In animal models, E1-deleted human adenoviral recombinants of the serotype 5 (AdHu5) have shown high efficacy as vaccine carriers for different Ags including those of HIV-1. Humans are infected by common serotypes of human adenovirus such as AdHu5 early in life and a significant percentage has high levels of neutralizing Abs to these serotypes, which will very likely impair the efficacy of recombinant vaccines based on the homologous virus. To circumvent this problem, a novel replication-defective adenoviral vaccine carrier based on an E1-deleted recombinant of the chimpanzee adenovirus 68 (AdC68) was developed. An AdC68 construct expressing a codon-optimized, truncated form of gag of HIV-1 induces CD8+ T cells to gag in mice which at the height of the immune response encompass nearly 20% of the entire splenic CD8+ T cell population. The vaccine-induced immune response provides protection to challenge with a vaccinia gag recombinant virus. Induction of transgene-specific CD8+ T cells and protection against viral challenge elicited by the AdC68 vaccines is not strongly inhibited in animals preimmune to AdHu5 virus. However, the response elicited by the AdHu5 vaccine is greatly attenuated in AdHu5 preimmune animals.
Most cancerous lesions of the uterine cervix are linked to persistent infections with human papillomaviruses (HPV), most notably HPV-16 or -18. Vaccine-induced immune responses to the HPV early antigens E6 and E7, which contribute to cell transformation and are thus expressed in these cervical cancers, could potentially eradicate malignant cells. We generated recombinant vaccines based on E1-deleted adenovirus human strain 5 or on vaccinia virus strain Copenhagen expressing either the E6 or E7 oncoproteins of HPV-16. The different vaccines were compared in two experimental mouse tumor models employing Balb/c or C57Bl/6 mice. Data presented here demonstrate that depending on the model either CD4(+) or CD8(+) T cells provide protection to tumor cell challenge, resulting in striking differences in the efficacy of the four vaccines under investigation.
DNA vaccines expressing the E6 or E7 oncoproteins of human papilloma virus type 16 (HPV-16) in either their wild-type form or fused to sequences that affect intracellular trafficking were tested for induction of protective immunity against tumor cell challenge in two models based on BALB/c and C57Bl/6 mice. The DNA vaccines to E7 gave uniformly disappointing results, while the DNA vaccine that expressed E6 linked to a viral leader sequence protected BALB/c mice against tumor cell challenge given before or after vaccination. The efficacy of this vaccine could be enhanced by a DNA vector prime/viral vector boost regimen. In contrast, priming of mice with the DNA vaccines to E7 reduced the efficacy of a viral vector expressing the same antigen. C ervical cancer is most commonly a consequence of sexually transmitted, persistent infections with oncogenic types of HPVs, most notably HPV-16. 1 Cervical cancer is the second most common cause of cancer death in women worldwide, claiming approximately 300,000-500,000 lives each year. Upon sexual transmission, HPV-16 (and other oncogenic types of sexually transmitted HPVs) infects the basal and parabasal cells of the cervical mucosa where transcription and translation of the early antigens of HPV-16 leads to cellular atypia followed by preinvasive neoplasia. 2 Cellular transformation is initiated by the three viral oncoproteins, E5, E6 and E7, which cause dysregulation of cell cycle control. 2,3 The oncoproteins of HPV-16 being causative for transformation of HPV-16-infected cells are thereby natural targets for active immunotherapy of HPV-16-associated cervical cancer.A number of vaccine modalities to HPV-16 oncoprotein-expressing tumor cell lines have been tested in preclinical animal models focusing mainly on vaccines to E7, 4-10 although studies with vaccines to E6 4,7,10 and E5 11 have also been reported. Our vaccine effort initially focused on viral recombinant vaccines expressing the E6 or E7 protein. They showed that E1-deleted adenoviral vectors to E7 induce potent and tumor-protective CD8 þ T-cell responses in C57Bl/6 mice. In contrast, BALB/c mice displayed partial CD4 þ T-cell-mediated protection induced by vaccinia or adenoviral recombinant vaccines expressing the E6 of HPV-16 but could not be protected by the vaccines to E7. 7 In this report, we extended our studies to DNA vaccines expressing the E7 or E6 proteins of HPV-16. In addition to those expressing wild-type versions of the oncoproteins, we also tested DNA constructs that express the oncoproteins linked to various polypeptides that affect intracellular trafficking. In one construct, the oncoproteins were fused to a viral leader sequence that prevents nuclear localization and instead affects secretion. A second modification involved addition of a leader sequence and the lysosome-associated membrane protein (LAMP)-1, which channels proteins upon secretion into lysosomes resulting in improved association with MHC class II determinants. This modification, used previously for HPV-16 E7 vaccines, was shown ...
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