Measles vaccine-induced sero-protection among children with sickle cell anemia

Abstract Introduction: Measles is a highly contagious and vaccine-preventable disease with increasing infection rates across the United States and persistent transmission globally. People with sickle cell anemia (SCA) may have decreased antibody titers after routine childhood vaccinations, due to early functional asplenia and altered humoral immunity. It is not known whether children with SCA have impaired antibody production in response to measles vaccination. Additionally, it is not known if hydroxyurea limits measles vaccine immunogenicity, as suggested from a small secondary analysis of the Phase III BABY HUG trial of hydroxyurea in young children with SCA (NCT00006400), an observation that warrants further exploration. Methods: To determine rates of sero-protection and antibody persistence after measles vaccination, we conducted a retrospective analysis of children with SCA enrolled in TREAT (NCT02286154), a prospective trial of pharmacokinetic-guided hydroxyurea dosing in Cincinnati, USA. Stored serum or plasma samples from study participants with documented measles vaccination were tested for anti-measles IgG levels via ELISA (Euroimmun, Lübeck, Germany). In accordance with recent measles literature, sero-protection was defined as an IgG level ≥200 IU/L. Elevated erythrocyte pit counts ≥5.0% indicated reduced splenic filtration. Results: A total of 145 samples, collected from 66 children between 2014 and 2022 and ranging from pre- to 16.1 years post-measles vaccination, were analyzed. Among 35 children with samples available after their first measles vaccine (MV1), the median age at MV1 was 1.1 (IQR 1.0-1.3) years, and 5 of 18 (28%) with available labs had elevated pit counts within one year of vaccination. Sero-protection was achieved in 33 (94%) of these children; the two children without sero-protective titers were substantially older at the time of MV1 (5.3 and 19.5 years old), and one had an elevated pit count. Hydroxyurea did not diminish antibody responses to MV1. Approximately half of the cohort (17/35, 49%) were taking hydroxyurea at the time of MV1, and 100% on hydroxyurea achieved sero-protection compared with 89% not on hydroxyurea (p=0.2). Among 48 children with samples available after their second measles vaccine (MV2), the median age at MV2 was 4.4 (IQR 4.1-4.9) years, 33 (69%) were on hydroxyurea, and 8 of 18 (44%) with available labs had elevated pit counts within one year of MV2. Sero-protection was reached by 44 (92%) children. Again, hydroxyurea did not reduce sero-protection after MV2: 94% who were on hydroxyurea achieved sero-protective antibody titers versus 85% of those not on hydroxyurea (p=0.3). Additionally, splenic filtrative function was not correlated with sero-protection as all (18 of 18, 100%) children with available pit counts within one year of vaccination achieved sero-protective titers after MV2. Children who did not reach sero-protection were significantly older (mean 5.6 ± 1.1 years) than those who did (4.5 ± 0.8 years, p=0.01). Over time, sero-protection after MV2 waned below protective thresholds: 100% (20/20 samples) had sero-protection in the first year, compared to 85% (46/54 samples) 1-10 years post-vaccination (p=0.07) and 63% (10/16 samples) 10-16 years post-vaccination (p=0.003 compared with year 1). No children were diagnosed with vaccine-associated or natural measles infection during the observation period. Conclusion: In this retrospective cohort, sero-protection from measles vaccinations in children with SCA was robust and comparable to rates observed in the general population. Notably, hydroxyurea treatment did not impair measles antibody responses. Older age at vaccination was associated with lower rates of sero-protection, an important finding for families considering delayed vaccine schedules. Post-vaccination, sero-protection waned over time. Future prospective studies with larger sample sizes and multiple institutions are needed to definitively determine measles sero-protection rates in children with SCA, confirm that hydroxyurea does not impair sero-protection, and clarify whether this vulnerable population is adequately protected against this vaccine-preventable disease.