The CD4+ cell percentage and counts at enrolment and subsequent visits in HIV-infected children are summarized in Table 1 and supplementary-Table S1 (http://links.lww.com/QAD/A321). At a mean age of 19.6 weeks, CD4+% were higher in Group-4 (41.6%) compared with Group-3 (29.9%; P = 0.0001) and Group-5 (31.5%; P = 0.003) children (Table 1). Similarly, CD4+% remained higher at the time of the first vaccine dose in Group-4 (39.1%) compared with Group-3 (31.0%; P = 0.0001) and Group-5 (30.6%; P = 0.011). Group-4a had lower CD4+% (27.8%) when measured 2 weeks postbooster dose compared with Group-3 (34.5%; P = 0.0001) and Group-4b (36.2%; P = 0.0001) (Table 1). The median age of ART initiation in Group-3 was 25.0 (18.4–40.0) weeks, and 65.3% (49/75) in this group had been initiated on ART by the time they received the first measles vaccine and 68 (98.6%) of the remaining 69 had been initiated on ART by the time of their booster dose of measles vaccine. Also, 67 (77.0%) of 87 Group-4a children had been re-initiated on ART by the time of their booster vaccine dose.
Prevaccination measles antibody kinetics
The proportion of HUU children who were sero-positive (78.3%) or had sero-protective titers (65.2%) was similar to HEU infants, but higher than in Group-3 (56.3 and 37.9%, respectively) and Group-4 (59.3 and 41.8%) (Fig. 2 and supplementary-Table S2, http://links.lww.com/QAD/A321). Also, GMTs were higher in HUU (963 mIU/ml) compared to Group-3 (657 mIU/ml, P = 0.04; Fig. 2) at enrollment. By 19.6 weeks of age, the proportion of children with sero-positive and sero-protective titers among HUU had declined to 28.9 and 16.7%, respectively; both higher than in Group-3 (5.7 and 0%,) and Group-4 (16.1 and 7.2%) (Fig. 2 and supplementary-Table S2, http://links.lww.com/QAD/A321). There was no difference in the fold-decrease of antibody titers in HUU (0.49) compared with HEU (0.39, P = 0.21), Group-3 (0.31, P = 0.97) and Group-4 (0.42, P = 0.96) between enrollment and 19.6 weeks of age (supplementary-Table S2, http://links.lww.com/QAD/A321).
Antibody kinetics postprimary and booster doses of measles vaccine
The first measles vaccine was administered at 39.7 (SD ± 2.3) weeks of age. Twenty-eight weeks thereafter (study visit 3), the proportion of HUU children with sero-positive (93.8%) or sero-protective titers (91.1%) was similar to other groups, except for a lower proportion of Group-4a (79.3%; P < 0.0001) having sero-protective titers (Fig. 3 and supplementary-Table S3, http://links.lww.com/QAD/A321). This occurred despite 77.0% (67 of 87) Group-4a children already having been re-initiated on ART at this stage. Group-4a were also less likely to have sero-protective titers compared to Group-3 (95.7%; P = 0.003) and Group-4b (92.1%; P = 0.018; Fig. 3); and also had lower GMTs compared with each of the other Groups at this time-point (Fig. 3).
The booster dose was given at 67.8 (SD ± 4.4) weeks of age, after which the proportion of children with sero-protective titers was equal to or greater than 90.2% and did not differ between groups when evaluated 1.9 weeks (SD ± 0.1) later (Fig. 3 and supplementary-Table S3, http://links.lww.com/QAD/A321). The GMTs postbooster were higher in HUU (3124 mIU/ml) compared with HEU (2532 mIU/ml, P = 0.015) and Group-4a (1435 mIU/ml, P ≤ 0.0001) (Fig. 3). GMTs in Group-4a also remained lower compared with Group-3 (3254 mIU/ml, P < 0.0001) and Group-4b (2740 mIU/ml, P = 0.002) postbooster dose (Fig. 3). The proportion of Group-5 children with sero-protective titers was 100% postprimary and postbooster vaccine.
Persistence of antibody was evaluated 41.4 (S.D. ± 0.3) weeks following the booster dose, at approximately 111 weeks of age, by when HUU were more likely to have sero-protective titers (94.3%) compared with HEU (79.6%; P = 0.002) and Group-4a (80.3%; P = 0.010) (Fig. 3 and supplementary-Table S3, http://links.lww.com/QAD/A321). Although 75.4% (46/61) of Group-4a children had been re-initiated on ART by this time-point, they remained less likely to have sero-protective titers compared to Group-3 (96.0%; P = 0.013) and similarly to Group-4b (86.4%; P = 0.360). At the same time-point, GMTs were higher in HUU (2248 mIU/ml) compared to HEU (1773 mIU/ml, P = 0.004) and Group-4a (1156 mIU/ml, P < 0.0001) (Fig. 3). Group-4a also had lower GMTs compared with Group-3 (2577 mIU/ml) P < 0.0001) and Group-4b (1924 mIU/ml, P = 0.009).
To our knowledge, this is the first study which systematically evaluated the kinetics of measles antibody pre- and post-vaccination in HIV-infected children managed according to the current WHO recommendations of immediate initiation of ART upon diagnosis of HIV in infants;  and also the first study to examine the effect which interruption of ART in healthy 1-year old immunologically stable HIV-infected children had on measles antibody kinetics. Significant findings of our study included the high susceptibility to measles infection as early as 7 weeks of age in the majority of HIV-infected children and in more than 83% of all groups by 20 weeks of age. Also, interruption of ART in HIV-infected children (Group-4a) was associated with them being less likely to have sero-protective levels 28-weeks following the primary dose of measles-vaccine and less likely to maintain sero-protective titers 9.5 months after the booster dose. Furthermore, there was also waning of immunity in HEU children 9.5 months postbooster indicated by a lower proportion with sero-protective titers and lower GMTs compared with HUU. This despite, the proportion of HEU with sero-protective titers being similar compared with HUU children following the initial and immediately following the booster dose.
This high susceptibility to measles in children under 6 months is corroborated by other African studies in HIV-infected (85–91%) and HEU children [19,20], and more recently among healthy infants in developed countries . In developed countries, the increased susceptibility to measles infection among young infants has been attributed to decrease in passive immunity acquired from transplacental maternal measles antibody transfer, because of lower measles antibody levels in pregnant women who acquired immunity from vaccination rather than by natural infection . Additional factors, which may contribute to the increased immunological susceptibility to measles infection in infants born to HIV-infected mothers compared with HUU infants, include lower measles antibody titers and impaired trans-placental transfer of antibody in HIV-infected mothers . Also, there may be greater decay of antibody in HIV-infected children . The observation that GMTs and proportion of children with sero-protective titers were similar between HUU and HEU children suggests that factors other than solely maternal HIV positivity contributed to increased susceptibility to measles at an earlier age in HIV-infected children. Possible reasons include that mothers’ of peripartum HIV-infected children had higher HIV viral load, which has been associated with increased perinatal HIV transmission and inversely associated with efficiency of trans-placental transfer of measles antibody [7,23,24].
The WHO has recommended that in settings of high HIV prevalence, infants should receive two doses of measles vaccine at 6 and 9 months of age . This recommendation has, however, not been widely implemented; for example in South Africa the initial dose is still scheduled for 9 months of age. Reasons for this include the inherent low immunogenicity of measles vaccine in younger children, coupled with interference in the immune response by prevailing maternal-derived measles antibody [25–27]. Based on our study, the low prevalence of maternal-derived antibody in young infants (<30% at 20 weeks of age) supports immunization at 6 months of age. A recent report from Guinea–Bissau indicated that vaccination as early as 4.5 months of age using the Edmonston–Zagreb measles vaccine strain induced sero-protective antibody levels in 77% of infants, as well as being associated with 94% efficacy against measles infection .
A limitation of our study includes that immune response following the first dose of measles vaccine was only evaluated 8 months after vaccination, as earlier evaluation had not been planned a priori in the parent study. Consequently, although we were unable to undertake a direct comparison of immune responses in the overall Group-4 compared with other Groups, Group-4b may be representative of the initial Group-4 cohort at least until 2 years of age. Persistence of antibody levels up until prior to the booster dose was similar in HUU compared with Group-4b, as well as the surviving children in Group-3. This indicated that the timing of ART did not affect immune responses to measles vaccine in those HIV-infected children with CD4+ more than 25% at enrolment. We have, however, previously reported higher early-childhood mortality rate in Group-3 compared with Group-4 children . Additionally, 100% of Group-5 children also had persistence of sero-protective titers 8 months postprimary dose. The good immune responses in HIV-infected children on ART corroborate reports that initiation of ART in the first year of life allows the normal development of T-cell and B-cell immunity [29–31].
Although the proportion of Group-4a with sero-protective titers 2-weeks following the booster dose of vaccine was similar (>90%) to the other Groups, their GMTs were lower compared with other Groups immediately postbooster dose. Furthermore, greater waning of immunity was observed in Group-4a following the initial and after the booster-dose, despite them being carefully monitored for clinical and immunological disease progression following ART interruption at 12-months of age, resulting in ART being re-initiated in 77% of them at the time of the booster dose. CD4+ cell counts and percentage were however lower in Group-4a compared with Group-3 and Group-4b immediately following the booster dose. This indicated that interruption of ART in Group-4a resulted in waning of immunity, including possibly decline in anamnestic responses to measles. This may be explained by the deterioration of antigen specific pools of memory B cells in the absence of ART . The proportion of Group-4a who had sero-protective titers at approximately 2-years of age was, however, higher compared with ART-naive HIV-infected children who had been vaccinated at 6 and 9 months of age and assessed at 20 months of age (41%) as reported by Fowlkes et al. .
In exploring the effect of HIV exposure on persistence of measles antibody following vaccination, we observed that GMTs were higher in HEU compared with HUU children prior to the booster dose. Lower prevaccination antibody levels in HEU children have been previously reported to be associated with more robust immune responses to some vaccines during early childhood . This was, however, unlikely to be the reason for the higher GMTs in HEU in our study as prevaccination measles antibody levels were similar to that of HUU children. The clinical relevance of the higher GMTs in HEU is unclear as the proportion of children with sero-protective titers was similar between the two groups. The higher GMTs in HEU children prior to the booster dose is also difficult to explain in the context of lower GMTs being observed 2-weeks thereafter in this Group compared with prebooster levels, as well as relative to HUU children postbooster. Lower GMTs persisted in HEU compared with HUU until 9.5 months postbooster, at which time HEU were also less likely to be sero-positive or have sero-protective titers. The underlying immune aberration which may cause waning of immunity in HEU, as well as the need for further booster doses of vaccine in these children remain to be explored.
Limitations of our study included only having a convenience sample of HIV-infected children with CD4+ less than 25% at screening (i.e. Group-5). Nevertheless, the observations in this group were similar to those of HIV-infected children on ART (i.e. Group-4b), suggesting that CD4+ percentage categorization at enrolment did not have an effect of immune responses to measles vaccine in children who had been initiated on ART upon confirmation of being HIV-infected. Furthermore, our study involved measuring measles antibody by ELISA as a surrogate of protection, which have been shown to miss low antibody level responses , rather than the plaque reduction neutralization assay which correlates more strongly with protection . We may therefore have over-estimated the protection against measles infection, particularly among HIV-infected children in whom poorer IgG avidity may affect neutralizing activity which has, however, only been observed in the absence of ART .
In conclusion, our study indicates that persistence of maternal measles antibody does not any longer appear to being an impediment to measles vaccination by 6 months of age, possibly with the Edmonston–Zagreb vaccine strain, irrespective of the child's HIV infection status . Reasonably good responses have been observed in ART-naive HIV-infected children when immunized with an Edmonston–Zagreb vaccine strain as early as 6 months, followed by a booster dose at 12 months of age . Sustainability of protection and need for further doses of measles vaccine in HIV-infected children in whom ART has been interrupted and in HEU remains to be explored, as does the issue of sustainability of protection in HIV-infected children who are maintained on ART.
Collaborators and Centers for study: South Africa: A.V., James McIntyre, Wilma Pelser, Ravindre Panchia, K.O., Afaaf Liberty, Nastassja Choolinal (Perinatal HIV Research Unit); M.F.C., Helena Rabie, Anita Janse van Rensburg, Els Dobbels, George Fourie, Marietjie Bester, Wilma Orange, Ronelle Arendze, Catherine Andrea, Marlize Smuts, Kurt Smith, Theresa Louw, Alec Abrahams, Kenny Kelly, Amelia Bohle, Irene Mong, Jodie Howard, Tanya Cyster, Genevieve Solomon, Galroy Benjamin, Jennifer Mkhalipi, Edward Barnes (Children's Infectious Diseases Clinical Research Unit); P.V.A.; S.A.M.; Nadia van Niekerk (Respiratory and Meningeal Pathogens Research Unit); United States of America: Karen Reese, Patrick Jean-Philippe (HJF-DAIDS). United Kingdom: Diana M Gibb, Abdel Babiker (Medical Research Council Clinical Trials Unit, London).
Funding: This study was funded through the Department of Science and Technology/National Research Foundation: South African Research Chair Initiative in Vaccine Preventable Diseases. The parent study was funded by National Institute of Allergy and Infectious Diseases (NIAID) of the US National Institutes for Health (NIH), through the Comprehensive International Program of Research on AIDS (CIPRA) network, grant number U19 AI53217. Additional support for this work was provided with Federal funds from the National Institute of Allergies & Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under Contract No. HHSN272200800014C.
Conflicts of interest
There are no conflicts of interest.
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Keywords:© 2013 Lippincott Williams & Wilkins, Inc.
antibody response; HIV; HIV exposure; measles vaccine