CBER Expertise
Improving vaccine potency through particle formation or by using live attenuated vectors to generate vaccines for HIV and select agents
Principal Investigator: Ira Berkower, MD, PhD
Office / Division / Lab: OVRR / DVP / LI
Overview
Public Health Issue: For HIV vaccines CBER is faced with challenging questions, such as: what should an effective HIV vaccine look like? Which viral proteins should it contain and in what form? Which type of host immune response predicts successful protection against a viral challenge, and how strong must the response be? How can we make HIV vaccines that are feasible for delivery in the developing world, where they are needed most?
Regulatory Contribution: In response to the AIDS epidemic, we have evaluated a number of candidate HIV vaccines. Each one must be assessed in terms of vaccine composition and the strength and type of immune response elicited. Currently, the lack of sufficient scientific knowledge in this area means that the search for an effective and safe vaccine has been a long process based on trial and error. By applying rational vaccine design, this laboratory facilitates more efficient development and evaluation of new HIV vaccines.
Research Approach: This lab made the original observation that HIV infected humans make neutralizing antibodies against a broad spectrum of HIV isolates. This was confirmed by monoclonal antibodies, including some of that neutralize virtually all North American isolates. We have focused on vaccine antigens that can elicit neutralizing antibodies of comparable titer and specificity to those elicited by the virus itself. We have developed a new method for incorporating HIV gp120 or gp41 into virus-like particles. Similar particles are the basis for a number of successful vaccines, such as hepatitis B vaccine. This is the first recombinant system that allows presentation of native viral antigens in their natural milieu on a lipid envelope. This combination is believed to be the target of the most broadly neutralizing antibodies yet found. Based on the crystal structure of two forms of gp120, we have identified structures that may help keep gp120 in a closed form, so it can evade immunity. We have mutated these structures to produce forms which are more accessible to neutralizing antibodies, as shown by increased binding of neutralizing monoclonal antibodies. Further studies will assess whether these modified antigens can elicit broadly reactive antibodies to determinants that are shared among nearly all HIV strains in circulation. The same method of particle formation works for envelope glycoproteins from Venezuela Equine Encephalitis virus and for the protective antigen of anthrax toxin. The particles are being evaluated as vaccines against select agents.
Mission Relevance and Outcomes: These studies will provide new scientific information and tools for developing and evaluating vaccines for HIV/AIDS, e.g., by demonstrating the need for envelope proteins in their native conformation and whether incorporation into virus-like particles can enhance vaccine potency. Further work will identify the correlates of immunity that can be applied to the evaluation of a broad range of HIV vaccines.
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 2004 Mar 30;321(1):75-86
Assembly, structure, and antigenic properties of virus-like particles rich in HIV-1 envelope gp120.
Berkower I, Raymond M, Muller J, Spadaccini A, Aberdeen A