ABSTRACTHuman cytomegalovirus (HCMV) is an important, ubiquitous pathogen that causes severe clinical disease in immunocompromised individuals, such as organ transplant recipients and infants infectedin utero. The envelope glycoprotein B (gB) of HCMV is a major antigen for the induction of virus-neutralizing antibodies. We have begun to define target structures within gB that are recognized by virus-neutralizing antibodies. Antigenic domain 5 (AD-5) of gB has been identified as an important target for neutralizing antibodies in studies using human monoclonal antibodies (MAbs). Anti-AD-5 MAbs share a target site on gB, despite originating from different, healthy, HCMV-infected donors. Mutational analysis of AD-5 identified tyrosine 280 in combination with other surface-exposed residues (the YNND epitope) as critical for antibody binding. The YNND epitope is strictly conserved among different HCMV strains. Recombinant viruses carrying YNND mutations in AD-5 were resistant to virus-neutralizing MAbs. Competition enzyme-linked immunosorbent assays (ELISAs) with human HCMV-convalescent-phase sera from unselected donors confirmed the conserved antibody response for the YNND epitope in HCMV-infected individuals and, because a significant fraction of the gB AD-5 response was directed against the YNND epitope, further argued that this epitope is a major target of anti-AD-5 antibody responses. In addition, affinity-purified polyclonal anti-AD-5 antibodies prepared from individual sera showed reactivity to AD-5 and neutralization activity toward gB mutant viruses that were similar to those of AD-5-specific MAbs. Taken together, our data indicate that the YNND epitope represents an important target for anti-gB antibody responses as well as for anti-AD-5 virus-neutralizing antibodies.IMPORTANCEHCMV is a major global health concern, and a vaccine to prevent HCMV disease is a widely recognized medical need. Glycoprotein B of HCMV is an important target for neutralizing antibodies and hence an interesting molecule for intervention strategies, e.g., vaccination. Mapping the target structures of neutralizing antibodies induced by naturally occurring HCMV infection can aid in defining the properties required for a protective capacity of vaccine antigens. The data presented here extend our knowledge of neutralizing epitopes within gB to include AD-5. Collectively, our data will contribute to optimal vaccine design and development of antibody-based therapies.

01 Apr 2013·VaccineQ3 · MEDICINE

Does participation in an HIV vaccine efficacy trial affect risk behaviour in South Africa?

Q3 · MEDICINE

Article

Author: Koleka Patience. Mlisana ; Maphoshane. Nchabeleng ; Zoe. Moodie ; Gavin J. Churchyard ; Glenda E. Gray ; James. Kublin ; Barbara. Metch ; Linda-Gail. Bekker ; Mary. Allen

BACKGROUNDIncreased sexual risk behaviour in participants enrolled in HIV prevention trials has been a concern. The HVTN 503/Phambili study, a phase 2B study of the Merck Ad-5 multiclade HIV vaccine in South Africa, suspended enrollment and vaccinations following the results of the Step study. Participants were notified of their treatment allocation and continue to be followed. We investigated changes in risk behaviour over time and assessed the impact of study unblinding.METHODS801 participants were enrolled. Risk behaviours were assessed with an interviewer-administered questionnaire at 6-month intervals. We assessed change from enrolment to the first 6-month assessment pre-unblinding and between enrolment and at least 6 months post-unblinding on all participants with comparable data. A one-time unblinding risk perception questionnaire was administered post-unblinding.RESULTSA decrease in participants reporting unprotected sex was observed in both measured time periods for men and women, with no differences by treatment arm. At 6 months (pre-unblinding), 29.6% of men and 35.8% of women reported changing from unprotected to protected sex (p<0.0001 for each). Men (22%) were more likely than women (14%) to report behaviour change after unblinding (p=0.009). Post-enrolment, 142 (45%) of 313 previously uncircumcised men underwent medical circumcision. 663 participants completed the unblinding questionnaire. More vaccine (24.6%) as compared to placebo recipients (12.0%) agreed that they were more likely to get HIV than most people (p<0.0001), and attributed this to receiving the vaccine.CONCLUSIONWe did not find evidence of risk compensation during this clinical trial. Some risk behaviour reductions including male circumcision were noted irrespective of treatment allocation.

01 Oct 2011·Cancer Gene TherapyQ2 · MEDICINE

Mining the adenovirus virome for oncolytics against multiple solid tumor types

Q2 · MEDICINE

Article

Author: Michael A. Barry ; Reeti Khare ; Christopher Y. Chen ; Shannon M. May ; Eric A. Weaver

Although there are 55 serotypes of adenovirus (Ad) that infect humans, Ad serotype 5 (Ad5) is the most widely studied because of the availability of commercial kits for its genetic manipulation. In fact, engineered Ad 5 is currently being used in all of the 87 global clinical trials utilizing Ad for the treatment of cancer. Unfortunately, Ad5 is one of the most seroprevalent serotypes, meaning that this virus has to confront additional immunological barriers to be effective in Ad5-immune patients. In this work, we compare Ad5 to 13 other adenoviral serotypes from species B, C, D and E for oncolytic potential in both immunodeficient mouse and immunocompetent hamster models. Our results indicate that species D Ads are not effective oncolytics against most solid tumors. Conversely, lower seroprevalent Ad6 and Ad11 had anti-cancer activity comparable to Ad5. This work strongly supports the consideration of Ad6-based oncolytic therapies for the treatment of breast, ovarian, kidney and liver tumors.

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