Vaccine protection against rectal acquisition of SIVmac239 in rhesus macaques

Lucas Gonzalez-Nieto, Isabelle M. Castro, Georg F. Bischof, Young C. Shin, Michael J. Ricciardi, Varian K. Bailey, Christine M. Dang, Nuria Pedreño-Lopez, Diogo M. Magnani, Keisuke Ejima, David B. Allison, Hwi Min Gil, David T. Evans, Eva G. Rakasz, Jeffrey D. Lifson, Ronald C. Desrosiers, Mauricio A. Martins

Research output: Contribution to journalArticle

Abstract

A prophylactic vaccine against human immunodeficiency virus (HIV) remains a top priority in biomedical research. Given the failure of conventional immunization protocols to confer robust protection against HIV, new and unconventional approaches may be needed to generate protective anti-HIV immunity. Here we vaccinated rhesus macaques (RMs) with a recombinant (r)DNA prime (without any exogenous adjuvant), followed by a booster with rhesus monkey rhadinovirus (RRV)-a herpesvirus that establishes persistent infection in RMs (Group 1). Both the rDNA and rRRV vectors encoded a near-full-length simian immunodeficiency virus (SIVnfl) genome that assembles noninfectious SIV particles and expresses all nine SIV gene products. This rDNA/rRRV-SIVnfl vaccine regimen induced persistent anti-Env antibodies and CD8+ T-cell responses against the entire SIV proteome. Vaccine efficacy was assessed by repeated, marginal-dose, intrarectal challenges with SIVmac239. Encouragingly, vaccinees in Group 1 acquired SIVmac239 infection at a significantly delayed rate compared to unvaccinated controls (Group 3). In an attempt to improve upon this outcome, a separate group of rDNA/rRRV-SIVnfl-vaccinated RMs (Group 2) was treated with a cytotoxic T-lymphocyte antigen-4 (CTLA-4)-blocking monoclonal antibody during the vaccine phase and then challenged in parallel with Groups 1 and 3. Surprisingly, Group 2 was not significantly protected against SIVmac239 infection. In sum, SIVnfl vaccination can protect RMs against rigorous mucosal challenges with SIVmac239, a feat that until now had only been accomplished by live-attenuated strains of SIV. Further work is needed to identify the minimal requirements for this protection and whether SIVnfl vaccine efficacy can be improved by means other than anti-CTLA-4 adjuvant therapy.

Original languageEnglish (US)
Article numbere1008015
JournalPLoS pathogens
Volume15
Issue number9
DOIs
StatePublished - Jan 1 2019
Externally publishedYes

Fingerprint

Macaca mulatta
Vaccines
Ribosomal DNA
CTLA-4 Antigen
HIV
Rhadinovirus
Infection
Simian Immunodeficiency Virus
Blocking Antibodies
Recombinant DNA
Herpesviridae
Proteome
Biomedical Research
Anti-Idiotypic Antibodies
Immunity
Immunization
Vaccination
Monoclonal Antibodies
Genome
T-Lymphocytes

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

Cite this

Gonzalez-Nieto, L., Castro, I. M., Bischof, G. F., Shin, Y. C., Ricciardi, M. J., Bailey, V. K., ... Martins, M. A. (2019). Vaccine protection against rectal acquisition of SIVmac239 in rhesus macaques. PLoS pathogens, 15(9), [e1008015]. https://doi.org/10.1371/journal.ppat.1008015

Vaccine protection against rectal acquisition of SIVmac239 in rhesus macaques. / Gonzalez-Nieto, Lucas; Castro, Isabelle M.; Bischof, Georg F.; Shin, Young C.; Ricciardi, Michael J.; Bailey, Varian K.; Dang, Christine M.; Pedreño-Lopez, Nuria; Magnani, Diogo M.; Ejima, Keisuke; Allison, David B.; Gil, Hwi Min; Evans, David T.; Rakasz, Eva G.; Lifson, Jeffrey D.; Desrosiers, Ronald C.; Martins, Mauricio A.

In: PLoS pathogens, Vol. 15, No. 9, e1008015, 01.01.2019.

Research output: Contribution to journalArticle

Gonzalez-Nieto, L, Castro, IM, Bischof, GF, Shin, YC, Ricciardi, MJ, Bailey, VK, Dang, CM, Pedreño-Lopez, N, Magnani, DM, Ejima, K, Allison, DB, Gil, HM, Evans, DT, Rakasz, EG, Lifson, JD, Desrosiers, RC & Martins, MA 2019, 'Vaccine protection against rectal acquisition of SIVmac239 in rhesus macaques', PLoS pathogens, vol. 15, no. 9, e1008015. https://doi.org/10.1371/journal.ppat.1008015
Gonzalez-Nieto L, Castro IM, Bischof GF, Shin YC, Ricciardi MJ, Bailey VK et al. Vaccine protection against rectal acquisition of SIVmac239 in rhesus macaques. PLoS pathogens. 2019 Jan 1;15(9). e1008015. https://doi.org/10.1371/journal.ppat.1008015
Gonzalez-Nieto, Lucas ; Castro, Isabelle M. ; Bischof, Georg F. ; Shin, Young C. ; Ricciardi, Michael J. ; Bailey, Varian K. ; Dang, Christine M. ; Pedreño-Lopez, Nuria ; Magnani, Diogo M. ; Ejima, Keisuke ; Allison, David B. ; Gil, Hwi Min ; Evans, David T. ; Rakasz, Eva G. ; Lifson, Jeffrey D. ; Desrosiers, Ronald C. ; Martins, Mauricio A. / Vaccine protection against rectal acquisition of SIVmac239 in rhesus macaques. In: PLoS pathogens. 2019 ; Vol. 15, No. 9.
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abstract = "A prophylactic vaccine against human immunodeficiency virus (HIV) remains a top priority in biomedical research. Given the failure of conventional immunization protocols to confer robust protection against HIV, new and unconventional approaches may be needed to generate protective anti-HIV immunity. Here we vaccinated rhesus macaques (RMs) with a recombinant (r)DNA prime (without any exogenous adjuvant), followed by a booster with rhesus monkey rhadinovirus (RRV)-a herpesvirus that establishes persistent infection in RMs (Group 1). Both the rDNA and rRRV vectors encoded a near-full-length simian immunodeficiency virus (SIVnfl) genome that assembles noninfectious SIV particles and expresses all nine SIV gene products. This rDNA/rRRV-SIVnfl vaccine regimen induced persistent anti-Env antibodies and CD8+ T-cell responses against the entire SIV proteome. Vaccine efficacy was assessed by repeated, marginal-dose, intrarectal challenges with SIVmac239. Encouragingly, vaccinees in Group 1 acquired SIVmac239 infection at a significantly delayed rate compared to unvaccinated controls (Group 3). In an attempt to improve upon this outcome, a separate group of rDNA/rRRV-SIVnfl-vaccinated RMs (Group 2) was treated with a cytotoxic T-lymphocyte antigen-4 (CTLA-4)-blocking monoclonal antibody during the vaccine phase and then challenged in parallel with Groups 1 and 3. Surprisingly, Group 2 was not significantly protected against SIVmac239 infection. In sum, SIVnfl vaccination can protect RMs against rigorous mucosal challenges with SIVmac239, a feat that until now had only been accomplished by live-attenuated strains of SIV. Further work is needed to identify the minimal requirements for this protection and whether SIVnfl vaccine efficacy can be improved by means other than anti-CTLA-4 adjuvant therapy.",
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