CBER Expertise
Evaluating Viral Antigens and Efficacy in Vaccines for HIV/AIDS and Smallpox
Principal Investigator: Carol D. Weiss, MD
Office / Division / Lab: OVRR / DVP / LI
Overview
Public Health Issue: Developing a safe and effective vaccine for HIV/AIDS one of the greatest public health problems of our time. Developing a safer smallpox vaccine is also a high national priority because of the threat of bioterrorism and severe adverse events associated with Dryvax, the current smallpox vaccine composed of live vaccinia virus.
Regulatory Contribution: Proteins on the surface (envelope proteins) of HIV and poxviruses can induce antibodies that protect against infection. For HIV, the envelope protein (gp120/41) has evolved ways to evade induction of protective antibodies. Naturally occuring gp120/41 does not efficiently induce broadly neutralizing antibodies that will protect against many HIV strains, so studies of the immunogenicity and antigenicity of conserved structures of gp120/41 are needed to develop potent and broadly-active HIV vaccines. For smallpox, several envelope proteins appear to induce protective antibodies, but it remains unclear which proteins are necessary or sufficient for complete protection. New vaccines will have to be evaluated for non-inferiority to Dryvax using available in vitro assays and animal models because it will not be possible to do efficacy trials that involve protection from smallpox. These non-inferiority studies will require assessments of vaccine-induced antibody responses. Our studies on antibody specificities that are important for protection should provide valuable information for evaluating new smallpox vaccines.
Research Approach: This research program is undertaking biochemical, immunological, and genetic approaches to investigate conserved neutralizing determinants in envelope proteins of HIV and vaccinia virus. For HIV studies, the program focuses on elucidating the conformation and structural determinants of the envelope protein that allow broadly neutralizing antibodies and broadly-active entry inhibitors to bind and how antibodies to these conserved regions can be induced by vaccines. For vaccinia studies, the research program focusses on dissecting protective antibodies elicited by Dryvax and developing new antigens that can aid evaluation and development of new smallpox vaccines.
Mission Relevance and Outcomes: The novel information obtained from our research will serve as a basis for developing and evaluating vaccines for HIV/AIDS and new vaccines for smallpox. The HIV program has influenced the field in new approaches for designing HIV vaccines. The smallpox program has dissected contributions of one key protein to protective immune responses induced by Dryvax.
Publications
J Infect Dis 2007 Oct 1;196(7):1026-32
Antibodies to the A27 Protein of Vaccinia Virus Neutralize and Protect against Infection but Represent a Minor Component of Dryvax Vaccine-Induced Immunity.
He Y, Manischewitz J, Meseda CA, Merchlinsky M, Vassell RA, Sirota L, Berkower I, Golding H, Weiss CD
Virology 2005 Dec 5;343(1):128-40
Identification and preliminary characterization of vaccinia virus (Dryvax) antigens recognized by vaccinia immune globulin.
Jones-Trower A, Garcia A, Meseda CA, He Y, Weiss C, Kumar A, Weir JP, Merchlinsky M
J Virol 2005 Apr;79(8):4774-81
Human Immunodeficiency Virus (HIV) gp41 Escape Mutants: Cross-Resistance to Peptide Inhibitors of HIV Fusion and Altered Receptor Activation of gp120.
Desmezieres E, Gupta N, Vassell R, He Y, Peden K, Sirota L, Yang Z, Wingfield P, Weiss CD
J Virol 2004 Mar 1;78(5):2627-2631
Binding of the 2F5 Monoclonal Antibody to Native and Fusion-Intermediate Forms of Human Immunodeficiency Virus Type 1 gp41: Implications for Fusion-Inducing Conformational Changes.
De Rosny E, Vassell R, Jiang S, Kunert R, Weiss CD
Blood 2004 Mar 1;103(5):1586-94
Thiol/disulfide exchange is a prerequisite for CXCR4-tropic HIV-1 envelope-mediated T-cell fusion during viral entry.
Markovic I, Stantchev TS, Fields KH, Tiffany LJ, Tomic M, Weiss CD, Broder CC, Strebel K, Clouse KA