Preservation of lymphocyte functional fitness in perinatally-infected and treated HIV+ pediatric patients displaying sub-optimal viral control.

Background: Host-pathogen dynamics associated with HIV infection are quite distinct in children versus adults. We interrogated the functional fitness of the lymphocyte responses in two cohorts of perinatally infected HIV+ pediatric subjects with early anti-retroviral therapy (ART) initiation but divergent patterns of virologic control. We hypothesized that sub-optimal viral control would compromise immune functional fitness. Methods: The immune responses in the two HIV+ cohorts (n = 6 in each cohort) were benchmarked against the responses measured in age-range matched, uninfected healthy control subjects (n = 11) by utilizing tests for normality, and comparison [the Kruskal-Wallis test, and the two-tailed Mann-Whitney U test (where appropriate)]. Lymphocyte responses were examined by intra-cellular cytokine secretion, degranulation assays as well as phosflow. A subset of these data were further queried by an automated clustering algorithm. Finally, we evaluated the humoral immune responses to four childhood vaccines in all three cohorts. Results: We demonstrate that contrary to expectations pediatric HIV+ patients with sub-optimal viral control display no significant deficits in immune functional fitness. In fact, the patients that display better virologic control lack functional Gag-specific T cell responses and compared to healthy controls they display signaling deficits and an enrichment of mitogen-stimulated CD3 negative and positive lymphocyte clusters with suppressed cytokine production. Conclusions: These results highlight the immune resilience in HIV+ children on ART with sub-optimal viral control. With respect to HIV+ children on ART with better viral control, our data suggest that this cohort might potentially benefit from targeted interventions that might mitigate cell-mediated immune functional quiescence.

Decreased humoral immunity to mumps in young adults immunized with MMR vaccine in childhood.

In the past decade, multiple mumps outbreaks have occurred in the United States, primarily in close-contact, high-density settings such as colleges, with a high attack rate among young adults, many of whom had the recommended 2 doses of mumps-measles-rubella (MMR) vaccine. Waning humoral immunity and the circulation of divergent wild-type mumps strains have been proposed as contributing factors to mumps resurgence. Blood samples from 71 healthy 18- to 23-year-old college students living in a non-outbreak area were assayed for antibodies and memory B cells (MBCs) to mumps, measles, and rubella. Seroprevalence rates of mumps, measles, and rubella determined by IgG enzyme-linked immunosorbent assay (ELISA) were 93, 93, and 100%, respectively. The index standard ratio indicated that the concentration of IgG was significantly lower for mumps than rubella. High IgG avidity to mumps Enders strain was detected in sera of 59/71 participants who had sufficient IgG levels. The frequency of circulating mumps-specific MBCs was 5 to 10 times lower than measles and rubella, and 10% of the participants had no detectable MBCs to mumps. Geometric mean neutralizing antibody titers (GMTs) by plaque reduction neutralization to the predominant circulating wild-type mumps strain (genotype G) were 6-fold lower than the GMTs against the Jeryl Lynn vaccine strain (genotype A). The majority of the participants (80%) received their second MMR vaccine ≥10 years prior to study participation. Additional efforts are needed to fully characterize B and T cell immune responses to mumps vaccine and to develop strategies to improve the quality and durability of vaccine-induced immunity.

Immunity to Measles, Mumps, and Rubella in US Children With Perinatal HIV Infection or Perinatal HIV Exposure Without Infection.

BACKGROUND: Children with perinatal human immunodeficiency virus (HIV) infection (PHIV) may not be protected against measles, mumps, and rubella (MMR) because of impaired initial vaccine response or waning immunity. Our objectives were to estimate seroimmunity in PHIV-infected and perinatally HIV-exposed but uninfected (HEU) children and identify predictors of immunity in the PHIV cohort. METHODS: PHIV and HEU children were enrolled in the Pediatric HIV/AIDS Cohort Study (PHACS) at ages 7-15 years from 2007 to 2009. At annual visits, demographic, laboratory, immunization, and clinical data were abstracted and serologic specimens collected. Most recent serologic specimen was used to determine measles seroprotection by plaque reduction neutralization assay and rubella seroprotection and mumps seropositivity by enzyme immunoassay. Sustained combination antiretroviral therapy (cART) was defined as taking cART for at least 3 months. RESULTS: Among 428 PHIV and 221 HEU PHACS participants, the prevalence was significantly lower in PHIV children for measles seroprotection (57% [95% confidence interval {CI}, 52%-62%] vs 99% [95% CI, 96%-100%]), rubella seroprotection (65% [95% CI, 60%-70%] vs 98% [95% CI, 95%-100%]), and mumps seropositivity (59% [95% CI, 55%-64%] vs 97% [95% CI, 94%-99%]). On multivariable analysis, greater number of vaccine doses while receiving sustained cART and higher nadir CD4 percentage between last vaccine dose and serologic testing independently improved the cumulative prediction of measles seroprotection in PHIV. Predictors of rubella seroprotection and mumps seropositivity were similar. CONCLUSIONS: High proportions of PHIV-infected children, but not HEU children, lack serologic evidence of immunity to MMR, despite documented immunization and current cART. Effective cART before immunization is a strong predictor of current seroimmunity.

Immunogenicity, immunologic memory, and safety following measles revaccination in HIV-infected children receiving highly active antiretroviral therapy.

BACKGROUND: Response rates and immunologic memory following measles vaccination are reduced in human immunodeficiency virus (HIV)-infected children in the absence of highly active antiretroviral therapy (HAART). METHODS: HIV-infected children 2 to <19 years old receiving HAART and with HIV loads <30,000 copies/mL, CD4% ≥15, and ≥1 prior measles-mumps-rubella vaccination (MMR) were given another MMR. Measles antibody concentrations before and 8, 32, and 80 weeks postvaccination were determined by plaque reduction neutralization (PRN). A subset was given another MMR 4-5 years later, and PRN antibody was measured before and 7 and 28 days later. RESULTS: At entry, 52% of 193 subjects were seroprotected (PRN ≥120 mIU/mL). Seroprotection increased to 89% 8 weeks postvaccination, and remained at 80% 80 weeks postvaccination. Of 65 subjects revaccinated 4-5 years later, 85% demonstrated memory based on seroprotection before or 7 days after vaccination. HIV load ≤400 copies/mL at initial study vaccination was associated with higher seroprotection rates, greater antibody concentrations, and memory. Grade 3 fever or fatigue occurred in 2% of subjects. CONCLUSIONS: Measles revaccination induced high rates of seroprotection and memory in children receiving HAART. Both endpoints were associated with HIV viral load suppression. CLINICAL TRIALS REGISTRATION: NCT00013871 (www.clinicaltrials.gov).

Laboratory characterization of measles virus infection in previously vaccinated and unvaccinated individuals.

Waning immunity or secondary vaccine failure (SVF) has been anticipated by some as a challenge to global measles elimination efforts. Although such cases are infrequent, measles virus (MeV) infection can occur in vaccinated individuals following intense and/or prolonged exposure to an infected individual and may present as a modified illness that is unrecognizable as measles outside of the context of a measles outbreak. The immunoglobulin M response in previously vaccinated individuals may be nominal or fleeting, and viral replication may be limited. As global elimination proceeds, additional methods for confirming modified measles cases may be needed to understand whether SVF cases contribute to continued measles virus (MeV) transmission. In this report, we describe clinical symptoms and laboratory results for unvaccinated individuals with acute measles and individuals with SVF identified during MeV outbreaks. SVF cases were characterized by the serological parameters of high-avidity antibodies and distinctively high levels of neutralizing antibody. These parameters may represent useful biomarkers for classification of SVF cases that previously could not be confirmed as such using routine laboratory diagnostic techniques.

Two case studies of modified measles in vaccinated physicians exposed to primary measles cases: high risk of infection but low risk of transmission.

In 2009, measles outbreaks in Pennsylvania and Virginia resulted in the exposure and apparent infection of 2 physicians, both of whom had a documented history of vaccination with >2 doses of measles-mumps-rubella vaccine. These physicians were suspected of having been infected with measles after treating patients who subsequently received a diagnosis of measles. The clinical presentation was nonclassical in regard to progression, duration, and severity. It is hypothesized that the 2 physicians mounted vigorous secondary immune responses typified by high avidity measles immunoglobulin G antibody and remarkably high neutralizing titers in response to intense and prolonged exposure to a primary measles case patient. Both of the physicians continued to see patients, because neither considered that they could have measles. Despite surveillance for cases among contacts, including unvaccinated persons, no additional cases were identified.