Immunogenicity and Safety of a 3-Dose Regimen of a SARS-CoV-2 Inactivated Vaccine in Adults: A Randomized, Double-Blind, Placebo-Controlled Phase 2 Trial.

BACKGROUND: Control of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic needs effective vaccines. METHODS: In a phase 2 randomized, double-blind, placebo-controlled trial, 500 adults aged 18-59 years or ≥60 years were randomized in 2:2:1 ratio to receive 3 doses of 5 µg or 10 µg of a SARS-CoV-2 inactivated vaccine, or placebo separated by 28 days. Adverse events (AEs) were recorded through day 28 after each dosing. Live virus or pseudovirus neutralizing antibodies, and receptor binding domain immunoglobulin G (RBD-IgG) antibody were tested after the second and third doses. RESULTS: Two doses of the vaccine elicited geometric mean titers (GMTs) of 102-119, 170-176, and 1449-1617 for the 3 antibodies in younger adults. Pseudovirus neutralizing and RBD-IgG GMTs were similar between older and younger adults. The third dose slightly (<1.5 fold) increased GMTs. Seroconversion percentages were 94% or more after 2 doses, which were generally similar after 3 doses. The predominant AEs were injection-site pain. All the AEs were grade 1 or 2 in intensity. No serious AE was deemed related to study vaccination. CONCLUSIONS: Two doses of this vaccine induced robust immune response and had good safety profile. A third dose given 28 days after the second dose elicited limited boosting antibody response.

The effect of maternal poliovirus antibodies on the immune responses of infants to poliovirus vaccines.

BACKGROUND: Maternal poliovirus antibodies could provide passive immunity to the newborns from poliovirus infection during their first few months of life, but they may impair the immune responses of infants to the poliovirus vaccine as well. In our study, we pooled the data from three clinical trials of the inactivated poliovirus vaccine (IPV) based on Sabin strains to investigate the effect of maternal poliovirus antibodies on the immune responses of infants to poliovirus vaccines. METHODS: There were five groups in the pooled analysis, including low-dose Sabin IPV, medium-dose Sabin IPV, high-dose Sabin IPV, control Sabin IPV, and control Salk IPV groups. We reclassified the infants in different groups according to their maternal poliovirus antibodies by two methods, the first one included maternal antibody negative (< 1:8) and maternal antibody positive (≥1:8), and the second one included maternal antibody titer < 1:8, 1:8 ~ < 1:32 and ≥ 1:32. Then, we compared the geometric mean titers (GMTs), geometric mean antibody fold increases (GMIs) and seroconversion rates of poliovirus type-specific neutralizing antibodies after vaccination among participants with different maternal poliovirus antibody levels. RESULTS: The GMTs and GMIs of three types of poliovirus antibodies after vaccination in maternal antibody negative participants were significantly higher than those in maternal antibody positive participants. The seroconversion rates of type II and type III poliovirus antibodies in maternal antibody positive participants were significantly lower than those in maternal antibody negative participants. Among participants with maternal antibody titer < 1:8, 1:8 ~ < 1:32 and ≥ 1:32, the GMTs and GMIs of three types of poliovirus antibodies after vaccination showed a tendency to decline with the increasing of maternal antibody levels. The seroconversion rates of three types of poliovirus antibodies in participants with maternal antibody titer ≥1:32 were significantly lower than those in participants with maternal antibody titer < 1:8 and 1:8 ~ < 1:32. CONCLUSIONS: Maternal poliovirus antibodies interfered with the immune responses of infants to poliovirus vaccines, and a high level of maternal antibodies exhibited a greater dampening effect. TRIAL REGISTRATION: ClinicalTrials.gov NCT04264598 February 11, 2020; ClinicalTrials.gov NCT04264546 February 11, 2020; ClinicalTrials.gov NCT03902054 April 3, 2019. Retrospectively registered.

Immunogenicity and Safety of a SARS-CoV-2 Inactivated Vaccine KCONVAC in Chinese Children: Randomized, Double-blind, Placebo-controlled Phase 1 and 2 Trials.

BACKGROUND: It is important to extend the indication of severe acute respiratory syndrome coronavirus 2 vaccine to children to improve the vaccine intake rate and reduce infection in this population. METHODS: In 2 phase 1 and phase 2 randomized, double-blind and placebo-controlled trials, 84 and 480 Chinese healthy children 3 to 17 years old were enrolled, respectively, and randomized in 3:1 ratio to receive 2 doses of a severe acute respiratory syndrome coronavirus 2 inactivated vaccine, KCONVAC or placebo. The 2 doses were given 28 days apart. Adverse events (AEs) were recorded through Day 28 after each dosing. Live virus neutralizing antibody and receptor binding domain antibody (RBD-IgG) were tested before vaccination and after the second dose. RESULTS: Two doses of the vaccine, KCONVAC, elicited geometric mean titers of 142-150 for neutralizing antibody and 4154-4253 for RBD-IgG 28 days after the second dose. Seroconversion rates were 100% after 2 doses for both antibodies in both trials. The predominant AEs were injection-site pain, cough and fever. Most AEs were grade 1 or 2 in intensity. Five participants reported 6 vaccination-unrelated serious AEs in the phase 2 trial. CONCLUSIONS: Two doses of this study vaccine, KCONVAC, were well tolerated and immunogenic in children 3 to 17 years of age.

Immunogenicity and safety of a 13-valent pneumococcal conjugate vaccine administered in a prime-boost regimen among Chinese infants: a randomized, double blind phase III clinical trial.

This study aimed to evaluate the immunogenicity and safety of a 13-valent pneumococcal conjugate vaccine (PCV13). In total, 1200 infants were randomized into two groups with a 1:1 allocation and received a three-dose series of tested PCV13 or control PCV13 at ages 2, 4 and 6 months, respectively, and a booster dose at 12-15 months. Blood samples were collected before and 30 days after primary and booster vaccination. Serotype-specific antibodies were measured using ELISA for immunoglobulin G (IgG) and OPA for functional antibodies. Safety data were collected for 30 days after each inoculation. Results showed that post primary vaccination seropositive rates of all 13 serotypes except type 3 were not significantly different between two groups. The seropositive rate for type 3 in Group T was significantly higher than Group C (P < .0001). For all 13 serotypes except type 7 F, the GMCs in Group T were significantly higher than Group C. The GMC for type 7 F in Group T (P < .0009) was significantly lower than Group C. The frequencies of overall adverse events (P = .0064) and solicited adverse reactions (P = .0019) in Group T were significantly lower than Group C. Post booster vaccination, seropositive rates for all serotypes in Group T were 100.00%. For all serotypes except type 23 F, IgG GMCs in Group T were significantly higher than Group C. Totally, 21 subjects reported SAEs and all but one were considered irrelevant or probably irrelevant to vaccination. In conclusion, the tested PCV13 showed non-inferior immunogenicity and had a good safety profile compared with control vaccine.

A phase 3 clinical trial of MINHAI PCV13 in Chinese children aged from 7 months to 5 years old.

BACKGROUND: Pneumococcus lead to various kinds of invasive disease such as pneumonia, otitis media, meningitis, bacteremia and so on. It has been a great threat to children under 5. A new 13-valent pneumococcal conjugate vaccine (PCV13) with carrier tetanus toxoid and diphtheria toxoid was developed by MINHAI, aiming to prevent pneumococcus infection. In this study, we reported the safety and immunogenicity of MINHAI PCV13 in Chinese children aged from 7 months to 5 years old. METHODS: A randomized, double-blinded, parallelized phase III clinical trial was operated in 900 participants. Haemophilus influenzae type B conjugate vaccine (Hib) served as negative control. PCV13 and Hib were intramuscular injected to participants at a ratio of 2:1. Local and systemic adverse events (AEs) and severe adverse events (SAEs) were recorded to evaluate the safety of PCV13. Blood samples were collected before and after immunization for the detecting of serotype-specific anti-polysaccharide immunoglobulin (Ig)G and opsonophagocytosis assay (OPA). The proportion of IgG concentration ≥ 0.35 µg/mL (IgG positive rate), IgG geometric mean concentration (GMC), OPA geometric mean titer (GMT), and other indicators were analyzed to evaluate the immunogenicity of PCV13. RESULTS: During the study period, no PCV13 associated SAE happened. Incidences of several AEs in PCV13 groups were higher than the Hib groups, but most of them were mild or moderate. For all 13 serotypes, IgG and OPA indicators of the PCV13 groups were generally superior to the Hib groups, and the differences were mostly statistically significant, which indicates that MINHAI PCV13 can effectively induce pneumococcal specific antibody. CONCLUSION: The study demonstrates that MINHAI PCV13 has sufficient immunogenicity and safety in Chinese children aged from 7 months to 5 years old. CLINICAL TRIAL REGISTRATION: NCT02494999.

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.

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 phase â ¡, randomized, controlled trial to evaluate the safety and immunogenicity of a Sabin strain-based inactivated polio vaccine.

This phase Ⅱ, randomized, controlled trial aimed to evaluate the safety and immunogenicity of a various Sabin IPV preparations. Six hundred infants aged 60 ~ 90 days received one of five different vaccines: low- (group A), medium- (group B) or high-D antigen content (group C) of an experimental Sabin IPV, control Sabin IPV (group D) or control Salk IPV (group E), on a 0-1-2 month schedule. Participants were observed and followed up within 30 days of each dose to assess safety. Serum samples were collected before the first dose and 30 days after the third dose to assess immunogenicity. After three doses, type-1 seroconversion rates of groups A-E were 99.1%, 100.0%, 99.1%, 99.0%, and 93.4%, respectively; type-2 seroconversion rates were 93.5%, 97.1%, 98.1%, 95.1%, and 91.5%, respectively; and type-3 seroconversion rates were 95.4%, 98.1%, 98.1%, 95.1%, and 100.0%, respectively. Only type-1 seroconversion rates differed significantly for group E. The incidences of injection-site redness (A: 21.9%, B: 23.7%, C: 29.4%, D: 16.2%, E: 12.7%), swelling (A: 6.7%, B: 6.8%, C: 5.0%, D: 0.0%, E: 1.7%) and pain (A: 5.0%, B: 6.8%, C: 7.6%, D: 0.0%, E: 0.9%) all were significantly higher for experimental vaccines relative to control groups. No SAEs were detected related to vaccination, and most adverse reactions were mild or moderate in severity. In conclusion, the experimental Sabin IPVs with low-, medium-, and high-D antigen content all revealed good safety and immunogenicity profiles although being more reactogenic than the control vaccines.

Willingness of parents to vaccinate their 6-60-month-old children with EV71 vaccines: a cross-sectional study in rural areas of northern Jiangsu Province.

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.

Vaccine profile of PPV23: Beijing Minhai Biotech 23-valent pneumococcal vaccine.

Introduction: Diseases caused by Streptococcus pneumoniae are a major public health problem worldwide, which can be effectively prevented by the 23-valent pneumococcal polysaccharide vaccines (PPV23).Areas covered: The Beijing Minhai PPV23 showed good safety and immunogenicity profiles in clinical trials. The immunogenicity of Beijing Minhai PPV23 was non-inferior to other licensed PPVs. Although PPV23 has been proved to be highly efficient and cost-effective, and was recommended for vaccination in high-risk populations in industrialized countries, the coverage of PPV23 vaccination was relatively low in developing countries.Expert commentary: The low vaccination proportions of PPV23 in China have not been improved in recent decades. Most of the populations with indications for receiving PPV23 were not aware of the possible benefits of PPV23. Moreover, PPV23 had some limitations, which called for the development of a new generation of vaccines against pneumococcal infection.

Safety and immunogenicity of 23-valent pneumococcal polysaccharide vaccine in 2 to 70 year old healthy people in China: A phase III double blind, randomized clinical trial.

To evaluate the safety and immunogenicity of 23-valent pneumococcal polysaccharide vaccine (PPV23), a randomized, double-blind and parallel controlled clinical trial was conducted in Yancheng, Jiangsu Province of China. There were 1200 subjects randomized into 2 groups with a 1:1 allocation. Subjects received 0.5 mL of tested PPV23 or control PPV23 by intramuscular injection in the deltoid, respectively. Results showed that seroconversion rates of all 23 types except type 3 were not significantly different between the 2 groups. The seroconversion rate of the Group T for type 3 (P = 0.0009) was significantly higher than the Group C. The post-vaccination GMCs of the Group T for types 1 (P = 0.0340), 3 (P = 0.0003), 9V (P = 0.0016), 11A (P = 0.0222) and 33F (P = 0.0344) were significantly higher than the Group C. The frequencies of local and general reactions were not significantly different and acceptable in both groups. In conclusion, The PPV23 showed a good immunogenicity and tolerability in 2 to 70 y old healthy people.

Safety and immunogenicity of a diphtheria, tetanus, acellular pertussis and Haemophilus influenzae Type b combination vaccine compared with separate administration of licensed equivalent vaccines in Chinese infants and toddlers for primary and booster immunization.

To evaluate the safety and immunogenicity of a diphtheria, tetanus, acellular pertussis and Haemophilus infuenzae Type b (DTaP/Hib) combination vaccine first developed by a Chinese manufacturer, a randomized, two-stage, parallel controlled, single center clinical trial was conducted in Dafeng, Jiangsu Province of China. A total of 720 infants were enrolled and randomly assigned to two groups with a 2:1 allocation. In Stage I, 480 subjects in Group T were administered with 3 doses of the DTaP/Hib vaccine at 3, 4 and 5 months of age, respectively, while 240 subjects in Group C received separate licensed DTaP vaccine and Hib conjugate vaccine on the same schedule. In Stage II, 633 primed toddlers (431 of Group T and 202 of Group C) were given a booster dose at 18 months of age. Sera samples were collected at pre-dose 1, 4 weeks post-dose 3, pre-dose 4 and 4 weeks post-dose 4, respectively. Levels of protective antibodies were measured by Enzyme Linked Immunoadsorbent Assay (ELISA). Immunogenicity was evaluated with regard to geometric mean concentrations (GMCs), seroconversion rates and seroprotection rates of the antibodies. Solicited adverse reactions were recorded for 3 days after each dose; unsolicited adverse events and serious adverse events were monitored for 28 days after vaccination. Results showed that seroconversion rates of anti-pertussis toxoid (PT), anti-filamentous hemagglutinin (FHA), anti-diphtheria toxoid (DT), anti-tetanus toxid (TT) and anti-polyribosyl-ribitol-phosphate (PRP) in Group T (Stage I: 98.06%, 97.33%, 100%, 100%, 98.79%; Stage II: 99.18%, 83.42%, 99.18%, 63.32%, 85.05%) were comparable to that of Group C (Stage I: 95.26%, 93.16%, 100%, 100%, 98.42%; Stage II: 98.89%, 83.89%, 98.33%, 53.89%, 76.67%). Nearly 100% of the subjects in both groups achieved seroprotective levels of anti-DT (> or = 0.1IU/ml), anti-TT (> or = 0.1IU/ml) and anti-PRP (> or = 0.15 microg/ml) after primary and booster vaccination. The frequencies of local induration, swelling and redness as well as general reactions such as fever, diarrhea and anaphylaxis were low and acceptable in both groups. In conclusion, the DTaP/Hib vaccine was demonstrated to be non-inferior to the control vaccines on safety and immunogenicity. There could be a bright future for the DTaP/Hib vaccine to be widely used in the universal vaccination of Chinese children.