TY - JOUR
T1 - Rectal Acquisition of Simian Immunodeficiency Virus (SIV) SIVmac239 Infection despite Vaccine-Induced Immune Responses against the Entire SIV Proteome
AU - Martins, Mauricio A.
AU - Gonzalez-Nieto, Lucas
AU - Ricciardi, Michael J.
AU - Bailey, Varian K.
AU - Dang, Christine M.
AU - Bischof, Georg F.
AU - Pedreño-Lopez, Nuria
AU - Pauthner, Matthias G.
AU - Burton, Dennis R.
AU - Parks, Christopher L.
AU - Earl, Patricia
AU - Moss, Bernard
AU - Rakasz, Eva G.
AU - Lifson, Jeffrey D.
AU - Desrosiers, Ronald C.
AU - Watkins, David I.
N1 - Funding Information:
We are grateful to a number of individuals who contributed to the execution of the present research. These individuals include all members of the Watkins laboratory at the University of Miami; all members of Immunology Services and Scientific Protocol Units at the WNPRC; Rebecca Shoemaker, Kelli Oswald, and Randy Fast at the AIDS and Cancer Virus Program at the Frederick National Laboratory; and Leydi Guzman for administrative assistance. This work was funded by Public Health Service grants R01 AI108421 (D.I.W.) and R37 AI052056 (D.I.W.) from the National Institute of Allergy and Infectious Diseases (NIAID). This work was also funded by PHS grant K01 OD023032 (M.A.M.) from the Office of the Director, National Institutes of Health (NIH). Partial support came from PHS grant R37 AI063928 (R.C.D.) from the NIAID and from federal funds from the Office of Research Infrastructure Programs (P51 OD011106) and the National Cancer Institute, NIH, under contract no. HHSN261200800001E (J.D.L.). Partial support was also provided by the NIAID Division of Intramural Research (P.E. and B.M.). We also acknowledge the Miami Center for AIDS Research (P30 AI073961) for their support. IAVI?s work is made possible by generous support from many donors, including The Bill & Melinda Gates Foundation, the Ministry of Foreign Affairs of Denmark, Irish Aid, the Ministry of Finance of Japan, the Ministry of Foreign Affairs of the Netherlands, the Norwegian Agency for Development Cooperation (NORAD), the United Kingdom Department for International Development (DFID), and the United States Agency for International Development (USAID). The full list of IAVI donors is available at www.iavi.org. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The contents are the responsibility of the International AIDS Vaccine Initiative and do not necessarily reflect the views of USAID or the United States Government.
Funding Information:
This work was funded by Public Health Service grants R01 AI108421 (D.I.W.) and R37 AI052056 (D.I.W.) from the National Institute of Allergy and Infectious Diseases (NIAID). This work was also funded by PHS grant K01 OD023032 (M.A.M.) from the Office of the Director, National Institutes of Health (NIH). Partial support came from PHS grant R37 AI063928 (R.C.D.) from the NIAID and from federal funds from the Office of Research Infrastructure Programs (P51 OD011106) and the National Cancer Institute, NIH, under contract no. HHSN261200800001E (J.D.L.). Partial support was also provided by the NIAID Division of Intramural Research (P.E. and B.M.). We also acknowledge the Miami Center for AIDS Research (P30 AI073961) for their support. IAVI’s work is made possible by generous support from many donors, including The Bill & Melinda Gates Foundation, the Ministry of Foreign Affairs of Denmark, Irish Aid, the Ministry of Finance of Japan, the Ministry of Foreign Affairs of the Netherlands, the Norwegian Agency for Development Cooperation (NORAD), the United Kingdom Department for International Development (DFID), and the United States Agency for International Development (USAID). The full list of IAVI donors is available at www.iavi.org. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Publisher Copyright:
Copyright © 2020 American Society for Microbiology. All Rights Reserved.
PY - 2020/12
Y1 - 2020/12
N2 - Given the complex biology of human immunodeficiency virus (HIV) and its remarkable capacity to evade host immune responses, HIV vaccine efficacy may benefit from the induction of both humoral and cellular immune responses of maximal breadth, potency, and longevity. Guided by this rationale, we set out to develop an immunization protocol aimed at maximizing the induction of anti-Envelope (anti-Env) antibodies and CD8+ T cells targeting non-Env epitopes in rhesus macaques (RMs). Our approach was to deliver the entire simian immunodeficiency virus (SIV) proteome by serial vaccinations. To that end, 12 RMs were vaccinated over 81 weeks with DNA, modified vaccinia Ankara (MVA), vesicular stomatitis virus (VSV), adenovirus type 5 (Ad5), rhesus monkey rhadinovirus (RRV), and DNA again. Both the RRV and the final DNA boosters delivered a near-full-length SIVmac239 genome capable of assembling noninfectious SIV particles and inducing T-cell responses against all nine SIV proteins. Compared to previous SIV vaccine trials, the present DNA-MVA-VSV-Ad5-RRV-DNA regimen resulted in comparable levels of Env-binding antibodies and SIV-specific CD8+ T-cells. Interestingly, one vaccinee developed low titers of neutralizing antibodies (NAbs) against SIVmac239, a tier 3 virus. Following repeated intrarectal marginal-dose challenges with SIVmac239, vaccinees were not protected from SIV acquisition but manifested partial control of viremia. Strikingly, the animal with the low-titer vaccine-induced anti-SIVmac239 NAb response acquired infection after the first SIVmac239 exposure. Collectively, these results highlight the difficulties in eliciting protective immunity against immunodeficiency virus infection. IMPORTANCE Our results are relevant to HIV vaccine development efforts because they suggest that increasing the number of booster immunizations or delivering additional viral antigens may not necessarily improve vaccine efficacy against immunodeficiency virus infection.
AB - Given the complex biology of human immunodeficiency virus (HIV) and its remarkable capacity to evade host immune responses, HIV vaccine efficacy may benefit from the induction of both humoral and cellular immune responses of maximal breadth, potency, and longevity. Guided by this rationale, we set out to develop an immunization protocol aimed at maximizing the induction of anti-Envelope (anti-Env) antibodies and CD8+ T cells targeting non-Env epitopes in rhesus macaques (RMs). Our approach was to deliver the entire simian immunodeficiency virus (SIV) proteome by serial vaccinations. To that end, 12 RMs were vaccinated over 81 weeks with DNA, modified vaccinia Ankara (MVA), vesicular stomatitis virus (VSV), adenovirus type 5 (Ad5), rhesus monkey rhadinovirus (RRV), and DNA again. Both the RRV and the final DNA boosters delivered a near-full-length SIVmac239 genome capable of assembling noninfectious SIV particles and inducing T-cell responses against all nine SIV proteins. Compared to previous SIV vaccine trials, the present DNA-MVA-VSV-Ad5-RRV-DNA regimen resulted in comparable levels of Env-binding antibodies and SIV-specific CD8+ T-cells. Interestingly, one vaccinee developed low titers of neutralizing antibodies (NAbs) against SIVmac239, a tier 3 virus. Following repeated intrarectal marginal-dose challenges with SIVmac239, vaccinees were not protected from SIV acquisition but manifested partial control of viremia. Strikingly, the animal with the low-titer vaccine-induced anti-SIVmac239 NAb response acquired infection after the first SIVmac239 exposure. Collectively, these results highlight the difficulties in eliciting protective immunity against immunodeficiency virus infection. IMPORTANCE Our results are relevant to HIV vaccine development efforts because they suggest that increasing the number of booster immunizations or delivering additional viral antigens may not necessarily improve vaccine efficacy against immunodeficiency virus infection.
KW - AIDS
KW - Human immunodeficiency virus
KW - Vaccines
UR - http://www.scopus.com/inward/record.url?scp=85096815708&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85096815708&partnerID=8YFLogxK
U2 - 10.1128/JVI.00979-20
DO - 10.1128/JVI.00979-20
M3 - Article
C2 - 33028714
AN - SCOPUS:85096815708
VL - 94
JO - Journal of Virology
JF - Journal of Virology
SN - 0022-538X
IS - 24
M1 - e00979-20
ER -