Adjuvanting a simian immunodeficiency virus vaccine with toll-like receptor ligands encapsulated in nanoparticles induces persistent antibody responses and enhanced protection in trim5α restrictive macaques

Sudhir Pai Kasturi, Pamela A. Kozlowski, Helder I. Nakaya, Matheus C. Burger, Pedro Russo, Mathew Pham, Yevgeniy Kovalenkov, Eduardo L.V. Silveira, Colin Havenar-Daughton, Samantha L. Burton, Katie M. Kilgore, Mathew J. Johnson, Rafiq Nabi, Traci Legere, Zarpheen Jinnah Sher, Xuemin Chen, Rama R. Amara, Eric Hunter, Steven E. Bosinger, Paul SpearmanShane Crotty, Francois Villinger, Cynthia A. Derdeyn, Jens Wrammert, Bali Pulendran

Research output: Contribution to journalArticle

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Abstract

Our previous work has shown that antigens adjuvanted with ligands specific for Toll-like receptor 4 (TLR4) and TLR7/8 encapsulated in poly(lactic-co-glycolic) acid (PLGA)-based nanoparticles (NPs) induce robust and durable immune responses in mice and macaques. We investigated the efficacy of these NP adjuvants in inducing protective immunity against simian immunodeficiency virus (SIV). Rhesus macaques (RMs) were immunized with NPs containing TLR4 and TLR7/8 agonists mixed with soluble recombinant SIVmac239-derived envelope (Env) gp140 and Gag p55 (protein) or with virus-like particles (VLPs) containing SIVmac239 Env and Gag. NPadjuvanted vaccines induced robust innate responses, antigen-specific antibody responses of a greater magnitude and persistence, and enhanced plasmablast responses compared to those achieved with alum-adjuvanted vaccines. NP-adjuvanted vaccines induced antigen-specific, long-lived plasma cells (LLPCs), which persisted in the bone marrow for several months after vaccination. NP-adjuvanted vaccines induced immune responses that were associated with enhanced protection against repeated low-dose, intravaginal challenges with heterologous SIVsmE660 in animals that carried TRIM5α restrictive alleles. The protection induced by immunization with protein-NP correlated with the prechallenge titers of Env-specific IgG antibodies in serum and vaginal secretions. However, no such correlate was apparent for immunization with VLP-NP or alum as the adjuvant. Transcriptional profiling of peripheral blood mononuclear cells isolated within the first few hours to days after primary vaccination revealed that NP-adjuvanted vaccines induced a molecular signature similar to that induced by the live attenuated yellow fever viral vaccine. This systems approach identified early blood transcriptional signatures that correlate with Envspecific antibody responses in vaginal secretions and protection against infection. These results demonstrate the adjuvanticity of the NP adjuvant in inducing persistent and protective antibody responses against SIV in RMs with implications for the design of vaccines against human immunodeficiency virus (HIV).

Original languageEnglish (US)
Article numbere01844-16
JournalJournal of virology
Volume91
Issue number4
DOIs
StatePublished - Jan 1 2017

Fingerprint

Simian immunodeficiency virus
Simian Immunodeficiency Virus
Toll-Like Receptors
Macaca
nanoparticles
Nanoparticles
Antibody Formation
Vaccines
vaccines
Ligands
antibodies
adjuvants
Toll-Like Receptor 4
alum
virus-like particles
Macaca mulatta
antigens
Antigens
Virion
Immunization

Keywords

  • Adjuvants
  • Antibody responses
  • HIV vaccines
  • Plasma cells
  • Plasmablasts
  • Rhesus macaques
  • SIV
  • TLR ligands
  • Vaccine

Cite this

Adjuvanting a simian immunodeficiency virus vaccine with toll-like receptor ligands encapsulated in nanoparticles induces persistent antibody responses and enhanced protection in trim5α restrictive macaques. / Kasturi, Sudhir Pai; Kozlowski, Pamela A.; Nakaya, Helder I.; Burger, Matheus C.; Russo, Pedro; Pham, Mathew; Kovalenkov, Yevgeniy; Silveira, Eduardo L.V.; Havenar-Daughton, Colin; Burton, Samantha L.; Kilgore, Katie M.; Johnson, Mathew J.; Nabi, Rafiq; Legere, Traci; Sher, Zarpheen Jinnah; Chen, Xuemin; Amara, Rama R.; Hunter, Eric; Bosinger, Steven E.; Spearman, Paul; Crotty, Shane; Villinger, Francois; Derdeyn, Cynthia A.; Wrammert, Jens; Pulendran, Bali.

In: Journal of virology, Vol. 91, No. 4, e01844-16, 01.01.2017.

Research output: Contribution to journalArticle

Kasturi, SP, Kozlowski, PA, Nakaya, HI, Burger, MC, Russo, P, Pham, M, Kovalenkov, Y, Silveira, ELV, Havenar-Daughton, C, Burton, SL, Kilgore, KM, Johnson, MJ, Nabi, R, Legere, T, Sher, ZJ, Chen, X, Amara, RR, Hunter, E, Bosinger, SE, Spearman, P, Crotty, S, Villinger, F, Derdeyn, CA, Wrammert, J & Pulendran, B 2017, 'Adjuvanting a simian immunodeficiency virus vaccine with toll-like receptor ligands encapsulated in nanoparticles induces persistent antibody responses and enhanced protection in trim5α restrictive macaques', Journal of virology, vol. 91, no. 4, e01844-16. https://doi.org/10.1128/JVI.01844-16
Kasturi, Sudhir Pai ; Kozlowski, Pamela A. ; Nakaya, Helder I. ; Burger, Matheus C. ; Russo, Pedro ; Pham, Mathew ; Kovalenkov, Yevgeniy ; Silveira, Eduardo L.V. ; Havenar-Daughton, Colin ; Burton, Samantha L. ; Kilgore, Katie M. ; Johnson, Mathew J. ; Nabi, Rafiq ; Legere, Traci ; Sher, Zarpheen Jinnah ; Chen, Xuemin ; Amara, Rama R. ; Hunter, Eric ; Bosinger, Steven E. ; Spearman, Paul ; Crotty, Shane ; Villinger, Francois ; Derdeyn, Cynthia A. ; Wrammert, Jens ; Pulendran, Bali. / Adjuvanting a simian immunodeficiency virus vaccine with toll-like receptor ligands encapsulated in nanoparticles induces persistent antibody responses and enhanced protection in trim5α restrictive macaques. In: Journal of virology. 2017 ; Vol. 91, No. 4.
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T1 - Adjuvanting a simian immunodeficiency virus vaccine with toll-like receptor ligands encapsulated in nanoparticles induces persistent antibody responses and enhanced protection in trim5α restrictive macaques

AU - Kasturi, Sudhir Pai

AU - Kozlowski, Pamela A.

AU - Nakaya, Helder I.

AU - Burger, Matheus C.

AU - Russo, Pedro

AU - Pham, Mathew

AU - Kovalenkov, Yevgeniy

AU - Silveira, Eduardo L.V.

AU - Havenar-Daughton, Colin

AU - Burton, Samantha L.

AU - Kilgore, Katie M.

AU - Johnson, Mathew J.

AU - Nabi, Rafiq

AU - Legere, Traci

AU - Sher, Zarpheen Jinnah

AU - Chen, Xuemin

AU - Amara, Rama R.

AU - Hunter, Eric

AU - Bosinger, Steven E.

AU - Spearman, Paul

AU - Crotty, Shane

AU - Villinger, Francois

AU - Derdeyn, Cynthia A.

AU - Wrammert, Jens

AU - Pulendran, Bali

PY - 2017/1/1

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N2 - Our previous work has shown that antigens adjuvanted with ligands specific for Toll-like receptor 4 (TLR4) and TLR7/8 encapsulated in poly(lactic-co-glycolic) acid (PLGA)-based nanoparticles (NPs) induce robust and durable immune responses in mice and macaques. We investigated the efficacy of these NP adjuvants in inducing protective immunity against simian immunodeficiency virus (SIV). Rhesus macaques (RMs) were immunized with NPs containing TLR4 and TLR7/8 agonists mixed with soluble recombinant SIVmac239-derived envelope (Env) gp140 and Gag p55 (protein) or with virus-like particles (VLPs) containing SIVmac239 Env and Gag. NPadjuvanted vaccines induced robust innate responses, antigen-specific antibody responses of a greater magnitude and persistence, and enhanced plasmablast responses compared to those achieved with alum-adjuvanted vaccines. NP-adjuvanted vaccines induced antigen-specific, long-lived plasma cells (LLPCs), which persisted in the bone marrow for several months after vaccination. NP-adjuvanted vaccines induced immune responses that were associated with enhanced protection against repeated low-dose, intravaginal challenges with heterologous SIVsmE660 in animals that carried TRIM5α restrictive alleles. The protection induced by immunization with protein-NP correlated with the prechallenge titers of Env-specific IgG antibodies in serum and vaginal secretions. However, no such correlate was apparent for immunization with VLP-NP or alum as the adjuvant. Transcriptional profiling of peripheral blood mononuclear cells isolated within the first few hours to days after primary vaccination revealed that NP-adjuvanted vaccines induced a molecular signature similar to that induced by the live attenuated yellow fever viral vaccine. This systems approach identified early blood transcriptional signatures that correlate with Envspecific antibody responses in vaginal secretions and protection against infection. These results demonstrate the adjuvanticity of the NP adjuvant in inducing persistent and protective antibody responses against SIV in RMs with implications for the design of vaccines against human immunodeficiency virus (HIV).

AB - Our previous work has shown that antigens adjuvanted with ligands specific for Toll-like receptor 4 (TLR4) and TLR7/8 encapsulated in poly(lactic-co-glycolic) acid (PLGA)-based nanoparticles (NPs) induce robust and durable immune responses in mice and macaques. We investigated the efficacy of these NP adjuvants in inducing protective immunity against simian immunodeficiency virus (SIV). Rhesus macaques (RMs) were immunized with NPs containing TLR4 and TLR7/8 agonists mixed with soluble recombinant SIVmac239-derived envelope (Env) gp140 and Gag p55 (protein) or with virus-like particles (VLPs) containing SIVmac239 Env and Gag. NPadjuvanted vaccines induced robust innate responses, antigen-specific antibody responses of a greater magnitude and persistence, and enhanced plasmablast responses compared to those achieved with alum-adjuvanted vaccines. NP-adjuvanted vaccines induced antigen-specific, long-lived plasma cells (LLPCs), which persisted in the bone marrow for several months after vaccination. NP-adjuvanted vaccines induced immune responses that were associated with enhanced protection against repeated low-dose, intravaginal challenges with heterologous SIVsmE660 in animals that carried TRIM5α restrictive alleles. The protection induced by immunization with protein-NP correlated with the prechallenge titers of Env-specific IgG antibodies in serum and vaginal secretions. However, no such correlate was apparent for immunization with VLP-NP or alum as the adjuvant. Transcriptional profiling of peripheral blood mononuclear cells isolated within the first few hours to days after primary vaccination revealed that NP-adjuvanted vaccines induced a molecular signature similar to that induced by the live attenuated yellow fever viral vaccine. This systems approach identified early blood transcriptional signatures that correlate with Envspecific antibody responses in vaginal secretions and protection against infection. These results demonstrate the adjuvanticity of the NP adjuvant in inducing persistent and protective antibody responses against SIV in RMs with implications for the design of vaccines against human immunodeficiency virus (HIV).

KW - Adjuvants

KW - Antibody responses

KW - HIV vaccines

KW - Plasma cells

KW - Plasmablasts

KW - Rhesus macaques

KW - SIV

KW - TLR ligands

KW - Vaccine

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