Head-to-head immunogenicity comparison of an Escherichia coli-produced 9-valent human papillomavirus vaccine and Gardasil 9 in women aged 18-26 years in China: a randomised blinded clinical trial.

BACKGROUND: An Escherichia coli-produced human papillomavirus (HPV) 16 and 18 bivalent vaccine (Cecolin) was prequalified by WHO in 2021. This study aimed to compare the immunogenicity of the E coli-produced HPV 9-valent vaccine Cecolin 9 (against HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58) with Gardasil 9. METHODS: This was a randomised, single-blind trial conducted in China. Healthy non-pregnant women aged 18-26 years, who were not breastfeeding and with no HPV vaccination history, were enrolled in the Ganyu Centre for Disease Control and Prevention (Lianyungang City, Jiangsu Province, China). Women were stratified by age (18-22 years and 23-26 years) and randomly assigned (1:1) using a permutated block size of eight to receive three doses of Cecolin 9 or Gardasil 9 at day 0, day 45, and month 6. All participants, as well as study personnel without access to the vaccines, were masked. Neutralising antibodies were measured by a triple-colour pseudovirion-based neutralisation assay. The primary outcomes, seroconversion rates and geometric mean concentrations (GMCs) at month 7, were analysed in the per-protocol set for immunogenicity (PPS-I). Non-inferiority was identified for the lower limit of the 95% CI of the GMC ratio (Cecolin 9 vs Gardasil 9) at a margin of 0·5 and a seroconversion rate difference (Cecolin 9-Gardasil 9) at a margin of -5%. This study was registered at ClinicalTrials.gov (NCT04782895) and is completed. FINDINGS: From March 14 to 18, 2021, a total of 553 potential participants were screened, of which 244 received at least one dose of Cecolin 9 and 243 received at least one dose of Gardasil 9. The seroconversion rates for all HPV types in both groups were 100% in the PPS-I, with the values of the lower limits of 95% CIs for seroconversion rate differences ranging between -1·8% and -1·7%. The GMC ratios of five types were higher than 1·0, with the highest ratio, for HPV 58, at 1·65 (95% CI 1·38-1·97), and those of four types were lower than 1·0, with the lowest ratio, for HPV 11, at 0·79 (0·68-0·93). The incidence of adverse reactions in both groups was similar (43% [104/244] vs 47% [115/243]). INTERPRETATION: Cecolin 9 induced non-inferior HPV type-specific immune responses compared with Gardasil 9 and is a potential candidate to accelerate the elimination of cervical cancer by allowing for global accessibility to 9-valent HPV vaccinations, especially in low-income and middle-income countries. FUNDING: National Natural Science Foundation, Fujian Provincial Natural Science Foundation, Xiamen Science and Technology Plan Project, Fundamental Research Funds for the Central Universities, CAMS Innovation Fund for Medical Sciences of China, and Xiamen Innovax.

Safety and immunogenicity of an Escherichia coli-produced 9-valent human papillomavirus L1 virus-like particle vaccine (types 6/11/16/18/31/33/45/52/58) in healthy adults: an open-label, dose-escalation phase 1 clinical trial.

Background: A safe and highly efficacious Escherichia coli (E. coli)-produced HPV 16/18 bivalent vaccine has been prequalified by the World Health Organization. Here, we conducted a single-center, open-label, dose-escalation phase 1 clinical trial to evaluate the safety and immunogenicity of the second-generation nonavalent HPV 6/11/16/18/31/33/45/52/58 vaccine. Method: Twenty-four eligible volunteers aged 18-45 years were enrolled in January 2019 in Dongtai, China and received 0.5 mL (135 µg) or 1.0 mL (270 µg) of the candidate vaccine with a 0/1/6-month dose-escalation schedule. Local and systemic adverse events (AEs) occurring within 30 days after each vaccination and serious adverse events (SAEs) occurring within 7 months were recorded. Blood samples from each participant were collected before and 2 days after the first and third vaccinations to determine changes in laboratory parameters. Serum IgG and neutralizing antibody (nAb) levels against each HPV type at month 7 were analyzed (ClinicalTrials.gov: NCT03813940). Findings: The incidences of total AEs in the 135 µg and 270 µg groups were 66.7% and 83.3%, respectively. All AEs were mild or moderate, and no SAEs were reported. No clinically significant changes were found in paired blood indices before or after any of the vaccinations. All the participants in the per-protocol set except for two who failed to seroconvert for HPV 11 or 58 in the 135 µg group seroconverted at month 7 for both IgG and nAbs. Interpretation: The candidate E. coli-produced 9vHPV vaccine has been preliminarily proven to be well tolerated and immunogenic, which encourages further studies in large cohorts with a wider age range. Funding: This study was supported by the National Natural Science Foundation of China, Fujian Provincial Natural Science Foundation, Fujian Province Health and Education Joint Research Program, Xiamen Science and Technology Plan Project, Fundamental Research Funds for the Central Universities, CAMS Innovation Fund for Medical Sciences of China, and Xiamen Innovax Biotechnology Co., Ltd.

Immunogenicity and safety of an Escherichia coli-produced human papillomavirus (types 6/11/16/18/31/33/45/52/58) L1 virus-like-particle vaccine: a phase 2 double-blind, randomized, controlled trial.

The Escherichia coli-produced human papillomavirus (HPV) 16/18 bivalent vaccine (Cecolin) has received prequalification by the World Health Organization based on its high efficacy and good safety profile. We aimed to evaluate the immunogenicity and safety of the second-generation nonavalent HPV 6/11/16/18/31/33/45/52/58 vaccine (Cecolin 9) through the randomized, blinded phase 2 clinical trial. Eligible healthy women aged 18-45 years were randomly (1:1) allocated to receive three doses of 1.0 mL (270 µg) of Cecolin 9 or placebo with a 0-1-6-month schedule. The primary endpoint was the seroconversion rate and geometric mean titer of neutralizing antibodies (nAbs) one month after the full vaccination course (month 7). The secondary endpoint was the safety profile including solicited adverse reactions occurring within 7 d, adverse events (AEs) occurring within 30 d after each dose, and serious adverse events (SAEs) occurring during the 7-month follow-up period. In total, 627 volunteers were enrolled and randomly assigned to Cecolin 9 (n = 313) or placebo (n = 314) group in Jiangsu Province, China. Almost all participants in the per-protocol set for immunogenicity (PPS-I) seroconverted for nAbs against all the nine HPV types at month 7, while two failed to seroconvert for HPV 11 and one did not seroconvert for HPV 52. The incidence rates of total AEs in the Cecolin 9 and placebo groups were 80.8% and 72.9%, respectively, with the majority of them being mild and recovering shortly. None of the SAEs were considered related to vaccination. In conclusion, the E. coli-produced 9-valent HPV (9vHPV) vaccine candidate was well tolerated and immunogenic, which warrants further efficacy studies in larger populations.

Efficacy, safety, and immunogenicity of an Escherichia coli-produced Human Papillomavirus (16 and 18) L1 virus-like-particle vaccine: end-of-study analysis of a phase 3, double-blind, randomised, controlled trial.

BACKGROUND: This Escherichia coli-produced bivalent HPV 16 and 18 vaccine was well tolerated and effective against HPV 16 and 18 associated high-grade genital lesions and persistent infection in interim analysis of this phase 3 trial. We now report data on long-term efficacy and safety after 66 months of follow-up. METHODS: This phase 3, double-blind, randomised, controlled trial was done in five study sites in China. Eligible participants were women aged 18-45 years, with intact cervix and 1-4 lifetime sexual partners. Women who were pregnant or breastfeeding, had chronic disease or immunodeficiency, or had HPV vaccination history were excluded. Women were stratified by age (18-26 and 27-45 years) and randomly (1:1) allocated by software (block randomisation with 12 codes to a block) to receive three doses of the E coli-produced HPV 16 and 18 vaccine or hepatitis E vaccine (control) and followed-up for 66 months. The primary outcomes were high-grade genital lesions and persistent infection (longer than 6 months) associated with HPV 16 or 18 in the per-protocol susceptible population. This trial was registered with ClinicalTrials.gov, NCT01735006. FINDINGS: Between Nov 22, 2012, and April 1, 2013, 8827 women were assessed for eligibility. 1455 women were excluded, and 7372 women were enrolled and randomly assigned to receive the HPV vaccine (n=3689) or control (n=3683). Vaccine efficacy was 100·0% (95% CI 67·2-100·0) against high-grade genital lesions (0 [0%] of 3310 participants in the vaccine group and 13 [0·4%] of 3302 participants in the control group) and 97·3% (89·9-99·7) against persistent infection (2 [0·1%] of 3262 participants in the vaccine group and 73 [2·2%] of 3271 participants in the control group) in the per-protocol population. Serious adverse events occurred at a similar rate between vaccine (267 [7·2%] of 3691 participants) and control groups (290 [7·9%] of 3681); none were considered related to vaccination. INTERPRETATION: The E coli-produced HPV 16 and 18 vaccine was well tolerated and highly efficacious against HPV 16 and 18 associated high-grade genital lesions and persistent infection and would supplement the global HPV vaccine availability and accessibility for cervical cancer prevention. FUNDING: National Natural Science Foundation of China, National Key R&D Program of China, Fujian Provincial Project, Fundamental Funds for the Central Universities, Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, and Xiamen Innovax.

[Simulation of δ18O in Platycladus orientalis leaf water with different kinetic fractionation coefficients].

Clarifying 18O isotope composition of leaf water (δL,b) would provide theoretical refe-rence for the study of leaf physiology and forest hydrology. We continuously monitored the concentration of atmospheric water vapor (Wa) and 18O isotope composition of atmospheric water vapor (δv) at the canopy of Platycladus lateralis plantation in the mountain area of Beijing. We analyzed the effects of kinetic fractionation coefficients Δk1(32%) and Δk2(28%) on the prediction of δL,b by combining the measured leaf water 18O isotope (δx) and δL,b of P. lateralis. The results showed that the diurnal variation of Wa was irregular. Atmospheric relative humidity (RH) showed a "V" shape of diurnal variation, and stomatal conductance (gs) increased first and then decreased at the diurnal scale. Wa, RH, and gs showed a significant negative correlation with δL,b when isotopes approached a steady-state equilibrium around noon. The kinetic fractionation coefficient Δk1 and Δk2 were applied to the Craig-Gordon model to predict δL,b under the isotopic quasi-steady-state condition. The results showed that the predicted values of Δk2 approached the observed values of δL,b. This result indicated that the application of Δk2 to the model was more consistent with the change of water isotope concentration in the leaves of P. lateralis in the mountain area of Beijing. These results would improve our understanding of water isotope enrichment model and evapotranspiration resolution model in leaves.

Safety and immunogenicity of hepatitis E vaccine in elderly people older than 65 years.

BACKGROUND: Hepatitis E virus (HEV) infection is a leading cause of acute hepatitis worldwide, and results in high morbidity and mortality rates among elderly people in China. The hepatitis E vaccine, Hecolin®, has been shown to be safe and highly efficacious among healthy adults aged 16-65 years old. However, there is no data about Hecolin® vaccination in elderly people older than 65 years (y). METHODS: An open-labeled, controlled trial was conducted to evaluate the safety and immunogenicity of Hecolin® among the elderly aged >65 y. A total of 601 eligible participants were enrolled. Among them, 200 elderly people aged >65 y and 201 adults aged 18-65 y were assigned to the Hecolin® groups and vaccinated at day 0, month 1 and month 6. Serum samples were collected for anti-HEV IgG determination at day 0 prior to immunization and at month 7. The remaining 200 elderly people aged >65 y were assigned to the safety control group and received no intervention but were instructed to report any adverse events that occurred during the whole study period in the same way as those in the Hecolin® groups. RESULTS: After receiving 3 doses of Hecolin® with the standard schedule, most (96.7%) of the vaccinated elderly people aged >65 y seroconverted at one month after the final dose (month 7). At month 7, the geometric mean concentrations of anti-HEV IgG were 5.36 (95% CI, 3.88-7.41) and 19.65 (95% CI, 16.81-22.98) among the baseline seronegative and seropositive elderly, respectively. Of the vaccinated elderly, 97.3% (177/182) had anti-HEV IgG levels higher than 1.0 WU/ml at month 7. Hecolin® was very well tolerated in this population. No vaccine-related SAEs were reported. CONCLUSIONS: Hecolin® is immunogenic and well tolerated in elderly people aged greater than 65 years.

DEPTOR inhibits cell proliferation and confers sensitivity to dopamine agonist in pituitary adenoma.

DEP domain-containing mechanistic target of rapamycin (mTOR)-interacting protein (DEPTOR) is an important modulator of mTOR, a highly conserved kinase whose hyperactivation is critically involved in a variety of human tumors. The role of DEPTOR playing in pituitary adenoma (PA) is largely unknown. Here, we reported that DEPTOR was downregulated in PA tissues, especially dopamine-resistant prolactinomas. Consistently, overexpression of DEPTOR inhibited pituitary tumor GH3 and MMQ cells proliferation in vitro and in vivo, and sensitized GH3 and MMQ cells to cabergoline (CAB), a dopamine agonist (DA). Conversely, knockdown of DEPTOR promoted GH3 and MMQ cells proliferation, and conferred cells resistance to CAB. Mechanistically, DEPTOR inhibited both mTOR Complex 1 (mTORC1) and 2 (mTORC2) activities in PA cells. In addition, DEPTOR expression level was increased to suppress mTOR kinase activity via decreasing E3 ubiquitin ligase, ßTrCP1, in response to CAB. Furthermore, DEPTOR enhanced autophagy-dependent cell death to confer cells sensitivity to CAB. Taken together, our results suggest that DEPTOR may be a potential target for the treatment of PAs.

Label-free detection of Cu(2+) and Hg(2+) ions using reconstructed Cu(2+)-specific DNAzyme and G-quadruplex DNAzyme.

Label-free metal ion detection methods were developed. To achieve these, a reconstructed Cu(2+)-specific DNA-cleaving DNAzyme (Cu(2+)-specific DNAzyme) with an intramolecular stem-loop structure was used. G-quadruplex-forming G-rich sequence(s), linked at the ends of double-helix stem of an intramolecular stem-loop structure, was partly caged in an intramolecular duplex or formed a split G-quadruplex. Cu(2+)-triggered DNA cleavage at a specific site decreased the stability of the double-helix stem, resulting in the formation or destruction of G-quadruplex DNAzyme that can effectively catalyze the 2,2'-azinobis(3-ethylbenzothiazoline)-6-sulfonic acid (ABTS)-H2O2 reaction. Based on these, two label-free, cost-effective and simple Cu(2+) sensors were designed. These two sensors followed different detection modes: 'turn-on' and 'turn-off'. As for the 'turn-on' sensor, the intramolecular stem-loop structure ensured a low background signal, and the co-amplification of detection signal by dual DNAzymes (Cu(2+)-specific DNAzyme and G-quadruplex DNAzyme) provided a high sensitivity. This sensor enabled the selective detection of aqueous Cu(2+) with a detection limit of 3.9 nM. Visual detection was possible. Although the 'turn-off' sensor gave lower detection sensitivity than the 'turn-on' one, the characteristics of cost-effectiveness and ease of operation made it an important implement to reduce the possibility of pseudo-positive or pseudo-negative results. Combining the ability of Hg(2+) ion to stabilize T-T base mismatch, above dual DNAzymes-based strategy was further used for Hg(2+) sensor design. The proposed sensor allowed the specific detection of Hg(2+) ion with a detection of 4.8 nM. Visual detection was also possible.