Live-virus exposure of vaccine-protected macaques alters the anti-HIV-1 antibody repertoire in the absence of viremia

Background: We addressed the question whether live-virus challenges could alter vaccine-induced antibody (Ab) responses in vaccinated rhesus macaques (RMs) that completely resisted repeated exposures to R5-tropic simian-human immunodeficiency viruses encoding heterologous HIV clade C envelopes (SHIV-Cs). Results: We examined the Ab responses in aviremic RMs that had been immunized with a multi-component protein vaccine (multimeric HIV-1 gp160, HIV-1 Tat and SIV Gag-Pol particles) and compared anti-Env plasma Ab titers before and after repeated live-virus exposures. Although no viremia was ever detected in these animals, they showed significant increases in anti-gp140 Ab titers after they had encountered live SHIVs. When we investigated the dynamics of anti-Env Ab titers during the immunization and challenge phases further, we detected the expected, vaccine-induced increases of Ab responses about two weeks after the last protein immunization. Remarkably, these titers kept rising during the repeated virus challenges, although no viremia resulted. In contrast, in vaccinated RMs that were not exposed to virus, anti-gp140 Ab titers declined after the peak seen two weeks after the last immunization. These data suggest boosting of pre-existing, vaccine-induced Ab responses as a consequence of repeated live-virus exposures. Next, we screened polyclonal plasma samples from two of the completely protected vaccinees by peptide phage display and designed a strategy that selects for recombinant phages recognized only by Abs present after – but not before – any SHIV challenge. With this “subtractive biopanning” approach, we isolated V3 mimotopes that were only recognized after the animals had been exposed to live virus. By detailed epitope mapping of such anti-V3 Ab responses, we showed that the challenges not only boosted pre-existing binding and neutralizing Ab titers, but also induced Abs targeting neo-antigens presented by the heterologous challenge virus. Conclusions: Anti-Env Ab responses induced by recombinant protein vaccination were altered by the multiple, live SHIV challenges in vaccinees that had no detectable viral loads. These data may have implications for the interpretation of “vaccine only” responses in clinical vaccine trials

Inducing Cross-Clade Neutralizing Antibodies against HIV-1 by Immunofocusing

Background: Although vaccines are important in preventing viral infections by inducing neutralizing antibodies (nAbs), HIV-1 has proven to be a difficult target and escapes humoral immunity through various mechanisms. We sought to test whether HIV-1 Env mimics may serve as immunogens. Methodology/Principal Findings: Using random peptide phage display libraries, we identified the epitopes recognized by polyclonal antibodies of a rhesus monkey that had developed high-titer, broadly reactive nAbs after infection with a simian-human immunodeficiency virus (SHIV) encoding env of a recently transmitted HIV-1 clade C (HIV-C). Phage peptide inserts were analyzed for conformational and linear homology using computational analysis; some peptides mimicked various domains of the original HIV-C Env, such as conformational V3 loop epitopes and the conserved linear region of the gp120 C-terminus. Next, we devised a novel prime/boost strategy to test the immunogenicity of such phage-displayed peptides and primed mice only once with HIV-C gp160 DNA followed by boosting with mixtures of recombinant phages. Conclusions/Significance: This strategy, which was designed to focus the immune system on a few Env epitopes (immunofocusing), not only induced HIV-C gp160 binding antibodies and cross-clade nAbs, but also linked a conserved HIV Env region for the first time to the induction of nAbs: the C-terminus of gp120. The identification of conserved antigen mimics may lead to novel immunogens capable of inducing broadly reactive nAbs

Modified Lattice of the Compact Storage Ring in the cSTART Project at Karlsruhe Institute of Technology

A very large ac­cep­tance com­pact stor­age ring (VLA-cSR) is under de­sign at the In­sti­tute for Beam Physics and Tech­nol­ogy (IBPT) of the Karl­sruhe In­sti­tute of Tech­nol­ogy (KIT, Ger­many). The com­bi­na­tion of a com­pact stor­age ring and a laser wake­field ac­cel­er­a­tor (LWFA) might be the basis for fu­ture com­pact light sources and ad­vanc­ing user fa­cil­i­ties. Mean­while, the post-LWFA beam should be adapted for stor­age and ac­cu­mu­la­tion in a ded­i­cated stor­age ring. Mod­i­fied geom­e­try and lat­tice of a VLA-cSR op­er­at­ing at 50 MeV en­ergy range have been stud­ied in de­tailed sim­u­la­tions. The main fea­tures of a new model are de­scribed here. The new de­sign, based on 45° bend­ing mag­nets, is suit­able to store the post-LWFA beam with a wide mo­men­tum spread (1% to 2%) as well as ul­tra-short elec­tron bunches in the fs range from the Fer­n­in­frarot Linac- Und Test- Ex­per­i­ment (FLUTE). The DBA-FDF lat­tice with re­laxed set­tings, split el­e­ments, and higher-or­der op­tics of tol­er­a­ble strength al­lows im­prov­ing the dy­namic aper­ture to an ac­cept­able level. This con­tri­bu­tion dis­cusses the lat­tice fea­tures in de­tail and dif­fer­ent pos­si­ble op­er­a­tion schemes of a VLA-cSR

On Possibility of Alpha-buckets Detecting at the KIT Storage Ring KARA (Karlsruhe Research Accelerator)

Computer studies of longitudinal motion have been performed with the objective to estimate the possibility of detection of alpha-buckets at the KIT storage ring KARA (Karlsruhe Research Accelerator). The longitudinal equations of motion and the Hamiltonian were expanded to high order terms of the energy deviation of particles in a beam. Roots of third order equation for three leading terms of momentum compaction factor and free energy independent term were derived in a form suitable for analytical estimations. Averaged quadratic terms of closed orbit distortions caused by misalignment of magnetic elements in a ring lead to orbit lengthening independent of particle energy deviation. Particle transverse excursions were estimated and are taken into account. Simulations have been bench-marked on existing experiments at Metrology Light Source (MLS) in Berlin (Germany) and SOLEIL (France). Parameters of three simultaneous beams and alpha buckets at MLS and SOLEIL have been reproduced with high accuracy. A computer model of KARA was used to predict behavior and the dynamics of possible simultaneous beams in the ring

Full Characterization of the Bunch-Compressor Dipoles for FLUTE

The Ferninfrarot Linac- Und Test-Experiment (FLUTE) is a KIT-operated linac-based test facility for accelerator research and development as well as a compact, ultra-broadband and short-pulse terahertz (THz) source. As a key component of FLUTE, the bunch compressor (chicane) consisting of four specially designed dipoles will be used to compress the 40-50 MeV electron bunches after the linac down to single fs bunch length. The maximum vertical magnetic field of the dipoles reach 0.22 T, with an effective length of 200 mm. The good field region is ±40 mm and ±10.5 mm in the horizontal and vertical direction, respectively. The latest measurement results of the dipoles in terms of field homogeneity, excitation and field reproducibility within the good field regions will be reported, which meet the predefined specifications. The measured 3D magnetic field distributions have been used to perform beam dynamics simulations of the bunch compressor. Effects of the real field properties on the beam dynamics, which are different from that of the ASTRA built-in dipole field, will be discussed

Effect of Negative Momentum Compaction Operation on the Current- Dependent Bunch Length

New operation modes are often considered during the development of new synchrotron light sources. An understanding of the effects involved is inevitable for a successful operation of these schemes. At the KIT storage ring KARA (Karlsruhe Research Accelerator), new modes can be implemented and tested at various energies, employing a variety of performant beam diagnostics devices. Negative momentum compaction optics at various energies have been established. Also, the influence of a negative momentum compaction factor on different effects has been investigated. This contribution comprises a short report on the status of the implementation of a negative momentum compaction optics at KARA. Additionally, first measurements of the changes to the current-dependent bunch length will be presented