Levels of vaccination coverage among HIV-exposed children in China: a retrospective study

Background Vaccination is crucial for human immunodeficiency virus (HIV)-exposed children because of their increased risk of morbidity and mortality from various vaccine-preventable diseases. However, studies have shown that they are at high risk of incomplete vaccination. Although China has developed prevention of mother-to-child transmission (PMTCT) of HIV programs substantially over the past decades, few studies have investigated the immunization levels of Chinese HIV-exposed children. Therefore, we aimed to evaluate vaccination coverage and its associated factors among HIV-exposed children in China during 2016‒2018. Methods We conducted a retrospective cohort review of all cases of Chinese HIV-exposed children born between July 1, 2016 and June 30, 2018 recorded in the Chinese information system on PMTCT. The vaccination coverage indicators refer to the percentage of children who received recommended basic vaccines, including Bacillus Calmette-Guérin (BCG), hepatitis B (HepB), polio, measles-containing vaccine (MCV), and diphtheria-tetanus-pertussis-containing (DTP) vaccine. Univariate and multivariate logistic regression analyses expressed as crude odds ratios (cORs) and adjusted odds ratios (aORs), each with 95% confidence intervals (95% CI), were performed to compare the proportional differences of factors associated with vaccine coverage. Results Among the enrolled 10 033 children, the vaccination rate was 54.1% for BCG, 84.5% for complete HepB vaccination, 54.5% for complete polio vaccination, 51.3% for MCV, and 59.5% for complete DTP vaccination. Children with perinatally acquired HIV (PHIV) were 2.46‒3.82 times less likely to be vaccinated than HIV-exposed uninfected children. Multivariate logistic regression indicated that children of Han ethnicity (aOR = 1.33‒2.04), children with early infant diagnosis (EID) of HIV (aOR = 1.86‒3.17), and children whose mothers had better education (college or above, aOR = 1.63‒2.51) had higher odds of being vaccinated. Most of the deceased children (aOR = 4.28‒21.55) missed vaccination, and PHIV (aOR = 2.46‒3.82) significantly affected immunization. Conclusions Chinese HIV-exposed children had low vaccination coverage, which is a serious health challenge that needs to be addressed thoroughly. Interventions should be developed with a focus on minority HIV-exposed children whose mothers do not have formal education. Particularly, more attention should be paid to EID to increase access to immunization. Graphical abstract


Background
Immunization has been identified as one of the most cost-effective interventions in global health. The World Health Organization (WHO) monitors vaccine coverage as a key indicator of children's health services [1]. However, studies have shown that children born to human immunodeficiency virus (HIV)-infected women have 30-70% chance of being incompletely immunized [2][3][4]. Compared to infants of uninfected mothers, these children are reported to have a markedly higher early life burden of infectious diseases for their immunological disorders [5,6]. Low vaccination coverage may increase the morbidity and mortality risk from vaccine-preventable diseases among such children [7][8][9].
With the effectiveness of prevention of mother-to-child transmission (PMTCT) interventions well established, China has reduced the mother-to-child transmission rate of HIV to 4.9% in 2017 [10]. Most children of Chinese HIV-infected mothers are not infected with HIV, but the mortality rate among those aged 0-18 months is as high as 4.9-7.8% [11][12][13], which is significantly higher than the Chinese national infant mortality rate of 0.61% [14]. Infectious diseases remain a major cause of death among HIV-exposed children [12,15,16].
Previous studies indicated that one reason for increased mortality among children born to HIV-positive mothers might be that those children are less likely to receive routine childhood vaccinations [4,17]. However, few studies have reported immunization levels in HIV-exposed Chinese children. Given the importance of vaccination for HIV-exposed children and the data from other countries, suggesting that they are at a higher risk of under-vaccination, we evaluated the vaccination rates and factors affecting the vaccination status of HIV-exposed children in China.

Study design and setting
This was a retrospective cohort study using data from the Chinese information system for PMTCT. This longitudinal, population-based health and vital event registration system monitors HIV-exposed children and their mothers. It is implemented through mandatory case reporting by health facilities in all 31 provincial-level administrative divisions of China. For each child, data collected include maternal demographic characteristics (e.g., maternal age, occupation, education, ethnicity, marital status, and parity), child's characteristics (e.g., sex, birth weight, and HIV status), and clinically standardized follow-up information (HIV laboratory assessment, vaccination history, HIV-related diseases and symptoms, and survival status). These data are prospectively collected both at birth and at 1, 3, 6, 9, 12, 15, and 18 months of age [13,18,19].

Study population
The target population in the study was perinatally HIVexposed children, with the following criteria: (1) born to HIV-infected women, (2) live birth, and (3) born between July 1, 2016 and June 30, 2018. Children who were lost to follow-up were excluded. All the appropriate cases in the PMTCT information system were included in this study.

Data source and variables
Variables and data related to vaccination status were extracted from PMTCT information system-belongs to China CDC, which is not open for the public-using a standardized data abstraction form. The study variables included maternal age, ethnicity, marital status, parity, education, and occupation; and the child's gender, birth weight, HIV status, HIV-related diseases (pathological jaundice, upper respiratory tract infection, pathological diarrhea, pneumonia, anemia, rickets, or severe malnutrition), HIV-related symptoms (intermittent or persistent fever, persistent cough, rash, systemic lymphadenopathy, Candida albicans infection, or hepatosplenomegaly), and survival status (alive or dead). HIV infection was diagnosed according to reactive HIV tests on two different occasions: positive virological tests under 18 months of age or positive antibody tests up to 18 months. Early infant diagnosis (EID) is used to diagnose babies born to HIV-infected mothers as recommended by the WHO. In our study, HIV-exposed children undergo EID at 42 days and 3 months of age to confirm HIV status by HIV virological tests. According to the WHO [20] and the Chinese National Immunization Programme schedule [21], vaccination coverage indicators refer to the percentage of children who received recommended basic vaccines, including one dose of Bacillus Calmette-Guérin (BCG) vaccine, three doses of hepatitis B (HepB) vaccine, three doses of polio vaccine (live oral poliovirus vaccine or inactivated poliovirus vaccine), one dose of measles-containing vaccine (MCV), and three doses of diphtheriatetanus-pertussis-containing (DTP) vaccine. Children were classified as up to date (UTD) if they had received whose mothers do not have formal education. Particularly, more attention should be paid to EID to increase access to immunization.
Keywords: HIV, Children, Coverage, Vaccination, China the recommended dose of vaccines before 12 months of age.

Immunization schedule
According to the Chinese immunization guidelines [21] ( Table 1), children born to HIV-infected mothers should not be vaccinated with oral poliomyelitis vaccine (OPV) and BCG; these vaccinations should be postponed until the children are confirmed as not infected with HIV. Children with HIV-related or immunosuppressive symptoms should not be vaccinated with MCV. HIV-exposed uninfected (HEU) infants are recommended to have immunization as is routinely administered to other children, including one dose of BCG after birth, three doses of HepB vaccine (at birth, 1 month, and 6 months of age), three doses of polio vaccine (at 2, 3, and 4 months of age), three doses of DTP vaccine (at 3, 4, and 5 months of age), and one dose of MCV (at 8 months).

Statistical analysis
Statistical analysis was performed using the statistical software SPSS 25.0 (International Business Machines Corporation, Armonk, USA). Immunization status was presented as numbers and percentages. Proportions were compared by Chi-square tests. Univariate and multivariate logistic regression analyses were performed to compare the proportional differences in factors associated with vaccination coverage. Univariate logistic regression was used for categorical variables to explore potential factors affecting immunization. Multivariate logistic regression using the forward likelihood ratio method was utilized to analyze factors associated with non-uptake of vaccines among the studied population. Crude odds ratio (cOR) and adjusted odds ratio (aOR) were calculated with logistic regression. Significance tests were two-tailed, and P values < 0.05 were considered statistically significant.

Overall characteristics of the population
We included 10 033 live-born HIV-exposed children born from July 1, 2016 to June 30, 2018, excluding 119 children lost to follow-up. The characteristics of the enrolled children and their mothers are reported in Table 2. There were 306 children with perinatally acquired HIV (PHIV), 341 with unknown HIV status, and 9386 HEU children among the 10 033 enrolled children. We found that 49.5% of the children were of Han ethnicity, 89.6% had EID to determine HIV status, 11.6% had at least one HIV-related symptom, and 17.0% had at least one HIV-related disease during the 18 months of follow-up. In all, 3.0% of the children died during the 18 months of follow-up. Most of the HIV-infected mothers lived with a spouse (92.7%), were aged 20-34 years (77.9%), graduated from middle school (48.8%), farmed at home (56.1%), and had given birth to 2-3 babies (55.9%).

Vaccination status Vaccination coverage
For the 10 033 children included in the analysis, the BCG vaccination rate was 54.1%, excluding 150 cases with unknown BCG vaccination status. The vaccination rates for three injections of HepB were respectively 97.1, 89.9, and 84.5%, excluding 131 cases of missing HepB vaccination data. The first dose of the polio vaccine was received by 63.5% of the children, the second by 58.7%, and the third by 54.5%, excluding 206 cases of insufficient reporting. MCV rate was 51.3%, excluding 211 cases of unknown vaccination status; DTP vaccination rate was 66.3% for the first dose, and the complete vaccination rate for three injections was 59.5%, excluding 212 cases of insufficient data. Compared with HEU children, children with PHIV were less likely to be vaccinated with BCG (28.9 vs 55.7%), HepB1 (90.5 vs 98.0%), Polio1 (33.0 vs  Children with PHIV were also less likely to have received the second and third doses of HepB, polio, and DTP vaccines than HEU children (Table 3).

Vaccination up to date status
HEU children were significantly (P < 0.05) more likely to be UTD for each vaccine by 12 months of age, and the probability of being UTD for HEU children was 3.00-4.65 times more than that of children with PHIV (  (Table 5).

Vaccination factors
In univariate analysis, there were significant (P < 0.05) associations of child characteristics (survival status, HIV status, HIV-related symptoms, and EID) and maternal features (ethnicity, education, and occupation)  Multivariate analysis showed that HIV-related symptoms were associated with BCG status (aOR = 0.86, 95% CI: 0.75-0.99) and MCV status (aOR = 0.84, 95% CI: 0.72-0.97). However, co-linearity diagnostics indicated that HIV-related symptoms correlated with survival status (Pearson correlation = 0.287, P < 0.05). In the subgroup analysis, HIV-related symptoms showed no difference for BCG or MCV vaccination status in both dead children (BCG: P = 0 0.200, MCV: P = 1.000) and living children (BCG: P = 0.066, MCV: P = 0.129). In contrast, survival status had a significant association with BCG or MCV vaccine status, with or without symptoms (P < 0.05). Therefore, we excluded HIV-related symptoms from multivariate analysis.

Discussion
This study is the first to examine immunization coverage in a cohort of HIV-exposed Chinese children. Our study showed low vaccination coverage among children born to HIV-infected women in China. Compared with the WHO-reported Chinese immunization coverage among 1-year-olds (99-100%) for the five examined vaccines [22], HIV-exposed children in this study had a significantly lower coverage level.
The administration of live attenuated vaccines (BCG and MCV) was different in HIV-exposed children from routine practice. For children with PHIV, the WHO recommends that BCG vaccination should be delayed until the infants start antiretroviral therapy (ART) and remain immunologically stable (CD4% > 25%) [23] and that MCV should be routinely administered to potentially susceptible, asymptomatic HIV-infected children [24]. It is also recommended that routine childhood vaccines, whether live-attenuated or killed, should be administered to HEU children. Our study showed that only 52.6% of the HEU group had received the BCG vaccine by their first birthday, which is lower than the figure reported in Latin America and the Caribbean (HEU, 94.2% at 12 months old) [25]. The MCV UTD rate was also lower than previously reported levels (HEU, 94.4% at 4 years old) [26]. Our study also shows that the subjects were under-vaccinated with inactivated vaccines, which should be administered as usual. One explanation for this may be that the HIV-related poor parental practices [27,28] block the availability of immunization services for children.     We analyzed maternal and child factors associated with insufficient vaccination coverage and found that maternal education remains a significant determinant of immunization, as previous studies have shown that the knowledge gap among uneducated women may be a barrier against immunization [2,29]. Children of Han ethnicity were more likely to be vaccinated-approximately two times more than those from minority groups-and this may be because the minority groups had poor living conditions and lower socioeconomic status [29,30]. Our study showed that most children had EID for HIV infection confirmation. Such children had 1.86-3.17 times greater odds of being vaccinated than those who did not have EID. Limited HIV diagnosis services for HIVexposed children prevents the implementation of routine immunization [31].
As the diagnosis of HIV in infants is complicated by the passage of maternal HIV antibodies across the placenta, the WHO recommends EID to diagnose HIV infection among children younger than 18 months [32]. In China, HIV-exposed children should undergo EID at 42 days and 3 months of age to confirm HIV status. Meanwhile, Chinese guideline advocate that neonates of unknown HIV status should not be vaccinated with BCG until confirmed to be uninfected, which is stricter than WHO recommendations that state that neonates of unknown HIV status should be vaccinated with BCG if they have no clinical evidence suggestive of HIV infection, regardless of whether or not the mother is receiving ART [24]. We believe that the stricter Chinese recommendation may explain the low coverage of BCG vaccination and the finding that children who had EID were more likely to be vaccinated. Limited laboratory capacity in resource-constrained areas may contribute to why some children did not undergo EID [31].
In our study, HIV-related symptoms had little influence on vaccination status and had interactive effects with survival status. The likely reason for this may be that most of the deceased children died soon after birth without registered HIV-related symptoms and missed immunization. Otherwise, HIV-related symptoms could lead to HIVrelated death, and HIV-related symptoms inhibit the uptake of vaccines. Further studies should be performed to investigate the time between the appearance of HIVrelated symptoms and child death.
With the increasingly successful use of ART, most HIV-exposed children are not infected; even children with PHIV can have a normal life expectancy. Therefore, attention should be given to low vaccine coverage among children born to HIV-infected women to improve survival in this vulnerable population. Interventions should be developed with a focus on HIV-infected mothers belonging to the uneducated and minority classes. The use of mass media tools may help to improve mothers' knowledge and understanding of immunization. PMTCT services should be integrated with immunization services in the future. Particularly, more attention should be paid to EID, and the government needs to optimize recommendations for the immunization of HIV-exposed children.
Our study had some limitations. First, the data were collected from the Chinese information system for PMTCT. This may be biased by low incidence reporting due to under-detection, misclassification, and underreporting because data collection on HIV-exposed children relies on health facility reporting. Second, there have been dramatic changes from the "basic" antigens that were used to define a fully vaccinated child in the early 1980s [20]: the new combined acellular pertussis, diphtheria, tetanus, inactivated poliomyelitis, and Haemophilus influenzae type b conjugate vaccine has become popular recently, which may lead to misunderstanding and misreporting of the vaccination status. Third, we did not consider the factors associated with healthcare providers. Healthcare workers who are responsible for child immunization may miss opportunities for immunizing HIV-infected children. This may be because they are unaware of vaccination recommendations in this population and are therefore overly concerned about possible risks associated with the use of vaccines [26,29,30] or because of limited EID services for confirming children's HIV status.

Conclusions
Chinese HIV-exposed children had low vaccination coverage. PHIV children were significantly less likely to be vaccinated than HEU children. Interventions to address this should be developed with a focus on minority children whose mothers do not have formal education. Particularly, more attention should be paid to EID to increase access to immunization. With the risk of mother-to-child transmission of HIV reduced to 5% or less, children can achieve the expected lifespan with effective treatment. More attention should be paid to the neglected immunization problem. We also strongly encourage further research on strategies to improve routine vaccination for HIV-exposed children.