Date Published: September 30, 2019
Publisher: Public Library of Science
Author(s): 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, Daniel C. Douek.
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.
Human immunodeficiency virus (HIV) continues to infect thousands of new people every day, despite advances in prevention modalities and antiretroviral therapy coverage . Mathematical models have suggested that combining current HIV prevention and treatment strategies with a prophylactic HIV vaccine could significantly restrict the growth of the HIV pandemic . Unfortunately, however, developing such a vaccine has been exceedingly difficult, as seen by the failure of most HIV vaccine trials conducted to date [3–7]. Although the RV144 trial remains the only report of vaccine-mediated reduction in HIV infection rates , the observed results were modest, short-lived, and continue to be questioned [9, 10]. Given the refractoriness of HIV to immune responses induced by conventional immunization protocols, new or unorthodox approaches may be needed to generate protective anti-HIV immunity.
Experimental challenge of RMs with SIV provides a valuable system for identifying immune correlates of protection and selecting the most promising vaccine approaches for human testing . Because a successful outcome in this model can be used to justify costly clinical trials, it is critical that the efficacy of pre-clinical AIDS vaccine concepts be assessed against stringent challenge viruses. The SIVmac239 molecular clone is well suited for this purpose. Consistent with its neutralization resistance and high replicative capacity in Indian-origin RMs, vaccine protection against SIVmac239 acquisition is exceedingly difficult to achieve, even when there is a complete match between vaccine-encoded sequences and the challenge virus. Several vaccine trials have reported significant reductions in post-acquisition SIVmac239 viremia in RMs but no protection from infection [29–34]. Even the rhesus cytomegalovirus-based vaccine platform developed by Picker and colleagues, which results in profound control and eventual clearance of SIVmac239 infection in half of vaccinees [35–37], does not block acquisition of SIVmac239. In fact, live-attenuated strains of SIVmac239 (e.g., SIVmac239Δnef) remain the only vaccine modality to consistently afford significant levels of apparent sterilizing immunity against SIVmac239 challenge in Indian-origin RMs [38–40]. Given the stringency of this challenge model, it is remarkable that following repeated IR challenges with SIVmac239, the Group 1 (rDNA/rRRV-SIVnfl) vaccine regimen significantly decreased the per-exposure probability of infection by 78%. This result is reinforced by our recent demonstration that delivery of the same vectors in reverse order (i.e., rRRV-SIVnfl prime/rDNA-SIVnfl boost) also significantly reduced the per-exposure probability of IV SIVmac239 infection by 79% in RMs . While the mechanisms of this protection remain unknown, we posit that the use of SIVnfl to prime and, in the case of the rRRV-SIVnfl vectors, continually boost SIV-specific immune responses facilitated the induction of protective anti-SIVmac239 immunity. From the standpoint of HIV vaccination, immunization with near full-length (nfl) viral genomes has both practical and biological advantages. For example, delivering the entire HIV proteome in a single rDNA plasmid or viral vector, as opposed to different genes in separate constructs, would likely reduce manufacturing costs and face fewer regulatory barriers down the translational pipeline. Additionally, since B-cells tend to respond with high avidity to virus-sized antigens , a properly adjuvanted HIVnfl-based vaccine could be expected to elicit high titers of anti-Env Ab responses, especially if this vaccine contains modifications to stabilize Env trimers and increase their surface expression . Furthermore, based on the ability of the SIVnfl insert to induce CD8+ T-cell responses against the entire SIV proteome, an HIVnfl-based vaccine could also be useful for generating broadly-targeted HIV-specific CD8+ T-cell responses, thereby providing an extra line of defense in the event of HIV transmission.