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      Phase 1 Safety and Immunogenicity Trial of Recombinant Lactococcus lactis Expressing Human Papillomavirus Type 16 E6 Oncoprotein Vaccine

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          Abstract

          The present study purposed to investigate the safety, tolerability, and immunogenicity of the therapeutic NZ8123-HPV16-optiE6 vaccine, following oral vaccination. The safety and tolerability were evaluated. Specific serum immunoglobulin G (IgG) and vaginal IgA antibodies were calculated by ELISA, and E6-specific IFN-γ-secreting T cells were counted by enzyme-linked immune absorbent spot (ELISpot) assay in cervical lymphocytes and PBMC samples. The vaccine was well tolerated, and no serious adverse effects were observed in vaccine recipients. Statistical analysis showed that all vaccine groups had significant increases in antibody levels at day 60 after baseline. The time to peak activation in E6-specific IFN-γ-secreting CD8 + CTL responses was seen at month 1 after last vaccination. According to the results, the humoral immune and cell-mediated responses for the vaccine groups that received 5 × 10 9 and 1 × 10 10 CFU/mL of vaccine were similar and were higher than those of the 1 × 10 9 CFU/mL group, indicating the dose-dependency of the NZ8123-HPV16-optiE6 vaccine following oral administration. Low antibody levels compared with the placebo groups were recorded at month 6 after the last vaccination. Interestingly, long-term E6-specific CTL responses were observed during follow-up. It was concluded that oral immunization with the NZ8123-HPV-16-optiE6 vaccine is safe, induces persistent immunity, and is reasonably well tolerated.

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          Most cited references 27

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          Human papillomavirus and cervical cancer.

          Of the many types of human papillomavirus (HPV), more than 30 infect the genital tract. The association between certain oncogenic (high-risk) strains of HPV and cervical cancer is well established. Although HPV is essential to the transformation of cervical epithelial cells, it is not sufficient, and a variety of cofactors and molecular events influence whether cervical cancer will develop. Early detection and treatment of precancerous lesions can prevent progression to cervical cancer. Identification of precancerous lesions has been primarily by cytologic screening of cervical cells. Cellular abnormalities, however, may be missed or may not be sufficiently distinct, and a portion of patients with borderline or mildly dyskaryotic cytomorphology will have higher-grade disease identified by subsequent colposcopy and biopsy. Sensitive and specific molecular techniques that detect HPV DNA and distinguish high-risk HPV types from low-risk HPV types have been introduced as an adjunct to cytology. Earlier detection of high-risk HPV types may improve triage, treatment, and follow-up in infected patients. Currently, the clearest role for HPV DNA testing is to improve diagnostic accuracy and limit unnecessary colposcopy in patients with borderline or mildly abnormal cytologic test results.
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            The first clinical use of a live-attenuated Listeria monocytogenes vaccine: a Phase I safety study of Lm-LLO-E7 in patients with advanced carcinoma of the cervix.

            Invasive carcinoma of the cervix (ICC) is the second most common cancer in women worldwide. Lm-LLO-E7 vaccine is a live-attenuated Listeria monocytogenes (Lm) that secretes the HPV-16 E7 antigen fused to a non-hemolytic fragment of the Lm protein listeriolysin O (LLO). In this Phase I trial, the safety of Lm-LLO-E7 was assessed in 15 patients with previously treated metastatic, refractory or recurrent ICC. Patients received 1 of 3 dose levels of Lm-LLO-E7 (1 x 10(9)CFU, 3.3 x 10(9)CFU or 1 x 10(10)CFU) as an intravenous infusion, followed by a second dose 3 weeks later. All patients experienced a flu-like syndrome which responded to non-prescription symptomatic treatment. Severe (grade 3) adverse events related to Lm-LLO-E7 were reported in 6 patients (40%), but no grade 4 adverse events were observed. At the highest dose some patients had severe fever and dose limiting hypotension. By the end of the study protocol, 2 patients had died, 5 had progressed, 7 had stable disease and 1 qualified as a partial responder. This study shows for the first time that a live-attenuated Lm is safe to be administered to late stage ICC patients.
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              Modulation of humoral immune response through probiotic intake.

               H Fang,  S Seppo,  T Elina (2000)
              Thirty healthy volunteers were randomised into three different treatment groups and consumed Lactobacillus GG, Lactococcus lactis or placebo (ethyl cellulose) for 7 days. On days 1, 3 and 5, an attenuated Salmonella typhi Ty21a oral vaccine was given to all subjects to mimic an enteropathogenic infection. All subjects responded well to the vaccine, but no significant differences were observed in numbers of IgA-, IgG- and IgM-secreting cells among the different groups. There was a trend towards a greater increase in specific IgA among the subjects receiving the vaccine in combination with Lactobacillus GG. Those receiving L. lactis with their vaccine evinced significantly higher CR3 receptor expression on neutrophils than those receiving either the placebo or Lactobacillus GG. These results indicate that probiotics may influence differently the immune response to oral S. typhi vaccine and that the immunomodulatory effect of probiotics is strain-dependent.
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                Author and article information

                Contributors
                Journal
                Mol Ther Methods Clin Dev
                Mol Ther Methods Clin Dev
                Molecular Therapy. Methods & Clinical Development
                American Society of Gene & Cell Therapy
                2329-0501
                29 August 2019
                13 December 2019
                29 August 2019
                : 15
                : 40-51
                Affiliations
                [1 ]Department of Microbiology, Faculty of Basic Sciences, Science and Research Branch, Islamic Azad University, Tehran 1477893855, Iran
                [2 ]Department of Virology, Faculty of Medicine, Iran University of Medical Sciences, Tehran 1449614535, Iran
                [3 ]Department of Parasitology, Pasteur Institute of Iran, Tehran 1316943551, Iran
                Author notes
                []Corresponding author: Amir Hossein Mohseni, Department of Microbiology, Faculty of Basic Sciences, Science and Research Branch, Islamic Azad University, Tehran 1477893855, Iran. amho.mohseni@ 123456gmail.com
                [∗∗ ]Corresponding author: Hossein Keyvani, Department of Virology, Faculty of Medicine, Iran University of Medical Sciences, Tehran 1449614535, Iran. keyvanlab@ 123456yahoo.com
                Article
                S2329-0501(19)30085-3
                10.1016/j.omtm.2019.08.005
                6804834
                © 2019 The Author(s)

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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