DNA Vaccine molecular adjuvants SP-D-BAFF and SP-D-APRIL enhance anti-gp120 immune response and increase HIV-1 neutralizing antibody titers

Sachin Gupta, Emily S. Clark, James M. Termini, Justin Boucher, Saravana Kanagavelu, Celia C. LeBranche, Sakhi Abraham, David C. Montefiori, Wasif Khan, Geoffrey Stone

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Broadly neutralizing antibodies (bNAbs) specific for conserved epitopes on the HIV-1 envelope (Env) are believed to be essential for protection against multiple HIV-1 clades. However, vaccines capable of stimulating the production of bNAbs remain a major challenge. Given that polyreactivity and autoreactivity are considered important characteristics of anti-HIV bNAbs, we designed an HIV vaccine incorporating the molecular adjuvants BAFF (B cell activating factor) and APRIL (a proliferation-inducing ligand) with the potential to facilitate the maturation of polyreactive and autoreactive B cells as well as to enhance the affinity and/or avidity of Env-specific antibodies. We designed recombinant DNA plasmids encoding soluble multitrimers of BAFF and APRIL using surfactant protein D as a scaffold, and we vaccinated mice with these molecular adjuvants using DNA and DNAprotein vaccination strategies. We found that immunization of mice with a DNA vaccine encoding BAFF or APRIL multitrimers, together with interleukin 12 (IL-12) and membrane-bound HIV-1 Env gp140, induced neutralizing antibodies against tier 1 and tier 2 (vaccine strain) viruses. The APRIL-containing vaccine was particularly effective at generating tier 2 neutralizing antibodies following a protein boost. These BAFF and APRIL effects coincided with an enhanced germinal center (GC) reaction, increased anti-gp120 antibody-secreting cells, and increased anti-gp120 functional avidity. Notably, BAFF and APRIL did not cause indiscriminate B cell expansion or an increase in total IgG. We propose that BAFF and APRIL multitrimers are promising molecular adjuvants for vaccines designed to induce bNAbs against HIV-1.

Original languageEnglish (US)
Pages (from-to)4158-4169
Number of pages12
JournalJournal of Virology
Volume89
Issue number8
DOIs
StatePublished - 2015

Fingerprint

Pulmonary Surfactant-Associated Protein D
DNA Vaccines
recombinant vaccines
Human immunodeficiency virus 1
Neutralizing Antibodies
neutralizing antibodies
adjuvants
HIV-1
immune response
Ligands
vaccines
B-lymphocytes
Vaccines
B-Lymphocytes
B-Cell Activating Factor
vaccine adjuvants
Antibody-Producing Cells
AIDS Vaccines
Synthetic Vaccines
recombinant DNA

ASJC Scopus subject areas

  • Immunology
  • Virology

Cite this

Gupta, S., Clark, E. S., Termini, J. M., Boucher, J., Kanagavelu, S., LeBranche, C. C., ... Stone, G. (2015). DNA Vaccine molecular adjuvants SP-D-BAFF and SP-D-APRIL enhance anti-gp120 immune response and increase HIV-1 neutralizing antibody titers. Journal of Virology, 89(8), 4158-4169. https://doi.org/10.1128/JVI.02904-14

DNA Vaccine molecular adjuvants SP-D-BAFF and SP-D-APRIL enhance anti-gp120 immune response and increase HIV-1 neutralizing antibody titers. / Gupta, Sachin; Clark, Emily S.; Termini, James M.; Boucher, Justin; Kanagavelu, Saravana; LeBranche, Celia C.; Abraham, Sakhi; Montefiori, David C.; Khan, Wasif; Stone, Geoffrey.

In: Journal of Virology, Vol. 89, No. 8, 2015, p. 4158-4169.

Research output: Contribution to journalArticle

Gupta, S, Clark, ES, Termini, JM, Boucher, J, Kanagavelu, S, LeBranche, CC, Abraham, S, Montefiori, DC, Khan, W & Stone, G 2015, 'DNA Vaccine molecular adjuvants SP-D-BAFF and SP-D-APRIL enhance anti-gp120 immune response and increase HIV-1 neutralizing antibody titers', Journal of Virology, vol. 89, no. 8, pp. 4158-4169. https://doi.org/10.1128/JVI.02904-14
Gupta, Sachin ; Clark, Emily S. ; Termini, James M. ; Boucher, Justin ; Kanagavelu, Saravana ; LeBranche, Celia C. ; Abraham, Sakhi ; Montefiori, David C. ; Khan, Wasif ; Stone, Geoffrey. / DNA Vaccine molecular adjuvants SP-D-BAFF and SP-D-APRIL enhance anti-gp120 immune response and increase HIV-1 neutralizing antibody titers. In: Journal of Virology. 2015 ; Vol. 89, No. 8. pp. 4158-4169.
@article{1d1262964d784a9083de7c72abec9402,
title = "DNA Vaccine molecular adjuvants SP-D-BAFF and SP-D-APRIL enhance anti-gp120 immune response and increase HIV-1 neutralizing antibody titers",
abstract = "Broadly neutralizing antibodies (bNAbs) specific for conserved epitopes on the HIV-1 envelope (Env) are believed to be essential for protection against multiple HIV-1 clades. However, vaccines capable of stimulating the production of bNAbs remain a major challenge. Given that polyreactivity and autoreactivity are considered important characteristics of anti-HIV bNAbs, we designed an HIV vaccine incorporating the molecular adjuvants BAFF (B cell activating factor) and APRIL (a proliferation-inducing ligand) with the potential to facilitate the maturation of polyreactive and autoreactive B cells as well as to enhance the affinity and/or avidity of Env-specific antibodies. We designed recombinant DNA plasmids encoding soluble multitrimers of BAFF and APRIL using surfactant protein D as a scaffold, and we vaccinated mice with these molecular adjuvants using DNA and DNAprotein vaccination strategies. We found that immunization of mice with a DNA vaccine encoding BAFF or APRIL multitrimers, together with interleukin 12 (IL-12) and membrane-bound HIV-1 Env gp140, induced neutralizing antibodies against tier 1 and tier 2 (vaccine strain) viruses. The APRIL-containing vaccine was particularly effective at generating tier 2 neutralizing antibodies following a protein boost. These BAFF and APRIL effects coincided with an enhanced germinal center (GC) reaction, increased anti-gp120 antibody-secreting cells, and increased anti-gp120 functional avidity. Notably, BAFF and APRIL did not cause indiscriminate B cell expansion or an increase in total IgG. We propose that BAFF and APRIL multitrimers are promising molecular adjuvants for vaccines designed to induce bNAbs against HIV-1.",
author = "Sachin Gupta and Clark, {Emily S.} and Termini, {James M.} and Justin Boucher and Saravana Kanagavelu and LeBranche, {Celia C.} and Sakhi Abraham and Montefiori, {David C.} and Wasif Khan and Geoffrey Stone",
year = "2015",
doi = "10.1128/JVI.02904-14",
language = "English (US)",
volume = "89",
pages = "4158--4169",
journal = "Journal of Virology",
issn = "0022-538X",
publisher = "American Society for Microbiology",
number = "8",

}

TY - JOUR

T1 - DNA Vaccine molecular adjuvants SP-D-BAFF and SP-D-APRIL enhance anti-gp120 immune response and increase HIV-1 neutralizing antibody titers

AU - Gupta, Sachin

AU - Clark, Emily S.

AU - Termini, James M.

AU - Boucher, Justin

AU - Kanagavelu, Saravana

AU - LeBranche, Celia C.

AU - Abraham, Sakhi

AU - Montefiori, David C.

AU - Khan, Wasif

AU - Stone, Geoffrey

PY - 2015

Y1 - 2015

N2 - Broadly neutralizing antibodies (bNAbs) specific for conserved epitopes on the HIV-1 envelope (Env) are believed to be essential for protection against multiple HIV-1 clades. However, vaccines capable of stimulating the production of bNAbs remain a major challenge. Given that polyreactivity and autoreactivity are considered important characteristics of anti-HIV bNAbs, we designed an HIV vaccine incorporating the molecular adjuvants BAFF (B cell activating factor) and APRIL (a proliferation-inducing ligand) with the potential to facilitate the maturation of polyreactive and autoreactive B cells as well as to enhance the affinity and/or avidity of Env-specific antibodies. We designed recombinant DNA plasmids encoding soluble multitrimers of BAFF and APRIL using surfactant protein D as a scaffold, and we vaccinated mice with these molecular adjuvants using DNA and DNAprotein vaccination strategies. We found that immunization of mice with a DNA vaccine encoding BAFF or APRIL multitrimers, together with interleukin 12 (IL-12) and membrane-bound HIV-1 Env gp140, induced neutralizing antibodies against tier 1 and tier 2 (vaccine strain) viruses. The APRIL-containing vaccine was particularly effective at generating tier 2 neutralizing antibodies following a protein boost. These BAFF and APRIL effects coincided with an enhanced germinal center (GC) reaction, increased anti-gp120 antibody-secreting cells, and increased anti-gp120 functional avidity. Notably, BAFF and APRIL did not cause indiscriminate B cell expansion or an increase in total IgG. We propose that BAFF and APRIL multitrimers are promising molecular adjuvants for vaccines designed to induce bNAbs against HIV-1.

AB - Broadly neutralizing antibodies (bNAbs) specific for conserved epitopes on the HIV-1 envelope (Env) are believed to be essential for protection against multiple HIV-1 clades. However, vaccines capable of stimulating the production of bNAbs remain a major challenge. Given that polyreactivity and autoreactivity are considered important characteristics of anti-HIV bNAbs, we designed an HIV vaccine incorporating the molecular adjuvants BAFF (B cell activating factor) and APRIL (a proliferation-inducing ligand) with the potential to facilitate the maturation of polyreactive and autoreactive B cells as well as to enhance the affinity and/or avidity of Env-specific antibodies. We designed recombinant DNA plasmids encoding soluble multitrimers of BAFF and APRIL using surfactant protein D as a scaffold, and we vaccinated mice with these molecular adjuvants using DNA and DNAprotein vaccination strategies. We found that immunization of mice with a DNA vaccine encoding BAFF or APRIL multitrimers, together with interleukin 12 (IL-12) and membrane-bound HIV-1 Env gp140, induced neutralizing antibodies against tier 1 and tier 2 (vaccine strain) viruses. The APRIL-containing vaccine was particularly effective at generating tier 2 neutralizing antibodies following a protein boost. These BAFF and APRIL effects coincided with an enhanced germinal center (GC) reaction, increased anti-gp120 antibody-secreting cells, and increased anti-gp120 functional avidity. Notably, BAFF and APRIL did not cause indiscriminate B cell expansion or an increase in total IgG. We propose that BAFF and APRIL multitrimers are promising molecular adjuvants for vaccines designed to induce bNAbs against HIV-1.

UR - http://www.scopus.com/inward/record.url?scp=84929636240&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84929636240&partnerID=8YFLogxK

U2 - 10.1128/JVI.02904-14

DO - 10.1128/JVI.02904-14

M3 - Article

C2 - 25631080

AN - SCOPUS:84929636240

VL - 89

SP - 4158

EP - 4169

JO - Journal of Virology

JF - Journal of Virology

SN - 0022-538X

IS - 8

ER -