Showing papers by "William Borkowsky published in 2018"

HIV-Exposed Infants Vaccinated with an MF59/Recombinant gp120 Vaccine Have Higher-Magnitude Anti-V1V2 IgG Responses than Adults Immunized with the Same Vaccine.

Abstract: In the RV144 vaccine trial, IgG responses against the HIV envelope variable loops 1 and 2 (V1V2) were associated with decreased HIV acquisition risk. We previously reported that infants immunized with an MF59-adjuvanted rgp120 vaccine developed higher-magnitude anti-V1V2 IgG responses than adult RV144 vaccinees. To determine whether the robust antibody response in infants is due to differences in vaccine regimens or to inherent differences between the adult and infant immune systems, we compared Env-specific IgG responses in adults and infants immunized with the same MF59- and alum-adjuvanted HIV envelope vaccines. At peak immunogenicity, the magnitudes of the gp120- and V1V2-specific IgG responses were comparable between adults and infants immunized with the alum/MNrgp120 vaccine (gp120 median fluorescence intensities [FIs] in infants = 7,118 and in adults = 11,510, P = 0.070; V1V2 median MFIs of 512 [infants] and 804 [adults], P = 0.50), whereas infants immunized with the MF59/SF-2 rgp120 vaccine had higher-magnitude antibody levels than adults (gp120 median FIs of 15,509 [infants] and 2,290 [adults], P < 0.001; V1V2 median FIs of 23,926 [infants] and 1,538 [adults]; P < 0.001). Six months after peak immunogenicity, infants maintained higher levels Env-specific IgG than adults. Anti-V1V2 IgG3 antibodies that were associated with decreased HIV-1 risk in RV144 vaccinees were present in 43% of MF59/rgp120-vaccinated infants but only in 12% of the vaccinated adults (P = 0.0018). Finally, in contrast to the rare vaccine-elicited Env-specific IgA in infants, rgp120 vaccine-elicited Env-specific IgA was frequently detected in adults. Our results suggest that vaccine adjuvants differently modulate gp120-specific antibody responses in adults and infants and that infants can robustly respond to HIV Env immunization.IMPORTANCE More than 150,000 pediatric HIV infections occur yearly, despite the availability of antiretroviral prophylaxis. A pediatric HIV vaccine could reduce the number of these ongoing infant infections and also prime for long-term immunity prior to sexual debut. We previously reported that immunization of infants with an MF59-adjuvanted recombinant gp120 vaccine induced higher-magnitude, potentially protective anti-V1V2 IgG responses than in adult vaccinees receiving the moderately effective RV144 vaccine. In the present study, we demonstrate that the robust response observed in infants is not due to differences in vaccine regimen or vaccine dose between adults and infants. Our results suggest that HIV vaccine adjuvants may differentially modulate immune responses in adults and infants, highlighting the need to conduct vaccine trials in pediatric populations.

Low Peripheral T Follicular Helper Cells in Perinatally HIV-Infected Children Correlate With Advancing HIV Disease

Abstract: Background T follicular helper cells (Tfh) are crucial for B cell differentiation and antigen-specific antibody production. Dysregulation of Tfh-mediated B cell help weakens B cell responses in HIV infection. Moreover, Tfh cells in the lymph node and peripheral blood comprise a significant portion of the latent HIV reservoir. There is limited data on the effects of perinatal HIV infection on Tfh cells in children. We examined peripheral Tfh (pTfh) cell frequencies and phenotype in HIV-infected children and their associations with disease progression, immune activation, and B cell differentiation. Methods In a Kenyan cohort of 76 perinatally HIV-infected children, comprised of 43 treatment-naive (ART-) and 33 on antiretroviral therapy (ART+), and 42 healthy controls (HIV-), we identified memory pTfh cells, T cell activation markers, and B cell differentiation states using multi-parameter flow cytometry. Soluble CD163 and I-FABP plasma levels were quantified by ELISA. Results ART- children had reduced levels of pTfh cells compared to HIV- children that increased with antiretroviral therapy. HIV+ children had higher PD-1 expression on pTfh cells, regardless of treatment status. Low memory pTfh cells with elevated PD-1 levels correlated with advancing HIV disease status, indicated by increasing HIV viral loads and T cell and monocyte activation, and decreasing %CD4 and CD4:CD8 ratios. Antiretroviral treatment, particularly when started at younger ages, restored pTfh cell frequency and eliminated correlations with disease progression, but failed to lower PD-1 levels on pTfh cells and their associations with CD4 T cell percentages and activation. Altered B cell subsets, with decreased naive and resting memory B cells and increased activated and tissue-like memory B cells in HIV+ children, correlated with low memory pTfh cell frequencies. Last, HIV+ children had decreased proportions of CXCR5+ CD8 T cell that associated with low %CD4 and CD4:CD8 ratios. Conclusions Low memory pTfh cell frequencies with high PD-1 expression in HIV+ children correlate with worsening disease status and an activated and differentiated B cell profile. This perturbed memory pTfh cell population may contribute to weak vaccine and HIV-specific antibody responses in HIV+ children. Restoring Tfh cell capacity may be important for novel pediatric HIV cure and vaccine strategies.

The Effect of Complete Blood Count Timing on Lumbar Puncture Rates in Asymptomatic Infants Born to Mothers with Chorioamnionitis.

Abstract: Background Maternal chorioamnionitis is a risk factor for sepsis but, often, these infants are asymptomatic at birth. Different markers for infections, such as the immature to total (I/T) white blood cell (WBC) ratio, are used to help determine which infants require lumbar punctures (LPs), in addition to blood cultures and antibiotics. The timing of when the complete blood count (CBC) is obtained may have some effect on the length of antibiotic treatment. Aims The purpose of this proof-of-concept study was to assess if obtaining a CBC at greater than four hours of life as compared to less than four hours of life has an impact on the incidence of LPs performed in asymptomatic, full-term infants undergoing evaluation for sepsis secondary to maternal chorioamnionitis. Methods We performed a retrospective study of full-term, asymptomatic infants admitted for sepsis evaluation secondary to maternal chorioamnionitis. Subjects were grouped based upon the timing of their initial CBC (early = four hours of life). The incidence of LPs, duration of antibiotic treatment, and length of hospitalization were compared between the groups. Results A total of 230 subjects were included in the study (early group = 124, late group = 106). Subjects in the late group underwent significantly fewer LPs than subjects in the early group, 5.7% vs. 22.6% (p<0.001). There was no difference in length of treatment or hospitalization. Conclusions Asymptomatic full-term infants undergoing evaluation for sepsis secondary to maternal chorioamnionitis are less likely to undergo an LP if their initial CBC is obtained at greater than four hours of life.

Prevalence of Asymptomatic Parasitemia and Gametocytemia in HIV-Infected Children on Differing Antiretroviral Therapy.

Abstract: Laboratory data and prior pediatric reports indicate that HIV protease inhibitor (PI)-based antiretroviral therapy (ARV) kills gametocytes and reduces rates of gametocytemia, but not asymptomatic parasitemia, in a high malaria-transmission area. To determine whether ARV regimen impacts these rates in areas with less-intense malaria transmission, we compared asymptomatic parasitemia and gametocytemia rates in HIV-infected children by ARV regimen in Lilongwe, Malawi, an area of low-to-moderate transmission intensity. HIV PI lopinavir-ritonavir (LPV-rtv) ARV- or non-nucleoside reverse transcriptase inhibitor nevirapine ARV-treated children did not differ in the rates of polymerase chain reaction-detected asymptomatic parasitemia (relative risk [RR] 0.43 95% confidence interval [CI] [0.16, 1.18], P value 0.10) or microscopically detected gametocytemia with LPV-rtv ARV during symptomatic malaria (RR 0.48 95% CI [0.22,1.04] P value 0.06). LPV-rtv ARV was not associated with reduced rates of asymptomatic parasitemia, or gametocytemia on days of symptomatic malaria episodes, in HIV-infected children. Larger studies should evaluate whether ARV impacts transmission.

Varicella Zoster Vaccine Experience in HIV-Infected Children and Adolescents

Abstract: Live-attenuated Varicella Zoster Virus (VZV) Vaccine was first developed in Japan and tested for safety in children who were steroid treated. It proved safe and immunogenic. This led to its testing in the United States in a population of children with acute lymphoblastic leukemia who were in remission. This study too showed that the vaccine was safe and immunogenic in this population. After the vaccine was approved for healthy children, it was tested in a population of HIV-infected children and adolescents with minimal to moderate immunosuppression (i.e., CD4 percentage of >25 and a count of >350). It also proved safe and relatively immunogenic in this population. Finally, it has been evaluated in a more immunocompromised population of HIV-infected children and adolescents (i.e., CD4 percentage >15 and a count >200). VZV vaccine also proved safe and relatively immunogenic in this population. It is suggested that two immunizations, 12 weeks apart, be the vaccination strategy for these HIV populations.