Studies on a Potential Vaccine for the Treatment of HIV Infection and Sensitive Immunoassays to Simultaneously Detect Multiple Infections and Monitor Post-vaccination Safety

Principal Investigator: Subhash Dhawan, PhD
Office / Division / Lab: OBRR / DETTD / LMV

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Overview

Public Health Issue: Infection with HIV, the causative agent of AIDS, is responsible for a large number of deaths every year worldwide and represents a significant threat to human health. Little progress has been made towards the development of a safe and effective vaccine to control progression of HIV disease and methods for monitoring post-vaccination safety.

Regulatory Contribution: Evaluations of design and manufacturing of vaccines, including chemistry and adequate biochemical characterization of antigens are critical regulatory requirements to ensure their consistent manufacturing process, safety, and effectiveness. Knowledge of how post-exposure vaccination selects and influences levels of HIV nucleic acids used in drug resistance monitoring tests, will be essential in evaluating the performance of monitoring tests for HIV.

Research Approach: The goals of this research program are to understand (a) the mechanisms underlying HIV pathogenesis, to identify functional domains of key regulatory proteins such as HIV-Tat, and evaluate their use as a potential candidate for a therapeutic (post-exposure) AIDS vaccine and (b) develop a one-step immunoassay to simultaneously detect antibodies against several pathogens. Our studies may provide a new approach in developing potentially effective and safe subunit vaccines, especially when a conventional vaccine may fail to induce an effective immune response due to problems associated with immunodominance, viral diversity, and mutation instability and help developing a simple assay for the detection of multiple infections in one sample.

Mission Relevance and Outcomes: Characterization and validation studies on synthetic vaccines may provide improved assay development for vaccine regulation, economical in vitro testing procedures, and possible replacement of conventional recombinant immunogens or attenuated pathogens as vaccine candidates. These studies, therefore, will have great impact in policy making for synthetic vaccines, providing knowledge for evaluating and supporting the development of safe vaccines, and development of highly sensitive in vitro diagnostic tests.

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Publications

Peptides 2007 Mar;28(3):496-504
Antibodies against a multiple-peptide conjugate comprising chemically modified human immunodeficiency virus type-1 functional Tat peptides inhibit infection.
Devadas K, Boykins RA, Hewlett IK, Wood OL, Clouse KA, Yamada KM, Dhawan S

Expert Rev Mol Diagn 2006 Sep;6(5):749-760
Signal amplification systems in immunoassays: implications for clinical diagnostics.
Dhawan S

Peptides 2006 Apr;27(4):611-21
Selective side-chain modification of cysteine and arginine residues blocks pathogenic activity of HIV-1-Tat functional peptides.
Devadas K, Boykins RA, Hardegen NJ, Philp D, Kleinman HK, Osa EO, Wang J, Clouse KA, Wahl LM, Hewlett IK, Rappaport J, Yamada KM, Dhawan S

J Immunol 2006 Apr 1;176(7):4252-7
Hemin Activation Ameliorates HIV-1 Infection via Heme Oxygenase-1 Induction.
Devadas K, Dhawan S

J Immunol 2004 Dec 1;173(11):6735-44
Mechanisms for Macrophage-Mediated HIV-1 Induction.
Devadas K, Hardegen NJ, Wahl LM, Hewlett IK, Clouse KA, Yamada KM, Dhawan S