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Am. J. Trop. Med. Hyg., 81(5), 2009, pp. 869–874 doi:10.4269/ajtmh.2009.09-0238 Copyright © 2009 by The American Society of Tropical Medicine and Hygiene

Coverage of and Influences on Timely Administration of Hepatitis B Vaccine Birth Dose in Remote Rural Areas of the People’s Republic of China Yuqing Zhou, Huaqing Wang,* Jingshan Zheng, Xu Zhu, Wei Xia, and David B. Hipgrave Department of National Immunization, China Center for Disease Control and Prevention, Beijing, People’s Republic of China; Department of Nutrition and Health, United Nations Children’s Fund, Beijing, People’s Republic of China

Abstract. A survey was conducted in 2006 to assess the coverage and timeliness of the birth dose of hepatitis B vaccine (HepB1) and related influences among children in rural areas of Guangxi, Guizhou, Tibet, and Shaanxi provinces, People’s Republic of China. A total of 3,390 children born in 2004 were surveyed in four counties in each province, where a project to strengthen routine immunization is being implemented by the China Ministry of Health, supported by the United National Children’s Fund. Two-stage stratified cluster sampling was undertaken to select those surveyed. A questionnaire was administered to parents or guardians and vaccination records were assessed. HepB1 administration was timely for 31.6% of the sample. Timeliness of HepB1 for children delivered at home (13%) was lower than for children born at county-level or higher facilities (54%) (odds ratio [OR] = 6.52, (95% confidence interval [CI] = 5.29–8.04, P < 10−3), at township hospitals (49%, OR = 7.14, 95% CI = 5.68–8.98, P < 10−3), or private clinics (59%, OR = 5.64, 95% CI = 3.68–8.64, P < 10−3). Children of Tibetan (24.8%, OR = 0.16, 95% CI = 0.12–0.21, P < 10−4), Zhuang (27.8%, OR = 0.73, 95% CI = 0.57–0.94, P < 0.02) or Meng, Miao, and Hui ethnicity (14.2%, OR = 0.36, 95% CI = 0.29–0.45, P < 10−4) were less likely than children of Han ethnicity (33.2%) to have received a timely birth dose. Children lacking vaccination registration cards (OR = 0.64, 95% CI = 0.51–0.80, P < 10−4) and children whose parents or guardians did not know the importance of timely HepB immunization (OR = 0.62, 95% CI = 0.46–0.84, P < 10−2) were also less likely to have received a timely birth dose. Parental knowledge and prioritization of birth-dosing was low among children who did not receive it. The timeliness of HepB1 should improve with increasing rates of hospital delivery, training of birth attendants, increasing staff and community awareness of the importance of the birth dose, and by focusing on vulnerable groups. vaccine is administered free of charge. A goal of at least 75% coverage of a timely birth dose of HepB1 applies in all of China’s approximately 2,860 counties.14 However, geographic and socioeconomic conditions, and access to health care (including vaccination) vary widely in China, and implementation of the national policy and the China GAVI Project was initially uneven. This was verified by the National EPI Review in 2004, which estimated that timely birth dose coverage among children born from January 1, 2001 to December 31, 2003 was substantially lower in western provinces (49.5%) than in central (72.7%) or eastern (81.9%) provinces.7,15 In 2006, the China Center for Disease Control (CCDC), supported by the United Nations Children’s Fund (UNICEF) launched a new project to model improvements to the routine EPI in poor rural areas of western China. The project focuses on 16 counties in Guangxi, Guizhou, Tibet, and Shaanxi provinces, which are considered representative of rural counties in western China and having a high proportion of ethnic minority residents. At the time of the 2004 National EPI Review, coverage rates of timely HepB1 in these provinces were 56.7%, 5.2%, 3.8% and 74.5% respectively.15 Only in Shaanxi did most counties reach the 75% target. To assess the status of and major factors influencing timely administration of HepB1 in the 16 counties at project commencement, in 2006 CCDC and UNICEF conducted a household survey of children born there during 2004. We report the conduct and results of the survey.

INTRODUCTION Globally, chronic cirrhosis and liver cancer caused by infection with hepatitis B virus (HBV) cause 600,000 deaths annually,1,2 and there are almost 800 HBV-related deaths per day in the Western Pacific Region.3 China has a high prevalence of chronic HBV infection. A national seroepidemiologic survey in 1992 found that carriage of HBV surface antigen (HBsAg) was 9.8%, ranging from 8.1% in urban areas to 10.5% in rural areas.4 Infection persists in approximately 90% of infants infected at birth and most chronic HBV infections result from exposure to the virus during the perinatal, infant, or early childhood periods.1,5 Vaccination of infants, beginning at birth, is the key strategy for preventing chronic HBV infection and primary hepatocellular carcinoma6–8 and has significantly decreased the prevalence of primary hepatocellular carcinoma in populations with a high rate of HBV infection.9–12 Hepatitis B vaccine (HepB1) was first recommended for vaccination of infants through China’s expanded program on immunization (EPI) in 1992, but because parents were required to pay administration and vaccine costs, coverage was low in poor areas. In 2002, the China Ministry of Health (MoH) embarked on a project with the Global Alliance for Vaccines and Immunization (GAVI) Alliance (the China GAVI Project) to ensure HepB availability in China’s 12 western provinces and in government-designated poor counties in 10 central provinces.7,13 Hepatitis B vaccine was also officially integrated into China’s EPI schedule. From 2002 through 2005, parents were required to pay a 3 Chinese Yuan (approximately $0.40 at this time) service fee per dose, but since then the

MATERIALS AND METHODS The survey was designed by CCDC and UNICEF staff, and comprised a questionnaire and assessments of parentheld vaccination/EPI records and the local EPI register. It was approved by the MoH, conducted during September– November 2006 by EPI staff from each of the four provinces, and overseen by CCDC and UNICEF staff.

* Address correspondence to Huaqing Wang, Department of National Immunization Program, China Center for Disease Control and Prevention, Beijing, People’s Republic of China. E-mail: susanz6@ hotmail.com

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Location and sampling. The 16 UNICEF-MoH project counties were selected on the basis of HepB1 coverage, EPI activity and economic status by the CCDC and UNICEF. All except two in Shaanxi and one in Guangxi are classified as rural type 3 or 4, the two weakest categories according to a group of health, economic, and social indicators first used to describe each county in China in 1982 and used again during the 2006 Joint Review of Maternal and Child Survival Strategies.16 These 13 types 3 and 4 counties are also national poverty counties,17 which confers additional funding for certain programs, including the EPI. Two-stage, stratified cluster sampling was undertaken to select those surveyed in the 12 project counties in Guizhou, Shaanxi, and Guangxi provinces. First, 30 villages were selected randomly from a list of all villages in each county. The population of each county averaged 253,000, and the number of villages averaged 271. Second, seven children were selected randomly from lists of those born in 2004 in each selected village, so that a planned total of 210 children would be surveyed in each county. This follows a standard 30-cluster EPI coverage survey method and yields coverage with confidence intervals of ±10%.18 In Tibet, the process differed because of the low population size at the village level. There, 10 townships were selected randomly (from an average of 15 per county, thus increasing confidence in the derived coverage estimate) and 21 of the children born in each township during 2004 were then selected, also randomly. The only exclusion criteria were refusal to participate, being a migrant to the surveyed village or township, and residency in the surveyed area for less than three months. Survey. A parent (mother or father) or guardian (usually a grandmother or grandfather) of each selected child was surveyed at home by provincial EPI staff using a standard, structured questionnaire developed by CCDC. The survey instrument was designed to assess a variety of issues related to knowledge and uptake of child vaccination services (i.e., not only vaccination against HBV) in the respondent’s locality. Standardized training was conducted beforehand to assure interviewer competency, and the survey was pre-tested in one county of Shaanxi province by CCDC and provincial EPI staff, and adjusted accordingly. Because parent-held EPI records must now be presented at school entry, whereupon catchup vaccines are administered to those with an incomplete record, retention is generally high. However, loss is not uncommon in rural areas. Health center EPI registers are kept indefinitely. The survey team also checked the child’s parentheld vaccination record or card and the EPI register at the responsible health facility. Data collection. Timely administration of HepB1 was assessed. The child was considered to have received HepB1 on time if either the card or EPI register recorded administration of the birth dose within 24 hours of delivery. If there was no immunization card or EPI register record, the child was recorded as unvaccinated. Knowledge and uptake of vaccination services were surveyed by the interviewers, with questions on whether the parent or guardian surveyed knew that infants should receive HepB vaccine; that newborns should receive HepB1 within 24 hours of delivery; that children should have an immunization book or card that will be checked upon entering kindergarten and primary school, and several other questions related to vaccination. For children who had not received HepB1

within 24 hours, the reason was sought from a short list of alternatives. The child’s place of birth was also recorded. The socioeconomic status, sex, ethnicity, and household location of each child and the education level of the parent or guardian surveyed and their migrant status were also recorded, at each household. Data analysis. The survey analysis design was developed in advance by CCDC staff, and data were entered into a database created in Epi-Info version 3.1 (Centers for Disease Control and Prevention, Atlanta, GA) by provincial EPI staff. The data were analyzed using SPSS software version 13.0 (SPSS Inc., Chicago, IL) at the CCDC. Crude comparisons across groups were conducted using the chi-square test. Logistic regression analysis was conducted to assess influences on the timeliness of HepB1 administration. RESULTS Basic information and demographic characteristics of the sample. A total of 3,390 children were recruited and their parents or guardians surveyed. This sample amounted to 7.5% of the children born in 2004 in the surveyed counties. The number surveyed in each province is shown in Table 1. Among the 3,390 children selected, 178 (5.3%) lived in the county capital, 228 (6.7%) in a township, and 2,984 (88%) in a village. A total of 1,915 (56.5%) were boys, with a ratio of 1.3:1 of boys to girls (not unusual in China).19 Most (96.6%) children were permanent residents of the locality where they were surveyed; the rest had migrated there or were not registered in the locality. Most migrants had lived in the area for more than three months and were thus included in the crude analyses. Table 2 shows that 898 (26.5%) children were born at county or higher-level hospitals, 611 (18%) at township-level hospitals, 118 (3.5%) at a private clinic, and 1,763 (52%) at home. Just less than half (n = 1,433, 42%) of the parents could not read. Almost one-third had attended school for less than six years (n = 414 or 12.2% for 1–3 years, and 600 or 17.7% for 4–6 years); 23% (n = 791) had completed junior high school, and 4% (n = 152) had senior high school education. Among the children investigated, 33% (n = 1,126) were of Han ethnicity; 28% (n = 942) were Zhuang; 25% (n = 842) were Tibetan, and 14% (480) were Meng, Miao, or Hui. Frequency of EPI service. The four counties in Shaanxi were conducting the EPI each month. Nine of the remaining 12 counties (all those in Guangxi and Guizhou and one in Tibet) were conducting it every two months and the other three in Tibet were conducting it only twice per year. Reasons given for children not receiving a timely HepB1. Among parents or guardians of the 1,075 children who had not received a HepB1 birth dose, 60.6% said that they had not Table 1 Number of children surveyed in four counties in each province, People’s Republic of China Province

2004 Birth cohort

No. surveyed

% Sampled

Guangxi Guizhou Tibet Shaanxi Total

14,033 10,294 1,794 19,049 45,170

852 840 855 843 3,390

6.1 8.2 47.7* 4.4 7.5†

* The sample in Tibet accounted for 48% of the 2004 birth cohort in the four counties because the density of population was low. † Excluding Tibet, the sample was composed of 5.8% of the 2004 birth cohort.

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Table 2 Timely coverage with the birth dose of hepatitis B vaccine among children by delivery place, People’s Republic of China* Province

No. surveyed

Timely HepB1 coverage (%)

HepB1 coverage (%)

No. (%) received timely HepB1 after delivery at county or higher level hospital

No. (%) received timely HepB1 after delivery at township hospital

No. (%) received timely HepB1 after delivery at a private clinic

No. (%) received timely HepB1 after delivery at home

Guangxi Guizhou Tibet Shaanxi Total

852 840 855 843 3,390

38.8 11.9 12.5 63.6 31.7

97.3 77.1 84.9 85.8 86.3

198 (73) 123 (33) 146 (21) 431 (62) 898 (54)

207 (69) 110 (27) 158 (16) 136 (76) 611 (49)

5 (40) 24 (17) 2 (0) 87 (74) 118 (59)

442 (10) 583 (4) 549 (9) 189 (54) 1,763 (13)

* HepB1 = hepatitis B vaccine.

been informed about its importance or availability, 20.8% said they did not have time or that the infant was ill, and 15.9% were concerned about an adverse event. Only 2.7% did not want their child to receive HepB1. Discussions at county level at the time of this survey also suggested that requests for informal payments may also play a role in reducing birth dose uptake. Logistic regression analysis of factors related to timely HepB1 vaccination. The influence on timely HepB1 coverage of sex, household location, parental education level, ethnicity, place of delivery, possession of an EPI card, knowledge of the importance of a birth dose of HepB, and migrant status were assessed using backwards multiple logistic regression. Crude rates of timely HepB1 among infants according to each of these variables (except for migrant status) are shown in Tables 2 and 3. Migrant status was excluded from the regression model because the number of migrant children was so small (3.4% of those surveyed). Results of the analysis are shown in Table 4. Sex, place of residence, and parental education were not associated with HepB1 timeliness. However, compared with those born at home, children delivered at county or higher level hospitals, township hospitals, and private clinics were more likely to receive a timely birth dose. In contrast, those

whose parents or guardians did not know the importance of administration of HepB1 within 24 hours of delivery and those who did not have an immunization card or record at home were less likely to have received a timely birth dose, as were children of minority ethnicity. DISCUSSION China’s national HBV seroepidemiology survey in 2006 found that since 1992, HBsAg carriage had decreased 2.6% to 7.2% among people 1–59 years of age, and 8.7% to less than 1% among children 1–4 years of age.7 These findings indicated the impact of routine HepB vaccination through China’s EPI. However, HBsAg carriage remained higher in western China, and prevalence of antibodies against HBsAg was lower in rural areas than in urban areas,20 which indicated that the introduction and impact of HepB1 was uneven. Given its enormous population and contribution to the global caseload of chronic HBV infection, it is important that high rates of protection against HBV are extended to all populations in the country. This survey adds to the available information on the progress of China’s introduction of infant HepB1 vaccination.

Table 3 Timely coverage with HepB1 among children by other variables, People’s Republic of China* Variable

Sex of child Male Female Household location County Township Village Education of parent/guardian Cannot read 1–3 years in school 4–6 years in school Junior high school Senior high school Ethnicity Han Zhuang Tibetan Meng, Miao, or Hui Possession of EPI card Yes No Parent/guardian knowledge about HepB1 Knew about it Did not know Parent/guardian knowledge about vaccination Knew about it Did not know * HepB1 = hepatitis B vaccine; EPI = Expanded Program on Immunization.

No. (%) surveyed

Timely HepB1 coverage (%)

HepB1 coverage (%)

1,915 (56.5) 1,475 (43.5)

632 (33.0) 442 (30.0)

1,658 (86.6) 12,68 (86.0)

178 (5.3) 228 (6.7) 2,984 (88.0)

94 (52.8) 130 (57.0) 850 (28.5)

137 (77.0) 196 (86.0) 2,593 (86.9)

1,433 (42.3) 414 (12.2) 600 (17.7) 791 (23.3) 152 (4.5)

324 (22.6) 122 (29.5) 190 (31.7) 359 (45.4) 79 (52.0)

1,209 (84.4) 369 (89.1) 518 (86.3) 702 (88.7) 128 (84.2)

1,126 (33.2) 942 (27.8) 842 (24.8) 480 (14.2)

594 (52.8) 104 (11.0) 206 (24.5) 168 (35.0)

933 (82.8) 718 (76.2) 805 (95.6) 460 (95.8)

1,070 (33.9) 4 (1.7)

2,917 (92.5) 9 (3.8)

876 (25.9) 2,514 (74.1)

360 (41.1) 714 (28.4)

747 (85.3) 2,179 (86.7)

1,852 (54.6) 1,538 (45.4)

708 (38.2) 366 (23.8)

1,625 (87.7) 1,301 (84.6)

3,154 (93) 236 (7.0)

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Table 4 Factors related to timely receipt of hepatitis B vaccine, People’s Republic of China* Variable

Odds ratio for timely vaccination with HepB1

95% confidence interval

P

1.21 0.80 0.93

0.73–2.01 0.52–1.21 0.78–1.11

0.45 0.29 0.42

1.09 0.97 0.98 1.06 0.64

0.81–1.47 0.74–1.26 0.76–1.25 0.68–1.66 0.51–0.80

0.57 0.79 0.86 0.80 < 0.0001

0.62

0.46–0.84

0.002

0.16 0.73 0.36

0.12–0.21 0.57–0.94 0.29–0.45

< 0.0001 0.016 < 0.0001

6.52 7.14 5.64

5.29–8.04 5.68–8.98 3.68–8.64

< 0.0001 < 0.0001 < 0.0001

Place of residence (county as reference) Township Village Sex (male as reference) Parents’ education level (cannot read as reference) Elementary school (1–3 years) Elementary school (4–6 years) Junior high school Senior high school Lack an immunization registration book or card Parents or guardians did not know infants should be given HepB1 within 24 hours after birth Ethnicity (Han as reference) Tibetan Zhuang Others (Meng, Miao, and Hui) Place of birth (born at home as reference) County hospital Township-level hospital Private clinic * HepB1 = hepatitis B vaccine.

We surveyed infants born in 2004, the second implementation year of the China GAVI Project. Although HepB was integrated into China’s EPI in 2002, progress varied between provinces. Guizhou, for example, was only able to offer universal HepB vaccination starting in late 2003 and Tibet in early 2004 because considerable preparation was required for remote and ethnic minority areas (advocacy, translation, cold chain preparation, transport, and training). We found that overall uptake of HepB1 was reasonably high (86.3%), but the timeliness of HepB1 in these counties in 2006, the same year as the national seroepidemiology survey, was only 31.7%. Birth dose coverage was particularly low in Guizhou and Tibet (although higher than in 2004). The 31.7% coverage is much lower than the 75% objective set by China’s National Plan,14 but is similar to the rate of timely HepB1 coverage reported in China’s 2007 Progress Report to the GAVI Alliance, which validated our findings and underscored the difficulty implementing the plan in western and central China. Given the importance of birth dosing in areas with a high prevalence of HBV and the high overall uptake of HepB, a high proportion of China’s success in reducing young child HBV infection must have resulted from birth dosing in more developed areas, and further reductions are possible. The analyses reported help to explain but also prompted questioning as to why birth dose coverage remains low in most of China’s rural west. In recent years, health authorities in China have given responsibility for birth dosing of babies delivered in health facilities to midwifery and obstetric staff, with good impact.7 HepB1 was far more likely to be timely for infants delivered at a health facility. However, even there coverage rates were disappointingly low, ranging from 49% to 59%.Why? A high proportion of persons whose child did not receive timely HepB1 did not know about or did not prioritize it. It is also possible that, as identified in Vietnam, poor coordination remains between hospital midwifery and local EPI staff.21 At township level (49% timely HepB1 coverage), lack of cold chain facilities and knowledge (of staff), resistance (of staff and the local community) to vaccinating newborns, and requests for informal payments are other possible reasons for low coverage, and some of these may also apply at county level in some areas.

We observed that the two provinces with highest rates of home delivery and the least frequent EPI services, Guizhou and Tibet, had the lowest rates of timely birth dosing. The findings concur with those of another survey in China’s Qinghai Province, where home birth is also common,22 and with surveys in Vietnam and Indonesia.22,23 Birth dosing of infants delivered at home is apparently logistically and/or administratively difficult or otherwise unacceptable.3 One solution to this problem has been addressed by several reports in recent years, including an overview of HepB vaccination in China7 and one overview24 and several field studies (in Indonesia,25,26 Vietnam,27 and Guangxi28), of storage of vials of HepB at ambient temperature in local clinics or maternity units, with a view to increasing access to HepB1 in areas lacking refrigeration. Each study indicated that storing HepB1 outside the cold chain may improve timely HepB1 in remote, rural areas where there is no cold chain, but an overview of Indonesia’s experience cast doubt on uptake of this strategy23 and it is not yet permitted by regulatory authorities in China or Vietnam. We also found that minority groups were less likely to receive a timely birth dose, even when we controlled for place of delivery and despite that great efforts have been made to improve the health status of China’s minority groups in recent years. Possible reasons for this might include 1) objections to birth dosing for religious or cultural reasons, 2) low awareness of the availability and benefits of a timely birth dose, and 3) lack of appropriate education materials. Other associations with low rates of birth dosing were the lack of a parent-held immunization record and lack of knowledge among parents and guardians that children should receive HepB1 within 24 hours of birth. These reasons all suggest avenues for improving rates of birth dosing in locations such as those surveyed. It seems that more than just easy access to vaccine is required to ensure birth dosing of babies delivered at home or in health facilities in rural China. Increasing the acceptability and implementation of birth dosing, even in locations where vaccine is kept on site, and increasing hospital (or at least attended) delivery rates, are required. Actions should be tailored to the local situation. Where hospital delivery rates are high, priority should be given to 1) education of nurses,

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doctors, and parents (especially mothers attending antenatal clinic) about the importance of timely birth dosing with HepB1, including the fact that it is safe and free of charge; 2) linking maternity and EPI services to ensure that HepB1 is administered to all babies delivered in a health facility; and 3) logistic support (cold chain, vaccine supplies, management systems) to ensure that HepB1 is available to all newborns. For areas with low hospital delivery rates, a broader focus on the physical and financial access to and quality of antenatal and maternity services is required, along with public education (locally adapted and appropriate to the prevailing ethnicity) on the importance and safety of timely HepB1. Improving managerial and administrative links between maternity and EPI services is again required in such areas. The Qinghai project was able to achieve 60% timely HepB1 coverage through education of parents and local midwives, tracking of pregnancies, and ensuring notification of births,29 similar to some of the locations surveyed in Vietnam.21 There were some limitations to this study, particularly the degree to which it represents all rural counties in China. The economic and geographic conditions in the counties surveyed are generally poor (most have a gross domestic product less than $450 per capita), and in most counties, the health and EPI services are relatively weak. Overall, these counties are also more isolated. There was also considerable variability between the project provinces. Locally, the results should apply to similar counties, but most likely not the entire provinces surveyed. Nationally, the findings should apply in similar economic and geographical areas, which we estimate to exist in most type 3 and 4 counties (which comprise approximately 35% of China’s counties and contain approximately 32% of China’s population), and also among China’s (overlapping) 592 national poverty counties.30 Second, despite that teams were informed that the survey was a baseline for future policy and strategy shaping, because the survey was conducted by staff from the surveyed provinces, there may be some observer bias. This finding would have influenced the results in a positive way, so it may be that the situation is worse than described. There may also have been some variability caused by disparity in the capacity of the different survey teams (although the same training was conducted for each). Third, other important variables that we did not measure may have greatly influenced the timeliness of HepB1, particularly the frequency and quality of antenatal clinics and the availability of vaccine at the place of birth. These variables will be included in follow-up surveys to be done as part of the UNICEF-MoH project. Finally, we acknowledge the bias in our summary statistics because of the high proportion of home deliveries in two of the four provinces surveyed (Guizhou and Tibet), and also the fact that a much higher proportion of the eligible population was selected in Tibet than in the other three provinces. However, we do not feel that these factors greatly influenced the conclusions reached. Notwithstanding all of the above, the 2008 report submitted by China’s EPI to the GAVI Alliance on the progress of the China GAVI Project and the Alliance’s response described the good recent performance of most of China’s Project provinces on introducing HepB1. As identified in this survey, the report describes an improving but still mixed picture on timely HepB1, with a wide range in coverage at county level.

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We anticipate further increases in rates of timely HepB1 as China’s rates of hospital delivery continue to improve31 and as the priorities listed above are implemented. Received May 5, 2009. Accepted for publication July 16, 2009. Acknowledgments: We thank the staff in the four project provinces and 16 counties for their support during the survey. Financial support: This study was supported by UNICEF. Authors’ addresses: Yuqing Zhou, Huaqing Wang, Jingshan Zheng, and Wei Xia, Department of National Immunization Program, China Center for Disease Control and Prevention, Beijing, People’s Republic of China. Xu Zhu and David B. Hipgrave, Department of Nutrition and Health, United Nations Children’s Fund, China Country Office, Beijing, People’s Republic of China.

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