Vaccine vectors derived from a large collection of simian adenoviruses induce potent cellular immunity across multiple species.
Replication-defective adenovirus vectors based on human serotype 5 (Ad5) induce protective immune responses against diverse pathogens and cancer in animal models, as well as elicit robust and sustained cellular immunity in humans. However, most humans have neutralizing antibodies to Ad5, which can impair the immunological potency of such vaccines. Here, we show that rare serotypes of human adenoviruses, which should not be neutralized in most humans, are far less potent as vaccine vectors than Ad5 in mice and nonhuman primates, casting doubt on their potential efficacy in humans. To identify novel vaccine carriers suitable for vaccine delivery in humans, we isolated and sequenced more than 1000 adenovirus strains from chimpanzees (ChAd). Replication-defective vectors were generated from a subset of these ChAd serotypes and screened to determine whether they were neutralized by human sera and able to grow in human cell lines. We then ranked these ChAd vectors by immunological potency and found up to a thousandfold variation in potency for CD8+ T cell induction in mice. These ChAd vectors were safe and immunologically potent in phase 1 clinical trials, thereby validating our screening approach. These data suggest that the ChAd vectors developed here represent a large collection of non-cross-reactive, potent vectors that may be exploited for the development of new vaccines.
Okairos, via dei Castelli Romani 22, 00040 Pomezia, Rome, Italy.
Stefano
S
Colloca
Eleanor
E
Barnes
Antonella
A
Folgori
Virginia
V
Ammendola
Stefania
S
Capone
Agostino
A
Cirillo
Loredana
L
Siani
Mariarosaria
M
Naddeo
Fabiana
F
Grazioli
Maria Luisa
ML
Esposito
Maria
M
Ambrosio
Angela
A
Sparacino
Marta
M
Bartiromo
Annalisa
A
Meola
Kira
K
Smith
Ayako
A
Kurioka
Geraldine A
GA
O'Hara
Katie J
KJ
Ewer
Nicholas
N
Anagnostou
Carly
C
Bliss
Adrian V S
AV
Hill
Cinzia
C
Traboni
Paul
P
Klenerman
Riccardo
R
Cortese
Alfredo
A
Nicosia
D000256:Adenoviridae; D000261:Adenoviruses, Simian / Q000235:genetics*; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000821:virology; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005822:Genetic Vectors; D006801:Humans; D007107:Immune System; D007111:Immunity, Cellular / Q000235:genetics / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism; D051379:Mice; D002679:Pan troglodytes; D010802:Phylogeny; D013045:Species Specificity
D007371:Interferon-gamma