Improving Vaccine-Induced Immunity: Can Baseline Predict Outcome?

Immune signatures measured at baseline and immediately prior to vaccination may predict the immune response to vaccination. Such pre-vaccine assessment might allow not only population-based, but also more personalized vaccination strategies ('precision vaccination'). If baseline immune signatures are predictive, the underlying mechanism they reflect may also determine vaccination outcome. Thus, baseline signatures might contribute to identifying interventional targets to be modulated prior to vaccination in order to improve vaccination responses. This concept has the potential to transform vaccination strategies and usher in a new approach to improve global health

Macaques vaccinated with live-attenuated SIV control replication of heterologous virus

An effective AIDS vaccine will need to protect against globally diverse isolates of HIV. To address this issue in macaques, we administered a live-attenuated simian immunodeficiency virus (SIV) vaccine and challenged with a highly pathogenic heterologous isolate. Vaccinees reduced viral replication by ∼2 logs between weeks 2–32 (P ≤ 0.049) postchallenge. Remarkably, vaccinees expressing MHC-I (MHC class I) alleles previously associated with viral control completely suppressed acute phase replication of the challenge virus, implicating CD8+ T cells in this control. Furthermore, transient depletion of peripheral CD8+ lymphocytes in four vaccinees during the chronic phase resulted in an increase in virus replication. In two of these animals, the recrudescent virus population contained only the vaccine strain and not the challenge virus. Alarmingly, however, we found evidence of recombinant viruses emerging in some of the vaccinated animals. This finding argues strongly against an attenuated virus vaccine as a solution to the AIDS epidemic. On a more positive note, our results suggest that MHC-I–restricted CD8+ T cells contribute to the protection induced by the live-attenuated SIV vaccine and demonstrate that vaccine-induced CD8+ T cell responses can control replication of heterologous challenge viruses

Стилистический эффект разговорной речи и его составляющие

В обучении русскому языку как иностранному на современном этапе большое внимание уделяется особенностям русской разговорной речи. Это обусловлено целым рядом причин, среди которых, на наш взгляд, можно выделить следующие: во-первых, разговорная речь всегда отличается активностью проникновения во все сферы жизнедеятельности людей и функционирует как в повседневном общении, так и в различных сферах (литературе, кино, политике и т.д.). Во-вторых, разговорная речь носит многожанровый характер, что зачастую затрудняет ее понимание иностранными студентами. В-третьих, в разговорную речь помимо слов нейтрального стиля все активнее стала проникать арготическая лексика. Именно в связи с этим особый интерес у нас вызывает разговорный стиль речи в преломлении на инофонную аудиторию

Multi-Omic Data Integration Allows Baseline Immune Signatures to Predict Hepatitis B Vaccine Response in a Small Cohort

Background: Vaccination remains one of the most effective means of reducing the burden of infectious diseases globally. Improving our understanding of the molecular basis for effective vaccine response is of paramount importance if we are to ensure the success of future vaccine development efforts. Methods: We applied cutting edge multi-omics approaches to extensively characterize temporal molecular responses following vaccination with hepatitis B virus (HBV) vaccine. Data were integrated across cellular, epigenomic, transcriptomic, proteomic, and fecal microbiome profiles, and correlated to final HBV antibody titres. Results: Using both an unsupervised molecular-interaction network integration method (NetworkAnalyst) and a data-driven integration approach (DIABLO), we uncovered baseline molecular patterns and pathways associated with more effective vaccine responses to HBV. Biological associations were unravelled, with signalling pathways such as JAK-STAT and interleukin signalling, Toll-like receptor cascades, interferon signalling, and Th17 cell differentiation emerging as important pre-vaccination modulators of response. Conclusion: This study provides further evidence that baseline cellular and molecular characteristics of an individual’s immune system influence vaccine responses, and highlights the utility of integrating information across many parallel molecular datasets

Broadly Neutralizing Human Anti-HIV Antibody 2G12 Is Effective in Protection against Mucosal SHIV Challenge Even at Low Serum Neutralizing Titers

Developing an immunogen that elicits broadly neutralizing antibodies (bNAbs) is an elusive but important goal of HIV vaccine research, especially after the recent failure of the leading T cell based HIV vaccine in human efficacy trials. Even if such an immunogen can be developed, most animal model studies indicate that high serum neutralizing concentrations of bNAbs are required to provide significant benefit in typical protection experiments. One possible exception is provided by the anti-glycan bNAb 2G12, which has been reported to protect macaques against CXCR4-using SHIV challenge at relatively low serum neutralizing titers. Here, we investigated the ability of 2G12 administered intravenously (i.v.) to protect against vaginal challenge of rhesus macaques with the CCR5-using SHIVSF162P3. The results show that, at 2G12 serum neutralizing titers of the order of 1∶1 (IC90), 3/5 antibody-treated animals were protected with sterilizing immunity, i.e. no detectable virus replication following challenge; one animal showed a delayed and lowered primary viremia and the other animal showed a course of infection similar to 4 control animals. This result contrasts strongly with the typically high titers observed for protection by other neutralizing antibodies, including the bNAb b12. We compared b12 and 2G12 for characteristics that might explain the differences in protective ability relative to neutralizing activity. We found no evidence to suggest that 2G12 transudation to the vaginal surface was significantly superior to b12. We also observed that the ability of 2G12 to inhibit virus replication in target cells through antibody-mediated effector cell activity in vitro was equivalent or inferior to b12. The results raise the possibility that some epitopes on HIV may be better vaccine targets than others and support targeting the glycan shield of the envelope

Influence of HAART on Alternative Reading Frame Immune Responses over the Course of HIV-1 Infection

Background: Translational errors can result in bypassing of the main viral protein reading frames and the production of alternate reading frame (ARF) or cryptic peptides. Within HIV, there are many such ARFs in both sense and the antisense directions of transcription. These ARFs have the potential to generate immunogenic peptides called cryptic epitopes (CE). Both antiretroviral drug therapy and the immune system exert a mutational pressure on HIV-1. Immune pressure exerted by ARF CD8(+) T cells on the virus has already been observed in vitro. HAART has also been described to select HIV-1 variants for drug escape mutations. Since the mutational pressure exerted on one location of the HIV-1 genome can potentially affect the 3 reading frames, we hypothesized that ARF responses would be affected by this drug pressure in vivo. Methodology/Principal findings: In this study we identified new ARFs derived from sense and antisense transcription of HIV-1. Many of these ARFs are detectable in circulating viral proteins. They are predominantly found in the HIV-1 env nucleotide region. We measured T cell responses to 199 HIV-1 CE encoded within 13 sense and 34 antisense HIV-1 ARFs. We were able to observe that these ARF responses are more frequent and of greater magnitude in chronically infected individuals compared to acutely infected patients, and in patients on HAART, the breadth of ARF responses increased. Conclusions/Significance: These results have implications for vaccine design and unveil the existence of potential new epitopes that could be included as vaccine targets.International AIDS Vaccine Initiative (IAVI

Structural Repertoire of HIV-1-Neutralizing Antibodies Targeting the CD4 Supersite in 14 Donors

The site on the HIV-1 gp120 glycoprotein that binds the CD4 receptor is recognized by broadly reactive antibodies, several of which neutralize over 90% of HIV-1 strains. To understand how antibodies achieve such neutralization, we isolated CD4-binding-site (CD4bs) antibodies and analyzed 16 co-crystal structures –8 determined here– of CD4bs antibodies from 14 donors. The 16 antibodies segregated by recognition mode and developmental ontogeny into two types: CDR H3-dominated and VH-gene-restricted. Both could achieve greater than 80% neutralization breadth, and both could develop in the same donor. Although paratope chemistries differed, all 16 gp120-CD4bs antibody complexes showed geometric similarity, with antibody-neutralization breadth correlating with antibody-angle of approach relative to the most effective antibody of each type. The repertoire for effective recognition of the CD4 supersite thus comprises antibodies with distinct paratopes arrayed about two optimal geometric orientations, one achieved by CDR H3 ontogenies and the other achieved by VH-gene-restricted ontogenies

The Human Vaccines Project: Towards a comprehensive understanding of the human immune response to immunization

Although the success of vaccination to date has been unprecedented, our inadequate understanding of the details of the human immune response to immunization has resulted in several recent vaccine failures and significant delays in the development of high-need vaccines for global infectious diseases and cancer. Because of the need to better understand the immense complexity of the human immune system, the Human Vaccines Project was launched in 2015 with the mission to decode the human immune response to accelerate development of vaccines and immunotherapies for major diseases. The Project currently has three programs: 1) The Human Immunome Program, with the goal of deciphering the complete repertoire of B and T cell receptors across the human population, termed the Human Immunome, 2) The Rules of Immunogenicity Program, with the goal of understanding the key principles of how a vaccine elicits a protective and durable response using a system immunology approach, and 3) The Universal Influenza Vaccine Initiative (UIVI), with the goal of conducting experimental clinical trials to understand the influence of influenza pre-exposures on subsequent influenza immunization and the mechanisms of protection. Given the dramatic advances in computational and systems biology, genomics, immune monitoring, bioinformatics and machine learning, there is now an unprecedented opportunity to unravel the intricacies of the human immune response to immunization, ushering in a new era in vaccine development