Adenoviral vector type 26 encoding Zika virus (ZIKV) M-Env antigen induces humoral and cellular immune responses and protects mice and nonhuman primates against ZIKV challenge

Abstract

In 2015, there was a large outbreak of Zika virus (ZIKV) in Brazil. Despite its relatively mild impact on healthy adults, ZIKV infection during pregnancy has been associated with severe birth defects. Currently, there is no ZIKV vaccine available, but several vaccine candidates based on the ZIKV membrane (M) and envelope (Env) structural proteins showed promising results in preclinical and clinical studies. Here, the immunogenicity and protective efficacy of a non-replicating adenoviral vector type 26 (Ad26) that encodes the ZIKV M-Env antigens (Ad26.ZIKV.M-Env) was evaluated in mice and non-human primates (NHP). Ad26.ZIKV.M-Env induced strong and durable cellular and humoral immune responses in preclinical models. Humoral responses were characterized by Env-binding and ZIKV neutralizing antibody responses while cellular responses were characterized by ZIKV reactive CD4+ and CD8+ T cells. Importantly, a single immunization with a very low dose of 4x107 vp of Ad26.ZIKV.M-Env protected mice from ZIKV challenge. In NHP, a single immunization with a typical human dose of 1x1011 vp of Ad26.ZIKV.M-Env also induced Env-binding and ZIKV neutralizing antibodies and Env and M specific cellular immune responses that associated with complete protection against viremia from ZIKV challenge as measured in plasma and other body fluids. Together these data provide the rationale to progress the Ad26.ZIKV.M-Env candidate vaccine to clinical testing.

CpG-Recoding in Zika Virus Genome Causes Host-Age-Dependent Attenuation of Infection With Protection Against Lethal Heterologous Challenge in Mice

“…Isolation and stimulation of splenocytes were performed as previously described (43,44). Freshly isolated mouse splenocytes (10 6 cells/well) were seeded in RPMI supplemented with 10% FBS, 1x MEM Non-Essential Amino Acids Solution (Gibco 11140-050) 1x Penicillin-Streptomycin, 50 µg/ml Gentamycin, 10 mM HEPES (MP Biomedicals 1688449), 1 mM Sodium Pyruvate (Gibco 11360-070), and 50 µM 2-mercaptoethanol and stimulated (20 h, +37 • C, 5% CO 2 ) with a pool of 146 15-meric overlapping peptides derived from E protein of ZIKV (JPT PM-ZIKV-E, 2 µg/ml per peptide).…”

Adenovirus serotype 26 utilises sialic acid bearing glycans as a primary cell entry receptor

“…Species D adenoviruses are of special interest as vaccine vectors. Their ability to induce robust cellular and humoral immunogenic responses in humans, coupled with low seroprevalence rates in the general population( 30, 33 ) makes them attractive platforms for vaccines, as evidenced by their progression through clinical trials for HIV( 55, 56 ), Zika( 57 ), and Ebola treatment( 58, 59 ). However, there remains a lack of understanding regarding their basic biology and mechanisms of cellular infection.…”

“…However, there remains a lack of understanding regarding their basic biology and mechanisms of cellular infection. This is exemplified by Adenovirus serotype 26 (HAdV-D26), which is being investigated as a vaccine vector for zika( 57 ), HIV( 60 ), respiratory syncytial virus( 61 ), and has entered phase III clinical trials as an Ebola vaccine( 58 ).…”

Characterization of a Species E Adenovirus Vector as a Zika virus vaccine

“…However, high levels of pre-existing immunity to Ad5 has led to the development of alternative Ad vectors based on low-seroprevalent human or animal Adenoviruses 24 . Along with Ad5 vectors [25][26][27] , vaccines for ZIKV have been developed using Adenovirus type Ad2 28 , Ad26 29,30 , rhesus monkey Ad52 8 , chimpanzee Ad7 31 , and gorilla Ad 32 .…”

“…(B) The dilution of sera required to inhibit 50% of RVP infection events (EC50) is reported. The limit of detection of these assays was a reciprocal serum dilution of 60, with negative samples reported as half the limit of detection(30). The magnitude of ADE is reported as the largest increase of GFPexpressing K562 cells observed at any serum dilution as compared to the no serum control (expressed as foldincrease over background).…”