Active surveillance of hepatitis E: A 10-year epidemiological analysis in a city in eastern China.

AbstractBackground Hepatitis E virus (HEV) is an important cause of acute hepatitis, however, is highly neglected and largely underreported. This study aimed to describe the detailed epidemiology of hepatitis E (HE) through a 10-year surveillance. Method A community-based active hepatitis surveillance was conducted between November 2007 and October 2017 in 11 townships of Dongtai City in China, involving 355,673 residents. Serum samples were obtained from patients presenting with hepatitis symptoms for more than 3 days. Serum alanine aminotransferase (ALT) levels greater than 2.5 times the upper limit of normal (ULN) were considered acute hepatitis. Samples were subsequently tested for IgG and IgM anti-HEV antibodies, HEV RNA, and hepatitis B surface antigen (HBsAg). Result The data indicated the incidence of HE fluctuated downward from 2007 to 2017, with an average annual age-standardized incidence of 17.50 per 100,000, exceeding the 10.26 per 100,000 in the National Notifiable Disease Report System (NNDRS). The incidence was notably higher among males (20.95 per 100,000) and individuals aged 50-69 years (37.47 per 100,000). Genotype 4 (HEV-4) was the predominantly circulating genotype during the study period. Furthermore, the study revealed the incidence of hepatitis with HEV and hepatitis B virus (HBV) co-infection was 4.99 per 100,000. Conclusion The active surveillance system identified a higher incidence of HE compared to NNDRS, with a decreased prevalence over a 10-year period. While efforts are still needed to prevent HE in high-risk populations, including individuals with hepatitis B and the elderly.

Efficacy, reactogenicity, and safety of the adjuvanted recombinant zoster vaccine for the prevention of herpes zoster in Chinese adults ≥ 50 years: A randomized, placebo-controlled trial.

Phase III multi-country studies (ZOE-50/70) demonstrated that the adjuvanted recombinant zoster vaccine (RZV) was well tolerated and prevented herpes zoster (HZ) in healthy ≥ 50-year-olds, with a vaccine efficacy (VE) > 90% across age groups. These pivotal trials did not enroll participants from mainland China where RZV is licensed, therefore similar clinical data are missing for this population. In this phase IV observer-blind study (NCT04869982) conducted between 2021 and 2023 in China, immunocompetent and medically stable ≥ 50-year-olds were randomized 1:1 to receive two RZV or placebo doses, 2 months apart. This study assessed the VE (overall, as confirmatory objective, and descriptively by age category [50-69-year-olds/≥ 70-year-olds]), reactogenicity, and safety of RZV in this Chinese population. Of the 6138 enrolled participants, 99.2% completed the study. During a mean follow-up period of 15.2 (±1.1) months, 31 HZ episodes were confirmed (RZV = 0; placebo = 31) for an incidence rate of 0.0 vs 8.2 per 1000 person-years and an overall VE of 100% (89.82-100). The descriptive VE was 100% (85.29-100) for 50-69-year-olds and 100% (60.90-100) for ≥ 70-year-olds. Solicited adverse events (AEs) were more frequent in the RZV vs the placebo group (median duration: 1-3 days for both groups). Pain and fatigue were the most frequent local and general AEs (RZV: 72.1% and 43.4%; placebo: 9.2% and 5.3%). The frequencies of unsolicited AEs, serious AEs, potential immune-mediated diseases, and deaths were similar between both groups. RZV is well tolerated and efficacious in preventing HZ in Chinese ≥ 50-year-olds, consistent with efficacy studies including worldwide populations with similar age and medical characteristics.

What is the context? Herpes zoster, commonly known as shingles, is a painful rash resulting from the reactivation of the dormant virus causing chickenpox.Vaccines preventing shingles, such as Shingrix, were shown to be well tolerated and efficacious in healthy adults over 50 years of age from Europe, North and Latin America, Australia, and Asia (Taiwan, Hong Kong, Korea, Japan).However, data on real-world protective effect of Shingrix are limited in some regions where the vaccine is licensed for use, such as mainland China.What is new? We analyzed data from Chinese adults aged 50 years or older to determine the efficacy and safety of Shingrix.Around 6000 participants were divided in two equal groups to receive two doses of Shingrix or two doses of a placebo, given 2 months apart.We found that, during the study period, the vaccine was 100% efficacious in preventing shingles.We showed that the vaccine had an acceptable safety profile in this Chinese population.What is the impact? Shingrix is efficacious and well tolerated in Chinese adults over 50 years of age, as it is in similarly aged populations from other evaluated regions.

Comparison of 1 Versus 2 Doses of Quadrivalent Influenza Vaccine in 3-8-Year-Old Children with Different Immunological States - Jiangsu Province, China, 2021.

What is already known about this topic?: The quadrivalent influenza vaccine (QIV) provides protection against a broader range of influenza strains by including strains of influenza A/H1N1, A/H3N2, B/Yamagata, and B/Victoria. What is added by this report?: This study aimed to assess the immunogenicity and safety of administering a single dose compared to two doses of QIV in children, taking into consideration their previous influenza vaccination history. What are the implications for public health practice?: This study provides evidence supporting the use of a single dose of the QIV in children aged 3-8 years who have previously received two or more doses of influenza vaccine. However, children who have not been previously vaccinated with influenza vaccine should still adhere to the recommended schedule of receiving two doses.

Efficacy, safety, and immunogenicity of SARS-CoV-2 mRNA vaccine (Omicron BA.5) LVRNA012: a randomized, double-blind, placebo-controlled phase 3 trial.

Background: We aimed to evaluate the efficacy, safety, and immunogenicity of a SARS-CoV-2 mRNA vaccine (Omicron BA.5) LVRNA012 given as the booster in immunized but SARS-CoV-2 infection-free adults in China. Methods: This is a single-center, randomized, double-blind, placebo-controlled phase 3 clinical trial enrolling healthy adult participants (≥18 years) who had completed two or three doses of inactivated COVID-19 vaccines at least 6 months before, in Bengbu, Anhui province, China. Eligible participants were randomly assigned (1:1) to receive a booster intramuscular vaccination with an LVRNA012 vaccine (100ug) or placebo. The primary endpoint was the protective efficacy of a booster dose of the LVRNA012 vaccine or placebo against symptomatic COVID-19 of any severity 14 days after vaccination. Laboratory-confirmed COVID-19 infections were identified from 14 days to 180 days after intervention, with active surveillance for symptomatic illness 8 times per month between 7 to 90 days and at least once per month between 90 to 180 days after intervention. Results: 2615 participants were recruited and randomly assigned in a 1:1 ratio to either the vaccine group (1308) or the placebo group (1307). A total of 141 individuals (46 in the LVRNA012 group and 95 in the placebo group) developed symptomatic COVID-19 infection 14 days after the booster immunization, showing a vaccine efficacy of 51.9% (95% CI, 31.3% to 66.4%). Most infections were detected 90 days after intervention during a period when XBB was prevalent in the community. Adverse reactions were reported by 64% of participants after the LVRNA012 vaccination, but most of them were mild or moderate. The booster vaccination with the LVRNA012 mRNA vaccine could significantly enhance neutralizing antibody titers against the Omicron variant XBB.1.5 (GMT 132.3 [99.8, 175.4]) than did those in the placebo group (GMT 12.5 [8.4, 18.7]) at day 14 for the previously immunized individuals. Conclusion: The LVRNA012 mRNA vaccine is immunogenic, and shows robust efficacy in preventing COVID-19 during the omicron-predominate period. Clinical trial registration: ClinicalTrials.gov, identifier NCT05745545.

Immunogenicity, Safety, and Immune Persistence of One Dose of SARS-CoV-2 Recombinant Adenovirus Type-5 Vectored Vaccine in Children and Adolescents Aged 6-17 Years: An Immunobridging Trial.

BACKGROUND: Though children infected by SARS-CoV-2 generally experience milder symptoms compared to adults, severe cases can occur. Additionally, children can transmit the virus to others. Therefore, the availability of safe and effective COVID-19 vaccines for children and adolescents is crucial. METHOD: A single-center, randomized, double-blind clinical trial was conducted in Funing County, Yancheng City, Jiangsu Province, China. Healthy children and adolescents were divided into two subgroups (6-12 years old or 13-17 years old) and randomly assigned to one of three groups to receive one dose of Ad5-nCoV (3 × 1010 vp/dose). Another group, aged 18-59, received one dose of Ad5-nCoV (5 × 1010 vp/dose) as the control group. At 28, 90, 180, and 360 days post-vaccination, we measured the geometric mean titer (GMT)/concentration (GMC) of neutralizing and binding antibodies against the prototype SARS-CoV-2 strain, as well as serum antibody levels against the BA.4/5 variant. We also evaluated the incidence of adverse events within 28 days post-vaccination. RESULTS: A total of 2413 individuals were screened from 3 June 2021 to 25 July 2021, of whom 2021 eligible participants were enrolled, including 1009 aged 6~17 years in the children and adolescent group and 1012 aged 18-59 years in the adults group. The GMT of anti-wild SARS-CoV-2 neutralizing antibodies was 18.6 (95% CI, 16.6-20.9) in children and adolescents and 13.2 (95% CI, 11.6-15.0) in adults on day 28. The incidence of solicited adverse reactions between the adult group (49.4% [124/251]) and the children and adolescent group (46.3% [156/337]) was not statistically significant. The neutralizing antibody levels decreased by a factor of 3.29 from day 28 to day 360 post-vaccination. CONCLUSIONS: A single dose of Ad5-nCoV at 3 × 1010 virus particles/dose is safe in children and adolescents, and it elicited significant immune response, which was not only non-inferior but also superior to that in adults aged 18-59 years.

Nasal Staphylococcus aureus Carriage and Antimicrobial Resistance Profiles Among Community-Dwelling Adults in Jiangsu, China.

INTRODUCTION: Persistent nasal carriage has been associated with Staphylococcus aureus infection. Previous S. aureus studies in Asia have primarily focused on clinical patients, providing limited information on persistent nasal carriage among the general adult population. METHODS: This study examined 143 healthy adults in a community in Jiangsu, China. Nasal swab samples were collected 10 times. The colonization status was identified using SPA typing. We also determined antimicrobial susceptibility, genotype, and genomic characteristics of S. aureus. RESULTS: The prevalence of S. aureus nasal carriage among the community individuals was on average 16.78%. The carriage rates of methicillin-resistant S. aureus and multidrug-resistant S. aureus were 6.29% and 7.69%, respectively. We identified 8.39% persistent carriers, 39.16% intermittent carriers, and 52.45% noncarriers. Furthermore, family members displayed concordance in terms of genotype and genomic characteristics. CONCLUSION: Persistent nasal sampling captured intermittent carriers that were missed during short-term sampling, thus highlighting the necessity for regular community testing. SPA typing can serve as a rapid method for determining S. aureus colonization. The potential for intrafamilial transmission of S. aureus is evident, with persistent carriers being the most probable source of infection.

Safety and immunogenicity of the SARS-CoV-2 LYB001 RBD-based VLP vaccine (CHO cell) phase 1 in Chinese adults: a randomized, double-blind, positive-parallel-controlled study.

BACKGROUND: Vaccination remains the cornerstone of defense against COVID-19 globally. This study aims to assess the safety and immunogenicity profile of innovative vaccines LYB001. RESEARCH DESIGN AND METHODS: This was a randomized, double-blind, parallel-controlled trial, in 100 healthy Chinese adults (21 to 72 years old). Three doses of 30 or 60 µg of SARS-CoV-2 RBD-based VLP vaccine (LYB001), or the SARS-CoV-2 RBD-based protein subunit vaccine (ZF2001, control group) were administered with a 28-day interval. Differences in the incidence of adverse events (AEs) and indicators of humoral and cellular immunity among the different groups were measured. RESULTS: No severe adverse events were confirmed to be vaccine-related, and there was no significant difference in the rate of adverse events between the LYB001 and control group or the age subgroups (p > 0.05). The LYB001 groups had significantly higher or comparable levels of seroconversion rates, neutralization antibody, S protein-binding antibody, and cellular immunity after whole vaccination than the control group. CONCLUSIONS: Our findings support that LYB001 developed on the VLP platform is safe and well tolerated with favorable immunogenicity for fundamental vaccination in healthy adults. Therefore, further larger-scale clinical studies are warranted. TRIAL REGISTRATION: This trial was registered with ClinicalTrials.gov (NCT05552573).

Immunogenicity and safety of an ORF7-deficient skin-attenuated and neuro-attenuated live vaccine for varicella: a randomised, double-blind, controlled, phase 2a trial.

BACKGROUND: The Oka varicella vaccine strain remains neurovirulent and can establish lifelong latent infection, raising safety concerns about vaccine-related herpes zoster. In this study, we aimed to evaluate the immunogenicity and safety of a skin-attenuated and neuro-attenuated varicella vaccine candidate (v7D vaccine). METHODS: We did this randomised, double-blind, controlled, phase 2a clinical trial in Jiangsu, China. Healthy children aged 3-12 years with no history of varicella infection or vaccination were enrolled and randomly assigned (1:1:1:1) to receive a single subcutaneous injection of the v7D vaccine at 3·3 log10 plaque forming units (PFU; low-dose v7D group), 3·9 log10 PFU (medium-dose v7D group), and 4·2 log10 PFU (high-dose v7D group), or the positive control varicella vaccine (vOka vaccine group). All the participants, laboratory personnel, and investigators other than the vaccine preparation and management staff were masked to the vaccine allocation. The primary outcome was assessment of the geometric mean titres (GMTs) and seroconversion rates of anti-varicella zoster virus immunoglobulin G (IgG) induced by different dose groups of v7D vaccine at 0, 42, 60, and 90 days after vaccination in the per-protocol set for humoral immune response analysis. Safety was a secondary outcome, focusing on adverse events within 42 days post-vaccination, and serious adverse events within 6 months after vaccination. This study was registered on Chinese Clinical Trial Registry, ChiCTR2000034434. FINDINGS: On Aug 18-21, 2020, 842 eligible volunteers were enrolled and randomly assigned treatment. After three participants withdrew, 839 received a low dose (n=211), middle dose (n=210), or high dose (n=210) of v7D vaccine, or the vOka vaccine (n=208). In the per-protocol set for humoral immune response analysis, the anti-varicella zoster virus IgG antibody response was highest at day 90. At day 90, the seroconversion rates of the low-dose, medium-dose, and high-dose groups of v7D vaccine and the positive control vOka vaccine group were 100·0% (95% CI 95·8-100·0; 87 of 87 participants), 98·9% (93·8-100·0; 87 of 88 participants), 97·8% (92·4-99·7; 91 of 93 participants), and 96·4% (89·8-99·2; 80 of 83 participants), respectively; the GMTs corresponded to values of 30·8 (95% CI 26·2-36·0), 31·3 (26·7-36·6), 28·2 (23·9-33·2), and 38·5 (31·7-46·7). The v7D vaccine, at low dose and medium dose, elicited a humoral immune response similar to that of the vOka vaccine. However, the high-dose v7D vaccine induced a marginally lower GMT compared with the vOka vaccine at day 90 (p=0·027). In the per-protocol set, the three dose groups of the v7D vaccine induced a similar humoral immune response at each timepoint, with no statistically significant differences. The incidence of adverse reactions in the low-dose, medium-dose, and high-dose groups of v7D vaccine was significantly lower than that in the vOka vaccine group (17% [35 of 211 participants], 20% [41 of 210 participants], and 13% [27 of 210 participants] vs 24% [50 of 208 participants], respectively; p=0·025), especially local adverse reactions (10% [22 of 211 participants], 14% [30 of 210 participants] and 9% [18 of 210 participants] vs 18% [38 of 208 participants], respectively; p=0·016). None of the serious adverse events were vaccine related. INTERPRETATION: The three dose groups of the candidate v7D vaccine exhibit similar humoral immunogenicity to the vOka vaccine and are well tolerated. These findings encourage further investigations on two-dose vaccination schedules, efficacy, and the potential safety benefit of v7D vaccine in the future. FUNDING: The National Natural Science Foundation of China, CAMS Innovation Fund for Medical Sciences, the Fundamental Research Funds for the Central Universities, and Beijing Wantai. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Relative effectiveness of a heterologous booster dose with adenovirus type 5 vectored COVID-19 vaccine versus three doses of inactivated COVID-19 vaccine in adults during a nationwide outbreak of omicron predominance, in China: a retrospective, individually matched cohort-control study.

Effectiveness of heterologous booster regimes with ad5 vectored COVID-19 vaccine in a large, diverse population during the national-scale outbreak of SARS-CoV-2 omicron predominance in China has not been reported, yet. We conducted a large-scale cohort-control study in six provinces in China, and did a retrospective survey on the COVID-19 attack risk during this outbreak. Participant aged ≥18 years in five previous trials who were primed with 1 to 3 doses of ICV received heterologous booster with either intramuscular or orally inhaled ad5 vectored COVID-19 vaccine were included in the heterologous-trial cohort. We performed propensity score-matching at a ratio of 1:4 to match participants in the heterologous-trial cohort individually with the community individuals who received three-dose of ICV as a control (ICV-community cohort). From February 4 to April 10, 2023, 41504 (74.5%) of 55710 individuals completed the survey. The median time since the most recent vaccination to the onset of the symptoms of COVID-19 was 303.0 days (IQR 293.0-322.0). The attack rate of COVID-19 in the heterologous-trial cohort was 55.8%, while that in the ICV-community cohort was 64.6%, resulting in a relative effectiveness of 13.7% (95% CI 11.9 to 15.3). In addition, a higher relative effectiveness against COVID-19 associated outpatient visits, and admission to hospital was demonstrated, which was 25.1% (95% CI 18.9 to 30.9), and 48.9% (95% CI 27.0 to 64.2), respectively. The heterologous booster with ad5 vectored COVID-19 vaccine still offered some additional protection in preventing COVID-19 breakthrough infection versus homologous three-dose regimen with ICV, 10 months after vaccination.

Vaccination with Adenovirus Type 5 Vector-Based COVID-19 Vaccine as the Primary Series in Adults: A Randomized, Double-Blind, Placebo-Controlled Phase 1/2 Clinical Trial.

This randomized, double-blind, placebo-controlled phase 1/2 trial aimed at evaluating the safety and immunogenicity of Ad5-nCoV via aerosolized or intramuscular or intramuscular-aerosolized routes in SARS-CoV-2-negative adults aged over 18 years. In the phase 1 trial, participants were sequentially enrolled into one of five regimen cohorts: Low-Dose (two doses of aerosolized Ad5-nCoV with 0.5 × 1010 viral particles [vps] per dose), Middle-Dose (two doses of aerosolized Ad5-nCoV with 1.0 × 1010 vps per dose), High-Dose (two doses of aerosolized Ad5-nCoV with 2.0 × 1010 vps per dose), Mixed (intramuscular Ad5-nCoV with 5.0 × 1010 vps [first dose] and aerosolized Ad5-nCoV with 2.0 × 1010 vps [second dose]), and Single-Dose (one dose of aerosolized Ad5-nCoV with 1.0 × 1010 vps). Eligible participants in the phase 2 trial were stratified by 18-59 years old or ≥60 years old and then were sequentially enrolled into one of six regimen cohorts: Low-Dose, Middle-Dose, High-Dose, Mixed, Single-Dose, and Intramuscular (one dose of intramuscular Ad5-nCoV with 1.0 × 1010 vps). The intervals between the two doses were 56 days. Participants were randomly allocated in 3:1 (phase 1) and 5:1 (phase 2) ratios to receive either Ad5-nCoV or the placebo in each cohort. This study is registered on ClinicalTrials.gov, NCT04840992. Most adverse reactions that occurred during the solicited period were mild and moderate. One serious adverse event (myelodysplastic syndrome) was considered potentially related to the aerosolized Ad5-nCoV. The GMTs of neutralizing antibodies in the Mixed group were the highest with 57.03 (95% CI: 23.95, 135.80) and 97.37 (95% CI: 74.30, 127.59) in phase 1 and 2 trials, respectively, 28 days after the second dose (p < 0.0001), which showed significantly higher immune responses compared to other regimens with aerosolized or intramuscular Ad5-nCoV alone.

Construction of immune-related molecular diagnostic and predictive models of hepatocellular carcinoma based on machine learning.

Background: To exploit hepatocellular carcinoma (HCC) diagnostic substances, we identify potential predictive markers based on machine learning and to explore the significance of immune cell infiltration in this pathology. Method: Three HCC gene expression datasets were used for weighted gene co-expression network analysis (WGCNA) and differential expression analysis. Least Absolute Shrinkage and Selection Operator (LASSO) and Random Forest were applied to identify candidate biomarkers. The diagnostic value of HCC diagnostic gene biomarkers was further assessed by the area under the ROC curve observed in the validation dataset. CIBERSORT was used to analyze 22 immune cell fractions from HCC patients and to analyze their correlation with diagnostic markers. In addition, the prognostic value of the markers and the sensitivity of the drugs were analyzed. Result: WGCNA and differential expression analysis were used to screen 396 distinct gene signatures in HCC tissues. They were mostly engaged in cytoplasmic fusion and the cell division cycle, according to gene enrichment analyses. Five genes were shown to have a high diagnostic value for use as diagnostic biomarkers for HCC, including EFHD1 (AUC = 0.77), KIF4A (AUC = 0.97), UBE2C (AUC = 0.96), SMYD3 (AUC = 0.91), and MCM7 (AUC = 0.93). T cells, NK cells, macrophages, and dendritic cells were found to be related to diagnostic markers in HCC tissues by immune cell infiltration analysis, indicating that these cells are intimately linked to the onset and spread of HCC. Concurrently, these five genes and their constructed models have considerable prognostic value. Conclusion: These five genes (EFHD1, KIF4A, UBE2C, SMYD3, and MCM7) may serve as new candidate molecular markers for HCC, providing new insights for future diagnosis, prognosis, and molecular therapy of HCC.

Long-term efficacy of a recombinant hepatitis E vaccine in adults: 10-year results from a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Hepatitis E virus (HEV) is a frequently overlooked causative agent of acute hepatitis. Evaluating the long-term durability of hepatitis E vaccine efficacy holds crucial importance. METHODS: This study was an extension to a randomised, double-blind, placebo-controlled, phase-3 clinical trial of the hepatitis E vaccine conducted in Dontai County, Jiangsu, China. Participants were recruited from 11 townships in Dongtai County. In the initial trial, a total of 112 604 healthy adults aged 16-65 years were enrolled, stratified according to age and sex, and randomly assigned in a 1:1 ratio to receive three doses of hepatitis E vaccine or placebo intramuscularly at month 0, month 1, and month 6. A sensitive hepatitis E surveillance system including 205 clinical sentinels, covering the entire study region, was established and maintained for 10 years after vaccination. The primary outcome was the per-protocol efficacy of hepatitis E virus vaccine to prevent confirmed hepatitis E occurring at least 30 days after administration of the third dose. Throughout the study, the participants, site investigators, and laboratory staff remained blinded to the treatment assignments. This study is registered with ClinicalTrials.gov (NCT01014845). FINDINGS: During the 10-year study period from Aug 22, 2007, to Oct 31, 2017, 90 people with hepatitis E were identified; 13 in the vaccine group (0·2 per 10 000 person-years) and 77 in the placebo group (1·4 per 10 000 person-years), corresponding to a vaccine efficacy of 83·1% (95% CI 69·4-91·4) in the modified intention-to-treat analysis and 86·6% (73·0 to 94·1) in the per-protocol analysis. In the subsets of participants assessed for immunogenicity persistence, of those who were seronegative at baseline and received three doses of hepatitis E vaccine, 254 (87·3%) of 291 vaccinees in Qindong at the 8·5-year mark and 1270 (73·0%) of 1740 vaccinees in Anfeng at the 7·5-year mark maintained detectable concentrations of antibodies. INTERPRETATION: Immunisation with this hepatitis E vaccine offers durable protection against hepatitis E for up to 10 years, with vaccine-induced antibodies against HEV persisting for at least 8·5 years. FUNDING: National Natural Science Foundation of China, Fujian Provincial Natural Science Foundation, Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, and the Fundamental Research Funds for the Central Universities.

Safety and Immunogenicity of a Recombinant Two-Component SARS-CoV-2 Protein Vaccine: Randomized, Double-Blind, Placebo-Controlled Phase I and Phase II Studies.

INTRODUCTION: ReCOV is a recombinant protein vaccine that aims to induce cross-neutralization against SARS-CoV-2 variants. The phase I and phase II studies were conducted in New Zealand and the Philippines, respectively, for ReCOV primary series. METHODS: Both studies were randomized, double-blind, placebo-controlled designed among COVID-19 vaccine-naïve healthy adults who received two doses of study vaccination with a 21-day interval. In phase I, 100 younger (15-55 years) and older (56-80 years) subjects were 4:1 randomized to receive ReCOV (20 µg or 40 µg) or placebo. In the phase II study, 347 subjects (≥ 18 years) were 2:1 randomized to receive 40 µg ReCOV or placebo. Subjects that received ReCOV were followed up for 6 months after the second dosing. The safety outcomes included solicited and unsolicited AEs, SAEs, and AESIs. The immunogenicity outcomes were live-virus neutralizing antibody (NAb) against prototype, while pseudovirus NAbs against several SARS-CoV-2 variants were included in phase II as well. RESULTS: No related SAE, AESI, or AE leading to early discontinuation were reported. The AE incidences were higher in ReCOV groups than placebo group in phase I while they were similar between study groups in phase II. The majority of solicited AEs were mild or moderate with median duration of 1.0-4.0 days. The common (≥ 10%) solicited AEs in phase I were injection site reactions, headache, pyrexia, fatigue, and myalgia, and common reported (≥ 5%) ones in phase II included injection site pain, headache, and pyrexia. Robust neutralizing activities against the prototype were observed in ReCOV groups, peaking at 14 days post the second dosing: in phase I, the GMTs for 20 µg and 40 µg ReCOV groups were 1643.2 IU/mL (95% CI 1188.5, 2271.9) and 1289.2 IU/mL (95% CI 868.3, 1914.1) in younger adults, and 1122.3 IU/mL (95% CI 722.6, 1743.1) and 680.3 IU/mL (95% CI 440.2, 1051.4) in older adults, respectively, while in the ReCOV group of phase II, the GMTs for subjects with seronegative and seropositive status at baseline were 3741.0 IU/mL (95% CI 3113.4, 4495.0) and 6138.3 IU/mL (95% CI 5255.1, 7169.9), respectively. In phase II, substantial levels of pseudovirus NAbs against SARS-CoV-2 variants were demonstrated; the peak GMTs for prototype, Omicron BA.2, and BA.4/5 were 8857, 4441, and 2644, and 15,667.3, 7334.3, and 4478.8 among seronegative and seropositive subjects, respectively. The neutralization persisted till 6 months post the second dosing, with only 2.5- to 5.2-fold declines for Omicron variants. CONCLUSIONS: Two doses of 20 µg and 40 µg ReCOV are safe and immunogenic against SARS-CoV-2 prototype. The cross-neutralizing activities against Omicron variants support ReCOV advance to late-stage clinical trials. TRIAL REGISTRATION: Phase I study, clinicaltrials.gov NCT04818801; phase II study, clinicaltrials.gov NCT05084989.

Research progress in the off-target effects of Bacille Calmette-Guérin vaccine.

ABSTRACT: Bacille Calmette-Guérin (BCG) vaccine is designed to provide protection against tuberculosis (TB). However, numerous epidemiological, clinical, and immunological studies have shown that BCG vaccination affects neonatal and infant mortality, which may be related to the reduction of TB-unrelated infections and diseases by BCG vaccine. We aimed to discuss the off-target effects of BCG vaccine on un-TB infections and diseases, as well as the potential mechanism and influencing factors. Literature was retrieved mainly from PubMed using medical subject headings "BCG, variations, and non-specific, heterologous or off-target". Studies have showed that BCG vaccination can prevent various heterologous infections, including respiratory tract infections, leprosy, and malaria, treat viral infections including human papillomavirus and herpes simplex virus infection as immunotherapy, and improve the immune responses as vaccine adjuvant. Besides, BCG vaccine can reduce the recurrence rate of non-muscle-invasive bladder cancer, and may provide protection against autoimmune diseases. These off-target effects of BCG vaccine are thought to be achieved by modulating heterologous lymphocyte responses or inducing trained immunity, which were found to be sex-differentiated and affected by the BCG vaccine strains, sequence or time of vaccination.

Safety and Immunogenicity of Homologous Recombinant Adenovirus Type 5-Vectored COVID-19 Vaccine Booster Dose in Healthy Adults Aged 18-60 Years: a Single-Center, Open-Label Trial.

INTRODUCTION: The waning antibody levels several months after prime vaccination and the persistent epidemics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) around the world have generated great interest in the evaluation of a booster dose. We aimed to assess the safety and immunogenicity of a homologous booster dose of the recombinant adenovirus type 5-vectored coronavirus disease 2019 (COVID-19) vaccine (Ad5-nCoV). METHODS: In this trial, we recruited healthy adults aged 18-60 years who had received one dose of Ad5-nCoV vaccine (low, middle, or high dose) in the previous phase 1 trial approximately 6 months earlier, and then all participants received a booster dose of 5 × 1010 viral particles (low dose) intramuscularly. The primary outcome was the incidence of adverse reactions within 14 days after booster vaccination. The specific binding antibodies were measured by enzyme-linked immunosorbent assay and the neutralizing antibody responses were assessed with live SARS-CoV-2 and pseudovirus neutralization assay. The cellular immune responses were analyzed by enzyme-linked immunospot assay and intracellular cytokine staining. RESULTS: From September 26 to 28, 2020, 108 volunteers were recruited and 89 eligible participants (52% male) were enrolled and received a booster dose of Ad5-nCoV vaccine: 28 (31%) had received a low prime dose, 30 (34%) a middle prime dose, and 31 (35%) a high prime dose in the previous phase 1 trial. All participants were included in the safety analysis and immunogenicity was assessed in 88 (99%) participants. Twenty-three (82%) participants in the low prime dose group, 23 (77%) participants in the middle prime dose group, and 26 (84%) participants in the high prime dose group reported at least one adverse reaction within the first 14 days post booster. Pain at the injection site and fatigue were the most common adverse reactions. Most adverse reactions were mild or moderate in all groups and no vaccine-related severe adverse event was noted within 12 months after booster vaccination. Neutralizing antibodies increased moderately at day 14 and peaked at 28 days post booster. T cell responses were also boosted at 14 days after vaccination. CONCLUSIONS: A homologous booster of Ad5-nCoV vaccine is well tolerated and immunogenic in healthy adults aged 18-60 years who had received a priming dose of Ad5-nCoV 6 months previously. The neutralizing antibodies against SARS-CoV-2 peaked at day 28 and specific T cell responses were noted at day 14 after booster. Ad5-nCoV vaccine can be considered as a homologous booster 6 months after a priming dose. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04568811.

The 6-Month Antibody Durability of Heterologous Convidecia Plus CoronaVac and Homologous CoronaVac Immunizations in People Aged 18-59 Years and over 60 Years Based on Two Randomized Controlled Trials in China.

Previous reports have shown that heterologous boosting with the AD5-vectored COVID-19 vaccine Convidecia based on a primary series of two doses of inactivated vaccine induces increasing immune responses. However, the immune persistence until 6 months after the heterologous prime-boost immunization was limited. Participants were from two single-center, randomized, controlled, observer-blinded trials, which involved individuals of 18-59 years of age and over 60 years of age. Eligible participants who previously primed with one dose or two doses of CoronaVac were stratified and randomly assigned to inoculate a booster dose of Convidecia or CoronaVac. Neutralizing antibodies against a live SARS-CoV-2 prototype virus and Delta and Omicron (B.1.1.529) variants, pseudovirus neutralizing antibodies against Omicron BA.4/5 variants, and anti-SARS-CoV-2 RBD antibodies at month 6 were detected, and the fold decreases and rate difference were calculated by comparing the levels of antibodies at month 6 with the peak levels at month 1. The neutralizing antibody titers against prototype SARS-CoV-2, RBD-specific IgG antibodies, and the Delta variant in the heterologous regimen of the CoronaVac plus Convidecia groups were significantly higher than those of the homologous prime-boost groups. In three-dose regimen groups, the geometric mean titers (GMTs) of neutralizing antibodies against prototype SARS-CoV-2 were 30.6 (95% CI: 25.1; 37.2) in the heterologous boosting group versus 6.9 (95% CI: 5.6; 8.6) in the homologous boosting group (p < 0.001) at month 6 in participants aged 18-59 years, and in the two-dose regimen, the neutralizing antibody GMTs were 8.5 (95% CI: 6.2; 11.7) and 2.7 (2.3 to 3.1) (heterologous regimen group versus CoronaVac regimen group, p < 0.001). Participants aged over 60 years had similar levels of neutralizing antibodies against the prototype, with GMTs of 49.1 (38.0 to 63.6) in the group receiving two doses of CoronaVac plus one dose of Convidecia versus 9.4 (7.7 to 11.4) in the group receiving three doses of CoronaVac (p < 0.001) and 11.6 (8.4 to 16.0) in the group receiving one dose of CoronaVac and one dose of Convidecia versus 3.3 (2.7 to 4.0) in the group receiving two doses of CoronaVac (p < 0.001). Compared with day 14, over sixfold decreases in neutralizing antibody GMTs were observed in the heterologous groups of the three- or two-dose regimen groups of younger and elderly participants, while in the homologous regimen groups, the GMTs of neutralizing antibodies decreased about fivefold in the two age groups. The heterologous prime-boost regimen with two doses of CoronaVac and one dose of Convidecia was persistently more immunogenic than the regimen of the homologous prime-boost with three doses of CoronaVac.

Safety and efficacy of the intranasal spray SARS-CoV-2 vaccine dNS1-RBD: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: The live-attenuated influenza virus vector-based intranasal SARS-CoV-2 vaccine (dNS1-RBD, Pneucolin; Beijing Wantai Biological Pharmacy Enterprise, Beijing, China) confers long-lasting and broad protection in animal models and is, to our knowledge, the first COVID-19 mucosal vaccine to enter into human trials, but its efficacy is still unknown. We aimed to assess the safety and efficacy (but not the immunogenicity) of dNS1-RBD against COVID-19. METHODS: We did a multicentre, randomised, double-blind, placebo-controlled, adaptive design, phase 3 trial at 33 centres (private or public hospitals, clinical research centres, or Centre for Disease Control and Prevention) in four countries (Colombia, Philippines, South Africa, and Viet Nam). Men and non-pregnant women (aged ≥18 years) were eligible if they had never been infected with SARS-CoV-2, and if they did not have a SARS-CoV-2 vaccination history at screening or if they had received at least one dose of other SARS-CoV-2 vaccines 6 months or longer before enrolment. Eligible adults were randomly assigned (1:1) to receive two intranasal doses of dNS1-RBD or placebo administered 14 days apart (0·2 mL per dose; 0·1 mL per nasal cavity), with block randomisation via an interactive web-response system, stratified by centre, age group (18-59 years or ≥60 years), and SARS-CoV-2 vaccination history. All participants, investigators, and laboratory staff were masked to treatment allocation. The primary outcomes were safety of dNS1-RBD in the safety population (ie, those who had received at least one dose of dNS1-RBD or placebo) and efficacy against symptomatic SARS-CoV-2 infection confirmed by RT-PCR occurring 15 days or longer after the second dose in the per-protocol population (ie, those who received two doses, were followed up for 15 days or longer after the second dose, and had no major protocol deviations). The success criterion was predefined as vaccine efficacy of more than 30%. This trial is registered with the Chinese Clinical Trial Registry (ChiCTR2100051391) and is completed. FINDINGS: Between Dec 16, 2021, and May 31, 2022, 41 620 participants were screened for eligibility and 31 038 participants were enrolled and randomly assigned (15 517 in the vaccine group and 15 521 in the placebo group). 30 990 participants who received at least one dose (15 496 vaccine and 15 494 placebo) were included in the safety analysis. The results showed a favourable safety profile, with the most common local adverse reaction being rhinorrhoea (578 [3·7%] of 15 500 vaccine recipients and 546 [3·5%] of 15 490 placebo recipients) and the most common systemic reaction being headache (829 [5·3%] vaccine recipients and 797 [5·1%] placebo recipients). We found no differences in the incidences of adverse reactions between participants in the vaccine and placebo groups. No vaccination-related serious adverse events or deaths were observed. Among 30 290 participants who received two doses, 25 742 were included in the per-protocol efficacy analysis (12 840 vaccine and 12 902 placebo). The incidence of confirmed symptomatic SARS-CoV-2 infection caused by omicron variants regardless of immunisation history was 1·6% in the vaccine group and 2·3% in the placebo group, resulting in an overall vaccine efficacy of 28·2% (95% CI 3·4-46·6), with a median follow-up duration of 161 days. INTERPRETATION: Although this trial did not meet the predefined efficacy criteria for success, dNS1-RBD was well tolerated and protective against omicron variants, both as a primary immunisation and as a heterologous booster. FUNDING: Beijing Wantai Biological Pharmacy Enterprise, National Science and Technology Major Project, National Natural Science Foundation of China, Fujian Provincial Science and Technology Plan Project, Natural Science Foundation of Fujian Province, Xiamen Science and Technology Plan Special Project, Bill & Melinda Gates Foundation, the Ministry of Education of China, Xiamen University, and Fieldwork Funds of Xiamen University.