Lewis AD, Chen R, Montefiori DC, Johnson PR, Clark KRGeneration of neutralizing activity against human immunodeficiency virus type 1 in serum by antibody gene transfer. J. Virol. 2002;76(17):8769-75
Although several human immunodeficiency virus (HIV) vaccine approaches have elicited meaningful antigen-specific T-cell responses in animal models, no single vaccine candidate has engendered antibodies that broadly neutralize primary isolates of HIV type 1 (HIV-1). Thus, there remains a significant gap in the design of HIV vaccines. To address this issue, we exploited the existence of rare human monoclonal antibodies that have been isolated from HIV-infected individuals. Such antibodies neutralize a wide array of HIV-1 field isolates and have been shown to be effective in vivo. However, practical considerations preclude the use of antibody preparations as a prophylactic passive immunization strategy in large populations. Our concept calls for an antibody gene of choice to be transferred to muscle where the antibody molecule is synthesized and distributed to the circulatory system. In these experiments, we used a recombinant adeno-associated virus (rAAV) vector to deliver the gene for the human antibody IgG1b12 to mouse muscle. Significant levels of HIV-neutralizing activity were found in the sera of mice for over 6 months after a single intramuscular administration of the rAAV vector. This approach allows for predetermination of antibody affinity and specificity prior to 'immunization' and avoids the need for an active humoral immune response against the HIV envelope protein.
Mwau M, McMichael AJ, Hanke T
Design and validation of an enzyme-linked immunospot assay for use in clinical trials of candidate HIV vaccines. AIDS Res. Hum. Retroviruses 2002;18(9):611-8
The enzyme-linked immunosorbent (ELISPOT) assay, which enumerates peripheral blood mononuclear cells (PBMCs) releasing interferon gamma (IFN-gamma) on specific antigen stimulation, is becoming the assay of choice for evaluation of vaccine-induced cell-mediated immune responses in many clinical trials. A properly conducted trial requires the assays to be validated, especially should the trial lead to vaccine licensure. Here, the design and validation of an ELISPOT assay are described for use in clinical trials of candidate human immunodeficiency virus (HIV) vaccines, using a particular immunogen termed HIVA. This assay employs eight pools of 20 to 23 peptides each: seven pools are derived from the immunogen and one pool is derived from cytotoxic T cell epitopes of common human viruses serving as an internal positive control. The validation determined that first, the overall variation of a positive response of approximately 500 spot-forming units (SFU)/10(6) cells was 21%, while second, the average of 5 SFU/10(6) cells was detected for the seven HIVA-derived pools in HIV-uninfected individuals; third, a positive response to a peptide added to the assay pools was not occluded by the other pool peptides; fourth, the frequencies detected in fresh PBMCs were 2- to 3-fold higher compared with the same samples that had been cryopreserved; and finally, all seven HIV-derived pools induced IFN-gamma responses in PBMCs isolated from HIV-infected individuals. The limits of the validation of assays involving biological responses of living cells are discussed.
Topics: HIV Assay Development
Schultz AM, Bradac JAThe HIV vaccine pipeline, from preclinical to phase III. AIDS 2001;15 Suppl 5:S147-58
McMichael A, Hanke TThe quest for an AIDS vaccine: is the CD8+ T-cell approach feasible? Nat. Rev. Immunol. 2002;2(4):283-91
The rationale for developing anti-HIV vaccines that stimulate cytotoxic T-lymphocyte responses is given. We argue that such vaccines will work, provided that attention is paid to the development of memory T-cell responses that are strong and preferably activated. Furthermore, the vaccine should match the prevailing virus clade as closely as possible. Vaccines will have to stimulate a wide range of responses, but it is not clear how this can be achieved.
Wee EG, Patel S, McMichael AJ, Hanke TA DNA/MVA-based candidate human immunodeficiency virus vaccine for Kenya induces multi-specific T cell responses in rhesus macaques. J. Gen. Virol. 2002;83(Pt 1):75-80
The minimum requirement for candidate human immunodeficiency virus (HIV) vaccines to enter clinical evaluation in humans should be their demonstrable immunogenicity in non-human primates: induction of antibodies neutralizing primary HIV isolates or elicitation of broad T cell-mediated immune responses. Here, we showed in rhesus macaques that the very same vaccines that had entered clinical trials in Oxford and Nairobi, plasmid pTHr.HIVA DNA and recombinant modified vaccinia virus Ankara MVA.HIVA in a prime-boost protocol (Hanke & McMichael, Nature Medicine 6, 951-955, 2000), induced cellular immune responses specific for multiple HIV-derived epitopes. This was demonstrated by using the intracellular cytokine staining and ELISPOT assays detecting interferon-gamma and pools of peptides employed in the clinical studies. These results have both boosted our expectations for the performance of these vaccines in humans and increased our confidence about the choice of these assays as the primary readouts in the on-going human trials.
Wheeler C, Berkley SInitial lessons from public-private partnerships in drug and vaccine development. Bull. World Health Organ. 2001;79(8):728-34
In recent years, venture capital approaches have delivered impressive results in identifying and funding promising health discoveries and bringing them to market. This success has inspired public sector experiments with 'social venture capital' approaches to address the dearth of affordable treatment and prevention for diseases of the developing world. Employing the same focus on well-defined and measurable objectives, and the same type of connections to pool and deploy resources as their for-profit counterparts, social venture capitalists seek to use the tools and incentives of capitalism to solve one of its biggest failures: the lack of drugs and vaccines for diseases endemic to low-income populations. As part of a larger trend of partnerships emerging in health product donation and distribution, public-private partnerships for pharmaceutical development have led research and development (R&D) efforts to generate more accessible and efficacious products for diseases such as malaria, tuberculosis, and AIDS. In this article, three R&D-focused partnerships are explored: the International AIDS Vaccine Initiative; the Medicines for Malaria Venture; and the newly formed Global Alliance for TB Drug Development. The article highlights key elements essential to the success of these ventures.
Johnston MIHIV/AIDS Vaccine Development: Challenges, Progress and Future Directions. Rev. Med. Virol. 1996;6(3):123-140
HIV vaccine development for the world: an idea whose time has come? AIDS Res. Hum. Retroviruses 1998;14 Suppl 3:S191-6
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