Diminished Long-term Vaccine Antibody Persistence in Perinatally Youth Living With HIV on cART

This is the authors' abstract. We don't add key points for this paper.

TO THE EDITOR—Combined antiretroviral therapy (cART) has significantly improved the clinical outcomes of individuals with perinatally acquired HIV (PHIV). However, impairments in B-cell function persist despite viral suppression, raising concerns about the long-term durability of vaccine-induced immunity [1, 2]. We investigated the persistence of antibodies to measles, mumps, rubella (MMR), and varicella (VZV) vaccines up to 16 years post-vaccination in PHIV compared to HIV-negative individuals. We assessed 21 PHIV on cART with known MMR and VZV vaccination histories. Plasma samples were obtained 4, 8, and 16 years after the last vaccination. Eleven HIV-negative adults from a blood bank served as controls; although their vaccination history was undocumented, they were presumed immune due to vaccination or prior infection. Enzyme-linked immunosorbent assays (ELISA; MyBioSource) were used to measure IgG antibodies against measles, mumps, rubella, and varicella. All procedures, calculations, and thresholds for determining seropositivity followed the manufacturer's instructions. Briefly, a positive result was defined as an antibody index >1.2 U/mL for rubella, and antibody levels >12 U/mL for measles, mumps, and varicella. Half-lives of vaccine-specific antibodies were estimated by using the standard exponential decay model, Nₜ = N₀ × (1/2)^(t/t₁/₂), where N₀ is the initial antibody concentration, Nₜ is the concentration at time t, and t₁/₂ is the half-life. Rearranging this equation (t₁/₂ = t × ln(2)/ln(N₀/Nₜ)) allowed calculation of the time required for antibody titers to decline by 50%. Statistical comparisons were made using the Wilcoxon Rank-Sum and Fisher’s exact tests. The PHIV cohort began cART at a median age of 3.02 years (IQR: 1.0–5.6) and remained in good clinical status throughout the study period (Figure 1A). At year 16, antibody levels in people living with HIV (PLHIV) were significantly lower across all timepoints compared to HIV-negative controls: mumps (8.3-fold), measles (2.5-fold), rubella (1.7-fold), and varicella (11.7-fold); all P-values <.003 except rubella (P = .056) (Figure 1A&B). Antibody titers declined gradually across 12 years of observation, with estimated half-lives of 96 years (mumps), 37 years (VZV), 29 years (measles), and 13 years (rubella). Notably, antibody levels in PLHIV remained below protective thresholds for measles and mumps (Figure 1A&B). The patterns of PLHIV to HIV- levels of antibodies found at year four after vaccination were maintained over the following 12 years of observation. Despite being on long-term cART and good clinical status, PLHIV had significantly lower levels of antibodies to mumps, measles, rubella, and VZV than HIV and compared to a published cohort of healthy children aged 15 years old [3]. Moreover, the estimated half-lives of vaccine-specific antibodies were markedly decreased compared to the adult population (fold reductions were measles 12.7; rubella 6.5; varicella 1.7, and mumps1.3) [4]. Longitudinal IgG Antibody Responses to Measles, Rubella, Varicella, and Mumps in People Living with HIV Compared to Controls and Clinical Characteristics. Panel A: § Antibody index > 1.2 U/ml for rubella; ↑ Antibody level > 12 U/ml for measles, mumps, and varicella. Bolded values exceed the threshold associated with protection. * Viremia copy-years (VCY—the number of copies of HIV RNA per mL of plasma over time). Panel B: Shaded areas denote antibody concentrations below established protective thresholds for each antigen. Dashed lines represent control antibody levels as cross-sectional point estimates. Since the exact time from the last vaccination is unknown, these lines are not intended to reflect longitudinal kinetics. IgG concentrations are presented as log2-transformed median values (Log2 IgG U/mL). Antibody titers were measured at 4, 8, and 16 y after the last vaccination among people living with HIV (PLHIV) and adult controls. Thresholds used for seroprotection were derived from assay manufacturer specifications. These findings are particularly concerning in light of the 2024–2025 global measles resurgence [5]. Despite timely vaccination and cART-mediated viral suppression, PHIV may silently lose vaccine-induced immunity as they age, increasing their vulnerability to preventable infections. Standard immunization schedules may be insufficient for ensuring long-term protection in this population. Our findings echo—but critically diverge from—those of van der Staak et al [6], who demonstrated accelerated measles antibody waning in immunocompetent children vaccinated before 8.5 months of age. While that decline was attributed to early-life immune immaturity and maternal antibody interference, we observed similar or greater waning in PHIV despite vaccination at recommended ages and robust virologic control. This suggests that PHIV suffers from a persistent, intrinsic impairment in immune memory formation and maintenance. Several limitations of this study should be considered. While our study provides valuable insight into humoral antibody persistence, it does not assess cellular immune responses, which may remain intact and contribute to protection despite waning antibody titers. Future studies incorporating T-cell and memory B-cell analyses are warranted to provide a more comprehensive assessment of long-term vaccine-induced immunity in PHIV. Given the lack of documented vaccination history for the HIV-negative controls, it is possible that some individuals had natural infection-induced immunity, particularly to measles, which may confer longer-lasting protection than vaccination alone [4]. This could have biased comparisons in favor of more robust antibody persistence among controls. Moreover, control samples were not time-matched to 4, 8, and 16 years post-vaccination, which we now acknowledge as a limitation of the study design. Clinically, this distinction is important. PHIV cannot rely on standard pediatric vaccination schedules alone. Targeted strategies—such as periodic serologic monitoring and booster doses—are essential to ensure sustained protection. As global measles transmission rises, these gaps in immunity among aging people with PHIV could undermine herd protection. These findings support consideration of long-term vaccine follow-up as part of routine care for PHIV, especially during adolescence and the transition to adulthood. Acknowledgment. German A Contreras has been sponsored by the NIH T32 Training Program in Emerging Infectious Diseases Research (5T32AI155385-02) Financial support. This work was supported by the State of Texas Pediatric HIV Initiative.