Article

Mechanism of Ad5 Vaccine Immunity and Toxicity: Fiber Shaft Targeting of Dendritic Cells

Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
PLoS Pathogens (Impact Factor: 7.56). 03/2007; 3(2):e25. DOI: 10.1371/journal.ppat.0030025
Source: PubMed

ABSTRACT

Recombinant adenoviral (rAd) vectors elicit potent cellular and humoral immune responses and show promise as vaccines for HIV-1, Ebola virus, tuberculosis, malaria, and other infections. These vectors are now widely used and have been generally well tolerated in vaccine and gene therapy clinical trials, with many thousands of people exposed. At the same time, dose-limiting adverse responses have been observed, including transient low-grade fevers and a prior human gene therapy fatality, after systemic high-dose recombinant adenovirus serotype 5 (rAd5) vector administration in a human gene therapy trial. The mechanism responsible for these effects is poorly understood. Here, we define the mechanism by which Ad5 targets immune cells that stimulate adaptive immunity. rAd5 tropism for dendritic cells (DCs) was independent of the coxsackievirus and adenovirus receptor (CAR), its primary receptor or the secondary integrin RGD receptor, and was mediated instead by a heparin-sensitive receptor recognized by a distinct segment of the Ad5 fiber, the shaft. rAd vectors with CAR and RGD mutations did not infect a variety of epithelial and fibroblast cell types but retained their ability to transfect several DC types and stimulated adaptive immune responses in mice. Notably, the pyrogenic response to the administration of rAd5 also localized to the shaft region, suggesting that this interaction elicits both protective immunity and vector-induced fevers. The ability of replication-defective rAd5 viruses to elicit potent immune responses is mediated by a heparin-sensitive receptor that interacts with the Ad5 fiber shaft. Mutant CAR and RGD rAd vectors target several DC and mononuclear subsets and induce both adaptive immunity and toxicity. Understanding of these interactions facilitates the development of vectors that target DCs through alternative receptors that can improve safety while retaining the immunogenicity of rAd vaccines.

Download full-text

Full-text

Available from: Rebecca L Sheets
  • Source
    • "Ad5 belongs to the human serotype C group, and its major cellular receptor is the coxsackie and adenovirus receptor (CAR). The highly immunogenic nature of Ad5 has been shown to relate to its ability to transduce broad antigen presenting cells including dendritic cells and monocytes, and to activate innate cytokine production [23,24]. The major obstacles to the use of these human adenovirus vectors as vaccine carriers are the high prevalence of anti-vector neutralizing antibodies in human populations as in the case of rAd5 or lower immunogenicity to the antigen inserts in the case of rAd28 and rAd35. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Adenoviral vector-based vaccines are currently being developed for several infectious diseases and cancer therapy, but pre-exising seroprevalence to such vectors may prevent their use in broad human populations. In this study, we investigated the potential of low seroprevalence non-human primate rAd vectors to stimulate cellular and humoral responses using HIV Env glycoprotein (gp) as the representative antigen. Mice were immunized with novel simian or chimpanzee rAd (rSAV or rChAd) vectors encoding HIV gp or SIV gp by single immunization or in heterologous prime/boost combinations (DNA/rAd; rAd/rAd; rAd/NYVAC or Ad/rLCM), and adaptive immunity was assessed. Among the rSAV and rChAd tested, SAV16 or ChAd3 vector alone generated the most potent immune responses. The DNA/rSAV regimen also generated immune responses similar to the DNA/Ad5 regimen. ChAd63 prime/ChAd3 boost and ChAd3 prime/NYVAC boost induced similar or even higher levels of CD4+ and CD8+ T-cell and IgG responses as compared to Ad28/Ad5, one of the most potent combinations of human rAds. The optimized vaccine regimen stimulated improved cellular immune responses and neutralizing antibodies against HIV compared to the DNA/rAd5 regimen. Based on these results, this type of novel rAd vector and its prime/boost combination regimens represent promising candidates for vaccine development.
    Full-text · Article · Oct 2015 · Vaccine
  • Source
    • "Many types of vaccine vectors have achieved varying degrees of scrutiny in the tumor immunology field and each have their advantages and disadvantages relating to issues of safety, patient compliance, financial cost, immune potency and labor intensiveness [34] [35]. Delivery of vaccines using attenuated viruses encoding tumor antigen can be a highly efficient way of generating antitumor cellular immune responses, however, such vaccines may be prone to inducing unwanted immune responses or be neutralized by the host's own antibodies [5] [36] [37] [38] [39]. Delivery of antigen complexed with alum tends to favor antibody responses at the expense of cellular immune responses and thus is considered unsuitable for use in cancer vaccines [40]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The aim of the research presented here was to determine the characteristics and immunostimulatory capacity, in vivo, of antigen and adjuvant co-loaded into microparticles made from a novel diaminosulfide polymer, poly(4,4'-trimethylenedipiperdyl sulfide) (PNSN), and to assess their potential as cancer vaccine vectors. PNSN microparticles co-loaded with the antigen, ovalbumin (OVA), and adjuvant, CpG 1826, (PNSN(OVA + CpG)) were fabricated and characterized for size (1.64 μm diameter; PDI = 0.62), charge (-23.1 ± 0.3), and loading efficiencies of antigen (7.32 μg/mg particles) and adjuvant (0.95 μg/mg particles). The ability of PNSN(OVA + CpG) to stimulate cellular and humoral immune responses in vivo was compared with other PNSN microparticle formulations as well as with poly(lactic-co-glycolic acid)(PLGA)-based microparticles, co-loaded with OVA and CpG (PLGA(OVA + CpG)), an adenovirus encoding OVA (Ad5-OVA), and OVA delivered with incomplete Freund's adjuvant (IFA(OVA)). In vivo OVA-specific IgG1 responses, after subcutaneous prime/boosts in mice, were similar when PNSN(OVA + CpG) and PLGA(OVA + CpG) were compared and the presence of CpG 1826 within the PNSN microparticles demonstrated significantly improved responses when compared to PNSN microparticles loaded with OVA alone (PNSN(OVA)), plus or minus soluble CpG 1826. Cellular immune responses to all particle-based vaccine formulations ranged from being negligible to modest with PNSN(OVA + CpG) generating the greatest responses, displaying significantly increased levels of OVA-specific CD8+ T lymphocytes compared to controls and IFA(OVA) treated mice. Finally, it was shown that of all vaccination formulations tested PNSN(OVA + CpG) was the most protective against subsequent challenge with an OVA-expressing tumor cell line, E.G7. Thus, microparticles made from poly(diaminosulfide)-based macromolecules possess promising potential as vaccine vectors and, as demonstrated here, may have impact as cancer vaccines in particular.
    Full-text · Article · Sep 2015 · Journal of Controlled Release
  • Source
    • "Aside from being one of the most efficient vectors for gene delivery in vivo, Ad5 and other Ad strains (e.g. Ad35) possess an inherent ability to, not only potently infect, but also stimulate dendritic cells [8], [9]. In a mouse model of prostate cancer it was shown that Ad5 encoding human PSA (Ad5-PSA) could induce functionally effective PSA-specific CD8+ T lymphocyte responses [10]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Standard cancer therapies, particularly those involving chemotherapy, are in need of modifications that both reduce short-term and long-term side effects as well as improve the overall survival of cancer patients. Here we show that combining low-dose chemotherapy with a therapeutic vaccination using an adenovirus encoding a model tumor-associated antigen, ovalbumin (Ad5-OVA), had a synergistic impact on survival in tumor-challenged mice. Mice that received the combinatorial treatment of Ad5-OVA plus low-dose 5-fluorouracil (5-FU) had a 95% survival rate compared to 7% and 30% survival rates for Ad5-OVA alone and 5-FU alone respectively. The presence of 5-FU enhanced the levels of OVA-specific CD8(+) T lymphocytes in the spleens and draining lymph nodes of Ad5-OVA-treated mice, a phenomenon that was dependent on the mice having been tumor-challenged. Thus 5-FU may have enhanced survival of Ad5-OVA-treated mice by enhancing the tumor-specific immune response combined with eliminating tumor bulk. We also investigated the possibility that the observed therapeutic benefit may have been derived from the capacity of 5-FU to deplete MDSC populations. The findings presented here promote the concept of combining adenoviral cancer vaccines with low-dose chemotherapy.
    Full-text · Article · Jun 2013 · PLoS ONE
Show more