An Effective AIDS Vaccine Based on Live Attenuated Vesicular Stomatitis Virus Recombinants

Rose, Nina; Marx, Preston A.; Luckay, Amara; Nixon, Douglas F.; Moretto, Walter J.; Donahoe, Sean M.; Montefiori, David C.; Roberts, Anjeanette; Buonocore, Linda; Rose, John K.

doi:10.1016/s0092-8674(01)00482-2

Cited by 420 publications

(370 citation statements)

References 44 publications

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“…The importance of cellular immunity in the control of HIV infection and the poor effectiveness of neutralizing antibodies to this pathogen form a formidable challenge for the development of protective HIV vaccines (17,65). Live attenuated vaccine candidates provide much better protection than protein-based or nucleic acidbased vaccines (4,47,53,87,101), and immunogens based upon the more aggressive X4 viruses (5,12,82,86) seem to protect somewhat better than those based on the more natural R5 viruses (2,44,73) that provide hardly any protection (65). Attenuated HIV is too dangerous to be used for vaccination in humans (43), and we investigate here why other vaccination approaches fail to provide sterilizing immunity.…”

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confidence: 99%

Understanding the Failure of CD8⁺T-Cell Vaccination against Simian/Human Immunodeficiency Virus

Boer

2007

J Virol

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Although CD8 ؉ T cells play an important role in controlling viral infections, boosting specific CD8 ؉ T cells by prophylactic vaccination with simian immunodeficiency virus (SIV) epitopes fails to provide sterilizing immunity. Viral replication rates and viral contraction rates after the peak viremia hardly depend on the presence of memory CD8 ؉ T cells. To study these paradoxical findings, we parameterize novel mathematical models for acute SIV and human immunodeficiency virus infection. These models explain that failure of vaccination is due to the fact that effector/target ratios are too low during the viral expansion phase. Because CD8 ؉ T cells require cell-to-cell contacts, immune protection requires high effector/target ratios at the primary site of infection. Effector/target ratios become favorable for immune control at the time of the peak in the viral load when the virus becomes limited by other factors, such as the availability of uninfected target cells. At the viral set point, effector/target ratios are much higher, and perturbations of the number of CD8 ؉ effector cells have a large impact on the viral load. Such protective effector/target ratios are difficult to achieve with nucleic acid-or protein-based vaccines.

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Understanding the Failure of CD8⁺T-Cell Vaccination against Simian/Human Immunodeficiency Virus

Boer

2007

J Virol

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“…A recent focus in our laboratory has been on the development of recombinant vesicular stomatitis virus (rVSV) as a live viral vaccine vector (39,40,42). VSV is a nonsegmented, negative-stranded RNA virus that can be easily manipulated to express foreign genes from additional transcription units (27,44).…”

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Robust Recall and Long-Term Memory T-Cell Responses Induced by Prime-Boost Regimens with Heterologous Live Viral Vectors Expressing Human Immunodeficiency Virus Type 1 Gag and Env Proteins

Haglund

Leiner

Kerksiek

et al. 2002

J Virol

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We investigated long-term memory and recall cellular immune responses to human immunodeficiency virus type 1 (HIV-1) Env and Gag proteins elicited by recombinant vesicular stomatitis viruses (VSVs) expressing Env and Gag. More than 7 months after a single vaccination with VSV-Env, ϳ6% of CD8 ؉ splenocytes stained with major histocompatibility complex class I tetramers containing the Env p18-I10 immunodominant peptide and showed a memory phenotype (CD44 Hi ). The level of tetramer-positive cells in memory was about 14% of the peak primary response. Recall responses elicited in these mice 5 days after boosting with a heterologous recombinant vaccinia virus expressing HIV-1 Env showed that 40 to 45% of CD8 ؉ splenocytes were tetramer positive and activated (CD62L Lo ), and these cells produced gamma interferon after stimulation with Env peptide, indicating that they were functional. Five months after the boost, the long-term memory cell population (tetramer positive, CD44 Hi ) constituted 30% of the CD8 ؉ splenocytes. Recall responses to HIV-1 Gag were examined in mice primed with VSV recombinants expressing HIV-1 Gag protein and boosted with a vaccinia virus recombinant expressing Gag. Using this protocol, we found that ϳ40% of CD8 ؉ splenocytes were activated (CD62L Lo ) and specific for a Gag immunodominant peptide (tetramer positive). The high-level Gag recall response elicited by the vaccinia virus-Gag was greater than that obtained by boosting with a VSV-Gag vector with a different VSV glycoprotein. The corresponding levels of CD44 Hi memory cells were also higher long after boosting with vaccinia virus-Gag than after boosting with a glycoprotein exchange VSV-Gag. Our results show that VSV vectors elicit high-level memory CTL responses and that these can be amplified as much as six-to sevenfold using a heterologous boosting vector.

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“…One focus is the development and optimization of viral vectors to deliver HIV-1 antigens. Virus-based vaccine vectors under investigation include adenoassociated virus (AAV) [1,2], adenovirus [3][4][5][6][7][8], alphaviruses [9][10][11][12][13], poxviruses [14,15] and herpes simplex virus type 1 (HSV-1) [16][17][18].…”

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confidence: 99%

HSV-1 amplicon vectors elicit polyfunctional T cell responses to HIV-1 Env, and strongly boost responses to an adenovirus prime

Duke

Maguire

Keefer

et al. 2007

Vaccine

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HSV-1 amplicon vectors elicit strong T-cell responses to encoded antigens but the qualitative nature of these responses is poorly understood. Antigen-specific CD4 + and CD8 + T-cell responses to amplicon and adenovirus (rAd5) vectors encoding HIV-1 gp120 were assessed following immunization of mice, by performing intracellular cytokine staining for IFNγ, IL-2 and TNFα, following stimulation of splenocytes with a HIV-1 Env peptide pool. The quality of the primary Tcell response to amplicon and rAd5 vectors was strikingly similar, but there were qualitative differences in responses to amplicon vectors that incorporated different promoters upstream of gp120 -suggesting that promoters can significantly influence immune response quality. When prime-boost combinations were studied, a rAd5 prime and amplicon boost elicited the highest T-cell response. Furthermore, protocols that incorporated a rAd5 prime consistently elicited a greater proportion of polyfunctional CD4 + T-cells -regardless of boost. This suggests that initial priming can shape immune response quality after a boost. Overall, these findings provide insight into effective vector combinations for HIV-1 vaccine development.

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An Effective AIDS Vaccine Based on Live Attenuated Vesicular Stomatitis Virus Recombinants

Cited by 420 publications

References 44 publications

Understanding the Failure of CD8⁺T-Cell Vaccination against Simian/Human Immunodeficiency Virus

Understanding the Failure of CD8⁺T-Cell Vaccination against Simian/Human Immunodeficiency Virus

Robust Recall and Long-Term Memory T-Cell Responses Induced by Prime-Boost Regimens with Heterologous Live Viral Vectors Expressing Human Immunodeficiency Virus Type 1 Gag and Env Proteins

HSV-1 amplicon vectors elicit polyfunctional T cell responses to HIV-1 Env, and strongly boost responses to an adenovirus prime

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An Effective AIDS Vaccine Based on Live Attenuated Vesicular Stomatitis Virus Recombinants

Cited by 420 publications

References 44 publications

Understanding the Failure of CD8+T-Cell Vaccination against Simian/Human Immunodeficiency Virus

Understanding the Failure of CD8+T-Cell Vaccination against Simian/Human Immunodeficiency Virus

Robust Recall and Long-Term Memory T-Cell Responses Induced by Prime-Boost Regimens with Heterologous Live Viral Vectors Expressing Human Immunodeficiency Virus Type 1 Gag and Env Proteins

HSV-1 amplicon vectors elicit polyfunctional T cell responses to HIV-1 Env, and strongly boost responses to an adenovirus prime

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Understanding the Failure of CD8⁺T-Cell Vaccination against Simian/Human Immunodeficiency Virus

Understanding the Failure of CD8⁺T-Cell Vaccination against Simian/Human Immunodeficiency Virus