Persistence of Immunogenicity of a Purified Inactivated Zika Virus Vaccine Candidate in Healthy Adults: 2 Years of Follow-up Compared With Natural Infection.

BACKGROUND: We report 2-year persistence of immune response to Takeda's prophylactic purified formalin-inactivated whole Zika virus vaccine candidate (TAK-426) compared with that observed after natural infection. METHODS: A randomized, observer-blind, placebo-controlled, dose-selection, phase 1 trial was conducted in 18-49-year-old adults at 9 centers (7 in the United States, 2 in Puerto Rico) from 13 November 2017 to 24 November 2020. Primary objectives were safety, tolerability, and immunogenicity of 3 increasing doses of TAK-426 administered as 2 doses 28 days apart to flavivirus (FV)-naive and FV-primed adults. Here, we report on safety and persistence of immunity up to 2 years after primary vaccination with 10-µg TAK-426, the highest dose, and compare neutralizing antibody responses with those observed after natural infection. RESULTS: TAK-426 at 10-µg had an acceptable safety profile in FV-naive and FV-primed adults up to 24 months after dose 2. Seropositivity for neutralizing antibodies was 100% at 1 year, and 93.8% and 76.2% at 2 years in FV-naive and FV-primed groups, respectively. TAK-426 responses were comparable in magnitude and kinetics with those elicited by natural Zika virus infection. CONCLUSIONS: These results support the further clinical development of TAK-426 for both FV-naive and FV-primed populations. CLINICAL TRIALS REGISTRATION: NCT03343626.

Characterization of B-cell and T-cell responses to a tetravalent dengue purified inactivated vaccine in healthy adults.

The increasing global impact of dengue underscores the need for a dengue virus (DENV) vaccine. We assessed B-cell and T-cell responses following vaccination with four formulations of a tetravalent dengue purified inactivated vaccine (DPIV) in dengue-primed and dengue-naive adults from two studies (NCT01666652, NCT01702857). Frequencies of DPIV-induced memory B cells specific to each DENV serotype remained high up to 12 months post-vaccination, and were higher in the dengue-primed than dengue-naive adults. A subsequent DPIV booster dose induced strong anamnestic B-cell responses. Multifunctional CD4+ T cells (predominantly expressing IL-2) were induced by DPIV, with higher frequencies in dengue-primed adults. DPIV-induced CD4+ T cells also demonstrated in vitro proliferative capacity and antigen-specific production of GM-CSF, IFN-γ, and IL-13. CD8+ T-cell responses were undetectable in dengue-naive adults and low in dengue-primed individuals. B- and T-cell responses persisted up to 12 months post-vaccination in both dengue-primed and dengue-naive adults.

Safety and immunogenicity of a purified inactivated Zika virus vaccine candidate in healthy adults: an observer-blind, randomised, phase 1 trial.

BACKGROUND: Zika virus, a flavivirus transmitted by Aedes aegypti and Aedes albopictus mosquitoes, is associated with cases of congenital malformations and neurological complications. Absence of specific treatment makes a prophylactic Zika virus vaccine an unmet medical need. We assessed safety and immunogenicity of three doses of a purified, inactivated, Zika virus vaccine candidate in healthy flavivirus-naive and flavivirus-primed adults. METHODS: This two-part, multicentre, observer-blind, randomised, placebo-controlled, phase 1 trial was done at seven medical clinics in the USA and two in Puerto Rico. Eligible participants were healthy adults aged 18-49 years. Participants were randomly assigned (1:1:1:1), using a sponsor-supplied randomisation scheme, to four groups to receive two intramuscular injections, 28 days apart, of saline placebo or TAK-426 containing 2 µg, 5 µg, or 10 µg antigen. Participants, investigators, and vaccine administrating personnel were masked to group assignment. Part 1 of the study assessed flavivirus-naive participants and part 2 assessed flavivirus-primed participants. The primary outcomes were safety, tolerability, and immunogenicity based on solicited local reactions and solicited systemic adverse events in the 7 days after each dose; unsolicited adverse events and serious adverse events in the 28 days after each dose; and geometric mean titres (GMTs) of neutralising anti-Zika virus antibodies at 28 days after the second dose. Safety assessments were done in all participants who received at least one dose of vaccine. Immunogenicity assessments were in the per-protocol set, comprising all participants who received at least one dose of vaccine and provided valid serology results at baseline and at least one post-vaccination timepoint, with no major protocol violations. The trial is ongoing and is registered at ClinicalTrials.gov (NCT03343626). FINDINGS: Between Nov 13, 2017, and Oct 24, 2018, 894 volunteers were screened and 271 enrolled (125 flavivirus-naive and 146 flavivirus-primed participants). All TAK-426 doses were well tolerated with no deaths, no vaccine-related serious adverse events, and similar rates of mainly mild to moderate adverse events. TAK-426 elicited dose-dependent increases in antibody GMTs in both flavivirus-naive and flavivirus-primed participants. 28 days after dose 2, plaque-reduction neutralisation test GMTs in flavivirus-naive participants were 1130 (95% CI 749-1703) in the 2 µg TAK-426 group, 1992 (1401-2833) in the 5 µg TAK-426 group, and 3690 (2677-5086) in the 10 µg TAK-426 group. In pairwise comparisons, responses after two vaccinations in the 10 µg group were significantly greater than in the 2 µg group (GMT ratio 3·27 [95% CI 1·98-5·39], p<0·0001) and the 5 µg group (GMT ratio 1·85 [1·15-2·98], p=0·012). INTERPRETATION: TAK-426 was well tolerated, with an acceptable safety profile, and was immunogenic in both flavivirus-naive and flavivirus-primed adults. Based on the safety and immunogenicity profiles of all TAK-426 doses assessed, the 10 µg TAK-426 dose was selected for further clinical development. FUNDING: Takeda Vaccines and the US Biomedical Advanced Research and Development Authority. TRANSLATION: For the Spanish translation of the abstract see Supplementary Materials section.

Effect of a Chikungunya Virus-Like Particle Vaccine on Safety and Tolerability Outcomes: A Randomized Clinical Trial.

Importance: Chikungunya virus (CHIKV) is a mosquito-borne Alphavirus prevalent worldwide. There are currently no licensed vaccines or therapies. Objective: To evaluate the safety and tolerability of an investigational CHIKV virus-like particle (VLP) vaccine in endemic regions. Design, Setting, and Participants: This was a randomized, placebo-controlled, double-blind, phase 2 clinical trial to assess the vaccine VRC-CHKVLP059-00-VP (CHIKV VLP). The trial was conducted at 6 outpatient clinical research sites located in Haiti, Dominican Republic, Martinique, Guadeloupe, and Puerto Rico. A total of 400 healthy adults aged 18 through 60 years were enrolled after meeting eligibility criteria. The first study enrollment occurred on November 18, 2015; the final study visit, March 6, 2018. Interventions: Participants were randomized 1:1 to receive 2 intramuscular injections 28 days apart (20 µg, n = 201) or placebo (n = 199) and were followed up for 72 weeks. Main Outcomes and Measures: The primary outcome was the safety (laboratory parameters, adverse events, and CHIKV infection) and tolerability (local and systemic reactogenicity) of the vaccine, and the secondary outcome was immune response by neutralization assay 4 weeks after second vaccination. Results: Of the 400 randomized participants (mean age, 35 years; 199 [50%] women), 393 (98%) completed the primary safety analysis. All injections were well tolerated. Of the 16 serious adverse events unrelated to the study drugs, 4 (25%) occurred among 4 patients in the vaccine group and 12 (75%) occurred among 11 patients in the placebo group. Of the 16 mild to moderate unsolicited adverse events that were potentially related to the drug, 12 (75%) occurred among 8 patients in the vaccine group and 4 (25%) occurred among 3 patients in the placebo group. All potentially related adverse events resolved without clinical sequelae. At baseline, there was no significant difference between the effective concentration (EC50)-which is the dilution of sera that inhibits 50% infection in viral neutralization assay-geometric mean titers (GMTs) of neutralizing antibodies of the vaccine group (46; 95% CI, 34-63) and the placebo group (43; 95% CI, 32-57). Eight weeks following the first administration, the EC50 GMT in the vaccine group was 2005 (95% CI, 1680-2392) vs 43 (95% CI, 32-58; P < .001) in the placebo group. Durability of the immune response was demonstrated through 72 weeks after vaccination. Conclusions and Relevance: Among healthy adults in a chikungunya endemic population, a virus-like particle vaccine compared with placebo demonstrated safety and tolerability. Phase 3 trials are needed to assess clinical efficacy. Trial Registration: ClinicalTrials.gov Identifier: NCT02562482.

Safety and Immunogenicity of Different Formulations of a Tetravalent Dengue Purified Inactivated Vaccine in Healthy Adults from Puerto Rico: Final Results after 3 Years of Follow-Up from a Randomized, Placebo-Controlled Phase I Study.

Four formulations of an investigational tetravalent dengue purified inactivated vaccine, administered as two doses one month (M) apart, were previously shown to be immunogenic and well-tolerated up to M13 of the phase I study NCT01702857. Here, we report results of the follow-up from M14 to year (Y) 3. One hundred healthy Puerto Rican adults, predominantly dengue virus (DENV)-primed, were randomized 1:1:1:1:1 to receive placebo or vaccine formulations: 1 µg/serotype/dose adjuvanted with aluminum, AS01E or AS03B, or aluminum-adjuvanted 4 µg/serotype/dose. No serious adverse events occurred. Two medically-attended potential immune-mediated disease cases, vaccination unrelated, were reported (groups 1 µg+Alum and 1 µg+AS03B). Of 14 instances of suspected dengue, none were laboratory confirmed. Geometric mean neutralizing antibody titers against DENV 1-4 waned from M14, but remained above pre-vaccination levels for DENV 1-3, with the highest values for group 1 µg+AS03B: 1220.1, 920.5, 819.4, and 940.5 (Y2), and 1329.3, 1169.2, 1219.8, and 718.9 (Y3). All formulations appeared to be safe and immunogenic during the 3-year follow-up.

Phase I Randomized Study of a Tetravalent Dengue Purified Inactivated Vaccine in Healthy Adults from Puerto Rico.

The safety and immunogenicity of four adjuvanted formulations of an investigational tetravalent dengue purified inactivated vaccine (DPIV) were evaluated in a predominantly dengue-primed population in Puerto Rico. In this placebo-controlled, randomized, observer-blind, phase I trial, 100 healthy adults were randomized 1:1:1:1:1 to receive DPIV at Day (D)0 and D28 (1 µg per dengue virus [DENV] type 1-4 adjuvanted with either alum, AS01E or AS03B, or 4 µg per DENV type adjuvanted with alum) or saline placebo. Functional antibody responses were assessed using a microneutralization assay at D56, Month (M)7, and M13. All DPIV formulations were well tolerated and no safety signals were identified through M13. The M13 according-to-protocol (ATP) immunogenicity cohort included 83 participants. The ATP analysis of immunogenicity was performed only on the 78 subjects seropositive for ≥ 1 DENV type at baseline: 69 tetravalent, three trivalent, two bivalent, and four monovalent. In all DPIV groups, geometric mean antibody titers (GMTs) increased from D0 to D56 and waned modestly through M13, while remaining well above prevaccination levels. The 4 µg + alum and the AS01E- and AS03B-adjuvanted formulations were highly immunogenic, with M13-neutralizing antibody GMTs against all four DENV types above 1,000. M13/D0 GMT ratios were highest in the 1 µg + AS03B group (ranging 3.2-3.7 depending on the DENV type). These results encourage continued clinical development of DPIV (ClinicalTrials.gov: NCT01702857).

Safety and Immunogenicity of Human Serum Albumin-Free MMR Vaccine in US Children Aged 12-15 Months.

BACKGROUND: M-M-R(TM)II (MMRII; Merck & Co) is currently the only measles-mumps-rubella (MMR) vaccine licensed in the United States. Another licensed vaccine would reinforce MMR supply. This study assessed the immunogenicity of a candidate vaccine (Priorix(TM), GlaxoSmithKline Vaccines [MMR-RIT]) when used as a first dose among eligible children in the United States. METHODS: In this exploratory Phase-2, multicenter, observer-blind study, 1220 healthy subjects aged 12-15 months were randomized (3:3:3:3) and received 1 dose of 1 of 3 MMR-RIT lots with differing mumps virus titers (MMR-RIT-1 [4.8 log10]; MMR-RIT-2 [4.1 log10]; MMR-RIT-3 [3.7 log10] CCID50) or MMRII co-administered with hepatitis A vaccine (HAV), varicella vaccine (VAR) and 7-valent pneumococcal conjugate vaccine (PCV7). Immune response to measles, mumps, and rubella viruses was evaluated at Day 42 post-vaccination. Incidence of solicited injection site, general, and serious adverse events was assessed. RESULTS: Seroresponse rates for MMR vaccine viral components in MMR-RIT lots were 98.3-99.2% (measles), 89.7-90.7% (mumps), and 97.5-98.8% (rubella), and for MMRII were 99.6%, 91.1%, and 100%, respectively. Immune responses to HAV, VAR, and PCV7 were similar when co-administered with any of the 3 MMR-RIT lots or MMRII. There were no apparent differences in solicited or serious adverse events among the 4 groups. CONCLUSIONS: Immune responses were above threshold levels for projected protection against the 3 viruses from MMR-RIT lots with differing mumps virus titers. MMR-RIT had an acceptable safety profile when co-administered with HAV, VAR, and PCV7. CLINICAL TRIALS REGISTRATION: NCT00861744; etrack; 111870.

A Phase II, Randomized, Safety and Immunogenicity Trial of a Re-Derived, Live-Attenuated Dengue Virus Vaccine in Healthy Children and Adults Living in Puerto Rico.

This was a double-blind, randomized, controlled, phase II clinical trial, two dose study of re-derived, live-attenuated, tetravalent dengue virus (TDEN) vaccine (two formulations) or placebo in subjects 1-50 years of age. Among the 636 subjects enrolled, 331 (52%) were primed, that is, baseline seropositive to at least one dengue virus (DENV) type. Baseline seropositivity prevalence increased with age (10% [< 2 years], 26% [2-4 years], 60% [5-20 years], and 93% [21-50 years]). Safety profiles of TDEN vaccines were similar to placebo regardless of priming status. No vaccine-related serious adverse events (SAEs) were reported. Among unprimed subjects, immunogenicity (geometric mean antibody titers [GMT] and seropositivity rates) for each DENV increased substantially in both TDEN vaccine groups with at least 74.6% seropositive for four DENV types. The TDEN vaccine candidate showed an acceptable safety and immunogenicity profile in children and adults ranging from 1 to 50 years of age, regardless of priming status. ClinicalTrials.gov: NCT00468858.

Shaping a new generation of Hispanic clinical and translational researchers addressing minority health and health disparities.

In 2011, research educators face significant challenges. Training programs in Clinical and Translational Research need to develop or enhance their curriculum to comply with new scientific trends and government policies. Curricula must impart the skills and competencies needed to help facilitate the dissemination and transfer of scientific advances at a faster pace than current health policy and practice. Clinical and translational researchers are facing also the need of new paradigms for effective collaboration, and resource sharing while using the best educational models. Both government and public policy makers emphasize addressing the goals of improving health quality and elimination of health disparities. To help achieve this goal, our academic institution is taking an active role and striving to develop an environment that fosters the career development of clinical and translational researchers. Consonant with this vision, in 2002 the University of Puerto Rico, Medical Sciences Campus School of Health Professions and School of Medicine initiated a multidisciplinary post-doctoral Master of Science in Clinical Research focused in training Hispanics who will address minority health and health disparities research. Recently, we proposed a curriculum revision to enhance this commitment in promoting competency-based curricula for clinician-scientists in clinical and translational sciences. The revised program will be a post-doctoral Master of Science in Clinical and Translational Research (MCTR), expanding its outreach by actively engaging in establishing new collaborations and partnerships that will increase our capability to diversify our educational efforts and make significant contributions to help reduce and eliminate the gap in health disparities.

Early immunological predictors of neurodevelopmental outcomes in HIV-infected children.

BACKGROUND: A previous analysis of children infected with human immunodeficiency virus (HIV) in the Women and Infants Transmission Study showed a strong correlation between low activated CD8(+) T lymphocytes in the first 2 months of life and good immunological prognosis. We sought to extend these observations to neurodevelopmental prognosis. METHODS: Ninety-eight HIV-infected children born before 1994 with flow cytometric data from the first 2 months of life and adequate neurodevelopmental testing through age 30 months were studied. Children were divided into those with low (5% CD8(+)HLA-DR(+) cells or >25% CD8(+)CD38(+) cells) immune activation at 1 and/or 2 months of age. Analysis was performed using survival analysis, Cox's proportional hazard regression, and longitudinal regression models. RESULTS: Absence of immune activation, measured as

Maternal neutralizing antibody and transmission of hepatitis C virus to infants.

To determine whether lower levels of hepatitis C virus (HCV)-specific neutralizing antibodies (nAb) are associated with an increased risk of mother-to-child transmission (MTCT) of HCV, HCV nAb titers were assessed in 63 mothers coinfected with HCV and human immunodeficiency virus (HIV) type 1. Of the mothers, 16 transmitted HCV to their infant, but no difference was detected between the ability of maternal plasma from transmitters and nontransmitters to neutralize heterologous HCV pseudoparticles (median nAb titer, 1:125 vs. 1:100; P = .23). In the setting of HIV/HCV coinfection, we found no evidence that HCV nAbs are associated with the prevention of MTCT of HCV.

CD4+/CD8+ T cell ratio for diagnosis of HIV-1 infection in infants: Women and Infants Transmission Study.

OBJECTIVE: In this study, we tested the hypothesis that the CD4(+)/CD8(+) T cell ratio could predict HIV infection status in HIV-exposed infants. METHODS: CD4(+)/CD8(+) T cell ratios were determined from data for live-born singleton infants who had been prospectively enrolled in the Women and Infants Transmission Study. Data for 2208 infants with known HIV infection status (179 HIV-infected and 2029 uninfected infants) were analyzed. RESULTS: Receiver operating characteristic curves indicated that the CD4(+)/CD8(+) T cell ratio performed better than the proportion of CD4(+) T cells for diagnosis of HIV infection as early as 2 months of age, and this relationship was unaffected by adjustment for maternal race/ethnicity, infant birth weight, gestational age, and gender. At 4 months of age, 90% specificity for HIV diagnosis was associated with 60% sensitivity. For ease of use, graphical estimates based on cubic splines for the time-dependent parameters in a Box-Cox transformation (L), the median (M), and the coefficient of variation (S) were used to create LMS centile curves to show the sensitivity and specificity of CD4(+)/CD8(+) T cell ratios in HIV-infected and uninfected infants until 12 months of age. At 6 months of age, a simplified equation that incorporated sequential CD4(+)/CD8(+) T cell ratios and hematocrit values resulted in improved receiver operating characteristic curves, with 94% positive predictive value and 98% negative predictive value. The positive and negative predictive values remained above 90% in simulated infant populations over a wide range of HIV infection prevalence values. CONCLUSIONS: In the absence of virological diagnosis, a presumptive diagnosis of HIV infection status can be made on the basis of CD4(+)/CD8(+) T cell ratios in HIV-1-exposed infants after 2 months of age; sensitivity and specificity can be improved at 6 months by using a discriminant analysis equation.

Increased incidence of asthma in HIV-infected children treated with highly active antiretroviral therapy in the National Institutes of Health Women and Infants Transmission Study.

BACKGROUND: Immunoreconstitution of HIV(+) patients after treatment with highly active antiretroviral therapy (HAART) appears to provoke inflammatory diseases. OBJECTIVE: We sought to determine whether HIV(+) children receiving HAART (HIV(+) HAART(+)) have a higher incidence of asthma than HIV(+) children not receiving HAART (HIV(+) HAART(-)). METHODS: Two thousand six hundred sixty-four children (193 HIV(+) and 2471 HIV(-) children) born to HIV(+) women were evaluated for the incidence and prevalence of asthma (ie, asthma medication use) and change of CD4(+) T-cell percentage with time. RESULTS: The HIV(+) HAART(+) children had higher CD4(+) T-cell percentages, lower CD8(+) T-cell percentages, and lower viral burdens than the HIV(+) HAART(-) children (P < or = .05 to P < or = .01). The cumulative incidence of asthma medication use in HIV(+) HAART(+) children at 13.5 years increased to 33.5% versus 11.5% in HIV(+) HAART(-) children (hazard ratio, 3.34; P = .01) and was equal to that in the HIV(-) children. In children born before the HAART era, the prevalence of asthma medication use for HIV(+) HAART(+) children at 11 years of age was 10.4% versus 3.8% for HIV(+) HAART(-) children (odds ratio, 3.38; P = .02) and was equal to that of the HIV(-) children. The rate of change of CD4(+) T cells around the time of first asthma medication for HIV(+) HAART(+) versus HIV(+) HAART(-) children was 0.81%/y versus -1.43%/y (P = .01). CONCLUSION: The increased incidence of asthma in HIV(+) HAART(+) children might be driven by immunoreconstitution of CD4(+) T cells.

Endocrine abnormalities and impaired growth in human immunodeficiency virus-infected children.

OBJECTIVES: Identify endocrine differences between human immunodeficiency virus- (HIV) infected versus uninfected children and evaluate associations of growth and body composition with endocrine measures. STUDY DESIGN: Nested case-control study in 21 HIV-infected and 46 age- and sex-matched uninfected children in the Women and Infant Transmission Study. Plasma specimens from children between 2.5 to 7.0 years of age, taken during 3-4 visits, were tested for insulin-like growth factor binding protein-3 (IGFBP-3), cortisol, dehydroepiandrosterone (DHEA), growth hormone and thyroid studies. Longitudinal mixed and generalized estimating equation models compared group means and examined effects of endocrine measures on growth and body composition, respectively. RESULTS: HIV-infected children had lower IGFBP-3 than uninfected children (1.96 +/- 0.09 mg/L versus 2.34 +/- 0.06 mg/L, P < 0.001). In infected but not in uninfected children, IGFBP-3 values and DHEA:cortisol ratios were associated with weight- and body mass index-for-age z scores ([WAZ] P = 0.019, <.001 respectively, and [BMZ] P = 0.029, 0.038). DHEA concentration was associated with height-for-age z score (P = 0.049). CONCLUSIONS: In these HIV-infected children compared with their uninfected counterparts, IGFBP-3 concentration was different between groups. Infected children had multiple endocrine associations with growth and body composition not found in their uninfected peers. We hypothesize that in HIV-infected children, growth hormone resistance and shunting of precursors from adrenal androgen to cortisol production contributes to altered body composition and stunting.

Reduction in the perinatal HIV transmission: the experience at the Maternal Infant Studies Center and Gamma Projects at the University of Puerto Rico School of Medicine.

The AIDS pandemic had a significant impact in Puerto Rico, especially among the heterosexual populations, in particular women. Women are one of the fastest growing risk groups with HIV/AIDS in the USA and constitute about half of the AIDS cases in the world. During the past 10 years Puerto Rico has ranked among the top 5 jurisdictions in the United States in AIDS cases rates, among men, women and children. In 1987 a universal prenatal HIV screening program was implemented in the University Hospital catchment area consisting of approximately 5,000 deliveries per year. Because of the early identification of pregnant women living with HIV, access to lifesaving clinical research and the implementation of multiple strategies and comprehensive care, the perinatal HIV transmission has been reduced to zero since 1997, with a blip of one case in 2002, and none since then. The availability and access to clinical and behavioral research has been one of the key elements for this success story. The programs involved and responsible for this spectacular outcome, namely the Maternal Infant Studies Center (CEMI-Spanish Acronym) and Gamma Projects at the University of Puerto Rico School of Medicine are described. The cost savings impact of stopping mother-infant perinatal HIV-1 transmission has been calculated to be approximately $34 to $58 million dollars in 10 years. The impact of the effectiveness of these programs in having healthy uninfected infants, prolonging and improving the quality of life of those living with HIV, and providing hope to families affected by this epidemic is incalculable.

Assessment of birth defects according to maternal therapy among infants in the Women and Infants Transmission Study.

BACKGROUND: To evaluate rate and types of birth defects according to timing of antiretroviral exposure among babies born to HIV-infected women. METHODS: Anomalies identified during the prenatal, neonatal, or follow-up period were classified using criteria of the Antiretroviral Pregnancy Registry. Antiretroviral use was classified as none, second or third trimester only, or first trimester. RESULTS: From January 1, 1990 through June 30, 2004, 2527 live births (LBs) occurred to 2353 women. Defects were identified in 90 babies for a rate of 3.56 defects per 100 LBs. The rate of defects was 3.19 per 100 LBs (24 of 752 LBs) with first-trimester antiretroviral exposure, 3.54 per 100 LBs (41 of 1158 LBs) with exposure later in pregnancy, and 4.05 of 100 LBs (25 of 617 LBs) with no antiretroviral use. Only genital abnormalities, specifically hypospadias, were significantly increased among babies born to women with first-trimester exposure to antiretrovirals (7 of 382 male LBs) compared with the 2 other groups (2 of 892 male LBs; P = 0.007). On logistic regression, use of zidovudine in the first trimester was associated with hypospadias (adjusted odds ratio = 10.68, 95% confidence interval: 2.11 to 54.13; P = 0.004). CONCLUSIONS: In general, data were reassuring, although the frequency of exposure to newer agents was limited. The increased risk of hypospadias after first-trimester exposure must be explored, because this association has not been detected previously.

Safety, tolerability, and immunogenicity of a two-dose regimen of high-titer varicella vaccine in subjects > or =13 years of age.

A new manufacturing process, known as process upgrade varicella vaccine (PUVV) was developed for a refrigerated formulation of varicella vaccine and for an investigational zoster vaccine. Safety and tolerability of a two-dose regimen of high-titered (approximately 50,000 PFU) PUVV were compared to a lower-titer formulation (approximately 5400 PFU) of VARIVAX; in 1366 healthy subjects > or =13 years old. Only one vaccine-related clinical serious adverse experience (pruritus; no hospitalization) was reported, in the VARIVAX group. Injection-site adverse experiences following any dose were higher in the PUVV group, 70.0%, than in the VARIVAX group, 56.2%, but generally were mild. Immunogenicity were similar in both groups in seronegative subjects. PUVV was generally well tolerated, and elicited an immune response similar to that induced by the marketed formulation of VARIVAX.

Effect of perinatal antiretroviral drug exposure on hematologic values in HIV-uninfected children: An analysis of the women and infants transmission study.

BACKGROUND: With the increasing use of antiretroviral (ARV) drugs to prevent mother-to-child transmission of human immunodeficiency virus (HIV), large numbers of infants are exposed, with possible consequent toxicity. METHODS: Hematologic values in 1820 uninfected HIV- and ARV-exposed children were compared with those in 351 ARV-unexposed children from the Women and Infants Transmission Study. Hemoglobin concentrations and platelet, neutrophil, lymphocyte, and CD4+ and CD8+ cell counts were analyzed at birth and ages 2, 6, 12, 18, and 24 months. Multivariate analysis was conducted age 0-2 and 6-24 months, with adjustment for multiple cofactors. RESULTS: Hemoglobin concentrations and neutrophil, lymphocyte, and CD4+ cell counts were significantly lower at age 0-2 months in infants exposed to ARV drugs than in those who were not. At 6-24 months, differences in hemoglobin concentrations and neutrophil counts were no longer significant, whereas differences in platelet, lymphocyte, and CD4+ cell counts persisted and CD8+ cell counts became significantly lower. In comparison with ARV monotherapy, combination therapy was associated with larger decreases in neutrophil, lymphocyte, and CD8+ cell counts at age 0-2 months but with only differences in CD8+ cell counts at age 6-24 months. Clinically significant abnormalities were rare and did not differ by exposure to ARV drugs. CONCLUSION: Infants exposed to ARV drugs have small but significant differences in several hematologic parameters for the first 24 months of life. These results indicate the need for long-term follow-up of uninfected infants with ARV exposure.

Gender differences in lymphocyte populations, plasma HIV RNA levels, and disease progression in a cohort of children born to women infected with HIV.

OBJECTIVE: We sought to document gender differences in lymphocyte subsets and plasma RNA levels in a pediatric cohort with presumed minimal hormonal differences (on the basis of age). METHODS: Blood samples from antiretroviral therapy-treated, HIV-infected children (n = 158) and HIV-uninfected children (n = 1801) who were enrolled in the Women and Infants Transmission Study were analyzed at specified study intervals with consensus protocols, and various parameters were compared. RESULTS: Antiretroviral therapy-treated, HIV-infected female children had, on average, 0.38 log10 copies per mL lower plasma RNA levels than did their male counterparts, but lymphocyte differences were not noted in this cohort. Despite their higher plasma RNA level, a greater proportion of male children survived through 8 years of age. There were no gender differences with respect to the age of diagnosis of HIV, time to antiretroviral therapy after diagnosis of HIV, or type of antiretroviral therapy. Lymphocyte differences were noted for uninfected children. CONCLUSIONS: Plasma RNA levels differed among antiretroviral therapy-treated, HIV-infected children according to gender, in a manner similar to that noted in previous pediatric and adult studies. Lymphocyte subsets varied according to gender in a cohort of HIV-exposed but uninfected children. Most importantly, overall mortality rates for this cohort differed according to gender.

Predictors of immunologic long-term nonprogression in HIV-infected children: implications for initiating therapy.

BACKGROUND: Early markers that predict immunologic long-term nonprogression in infants with perinatally acquired HIV infection might assist in subsequent antiretroviral treatment decisions. OBJECTIVES: We sought to identify early markers of immunologic long-term HIV disease nonprogression. METHODS: We analyzed immunologic and virologic characteristics at 1 and 2 months of age in HIV-infected children who were enrolled in the Women and Infants Transmission Study and born before 1995, comparing immunologic long-term nonprogressors (ILTNPs; n = 10) with non-ILTNPs (n = 127). ILTNPs were children who survived to 8 years or older with CD4 percentages of 25% or greater and counts of 500 cells/mm 3 or more without receiving highly active antiretroviral therapy. Non-ILTNPs were defined as all other HIV-infected children. Receiver operating characteristic curve analysis was used to assess combined sensitivity and specificity for each of these characteristics and to determine potential threshold values to discriminate between ILTNPs and non-ILTNPs. RESULTS: Characteristics in the first 2 months of life associated with ILTNP status in univariate analysis included higher CD4 percentages, lower CD8 + percentages, lower CD8 + HLA-DR + percentages, and lower HIV-1 RNA PCR values. In receiver operating characteristic analysis CD8 + HLA-DR + percentage had the best combined sensitivity and specificity for discriminating between ILTNPs and non-ILTNPs. CD8 + HLA-DR + percentages of 5% or less predicted ILTNP status with 80% sensitivity and 80% specificity. In multivariate analysis CD8 + HLA-DR+ percentage of 5% or less remained a significant predictor of ILTNP status after adjusting for CD3 + CD4 + percentage and HIV-1 RNA PCR value (odds ratio, 15.4; 95% CI, 1.9-124.7). CONCLUSION: CD8 + HLA-DR + T-lymphocyte percentage of less than 5% at 1 to 2 months of age might be predictive for ILTNP status but should not be used at this time to make treatment-deferral decisions. Immune activation in HIV-infected infants might herald more disease progression. Further study of the use of this subpopulation in early infancy to predict ILTNP status is warranted.