ABSTRACT
Through the Chinese National Immunization Adverse Event Surveillance System (CNAEFIS), we collected reports of Adverse Event Following Immunization (AEFI) deaths in Shenyang from 2009 to 2021 with the aim of analyzing AEFI-related deaths and assessing the safety of vaccination. From 2009 to 2021, a total of 12 AEFI-related deaths were reported in Shenyang City, and autopsies were performed in 6 deaths. According to the assessment of the Expert Committee on Investigation and Diagnosis of AEFI 3 (25.0%) deaths were classified as severe vaccine reactions, 9 (75.0%) deaths were classified as coincidental events, and there were no immunization errors or psychological reactions. The overall estimated AEFI-related mortality rate was 0.12 per 100,000 vaccination doses. Spearman’s rank correlation analysis showed no correlation between AEFI, severe vaccine reactions, and suspected vaccination-related deaths. Coincidental events are the most common type of death following vaccination, meaning that the risk of death following immunization is low, and ongoing AEFI surveillance and scientific causality assessment are essential to ensure the vaccine confidence. Detailed pre-vaccination health status questioning is also key to avoiding and reducing adverse events.
Introduction
Vaccination is considered one of the top ten public health achievements of the 20th century.Citation1,Citation2 According to the estimation of WHO, 116.2 million children were vaccinated worldwide in 2017, saving 2 million to 3 million lives annually.Citation3 Immunization program depends on the foundation of a strong and efficient health service system that can deliver and scale-up the vaccination service. As the morbidity and mortality of vaccine-specific infectious diseases have declined, public concern about vaccine safety has increased. Although vaccine reactions, especially mortality, are extremely low, they can significantly impact today’s society, sometimes even causing a massive impact on vaccination efforts and causing some parents of children to be hesitant about vaccines.Citation4 Loss of confidence in the safety of the vaccine, low vaccination rates, and even the reemergence of vaccine-preventable diseases (VPDs) can result.
Shenyang is an important central city in northeast China and the capital city of Liaoning Province, with a population of about 9000,000,50,000 births per year and over 1.5 million doses of vaccines annually. Shenyang began its Expanded Programme on Immunisation (EPI) in 1978 with only four vaccines and expanded to the 11 vaccines in the National Immunisation Programme at the end of 2008 to protect against 12 VPDs.Citation5,Citation6 The 11 vaccines include Bacillus Calmette Guerin (BCG), diphtheria, tetanus and acellular pertussis combined vaccine (DTaP), diphtheria–tetanus combined vaccine (DT), oral poliomyelitis vaccine (OPV), measles vaccine (MV), measles-mumpsrubella combined live attenuated vaccine (MMR), hepatitis B vaccine (HepB), hepatitis A live attenuated vaccine (HepA-l), meningococcal polysaccharide vaccine type A (MPV-A), meningococcal polysaccharide vaccine types A and C (MPV-AC), and Japanese encephalitis attenuated live vaccine (JEV-L). It is essential to correctly assess the risks associated with vaccination and to reduce public misconceptions about vaccination. Since 2009 Shenyang has officially joined the Chinese National Adverse Event Surveillance System (CNAEFIS), a national AEFI surveillance system,Citation7 the Shenyang Centre for Disease Control and Prevention has monitored AEFI reports, which are recorded through the CNAEFIS. To understand the epidemiological characteristics, causes of death and risk of post-vaccination mortality in Shenyang, we reviewed and analyzed the reports of post-immunization deaths from 2009 to 2021.
Material and methods
Source of information
Information on deaths reported in Shenyang from January 2009 to December 2021 was collected through the CNAEFIS. CNAEFIS is the only official surveillance system in China developed in 2007 to detect new, unusual or rare AEFIs, assess the safety of licensed vaccines and identify potential risk factors for AEFIs.Citation8
Healthcare facilities, vaccination clinics, CDCs at all levels, vaccine manufacturers, and vaccinees (or guardians) are all responsible for reporting AEFI cases, and cases are collected by the vaccination unit, which is responsible for filling out the AEFI report form to report in the surveillance system, and CDCs at all levels can see the reported cases within their jurisdictions.
Information collected included the investigation report for each case, clinical information, the findings of the causality assessment, and the results of the autopsy report. The investigation report includes the basic situation of the patient, the incident, information related to vaccination, etc. The autopsy results of AEFI fatal cases are derived from the autopsy report issued by a qualified organization.
The denominators (number of doses of each vaccine associated with death) used to calculate the incidence of AEFIs, the incidence of serious adverse reactions to vaccines, and the mortality rate were derived from doses collected at vaccination clinics.
AEFI definition and classification
In June 2010, China’s Ministry of Health and Food and Drug Administration jointly released the National Guideline for the Surveillance of AEFI [8]. AEFI records were divided into five categories according to the guidelines: (1) vaccine reaction (minor reaction and severe reaction), (2) vaccine quality reactions, (3) procedural errors or immunization errors, (4) coincidental events, and (5) psychogenic reactions or immune anxiety-related reactions.
AEFI means a reaction that may cause damage to the tissues, organs, and functions of the body of the vaccinee and is suspected to be related to vaccination, which occurs during or after vaccination.
A severe reaction to vaccine refers to an adverse drug reaction in which a qualified vaccine causes damage to the tissue organs and functions of the body of the vaccinated person in the course of or after the implementation of a standardized vaccination, and in which all the parties concerned are not at fault.
Methods
All reported deaths were diagnosed by provincial AEFI investigation and diagnosis expert committees, which consisted of experts from clinical medicine, epidemiology, pharmacology, immunology, and other related fields, and assessed causality by comprehensively analyzing the information collected on the cases and classifying them in accordance with the National Guidelines for AEFI Surveillance.
Important information about each fatal case, including region, sex, date of birth, vaccination and dose, time of vaccination, time of reaction, time of death, major signs and symptoms, clinical diagnosis, autopsy findings, and judgment of vaccination causation. The data were organized and counted using Excel 2010 software for descriptive analysis of the characteristics of death cases after vaccination, and the incidence of AEFIs, the incidence of severe reactions to vaccines, and the incidence of deaths (per 100,000 doses) were calculated for vaccines associated with deaths, by vaccine type and by reaction type, respectively. Correlations between AEFI, severe vaccine reactions, and death were analyzed using the Spearman rank correlation test, and differences were considered statistically significant at P < .05.
Ethical approval
Ethical approval for the study was not deemed necessary because it was a records-based study and there was no direct intervention involvement with patients
Results
Characteristics of AEFI-related deaths
From 2009 to 2021, 12 cases of death after vaccination were reported in Shenyang. Among them, there were three cases in 2009, one case each year from 2012 to 2017, one case in 2019, and two cases in 2021. Among them, there were eight cases of less than 1 year old, 3 cases of 1–3 years old group, and 1 case of an adult. The minimum age is one month old, and the maximum is 21 years old; seven cases were male, and five cases were female; five cases were urban, and seven cases were rural.
Eight different vaccines or vaccine combinations were associated with reported deaths. The vaccines or vaccine combinations were (1) Bacillus Calmette Guerin (BCG) (3,25.0%), (2) Hepatitis B vaccine (HepB) (2,16.7%), (3) Inactivated poliovirus vaccine (IPv) (1,8.3%), (4) oral poliomyelitis vaccine (OPV) (1,8.3%), (5) Diphtheria, tetanus, and acellular pertussis combined vaccine (DTaP) (1,8.3%), (6) Japanese encephalitis attenuated live vaccine (JEV-L) (2,16.7%), (7) Enterovirus type 71 inactivated vaccine (EV71) (1,8.3%), and (8) Rabies vaccine (RabV) (1,8.3%).
Seven cases occurred after the first dose of vaccination and five cases after the second dose of vaccination. Four cases (33.3%) occurred in the third quarter (July to September), three cases (25.0%) each in the first quarter (January to March) and the fourth quarter (October to December), and two cases (16.7%) in the second quarter (April to June).
Most of the time intervals between vaccination and death were within 7 months after vaccination (11, 91.7%), with 6 cases <24 hours, and the shortest was 2 hour, 4–16 days in two cases, 2–7 months in three cases, and 1 case had a longer interval of 3.3 years ().
Table 1. Reports of AEFI-related deaths by year, 2009–2021.
Diagnosis and classification
Twelve deaths were evaluated for causality by the provincial AEFI Investigation and Diagnosis Expert Committee, with nine coincidental events and three severe vaccine reactions, and no immunization errors, or psychological reactions. Autopsies were performed in 6 (50.0%) cases, all coincidental events, of which 1 died of acute circulatory dysfunction due to a septal defect, 1 died of acute respiratory and circulatory failure due to interstitial pneumonia, 1 died of multi-organ failure due to asphyxia, 1 case died of asphyxia due to milk regurgitation, 1 case died of acute hypertrophic cardiomyopathy, and 1 case of congenital hereditary mitochondrial disease. No autopsy was performed in another 6 cases (50.0%), 3 cases were coincidental events (including 1 case of asphyxia, 1 case of acute brain failure, and 1 case of sudden death), and 3 cases were severe vaccine reactions (1 case of systemic disseminated BCG infection and 2 cases of axillary lymphadenitis) ().
Table 2. Results of AEFI death case investigation, 2009–2021.
Risk estimation of AEFI-related deaths
All reported AEFIs in Shenyang from 2009 to 2021 were 3,252, of which 1,672 were AEFIs from death-associated vaccines. The vaccine with the highest incidence of AEFIs from death-associated vaccines was the combined diphtheria, tetanus, and acellular pertussis vaccine (DTaP) (28.86/100,000 doses), followed by JEV-L (19.87/100,000 doses); the vaccine with the highest incidence of serious reactions from death-associated vaccines was the DTaP vaccine (0.33/100,000 doses), followed by the hepatitis B vaccine (0.29/100,000 doses), while IPV and rabies vaccines were not reported; the highest incidence of deaths from death-associated vaccines was from BCG (0.37/100,000 doses), followed by Hepatitis B (0.29/100,000 doses), and the lowest was from OPV and DTaP (0.03/100,000 doses) (). Of the vaccines involved in death-associated, Spearman rank correlation analysis showed no correlation between the incidence of AEFIs and mortality (r = −0.180, P = .670) and no correlation between the incidence of serious reactions to vaccines and mortality (r = −0.120, P = .776).
Table 3. Reported incidence of AEFI for death-associated vaccines,2009–2021 [/100,000 vaccination doses (95% CI)].
Discussion
Vaccines have been evaluated for efficacy and safety before marketing, although phase III clinical trials include up to tens of thousands of subjects, the power to detect the most rare and AEFI during the clinical development of vaccines remains low,Citation9 and a large amount of safety monitoring data has been accumulated after marketing, which is an important basis for the value of vaccines. During the AEFI surveillance period 2009–2021,12 AEFI-related deaths occurred in Shenyang, distributed among eight vaccines: BCG, hepatitis B vaccine, OPV, IPV, DTaP, JEV-L, EV71, and RabV. Of these, BCG, Hepatitis B, OPV, DTaP, and JEV-L are National Immunization Program (NIP) vaccines, while IPV, EV71, and RabV are non-National Immunization Program (non-NIP) vaccines. Eleven cases were children and one was an adult case who was vaccinated with rabies vaccine, which is a non-NIP vaccine. In Shenyang City, about 1.5 million doses are inoculated annually, and a total of nearly 20 million doses were inoculated from 2009 to 2021. Deaths after vaccination are rare and only 12 deaths were discussed, which is a limitation of this study. Deaths accounted for 0.3% of all AEFI cases, which was higher than Australia’s 0.07% in 2015,Citation10 and higher than the zero deaths reported in Oman during 2006–2015,Citation11 and close to China’s Zhejiang Province’s 0.2% in 2008–2011.Citation12 The overall incidence of death from death-related vaccines was 0.12/100,000 doses, which was higher than the Nigeria’s 2017–2018 measles vaccine campaign death incidence rate of 0.02/100,000 doses,Citation13 close to the reported incidence rate of related deaths of 0.1/100,000 doses in Shanghai, China, in 2006–2008Citation14 and 0.06/10,000 in Guangdong Province, China, in 2009–2011.Citation15 Analyzing the reasons for the relatively high composition of deaths in Shenyang may be due to reporting bias, the possibility of underreporting of the number of AEFI cases, and limitations in the calculation of the mortality denominator due to the fact that it may come from different resources in different parts of the country. In China, compensation is available for reactions determined to be vaccine-related. If no other cause of death is identified by the panel of experts, it is possible that a causality assessment may conclude that vaccination contributed to the death. In this case, the family of the deceased would be eligible to apply for compensation. This policy may increase the number of reports of vaccine-related reactions. Three-fourths of the AEFI-related deaths reported in this study were caused by coincidental events, 25% of which were attributable to vaccination by causality assessment, and all of which occurred after BCG vaccination. Autopsies were performed in six of the 12 deaths, all of which were classified as coincidental events after vaccination, and in the other six cases without autopsies, three were classified as severe vaccine reactions after BCG vaccination, and three were classified as coincidental events.
Causality assessments are performed in accordance with WHO guidelines. The documented causes of death that could possibly occur due to the inherent properties of a vaccine are limited and include anaphylaxis, viscerotropic disease following yellow fever vaccine, disseminated attenuated live vaccine agent infection in severely immune-compromised individuals and death from intussusception following rotavirus vaccine.Citation16 An analysis of the U.S. Vaccine Injury Compensation Program from 2000 to 2010 by the U.S. Department of Health found that only five deaths occurred due to anaphylaxis caused by vaccination.Citation17 In China, yellow fever vaccine is not recommended, and rotavirus vaccines differ from those used internationally; the most common causes of death from vaccine-related reactions are anaphylaxis and disseminated BCG infection. Of the three cases of severe vaccine reactions in this study, all occurred after BCG vaccination, including one case of disseminated BCG infection. Signs and symptoms of disseminated BCG include fever, weight loss, enlarged lymph nodes or skin abscesses, pneumonia, osteomyelitis, and hepatosplenomegaly,Citation18 skin involvement usually manifests as cutaneous and subcutaneous nodules and necrotic ulcers. Disseminated BCG infection has a poor prognosis and may result in death in the first decade of life, with mortality rates ranging from 50% to 70%,Citation19,Citation20 usually due to underlying immunodeficiencies such as HIV infection, severe combined immunodeficiency (SCID), chronic granulomatous disease (CGD), or susceptibility to Mendelian mycobacterial disease (MSMD).Citation21 In patients with underlying immunodeficiencies, antituberculosis drug chemotherapy should be initiated as early as possible and continued for more than 6 months, and the mortality rate in such patients can be as high as 50% even with antituberculosis treatment.Citation18 In China，BCG is recommended at birth, without screening to determine the status of the immune system at that time. The presence of an IL-12β1 receptor defect was identified on clinical examination in this child. First described in 1998, IL-12 Rβ1 deficiency, the most common genetic alteration of the IL-12/IFN-γ axis, has been diagnosed in more than 40 countries on five continents and is one of five rare genetic defects that characterize Mendelian susceptibility to mycobacterial diseases.Citation22–24 Affected individuals have increased susceptibility to Mycobacterium tuberculosis, and BCG is one of the causative agents.Citation19 A diagnosis of IL-12/IL-23Rb1 deficiency or other defects of MSMD should be considered in patients with BCG infection even in patients only with marked BCG adenitis (although not disseminated), because early treatment and genetic counseling have great importance in these patients.Citation25 The other two vaccine reactions in this study occurred with axillary lymphadenitis with severe systemic multiorgan infections, diagnosing the presence of an innate immune deficiency, and presumably severe secondary multiorgan infections as the direct cause of death. No autopsy was performed in any of the three BCG post-vaccination deaths to determine the immediate cause of death, and according to the National Guideline for the Surveillance of AEFI, the children were not examined for immune function prior to vaccination, and none of the parties involved were at fault, and were therefore classified as severe vaccine reactions. In order to avoid the occurrence of BCG diseases, effective genetic screening and prenatal diagnosis should be carried out before BCG vaccination, which will be the direction of future efforts by medical workers.
A coincidental event is a coincidental onset of disease after vaccination when the recipient is in the incubation or prodromal stage of a disease at the time of vaccination. Triggering or exacerbating an underlying or preexisting disease after vaccination is also an eventuality, and coincidental events are the most common cause of death in children after vaccination. Multiple published reviews of Vaccine Adverse Event Reporting System（VAERS）data for specific vaccines and vaccine types have found no concerning patterns suggesting a causal relationship between vaccination and deaths.Citation26,Citation27 The incidence of AEFI and vaccine reactions involved in the case was not statistically correlated with mortality, suggesting that vaccination did not lead to an increase in mortality and that the deaths occurred mainly by chance. The surveillance data showed that 75.0% of the AEFI deaths were coincidental, the age of death was mainly infants and children, which was similar to the national surveillance results in terms of cause of occurrence, including severe atrial septal defect, interstitial pneumonia, asphyxia, hypertrophic cardiomyopathy, and congenital hereditary mitochondrial disease. Of the nine incidental deaths in this paper, four were diagnosed as sudden death, accounting for 44.4%, which is similar to the results of the US VAERS.Citation28
Understandably, deaths following immunization are always of concern to the public and the medical establishment, and may pre-cipitate a crisis. Although vaccines play a vital role in preventing diseases in children, vaccine hesitancy has become an issue in many countries, including China.Citation29,Citation30 According to the Expanded National Immunization Program (ENIP) in Shenyang, a newborn baby needs a total of 22 doses of NIP vaccines within 6 years of birth, of which 14 doses are needed within 1 year of age, accounting for 63.6% of all doses, and even more if non-NIP vaccines are added, making the period from birth to 1 year of age the peak period for vaccination. At the same time, infant mortality is high due to disease or other injurious factors, especially sudden infant death syndrome (SIDS), which is the most common cause of death in infants between 2 weeks and 1 year of age, during a period that coincides with the peak of vaccination and when the occurrence of incidental cases is inevitable,Citation31 and it has been confirmed abroad that vaccination neither causes SIDS nor is it associated with death in children <7 years old.Citation32,Citation33 In Shenyang, there were 11 cases of death within 1 year of age among the cases of death after vaccination from 2009 to 2021, among which 7 cases died within 24 h of vaccination, all of which were incidental events in the year, and the infant mortality rate in Shenyang in 2014 was 0.36%, and the average monthly infant death in the city was 23 cases, while about 136,800 doses of vaccines were given to infants every month, which were prone to incidental cases after vaccination, so the simple time association cannot be used as the basis for causal judgment.
In order to reduce the medical disputes caused by coincidental events and improve the safety of preventive vaccination, the staff should pay attention to the pre-screening work when carrying out preventive vaccination services, and during the pre-screening, they should inquire in detail about the children’s birth conditions, recent illnesses, and the presence of contraindications to vaccination, etc., and carry out the relevant examinations when necessary, so as to reduce the occurrence of coincidental events.
Conclusions
In Shenyang, China, vaccination is safe, deaths that occur after vaccination are mainly incidental, and vaccination does not increase the risk of death. For those where the cause of death cannot be determined, autopsy is an important measure to confirm whether the death is related to vaccination. As passive surveillance may be stimulated by media reports and public attention, continuous surveillance and scientific causality assessment of reports of serious AEFIs, including AEFI-related deaths, are essential to ensure public confidence in vaccination. Effective pre-vaccination pre-screening is also necessary to avoid and reduce the occurrence of adverse vaccine events.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Additional information
Funding
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