Pre-existing immunity against Ad vectors: Humoral, cellular, and innate response, what's important?

Fausther-Bovendo, Hugues; Kobinger, Gary P

Prime-boost regimens may also help to overcome pre-existing Ad immunity. Prime-boost regimens do not bypass pre-existing Ad immunity per se. Immune responses induced by prime-boost regimens are still decreased by pre-existing immunity; however they are of sufficient magnitude to still confer protection. Indeed, more robust immune responses are obtained after heterologous prime-boost regimens compared with single vaccination or homologous prime-boost immunizations. 91, 92 This rule also holds true for heterologous Ad prime/boost regimens. 12, 45, [93] [94] [95] [96] The usefulness of prime-boost regimens in overcoming preexisting Ad immunity was demonstrated more than a decade ago using several DNA primes followed by a single Ad boost. Yang and colleagues demonstrated that cellular responses generated by DNA primes and HAd boost (DNA/HAd5) were not affected by pre-existing HAd5 immunity. In addition, although generated humoral responses were significantly reduced by pre-existing immunity, the antibody titers obtained were similar to those generated in na€ ıve mice immunized with homologous HAd5 prime-boost. 97 The ability of a DNA prime to circumvent pre-existing immunity was further suggested in a clinical trial. In tested individuals, pre-existing HAd5 immunity did not affect T cell responses induced by a DNA prime, HAd5 boost regimen, while pre-existing HAd5 immunity decreases cellular responses generated after a single HAd5 injection. 98 In addition to DNA/HAd, heterologous prime-boost regimens involving Ad from different serotypes may also prove protective in HAd5 immune subjects. Pre-clinical studies involving ChAd68/ChAd1 prime-boost immunizations have shown encouraging signs. Indeed, although compare with na€ ıve animals immune responses generated after ChAd68/ChAd1 prime-boost immunization were decreased in HAd5 pre-immune NHPs, stronger humoral responses were obtained compared with HAd5 homologous prime-boost. 99 Finally, it will be a great interest to determine whether prime-boost regimens including Ad vectors in combination with other vaccine platforms such as modified vaccinia virus ankara (MVA)are also able to provide protection despite pre-existing immunity. Indeed in pre-clinical studies, regimens involving MVA and Ad encoding plasmodium berghei CS protein or severe acute respiratory syndrome (SARS) S protein were able to induce very robust T cell and Ab responses of higher magnitude than Ad/DNA regimens expressing the same insert. 93, 100 ChAd63/MVA prime-boost are even being tested in various stages of clinical trials against Malaria, HIV and HCV. 101 Results from these trials will be crucial in terms of determining the ability of ChAd/MVA prime-boost regimens to overcome pre-existing HAd immunity. It is worth noting that prime-boost immunization has also been used to overcome preexisting MVA immunity. 102 One attractive feature of developing prime-boost regimens to circumvent pre-existing immunity is that it does not require the development of additional Ad vectors. Existing Ad vectors, especially those with robust immunogenicity can be used. However, determining which of the numerous vaccine platforms available, including DNA, VSV, AAV, and MVA, are best suited for priming or boosting of Ad vectors will be crucial. In addition, prime-boost regimens are time consuming thus precluding the rapid induction of protective immunity, which can be desirable in emergency vaccination situations, for example against pathogens tha