[Application of seamless phase â ¡/â ¢ design in vaccine clinical trials].

The seamless phase Ⅱ/Ⅲ design integrates independent phase Ⅱ and phase Ⅲ clinical trials into a continuous, phased adaptive clinical trial design. Compared with traditional independent phase Ⅱ and phase Ⅲ clinical trials, the seamless design offers significant advantages in accelerating drug or vaccine development and improving clinical trial efficiency. Currently, the application of this design in anti-tumor drug research is becoming increasingly mature, and it is gradually expanding to clinical trials of vaccines, including the 9-valent human papillomavirus vaccine, sabin strain inactivated polio vaccine, and others. This paper aims to clarify the seamless phase Ⅱ/Ⅲ design concept and offer valuable insights into its implementation. It accomplishes this by presenting a clinical trial example featuring a phase Ⅱ/Ⅲ seamless design for a 9-valent human papillomavirus vaccine. The article delves into the specific considerations and potential challenges related to implementing the seamless design, aiming to provide valuable insights for optimizing vaccine clinical trials within our country.

[Application of bridging study design in preventive vaccine clinical trials].

Bridging study in vaccine clinical trials means a series of small-scale additional tests on the basis that the original safety and effectiveness of a vaccine have been confirmed in clinical trials, to prove that the characteristics of safety, immunogenicity and effectiveness of a vaccine are similar or consistent after component, population and immunization procedure change to other types which can extrapolate data from existing clinical trials. Compared with traditional vaccine clinical trials, bridging trials can promote the approval of vaccines to the market, accelerate the expansion of vaccine application, and promote the use of vaccines across regions and populations. In recent years, the application of bridge study design in vaccine clinical research has become more and more common. In order to better guide and promote the application of bridging trial design in the field of vaccine clinical research, we reviewed the design characteristics and application examples of bridging study design in vaccine clinical trials, and systematically elaborated the design ideas, key points and statistical evaluation methods of bridging study.

[Kinetics of SARS-CoV-2-specific antibodies among inactivated COVID-19 vaccine recipients, SARS-CoV-2 natural infection cases, and breakthrough cases].

Between August and September, 2021, this study included 605 SARS-CoV-2 natural infection cases and 589 SARS-CoV-2 breakthrough cases from Nanjing and Yangzhou, as well as 690 inactivated COVID-19 vaccine recipients from Changzhou, China. In SARS-CoV-2 natural infection cases, the age range was 19-91 years (median age: 66 year), and the medians(Q1,Q3) of IgG titers were 0.19 (0.06-1.31), 3.70 (0.76-69.48), 15.31 (2.59-82.16), 4.41 (0.99-31.74), 2.31 (0.75-13.83), 2.28 (0.68-9.94) and 2.80 (1.00-9.53) at one to seven weeks after SARS-CoV-2 infection, respectively. In SARS-CoV-2 breakthrough cases, the age range was 18-76 years (median age: 45 year), and the medians(Q1,Q3)of IgG titers were 1.93 (0.34-26.67), 38.87 (7.90-121.0), 75.09 (11.85-123.70), 21.97 (5.20-95.58), 13.97 (3.47-46.82), 9.56 (2.48-33.38) and 4.38 (1.87-11.00) at one to seven weeks after SARS-CoV-2 infection, respectively. In inactivated COVID-19 vaccine recipients, the age range was 18-87 years (median age: 47 years), and the medians(Q1,Q3)of IgG titers were 16.22 (15.84-33.42), 5.35 (2.96-13.23), 3.30 (2.18-6.18), 3.14 (1.16-5.70), 2.77 (1.50-4.52), 2.72 (1.76-4.36), 2.01 (1.27-3.51) and 1.94 (1.35-3.09) at one to eight months after SARS-CoV-2 infection, respectively. The results suggested that IgG antibodies increased gradually within two weeks after SARS-CoV-2 infection, then declined gradually at three to seven weeks in SARS-CoV-2 natural infection cases. In SARS-CoV-2 breakthrough cases, IgG antibodies increased rapidly within two weeks, then declined gradually at three to seven weeks after SARS-CoV-2 infection. Additionally, IgG antibodies decreased rapidly within three months, then decreased gradually and remained at a low level within three months after immunization.

[Five-year immunity persistence following immunization with haemophilus influenzae type b conjugate vaccine].

Objective: To evaluate the immunity persistence five years later after immunization with Haemophilus influenzae type b (Hib) conjugate vaccine in healthy infants/children aged 3 months to 5 years in China. Methods: The children were subjects who completed the whole-schedule immunization in the phase Ⅲ clinical trial in Lianshui county of Jiangsu povince was selected for the collection of blood samples at 5 years after vaccination from November to December, 2019. The enzyme-linked immunosorbent assay (ELISA) was used to detect Hib polyribosyl-ribitol-phosphate antibody (anti-Hib-PRP), and the long-term/short-term protection rate, geometric mean concentration (GMC) and geometric mean concentration increase fold (GMFI) of serum anti-Hib-PRP were calculated. Results: A total of 580 children were enrolled in this study, of which 158, 207 and 215 belonged to 3-5 month age group, 6-11 month age group and 1-5 year age group, respectively. The short-term (≥0.15 µg/ml)/long-term (≥1.0 µg/ml) protection rates of serum anti-PRP in the three groups after immunization were 89.24%, 90.34% and 98.60%, respectively; the GMC were 3.95 µg/ml, 3.11 µg/ml and 10.01 µg/ml respectively, and the GMFI were 29.04, 11.01 and 3.26 respectively. Conclusions: Hib conjugate vaccine can still have good immunogenicity after 5 years of primary immunization in healthy infants/children aged 3 months to 5 years in China.

[Advances in clinical research of virus vector-based COVID-19 vaccines].

The COVID-19 outbreak at the end of 2019 has accelerated the development and research for COVID-19 vaccines worldwide. Among the COVID-19 vaccines in clinical trials developed via different platforms, recombinant virus vector-based vaccines have shown excellent immunogenicity and efficacy. However, at the same time, there are serious issues such as vaccine safety and pre-existing antibodies against vectors. This article summarizes the design concept and development history of recombinant virus vector-based vaccines, and focuses on the progress in the clinical studies of vector-based COVID-19 vaccines as well as the challenges, in order to provide reference for the research of recombinant vector-based vaccines.

[Association between metabolic risk factors and the hepatitis B reactivation of inactive HBsAg carriers in Jiangsu province: a cohort study].

Objective: To analyze the impact of metabolic risk factors on the epidemiological characteristics of the reactivation of inactive HBsAg carriers (IHC) and provide effective intervention measures to standardize the management of chronic hepatitis B infections. Methods: Based on the chronic hepatitis B infection cohort established in 2010 in Jiangsu province, six follow-up visits from 2012 to 2020 were conducted to analyze the characteristics and influencing factors of the hepatitis B reactivation of IHC and the impact of metabolic risk factors, including obesity, high blood pressure, diabetes and hyperglycemia. Results: From 2012 to 2020, 2 527 IHC and 17 730 person-years were observed during a median follow-up period of 7.0 person-years. Ninety-eight cases of hepatitis B reactivation, with a cumulative reaction rate, was 3.9%, and the incidence density was 5.53/1 000 person-years. Multivariate Cox proportional risk regression analysis showed that age and baseline HBV DNA were independent risk factors of HBV reactivation. Compared with the patients ≥60 years, 40-49 age group (aHR=2.16, 95%CI:1.20-3.90) and 20-29 age group (aHR=5.48, 95%CI:2.07-14.48) were significantly associated with hepatitis B reactivation. Compared with the HBV DNA negative patients at baseline, the risk of hepatitis B reactivation was higher in the group with low HBV DNA level 100-1 999 IU/ml (aHR=1.67, 95%CI:1.11-2.52). Stratification analysis results showed that compared with those without metabolic risk factors, in the ≥50 age group, patients with ≥2 metabolic risk factors showed adjusted HR of 2.73 (95%CI:1.08-6.96). Conclusions: The risk of hepatitis B being reactive is the persistent existence of IHC in communities in Jiangsu province, especially young adults, low-level HBV DNA carriers, and IHC with ≥2 metabolic risk factors. Follow-up for these IHC should be strengthened to reduce the risk of disease progression by antiviral treatment at the right time.

[Application of cluster randomization design in vaccine clinical trials].

When the coverage of the vaccinated people reaches a certain percentage of the population, the herd protection will protect the unvaccinated persons. However, the traditional clinical evaluation of vaccines performing individual randomized design fails to evaluate the herd protection of vaccines. Compared with the individual randomized design, the cluster-randomized design can determine the overall protection by the vaccine more comprehensively. It has become increasingly common to perform a cluster-randomized design in clinical trials of vaccines in Phase Ⅲ and Ⅳ clinical trials. However, little is known about the application of cluster randomized design in vaccine clinical trials in China. We, at this moment, do a review of the application of random cluster design in vaccine clinical trials and provide references for future research in China.

[Progress in research of influential factors for non- or low-immune response to hepatitis B vaccination].

Hepatitis B virus (HBV) can cause a variety of hepatitis B-related diseases in infected people, and there is no specific drug for treatment. China, with a large population base, is the country with the heaviest burden of HBV infection in the world. Therefore, hepatitis B vaccination is particularly important in the prevention and control of this disease. However, some vaccinees did not produce effective protective immune response after vaccination according to the recommended hepatitis B vaccine immunization schedule. The purpose of this review is to analyze the influential factors of non/low immune response after hepatitis B vaccination from the aspects of organism and vaccine, and explore the mechanism of non/low immune response, so as to provide scientific basis for the prevention and treatment of hepatitis B in China.

[Progress in research of avian influenza virus and human monoclonal antibody and vaccines against H7N9 virus].

Avian influenza virus (AIV) is a kind of zoonotic virus which can cause acute respiratory infectious diseases. Since the report of the world's first human infection case of avian influenza A (H7N9) virus in China in 2013, close attention has been paid to the virus. AIV spreads widely around the world, and human infection with different types of AIV continues to occur, causing huge economic losses. At present, there are no specific treatment and drugs against the disease, and vaccination is considered as the most promising and effective method to control the human infection with AIV. So far, there are many kinds of veterinary and human vaccines for H7N9 AIV, among which four types of human H7N9 AIV vaccines have entered the clinical trial stage, including virus-like particles vaccine, attenuated live vaccine, inactivated vaccine and DNA vaccine, which have shown good safety and immunogenicity. However, the true efficacies of the AIV vaccines remain unknown because no human vaccines are currently available in the market. In addition, although the existing influenza vaccine has good safety and immunogenicity in the human population, there is no cross-antibody response to H7N9 AIV. This paper summarizes the research progress of AIV etiology and epidemiology, the occupational exposure population investigation, the infection prevention and control strategies, and H7N9 AIV vaccine and H7N9 AIV anthropogenic monoclonal antibody, and discuss the remained problems, challenges and future trends in the research of AVI to improve the understanding of the disease and the prevention and control of global spread of AIV.

[Exploration and application of a novel attempt to recruit participants in clinical trials of vaccines under the emergency].

Objective: To evaluate and share the novel method for recruiting participants in clinical trials of vaccines in emergency situations. Methods: To publish recruitment notice in local areas of Wuhan through websites and medium, and guide interested persons to log in to the"Clinical Trials of SARS-CoV-2 Vaccine Reservation and Health Declaration System"to appoint and register their health information. The "Health Declaration System" provides each volunteer evaluation and risk levels to preliminarily exclude those who do not meet the inclusion criteria. Researchers review the qualified volunteers by telephone, organize them to go to the vaccination site, and finally conduct a strict medical screening to determine the final subjects. Results: A total of 4 819 people and 5 132 people registered in the Phase Ⅰ and Phase Ⅱ recruitment system respectively, with men 2 912 (60.43%) and 2 887 (56.25%) more than women 1 907 (39.57%) and 2 245 (43.75%), mostly in the 20-39 age group, with 3 211 (66.63%) and 3 966 (77.28%). All 13 districts in Wuhan have interested residents to participate clinical research.The initial qualified rate of the Phase Ⅱ recruitment system was higher than that of Phase Ⅰ, with men 2 047 (70.28%) and 2 135(73.95%), higher than women 1 083 (56.80%) and 1 472 (65.57%); 440 and 689 people were reviewed by telephone in Phase Ⅰ and Phase Ⅱ respectively, and the number of verified volunteers was about 440 (35.00%) and 689 (67.20%); Of the 201 603 people who arrived at the vaccination site, 12 and 26 of them were positive for the SARS-CoV-2 antibody with an antibody positive rate of 6.00% and 4.31% respectively. Conclusion: The novel method for recruiting subjects in this clinical study is efficient and reliable, and the recruitment situation of Phase Ⅰ had set a good example for Phase Ⅱ but the medium-and long-term compliance of subjects and the separation of willingness and behaviors still need to be further studied.

[Research on the main factors influencing influenza vaccine effectiveness].

Effectiveness of seasonal influenza vaccines varies greatly during the different flu seasons. Although the WHO assesses and updates influenza vaccine strains every year, the effectiveness of vaccine is sometimes not good. This review explores the various factors that influencing influenza vaccine effects in order to improve the effectiveness of influenza vaccines and provide a scientific basis for influenza vaccination. The results reveal that the degree of matching between epidemic strains and vaccine strains, pre-exposure (natural infection, vaccination), age, and immune status could all affect the vaccine effectiveness.

[Application of test-negative design in vaccine efficacy evaluation].

Vaccine efficacy can be assessed by a randomized placebo-control trial prior to marketing. However, after the marketing of a vaccine, if a placebo-randomized control trial is used to evaluate the efficacy of the vaccine, ethical issues will arise. Therefore, the evaluation of the efficacy of a vaccine after marketing has become a difficult problem in the public health field. In recent years, the research method of test-negative design has been widely used in the world for the evaluations of the efficacies of different post-marketing vaccines, such as influenza vaccine, rotavirus vaccine, cholera vaccine, pneumonia vaccine and EV71 vaccine. However, there are limited reports in the domestic literature on the test-negative design. Therefore, we summarize the basic principles, application steps, advantages and disadvantages of the test-negative design to provide theoretical methods and basis for the future study of test-negative design in China.

[Meta-analysis on effectiveness of live attenuated influenza vaccine against seasonal influenza in children].

Objective: To evaluate the effectiveness of live attenuated influenza vaccine (LAIV) in the prevention of seasonal influenza in children aged 2-17 years. Methods: 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. Results: 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%CI: 40%-57%). Subgroup analysis found that the protection rate of LAIV was 35% against influenza A (H1N1) pdm09 (95%CI: 5%-56%), 35% against influenza A (H3N2) (95%CI: 21%-46%), and 71% against influenza B (95%CI: 55%-82%). The protection rates of trivalent LAIV and quadrivalent LAIV in children were 56% (95%CI: 48%-63%) and 44% (95%CI: 27%-57%), respectively. The protection rates of LAIV in Europe and North America were 65% (95%CI: 47%-77%) and 46% (95%CI: 36%-55%), respectively. Conclusion: LAIV has a certain preventive effect on seasonal influenza in children aged 2-17 years.

Age distribution of human papillomavirus infection and neutralizing antibodies in healthy Chinese women aged 18-45 years enrolled in a clinical trial.

OBJECTIVES: Data from clinical trials of human papillomavirus (HPV) vaccines showed that women naïve (negative for both type-specific antibodies and DNA) to vaccine types would derive benefit from vaccination; therefore, an understanding of the proportion of naïve women in different age groups is important for developing HPV vaccination strategies. METHODS: From November 2012 to April 2013, a total of 7372 healthy women aged 18-45 years were recruited in five provinces in China. Cervical specimens and serum samples were collected for each woman at entry. Cervical specimens were first tested by the HPV DNA enzyme immunoassay method; if positive, the specimens were then tested by reverse hybridization line probe assay and HPV-16 and HPV-18 specific polymerase chain reactions. Neutralizing antibodies against HPV-16 or HPV-18 were tested with a pseudovirion-based neutralization assay. RESULTS: The overall prevalence of high-risk HPV DNA was 14.8% (1088/7367, 95% CI 14.0-15.6), and the seroprevalence of neutralizing antibodies against HPV-16 and HPV-18 was 12.6% (925/7367) and 4.9% (364/7367), respectively. In younger women (18-26 years) and middle-aged women (27-45 years), 83.8% (3116/3719) and 81.4% (2968/3648) were naïve to both HPV-16 and HPV-18 (both neutralizing antibodies and DNA were negative), respectively. In addition, 98.5% (3664/3719) and 98.0% (3575/3648) of the younger or middle-aged women were naïve to at least one HPV type (HPV-16 or HPV-18). DISCUSSION: This study revealed that the majority of Chinese women aged 18-26 years and 27-45 years were naïve to both HPV-16 and HPV-18 and would thus derive full benefit from bivalent HPV vaccination.

[Original antigenic sin in the influenza vaccination and its influence].

Original antigenic sin may exist in the influenza virus infection or vaccination, which possibly reduces the protective efficacy in repeated influenza vaccination. This paper reviews the literature on the original antigenic sin and its influence in influenza vaccination, and interprets the possible mechanism of this phenomenon from the three aspects of influenza virus structure, humoral immunity and cellular immunity. A large number of studies have shown that original antigen sin has a negative impact on influenza vaccination, but the evidence disproveing this phenomenon also exist, so multi-center large-scale clinical trials should be conducted to provide evidence-based basis for reaearching whether original antigen sin exists and its effects. in order to provide reference for the development and update of noval influenza vaccines and its formulation of immunization strategies.

[Interpretation for diagnosis of Yersiniosis].

Yersiniosis is one of the "other infectious diarrhea" of the notifiable infectious diseases and also an important food-borne disease. However, it lacked the basis or standard for diagnosis. The Chinese Preventive Medicine Association coordinated experienced researchers from National Institute for Communicable Disease Control and Prevention, China CDC and other institutes to produce the group standard entitled "Diagnosis of Yersiniosis" (T/CPMA 005-2019). Based on the principle of "legality, scientificity, advancement, and feasibility" , the standard gives a clear definition for Yerisiniosis, stipulates diagnosis basis, principles and main differential diagnosis and provides two informative appendixes for epidemiological and clinical characteristics and a normative appendix for laboratory detection. The standard provides accurate basis and methods of Yersiniosis diagnosis for hospitals and CDCs at all levels in China. It will solve the problems that Yersiniosis cannot be clearly diagnosed for clinical cases and in the outbreaks.

[Research progress of the surrogate of protection of pneumococcal conjugate vaccine].

There are many limitations in evaluating vaccine efficacy by comparing the incidence of clinical endpoint events (such as morbidity, bacterial colonization) between the vaccine group and the control group. Therefore, the researchers put forward the concept of Surrogate of protection to predict vaccine protection with immunological indicators. In 2012, WHO put forward the immunological substitution endpoint of pneumococcal vaccine, using 0. 35 µg/ml as the protective antibody level of pneumococcal vaccine. But subsequent studies have found that using this threshold to assess all vaccine serotypes may not be accurate.

[Research progress of maternal immunization].

Maternal immunization is an immune strategy that protects both mothers and early-life infants from disease by the vaccination of pregnant women. The effect of maternal immunization is influenced by the types of vaccines, the timing of vaccination, the subtypes of antibodies induced by vaccines, and the health status of mothers themselves. Inactivated influenza vaccination during pregnancy and DPT vaccination during the third trimester of pregnancy have been widely used in the world, while Hepatitis B vaccine, pneumococcal and meningococcal vaccines also show good efficacy and safety in pregnant women. This article reviews the research progress of Maternal Immunization in order to provide a reference for Maternal Immunization planning and policymaking in China.

[Progress in research of influence of gene polymorphisms on immune response].

Genes play an important role in the immune system response, and different gene loci may result in different vaccine immune response rates. This review focuses on the correlation between gene polymorphisms and vaccine immune response in order to investigate the influence of gene polymorphisms on the immune response to vaccines. It discusses the effect of an individual's immune response after vaccination at genetic level and provides a scientific basis for individualized immune development strategies. It reveals that human leukocyte antigen genes, various cytokines and their receptor genes, and Toll-like receptor genes all affect the vaccine immune response.

[Research progress in immunization status and immunization effect of preterm infants].

Due to immature development of the immune system, preterm infants are at increased risk of infections from vaccine-preventable diseases. But at the same time, premature vaccination may not induce a good immune response because of the incomplete development of the neonatal immune system, and may cause serious adverse reactions risk due to the poor immune tolerance, thus vaccination of preterm infants at the appropriate time is the key to reducing the risk of infectious disease and obtaining vaccine protection. At present, it is generally recommended that the gestational age and birth weight should be considered in the vaccination of preterm infants. The timing, type and even the immunization schedule of the vaccine should be differ from that of the full term infants. However, there is a lack of research results and data on immunization program in preterm infants in China, and there is still no provided universal guidelines for their vaccine immunization. This article aims to summarize the guidelines and clinical trials of vaccination of preterm infants in foreign countries, and to provide reference for the formulation and implementation of immunization strategies for preterm infants in China.