Perinatally HIV-infected (PHIV) and HIV-exposed uninfected (HEU) children are vulnerable to vaccine-preventable infectious diseases, which can result in high mortality and morbidity, especially in the early years of life. This risk may be compounded by missed opportunities for recommended immunizations in PHIV despite specific immunization guidelines for HIV-infected children,1–3 perhaps because healthcare providers may be unaware of the recommendations or concerned that vaccination poses greater risks in this population. In a previous study of Latin American and Caribbean PHIV and HEU children enrolled in the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) International Site Development Initiative (NISDI), the rates of complete vaccination of children at age 24 months varied from 43.5% to 74.5% in the PHIV group and 74.2% to 94.2% in the HEU group with PHIV children being significantly less likely to be vaccinated for all vaccines examined.4
In addition to suboptimal vaccination rates, PHIV children may not respond serologically with the same magnitude or durability as children without HIV infection. Before the introduction of combination antiretroviral therapy (cART), the development of protective antibody levels after primary immunization in asymptomatic or symptomatic HIV-infected children was 40%–100% for tetanus and diphtheria vaccines, 25%–50% for hepatitis B virus (HBV) vaccine, and 37%–86% for Haemophilus influenzae type b (Hib) conjugate vaccine.5 Even in children who received cART, the prevalence of measles and rubella antibodies after primary immunization was only 38%–42%.6,7
The objective of this study was to compare coverage rates between PHIV and HEU children in the NISDI cohort at age 4 years for routine childhood vaccinations (HBV, tetanus, Hib, measles and rubella) and compare cohort serologic immune responses between PHIV and HEU who had received these vaccines according to standard recommendations by age 4 years. The analysis examines the subset of patients included in the prior analysis who had serum specimens available for testing at age 4 years, the time point where the largest number of specimens were available for the comparison between PHIV and HEU children.
MATERIALS AND METHODS
The Eunice Kennedy Shriver National Institute of Child Health and Human Development International Site Development Initiative (NISDI) enrolled PHIV and HEU children into 2 prospective cohort studies conducted at 15 sites in Latin America and the Caribbean between 2002 and 2009. Detailed protocol information has been published.8 In brief, between 2002 and 2007, the Pediatric protocol enrolled PHIV infants, children and adolescents (up to 21 years old) and HEU children (up to 12 months old) at sites in Brazil, Mexico, Argentina, Peru and Jamaica. The Pediatric Latin American Countries Epidemiologic Study (PLACES) was an extension of the prior Pediatric protocol that only enrolled PHIV. Between 2008 and 2011, PLACES enrolled PHIV children <6 years of age at sites in Brazil, Mexico and Peru. Both protocols had the primary objective to describe the demographic, clinical, immunologic and virologic characteristics of enrolled HIV-exposed and/or HIV-infected children. The forms and procedures used to collect vaccination information included in this analysis were identical across the 2 protocols. The protocols were approved by the ethical review boards of each participating clinical site, by the sponsoring institution (NICHD), the data management and statistical center (Westat), the Peruvian Ministry of Health and the Brazilian National Ethics Committee. Informed consent was obtained from parents or legal guardians of all participants.
Information was collected from all enrolled children, including gestational age, birth weight and vaccinations received from birth up to the age of enrollment. The vaccination history up to enrollment was obtained through retrospective review of medical records. All children were clinically evaluated in a standardized fashion every 6 months, including laboratory assessments (CD4+ T-lymphocyte [CD4] percent, CD4 counts and HIV RNA viral load [VL], for PHIV), use of cART (defined as regimen of at least 3 antiretroviral drugs) and any additional vaccinations.
HIV infection was based on reactive HIV tests on 2 different occasions (virologic tests if under age 18 months, virologic and/or antibody tests if age ≥18 months). HEU children had negative HIV virologic testing at ages ≥1 month and ≥4 months or repeatedly nonreactive HIV antibody testing at age ≥6 months. Eligibility for this analysis was limited to HEU and PHIV children who had serum specimens available at their 4-year-old visit (48 months of age ±3 months). Only vaccinations received at least 14 days before the date of serum specimen collection were considered in determining children’s vaccination status.
Children were considered fully vaccinated for a specific vaccine if they had received the recommended number of doses for that vaccine, and the doses followed minimum age and minimum interval guidelines, according to World Health Organization recommendations.9 Fully vaccinated at 4 years of age was defined for each vaccination as follows: 3 doses of HBV vaccine; 4 doses of any tetanus toxoid-containing vaccine; 3 doses of Hib vaccine by 12 months of age or at least one dose of Hib given after 12 months of age; one dose of measles-containing vaccine; and one dose of rubella-containing vaccine.
Diasorin testing kits (Saluggia, Italy) were used to measure antibody for HBV (ETI-AB-AUK-3) and rubella (ETI-RUBEK-G PLUS), with estimates of antibody titers calculated from calibration curves for HBV based on 5 calibrators (0, 10, 100, 500 and 1000 IU/mL) and rubella based on 4 calibrators (10, 25, 50 and 200 IU/mL). Tetanus antibodies were measured by in-house double-antigen enzyme-linked immunosorbent assay as described by Kristiansen et al.10 Hib IgG antibodies were measured by indirect enzyme-linked immunosorbent assay.11 Measles IgG antibodies were measured by indirect enzyme-linked immunosorbent assay as previously described.12 All the tests were performed at the same laboratory.
A child was considered immune at 4 years of age for each disease as follows: HBV surface antibody titer ≥10 IU/L,13 tetanus antibody titer ≥0.1 IU/mL,14 Hib antibody titer ≥1.0 µg/mL,15 measles antibody titer ≥0.120 IU/mL16 and rubella antibody titer ≥10 IU/mL.17
Descriptive statistics (frequencies, proportions, means, standard deviations [SD], medians and ranges) were used to summarize characteristics of the study population. Fisher’s exact test was used to evaluate relationships between categorical-scaled characteristics and HIV status, while the Student’s t test was used to examine associations with continuous-scaled characteristics. The association of vaccination status (fully vaccinated vs. not fully vaccinated) with HIV status was examined for each vaccine at 4 years of age using Fisher’s exact test. Among those fully vaccinated, the associations of serologic immunity with HIV status and (for PHIV only) with HIV-1 VL, CD4% and timing of initiation of cART were also examined using Fisher’s exact test. The geometric mean antibody titers were described by HIV status for each vaccine, as was the median days from last vaccine dose comparing PHIV to HEU children separately for those who were immune and those nonimmune (compared by Nonparametric Kruskal–Wallis test).
All analyses were conducted using the SAS statistical software, version 9.2 or later (SAS Institute Inc., Cary, NC), with an alpha level of <0.05 used to identify significant associations.
Among the 1926 children enrolled in the NISDI Pediatric protocols, 1293 were enrolled before age 4 years, of which 519 had at least one visit at 48 ± 3 months of age; 314 were PHIV and 205 were HEU. Of these, 43.6% (137/314) of PHIV children and 26.3% (54/205) of HEU had serum specimens available for testing at 4 years of age and therefore were eligible for this analysis (62 enrolled in Pediatric protocol only, 119 in PLACES only, 10 in both protocols). Children with serum specimens available (ie, included in the analysis) were similar to those without specimens available (ie, excluded from the analysis) on the basis of general demographic and clinical characteristics (Table, Supplemental Digital Content 1, http://links.lww.com/INF/C871). PHIV children were significantly older at enrollment than HEU children (mean of 34.7 vs. 4.4 months, respectively, P < 0.001), reflecting the differing enrollment criteria of the protocols (Table 1). PHIV subjects did not differ from HEU in gestational age at birth, gender or body mass index at 4 years of age (P > 0.5). For descriptive purposes, HIV-related characteristics of PHIV children are also shown in Table 1. At the 4-year visit, 65% of PHIV children showed no immunosuppression, most (59.9%) were receiving protease inhibitor-containing cART, and nearly half (49.6%) had VLs less than 500 copies/mL. At age 4 years, significantly (P < 0.01) smaller proportions of PHIV than HEU children were fully vaccinated for tetanus, measles and rubella (Table 2).
Subsequent analyses were restricted to those who were fully vaccinated by age 4 years. Among fully vaccinated children, serologic status at the 4-year visit for each vaccine-preventable disease tested was significantly associated with the children’s HIV status (Table 3). Compared with HEU children, PHIV children were less likely to be immune to HBV (20.9% vs. 37.8%; P = 0.04), tetanus (72.0% vs. 90.5%; P = 0.02) and Hib (51.4% vs. 68.8%; 0.05). Only 80.2% of PHIV children were immune to measles, while all HEU children who received at least one dose of measles-containing vaccine by age 4 years were immune (P < 0.001) with similar results for rubella (72.9% vs. 98.0 %; P < 0.001).
Among those considered serologically immune, the geometric mean antibody titer was significantly lower for PHIV than HEU subjects for tetanus, measles and rubella, but not for HBV and Hib (Table 3). Median time from last vaccine dose was shorter for PHIV than HEU children, but only significantly less for HBV (immune and nonimmune, P < 0.001), Hib (nonimmune, P < 0.001) and tetanus (immune, P < 0.036) vaccination.
The association of VL and CD4% with serologic immunity was examined among PHIV children (Table 4). VL (<1000 vs. ≥1000 copies/mL) and CD4% (≥25% vs. <25%) measured at 4 years of age were not associated with serologic immunity to most vaccines; however, a higher proportion of those with VL <1000 copies/mL were immune to tetanus than among those with VL >1000 copies/mL (85.1% vs. 50.0%, P < 0.01). Serologic immunity was associated with timing of cART initiation only for HBV (P = 0.049) (Table 5). A larger proportion of children who started cART before 12 months of age were immune to HBV (31.9%), compared with those initiating cART at or after 12 months of age (14.9%) and those that did not initiate cART (6.2%).
In this cohort of Latin American children, significantly smaller proportions of PHIV than HEU children were fully vaccinated for tetanus, measles and rubella by 4 years of age. Among fully vaccinated children, PHIV children were significantly less likely to have serologic evidence of immunity at 4 years of age than HEU children for all vaccine-related diseases tested. With the exception of tetanus, VL and CD4% at 4 years of age were not associated with serologic immunity among PHIV children. Serologic immunity was associated with timing of cART initiation for HBV vaccine, with a larger proportion of children initiating cART before 12 months of age having seroprotection at age 4 years. Previous studies had already demonstrated that early cART initiation permits better immune response to vaccines18 and maintenance of the memory B cells.19
A protective level of an antitetanus antibody is a major factor determining protection against this disease. Among those fully immunized, 72% of PHIV children in our cohort had protective immunity at 4 years of age. Other studies have reported that a significant proportion of HIV-infected children are not initially protected against tetanus and many who mount an initial immune response end up experiencing waning antibody response long-term. A study of 90 newly diagnosed, HIV-infected Kenyan children (median age at enrollment 4.9 years, all WHO Stage III and IV, with a history of prior tetanus vaccination) not yet started on ART found 78% had protective titers of tetanus antibodies.20 Among 24 HIV-infected American children (not on ART) that received 4 (74% were protected) or 5 (54% were protected) doses of diphtheria, tetanus and pertussis vaccine, declining antibody levels were observed on 10 months follow-up.21
There are limited studies about the protection against invasive Hib diseases in HIV-infected children.22 In our study, only 79.6% of PHIV children were fully vaccinated and among those fully vaccinated, 48.6% did not have protective Hib antibody levels at 4 years of age. The proportion of unprotected children observed in 18 American HIV-infected children treated with cART was 22% even though they were previously immunized with 1–4 doses of conjugate Hib vaccine; however, their results could be explained by the different timing of evaluation between immunization and serologic testing (median age 7 years).23
In our study, the rate of protective immunity was lowest for HBV—37.8% versus 20.9% for HEU and PHIV, respectively—with HEU children significantly more likely to be immune (P = 0.04). HBV serologic immunity was associated with timing of cART initiation (P = 0.049), with a larger proportion of immune response among children initiating early cART (<12 months of age). Seroprotection after the HBV vaccine series is less likely in untreated HIV-infected children (even after subsequent immune reconstitution with cART) when compared with HIV-uninfected children,24,25 and many vertically HIV-infected children who respond to HBV reimmunization after cART lose seroprotection within 3 years.26,27
The proportion of fully vaccinated, PHIV children found to be immune to measles and rubella at 4 years (80.2% and 72.9%, respectively) was significantly lower than HEU children (100% and 98.0%, respectively). Our findings are similar to a Brazilian study that demonstrated an 80% seroconversion rate for rubella vaccine among 15 HIV-infected children on cART after measles–mumps–rubella vaccination at 15 months of age.28 In the Pediatric Amsterdam Cohort of 59 HIV-1 infected children who started treatment with cART at a median age of 4.3 years and reported to be immunized with measles–mumps–rubella vaccine, only 35 children (63%) had specific antibodies against measles and 45 (80%) against rubella7; moreover 40% of the measles-seropositive children and 11% of the rubella-seropositive children lost their specific antibodies during a period of 192 weeks follow-up. A US American study of 428 PHIV and 221 HEU children 7–15 years of age observed seroprotection of 57% (PHIV) versus 99% (HEU) for measles, 65% versus 98% for rubella and 59% versus 97% for mumps.29
High levels of immunization coverage caused endemic transmission of measles to end in the Americas by 2002. Recent measles outbreaks in the United States and Brazil suggest that immunization rates in some areas have dropped below levels needed to prevent the spread of cases imported into the Americas.28 These outbreaks could allow measles and other vaccine-preventable diseases to spread particularly in the immunocompromised population.
Limitations of this study that was based on the review of medical records include the possibility that records may not be complete, and because subjects were enrolled from 4 countries, the dosing schedules and the vaccine products themselves could be different. However, we included only children with evidence of full vaccination with proper dosing schedules in the determination of immunity to mitigate these potential issues. In addition, this study benefits from systematic data collection using standardized forms and training and large sample size for assessing statistical associations although for some comparisons the sample size is small. One additional strength is that the measurements of antibodies in all samples have been performed by the same laboratory, which could minimize intra-assay, interassay and inter-laboratory variabilities.
HIV-infected children may experience failure to receive appropriate vaccinations, poorer immunologic response, and accelerated loss of antibodies after immunization. Complete and timely vaccination of PHIV according to the immunization schedule recommended for this group is critical. In communities with high immunization coverage levels, the risk could be reduced by herd immunity, but outbreaks of infectious disease like measles and rubella can occur. Knowledge of waning immunity to HBV, tetanus, Hib, measles and rubella in HIV-infected and HEU children, as well as the need for booster doses, is not well studied and larger studies are warranted.7,21,30,31
Even once fully vaccinated, significantly lower proportions of PHIV children are immune to vaccine-preventable diseases. Strategies to improve routine PHIV vaccine coverage and to increase PHIV immunity after vaccination require further study. In addition, maintenance of immunity should be investigated in this high risk group. This is especially important if we consider the recent measles outbreaks in different parts of the Americas.
The NISDI Study Group
Principal investigators, co-principal investigators, study coordinators, data management center representatives and NICHD staff include: Argentina: Buenos Aires: Marcelo H. Losso, Irene Foradori, Alejandro Hakim, Silvina Ivalo, Erica Stankievich (Hospital General de Agudos José María Ramos Mejía); Brazil: Belo Horizonte: Jorge A. Pinto, Victor H. Melo, Flávia F. Faleiro, Fabiana Kakehasi, Beatriz M. Andrade (Universidade Federal de Minas Gerais); Caxias do Sul: Rosa Dea Sperhacke, Nicole Golin, Sílvia Mariani Costamilan (Universidade de Caxias do Sul/Serviço Municipal de Infectologia); Nova Iguacu: Jose Pilotto, Luis Eduardo Fernandes, Ivete Gomes, Luis Felipe Moreira, Gisely Falco (Hospital Geral Nova de Iguacu – HIV Family Care Clinic); Porto Alegre: Rosa Dea Sperhacke, Breno Riegel Santos, Rita de Cassia Alves Lira (Universidade de Caxias do Sul/Hospital Conceição); Rosa Dea Sperhacke, Mario Ferreira Peixoto, Elizabete Teles (Universidade de Caxias do Sul/Hospital Fêmina); Rosa Dea Sperhacke, Marcelo Goldani, Carmem Lúcia Oliveira da Silva, Margery Bohrer Zanetello (Universidade de Caxias do Sul /Hospital de Clínicas de Porto Alegre); Regis Kreitchmann, Fabrizio Motta, Luis Carlos Ribeiro, Marcelo Comerlato Scotta, Debora Fernandes Coelho (Irmandade da Santa Casa de Misericordia de Porto Alegre); Ribeirão Preto: Marisa M. Mussi-Pinhata, Maria Célia Cervi, Geraldo Duarte, Fabiana Rezende Amaral, Adriana A. Tiraboschi Bárbaro, Conrado Milani Coutinho, Márcia L. Isaac, Anderson Sanches de Melo, Bento V. Moura Negrini, Fernanda Tomé Sturzbecher (Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo); Rio de Janeiro: Ricardo Hugo S. Oliveira, Elizabeth S. Machado, Maria C. Chermont Sapia (Instituto de Puericultura e Pediatria Martagão Gesteira); Esau Custodio Joao, Maria Leticia Cruz, Maria Isabel Gouvêa, Leon Claude Sidi, Mariza Curto Saavedra, Clarisse Bressan, Fernanda Cavalcanti A. Jundi (Hospital dos Servidores do Estado); São Paulo: Regina Celia de Menezes Succi, Prescilla Chow, Daisy Maria Machado (Escola Paulista de Medicina- Universidade Federal de São Paulo); Marinella Della Negra, Yu Ching Lian, Wladimir Queiroz (Instituto de Infectologia Emilio Ribas); Mexico: Mexico City: Noris Pavía-Ruz, Karla Ojeda-Diezbarroso, Dulce Morales-Pérez (Hospital Infantil de México Federico Gómez); Peru: Lima: Jorge O. Alarcón Villaverde (Instituto de Medicina Tropical “Daniel Alcides Carrión”—Sección de Epidemiologia, UNMSM), María Castillo Díaz, Carlos Velásquez Vásquez (Instituto Nacional de Salud del Niño), Mary Felissa Reyes Vega, César Gutiérrez Villafuerte (Instituto de Medicina Tropical “Daniel Alcides Carrión”—Sección de Epidemiologia, UNMSM); Data Management and Statistical Center: Yolanda Bertucci, Rachel Cohen, Laura Freimanis-Hance, René Gonin, D. Robert Harris, Roslyn Hennessey, James Korelitz, Margot Krauss, Sue Li, Karen Megazzini, Orlando Ortega, Sharon Sothern de Sanchez, Sonia K. Stoszek, Qilu Yu (Westat, Rockville, MD); NICHD: Rohan Hazra, George K. Siberry, Lynne M. Mofenson (Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland).
We also want to thank the study participants and staff at the clinical sites.
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