Breakthrough of SIV strain smE660 challenge in SIV strain mac239-vaccinated rhesus macaques despite potent autologous neutralizing antibody responses

Abstract

Although the correlates of immunological protection from human immunodeficiency virus or simian immunodeficiency virus infection remain incompletely understood, it is generally believed that medium to high titers of serum neutralizing antibodies (nAbs) against the challenge virus will prevent infection. This paradigm is based on a series of studies in which passive transfer of HIV-specific nAbs protected rhesus macaques (RMs) from subsequent mucosal challenge with a chimeric human/simian immunodeficiency virus. However, it is unknown whether nAb titers define protection in the setting of active immunization. Here we determined serum nAb titers against breakthrough transmitted/founder (T/F) SIVsmE660-derived envelope glycoprotein (Env) variants from 14 RMs immunized with SIVmac239-based DNA-prime/modified vaccinia virus Ankara-boost vaccine regimens that included GM-CSF or CD40L adjuvants and conferred significant but incomplete protection against repeated low-dose intrarectal challenge. A single Env variant established infection in all RMs except one, with no identifiable genetic signature associated with vaccination breakthrough compared with T/F Envs from four unvaccinated monkeys. Breakthrough T/F Env pseudoviruses were potently neutralized in vitro by heterologous pooled serum from chronically SIVsmE660-infected monkeys at IC50 titers exceeding 1:1,000,000. Remarkably, the T/F Env pseudoviruses from 13 of 14 monkeys were also susceptible to neutralization by autologous prechallenge serum at in vitro IC50 titers ranging from 1:742–1:10,832. These titers were similar to those observed in vaccinated RMs that remained uninfected. These data suggest that the relationship between serum nAb titers and protection from mucosal SIV challenge in the setting of active immunization is more complex than previously recognized, warranting further studies into the balance between immune activation, target cell availability, and protective antibody responses.

Breakthrough Virus Neutralization Resistance as a Correlate of Protection in a Nonhuman Primate Heterologous Simian Immunodeficiency Virus Vaccine Challenge Study

“…This finding has been questioned in recent analyses of different SIVsmE660 vaccine challenge experiments (46)(47)(48) that showed neither enrichment for the C1 genetic signature nor a neutralization sieve effect (21,58). While the characterization of breakthrough Envs by Burton et al (58) was methodologically similar to our study, the SIV vaccine trials from which the breakthrough TF Envs were identified were substantially different (46)(47)(48).…”

“…First, we aimed to test the concept of vaccine-mediated sieving of neutralization-sensitive viruses and demonstrate a proof-of-concept that these types of studies can be a valuable component of correlates analysis. Second, we aimed to test the predictive capacity of the genetic signature of neutralization resistance found in VRC-10-332 (4), as it has been challenged by posttrial assessments of other SIVsmE660 vaccine challenge studies (21,58). Third, we sought to assess the impact of the unique pattern of diversity in neutralization sensitivity of the SIVsmE660 challenge stock (20) on the outcome and interpretation of data from a preclinical trial of a vaccine that generated a substantial antibody-mediated immune response (4).…”

Adjuvanting a Simian Immunodeficiency Virus Vaccine with Toll-Like Receptor Ligands Encapsulated in Nanoparticles Induces Persistent Antibody Responses and Enhanced Protection in TRIM5α Restrictive Macaques

“…Virus neutralization assays were carried out as described previously (62,63). The SIVsmE660.11 Env pseudovirus was generated by transfecting Env-expressing plasmid DNA alongside HIV-1 SG3Δ Env proviral backbone DNA into 293T cells, using the Fugene HD reagent as recommended by the manufacturer (Promega).…”

Signatures in Simian Immunodeficiency Virus SIVsmE660 Envelope gp120 Are Associated with Mucosal Transmission but Not Vaccination Breakthrough in Rhesus Macaques

“…A primary focus of nonhuman primate simian immunodeficiency virus (SIV) challenge models is therefore to recapitulate the critical events that occur during HIV-1 transmission so that any observed effect, including protection, is accurately reflected by the model. An approach in which rhesus macaques are inoculated intravaginally or intrarectally at regular intervals with a relatively low dose of SIV has been shown to recapitulate the hallmark reduction in viral diversity characteristic of HIV-1 transmission (11)(12)(13)(14). As a result, the repeated, low-dose challenge method has become widely accepted and commonly utilized to model protection against mucosal SIV infection (14-32).…”

“…An approach in which rhesus macaques are inoculated intravaginally or intrarectally at regular intervals with a relatively low dose of SIV has been shown to recapitulate the hallmark reduction in viral diversity characteristic of HIV-1 transmission (11)(12)(13)(14). As a result, the repeated, low-dose challenge method has become widely accepted and commonly utilized to model protection against mucosal SIV infection ( [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32]. Despite these numerous studies, the characteristics of the virus that influence intravaginal and intrarectal transmission and protection are incompletely understood.…”