From the Network's inception, it was recognized that a centralized laboratory program was needed to define and compare immunogenicity end points in vaccine trials. A major achievement of the HVTN has been to not only establish this program, but to endow it with standardized processes and comprehensive quality assurance measures that ensure data integrity for complex immunogenicity assays, which are increasingly a major trial end point. To achieve this success, a significant effort is invested in assay development and, specifically, standardizing and validating assays. Typically, a large number of assays are performed for each trial, including numerous `validated' assays for which stringent pass/fail criteria are defined. Current fully validated assays typically performed include those for viral neutralizing antibodies, T-cell intracellular cytokine staining (ICS), IFN-γ ELISpot, and antibody binding via ELISA and bead arrays [1
]. In addition, a number of `qualified' assays, for which optimization studies have been completed, are performed and often include cytokine multiplex bead arrays, B-cell ELISpot, viral sequencing and viral inhibition assays. Finally, a large number of exploratory assays are conducted for example; mucosal tissue immunohistochemistry, gene expression from specimens or sorted cells, antibody avidity and various cellular functional assays. The Laboratory Program also focuses on understanding the impact of prior immunity to vaccine vectors on the immune responses induced to the HIV gene inserts and have recently found that both antibodies and cellular responses to the vector can lower the immunogenicity to HIV-1 epitopes [6
Standardization of assays provides the HVTN a unique opportunity to compare data across protocols, making it a neutral environment for testing products from diverse sources. It also permits the emergence of novel findings by combining data from multiple trials. In addition, because the assays and reagents are openly shared outside the network, they frequently become standards for the field. Examples of this include standard peptide sets for T-cell analyses and a panel of virus isolates used to rank antibody neutralization activity [1
Robust immunogenicity data requires not only well functioning assays, but also high quality specimens. Many key assays, such as ICS, rely on viability of cells upon thawing, for example peripheral blood mononuclear cells. Therefore, the HVTN laboratory program has developed a comprehensive training program and system for monitoring specimen handling at the clinical trial sites, with particular emphasis on peripheral blood mono nuclear cell processing [8
To further ensure data integrity, SCHARP programmers and laboratory staff have worked together to create an integrated and robust data management system. The scope of the clinical research program conducted by the HVTN presents a number of specific challenges to the systems used for acquisition quality control, annotation, integration and analysis of data. The Phase I/II trials program places high priority on rapid access to curated vaccine safety data, in order to ensure that adverse events are identified and interpreted in an efficient and accurate manner. Another high priority for the Phase I/II trials program is the acquisition, annotation and analysis of complex and richly annotated immunological data. Due to the fact that the HVTN research program also encompasses Phase IIb and III efficacy trials, the data systems must meet the standards of validation and documentation required by multiple regulatory agencies that would ultimately guide policy for use of an efficacious vaccine. Finally, because the HVTN research program is global in its character, engaging those communities most impacted by the HIV pandemic, there is diversity amongst HVTN clinical sites in the physical and technical infrastructure and the human resources that can support data systems used for HVTN studies.
To meet these varied challenges in laboratory-based data management, the HVTN has developed a web-portal, with customized data pipelines built from the central data management center into the HVTN laboratories and integrated with assay instrumentation. A major advance in this effort has been that specimen information is made accessible via online tools that allow incoming safety and immunogenicity data to be monitored daily from any computer. This allows laboratory staff to respond immediately to any deviations in specimen or assay data at specific sites and allows clinical development staff to assess safety data in a continuous manner. Ultimately, this system, which is nearing completion, will also provide public access to published data for completed HVTN trials, as well as access for HVTN investigators to unpublished data, for the purposes of monitoring trial progress and data mining for the generation of novel scientific insights and hypotheses.
Since the majority of products tested by the HVTN to date have not generated adverse safety concerns, immunogenicity data typically serves as the driving force for critical decisions on advancing products through clinical phases [9
]. Thus, the processes that maximize generation and management of high quality immunogenicity data provide the HVTN with the best possible means with which to address key scientific questions and drive vaccine development. In addition, these measures provide a wealth of valuable resources to the field through assay methodology, reagent sharing and the provision of high quality specimens to collaborators conducting ancillary studies.