On December 3, 2015, a new type of preventive biological product independently developed by China, the inactivated enterovirus 71 (EV71) vaccine, was approved. This news boarded the CCTV News Network.
EV71 belongs to enterovirus, which is highly contagious and can be infected through contact. Past data have shown that generally children are febrile but not fatal. However, since 2009, reports of fatal cases of hand, foot and mouth disease have appeared in the newspapers. After investigation, it was found that most of the fatal cases were caused by EV71/C4 virus infection. Through epidemiological observation, children under 5 years old are high-risk groups, and the highest fatality rate of critical cases is between 6 months and 2 years old.
In the widespread epidemic areas and seasons of hand, foot and mouth disease, how much is the incidence of hand, foot and mouth infection in the vaccine immunized group lower than that in the non-immunized group? Does the new vaccine have the expected clinical protective efficacy and good safety profile? Has the severity rate decreased? How to monitor the effectiveness and safety of EV71 inactivated vaccine for infants and young children in the future? Facing our questions, Xu Jiaqi, director of the Center for Drug Evaluation, sent an invitation, so we got the opportunity to have an in-depth conversation with the front-line reviewers.
”Speaking of vaccines for the prevention of hand, foot and mouth disease caused by EV71, it is really something that we drug reviewers can be proud of.” Yang Huan, a senior reviewer in charge of vaccine clinical review, said.
R&D from scratch
In 2007, severe and fatal cases of hand, foot and mouth disease broke out in children. In response to this epidemic, many domestic vaccine research and development companies began to set up research and development projects in 2008. The National Health and Family Planning Commission included it in the national major new drug creation science and technology major project to support it.
According to clinical feedback, the clinical manifestations of some children with severe HFMD do not show typical herpes on the hands and feet. The initial symptom is high fever, which rapidly progresses to encephalitis and cardiopulmonary failure, and severe cases can lead to death. Follow-up testing and research found that the correlation between the death of these patients and EV71 virus infection reached more than 90%. “There is a clinical demand for hand, foot and mouth disease vaccines.” Yang Zhimin, director of the clinical department of the Center for Drug Evaluation, said.
EV71 was discovered in 1969 and has caused many outbreaks of hand, foot and mouth disease worldwide. In recent years, it is mainly prevalent in Southeast Asia, while the incidence rate in Europe and the United States is not high, and developed countries do not pay much attention. However, since the disease appeared in my country in 1981, there have been many large-scale outbreaks or epidemics, seriously threatening the lives and health of hundreds of millions of children.
In 2008, my country officially included HFMD in the reporting management of Category C cases of national statutory infectious diseases. In recent years, the number of cases of hand, foot and mouth disease in my country has always been at the forefront of legal infectious diseases. At present, there is still a lack of specific therapeutic drugs, and severe cases and death cases occur from time to time. Therefore, the development and use of vaccines are crucial to the prevention and control of the epidemic. Yang Huan said that the first step in developing a vaccine is to isolate the virus strain based on the study of the biological characteristics of the EV71 pathogen and its infection mechanism. Detailed information records. In the early stage, three companies used human diploid and Vero cells as expression systems to comprehensively study the adaptation and passage of EV71 on cells, as well as immunogenicity, safety and genetic characteristics.
Screening strains and subculture adaptive production are only the first step in the preliminary pharmaceutical research, and the next step is to determine the dosage form. At this time, it is necessary to explore on animal models, including whether the vaccine formulation needs to add adjuvants and the determination of preparation process parameters. Vaccine doses and vaccination procedures should also be studied preclinically, that is, how long antibodies can be produced after injection. In addition, to explore the mechanism of action of the vaccine, it generally stimulates the body’s humoral immune response, which can be reflected by detecting antibody levels. However, like tuberculosis and HIV vaccines, it also stimulates the human cellular immune system, and cellular immune response needs to be detected.
In the absence of similar vaccine research and development at home and abroad to learn from experience, the EV71 inactivated vaccine should break through the key technical bottlenecks in the large-scale production and quality control of vaccines in stromal cells, and establish a large-scale production process system as well as quality control and quality control. The standard system lays the foundation for the production of safe, effective and quality-controllable vaccine products.
Finally, the key issues involved before entering human trials are how to determine the potency and quality control of the vaccine, and establish standards. Regarding the potency, the vaccine review team of the Center for Drug Evaluation has communicated many times with R&D companies, the China Inspection Institute, and WHO. The vaccine standard product is closely assisted by the enterprise and the China Inspection Institute to make the national standard product, and the national standard product will be upgraded to the international standard product to be recognized. This is mainly due to the fact that even if the new vaccines independently developed by each company have differences in their respective formulations and production processes, the antigenic units, protein content, and potency of the final product must still have relatively scientific and reasonable standards and quality controls. Important issues to consider in terms of review.
Because there is no comparable and reference data support for the new viral vaccine in its development and review process; and the current basic research on EV71 virus at home and abroad, such as the pathogenesis and immune type of clinically severe and fatal diseases Therefore, the technical review and inspection and verification of EV71 inactivated vaccines have encountered great challenges.
Enter the special approval channel
The fatal mechanism of hand, foot and mouth disease is still unclear. Although the clinical symptoms of children’s death are usually central nervous system infection (such as encephalitis), no virus is found in the cerebrospinal fluid. Some basic research suspects that the cause of death is immunopathological reaction. Because of this, the EV71 inactivated vaccine has done sufficient pharmacology and toxicology research before going to human clinical trials, and reminded researchers in the clinical approval documents to strengthen safety monitoring and pay full attention to pathological immune responses.
According to Yang Huan, when the first application for clinical research was submitted in 2010, the Center for Drug Evaluation decided to expedite the review of such vaccines in accordance with the special approval procedures of the 2007 “Measures for the Administration of Drug Registration” and the 2009 “Regulations for the Administration of Special Approval of New Drug Registration” , obtained the clinical approval document on December 23, 2010. During the phase I, II, and III clinical trials from the end of 2010 to 2013, the Drug Evaluation Center intervened early, organized review personnel to conduct on-site investigations of production and clinical research, and closely tracked progress. Provide technical support, analyze and discuss the results of phase I/II clinical trials through meeting communication, and gradually and steadily promote the clinical trial process of vaccines. The review of supplementary materials was completed in July 2014, and an expert seminar and consultation meeting on EV71 inactivated vaccine was held in August 2014.
In February 2015, the Center for Drug Evaluation held an expert seminar on several major decision-making issues for EV71 inactivated vaccines. It is agreed that, based on the HFMD epidemic situation and epidemiological considerations, the clinical demand for EV71 inactivated vaccine is urgent, and the focus of HFMD prevention and control should be to prevent and reduce deaths and severe cases; The deaths and severe cases are of great significance and have great public health value.