Abstract
The encouraging results of the RV144 vaccine trial have spurred interest in poxvirus prime-protein boost human immunodeficiency virus (HIV) vaccine modalities as a strategy to induce protective immunity. Because vaccine-induced protective immunity is critically determined by HIV envelope (Env) conformation, significant efforts are directed toward generating soluble trimeric Env immunogens that assume native structures. Using the simian immunodeficiency virus (SIV)-macaque model, we tested the immunogenicity and efficacy of sequential immunizations withDNA(D), modified vaccinia virus Ankara (MVA) (M), and protein immunogens, all expressing virus-like particles (VLPs) displaying membrane-anchored trimeric Env. A single VLP protein boost displaying trimeric gp160 adjuvanted with nanoparticle-encapsulated Toll-like receptor 4/7/8 (TLR4/7/8) agonists, administered 44 weeks after the secondMVA immunization, induced up to a 3-fold increase in Env-specific IgG binding titers in serum and mucosa. Importantly, the VLP protein boost increased binding antibody against scaffolded V1V2, antibody-dependent phagocytic activity against VLP-coated beads, and antibody breadth and neutralizing antibody titers against homologous and heterologous tier 1 SIVs. Following 5 weekly intrarectal SIVmac251 challenges, two of sevenDNA/MVAand VLP (DM+VLP)-vaccinated animals were completely protected compared to productive infection in all seven DM-vaccinated animals. Vaccinated animals demonstrated stronger acute viral pulldown than controls, but a trend for higher acute viremia was observed in the DM+VLP group, likely due to a slower recall of Gag-specific CD8 T cells. Our findings support immunization with VLPs containing trimeric Env as a strategy to augment protective antibody but underscore the need for optimal engagement of CD8 T cells to achieve robust early viral control.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 8842-8854 |
| Number of pages | 13 |
| Journal | Journal of Virology |
| Volume | 90 |
| Issue number | 19 |
| DOIs | |
| State | Published - Jan 1 2016 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Microbiology
- Immunology
- Insect Science
- Virology
Cite this
Virus-like particles displaying trimeric simian immunodeficiency virus (SIV) envelope gp160 enhance the breadth of DNA/modified vaccinia virus Ankara SIV vaccine-induced antibody responses in rhesus macaques. / Iyer, Smita; Gangadhara, Sailaja; Victor, Blandine; Shen, Xiaoying; Chen, Xuemin; Nabi, Rafiq; Kasturi, Sudhir P.; Sabula, Michael J.; Labranche, Celia C.; Reddy, Pradeep B.J.; Tomaras, Georgia D.; Montefiori, David C.; Moss, Bernard; Spearman, Paul; Pulendran, Bali; Kozlowski, Pamela A.; Amara, Rama Rao.
In: Journal of Virology, Vol. 90, No. 19, 01.01.2016, p. 8842-8854.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Virus-like particles displaying trimeric simian immunodeficiency virus (SIV) envelope gp160 enhance the breadth of DNA/modified vaccinia virus Ankara SIV vaccine-induced antibody responses in rhesus macaques
AU - Iyer, Smita
AU - Gangadhara, Sailaja
AU - Victor, Blandine
AU - Shen, Xiaoying
AU - Chen, Xuemin
AU - Nabi, Rafiq
AU - Kasturi, Sudhir P.
AU - Sabula, Michael J.
AU - Labranche, Celia C.
AU - Reddy, Pradeep B.J.
AU - Tomaras, Georgia D.
AU - Montefiori, David C.
AU - Moss, Bernard
AU - Spearman, Paul
AU - Pulendran, Bali
AU - Kozlowski, Pamela A.
AU - Amara, Rama Rao
PY - 2016/1/1
Y1 - 2016/1/1
N2 - The encouraging results of the RV144 vaccine trial have spurred interest in poxvirus prime-protein boost human immunodeficiency virus (HIV) vaccine modalities as a strategy to induce protective immunity. Because vaccine-induced protective immunity is critically determined by HIV envelope (Env) conformation, significant efforts are directed toward generating soluble trimeric Env immunogens that assume native structures. Using the simian immunodeficiency virus (SIV)-macaque model, we tested the immunogenicity and efficacy of sequential immunizations withDNA(D), modified vaccinia virus Ankara (MVA) (M), and protein immunogens, all expressing virus-like particles (VLPs) displaying membrane-anchored trimeric Env. A single VLP protein boost displaying trimeric gp160 adjuvanted with nanoparticle-encapsulated Toll-like receptor 4/7/8 (TLR4/7/8) agonists, administered 44 weeks after the secondMVA immunization, induced up to a 3-fold increase in Env-specific IgG binding titers in serum and mucosa. Importantly, the VLP protein boost increased binding antibody against scaffolded V1V2, antibody-dependent phagocytic activity against VLP-coated beads, and antibody breadth and neutralizing antibody titers against homologous and heterologous tier 1 SIVs. Following 5 weekly intrarectal SIVmac251 challenges, two of sevenDNA/MVAand VLP (DM+VLP)-vaccinated animals were completely protected compared to productive infection in all seven DM-vaccinated animals. Vaccinated animals demonstrated stronger acute viral pulldown than controls, but a trend for higher acute viremia was observed in the DM+VLP group, likely due to a slower recall of Gag-specific CD8 T cells. Our findings support immunization with VLPs containing trimeric Env as a strategy to augment protective antibody but underscore the need for optimal engagement of CD8 T cells to achieve robust early viral control.
AB - The encouraging results of the RV144 vaccine trial have spurred interest in poxvirus prime-protein boost human immunodeficiency virus (HIV) vaccine modalities as a strategy to induce protective immunity. Because vaccine-induced protective immunity is critically determined by HIV envelope (Env) conformation, significant efforts are directed toward generating soluble trimeric Env immunogens that assume native structures. Using the simian immunodeficiency virus (SIV)-macaque model, we tested the immunogenicity and efficacy of sequential immunizations withDNA(D), modified vaccinia virus Ankara (MVA) (M), and protein immunogens, all expressing virus-like particles (VLPs) displaying membrane-anchored trimeric Env. A single VLP protein boost displaying trimeric gp160 adjuvanted with nanoparticle-encapsulated Toll-like receptor 4/7/8 (TLR4/7/8) agonists, administered 44 weeks after the secondMVA immunization, induced up to a 3-fold increase in Env-specific IgG binding titers in serum and mucosa. Importantly, the VLP protein boost increased binding antibody against scaffolded V1V2, antibody-dependent phagocytic activity against VLP-coated beads, and antibody breadth and neutralizing antibody titers against homologous and heterologous tier 1 SIVs. Following 5 weekly intrarectal SIVmac251 challenges, two of sevenDNA/MVAand VLP (DM+VLP)-vaccinated animals were completely protected compared to productive infection in all seven DM-vaccinated animals. Vaccinated animals demonstrated stronger acute viral pulldown than controls, but a trend for higher acute viremia was observed in the DM+VLP group, likely due to a slower recall of Gag-specific CD8 T cells. Our findings support immunization with VLPs containing trimeric Env as a strategy to augment protective antibody but underscore the need for optimal engagement of CD8 T cells to achieve robust early viral control.
UR - http://www.scopus.com/inward/record.url?scp=84990226849&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84990226849&partnerID=8YFLogxK
U2 - 10.1128/JVI.01163-16
DO - 10.1128/JVI.01163-16
M3 - Article
C2 - 27466414
AN - SCOPUS:84990226849
VL - 90
SP - 8842
EP - 8854
JO - Journal of Virology
JF - Journal of Virology
SN - 0022-538X
IS - 19
ER -