Antibody Persistence and Safety through 6 Months after Heterologous Orally Aerosolised Ad5-nCoV in individuals primed with two-dose CoronaVac previously

BackgroundHeterologous orally administered adenovirus type-5 vector-based COVID-19 vaccine (Ad5-nCoV) in individuals who were primed with two-dose CoronaVac (an inactivated SARS-CoV-2 vaccine, by Sinovac) previously, has been reported to be safe and highly immunogenic within 28 days post-boosting. However, antibody persistence and safety up to 6 months of this regimen are not been reported yet. MethodsThis is a randomized, open label, single-center trial on safety and immunogenicity of heterologous boost immunization with an orally administered aerosolised Ad5-nCoV vs. homologous boost immunization with CoronaVac after two-dose priming with CoronaVac in Chinese adults aged 18 years and older (NCT05043259). We followed the participants in this trial, including 140 in the low-dose aerosolised Ad5-nCoV group, 139 in the high-dose aerosolised Ad5-nCoV group, and 140 in the CoronaVac group for 6 months. Neutralising antibodies (NAbs) against live wild-type SARS-CoV-2 virus and omicron variant, and receptor-binding domain (RBD)-specific IgG antibodies were detected in serum samples collected at 28 days, 3 months, and 6 months after the booster dose. Serious adverse events (SAEs) were documented till month 6. ResultsThe low-dose and high-dose heterologous boost immunisation groups had NAb GMTs against live wild-type SARS-CoV-2 of 1937.3 [95% CI 1466.9, 2558.4] and 1350.8 [95% CI 952.6, 1915.3], which were 26.4 folds and 18.4 folds higher than that the CoronaVac group did (73.5 [95% CI 52.3, 103.3]) at 28 days. The low-dose and high-dose heterologous boost immunisation groups had NAb GMTs against live wild-type SARS-CoV-2 of 530.1 (95% CI 412.5, 681.1) and 457.6 (95%CI 349.4, 599.2), which were 26.0 folds and 22.4 folds higher than that the CoronaVac group did (20.4 [95%CI 14.3, 29.1]) at 3 months, respectively. At 6 months, the low-dose and high-dose heterologous booster groups had NAb GMTs against live wild-type SARS-CoV-2 of 312.9 (95% CI 237.7, 411.8) and 251.1 (95% CI 178.2, 354.0), which were 30.1 folds and 24.1 folds higher than the CoronaVac group did (10.4 [95% CI 7.8, 14.0]), respectively. Additionally, the low-dose and high-dose heterologous booster groups had NAb GMTs against live omicron variant of 52.0 (95% CI 37.2, 72.6) and 23.1 (95% CI 15.7, 33.9) at 28 days, 27.9 (95% CI 18.8, 41.3) and 23.3 (95% CI 16.2, 33.3) at 3 months, 16.0 (95% CI 10.9, 23.5) and 12.0 (95% CI 8.5, 16.8) at 6 months, respectively. However, nearly all participants had no detectable NAbs for omicron variant in the CoronaVac group at either 28 days, 3 months, or 6 months. No vaccine-related SAEs were observed. ConclusionsThese data suggested that heterologous aerosolised Ad5-nCoV following two-dose CoronaVac priming was safe and persistently more immunogenic than three-dose CoronaVac, although immune responses waned over time.

The preliminary safety and immunogenicity results of a randomized, double-blind, placebo-controlled Phase I trial for a recombinant two-component subunit SARS-CoV-2 vaccine ReCOV

BackgroundThe ReCOV is a recombinant trimeric two-component SARS-CoV-2 subunit vaccine adjuvanted with BFA03. We report the preliminary safety and immunogenicity results for the ReCOV. MethodsThis first in human, randomized, double-blind, placebo-controlled phase I study, was conducted at 2 study sites in New Zealand. Subjects were stratified into two age cohorts (18-55 years and 56-80 years old) and then randomly assigned in a 4:1 ratio to receive two 0.5 mL intramuscular doses of the ReCOV vaccine (20{micro}g or 40{micro}g, adjuvanted with BFA03 in each) or placebo, 21 days apart. The primary endpoints were incidence of solicited local and systemic adverse events (AEs) and unsolicited AEs after each dose; incidence of serious adverse events (SAEs) up to 30 days after the second dose; changes in clinical laboratory tests from baseline up to 7 days after each dose; and changes in vital signs from baseline up to 30 days after the second dose. The key secondary endpoints for immunogenicity were neutralizing antibody titers against SARS-CoV-2, S1 receptor binding domain (RBD) and N-terminal domain (NTD) IgG titers post-vaccination. The T cell-specific immune response elicited by ReCOV were also evaluated. The trial was registered with ClinicalTrials.gov (NCT04818801). FindingsOne hundred participants (50 for each age group) were randomized. The incidence of solicited local AEs in 20g ReCOV, 40g ReCOV, and pooled placebo group among younger adults were 60.0%, 70.0%, and 10.0%, respectively, while among older adults were 55.0%, 84.2%, and 10.0%, respectively. The incidence of solicited systemic AEs in 20g ReCOV, 40g ReCOV, and pooled placebo group among younger adults were 60.0%, 60.0%, and 30.0%, respectively, while among older adults were 50.0%, 52.6%, and 50.0%, respectively. All solicited AEs and unsolicited AEs were mild. No vaccination-related SAE, adverse events of special interest, and AE leading to early discontinuation were reported. ReCOV elicited SARS-CoV-2 neutralizing antibody after the first vaccination, which were increased further after the second vaccination irrespective of dose and age groups. The neutralizing antibody against wild-type SARS-CoV-2 peaked at 14 days post the second vaccination in both 20{micro}g and 40{micro}g ReCOV groups, with GMT of 1643.17 IU/mL and 1289.21 IU/mL among younger adults, and 1122.32 IU/mL and 680.31 IU/mL among older adults, respectively. Similarly, both anti-RBD and anti-NTD specific IgG were elicited after the first vaccination, and peaked at 14 days after the second vaccination. T helper 1 biased cellular responses were observed after ReCOV vaccinations. InterpretationBoth 20 and 40{micro}g ReCOV showed good safety profiles and elicited strong immune responses in the younger and the older adults. The results of this study support the accelerated development of ReCOV. FundingJiangsu Recbio Technology Co., Ltd.

Safety and immunogenicity of heterologous boost immunization with an adenovirus type-5-vectored and protein-subunit-based COVID-19 vaccine (Convidecia/ZF2001): a randomized, observer-blinded, placebo-controlled trial

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 COVID-19 vaccine (Convidecia) and a protein-subunit-based COVID-19 vaccine (ZF2001). Methods and FindingsWe did a randomized, observer-blinded, placebo-controlled trial in healthy adults previously received one dose of Convidecia. Participants were randomly assigned (2:1) to receive either ZF2001 (vaccine group) or a trivalent inactivated influenza vaccine (TIV) (placebo group) at either 28-day or 56-day intervals. For both regimens, all participants received the 2nd injection with ZF2001 at 4 months after a dose of ZF2001 or TIV, with three-dose schedules of Convidecia/Convidecia/ZF2001 at day 0, day 28 and month 5 (referred to as CV/ZF/ZF (D0-D28-M5)) and CV/ZF/ZF (D0-D56-M6), and two-dose schedules of CV/ZF (D0-M5) and CV/ZF (D0-M6). The primary outcome was the geometric mean titer (GMT) of the neutralizing antibodies against live SARS-CoV-2 virus 14 days after each boost vaccination. The safety outcome was 7-day reactogenicity, measured as solicited local or systemic adverse reactions after each vaccination. Between April 7, 2021, and May 6, 2021, 120 participants were enrolled, among whom 60 were randomly assigned to receive ZF2001 (n=40) or TIV (n=20) at a 28-day interval, and 60 were randomly assigned to receive ZF2001 (n=40) or TIV (n=20) at a 56-day interval. 113 (94.2%) participants received the 2nd injection with ZF2001 4 months after a dose of ZF2001 or TIV. A total of 26 participants (21.7%) reported solicited adverse events within 7 days post boost vaccinations, and all the reported adverse reactions were mild. Among participants receiving ZF001 as second dose, the GMTs of neutralizing antibodies increased to 58.4 IU/ml (42.8-79.8) in 0-28 regimen, and to 80.8 IU/ml (53.1-122.9) in 0-56 regimen at 14 days post first boost dose. The GMTs of neutralizing antibodies increased to 334.9 IU/ml (95% CI 230.4, 486.9) in C/Z/Z (D0-D28-M5) regimen, and 441.2 IU/ml (260.8, 746.4) in C/Z/Z (D0-D56-M6) regimen at 14 days after the third dose. Two-dose schedules of CV/ZF (D0-M5) and CV/ZF (D0-M6) induced comparable antibody level comparable with that elicited by three-dose schedules, with the GMTs of 282.9 IU/ml (142.5, 561.8) and 293.9 IU/ml (137.6, 627.9), respectively. Study limitations include the absence of vaccine effectiveness in real-world, and current lack of immune persistence data and the neutralizing antibodies to Omicron. ConclusionsHeterologous boosting with ZF001 following primary vaccination of Convidecia is safe and more immunogenic than a single dose of Convidecia. These results support flexibility in cooperating viral vectored vaccines and recombinant protein vaccine. Trial RegistrationClinicalTrial.gov NCT04833101

A trimeric NTD and RBD SARS-CoV-2 subunit vaccine induced protective immunity in CAG-hACE2 transgenic mice and rhesus macaques

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to significant public health, economic and social problems. Development of effective vaccines is still a priority to contain the virus and end the global pandemic. In this study, we reported that ReCOV, a recombinant trimeric NTD and RBD two-component SARS-CoV-2 subunit vaccine adjuvanted with BFA03 (an AS03-like squalene adjuvant), induced high levels of neutralizing antibodies against SARS-CoV-2 and the circulating variants in mice, rabbits and rhesus macaques. Notably, two-dose immunizations of ReCOV provided complete protection against challenge with SARS-CoV-2 in hACE2 transgenic mice and rhesus macaques, without observable antibody-dependent enhancement of infection. These results support further clinical development of ReCOV and the vaccine is currently being evaluated in a phase I clinical trial in New Zealand (NCT04818801).

Previously unrecognized non-reproducible antibody-antigen interactions and their implications for diagnosis of viral infections including COVID-19

Antibody-antigen (Ab-Ag) interactions are canonically described by a model which exclusively accommodates non-interaction (0) or reproducible-interaction (RI) states, yet this model is inadequate to explain often-encountered non-reproducible signals. Here, by monitoring diverse experimental systems and confirmed COVID-19 clinical sera using a peptide microarray, we observed that non-specific interactions (NSI) comprise a substantial proportion of non-reproducible antibody-based results. This enabled our discovery and capacity to reliably identify non-reproducible Ab-Ag interactions (NRI), as well as our development of a powerful explanatory model ("0-RI-NRI-Hook four-state model") that is [mAb]-dependent, regardless of specificity, which ultimately shows that both NSI and NRI are not predictable yet certain-to-happen. In experiments using seven FDA-approved mAb drugs, we demonstrated the use of NSI counts in predicting epitope type. Beyond challenging the centrality of Ab-Ag interaction specificity data in serology and immunology, our discoveries also facilitated the rapid development of a serological test with uniquely informative COVID-19 diagnosis performance.

Immunogenicity and Safety of a SARS-CoV-2 Inactivated Vaccine (KCONVAC) in Healthy Adults: Two Randomized, Double-blind, and Placebo-controlled Phase 1/2 Clinical Trials

BackgroundThe significant morbidity and mortality resulted from the infection of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) call for urgent development of effective and safe vaccines. We report the immunogenicity and safety of a SARS-CoV-2 inactivated vaccine, KCONVAC, in healthy adults. MethodsTwo phase 1 and phase 2 randomized, double-blind, and placebo-controlled trials of KCONVAC were conducted in Chinese healthy adults aged 18 through 59 years. The phase 1 trial was conducted in a manner of dosage escalation. The first 30 participants were randomized in a ratio of 4:1 to receive two doses of either KCONVAC at 5 g per dose or placebo on Day 0 and Day 14, and the second 30 participants were randomized to receive either KCONVAC at 10 g per dose or placebo following the same procedures. The participants in the phase 2 trial were randomized in a ratio of 2:2:1 to receive either KCONVAC at 5 g or 10 g per dose, or placebo on Day 0 and Day 14, or Day 0 and Day 28. In the phase 1 trial, the primary safety endpoint was the proportion of participants experiencing adverse reactions/events within 28 days following each vaccination. Antibody response and cellular response were assayed in the phase 1 trial. In the phase 2 trial, the primary immunogenicity endpoint was the seroconversion and titre of neutralization antibody, and the seroconversion of receptor binding domain (RBD)-IgG 28 days after the second dose. FindingsIn the phase 1 trial, 60 participants were enrolled and received at least one dose of 5-g vaccine (N=24), 10-g vaccine (N=24), or placebo (N=12). In the phase 2 trial, 500 participants were enrolled and received at least one dose of 5-g vaccine (N=100 for 0/14 or 0/28 regimens), 10-g vaccine (N=100 for each regimen), or placebo (N=50 for each regimen). In the phase 1 trial, 13 (54%), 11(46%), and 7 (58%) participants reported at least one adverse event (AE), of whom 10 (42%), 6 (25%), and 6 (50%) participants reported at least one vaccination-related AE after receiving 5-g vaccine, 10-g vaccine, or placebo, respectively. In the phase 2 trial, 16 (16%), 19 (19%), and 9 (18%) participants reported at least one AE, of whom 13 (13%), 17 (17%), and 6 (12%) participants reported at least one vaccination-related AE after receiving 5-g vaccine, 10-g vaccine, or placebo at the regimen of Day 0/14, respectively. Similar results were observed in the three treatment groups of Day 0/28 regimen. All the AEs were grade 1 or 2 in intensity. No AE of grade 3 or more was reported. One SAE (foot fracture) was reported in the phase 1 trial. KCONVAC induced significant antibody response. 87{middle dot}5% (21/24) to 100% (24/24) of participants in the phase 1 trial and 83{middle dot}0% (83/100) to 100% (99/99) of participants in the phase 2 trial seroconverted for neutralising antibody to live virus, neutralising antibody to pseudovirus, and RBD-IgG after receiving two doses. Across the treatment groups in the two trials, the geometric mean titres (GMTs) of neutralising antibody to live virus ranged from 29{middle dot}3 to 49{middle dot}1 at Day 0/14 regimen and from 100{middle dot}2 to 131{middle dot}7 at Day 0/28 regimen, neutralising antibody to pseudovirus ranged from 69{middle dot}4 to 118{middle dot}7 at Day 0/14 regimen and from 153{middle dot}6 to 276{middle dot}6 at Day 0/28 regimen, and RBD-IgG ranged from 605{middle dot}3 to 1169{middle dot}8 at Day 0/14 regimen and from 1496{middle dot}8 to 2485{middle dot}5 at Day 0/28 regimen. RBD-IgG subtyping assay showed that a significant part of RBD-IgG was IgG1. The vaccine induced obvious T-cell response with 56{middle dot}5% (13/23) and 62{middle dot}5% (15/24) of participants in 5-g and 10-g vaccine groups showed positive interferon-{gamma} enzyme-linked immunospot responses 14 days after the second dose in the phase 1 trial, respectively. InterpretationKCONVAC is well tolerated and able to induce robust antibody response and cellular response in adults aged 18 to 59 years, which warrants further evaluation with this vaccine in the upcoming phase 3 efficacy trial. FundingGuandong Emergency Program for Prevention and Control of COVID-19 (2020A1111340002) and Shenzhen Key Research Project for Prevention and Control of COVID-19.

Coronavirus disease 2019 vaccines: landscape of global studies and potential risks / 中华医学杂志(英文版)

With the outbreak of the coronavirus disease 2019 (COVID-19) pandemic, the importance of vaccines in epidemic prevention and public health has become even more obvious than ever. However, the emergence of multiple severe acute respiratory syndrome coronavirus 2 variants worldwide has raised concerns about the effectiveness of current COVID-19 vaccines. Here, we review the characteristics of COVID-19 vaccine candidates in five platforms and the latest clinical trial results of them. In addition, we further discuss future directions for the research and development of the next generation of COVID-19 vaccines. We also summarize the serious adverse events reported recently after the large-scale vaccination with the current COVID-19 vaccines, including the thromboembolism caused by the AstraZeneca and Johnson & Johnson vaccines.

Immunogenicity and safety of a severe acute respiratory syndrome coronavirus 2 inactivated vaccine in healthy adults: randomized, double-blind, and placebo-controlled phase 1 and phase 2 clinical trials / 中华医学杂志(英文版)

BACKGROUND@#The significant morbidity and mortality resulted from the infection of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) call for urgent development of effective and safe vaccines. We report the immunogenicity and safety of an inactivated SARS-CoV-2 vaccine, KCONVAC, in healthy adults.@*METHODS@#Phase 1 and phase 2 randomized, double-blind, and placebo-controlled trials of KCONVAC were conducted in healthy Chinese adults aged 18 to 59 years. The participants in the phase 1 trial were randomized to receive two doses, one each on Days 0 and 14, of either KCONVAC (5 or 10 μg/dose) or placebo. The participants in the phase 2 trial were randomized to receive either KCONVAC (at 5 or 10 μg/dose) or placebo on Days 0 and 14 (0/14 regimen) or Days 0 and 28 (0/28 regimen). In the phase 1 trial, the primary safety endpoint was the proportion of participants experiencing adverse reactions/events within 28 days following the administration of each dose. In the phase 2 trial, the primary immunogenicity endpoints were neutralization antibody seroconversion and titer and anti-receptor-binding domain immunoglobulin G seroconversion at 28 days after the second dose.@*RESULTS@#In the phase 1 trial, 60 participants were enrolled and received at least one dose of 5-μg vaccine (n = 24), 10-μg vaccine (n = 24), or placebo (n = 12). In the phase 2 trial, 500 participants were enrolled and received at least one dose of 5-μg vaccine (n = 100 for 0/14 or 0/28 regimens), 10-μg vaccine (n = 100 for each regimen), or placebo (n = 50 for each regimen). In the phase 1 trial, 13 (54%), 11 (46%), and seven (7/12) participants reported at least one adverse event (AE) after receiving 5-, 10-μg vaccine, or placebo, respectively. In the phase 2 trial, 16 (16%), 19 (19%), and nine (18%) 0/14-regimen participants reported at least one AE after receiving 5-, 10-μg vaccine, or placebo, respectively. Similar AE incidences were observed in the three 0/28-regimen treatment groups. No AEs with an intensity of grade 3+ were reported, expect for one vaccine-unrelated serious AE (foot fracture) reported in the phase 1 trial. KCONVAC induced significant antibody responses; 0/28 regimen showed a higher immune responses than that did 0/14 regimen after receiving two vaccine doses.@*CONCLUSIONS@#Both doses of KCONVAC are well tolerated and able to induce robust immune responses in healthy adults. These results support testing 5-μg vaccine in the 0/28 regimen in an upcoming phase 3 efficacy trial.@*TRIAL REGISTRATION@#http://www.chictr.org.cn/index.aspx (No. ChiCTR2000038804, http://www.chictr.org.cn/showproj.aspx?proj=62350; No. ChiCTR2000039462, http://www.chictr.org.cn/showproj.aspx?proj=63353).

A proof of concept for neutralizing antibody-guided vaccine design against SARS-CoV-2

Mutations and transient conformational movements of receptor binding domain (RBD) that make neutralizing epitopes momentarily unavailable, present immune escape routes to SARS-CoV-2. To mitigate viral escape, we developed a cocktail of neutralizing antibodies (NAbs) targeting epitopes located on different domains of spike (S) protein. Screening of a library of monoclonal antibodies generated from peripheral blood mononuclear cells of COVID-19 convalescent patients yielded potent NAbs, targeting N-terminal domain (NTD) and RBD domain of S, effective at nM concentrations. Remarkably, combination of RBD-targeting NAbs and NTD-binding NAb, FC05, dramatically enhanced the neutralization potency in cell-based assays and animal model. Results of competitive SPR assays and cryo-EM structures of Fabs bound to S unveil determinants of immunogenicity. Combinations of immunogens, identified in NTD and RBD of S, when immunized in rabbits elicited potent protective immune responses against SARS-CoV-2. These results provide a proof-of-concept for neutralization-based immunogen design targeting SARS-CoV-2 NTD and RBD. One sentence summaryImmunogens identified in the NTD and RBD of the SARS-CoV-2 spike protein using a cocktail of non-competing NAbs when injected in rabbits elicited a potent protective immune response against SARS-CoV-2.

Immunogenicity and Safety of a SARS-CoV-2 Inactivated Vaccine in Healthy Adults Aged 18-59 years: Report of the Randomized, Double-blind, and Placebo-controlled Phase 2 Clinical Trial

BACKGROUNDThe top priority for the control of COVID-19 pandemic currently is the development of a vaccine. A phase 2 trial conducted to further evaluate the immunogenicity and safety of a SARS-CoV-2 inactivated vaccine (CoronaVac). METHODSWe conducted a randomized, double-blind, placebo-controlled trial to evaluate the optimal dose, immunogenicity and safety of the CoronaVac. A total of 600 healthy adults aged 18-59 years were randomly assigned to receive 2 injections of the trial vaccine at a dose of 3 g/0.5 mL or 6 g /0.5mL, or placebo on Day 0,14 schedule or Day 0,28 schedule. For safety evaluation, solicited and unsolicited adverse events were collected after each vaccination within 7 days and 28 days, respectively. Blood samples were taken for antibody assay. RESULTSCoronaVac was well tolerated, and no dose-related safety concerns were observed. Most of the adverse reactions fell in the solicited category and were mild in severity. Pain at injection site was the most frequently reported symptoms. No Grade 3 adverse reaction or vaccine related SAEs were reported. CoronaVac showed good immunogenicity with the lower 3 g dose eliciting 92.4% seroconversion under Day 0,14 schedule and 97.4% under Day 0,28 schedule. 28 days after two-dose vaccination, the Nab levels of individual schedules range from 23.8 to 65.4 among different dosage and vaccination schedules. CONCLUSIONSFavorable safety and immunogenicity of CoronaVac was demonstrated on both schedules and both dosages, which support the conduction of phase 3 trial with optimum schedule/dosage per different scenarios.

Meta-analysis on effectiveness of live attenuated influenza vaccine against seasonal influenza in children / 中华流行病学杂志

To evaluate the effectiveness of live attenuated influenza vaccine (LAIV) in the prevention of seasonal influenza in children aged 2-17 years. Literature retrieval of case-control studies on the effectiveness of LAIV against seasonal influenza in children published from January 2003 to November 2018 was conducted through Web of Science, PubMed, and ScienceDirect databases. The Stata 13.1 software was used for Meta-analysis. A total of 14 studies were included in this study, and all were test-negative design (TND) studies. Our Meta-analysis showed that the effectiveness of LAIV in children was 49 (95: 40-57). Subgroup analysis found that the protection rate of LAIV was 35 against influenza A (H1N1) pdm09 (95: 5-56), 35 against influenza A (H3N2) (95: 21-46), and 71 against influenza B (95: 55-82). The protection rates of trivalent LAIV and quadrivalent LAIV in children were 56 (95: 48-63) and 44 (95: 27-57), respectively. The protection rates of LAIV in Europe and North America were 65 (95: 47-77) and 46 (95: 36-55), respectively. LAIV has a certain preventive effect on seasonal influenza in children aged 2-17 years.

Progress in research of clinical trials of herpes zoster vaccines / 中华疾病控制杂志

Herpes zoster (HZ) is more common in middle-aged and elderly people, and is caused by varicella-zoster virus (VZV) that is latent in sensory ganglia. In recent years, due to various reasons, especially the aging of China's population has become more serious, the incidence of HZ in China has risen sharply. Although HZ is self-limited, its complications will still reduce the quality of life of patients and increase the economic burden of patients' families and society. In order to reduce the incidence and improve the quality of life of the elderly in their later years, the development of safe and effective HZ vaccine may be an important and effective measure. This article aims to make a brief review of the progress in research for clinical trials of HZ vaccines, so as to provide a reference for the use of HZ vaccine and the prevention and control of HZ disease in China.

The great contribution of vaccination to the prevention and control of communicable diseases in China / 中华疾病控制杂志

During the past 70 years since the founding of New China, Chinese public health especially the prevention and control of infectious diseases have made remarkable achievements, which benefited from the vaccination. This study is to summarize the progress of immunization and vaccines, the achievements and contributions of vaccines including polio vaccine, hepatitis B vaccine, diphtheria, tetanus and acellular pertussis combined vaccine, measles vaccine and hepatitis A vaccine to the prevention and control of infectious diseases in China in the past 70 years and to review the research and development of innovative vaccines in China in recent years, which may provide clues for the development of the expanded programe on immunization in China in the future.

A dynamic model of hand foot and mouth disease in Jiangsu Province based on EV71 vaccination / 中华疾病控制杂志

Objective To establish a dynamic model of hand foot and mouth disease in Jiangsu Province, analyze the epidemic of hand foot and mouth disease in Jiangsu, predict the trend of this disease and simulate the effect of EV71 vaccination on the control of hand foot and mouth disease caused by EV71. Methods A compartmental model of hand foot and mouth disease was constructed.A group of differential equations was established. The incidence data of hand foot and mouth disease was used to fit the model and calculate the basic reproduction number of this disease in Jiangsu. Then, vaccination was added to the model and the incidence of hand foot and mouth disease under different vaccination coverage rates was simulated. Results The basic reproduction numbers of hand foot and mouth disease in Jiangsu between 2013 and 2016 were 1.31 (IQR:0.99-1.48), 1.37 (IQR:0.97-1.52), 1.34 (IQR:1.00-1.61) and 1.38 (IQR:1.00-1.76) , respectively. With the increase of immunization coverage of EV71 vaccine, the cases of hand foot and mouth disease caused by EV71 decreased accordingly. When the annual immunization rate of EV71 vaccine was maintained at a high level (75%), the annual incidence of hand foot and mouth disease caused by EV71 after 5 years reduced to 10% of that in the same year when there was no vaccination. Conclusions The epidemic trend of hand foot and mouth disease in Jiangsu is stable from 2013 to 2016. Vaccination plays an important role in controlling hand foot and mouth disease caused by EV71.

Epidemiology and etiology of hand-foot-and-mouth disease seen in Jiangsu province from 2008 to 2010 / 中华儿科杂志

<p><b>OBJECTIVE</b>To analyze the etiological and epidemiological characteristics of hand-foot-and-mouth disease (HFMD) seen in Jiangsu province from 2008 to 2010, and provide evidence for its prevention and control.</p><p><b>METHODS</b>Based on the requirement of supervision program of HFMD, surveillance and report were done according to National Disease Supervision Information Management System. Descriptive epidemiological method, performed between 2008 and 2010, was used to analyze the time, region and population distribution and results of etiologic analysis of HFMD. Nucleic acid of enterovirus (EV) genome was detected by real-time RT-PCR.</p><p><b>RESULTS</b>The average incidence rate of HFMD was 86.70 per million between 2008 and 2010, the peak incidence occurred in April to July. There were significant differences among the incidence in different districts (P<0.05), and the highest incidence was seen in the densely inhabited southern areas of Jiangsu province. Most of the cases were infants and children aged less than 5 years. The number of male cases (2008: 17,008, 2009: 48 768, 2010: 50,231) was much larger than that of the female cases 2008: 9662, 2009: 29 151, 2010: 30,655. The HFMD cases with mild symptoms were caused mainly by enterovirus 71 (EV71) and coxsackievirus A16 (Cox A16) and there was difference among different years. The severe HFMD cases and deaths were mainly caused by EV71 infection.</p><p><b>CONCLUSIONS</b>The epidemiologic characteristics of HFMD in Jiangsu province from 2008 to 2010 had close relationship with season, population and region. The mild cases of HFMD were mainly infected with EV71 and Cox A16. However, EV71 illness seemed to be more severe and had significantly greater frequency of serious complications and fatality than the illness caused by Cox A16.</p>

Multi-center matching study on antibody response between preterm and full-term infants after primary immunization of hepatitis B vaccine / 中华流行病学杂志

Objective To compare the antibody response between preterm and full-term infants after primary immunization of hepatitis B vaccine (HepB).Methods Infants who were aged 7-12 months and had completed primary immunization with 5 μg HepB made by recombinant dexyribonucleic acid techniques in saccharomyces cerevisiae (HepB-SC) or 10 μg HepB made by recombinant dexyribonucleic acid techniques in Hansenula polymorpha (HepB-HP) on 0-1-6 schedule were investigated in four provinces (municipality) including Beijing,Shandong,Jiangsu and Guangxi of China.Among them,all preterm infants were selected to form the preterm group and the 1:1 matching full-term infants with the same month-age,gender and residence were randomly selected to form the full-term group.Their HepB history was determined by immunization certificate and all of their parents were interviewed with standard questionnaire to get their birth information.Blood samples were obtained from all anticipants and were tested for Anti-HBs by chemiluminescence microparticle immuno-assay (CMIA).Results Total anticipants were 648 pairs of infants.The rates of non-response,low-response,normal-response and high-response after the primary immunization were 1.39％,8.64％,45.83％ and 44.14％ in the preterm group,respectively.The corresponding rates were 1.08％,9.26％,44.91％ and 44.75％ in the full-term group.The above four rates did not show significant differences between the two groups (P＞0.05).The geometric mean concentrations (GMC) of anti-HBs in the pre-term and full-term group were 755.14 and 799.47 mIU/ml respectively.There was no significantly difference in the GMCs between the two groups (P＞0.05).Results from multivariable conditional logistic analysis showed that preterm was not an influencing factor to the antibody response after HepB primary immunization among newborns even after debugging the other influencing factors.Conclusion The autibody response after HepB primary immunization were similar among the preterm and full-term infants.The preterm newborns could be immunized under the same HepB immunization strategy.

Comparison on the antibody response after primary immunization of 5 μg and 10 μg hepatitis B vaccine made bv recombinant DNA techniques among newborns / 中华流行病学杂志

Objective To compare the antibody response induced by primary immunization with 5 μ g and 10 μ g hepatitis B vaccine made by recombinant DNA techniques among the newborns.Methods Healthy infants who had completed primary immunization with 5 μg hepatitis B vaccine made by recombinant dexyribonucleic acid techniques in Saccharomyces (Hep-SC) or 10 μg hepatitis B vaccine made by recombinant dexyribonucleic acid techniques in Hansenula polymorpha (HepB-HP) were included in the study.Kids under study were 7-12 months of age and had been on 0-1-6 schedule.Standardized questionnaire was used and blood samples were collected.The titer of antibody to hepatitis B surface antigen (anti-HBs) was detected by Chemiluminescence Microparticle Imunoassay (CMIA).If anti-HBs happened to be under 10 mIU/ml,HBV DNA was further detected by nested-PCR to distinguish occult hepatitis B virus infection.Sero-conversion rate and titer of anti-HBs were compared between the two kinds of hepatitis B vaccines.Multivariate analysis was used to find the relationship between the kind of hepatitis B vaccine as well as the antibody response after debugging the other influencing factors including month-age,gender,birth-weight,premature birth and mother' s HBsAg status.Results 8947 infants vaccinated with 5 μg HepB-SC and 4576 infants vaccinated with 10 μg HepB-HP were investigated.In the 5 μg group,the rates of non-,low-,normal- and high-response were 1.88％,15.18％,61.42％ and 21.52％ respectively.In the 10 μg group,the corresponding rates were 0.15％,2.16％,29.42％ and 68.26％ respectively.The non-,low-,normal-response rates were all higher in 5 μg group than in 10 μg group (P＜0.01),while the high-response rate was much higher in 10 μg group than in 5 μ g group (P＜0.01).The geometric mean concentration (GMC) of anti-HBs were 354.81 mIU/ml (95％ CI:338.84-363.08 mIU/ml) and 1778.28 mIU/ml (95％CI:1698.24-1819.70 mIU/ml) in the 5 μg group and 10 μg group respectively.The GMC was statistically higher in the 10 μg group than in the 5 μg group (P＜0.001).The seroconversion rate and GMC were significantly different between the two groups even after debugging the other influencing factors.Conclusion Better anti-HBs response could be achieved by primary immunization with 10 μg HepB-HP than with 5 μg HepB-SC among newborns.

Safety and immunogenicity of human papillomavirus-16/18 AS04-adjuvanted vaccine in healthy Chinese females aged 15 to 45 years: a phase I trial / 癌症

Globally, about 70% of cervical cancers are associated with human papillomavirus (HPV)-16 or HPV-18 infection. A meta-analysis of epidemiologic studies in China showed that HPV was present in 98% of cervical cancer samples. The HPV-16/18 AS04-adjuvanted vaccine Cervarix has shown a high level of protection against HPV-16/18 infections and associated cervical lesions. This phase I trial (NCT00549900) assessed the safety, tolerability, and immunogenicity of the vaccine in Chinese. Thirty healthy Chinese females, aged 15 to 45 years with a median age of 29.5 years, received three doses of Cervarix in Months 0, 1, and 6. Safety was assessed via recording solicited local and systemic symptoms within 7 days and unsolicited symptoms within 30 days after each vaccination. Serious adverse events, new onset of chronic diseases, and other medically significant conditions were recorded throughout this trial. As an exploratory objective, HPV-16/18 antibody titers were determined by enzyme-linked immunosorbent assay in serum samples collected in Months 0 and 7. Pain at the injection site was the most frequently reported local symptom. Two subjects reported medically significant adverse events. Both cases were assessed as unrelated to vaccination by the investigator. In Month 7, 100% seroconversion was observed for both anti-HPV-16 and anti-HPV-18 with high geometric mean antibody titers. HPV-16/18 AS04-adjuvanted vaccine, evaluated for the first time in Chinese females, was generally well tolerated and immunogenic, as previously shown in global studies.

Study on the status of infection and distribution of rabies virus in China / 中华流行病学杂志

Objective To investigate the status of infection and distribution of rabies virus (RV) in different epidemic areas in China. Methods Brain specimens from animals and suspected patients were collected at the districts of high-, medium- and low incidence rates of human rabies and detected by both direct Immunofluorescence assay (DFA) and RT-PCR. Results 254 of 3007 specimens of dog brains showed RV positive by DFA (positive rate of 8.4% ). Among these 254 samples, 78 showed positive (positive rate of 30.7% ) by RT-PCR. 93 specimens from dogs and cats that had attacked human beings, 63 of them showed positive by DFA (positive rate of 67.7%) and all of them were also positive by RT-PCR. In addition, RV could also be detected in Apodemus agrarius,ferret badger, and suspected patients specimens from the districts under survey. There was no statistical difference between the infection rates of RV in different provinces and regions with different incidence of rabies. Conclusion There might be a relatively high infection rate of RV among the domestic dogs/cats in the endemic areas in China. Wild animals might have been infected with RV in the districts under survey.

Dynamic change of mother-source neutralizing antibodies against enterovirus 71 and coxsackievirus A16 in infants / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Enterovirus 71 (EV71) and coxsackievirus A16 (Cox A16) are major causative agents for hand, foot and mouth disease (HFMD). Studies indicate that the frequent HFMD outbreaks result in a few hundreds children's death in China in recent years. The vaccine and other research for HFMD need to be developed urgently.</p><p><b>THE AIMS OF OUR STUDY WERE</b>to explore dynamic development of mother-source neutralizing antibodies against EV71 and Cox A16 in infants from Jiangsu Province, China, and to provide the fundamental data for further establishing of corresponding immunization course.</p><p><b>METHODS</b>Peripheral blood samples were collected from 133 of parturient women once immediately before delivery and their infants at two and seven months of age. Method of micro-dose cytopathogenic effect was used to measure neutralizing antibodies against EV71 and Cox A16, respectively.</p><p><b>RESULTS</b>Seropositive rates of anti-EV71 and anti-Cox A16 in prenatal women were 79.7% (106/133) and 92.5% (123/133), respectively; geometric mean titers (GMTs) were 29.0 and 61.9; 75.9% (101/133) prenatal women were both positive in anti-EV71 and anti-Cox A16; seropositive rates of anti-EV71 and anti-Cox A16 were 25.6% (34/133) and 38.3% (51/133) in infants at two months of age; GMTs were 12.3 and 18.0, respectively. GMTs of anti-EV71 were significantly higher for infants at seven months (82.6) compared with that at two months (P < 0.05), showing infants had inapparently infected by EV71 during two to seven months. Although only one offspring (0.75%) at seven months was found having anti-Cox A16 transfered from maternal, this observation suggested no maternal antibody may remain in infants at seven months.</p><p><b>CONCLUSIONS</b>The prevalence of EV71 and Cox A16 were relatively high in Jiangsu Province. Bivalent vaccine against both EV71 and Cox A16 should be developed, and the ideal time point for prime immunization for infants is around 2-5 months of age.</p>