A trivalent recombinant Ad5 gag/pol/nef vaccine fails to protect rhesus macaques from infection or control virus replication after a limiting-dose heterologous SIV challenge

Matthew R. Reynolds, Andrea M. Weiler, Shari M. Piaskowski, Michael Piatak, Henry T. Robertson, David B. Allison, Andrew J. Bett, Danilo R. Casimiro, John W. Shiver, Nancy A. Wilson, Jeffrey D. Lifson, Wayne C. Koff, David Watkins

Research output: Contribution to journalArticle

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Abstract

It has been suggested that poor immunogenicity may explain the lack of vaccine efficacy in preventing or controlling HIV infection in the Step trial. To investigate this issue we vaccinated eight Indian rhesus macaques with a trivalent replication-incompetent adenovirus serotype 5 vaccine expressing SIV Gag, Pol, and Nef using a regimen similar to that employed in the Step trial. We detected broad vaccine-induced CD8 + (2-7 pool-specific responses) and CD4 + (5-19 pool-specific responses) T-cell responses in IFN-γ ELISPOT assays at one week post-boost using fresh PBMC. However, using cryopreserved cells at one and four weeks post-boost we observed a reduction in both the number and magnitude of most vaccine-induced responses. This demonstrates that the time points and conditions chosen to perform immune assays may influence the observed breadth and frequency of vaccine-induced T-cell responses. To evaluate protective efficacy, we challenged the immunized macaques, along with naïve controls, with repeated, limiting doses of the heterologous swarm isolate SIVsmE660. Vaccination did not significantly affect acquisition or control of virus replication in vaccinees compared to naïve controls. Post-infection we observed an average of only two anamnestic CD8 + T-cell responses per animal, which may not have been sufficiently broad to control heterologous virus replication. While the trivalent vaccine regimen induced relatively broad T-cell responses in rhesus macaques, it failed to protect against infection or control viral replication. Our results are consistent with those observed in the Step trial and indicate that SIV immunization and challenge studies in macaque models of HIV infection can be informative in assessing pre-clinical HIV vaccines.

Original languageEnglish
Pages (from-to)4465-4475
Number of pages11
JournalVaccine
Volume30
Issue number30
DOIs
StatePublished - Jun 22 2012

Fingerprint

Infection Control
Virus Replication
virus replication
Macaca mulatta
Vaccines
vaccines
T-Lymphocytes
dosage
infection
T-lymphocytes
Macaca
HIV Infections
SAIDS Vaccines
HIV infections
Enzyme-Linked Immunospot Assay
AIDS Vaccines
Adenoviridae
Immunization
Vaccination
swarms

Keywords

  • Adenovirus serotype 5
  • CD4 T cells
  • CD8 T cells
  • HIV vaccine
  • Simian immunodeficiency virus
  • Step trial

ASJC Scopus subject areas

  • Immunology and Microbiology(all)
  • Infectious Diseases
  • Public Health, Environmental and Occupational Health
  • veterinary(all)
  • Molecular Medicine

Cite this

A trivalent recombinant Ad5 gag/pol/nef vaccine fails to protect rhesus macaques from infection or control virus replication after a limiting-dose heterologous SIV challenge. / Reynolds, Matthew R.; Weiler, Andrea M.; Piaskowski, Shari M.; Piatak, Michael; Robertson, Henry T.; Allison, David B.; Bett, Andrew J.; Casimiro, Danilo R.; Shiver, John W.; Wilson, Nancy A.; Lifson, Jeffrey D.; Koff, Wayne C.; Watkins, David.

In: Vaccine, Vol. 30, No. 30, 22.06.2012, p. 4465-4475.

Research output: Contribution to journalArticle

Reynolds, MR, Weiler, AM, Piaskowski, SM, Piatak, M, Robertson, HT, Allison, DB, Bett, AJ, Casimiro, DR, Shiver, JW, Wilson, NA, Lifson, JD, Koff, WC & Watkins, D 2012, 'A trivalent recombinant Ad5 gag/pol/nef vaccine fails to protect rhesus macaques from infection or control virus replication after a limiting-dose heterologous SIV challenge', Vaccine, vol. 30, no. 30, pp. 4465-4475. https://doi.org/10.1016/j.vaccine.2012.04.082
Reynolds, Matthew R. ; Weiler, Andrea M. ; Piaskowski, Shari M. ; Piatak, Michael ; Robertson, Henry T. ; Allison, David B. ; Bett, Andrew J. ; Casimiro, Danilo R. ; Shiver, John W. ; Wilson, Nancy A. ; Lifson, Jeffrey D. ; Koff, Wayne C. ; Watkins, David. / A trivalent recombinant Ad5 gag/pol/nef vaccine fails to protect rhesus macaques from infection or control virus replication after a limiting-dose heterologous SIV challenge. In: Vaccine. 2012 ; Vol. 30, No. 30. pp. 4465-4475.
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abstract = "It has been suggested that poor immunogenicity may explain the lack of vaccine efficacy in preventing or controlling HIV infection in the Step trial. To investigate this issue we vaccinated eight Indian rhesus macaques with a trivalent replication-incompetent adenovirus serotype 5 vaccine expressing SIV Gag, Pol, and Nef using a regimen similar to that employed in the Step trial. We detected broad vaccine-induced CD8 + (2-7 pool-specific responses) and CD4 + (5-19 pool-specific responses) T-cell responses in IFN-γ ELISPOT assays at one week post-boost using fresh PBMC. However, using cryopreserved cells at one and four weeks post-boost we observed a reduction in both the number and magnitude of most vaccine-induced responses. This demonstrates that the time points and conditions chosen to perform immune assays may influence the observed breadth and frequency of vaccine-induced T-cell responses. To evaluate protective efficacy, we challenged the immunized macaques, along with na{\"i}ve controls, with repeated, limiting doses of the heterologous swarm isolate SIVsmE660. Vaccination did not significantly affect acquisition or control of virus replication in vaccinees compared to na{\"i}ve controls. Post-infection we observed an average of only two anamnestic CD8 + T-cell responses per animal, which may not have been sufficiently broad to control heterologous virus replication. While the trivalent vaccine regimen induced relatively broad T-cell responses in rhesus macaques, it failed to protect against infection or control viral replication. Our results are consistent with those observed in the Step trial and indicate that SIV immunization and challenge studies in macaque models of HIV infection can be informative in assessing pre-clinical HIV vaccines.",
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