Year: 2019
Type: dissertation
Abstract: The development of vaccines is one of the most important public health achievements. The goal of immunization is to protect individuals and the population from vaccine-preventable diseases (VPD). Although modern vaccines generally are safe, there is always a risk of adverse events, as is the case with any medical technology. Vaccines licensed by the National Regulatory Authorities are considered safe, but rare adverse reactions cannot be detected in pre-licensure clinical trials because of their limited size and duration. Once vaccines are licensed and used widely in the population, the main way to evaluate their safety is by conducting postlicensure surveillance and related observational epidemiology studies. An adverse event following immunization (AEFI) is defined as a reaction or an event occurring after vaccine administration that is suspected to be related to the vaccination. All detected AEFIs do not have a causal relationship with vaccines, but the public may perceive them to be related to vaccination, which may raise concern, influence public confidence and hamper the implementation of immunization programs. As more vaccines are being introduced worldwide, high quality safety surveillance is becoming even more important to maintain public confidence in vaccines and vaccine programs. \n \n Many developed countries have established well-functioning AEFI surveillance systems, such as the Vaccine Adverse Event Reporting System (VAERS) in the U.S. However, it may be difficult to compare the safety profiles of vaccines used in developed countries to those in low and middle-income countries because the vaccines used and the types of serious AEFIs may be different due to local programmatic, health care system, environmental and genetic differences. China has a total population of over 1.3 billion people and an annual birth cohort of 16 million. With the increasing demand for vaccines and the development of vaccine manufacturing, China now ranks among the world’s largest vaccine manufacturers producing more than one billion vaccine doses annually. In 2010, the Chinese Food and Drug Administration’s (CFDA) website listed 46 registered Chinese vaccine manufacturers of public or private status, collectively manufacturing 24 licensed vaccines. \n \nIn mainland China, vaccine safety surveillance began first in provinces with enough economic resources, such as Shanghai and Jiangsu, in the 1980s. However, varying guidelines and definitions made comparing the collected data between provinces difficult. Based on National AEFI guideline issued by CFDA and the Ministry of Health (MoH) in 2010, the National Immunization Program (NIP) of the Chinese Center for Disease Control and Prevention (CDC) implemented the National AEFI Surveillance System (CNAEFIS) to establish a uniform nation-wide monitoring system which covers all NIP vaccines as well as those administered in private practices. The CNAEFIS is currently the only data source available for postlicensure safety monitoring for vaccines manufactured and used in mainland China. \n \nThe studies in this dissertation focus on evaluating the performance of the CNAEFIS and on using the collected data to assess vaccine safety issues. The four studies (I to IV) describe and evaluate the national AEFI surveillance system and assess the safety of selected vaccines used in mainland China. Study I described the CNAEFIS and its performance attributes to understand its overall functioning and to identify areas needing strengthening. Studies II to IV are case studies that evaluate vaccine safety in the following topics: recipient vaccine-associated paralytic poliomyelitis (VAPP), AEFI-associated deaths and, the AEFIs associated with the Japanese Encephalitis (JE) vaccines manufactured and used in China. The findings from these studies helped to identify vaccine-related safety concerns, assess whether these concerns were associated with vaccines and find ways to strengthen surveillance and investigation capacity for the immunization services in China. \n \n The CNAEFIS is a passive surveillance system that can collect timely national AEFI data and detect rare and severe events. With cumulating experience and data since its implementation in 2005, the CNAEFIS provides baseline data on AEFIs in the world’s largest population. By using different sources of denominator data, the CNAEFIS may also have the unique ability and statistical power to detect changes in reporting rates of known adverse events to help determine whether potential changes in observed rates may reflect uneven reporting. \n \n With the end game in progress for global eradication of polio, the schedule of polio vaccine administration in China was changed in 2016: one dose of inactivated polio vaccine (IPV) was introduced as the first polio vaccine dose and the subsequent three doses of trivalent Oral Poliovirus Vaccine (OPV) were replaced with bivalent OPV. The evaluation of VAPP cases reported in CNAEFIS provided information on the safety of trivalent OPV and will serve as reference data for VAPP occurrence after bivalent OPV in future evaluations. In Study II, the epidemiological characteristics of recipient VAPP cases, such as age distribution, were comparable v to those in previous studies from other countries. The risk of recipient VAPP, using either estimated births or vaccination doses as the denominator, was comparable to that observed in the U.S. and Japan. To further decrease the number of recipients VAPP cases in China, use of IPV was recommended. \n \nStudy III was initiated because of media reports of deaths following administration of hepatitis B vaccine in Hunan province in December 2013. These reports had raised concerns about safety of vaccines among parents and the public and had resulted in marked decline in parental and public confidence in vaccines in the province. Childhood deaths are very rare and concerning events, but vaccinations in childhood are common. Therefore, a temporal association of reported fatalities with hepatitis B vaccination may have occurred by chance, without a causal link to vaccination. Our analysis provided reassuring information about the small risk of death following immunization. The reporting peak of AEFI-associated deaths in late 2013 to early 2014 illustrated the sensitivity of passive reporting systems to public information. It also highlighted the caution that should be exercised in interpreting peaks in reports of serious AEFIs. Although the analysis was limited by small number of cases, our review of the characteristics of AEFIs and causes of death identified no vaccine safety concerns. This finding addressed the public’s concerns and should bolster confidence in the vaccine program. \n \nJE vaccines were introduced in the national immunization schedule in the mainland of China at the end of 2007. In 2013, the Japanese Encephalitis Vaccine Live (JEV-L) was the first Chinese-produced vaccine to be prequalified by the World Health Organization (WHO). Limited data were available on the safety of JE vaccines after their inclusion in the national immunization schedule and, consequently, on its large-scale use in China. In Study IV, the majority of AEFIs following JE vaccines were minor and comprised common adverse reactions. There were no significant differences between the estimated reported rates of serious AEFIs following JE Inactivated (JEV-I) and JEV-L. Most patients with serious AEFIs recovered fully. We recommended further studies to differentiate the effects of concurrent vaccination of other vaccines from those of JE vaccines and adoption of more sensitive methods to detect safety signals. \n \nThis dissertation illustrates the progress made with vaccine safety monitoring during recent years in China. In these studies, we found that national AEFI surveillance was functional and able to provide useful data to evaluate safety of vaccines in the world’s largest population. The assessment of recipient VAPP, AEFIassociated deaths, and the safety of JE vaccines suggested acceptable vaccine safety profiles. However, we also identified several challenges, such as lack of standard international diseases and symptoms coding system and case definitions, which should be introduced to reduce misclassification and strengthen the system. In addition, the causality assessment procedures should be standardized and made more rigorous. Finally, new statistical methods should be introduced for safety signal detection and hypothesis generation in future studies. These scientific improvements in the world’ largest vaccine safety data source would continue building public confidence in vaccine programs in China, and perhaps serve as a model to surveillance system development in other countries.
Author: Wendi Wu
Language: English
Subfield: Toxicology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2970531698