Radical C-H Sulfonation of Arenes: Its Applications on Bioactive and DNA-Encoded Molecules.

The photocatalyst-free electron donor-acceptor (EDA) complex photochemistry was deemed to expand the potential of photodriven radical chemistry. Here, we report a cross-coupling reaction of thianthrenium salt functionalized arenes and sodium sulfinates via a photopromoted single electron transfer (SET) process of an EDA complex. A series of biarylsulfones were obtained with high site-selectivity and reactivity. This mild and practical radical reaction could be applied on the bioactive and DNA-encoded molecules.

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.

Safety and immunogenicity of an Escherichia coli-produced bivalent human papillomavirus type 6/11 vaccine: A dose-escalation, randomized, double-blind, placebo-controlled phase 1 trial.

A dose-escalation, randomized, double-blind, placebo-controlled phase 1 clinical trial enrolled 145 eligible participants aged 18-55 years in March 2015 in Liuzhou, China. Stratified by age and sex, the participants were randomly assigned to receive either 30, 60, or 90 µg of the HPV-6/11 vaccine (n = 41/40/40) or the parallel placebo vaccine (n = 8/8/8) with a 0/1/6-month dose-escalation schedule. Participants were actively followed-up to record local and systemic AEs occurring within 30 days after each vaccination, and SAEs occurred in 7 months. Blood and urine samples of each participant were collected before and 2 days after the first and third vaccination to determine changes in routine blood, serum biochemical, and urine indexes. Serum HPV-6/11-specific IgG and neutralizing antibody levels at month 7 were analyzed. A total of 79 adverse events were reported, and no SAEs occurred. The incidences of total adverse reactions in the 30 µg, 60 µg, and 90 µg HPV vaccine groups and the control group were 31.7%, 50.0%, 42.5%, and 62.5%, respectively. All but one of the adverse reactions was mild or moderate with grade 1 or 2. No vaccine-related changes with clinical significance were found in paired blood and urine indexes before and after vaccinations. All the participants in the per-protocol set seroconverted at month 7 for both IgG and neutralizing antibodies. The candidate novel Escherichia-coli-produced bivalent HPV-6/11 vaccine has been preliminarily proven to be well tolerated and with robust immunogenicity in a phase 1 clinical study, supporting further trials with larger sample size. The study has been registered at ClinicalTrials.gov (NCT02405520).

Comparison of HPV neutralizing and IgG antibodies in unvaccinated female adolescents.

Aims: To analyze the consistency between HPV-neutralizing antibodies and specific total IgG antibodies in unvaccinated females. Materials & methods: Serum samples from 978 unvaccinated Chinese females aged 9-26 years were measured for antibodies against HPV-16 and HPV-18 using simultaneous pseudovirus-based neutralization assay and ELISA. Results: There was a moderate level of consistency between HPV-neutralizing antibodies and specific IgG in females aged 18-26 years (Cohen's κ coefficient for HPV-16 and HPV-18: 0.52 and 0.38) and poor consistency in those aged 9-17 years (Cohen's κ coefficient <0.05). However, Cohen's κ coefficient remained almost unchanged in sensitivity analysis when the IgG antibody cutoff value was raised. Conclusion: HPV-neutralizing antibodies are a more specific indicator for the evaluation of HPV natural humoral immunity.

Long-Term immunopersistence and safety of the Escherichia coli-produced HPV-16/18 bivalent vaccine in Chinese adolescent girls.

The study assessed long-term immunopersistence and safety of the Escherichia coli (E. coli)-produced HPV-16/18 bivalent vaccine. In total, 979 participants in the initial immunogenicity noninferiority study, including girls aged 9-14 years who were randomized in a 1:1 ratio to receive 2 doses at months 0 and 6 (n = 301) or 3 doses at months 0, 1 and 6 (n = 304); girls aged 15-17 years (n = 149) and women aged 18-26 years (n = 225) who received 3 doses of the vaccine, were invited to participate in follow-up to 30 months post vaccination (NCT03206255). Serum samples were collected at months 18 and 30, and anti-HPV-16/18 IgG antibodies were measured by enzyme-linked immunosorbent assay. Serious adverse events (SAEs) occurred from month 7 through month 30 were recorded. At month 30, in the per-protocol set, all participants remained seropositive, except for one girl in the 9-14 years (2 doses) group who seroconverted to negative for HPV-18. HPV-16 and HPV-18 antibody levels were higher in girls aged 9-17 years who received 3 doses (125.3 and 60.2 IU/ml) than in women aged 18-26 years who received 3 doses (72.6 and 28.3 IU/ml), and those in girls aged 9-14 years who received 2 doses (73.2 and 24.9 IU/ml) were comparable to those in women aged 18-26 years who received 3 doses. No SAEs were reported to be causally related to vaccination. The E. coli-produced bivalent HPV-16/18 vaccine is safe and induces persistent protective antibodies for up to 30 months after vaccination in girls aged 9-17 years receiving 2 or 3 doses.

Enhancing the Potential of Miniature-Scale DNA-Compatible Radical Reactions via an Electron Donor-Acceptor Complex and a Reversible Adsorption to Solid Support Strategy.

DNA-encoded library (DEL) technology is a powerful tool in the discovery of bioactive probe molecules and drug leads. Mostly, the success in DEL technology stems from the molecular diversity of the chemical libraries. However, the construction of DELs has been restricted by the idiosyncratic needs and the required low concentration (∼1 mM or less) of the library intermediate. Here, we report visible-light-promoted on-DNA radical coupling reactions via an electron donor-acceptor (EDA) complex and a reversible adsorption to solid support (RASS) strategy. This protocol provides a unique solution to the challenges of increasing the reactivity of highly diluted DNA substrates and reducing the residues of heavy metals from photocatalysts. A series of on-DNA indole sulfone and selenide derivatives were obtained with good to quantitative conversions. It is anticipated that these mild-condition on-DNA radical reactions will significantly improve the chemical diversity of DELs and find widespread utility to DEL construction.

Naturally acquired HPV antibodies against subsequent homotypic infection: A large-scale prospective cohort study.

BACKGROUND: Although recent studies have suggested that naturally acquired Human papillomavirus (HPV) antibodies are partly protective against subsequent homotypic infection, the extent of protection remains indecisive. Here, we evaluate the protective effect of neutralizing and IgG antibodies simultaneously. METHODS: In a cohort of 3634 women aged 18-45 years from the control arm of a phase III trial of the HPV-16/18 bivalent vaccine, participants were tested for neutralizing antibodies by pseudovirion-based neutralization assay (PBNA) and IgG antibodies by enzyme-linked immunosorbent assay (ELISA) at baseline. HPV-16/18 incident and persistent infections were identified using cervical specimens periodically collected during the 5·5 years of follow-up. The protective effects of HPV-16/18 neutralizing and IgG antibodies against homotypic infection were assessed using a Cox proportional hazard model. FINDINGS: For the persistent infection (PI) endpoints of HPV-16/18 lasting for over 6/12 months, a prevalence of type-specific neutralizing antibodies was highly protective (6-month PI: hazard ratio (HR) = 0·16, 95% confidence interval (CI): 0·04, 0·65; 12-month PI: HR = 0·23, 95% CI: 0·06, 0·94), whereas a prevalence of IgG antibodies was associated with minor and non-significant protection (6-month PI: HR = 0·66, 95% CI: 0·40, 1·09; 12-month PI: HR = 0·66, 95% CI: 0·36, 1·20). After increasing the cut-off value to the median IgG level, the risk of 6-month PI was significantly lower in seropositive vs seronegative women (HR = 0·38, 95% CI: 0·18, 0·83). INTERPRETATION: Naturally acquired antibodies are associated with a substantially reduced risk of subsequent homotypic infection. FUNDING: NSFC; The Fujian Province Health Education Joint Research Project; Xiamen Science and Technology Major Project; CIFMS; and Xiamen Innovax.

Inflammation-related adverse reactions following vaccination potentially indicate a stronger immune response.

Concerns about vaccine safety are an important reason for vaccine hesitancy, however, limited information is available on whether common adverse reactions following vaccination affect the immune response. Data from three clinical trials of recombinant vaccines were used in this post hoc analysis to assess the correlation between inflammation-related solicited adverse reactions (ISARs, including local pain, redness, swelling or induration and systematic fever) and immune responses after vaccination. In the phase III trial of the bivalent HPV-16/18 vaccine (Cecolin®), the geometric mean concentrations (GMCs) for IgG anti-HPV-16 and -18 (P<0.001) were significantly higher in participants with any ISAR following vaccination than in those without an ISAR. Local pain, induration, swelling and systemic fever were significantly correlated with higher GMCs for IgG anti-HPV-16 and/or anti-HPV-18, respectively. Furthermore, the analyses of the immunogenicity bridging study of Cecolin® and the phase III trial of a hepatitis E vaccine yielded similar results. Based on these results, we built a scoring model to quantify the inflammation reactions and found that the high score of ISAR indicates the strong vaccine-induced antibody level. In conclusion, this study suggests inflammation-related adverse reactions following vaccination potentially indicate a stronger immune response.

Comparing immunogenicity of the Escherichia coli-produced bivalent human papillomavirus vaccine in females of different ages.

BACKGROUND: The safety and efficacy of a recently licensed Escherichia coli (E. coli)-produced bivalent HPV vaccine have been shown. Specific antibody levels are important indicators to evaluate the efficacy of vaccination. Therefore, we compared the immunogenicity of this HPV 16/18 vaccine in females of different ages in this study. METHODS: Immunogenicity of the vaccine was analyzed in the per-protocol sets for immunogenicity (PPS-I) of a phase III trial and an immune-bridging trial. The serum samples were collected at month 0 and one month after the final dose (month 7) to assess the specific IgG antibody levels by ELISA. The seroconversion rates, geometric mean concentration (GMC), and geometric mean increase (GMI) were used to assess the immunogenicity of the test vaccine. The non-linear association of antibody levels with age was estimated via natural cubic splines and the Akaike information criterion was used to assess optimal model. RESULTS: By combining the PPS-I data from the two trials, nearly all of the females seroconverted for both HPV types. In the 3-dose group, the GMC of IgG to both HPV types decreased with increasing age, especially in adolescent girls and young women. For HPV-16 and -18, the declining trend slowed down in women older than 32 and 35 years old, respectively. The GMI ranged from 648 to 80 for HPV-16 and from 218 to 42 for HPV-18. In the 2-dose group, the specific antibodies for HPV-16 and -18 peaked in girls aged 10 years with GMIs of 401 and 98, respectively, and then decreased with age. CONCLUSIONS: The E. coli-produced bivalent HPV-16/18 vaccine induced specific antibody responses in females aged 9-45 years. The antibody levels were inversely associated with age, and the declining trends slowed down in women older than 32 or 35 years for HPV-16 and -18, respectively.

Immunogenicity of an Escherichia coli-produced bivalent human papillomavirus vaccine under different vaccination intervals.

A new Escherichia coli-produced human papillomavirus (HPV)-16/18 vaccine has been shown to be safe and highly efficacious and was recently licensed in China. As a post hoc analysis of the phase III trial, this study aimed to assess the impact of vaccination time deviations on the specific antibody response and guide the better usage of this vaccine in the real world. A total of 3689 healthy women aged 18-45 years old were randomly assigned to receive the bivalent HPV-16/18 vaccine according to a 0-, 1- and 6-month schedule with a wide vaccination interval. The first vaccination interval between the 1st and 2nd doses (the 1st interval) was divided into three groups: 28-40 d, 41-50 d and 51-60 d. The second vaccination interval between the 2nd and 3rd doses (the 2nd interval) was divided into three groups: 103-139 d, 140-160 d and 161-198 d. The reverse cumulative curves for the IgG of the three groups with different 1st vaccination intervals or with different 2nd vaccination intervals at month 7 almost overlapped for both HPV-16 and HPV-18. Compared with the standard vaccination schedule (a 1st interval of 28-40 d and a 2nd interval of 140-160 d) subgroup, all the subgroups had GMC ratios greater than 0.83, with the lower limit of 95% CIs higher than 0.64. In conclusion, a slight deviation in the vaccination time of the 2nd and 3rd doses has only a minor, insignificant impact on the immune response induced by the Escherichia coli-produced HPV-16/18 vaccine.

Immunogenicity noninferiority study of 2 doses and 3 doses of an Escherichia coli-produced HPV bivalent vaccine in girls vs. 3 doses in young women.

A new HPV-16/18 bivalent vaccine expressed by the Escherichia coli has been proven to be efficacious in adult women. A randomized, immunogenicity noninferiority study of this candidate vaccine was conducted in December 2015 in China. Girls aged 9-14 years were randomized to receive 2 doses at months 0 and 6 (n=301) or 3 doses at months 0, 1 and 6 (n=304). Girls aged 15-17 years (n=149) and women aged 18-26 years (n=225) received 3 doses. The objectives included noninferiority analysis of the IgG geometric mean concentration (GMC) ratio (95% CI, lower bound>0.5) to HPV-16 and HPV-18 at month 7 in girls compared with women. In the per-protocol set, the GMC ratio of IgG was noninferior for girls aged 9-17 years receiving 3 doses compared with women (1.76 (95% CI, 1.56, 1.99) for HPV-16 and 1.93 (95% CI, 1.69, 2.21) for HPV-18) and noninferior for girls aged 9-14 years receiving 2 doses compared with women (1.45 (95% CI, 1.25, 1.62) for HPV-16 and 1.17 (95% CI, 1.02, 1.33) for HPV-18). Noninferiority was also demonstrated for neutralizing antibodies. The immunogenicity of the HPV vaccine in girls receiving 3 or 2 doses was noninferior compared with that in young adult women.

Lot-to-lot consistency study of an Escherichia coli-produced bivalent human papillomavirus vaccine in adult women: a randomized trial.

An Escherichia. coli-produced HPV-16/18 bivalent vaccine has been proved to be well-tolerated and highly efficacious against diseases associated with vaccine HPV types. As a part of the multi-center, randomized, double-blind phase III clinical trial, this lot-to-lot consistency study aimed to assess the safety and immunogenicity consistency of this novel HPV vaccine, which is also one of the objectives of the phase III trial. A total of 3689 healthy women aged 18-45 years were enrolled and randomly assigned 1:1:1 to three lots of the HPV vaccine groups. The primary outcomes were the IgG antibody level at 1 month after the last dose (month 7). In the immunogenicity per-protocol set (PPS), almost all of the participants seroconverted at month 7 and remained seropositive at month 42. For each paired comparison of the three lot groups, the two-sides of 90% CIs of GMC ratios for both IgG and neutralizing antibodies for HPV-16 and HPV-18 at month 7 were within the equivalence interval [0.5, 2]. Lot consistency was also demonstrated at month 42. The majority of recorded solicited reactions were mild or moderate. The incidences of solicited reactions of Lot 2 and Lot 3 were slightly higher than Lot 1. However, the incidences of solicited reactions of ≥ grade 3 and solicited reactions by symptoms were all similar among the three lot groups. None of the SAEs was considered related to vaccination by the investigator. In conclusion, this study demonstrates lot-to-lot consistency of the 3 consecutive lots of the E. coli-produced HPV-16/18 bivalent vaccine.