Phase 1 safety and immunogenicity trial of recombinant Lactococcus lactis expressing human papillomavirus Type 16 E6 oncoprotein vaccine in healthy females

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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 × 109 and 1 × 1010 CFU/mL of vaccine were similar and were higher than those of the 1 × 109 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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Human papillomavirus and cervical cancer.

Eileen M. Burd (2003)

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.

Paulo Maciag, Sinisa Radulovic, John Rothman (2009)

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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Probiotic supplementation restores normal microbiota composition and function in antibiotic-treated and in caesarean-born infants

Katri Korpela, Anne H Salonen, Outi Vepsäläinen … (2018)

Background Infants born by caesarean section or receiving antibiotics are at increased risk of developing metabolic, inflammatory and immunological diseases, potentially due to disruption of normal gut microbiota at a critical developmental time window. We investigated whether probiotic supplementation could ameliorate the effects of antibiotic use or caesarean birth on infant microbiota in a double blind, placebo-controlled randomized clinical trial. Mothers were given a multispecies probiotic, consisting of Bifidobacterium breve Bb99 (Bp99 2 × 108 cfu) Propionibacterium freundenreichii subsp. shermanii JS (2 × 109cfu), Lactobacillus rhamnosus Lc705 (5 × 109 cfu) and Lactobacillus rhamnosus GG (5 × 109 cfu) (N = 168 breastfed and 31 formula-fed), or placebo supplement (N = 201 breastfed and 22 formula-fed) during pregnancy, and the infants were given the same supplement. Faecal samples of the infants were collected at 3 months and analyzed using taxonomic, metagenomic and metaproteomic approaches. Results The probiotic supplement had a strong overall impact on the microbiota composition, but the effect depended on the infant’s diet. Only breastfed infants showed the expected increase in bifidobacteria and reduction in Proteobacteria and Clostridia. In the placebo group, both birth mode and antibiotic use were significantly associated with altered microbiota composition and function, particularly reduced Bifidobacterium abundance. In the probiotic group, the effects of antibiotics and birth mode were either completely eliminated or reduced. Conclusions The results indicate that it is possible to correct undesired changes in microbiota composition and function caused by antibiotic treatments or caesarean birth by supplementing infants with a probiotic mixture together with at least partial breastfeeding. Trial registration clinicaltrials.gov NCT00298337. Registered March 2, 2006. Electronic supplementary material The online version of this article (10.1186/s40168-018-0567-4) contains supplementary material, which is available to authorized users.