Repeated Low-Dose Mucosal Simian Immunodeficiency Virus SIVmac239 Challenge Results in the Same Viral and Immunological Kinetics as High-Dose Challenge: a Model for the Evaluation of Vaccine Efficacy in Nonhuman Primates

Abstract

Simian immunodeficiency virus (SIV) challenge of rhesus macaques provides a relevant model for the assessment of human immunodeficiency virus (HIV) vaccine strategies. To ensure that all macaques become infected, the vaccinees and controls are exposed to large doses of pathogenic SIV. These nonphysiological high-dose challenges may adversely affect vaccine evaluation by overwhelming potentially efficacious vaccine responses. To determine whether a more physiologically relevant low-dose challenge can initiate infection and cause disease in Indian rhesus macaques, we used a repeated low-dose challenge strategy designed to reduce the viral inoculum to more physiologically relevant doses. In an attempt to more closely mimic challenge with HIV, we administered repeated mucosal challenges with 30, 300, and 3,000 50% tissue culture infective doses (TCID 50 ) of pathogenic SIVmac239 to six animals in three groups. Infection was assessed by sensitive quantitative reverse transcription-PCR and was achieved following a mean of 8, 5.5, and 1 challenge(s) in the 30, 300, and 3,000 TCID 50 groups, respectively. Mortality, humoral immune responses, and peak plasma viral kinetics were similar in five of six animals, regardless of challenge dose. Interestingly, macaques challenged with lower doses of SIVmac239 developed broad T-cell immune responses as assessed by ELISPOT assay. This low-dose repeated challenge may be a valuable tool in the evaluation of potential vaccine regimes and offers a more physiologically relevant regimen for pathogenic SIVmac239 challenge experiments.

Multiple Vaccine-Elicited Nonneutralizing Antienvelope Antibody Activities Contribute to Protective Efficacy by Reducing both Acute and Chronic Viremia following Simian/Human Immunodeficiency Virus SHIV89.6PChallenge in Rhesus Macaques

“…In contrast to the outcome of the RV144 human trial, protection from SHIV acquisition was not achieved; however, this may reflect the single high-dose intravenous challenge used here in the nonhuman primate protocol. Others have suggested that a repetitive low-dose challenge is more comparable to the human situation (37,46,62), and in fact protection from systemic infection following repeated lowdose challenge has been demonstrated with some immunized macaques (33). Protective efficacy elicited by our replicating Ad-recombinant prime/envelope boost regimen against a repetitive low-dose challenge will be evaluated in future preclinical studies.…”

Characterization and Implementation of a Diverse Simian Immunodeficiency Virus SIVsm Envelope Panel in the Assessment of Neutralizing Antibody Breadth Elicited in Rhesus Macaques by Multimodal Vaccines Expressing the SIVmac239 Envelope

“…SIV vaccine models should faithfully model the biology of HIV-1 acquisition (1). To mimic HIV-1 transmission, current SIV-based nonhuman primate vaccine approaches, including those studied here, generally utilize a low-to moderate-dose repeat mucosal challenge with a viral quasispecies, such as neutralization-sensitive SIVsmE660 or neutralization-resistant SIVmac251 (124,125). SIVsmE660 serves as a heterologous challenge virus for SIVmac239 immunogens, because, unlike SIVmac251, it is genetically distinct from SIVmac239.…”

AIDS Vaccines and Preexposure Prophylaxis: Is Synergy Possible?

“…[56][57][58] By reducing initial HIV viral replication, PrEP might convert a strong HIV ''challenge'' (through natural exposure) into a weaker challenge that a modest level of vaccine-induced immunity could overcome, preventing establishment of HIV infection or leading to a lower viral load and slower disease progression in the long term. Additionally, when given around the time of vaccination, PrEP might provide a protective ''cover'' if there is a transient period of enhanced susceptibility during and shortly after vaccination, followed by a period of immunity.…”