Showing papers by "William A. Blattner published in 2011"

Phase 1 Safety and Immunogenicity Testing of DNA and Recombinant Modified Vaccinia Ankara Vaccines Expressing HIV-1 Virus-like Particles

Abstract: Background. Recombinant DNA and modified vaccinia virus Ankara (rMVA) vaccines represent a promising approach to an HIV/AIDS vaccine. This Phase 1 clinical trial compared the safety and immunogenicity of a rMVA vaccine administered with and without DNA vaccine priming Methods. GeoVax pGA2/JS7 DNA (D) and MVA/HIV62 (M) vaccines encode noninfectious virus-like particles. Intramuscular needle injections were used to deliver placebo, 2 doses of DNA followed by 2 doses of rMVA (DDMM), one dose of DNA followed by 2 doses of rMVA (DMM), or 3 doses of rMVA (MMM) to HIV-seronegative participants. Results. Local and systemic symptoms were mild or moderate. Immune response rates for CD4 + and CD8 + T cells were highest in the DDMM group and lowest in the MMM group (77% vs 43% CD4 + and 42% vs 17% CD8 +). In contrast, response rates for Env binding and neutralizing Ab were highest in the MMM group. The DMM group had intermediate response rates. A 1/10th-dose DDMM regimen induced similar T cell but reduced Ab response rates compared with the full-dose DDMM. Conclusions. MVA62 was well tolerated and elicited different patterns of T cell and Ab responses when administered alone or in combination with the JS7 DNA vaccine.

A Phase IIA Randomized Clinical Trial of a Multiclade HIV-1 DNA Prime Followed by a Multiclade rAd5 HIV-1 Vaccine Boost in Healthy Adults (HVTN204)

Abstract: Background: The safety and immunogenicity of a vaccine regimen consisting of a 6-plasmid HIV-1 DNA prime (envA, envB, envC, gagB, polB, nefB) boosted by a recombinant adenovirus serotype-5 (rAd5) HIV-1 with matching inserts was evaluated in HIV-seronegative participants from South Africa, United States, Latin America and the Caribbean. Methods: 480 participants were evenly randomized to receive either: DNA (4 mg IM by Biojector) at 0, 1 and 2 months, followed by rAd5 (10 10 PU IM by needle/syringe) at 6 months; or placebo. Participants were monitored for reactogenicity and adverse events throughout the 12-month study. Peak and duration of HIV-specific humoral and cellular immune responses were evaluated after the prime and boost. Results: The vaccine was well tolerated and safe. T-cell responses, detected by interferon-c (IFN-c) ELISpot to global potential T-cell epitopes (PTEs) were observed in 70.8% (136/192) of vaccine recipients overall, most frequently to Gag (54.7%) and to Env (54.2%). In U.S. vaccine recipients T-cell responses were less frequent in Ad5 sero-positive versus seronegative vaccine recipients (62.5% versus 85.7% respectively, p=0.035). The frequency of HIV-specific CD4+ and CD8+ T-cell responses detected by intracellular cytokine staining were similar (41.8% and 47.2% respectively) and most secreted $2 cytokines. The vaccine induced a high frequency (83.7%–94.6%) of binding antibody responses to consensus Group M, and Clades A, B and C gp140 Env oligomers. Antibody responses to Gag were elicited in 46% of vaccine recipients. Conclusion: The vaccine regimen was well-tolerated and induced polyfunctional CD4+ and CD8+ T-cells and multi-clade anti-Env binding antibodies. Trial Registration: ClinicalTrials.gov NCT00125970

Recurrent Signature Patterns in HIV-1 B Clade Envelope Glycoproteins Associated with either Early or Chronic Infections

Abstract: Here we have identified HIV-1 B clade Envelope (Env) amino acid signatures from early in infection that may be favored at transmission, as well as patterns of recurrent mutation in chronic infection that may reflect common pathways of immune evasion. To accomplish this, we compared thousands of sequences derived by single genome amplification from several hundred individuals that were sampled either early in infection or were chronically infected. Samples were divided at the outset into hypothesis-forming and validation sets, and we used phylogenetically corrected statistical strategies to identify signatures, systematically scanning all of Env. Signatures included single amino acids, glycosylation motifs, and multi-site patterns based on functional or structural groupings of amino acids. We identified signatures near the CCR5 co-receptor-binding region, near the CD4 binding site, and in the signal peptide and cytoplasmic domain, which may influence Env expression and processing. Two signatures patterns associated with transmission were particularly interesting. The first was the most statistically robust signature, located in position 12 in the signal peptide. The second was the loss of an N-linked glycosylation site at positions 413–415; the presence of this site has been recently found to be associated with escape from potent and broad neutralizing antibodies, consistent with enabling a common pathway for immune escape during chronic infection. Its recurrent loss in early infection suggests it may impact fitness at the time of transmission or during early viral expansion. The signature patterns we identified implicate Env expression levels in selection at viral transmission or in early expansion, and suggest that immune evasion patterns that recur in many individuals during chronic infection when antibodies are present can be selected against when the infection is being established prior to the adaptive immune response.

Timing of Plasmid Cytokine (IL-2/Ig) Administration Affects HIV-1 Vaccine Immunogenicity in HIV-Seronegative Subjects

Abstract: The development of a safe and effective vaccine against human immunodeficiency virus type 1 (HIV-1) is a major goal of biomedical research and public health efforts [1–5]. The precise immune responses that might provide protection against HIV infection remain undefined, and multiple approaches to vaccination against HIV-1 have therefore been studied [6–8]. Evidence suggests that virus-specific cytotoxic T lymphocyte CD8+ responses are particularly important for control of HIV-1 replication in humans [9, 10] and simian immunodeficiency virus (SIV) infection in nonhuman primates [11–13]. In addition, virus-specific CD4+ T cell responses have also been associated with control of HIV-1 viremia [14]. One approach to developing a vaccine against HIV-1 has been to use plasmid DNA that encodes HIV antigens and stimulates T-cell and antibody responses in mice and nonhuman primates and humans [3, 15–19]. This approach has been safe and partially efficacious, and coadministration of plasmid-encoded immunomodulator molecules has been used to improve DNA vaccine–elicited HIV-specific cellular immune responses in mice [20]. Interleukin (IL) 2 has been evaluated as a potential adjuvant to augment immune responses in HIV infection and as a potential antitumor agent. Given its short half-life, large systemic doses of IL-2 have been used in clinical studies [21–23]. However, the in vitro half-life of IL-2 can be prolonged by fusion of IL-2 with the Fc protein of immunoglobulin G (IgG) 2 and still retain IL-2 activity. The IL-2–immunoglobulin (IL-2/Ig) fusion protein has been shown to be significantly more effective than IL-2 alone in augmenting immune responses to HIV-1 gp120 plasmid DNA in mice [24]. Augmented immune responses have also been observed with use of a plasmid DNA coding IL-2/Ig. However, these data suggested that the timing of cytokine administration may be an important variable, because the highest immune responses were seen when plasmid IL-2/Ig was administered 2 days after the HIV-1 gp120 plasmid DNA vaccine, rather than concurrently with the vaccine. A subsequent study in rhesus monkeys showed that administration of plasmid IL-2/Ig was more effective than administration of IL-2/Ig protein in augmentation of immune responses to SIV DNA vaccine [25]. Vaccination of rhesus monkeys with DNA vaccines expressing SIVmac239 gag and SHIV-89.6P env, along with either plasmid IL-2/Ig (given 48 hours after DNA vaccination) or IL-2/Ig protein, and subsequently challenge with SHIV-89.6P, resulted in a low to undetectable viral load set point and lack of clinical disease [13]. These findings provided the rationale and guidance for the experimental design of the clinical trial that we conducted. The clinical study was designed as a randomized, double-blind, placebo-controlled dose escalation phase I trial to determine the safety, tolerability, and immunogenicity of an HIV-1 DNA vaccine [3] administered with plasmid IL-2/Ig to HIV-1–uninfected healthy adults. The regimen of the maximum tolerated dose of plasmid IL-2/Ig administered simultaneously with the plasmid HIV-1 vaccine, was then compared with the regimen of IL-2/Ig administered 48 hours after the HIV-1 DNA vaccine.

Significantly longer envelope V2 loops are characteristic of heterosexually transmitted subtype B HIV-1 in Trinidad.

Abstract: Background In Trinidad and the wider Caribbean, subtype B Human Immunodeficiency Virus-type 1 (HIV-1B) overwhelmingly accounts for HIV infection among heterosexuals; this contrasts with the association of HIV-1B with homosexual transmission and injecting drug use globally. The HIV envelope contains genetic determinants of cell tropism and evasion from immune attack. In this study we investigate the genetic properties of the env V1-C4 of HIV-1B soon after transmission to Trinidadian heterosexuals. This will reveal distinctive genetic features of the strains that cause the HIV-1B epidemic in Trinidad and generate insights to better understand their properties. Methodology/Principal Findings Quasispecies sampling was performed on the env V1-C4 of HIV-1B strains soon after transmission to heterosexual Trinidadians in a cohort of seroconverters. Phylogenetic relationships were determined for these quasispecies and the length and number of asparagine (N) linked glycosylation sites (NLGS) in their variable loops compared to that for HIV-1B globally. Signature amino acids within the constant domains of the env V1-C4 were identified for heterosexually transmitted HIV-1B from Trinidad relative to HIV-1B globally. HIV-1B obtained from Trinidadian heterosexuals soon after seroconversion had significantly longer V2 loops with one more glycosylation site, shorter V3 loops and no significant difference in V1 or V4 when compared to HIV-1B obtained soon after seroconversion from infected individuals in the rest of the world. HIV-1B soon after seroconversion and during chronic infection of Trinidadians was not significantly different, suggesting that distinctly long V2 loops are characteristic of HIV-1B in Trinidad. A threonine deletion at position 319 (T319-) along with the substitutions R315K and S440R were found to be distinctly associated with HIV-1B from Trinidad compared to HIV-1B globally. Conclusions This finding of distinctive genetic features that are characteristic of HIV-1B strains from Trinidad is consistent with the Trinidad epidemic being established by a founder strain or closely related founder strains of HIV-1B.

201 Adherence to Highly Active Antiretroviral Therapy Among HIV Infected Children in Kano, Nigeria

Abstract: Background: HIV has emerged as one of the leading causes of childhood mortality and morbidity in sub Saharan Africa. Antiretroviral therapy (ART) in children in Africa has resulted in dramatically improved survival. However, excellent adherence is one of the most important factors in determining treatment success and preventing viral resistance. While studies of African adults showed that good adherence to ART is possible despite poor social circumstances, there are limited data on ART adherence among African children, and hence the need for the current study. This study determined factors associated with adherence to highly active antiretroviral therapy (HAART) among HIV-infected children in Kano, Nigeria. Method: A cross-sectional study was conducted at the Special Treatment Clinic (STC) of Aminu Kano Teaching Hospital, Kano, Nigeria. The study population comprised HIV- infected children taking ARV medications, which accessed care at the Clinic between June and August 2010, and met the eligibility criteria. A list of all children who were on HAART and had a clinic appointment within the study period was generated. From this list, participants were randomly selected using a computer-based random number generator. Caregivers were interviewed at the clinic using a structured questionnaire Results: A total of 122 children (64% males) out of 130 contacted, whose caregivers provided consent, were recruited into the study. The median age of the study children was 5.5 years (IQR: 1.3 to 14 years). A total of 80 children (65.6%) were adherent to the prescribed antiretroviral drugs for the 7 days preceding the interview. Non-adherence was found to be significantly associated with caregiver's report of missing at least one clinic appointment in the last six months (p-value 0.000) and children on second line HAART regimen (p-value 0.01). However, children whose caregivers were older than 25 years (p-value 0.012) were more likely to be adherent than their respective counterparts. Conclusion: Adherence to HAART in children in Kano, Nigeria was similar to reported adherence levels from other sub-Saharan African countries. Keeping clinic appointments was strong predictor of good adherence to HAART.