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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.

ABSTRACTBackground 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).

Abstract 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.

BackgroundHeterologous booster vaccines are more effective than homologous booster vaccines in combating the coronavirus disease 2019 (COVID-19) outbreak. However, our understanding of homologous and heterologous booster vaccines for COVID-19 remains limited.MethodsWe recruited 34 healthy participants from two cohorts who were primed with two-dose inactivated COVID-19 vaccine before, vaccinated with COVID-19 inactivated vaccine and adenovirus-vectored vaccine (intramuscular and aerosol inhalation of Ad5-nCoV) as a third booster dose. We assessed the immune responses of participants before and 14 days after vaccination, including levels of neutralizing antibodies, IgG, and cytokines, and quantified the transcriptional profile of peripheral blood mononuclear cells (PBMCs).ResultsThe Ad5-nCoV group showed a significantly higher neutralizing antibody geometric mean titer (GMT) compared to the ICV group after 14 days of heterologous boosting. The intramuscular Ad5-nCoV group had a GMT of 191.8 (95% CI 129.0, 285.1) compared to 38.1 (95% CI 23.1, 62.8) in the ICV1 group (p

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. 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). 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. 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.

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.

ABSTRACTEffectiveness 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.

BackgroundWe 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.MethodsThis 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.Results2615 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.ConclusionThe LVRNA012 mRNA vaccine is immunogenic, and shows robust efficacy in preventing COVID-19 during the omicron-predominate period.Clinical trial registrationClinicalTrials.gov, identifier NCT05745545.

Abstract 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.

Abstract 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.

Background: Currently, the recombinant subunit vaccine and live attenuated vaccine in the prevention of herpes zoster are approved for marketing in China. This study aims to evaluate the cost-effectiveness of the recombinant subunit vaccine and the live attenuated vaccine in the Chinese population. Methods: A decision tree–Markov analysis model was utilized to estimate expected costs and quality-adjusted life years (QALYs), comparing the lifetime cost-effectiveness of vaccination with the recombinant subunit vaccine (London, United Kingdom, Shingrix, GSK) to that of the live attenuated vaccine (Changchun, China, Ganwei, Changchun Bcht) in the Chinese population, with the primary outcome measure being the incremental cost-effectiveness ratio (ICER). Results: In the base-case analysis, the ICERs for the recombinant subunit vaccine ranged by age from USD 3428 to USD 5743 per QALY, while the ICERs for the live attenuated vaccine ranged from USD 4017 to USD 18,254 per QALY, compared with no vaccination. Among all age groups, the category of 60 to 69 years was the optimal age for vaccination. The results were most sensitive to changes in herpes zoster incidence, vaccine efficacy, and discount rate. Even with a two-dose compliance rate of 20% for the recombinant subunit vaccine, vaccination remained cost-effective. ZVL would need to reduce costs by at least 12.2% compared to RZV to have a cost-effectiveness advantage. Conclusions: The recombinant subunit vaccine and the live attenuated vaccine were both cost-effective in the Chinese population, but, relatively, the recombinant subunit vaccine had a greater advantage in disease prevention and cost-effectiveness in all age groups above 50 years.

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.

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.

ABSTRACTAntibody persistence and safety up to 12 months of heterologous orally administered adenovirus type-5 vector-based COVID-19 vaccine (Ad5-nCoV) in individuals who were primed with two-dose inactivated SARS-CoV-2 vaccine (CoronaVac) previously, has not been reported yet. This randomized, open-label, single-centre trial included Chinese adults who have received two-dose CoronaVac randomized to low-dose or high-dose aerosolised Ad5-nCoV group, or CoronaVac group. In this report, we mainly evaluated the geometric mean titres (GMTs) of neutralizing antibodies (NAbs) against live wild-type SARS-CoV-2 virus and omicron BA.4/5 pseudovirus at 12 months after the booster dose and the incidence of serious adverse events (SAEs) till month 12. Of 419 participants, all were included in the safety analysis and 120 (28.64%) were included in the immunogenicity analysis. Serum NAb GMT against live wild-type SARS-CoV-2 was 204.36 (95% CI 152.91, 273.14) in the low-dose group and 171.38 (95% CI 121.27, 242.19) in the high-dose group at month 12, significantly higher than the GMT in the CoronaVac group (8.00 [95% CI 4.22, 15.17], p

ABSTRACTHow much the vaccine contributes to the induction and development of neutralizing antibodies (NAbs) of breakthrough cases relative to those unvaccinated-infected cases is not fully understood. We conducted a prospective cohort study and collected serum samples from 576 individuals who were diagnosed with SARS-CoV-2 Delta strain infection, including 245 breakthrough cases and 331 unvaccinated-infected cases. NAbs were analysed by live virus microneutralization test and transformation of NAb titre. NAbs titres against SARS-CoV-2 ancestral and Delta variant in breakthrough cases were 7.8-fold and 4.0-fold higher than in unvaccinated-infected cases, respectively. NAbs titres in breakthrough cases peaked at the second week after onset/infection. However, the NAbs titres in the unvaccinated-infected cases reached their highest levels during the third week. Compared to those with higher levels of NAbs, those with lower levels of NAbs had no difference in viral clearance duration time (P>0.05), did exhibit higher viral load at the beginning of infection/maximum viral load of infection. NAb levels were statistically higher in the moderate cases than in the mild cases (P

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.

We aimed to evaluate the effectiveness or efficacy of heterologous or homologous COVID-19 vaccine regimens against COVID-19-related outcomes after primary immunization with two doses of CoronaVac or Sinopharm COVID-19 vaccines. PubMed, EMBASE, Web of Science, and Cochrane Library databases were searched up to 31 October 2022. The primary measure was vaccine effectiveness against COVID-19 infection with homologous or heterologous booster. The results showed heterologous and homologous booster significantly improved effectiveness against COVID-19 infection compared to primary immunization. The effectiveness against COVID-19 infection was 89.19% (95%CI 78.49, 99.89) for heterologous mRNA vaccine booster, 87.00% (95%CI 82.14, 91.85) for non-replicating vector vaccine booster, 69.99% (95%CI 52.16, 87.82) for homologous booster, and 51.48% (95%CI 41.75, 61.21) for two doses of inactivated vaccine. Homologous and heterologous regimens were also effective against SARS-CoV-2 variants, and more evidence is still needed to confirm our findings.

ABSTRACT In the situation of mass vaccination against COVID-19, few studies have reported on the early kinetics of specific antibodies (IgG/IgM/IgA) of vaccine breakthrough cases. There is still a lack of epidemiological evidence about the value of serological indicators in the auxiliary diagnosis of COVID-19 infection, especially when the nucleic acid results were undetectable. Omicron breakthrough cases post-inactivated vaccination (n = 456) and COVID-19-naive individuals with two doses of inactivated vaccination (n = 693) were enrolled. Blood samples were collected and tested for SARS-CoV-2 antibody levels based on the magnetic chemiluminescence enzyme immunoassay. Among Omicron breakthrough cases, the serum IgG antibody level was 36.34 Sample/CutOff (S/CO) (95% confidence interval [CI], 31.89 to 40.79) in the acute phase and 88.45 S/CO (95% CI, 82.79 to 94.12) in the recovery phase. Serum IgA can be detected in the first week post-symptom onset (PSO) and showed an almost linear increase within 5 weeks PSO. Compared with those of breakthrough cases, IgG and IgA titers of the postimmune group were much lower (4.70 S/CO and 0.46 S/CO, respectively). Multivariate regression showed that serum IgG and IgA levels in Omicron breakthrough cases were mainly affected by the weeks PSO (P

The rapid widespread Omicron subvariant BA.5 of SARS-CoV-2 has become a potential imminent pandemic threat, but available vaccines lack high efficacy against this subvariant. Thus, it is urgent to find highly protective vaccination strategies within available SARS-CoV-2 vaccines. Here, by using a SARS-CoV-2 pseudovirus neutralization assay, we demonstrated that the aerosol inhalation of adenoviral vector COVID-19 vaccine after two dose of inactivated vaccine (I-I-Ad5) led to higher levels of neutralizing antibodies against D614G strain (2041.00[95% CI, 1243.00–3351.00] vs 249.00[149.10–415.70]), Omicron BA.2 (467.10[231.00–944.40] vs 72.21[39.31–132.70]), BA.2.12.1(348.5[180.3–673.4] vs 53.17[31.29–90.37]), BA.2.13 (410.40[190.70–883.3] vs 48.48[27.87–84.32]), and BA.5 (442.40 vs 56.08[35.14–89.51]) than three inactivated vaccine doses (I-I-I). Additionally, the level of neutralizing antibodies against BA.5 induced by I-I-Ad5 was 2.41-fold higher than those boosted by a third dose of RBD subunit vaccine (I-I-S) (p = 0.1308). The conventional virus neutralizing assay confirmed that I-I-Ad5 induced higher titre of neutralizing antibodies than I-I-I (116.80[84.51–161.5] vs 4.40[4.00–4.83]). In addition, I-I-Ad5 induced higher, but later, anti-RBD IgG and IgA in plasma than I-I-I. Our study verified that mucosal immunization with aerosol inhalation of adenoviral vector COVID-19 vaccine may be an effective strategy to control the probable wave of BA.5 pandemic in addition to two inactivated vaccines.

Summary Numerous viral outbreaks have threatened us throughout history. Here, we demonstrated a nucleic acid‐based antiviral strategy named AntiV‐SGN. Unlike those CRISPR‐mediated methods, AntiV‐SGN has advantages of no targets' sequence limitation, such as protospacer adjacent motif (PAM) or protospacer flanking sequence (PFS), being universal for both DNA and RNA viruses. AntiV‐SGN was composed of a FEN1 protein and specific hpDNAs targeting viruses' nucleic acid. Its antiviral ability was tested on SARS‐CoV‐2 and HBV respectively. Reporter assays in human cells first illustrated the feasibility of AntiV‐SGN. Then, it was verified that AntiV‐SGN destroyed about 50% of live RNAs of SARS‐CoV‐2 in Vero cells and 90% cccDNA of HBV in HepG2.2.15 cells. It was also able to remove viral DNA integrated into the host's genome. In the mouse model, AntiV‐SGN can be used to significantly reduce HBV expression at a level of 90%. Actually, in some cases, when viruses mutate to eliminate PAM/PFS or hosts were infected by both DNA and RNA viruses, AntiV‐SGN could be a choice. Collectively, this study provided a proof‐of‐concept antiviral strategy of AntiV‐SGN, which has potential clinical value for targeting a wide variety of human pathogens, both known and newly identified.

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.

Abstract. A large-scale vaccination of coronavirus disease-19 (COVID-19) in adults has been conducted for nearly a year, and there is a growing recognition that immunization for children is also essential. It has been months since emergency use of pediatric COVID-19 vaccine was approved, we reviewed the prevalence and transmission of COVID-19 in children. The prevalence of COVID-19 in children is reduced due to vaccination even in a Delta prevalent period, so an increase in the vaccination rate is needed in children. Although the precise role of children in the transmission requires more research to uncover, they likely played a significant role, according to the available literature. We also described four candidate COVID-19 vaccines for children on their safety and immunogenicity and the impact of severe acute respiratory syndrome coronavirus 2 variants on childhood vaccination. Safety issues on pediatric vaccines post-approval, like adverse events following immunization and adverse events of special interest require studies on long-term and effective regulatory mechanisms.

Abstract. Background:. The new emerging avian influenza A H7N9 virus, causing severe human infection with a mortality rate of around 41%. This study aims to provide a novel treatment option for the prevention and control of H7N9. Methods:. H7 hemagglutinin (HA)-specific B cells were isolated from peripheral blood plasma cells of the patients previously infected by H7N9 in Jiangsu Province, China. The human monoclonal antibodies (mAbs) were generated by amplification and cloning of these HA-specific B cells. First, all human mAbs were screened for binding activity by enzyme-linked immunosorbent assay. Then, those mAbs, exhibiting potent affinity to recognize H7 HAs were further evaluated by hemagglutination-inhibiting (HAI) and microneutralization in vitro assays. Finally, the lead mAb candidate was selected and tested against the lethal challenge of the H7N9 virus using murine models. Results:. The mAb 6-137 was able to recognize a panel of H7 HAs with high affinity but not HA of other subtypes, including H1N1 and H3N2. The mAb 6-137 can efficiently inhibit the HA activity in the inactivated H7N9 virus and neutralize 100 tissue culture infectious dose 50 (TCID50) of H7N9 virus (influenza A/Nanjing/1/2013) in vitro, with neutralizing activity as low as 78 ng/mL. In addition, the mAb 6-137 protected the mice against the lethal challenge of H7N9 prophylactically and therapeutically. Conclusion:. The mAb 6-137 could be an effective antibody as a prophylactic or therapeutic biological treatment for the H7N9 exposure or infection.

BackgroundThe quantitative level and kinetics of neutralizing antibodies (NAbs) in individuals with Omicron breakthrough infections may differ from those of vaccinated individuals without infection. Therefore, we aimed to evaluate the difference in NAb levels to distinguish the breakthrough cases from the post-immunized population to identify early infected person in an outbreak epidemic when nasal and/or pharyngeal swab nucleic acid real-time PCR results were negative.MethodsWe collected 1077 serum samples from 877 individuals, including 189 with Omicron BA.2 breakthrough infection and 688 post-immunized participants. NAb titers were detected using the surrogate virus neutralization test, and were log(2)-transformed to normalize prior to analysis using Student’s unpaired t-tests. Geometric mean titers (GMT) were calculated with 95% confidence intervals (CI). Linear regression models were used to identify factors associated with NAb levels. We further conducted ROC curve analysis to evaluate the NAbs’ ability to identify breakthrough infected individuals in the vaccinated population.ResultsThe breakthrough infection group had a consistently higher NAb levels than the post-immunized group according to time since the last vaccination. NAb titers in the breakthrough infection group were 6.4-fold higher than those in the post-immunized group (GMT: 40.72 AU/mL and 6.38 AU/mL, respectively; p

Summary: Background: BNT162b2, an mRNA vaccine against COVID-19, is being utilised worldwide, but immunogenicity and safety data in Chinese individuals are limited. Methods: This phase 2, randomised, double-blind, placebo-controlled trial included healthy or medically stable individuals aged 18–85 years enrolled at two clinical sites in China. Participants were stratified by age (≤55 or >55 years) and randomly assigned (3:1) by an independent randomisation professional to receive two doses of intramuscular BNT162b2 30 μg or placebo, administered 21 days apart. Study participants, study personnel, investigators, statisticians, and the sponsor's study management team were blinded to treatment assignment. Primary immunogenicity endpoints were the geometric mean titers (GMTs) of neutralising antibodies to live severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and seroconversion rates (SCR) 1 month after the second dose. Safety assessments included reactogenicity within 14 days of vaccination, adverse events (AEs), and clinical laboratory parameters. Randomised participants who received at least one dose were included in the efficacy and safety analyses on a complete case basis (incomplete/missing data not imputed). Results up to 6 months after the second dose are reported. Findings: Overall, 959 participants (all of Han ethnicity) who were recruited between December 5th, 2020 and January 9th, 2021 received at least one injection (BNT162b2, n=720; placebo, n=239). At 1 month after the second dose, the 50% neutralising antibody GMT was 294.4 (95% CI; 281.1–308.4) in the BNT162b2 group and 5.0 (95% CI; 5.0–5.0) in the placebo group. SCRs were 99.7% (95% CI; 99.0%–100.0%) and 0% (95% CI; 0.0%–1.5%), respectively (p

The presence of maternal poliovirus antibodies may interfere with the immune response to inactivated polio vaccine (IPV), and its influence on the safety of vaccination is not yet understood. A total of 1146 eligible infants were randomly assigned (1:1) to the IPV and Sabin IPV (SIPV) groups to compare and analyze the efficacy of the two vaccines in preventing poliovirus infection. We pooled the SIPV and IPV groups and reclassified them into the maternal poliovirus antibody-positive group (MAPG; ≥1: 8) and the maternal poliovirus antibody-negative group (MANG;

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) variants have been reported to be resistant to several neutralizing antibodies (NAbs) targeting Receptor Binding Domain (RBD) and N Terminal Domain (NTD) of spike (S) protein and thus inducing immune escape. However, fewer studies were carried out to investigate the neutralizing ability of S2-specific antibodies. In this research, 10 monoclonal antibodies (mAbs) targeting SARS-CoV-2 S2 subunit were generated from Coronavirus Disease 2019 (COVID-19) convalescent patients by phage display technology and molecular cloning technology. The binding activity of these S2-mAbs toward SARS-CoV-2 S, SARS-CoV-2 S2, SARS-CoV-2 RBD, SARS-CoV-2 NTD, severe acute respiratory syndrome coronavirus (SARS-CoV) S, SARS-CoV S2 and Middle East Respiratory Syndrome Coronavirus (MERS-CoV) S proteins were evaluated by enzyme-linked immunosorbent assay (ELISA). Their neutralizing potency toward SARS-CoV-2 wild-type (WT), B.1.1.7, B.1.351, P.1, B.1.617.2, B.1.1.1 and B.1.621 variants were determined by pseudo-virus-based neutralization assay. Results showed that S2E7-mAb had cross-activity to S or S2 proteins of SARS-CoV-2, SARS-CoV and MERS-CoV, while with limited neutralizing activity to pseudo-viruses of SARS-CoV-2 WT and variants. It is undeniable that the binding and neutralizing activities of the S2-targeting mAbs are significantly weaker than the previously reported antibodies targeting RBD and NTD, but our study may provide some evidences for understanding immune protection and identifying targets for vaccine design based on the conserved S2 subunit.

Objective To evaluate the immunogenicity, safety and lot-to-lot consistency of an inactivated enterovirus 71 (EV71) vaccine cultured in bioreactors with different specifications after full immunization. Methods A randomized, double-blind trial was performed in 3,000 children aged 6 ~ 35 months with six vaccine batches, which were prepared in 40 L and 150 L bioreactors for three consecutive batches respectively. Children were immunized on day 0 and 28, serum samples were collected on day 0 and 56, and neutralizing antibody titers were determined by the microcytopathic method. Immediate reactions were recorded within 30 min, local and systemic symptoms were recorded within 0 ~ 28 days, and serious adverse events were recorded within 6 months. Results After immunization with two doses of the inactivated EV71 vaccine, the neutralizing antibody GMT was 825.52 ± 4.09, and the positive conversion rate was 96.18%, with no significant difference. The 95% CI of the serum neutralizing antibody GMT ratio between the two groups after immunization with the three vaccine batches produced in the 150 L and 40 L bioreactors ranged from .67 ~ 1.5. The overall incidence of adverse reactions, mainly grade 1 reactions, for all 6 batches from 0 to 28 days after vaccination was 49.62%, with no significant difference (p = .8736). The incidence of systemic adverse reactions, primarily fever and diarrhea, was 45.14%; the incidence of local adverse reactions, primarily erythema and tenderness, was 9.43%. Conclusion The EV71 vaccine was highly immunogenic and safe in children aged 6–35 months, and 6 consecutive batches produced by the two bioreactors with different specifications were consistent.

Since TND could be an appropriate method to assess vaccine effectiveness, we want to know whether it may be used for the estimation of vaccine immunological surrogate endpoints, like case-control study. We conducted two study designs (test-negative design (TND) VS matched case-control design (MCC)) to evaluate immunological surrogate endpoint against EV71-associated diseases. We calculated sensitivity (proportion of participants with EV71-associated disease who have a titer less than the cutoff at day 56), specificity (proportion of matched controls who have a titer equal or greater than the cutoff at day 56), and corresponding Youden index ([sensitivity + specificity] − 1). Then, we compared them between TND and MCC. In test-negative design, we totally enrolled 7029 subjects, 49 tested positive as cases and 6980 tested negative as controls in per-protocol population. In matched case-control design, we totally enrolled 305 subjects, 51 as cases, and 254 as controls in whole cohort. In sensitivity and specificity comparison, TND and MCC’s results were similar to each other, except for a titer of 1:4. Nonetheless, in Youden index comparison, MCC’s results were slightly higher than the TND’s, except for a titer of 1:4. EV71 vaccine immunological surrogate endpoints derived from TND was similar to MCC’s. Our results supported that TND could become an alternative research design with the progress of surveillance.

CoronaVac, also known as the Sinovac inactivated SARS-CoV-2 vaccine, has been widely implemented in combating the COVID-19 pandemic. We summarized the results of clinical trials and real-world studies of CoronaVac in this review. The overall efficacy for the prevention of symptomatic COVID-19 (before the emergence of variants of concern) using two doses of 3 μg CoronaVac was 67.7% (95% CI, 35.9% to 83.7%). Effectiveness in preventing hospitalizations, ICU admissions, and deaths was more prominent than that in preventing COVID-19. A third dose inherited the effectiveness against non-variants of concern and increased effectiveness against severe COVID-19 outcomes caused by omicron variants compared to two doses. Most adverse reactions were mild. Few vaccine-related serious adverse reactions have been reported. Moreover, three-dose regimen significantly increased the seroconversion levels of neutralizing antibodies against omicron as compared to two-dose regimen. This review of CoronaVac may provide a scientific basis for optimizing global immunization strategies.

Background: To evaluate the persistence of antibody for 10 years, and investigate the effect of one or two booster doses with Kanghua human diploid cells rabies vaccine (HDCV) in China. Methods: Participants were re-recruited at year 10 post the primary phase 3 clinical study. Some of them in Kanghua HDCV group who had been boosted one dose at year 8, received one more dose at this boosted study. Participants who never boosted were randomly assigned to boost 1 or 2 doses of Kanghua HDCV. Blood samples were collected at day 0, 1, 3, 7, and 14. Safety was evaluated from day 0–14. Results: At year 10 after primary vaccination, the seroconversion rates of neutralizing antibody were 98.28–100% in Kanghua and Pasteur groups. After booster, the seroconversion rate in each group reached to 100% from day 7 to day 14. GMCs were similar in the groups with the same booster doses, and two doses of booster induced higher levels of antibody. The reported rates of solicited local and systemic adverse reaction were low, and no serious adverse events were found through the boosted study. Conclusion: 5 doses of Kanghua HDCV maintained long-term immunity at least 10 years. One or two doses of booster, rapidly triggered 100% protection against rabies virus. Trial registration: ClinicalTrials.gov: NCT03774628

This study consisted of two rounds of cross-sectional observations designed to evaluate the persistence of immune protection induced high antigen content hepatitis B (HB) vaccine at 60 μg/1.0 ml formulations administered at a three-dose schedule (Days 0, 28, and 56) in non-responders to routine HB vaccination. In the original phase 3 study, we enrolled 1091 healthy participants (16–60 years old) seronegative for antibody against HB surface antigen (anti-HBs) after primary vaccination. Participants were randomized (2:2:1) to receive three booster doses of HB vaccine containing 60 μg, 30 μg, or 10 μg of antigen per dose 28 days apart. In the group receiving the 60 μg HB vaccine, 428 participants’ serum samples were available at pre-vaccination and 28 days after each vaccine dose and were included in immunogenicity analysis. With two written informed consents, we collected blood samples from 276 (67.2%) participants in 2014 and 239 (58.2%) in 2019, who had completed the full course of revaccination and reached the seropositive (anti-HBs≥10 mIU/ml) standard in the 60 μg vaccine group of the original phase 3 study. The HBV seropositive rate was found to decrease from 96.0% in 28 days after receiving the third dose of 60 μg HB vaccine, to 48.2% in 2014, and to 40.6% in 2019, with anti-HBs GMC of seropositive individuals was 584.0 mIU/ml, 142.4 mIU/ml, and 169.1 mIU/ml, respectively. Analysis of 181 vaccinees who had serologic test results available both in 2014 and in 2019, and results revealed a dynamic trend in anti-HBs titer similar to that for the whole immune persistence cohort. Of paramount importance, the serologic test results found that 24.9% (45/181) participants had higher anti-HBs concentrations in 2019 than in 2014, this could be interpreted as natural boosters, secondary to HBV exposure without infection because protected. In conclusion, protective antibody persists about 11 years after immunization of Chinese non-responders with 3 doses of 60 μg HB vaccine. Booster doses of vaccine do not seem necessary to ensure long-term protection.

Background: The test-negative design has been used widely in evaluation of various vaccines’ effectiveness, such as influenza, rotavirus, and so on. Recently, there have been some studies about EV-71 vaccine effectiveness by using test-negative design(TND). However, the validity of the TND application in EV-71 vaccines has not been evaluated. Methods: This study is set upon prior methods to evaluate the validity of TND for influenza vaccine by using a randomized controlled clinical trial database. Vaccine effectiveness estimated by TND (VE-TND) in modified intention-to-treat population (mITT) and per-protocol-set population(PPS) was derived from a large randomized placebo-controlled clinical trial (RCT) of inactivated monovalent EV-71 vaccine in China. Derived VE-TND estimates were compared to the original vaccine efficacy results in RCT (VE-RCT). Results: We totally enrolled 7325 participants who seeked medical care for suspected EV-71 infected diseases during the surveillance. There are no significant differences between cases(test-positive) and controls(test-negative) on sex, age, height, and weight. TND vaccine effectiveness estimates were similar to original RCT vaccine efficacy estimates, both in modified intention-to-treat population and per-protocol populations. Conclusions: This study supports that TND, as an appropriate observational study design is valid to measure EV-71 vaccine effectiveness.

Abstract Background To determine an appropriate dose of, and immunization schedule for, a vaccine SCoK against COVID‐19 for an efficacy study; herein, we conducted randomized controlled trials to assess the immunogenicity and safety of this vaccine in adults. Methods These randomized, double‐blind, placebo‐controlled phase 1 and 2 trials of vaccine SCoK were conducted in Binhai District, Yan City, Jiangsu Province, China. Younger and older adult participants in phase 1 and 2 trials were sequentially recruited into different groups to be intramuscularly administered 20 or 40 μg vaccine SCoK or placebo. Participants were enrolled into our phase 1 and 2 studies to receive vaccine or placebo. Results No serious vaccine‐related adverse events were observed in either trial. In both trials, local and systemic adverse reactions were absent or mild in most participants. In our phase 1 and 2 studies, the vaccine induced significantly increased neutralizing antibody responses to pseudovirus and live SARS‐CoV‐2. The vaccine induced significant neutralizing antibody responses to live SARS‐CoV‐2 on day 14 after the last immunization, with NT50s of 80.45 and 92.46 in participants receiving 20 and 40 μg doses, respectively; the seroconversion rates were 95.83% and 100%. The vaccine SCoK showed a similar safety and immunogenicity profiles in both younger participants and older participants. The vaccine showed better immunogenicity in phase 2 than in phase 1 clinical trial. Additionally, the incidence of adverse reactions decreased significantly in phase 2 clinical trial. The vaccine SCoK was well tolerated and immunogenic.

Human papillomavirus (HPV) vaccines are efficacious against HPV infections and associated lesions in women HPV-naïve at vaccination. However, vaccine efficacy (VE) against oncogenic, high-risk HPV (HR-HPV) types in women infected with any other HR-HPV type at first vaccination (baseline) remains unclear. This post-hoc analysis of a phase II/III study (NCT00779766) evaluated AS04-adjuvanted HPV-16/18 (AS04-HPV-16/18) VE against HR-HPV type infection in 871 Chinese women aged 18–25 years over a 72-month follow-up period. Study participants were DNA-negative at baseline to HR-HPV type(s) considered for VE and DNA-positive to any other HR-HPV type. Initial serostatus was not considered. Baseline DNA prevalence was 14.6% for any HR-HPV type and 10.6% excluding HPV-16/18. In the total vaccinated cohort for efficacy, VE against 6-month and 12-month HPV-16/18 persistent infections (PIs) in women DNA-negative to HPV-16/18 but DNA-positive to any other HR-HPV type at baseline was 100.0% (95% Confidence Interval [CI]: 79.8–100.0) and 100.0% (95%CI: 47.2–100.0), respectively. VE against HPV-16/18 incident infections in women DNA-positive to one vaccine type but DNA-negative to the other one at baseline was 66.8% (95%CI: −18.9–92.5). VE against HPV-31/33/45 incident infections, in women DNA-positive to HPV-16/18 and DNA-negative to the considered HPV type at baseline was 71.0% (95%CI: 27.3–89.8). No HPV-16/18 PIs were observed in vaccinated women with non-vaccine HPV A7/A9 species cervical infection at baseline. These findings indicated that women with existing HR-HPV infection at vaccination might still benefit from the AS04-HPV-16/18 vaccine. However, this potential benefit needs further demonstration in the future.

Abstract The global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) requires an urgent need to find effective therapeutics for the treatment of coronavirus disease 2019 (COVID-19). In this study, we developed an integrative drug repositioning framework, which fully takes advantage of machine learning and statistical analysis approaches to systematically integrate and mine large-scale knowledge graph, literature and transcriptome data to discover the potential drug candidates against SARS-CoV-2. Our in silico screening followed by wet-lab validation indicated that a poly-ADP-ribose polymerase 1 (PARP1) inhibitor, CVL218, currently in Phase I clinical trial, may be repurposed to treat COVID-19. Our in vitro assays revealed that CVL218 can exhibit effective inhibitory activity against SARS-CoV-2 replication without obvious cytopathic effect. In addition, we showed that CVL218 can interact with the nucleocapsid (N) protein of SARS-CoV-2 and is able to suppress the LPS-induced production of several inflammatory cytokines that are highly relevant to the prevention of immunopathology induced by SARS-CoV-2 infection.

BackgroundHeterologous boost vaccination has been proposed as an option to elicit stronger and broader, or longer-lasting immunity. We assessed the safety and immunogenicity of heterologous immunization with a recombinant adenovirus type-5-vectored Coronavirus Disease 2019 (COVID-19) vaccine (Convidecia, hereafter referred to as CV) and a protein-subunit-based COVID-19 vaccine (ZF2001, hereafter referred to as ZF).Methods and findingsWe conducted a randomized, observer-blinded, placebo-controlled trial, in which healthy adults aged 18 years or older, who have received 1 dose of Convidecia, with no history of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, were recruited in Jiangsu, China. Sixty participants were randomly assigned (2:1) to receive either 1 dose of ZF2001 or placebo control (trivalent inactivated influenza vaccine (TIV)) administered at 28 days after priming, and received the third injection with ZF2001 at 5 months, referred to as CV/ZF/ZF (D0-D28-M5) and CV/ZF (D0-M5) regimen, respectively. Sixty participants were randomly assigned (2:1) to receive either 1 dose of ZF2001 or TIV administered at 56 days after priming, and received the third injection with ZF2001 at 6 months, referred to as CV/ZF/ZF (D0-D56-M6) and CV/ZF (D0-M6) regimen, respectively. Participants and investigators were masked to the vaccine received but not to the boosting interval. Primary endpoints were the geometric mean titer (GMT) of neutralizing antibodies against wild-type SARS-CoV-2 and 7-day solicited adverse reactions. The primary analysis was done in the intention-to-treat population. Between April 7, 2021 and May 6, 2021, 120 eligible participants were randomly assigned to receive ZF2001/ZF2001 (n = 40) or TIV/ZF2001 (n = 20) 28 days and 5 months post priming, and receive ZF2001/ZF2001 (n = 40) or TIV/ZF2001 (n = 20) 56 days and 6 months post priming. Of them, 7 participants did not receive the third injection with ZF2001. A total of 26 participants (21.7%) reported solicited adverse reactions within 7 days post boost vaccinations, and all the reported adverse reactions were mild, with 13 (32.5%) in CV/ZF/ZF (D0-D28-M5) regimen, 7 (35.0%) in CV/ZF (D0- M5) regimen, 4 (10.0%) in CV/ZF/ZF (D0-D56-M6) regimen, and 2 (10.0%) in CV/ZF (D0-M6) regimen, respectively. At 14 days post first boost, GMTs of neutralizing antibodies in recipients receiving ZF2001 at 28 days and 56 days post priming were 18.7 (95% CI 13.7 to 25.5) and 25.9 (17.0 to 39.3), respectively, with geometric mean ratios of 2.0 (1.2 to 3.5) and 3.4 (1.8 to 6.4) compared to TIV. GMTs at 14 days after second boost of neutralizing antibodies increased to 107.2 (73.7 to 155.8) in CV/ZF/ZF (D0-D28-M5) regimen and 141.2 (83.4 to 238.8) in CV/ZF/ZF (D0-D56-M6) regimen. Two-dose schedules of CV/ZF (D0-M5) and CV/ZF (D0-M6) induced antibody levels comparable with that elicited by 3-dose schedules, with GMTs of 90.5 (45.6, 179.8) and 94.1 (44.0, 200.9), respectively. Study limitations include the absence of vaccine effectiveness in a real-world setting and current lack of immune persistence data.ConclusionsHeterologous boosting with ZF2001 following primary vaccination with Convidecia is more immunogenic than a single dose of Convidecia and is not associated with safety concerns. These results support flexibility in cooperating viral vectored and recombinant protein vaccines.Trial registrationStudy on Heterologous Prime-boost of Recombinant COVID-19 Vaccine (Ad5 Vector) and RBD-based Protein Subunit Vaccine; ClinicalTrial.gov NCT04833101.

Rotavirus, which causes acute gastroenteritis and severe diarrhea, has posed a great threat to children worldwide over the last 30 y. Since no specific drugs and therapies against rotavirus are available, vaccination is considered the most effective method of decreasing the morbidity and mortality related to rotavirus-associated gastroenteritis. To date, six rotavirus vaccines have been developed and licensed by local governments. Notably, Rotarix™ and RotaTeq™ have been recommended as universal agents against rotavirus infection by the World Health Organization; however, lower efficacies were found in less-developed and developing regions with medium and high child mortality than well-developed ones with low child mortality. For now, two promising novel vaccines, Rotavac™ and RotaSiil™ were pre-qualified by the World Health Organization in 2018. Other rotavirus vaccines in the pipeline including neonatal strain (RV3-BB) and several non-replicating rotavirus vaccines with a parenteral delivery strategy are currently undergoing investigation, with the potential to improve the performance of, and eliminate the safety concerns associated with, previous live oral rotavirus vaccines. This paper reviews the important developments in rotavirus vaccines in the last 20 y and discusses problems and challenges that require investigation in the future.

Abstract In response to the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic, over 200 vaccine candidates against coronavirus disease 2019 (COVID-2019) are under development and currently moving forward at an unparalleled speed. The availability of surrogate endpoints would help to avoid large-scale filed efficacy trials and facilitate the approval of vaccine candidates, which is crucial to control COVID-19 pandemic. Several phase 3 efficacy trials of COVID-19 vaccine candidates are under way, which provide opportunities for the determination of COVID-19 correlates of protection. In this paper, we review current knowledge for existence of COVID-19 correlates of protection, methods for assessment of immune correlates of protection and issues related to COVID-19 correlates of protection.

As a high-risk factor of perinatal HBV transmission, the potential role of maternal hepatitis B e antigen (HBeAg) to guide antiviral prophylaxis has not yet been fully reported. This large prospective cohort study enrolled 1177 hepatitis B surface antigen (HBsAg)-positive pregnant women without antiviral treatment and their newborns. HBeAg, HBsAg, and viral load in maternal serum collected before delivery were measured. All the newborns were given standard passive–active immunoprophylaxis within 12 h after birth, and post-vaccination serologic testing was performed at 7 (±7d) months of age. The results revealed that 20 of the 1177 infants (1.70%) were immunoprophylaxis failure, and all their mothers were HBeAg positive. Maternal quantitative HBeAg was positively correlated with viral load (r = 0.83; P 2 × 105 IU/mL, the sensitivity and specificity of maternal qualitative HBeAg to identify the risk of HBV MTCT for pregnant women and determine the necessity for antiviral prophylaxis was 95.5% and 92.6%, respectively. This study showed that maternal HBeAg can be a surrogate marker of HBV DNA for monitoring and evaluating whether antiviral prophylaxis is necessary for preventing perinatal HBV transmission.

Background: Compared with trivalent influenza vaccines, quadrivalent influenza vaccines are expected to provide wider protection against influenza B virus infections. We developed a novel quadrivalent subunit influenza vaccine which was distinct from the influenza vaccines available on the market in production process. In this research, we evaluated the safety and immunogenicity of the quadrivalent subunit influenza vaccine in animal models. Methods: In toxicity assessment, 40 SD rats were randomly assigned to be intramuscularly injected with 1.0 ml of the tested vaccine (33 μg/ml) or 0.9% sodium chloride solution. In irritation assessment, eight rabbits were randomly assigned to receive 0.5 ml of tested vaccine or phosphate buffer solution intramuscularly. Thirty-two guinea pigs were randomly assigned to be intramuscularly injected with high-dose tested vaccine (0.5 ml), low-dose tested vaccine (0.05 ml), ovalbumin, or 0.9% sodium chloride solution, respectively, for sensitization assessment. In immunogenicity assessment, 50 BALB/c mice were equally randomized to receive one dose of tested vaccine, two doses of tested vaccine with an interval of 14 days, 0.5 ml of trivalent subunit influenza vaccine, 0.5 ml of monovalent subunit influenza vaccine, or 0.5 ml of phosphate buffer solution. Orbital blood was collected before and 28 and 42 days after administration of the injections for detecting influenza antibody titers. Results: No abnormal toxicity and irritation in rats and rabbits showed in the gross autopsy and histopathological examinations. The results of sensitization in guinea pigs indicated that no obvious allergic symptoms observed in the high-dose and low-dose vaccine groups within 30 min after twice provocations, and the result of sensitization evaluation was negative. Vaccine induced significant immune responses in mice with 100% seroconversion rates at 28 and 42 days after the first dose. The geometric mean titers (GMTs) of hemagglutination inhibition (HI) antibodies at day 28 in one-dose quadri–vaccine and two-dose quadri–vaccine groups were comparable to those in the tri–vaccine or mono-vaccine groups for shared influenza strains. However, the GMTs of HI antibodies against H1N1 (P = 0.025) and BV (P = 0.049) at day 42 in one-dose quadri–vaccine group were significantly lower than those in the tri–vaccine or mono-vaccine groups. The GMTs of HI antibodies against H1N1, H3N1, BY, and BV at day 28 and day 42 were comparable between one-dose quadri–vaccine and two-dose quadri–vaccine groups. Conclusions: The quadrivalent subunit influenza vaccine was safe and immunogenic in animal models. One dose of the vaccine could elicit a satisfactory antibody response in mice.

Rabies is a highly fatal zoonotic disease caused by the rabies virus invading the central nervous system. When suspected of exposure to the rabies virus, post-exposure prophylaxis should be administered as soon as possible. Monoclonal antibodies (mAbs) neutralizing the rabies virus could be better in human rabies post-exposure prophylaxis than equine or human rabies immune globulin in terms of supply, cost, and efficacy. This article reviews anti-rabies mAbs produced by multiple techniques, and the results of clinical trials for anti-rabies mAbs cocktails recognizing non-overlapping epitopes are also discussed.

BackgroundUnderstanding the long-term kinetic characteristics of SARS-CoV-2 antibodies and the impact of inactivated vaccines on SARS-CoV-2 antibodies in convalescent patients can provide information for developing and improving vaccination strategies in such populations.MethodsIn this cohort, 402 convalescent patients who tested positive for SARS-CoV-2 by RT-PCR from 1 January to 22 June 2020 in Jiangsu, China, were enrolled. The epidemiological data included demographics, symptom onset, and vaccination history. Blood samples were collected and tested for antibody levels of specific IgG, IgM, RBD-IgG, S-IgG, and neutralizing antibodies using a the commercial magnetic chemiluminescence enzyme immunoassay.ResultsThe median follow-up time after symptom onset was 15.6 months (IQR, 14.6 to 15.8). Of the 402 convalescent patients, 44 (13.84%) received an inactivated vaccine against COVID-19. A total of 255 (80.19%) patients were IgG-positive and 65 (20.44%) were IgM-positive. The neutralizing antibody was 83.02%. Compared with non-vaccinated individuals, the IgG antibody levels in vaccinated people were higher (P=0.007). Similarly, antibody levels for RBD-IgG, S-IgG, and neutralizing antibodies were all highly increased in vaccinated individuals (P0.05). Similar conclusions were drawn for RBD-IgG and the neutralizing antibody.Conclusion15.6 months after symptom onset, the majority of participants remained positive for serum-specific IgG, RBD-IgG, S-IgG, and neutralizing antibodies. For convalescent patients, a single dose of inactivated vaccine against COVID-19 can further boost antibody titres.

So far no vaccine or antiviral therapy is available for Echovirus 30 (E30) that causes aseptic meningitis. Here, the authors generate and characterise two E30-specific monoclonal antibodies that block binding of the virus to its attachment receptor CD55 and uncoating receptor FcRn, and determine the cryo-EM structures of E30 with the bound neutralizing antibodies.

Echovirus 30 (E30) belongs to the Enterovirus-B group and causes aseptic meningitis in humans. Here, the authors present the cryo-EM structures of the E30 E-particle, A-particle and the mature virion, as well as structures of E30 in complex with its receptor FcRn and CD55, and furthermore they describe a structure-based algorithm that allows the prediction of EV receptor usage.

Purpose: To explore the molecular genetic mechanisms underlying different responsiveness to Enterovirus 71 (EV71) vaccine. Methods: We recruited 10,245 healthy children into a phase 3 clinical trial to evaluate the efficacy of EV71 vaccine in 2012. Fifty subjects from the trial were divided into the potent immune response group (20 subjects) and the ineffective immune response group (30 subjects). Whole-exome sequencing was performed for these 50 samples and we conducted bioinformatics analyses based on online public database. Results: A total of 222,180 germline variants were detected across 50 subjects. Single nucleotide variant (SNV)-based screening of the subjects with potent or ineffective immune response allowed the identification of a potentially detrimental heterozygous missense variant (c.3784C>T) in EEA1. We also retained TRIM59 and ABCA7 genes that contain different loss of function (LoF) variants shared in two cases and involved in the immune response process. Then, we conducted high-resolution typing of 9 classical HLA genes, HLA-DRB1*03:01, HLA-DQA1*05:01 and HLA-DQB1*02:01 alleles were frequently (recurrence ≥5) observed only in ineffective immune responders. Conclusions: Our study is a meaningful attempt on the comparison of genomic profiles between potent and ineffective immune responders induced by EV71 vaccine, and several candidate potentially detrimental genes were identified.

Mismatch between circulating influenza B viruses and vaccine strains occurs frequently. In a randomized, double-blind, controlled phase III clinical study, healthy children aged 6–35 months were randomized into three groups at a ratio of 2:1:1, received two doses of quadrivalent influenza vaccines (QIVs) or licensed trivalent influenza vaccines (TIVs). The primary objective was to evaluate the non-inferiority immunogenicity of QIV compared with the two TIVs, containing B/Victoria or B/Yamagata strain. Safety information was collected for 28 days after each vaccination. Serious adverse events (SAEs) were monitored for 6 months after the second vaccination. A total of 2146 subjects (QIV: 1069, TIV–Vic: 540, TIV-Yam: 537) were enrolled in this study. QIV was found non-inferior to TIVs for shared strains (A/H1N1 and A/H3N2) and corresponding BY strain based on hemagglutination inhibition (HI) antibodies 28 days after the second dose of vaccination. The resulted geometric mean titer (GMT) ratios (QIV/TIV) were 0.98 (0.89, 1.07) for H1N1, 0.95 (0.85, 1.05) for H3N2 and 0.89 (0.81, 0.98) for BY. And the seroconversion rate differences (QIV-TIV) were −0.46% (−3.24%, 2.31%) for H1N1, −1.95% (−5.54%, 1.65%) for H3N2 and −3.58% (−8.11%, 0.95%) for BY. The BV strain in QIV did not reach the non-inferiority criteria, with GMT of 1:52.25 (vs. 1:61.02 of TIV–Vic) and seroconversion rate of 59.49% (vs. 66.85% of TIV–Vic). No increased safety concerns occurred in QIV group. Candidate QIV can provide good protection for children aged 6 to 35 months, and its immunogenicity and safety were proved. Clinical Trials Registration ClinicalTrials.gov number: NCT03859141.

Enterovirus 71 (EV71) is the dominant pathogen in severe and fatal hand–foot–mouth disease (HFMD) cases. Since 2015, three inactivated EV71 vaccines have been approved in China. The vaccination coverage of the EV71 vaccine has been relatively low, especially in rural areas. A cross-sectional survey from July 19 to August 22, 2018, was conducted in three rural counties of northern Jiangsu Province among parents of children aged 6–60 months. We adopted a pretested validated questionnaire to assess knowledge, awareness, and attitude of HFMD and EV71 vaccines among respondents and used univariate and multivariate binary logistic analyses to explore potential factors associated with the acceptance of EV71 vaccines. Of the 1,112 parents who participated, 87.8% were willing to vaccinate their children with EV71 vaccines. Parents over 40 y old were less likely to have their children vaccinated [adjusted odds ratio (aOR) = 2.12, 95% confidence interval (CI): 1.13–3.97]. Parents who lived in Ganyu (aOR = 0.50, 95% CI: 0.31–0.79) or Xinyi county (aOR = 0.33, 95% CI: 0.20–0.53), had a university or higher degree (aOR = 0.26, 95% CI: 0.11–0.64), had good knowledge of EV71 vaccines (aOR = 0.81, 95% CI: 0.67–0.98), perceived their children’s disease susceptibility, and worried about the severity of HFMD had a higher willingness to vaccinate their children. Most parents were willing to vaccinate their children against EV71-related HFMD. Parental age, location, education level, knowledge of EV71 vaccines, concern about susceptibility, and severity of HFMD were all factors that influenced willingness to vaccinate.

Vaccination has been one of the major revolutions in the history of human health. Vaccination programs have targeted entire populations such as infants or elderly subjects as a matter of being efficient with time and resources. These general populations are heterogeneous in terms of factors such as ethnicity, health status, and socio-economics. Thus, there have been variations in the safety and effectiveness profiles of certain vaccinations according to current population-wide strategies. As the concept of precision medicine has been raised in recent years, many researchers have suggested that vaccines could be administered more precisely in terms of particular target populations, vaccine formulations, regimens, and dosage levels. This review addresses the concept and framework of precision immunization, summarizes recent and representative clinical trials of among specific populations, mentions important factors to be addressed in customizing vaccinations, and provides suggestions on the establishment of precision immunization with the goal of maximizing the effectiveness of vaccines in general.