Abstract
Introduction:
The National Culture Collection for Pathogens (NCCP) in the Korea Disease Control and Prevention Agency (KDCA) is in charge of the collection, quality control, and commercialization of pathogens and of information on pathogens that cause infectious diseases, and distributes them to be utilized for promoting public health and the health care industry. Since the NCCP Task Force was established in 2009 and the law for collection, management, and exploitation of pathogen resources became effective in 2017, NCCP has been responsible for the deposition, registration, and preservation of pathogen resources. Herein, we provide information on the recent status of pathogen resource distribution over the past 5 years and pathogen resources that are available for distribution presently.
Results:
Within the past 5 years, the numbers of pathogen resources distributed were 1659, 1823, 1457, 1156, and 1706 in the years 2015, 2016, 2017, 2018, and 2019, respectively. In addition, more pathogens were distributed in February, March, September, and October than in other months. When categorized by the type of institution, profit organizations (3069) requested more pathogen resources than national and public research institutes (2291). Furthermore, based on the purpose of distribution, 440 cases were for vaccine or therapeutic development, 3041 for diagnostic technology development, 2487 for education, and 1134 for quality control.
Conclusion:
Based on these findings, we publicized the information on the distribution of pathogen resources to encourage their widespread use in infectious disease research and public health.
Introduction
In 2014,
The National Culture Collection for Pathogens (NCCP) is designated as a national organization and plays a role in legislative, administrative, and policy measures on access and benefit sharing in accordance with the Pathogen Resource Act with regard to Article 13 (National Focal Points and Competent National Authorities) and Article 14 (Access and Benefit-Sharing Clearing-House and Information-Sharing) of the Nagoya Protocol. In addition, it is responsible for reporting access to genetic resources (pathogens) and plays a role in accordance with Article 16 (Approval for Outbound Transfer), Article 17 (Revocation of Approval for Outbound Transfer and Other Relevant Matters), and has also played various roles for Article 18 (Acquisition of Pathogen Resources by Foreigners and Other Relevant Matters) of the Pathogen Resource Act regarding Article 6 (Access to Genetic Resources) and Article 7 (Access to Traditional Knowledge Associated with Genetic Resources) of the Nagoya Protocol.
The NCCP in the National Institute of Health (NIH), Korea Disease Control and Prevention Agency (KDCA), in compliance with the Pathogen Resource Act, serves as a national organization responsible for the deposition, registration, preservation, quality control, commercialization, and distribution of pathogen resources. These resources are utilized in developing therapeutics, vaccines, diagnostic technologies, products, and quality control at the infectious disease research and academic institutions and public health, food, and biopharmaceutical industries.
The NCCP as a national biobank responsible for pathogen resource based on the Pathogen Resources Act collects, performs quality control, and stores pathogenic microorganisms and derivatives derived from domestically isolated pathogenic microorganisms that cause infectious diseases in humans, according to the definition of pathogen resources in Article 1 of the Pathogen Resources Act. To date, ∼27,000 strains have been stored, of which 7100 strains have been quality checked and registered on the NCCP list. Among them, ∼3000 Korean isolates and 38 kinds of bacterial resources from DSMZ in Germany secured through resource exchanges in 2017 and 2019, after signing a MOU in 2011, have been distributed.
The registered pathogen resources are mainly distributed to track the route of infection for infectious diseases caused by new and mutated strains and multidrug-resistant nosocomial infections, to understand the characteristics of causative pathogens, study pathogenic mechanisms, achieve positive control during development of treatments and vaccine candidates, and develop diagnostic test methods. They are used in cross-sectional analyses for determining the sensitivity and specificity rates of diagnostic methods during efficacy evaluation.
For high-value addition and high-quality control of the pathogen resources, the NCCP operates a quality management system (ISO 9001) annually to perform standardized and systematic preservation and management of pathogen resources. It also verifies the quality certificates from institutions requesting the pathogen resources that are available for distribution.
Herein, we present in detail the recent status of pathogen resource distribution over the past 5 years, including information regarding the resource types, purpose of distribution, research areas, and activity of the resource bank, such as the current national status of isolated strains, thereby promoting pathogen distribution toward infectious disease research and public health.
Materials and Methods
Purpose and domestic institutions of NCCP resource utilization
For the past 5 years, all clinical microbial pathogen resources isolated from Korea have been distributed to domestic universities, health care-related research institutes, and pharmaceutical-related industries in South Korea. The purpose of this study was to develop a rapid molecular diagnostic kit for detection of the causative pathogens of respiratory viral diseases such as respiratory syncytial virus and influenza, and carrier transmission infectious diseases such as severe fever with thrombocytopenia syndrome (SFTS) or dengue, and to develop an antibody test kit to confirm infection and to discover vaccine candidates. For this purpose, the distribution of resources was mainly applied by the medical and microbiological research laboratory of the university, research institutes affiliated with the national funding, and institutes belonging to pharmaceutical production industry. In addition, Escherichia coli, Vibrio spp. bacteria, and Salmonella spp. were distributed for the purpose of quality control to check the performance of media during food development and for use as control strain for practical training in microbiology classes at health and medical institutions and medical schools.
Procedure for distributing pathogen resources in the NCCP
To request distribution of the pathogen resources owned by the NCCP, users should search the NCCP website (http://nccp.cdc.go.kr) and the Pathogen Resource Online Distribution Desk (http://is.cdc.go.kr) to identify the pathogen resources available. Then, they should submit a distribution application, including a letter of request from the institution, the purpose of use, duration, user information, and a certificate for the facility and equipment verifying the institution's capability of handling the pathogen resources. After reviewing the submitted documents, a distribution discussion confirming the availability of resources, and receiving a response from the NCCP, the institution will acquire the requested pathogen resources by submitting an agreement on the transfer of materials and a certificate of acquisition to the NCCP. All distribution applications are conducted through the Pathogen Resource Online Distribution Desk (http://is.cdc.go.kr), and anyone who gets permission to use the system can have access to the website.
Results
Yearly and monthly distribution status
From 2015 to 2019, the total number of pathogen resources distributed was 7801 strains (cases). The numbers of pathogen resources distributed were 118 species and 1659 cases in 2015, 165 species and 1823 cases in 2016, 130 species and 1457 cases in 2017, 116 species and 1156 cases in 2018, and 155 species and 1706 cases in 2019 (annual average, ∼1500 cases). By month, the overall distribution numbers were the highest in February, March, September, and October compared with those of other months (Table 1).
Monthly Distribution Status from 2015 to 2019
Status of distribution by resource type
From 2015 to 2019, a total of 7801 cases, including 1016 viral, 5128 bacterial, 369 fungal, and 1288 derivative cases were distributed. We found that all resource types, except derivatives, were distributed in 2016 followed by a decrease, and then started to increase in 2019. On average, bacteria were distributed more than other resource types. Annually, ∼203 viral, 1025 bacterial, 74 fungal, and 258 derivative cases were distributed (Table 2).
Pathogen Resource Distribution Status from 2015 to 2019
(), cases of derivatives that overlapped with other resources' species were excluded.
Status of distribution by agency type
When categorized by the type of institution, 2291 (29.4%), 2441 (31.3%), and 3069 (39.3%) cases were distributed to the national and public research institutions, universities and nonprofit institutions, and industries and private profit organizations, respectively.
The annual average distribution to the national and public research institutions was 458 cases, but the number of distributions gradually decreased from 2017. Therefore, compared with the annual average, there was a 15% reduction in 2019. About 486 cases were distributed on average annually, except in 2016, to universities and nonprofit organizations. Compared with the annual average, a decrease of 38.4% and 23.4% was observed in 2018 and 2019, respectively. Approximately 616 cases were distributed on average annually to industries and private profit organizations. Compared with other institutions, an average distribution of 30% more occurred to these institutions. In addition, the distribution continued to decrease from 2015 to 2018; however, in 2019, compared with the annual average, there was a significant increase in distribution of ∼50% (Table 3).
Distribution Status by Type of Agencies from 2015 to 2019
Status of distribution by the purpose of resource utilization
The analysis categorized by the purpose of pathogen resource distribution to the requesting institutions revealed that most distributions were made for developing diagnostic technology [3188 cases (40.9%)] and education [2487 cases (31.9%)]. The analyzed annual average distributions were for vaccine and therapeutics studies (88), education (497), developing diagnostic technology (638), quality control (227), and others (110).
The distribution toward vaccine and therapeutics research has steadily increased since 2015. In 2019, there were 191 cases, a 135.8% increase compared with 2018. Most of the resources distributed for educational purposes were requested to be used in educating the infectious disease screening staff at public health centers and as reference bacteria for basic microbiology training at medical schools. The number of distributions for educational purposes has decreased each year from 2016. In addition, 1134 cases (14.5%) were distributed for food microorganism inspection and quality control purposes. This number has increased each year since 2015, and by 2019, there was a 33.0% increase compared with the annual average. The number of distributions for developing diagnostic technology continued to decrease from 2015 to 2018 and then started increasing in 2019 (Table 4).
Distribution Status by Purpose of Utilization from 2015 to 2019
Others: technology developments, cross-reaction, genome sequences.
Status of distribution by resource type and purpose
Most of the viral resources were distributed for developing vaccine and therapeutics, and diagnostic technology. In descending order, influenza A, dengue, and influenza B viruses had the greatest numbers of distributions. Zika and SFTS viruses had been distributed since 2017 and 2018, respectively. Based on the analysis, Enterovirus A and Japanese encephalitis virus were steadily distributed each year (Table 5).
Distribution of Viral Resources and the Main Purpose of Use
SFTS, severe fever with thrombocytopenia syndrome.
Furthermore, the most distributed bacteria included Salmonella enterica, E. coli, Staphylococcus aureus, and Bacillus cereus, which are associated to intestinal infectious diseases. S. enterica and E. coli were mostly distributed for the following reasons: educating infectious disease staff at public health centers and medical science education, and quality control at food and pharmaceutical product testing facilities. S. aureus was usually distributed for quality control at food and pharmaceutical product testing facilities and developing diagnostic technology. Moreover, Pseudomonas aeruginosa, a standard pathogen causing antibiotic-resistant nosocomial infections, and Klebsiella pneumoniae, the causative pathogen of acute pneumonia, were usually distributed for evaluating the cross-reaction during the development of diagnostic materials for antibiotic-resistant pathogens and their performance evaluation (Table 6).
Distribution of Bacterial Resources and the Main Purpose of Use
Salmonella enterica serotypes (931): Typhi (124), Paratyphi A (119), Paratyphi B (98), Typhimurium (249), Enteritidis (187), Enterica, etc. 58 serotypes (∼10 strains).
The total number of fungal resource distributions was 369 (45 species), with an annual average of ∼73 cultures, which was less than that of bacterial and viral resources. We observed that within the genus Candida (147 strains), Candida albicans (39) was distributed the most. Furthermore, Cryptococcus neoformans (36), Saccharomyces cerevisiae (31), Aspergillus fumigatus (28), and Trichophyton rubrum (25) accounted for many distributions.
Most fungal resources were distributed for the performance evaluation of diagnostic agents and test products while developing diagnostic technology as well as for the positive control and as educational material for basic microbiology class at medical schools. C. albicans was distributed for research on medicines, such as antifungal agents. In 2016 and 2017, species belonging to the genera Candida, Cryptococcus, Geotrichum, Kloeckera, Rhodotorula, Malassezia, and Trichosporon were distributed for developing databases that identify drug-resistant pathogens based on mass spectrometry properties (Table 7).
Distribution of Fungal Resources and the Main Purpose of Use
The total number of distributions for derivatives from pathogens was 1288 cases. The distribution was in the form of nucleic acids, with 387 cases of 20 species with viral RNA, 393 cases of 96 species with bacterial DNA, and 10 cases of 10 species with fungal DNA (omitted list). Among these, RNAs of norovirus (synthetic) and influenza A virus and DNAs of E. coli and Orientia tsutsugamushi were distributed the most. In addition, 498 cases, including antiserum, antibody, and recombinant substances, were distributed (Table 8).
Distribution Status for Derivatives from 2015 to 2019
Others (498): Legionella busanensis anti-serum (2), mouse anti-influenza HA mAb (462), mouse anti-TBEV envelope protein mAb (7), ferret anti-influenza A serum (20), recombinant vector (4), rabbit anti-influenza A serum (3).
HA, hemaagglutination; mAB, monoclonal antibody; TBEV, tick borne encephalitis virus.
Discussion
The NCCP began operating in 2004 with the goal of securing and utilizing national pathogenic resources. NCCP plays a pivotal role in managing microorganism (pathogen) bioresources. 1 In 2012, a newly formed NCCP Task Force began systematic management of the resource bank. In addition, the NCCP facilitates exchange and cooperation among domestic and international pathogen resource-related institutions to expand the collection of useful pathogen resources. Through the development of high value-added useful resources, the NCCP has tried to contribute to developing the health care industry and achieve its vision of becoming a resource powerhouse. In addition, the NCCP diseminates information on the distribution methods and available resources using various methods, such as participation in promotional booths at relevant conferences at least seven times a year, and publication of annual reports and guidebooks in Korean and English to promote utilization of domestic pathogen isolates.
This study analyzed the pathogen resources distributed by the NCCP from 2015 to 2019, categorized by the year, purpose of distribution, type of pathogen, and type of institutions. Through this analysis, we wanted to determine the status of how resources are being utilized in vaccine and therapeutics development; quality control and evaluation of pharmaceutical, medical, and food testing facilities; as reference for research on diagnostic agents and kits; and as substances for cross-tabulation analysis.
Over the past 5 years, the major distribution occurred in 2016. This peak occurred mostly after the Nagoya Protocol became effective (October 12, 2014) when the need for a bioresource management system emerged in every country to share profits equitably or prepare for international disputes. Consequently, the establishment of the Pathogen Resource Act and the national management of pathogen resources led to reporting and advertisement of related materials, which may have increased the distribution. The major distribution observed in 2016 is believed to be owing to the active advertisement of developed reference microorganisms (35 genera, 39 species) for use in public health centers and medical science education by the NCCP.
Furthermore, in 2019, it is believed that several factors helped increase pathogen resource requests. These include the increased awareness of domestic pathogenic microorganism isolates by implementing the Genetic Resources Act in August 2018, which eased the accessibility of applicants and reduced the time spent on administrative procedures by improving the application process, allowing people to request pathogen resource distribution online. The distribution was noticeably higher in February, March, September, and October than in other months. This is most likely owing to institutions preparing project plans, executing research tasks, and verifying results during these periods.
Out of the 7801 distributed cases, the number of distributions was similar between the national and public research institutions (2291) and universities and nonprofit organizations (2441), with the most distributions occurring toward private profit institutions or industries (3069). Furthermore, the majority of the distributions accounted for developing diagnostic agents and kits for infectious diseases (3188). More than 68.6% of the distributions to private industries were used for quality control and research on diagnostic technology. This may be owing to the recent outbreak of new infectious diseases, which increased investment and interest in biopharmaceutical industries, resulting in the development and commercialization of related products.
According to resource-specific analysis, dengue viruses and influenza viruses A and B were the most distributed. In 2018, 100 strains of dengue viruses were distributed to detect the causative pathogens of mosquito-mediated diseases and develop a diagnostic agent for a novel virus. The incidence of dengue fever has increased since 2012. A total of 149 patients were reported in 2012, 252 in 2013, 165 in 2014, 255 in 2015, 313 in 2016, and 171 in 20172–4 in South Korea. The sudden increase in the number of pathogens from 4 cases in 2015 to 63 in 2016 is related to a 54.5% increase in patient reports in 2015 compared with 2014 and believed to influence the enhancement of diagnostic technology development to confirm and diagnose pathogens.
Influenza virus is continuously distributed and is usually used for the identification of mutations in the development of molecular diagnostic agents and quantitative diagnostic sensors. Seasonal detection of influenza virus for surveillance of influenza patients was the highest in 2017–2018, with 2013 and 1101 cases of influenza types A and B, respectively. The average number of influenza type A cases was 1400 in 2015, 2016, and 2019. The average number of influenza type B cases was 675, which was similar between the seasons of 2015–2016 and 2018–2019. However, the number was the lowest (322) in the season of 2016–2017.5,6 In 2018, 2304 cases were detected, wherein 799 cases were of type B, 660 of type A (H3N2), and 575 of type A (H1N1pdm09). The number was the highest in the season of 2017–2018, which could be the potential reason for the renewed increase in distribution of these pathogen resources in 2019.
The types of bacterial resources distributed in 2015–2019 included B. cereus, Campylobacter jejuni, Clostridium perfringens, E. coli, Haemophilus influenzae, Listeria monocytogenes, Salmonella enterica serotypes (Typhimurium, Enteritidis) S. aureus, Streptococcus pneumoniae, and Vibrio parahaemolyticus. These bacteria are usually related to infectious diseases of biosafety levels 2 and 4 and are causative pathogens for intestinal infectious diseases. In addition, Salmonella enterica serotype Typhi and Paratyphi A/B, the causative pathogens of typhoid and paratyphoid, grade 2 infectious diseases, were steadily distributed. In addition, the genus Shigella, the causative pathogen of bacterial dysentery and cholera, and Vibrio cholerae species were distributed widely. These pathogenic microorganisms are known to cause waterborne and foodborne infectious diseases and have been distributed for utilization in the quality control of food testing facilities' periodic assessment and infectious disease test training at public health agencies.
Based on the annual surveillance report of the KDCA, the number of patients with pneumonia caused by S. pneumoniae has steadily increased since 2015 (36 people in 2014, 228 people in 2015, 441 in 2016, 523 in 2017, 670 in 2018, and 526 in 2019). 3 Furthermore, except in 2018, the number of pathogen distribution steadily increased until 2019. The distribution was usually for vaccine and therapeutics research, development of diagnostic technology, and quality control.
Scarlet fever, a standardized example of bacterial respiratory disease, had an increased patient incidence from 2013 to 2017 owing to the inclusion of pathogen isolation culture for patient screening but decreased in 2018 and 2019. 3 The pathogen resource distribution of Streptococcus pyogenes, the causative pathogen of scarlet fever, has also been reported to decrease since 2017. Furthermore, since the mass outbreaks in North Gyeongsang Province in 2015, the incidence of whooping cough has continuously increased. The reported cases were 5809 in 2014, 7002 in 2015, 11,911 in 2016, 22,838 in 2017, 15,777 in 2018, and 7562 in 2019. The number of pathogen resource distribution for Bordetella pertussis, the causative pathogen of whooping cough, was ≤4 cases annually, which confirms that the increased incidence of bacterial infection does not necessarily correlate with the number of pathogen resource distribution.
In 2020, the government set a goal for reducing the use of antibiotics by 20%. The government came up with a plan to manage national antibiotic resistance in August 2016 and to conduct a survey targeted at medical institutions after conducting a national survey on medical-related infections in February 2018, followed by a comprehensive plan for their prevention management in 2018–2022. 7 As part of the government's policy to expand and enhance the surveillance system and the operation of a reporting system for various multidrug-resistant infections, many of the relevant pathogens were distributed to examine the causative pathogens and develop treatments.
K. pneumoniae, a carbapenem-resistant Enterobacteriaceae; Acinetobacter baumannii, a multidrug-resistant A. baumannii; and P. aeruginosa, a multidrug-resistant P. aeruginosa, were distributed more in 2019 than in other years, with 62, 72, and 54 cases, respectively. 1 This increase could be owing to the expansion and enhancement of surveillance systems and a comprehensive plan for nosocomial infections.
For derivatives, there was nothing specific other than the nucleic acid resources of viruses being largely distributed in 2018, and those of bacteria in 2019. Requests for these derivatives were usually from middle- and small-sized industries and small research institutes without the appropriate biosafety research facilities to handle viruses based on their risk level. Recently, the NCCP has planned to expand the management of derivative resources to promote research and product development by these small- and medium-sized organizations such that all available resources can be distributed. 8
At present, the profits and values of bioresources are emphasized in all countries globally. Moreover, the competition to secure resources and economic burdens continues to increase since the Convention on Biological Diversity and Nagoya Protocol proclamation. Therefore, this article was written to enhance the recognition of pathogen resources and promote pathogen resource distribution by presenting the current status of utilization of domestically distributed pathogens for various purposes, thereby publicly announcing the activities of the NCCP.
In the future, the NCCP, in compliance with the Pathogen Resource Act, will strengthen the cooperation among related ministries of living genetic resource. In addition, through reinforcement and scientific management of the characteristic, including biological information of additional resources, we will endeavor to further the utilization of high value-added pathogen resources in the field of public health and related industries.
Footnotes
Acknowledgments
The authors thank the collaborators within the NCCP and many researchers depositing microorganisms.
Author Disclosure Statement
No conflicting financial interests exist.
Funding Information
This study was funded by the Korea DCA (Funding No. 4800-4837-301-210-13).