted, as Ad5 has become the single most popular gene therapy vector because of these attributes, and there is no guarantee that they would apply to other serotypes.…”

Status and challenges of filovirus vaccines

“…There are recent reports in mice and rhesus macaques that pre-existing immunity to Ad5 did diminish the response to Ad5-vectored vaccines [90,91], however, another study in mice using Ad5-vectors have found that pre-existing immunity did not prevent the development of immunity [92]. Priming with DNA plasmids expressing the gene of interest may be sufficient to overcome pre-existing immunity to the viral vector; however, to date this has only been demonstrated in mice [93][94][95]. Other serotypes that are not as prevalent in the human population (or that do not typically infect humans at all) might be used in place of Ad5 [90] but the original studies would have to be repeated with the new constructs to demonstrate comparable protection.…”