Identification of a Consolidation Phase in Immunological Memory

Long lasting antibody responses and immunological memory are the desired outcomes of vaccination. In general, multiple vaccine doses result in enhanced immune responses, a notable exception being booster-induced hyporesponsiveness, which has been observed with polysaccharide and glycoconjugate vaccines. In this study, we analyzed the effect of early booster doses of multimeric protein vaccine (1-11)E2 on recall memory to B epitope 1-11 of β-amyloid. Mice immunized with a single dose of (1-11)E2 stochastically display, when immunized with a recall dose 9 months later, either memory, i.e., an enhanced response to epitope 1-11, or hyporesponsiveness, i.e., a reduced response. Memory is the most common outcome, achieved by 80% of mice. We observed that a booster dose of vaccine (1-11)E2 at day 15 significantly reduced the ratio between the magnitude of the secondary and primary response, causing an increase of hyporesponsive mice. This booster-dependent disruption of recall memory only occurred in a limited time window: a booster dose at day 21 had no significant effect on the ratio between the secondary and primary response magnitude. Thus, this study identifies a consolidation phase in immunological memory, that is a time window during which the formation of memory is vulnerable, and a disrupting stimulus reduces the probability that memory is achieved

Vaccination with (1-11)E2 in alum efficiently induces an antibody response to β-amyloid without affecting brain β-amyloid load and microglia activation in 3xTg mice.

peer reviewedImmunization against β-amyloid (Aβ) is pursued as a possible strategy for the prevention of Alzheimer's disease (AD). In clinical trials, Aβ 1-42 proved poorly immunogenic and caused severe adverse effects; therefore, safer and more immunogenic candidate vaccines are needed. Multimeric protein (1-11)E2 is able to induce an antibody response to Aβ, immunological memory, and IL-4 production, with no concomitant anti-Aβ T cell response. Antisera recognize Aβ oligomers, protofibrils, and fibrils. In this study, we evaluated the effect of prophylactic immunization with three doses of (1-11)E2 in alum in the 3xTg mouse model of AD. Immunization with (1-11)E2 efficiently induced anti-Aβ antibodies, but afforded no protection against Aβ accumulation and neuroinflammation. The identification of the features of the anti-Aβ immune response that correlate with the ability to prevent Aβ accumulation remains an open problem that deserves further investigation

Filamentous Bacteriophage Fd as an Antigen Delivery System in Vaccination

Peptides displayed on the surface of filamentous bacteriophage fd are able to induce humoral as well as cell-mediated immune responses, which makes phage particles an attractive antigen delivery system to design new vaccines. The immune response induced by phage-displayed peptides can be enhanced by targeting phage particles to the professional antigen presenting cells, utilizing a single-chain antibody fragment that binds dendritic cell receptor DEC-205. Here, we review recent advances in the use of filamentous phage fd as a platform for peptide vaccines, with a special focus on the use of phage fd as an antigen delivery platform for peptide vaccines in Alzheimer’s Disease and cancer

Massive-Scale RNA-Seq Analysis of Non Ribosomal Transcriptome in Human Trisomy 21

Hybridization- and tag-based technologies have been successfully used in Down syndrome to identify genes involved in various aspects of the pathogenesis. However, these technologies suffer from several limits and drawbacks and, to date, information about rare, even though relevant, RNA species such as long and small non-coding RNAs, is completely missing. Indeed, none of published works has still described the whole transcriptional landscape of Down syndrome. Although the recent advances in high-throughput RNA sequencing have revealed the complexity of transcriptomes, most of them rely on polyA enrichment protocols, able to detect only a small fraction of total RNA content. On the opposite end, massive-scale RNA sequencing on rRNA-depleted samples allows the survey of the complete set of coding and non-coding RNA species, now emerging as novel contributors to pathogenic mechanisms. Hence, in this work we analysed for the first time the complete transcriptome of human trisomic endothelial progenitor cells to an unprecedented level of resolution and sensitivity by RNA-sequencing. Our analysis allowed us to detect differential expression of even low expressed genes crucial for the pathogenesis, to disclose novel regions of active transcription outside yet annotated loci, and to investigate a plethora of non-polyadenilated long as well as short non coding RNAs. Novel splice isoforms for a large subset of crucial genes, and novel extended untranslated regions for known genes—possibly novel miRNA targets or regulatory sites for gene transcription—were also identified in this study. Coupling the rRNA depletion of samples, followed by high-throughput RNA-sequencing, to the easy availability of these cells renders this approach very feasible for transcriptome studies, offering the possibility of investigating in-depth blood-related pathological features of Down syndrome, as well as other genetic disorders

Memory immune response: a major challenge in vaccination

AbstractA crucial challenge for vaccine development is to design vaccines that induce a long-lasting protective immune response, i.e., immune memory. The persistence of antigen-specific antibody titers over a protective threshold, and the ability to exibit a 'recall response' to a subsequent encounter with an antigen have long been the only measurable correlates of vaccine take and immune memory development, suffering from the disadvantage of relying on long-term monitoring of the immune response. In the last few years, advances in the technologies for the identification and characterization of the cell subsets and molecular pathways involved in the immune response to vaccination have allowed innovative approaches to the identification of early correlates of immune memory. In this review, we discuss recent data and hypotheses on early correlates of the development of immune memory, with special emphasis on the gene expression signatures that underlie the self-renewal ability of some lymphocyte subsets, and their similarities with gene expression signatures in stem cells

Analysis of the Consolidation Phase of Immunological Memory within the IgG Response to a B Cell Epitope Displayed on a Filamentous Bacteriophage

Immunological memory can be defined as the ability to mount a response of greater magnitude and with faster kinetics upon re-encounter of the same antigen. We have previously reported that a booster dose of a protein antigen given 15 days after the first dose interferes with the development of memory, i.e., with the ability to mount an epitope-specific IgG response of greater magnitude upon re-encounter of the same antigen. We named the time-window during which memory is vulnerable to disruption a “consolidation phase in immunological memory”, by analogy with the memory consolidation processes that occur in the nervous system to stabilize memory traces. In this study, we set out to establish if a similar memory consolidation phase occurs in the IgG response to a B cell epitope displayed on a filamentous bacteriophage. To this end, we have analyzed the time-course of anti-β-amyloid IgG titers in mice immunized with prototype Alzheimer’s Disease vaccine fdAD(2-6), which consists of a fd phage that displays the B epitope AEFRH of β -amyloid at the N-terminus of the Major Capsid Protein. A booster dose of phage fdAD(2-6) given 15 days after priming significantly reduced the ratio between the magnitude of the secondary and primary IgG response to β-amyloid. This analysis confirms, in a phage vaccine, a consolidation phase in immunological memory, occurring two weeks after priming

Arming Filamentous Bacteriophage, a Nature-Made Nanoparticle, for New Vaccine and Immunotherapeutic Strategies

The pharmaceutical use of bacteriophages as safe and inexpensive therapeutic tools is collecting renewed interest. The use of lytic phages to fight antibiotic-resistant bacterial strains is pursued in academic and industrial projects and is the object of several clinical trials. On the other hand, filamentous bacteriophages used for the phage display technology can also have diagnostic and therapeutic applications. Filamentous bacteriophages are nature-made nanoparticles useful for their size, the capability to enter blood vessels, and the capacity of high-density antigen expression. In the last decades, our laboratory focused its efforts in the study of antigen delivery strategies based on the filamentous bacteriophage ‘fd’, able to trigger all arms of the immune response, with particular emphasis on the ability of the MHC class I restricted antigenic determinants displayed on phages to induce strong and protective cytotoxic responses. We showed that fd bacteriophages, engineered to target mouse dendritic cells (DCs), activate innate and adaptive responses without the need of exogenous adjuvants, and more recently, we described the display of immunologically active lipids. In this review, we will provide an overview of the reported applications of the bacteriophage carriers and describe the advantages of exploiting this technology for delivery strategies

HIV Vaccination: A Roadmap among Advancements and Concerns

Since the identification of the Human Immunodeficiency Virus type 1 (HIV-1) as the etiologic agent of AIDS (Acquired Immunodeficiency Syndrome), many efforts have been made to stop the AIDS pandemic. A major success of medical research has been the development of the highly active antiretroviral therapy and its availability to an increasing number of people worldwide, with a considerable effect on survival. However, a safe and effective vaccine able to prevent and eradicate the HIV pandemic is still lacking. Clinical trials and preclinical proof-of-concept studies in nonhuman primate (NHP) models have provided insights into potential correlates of protection against the HIV-1 infection, which include broadly neutralizing antibodies (bnAbs), non-neutralizing antibodies targeting the variable loops 1 and 2 (V1V2) regions of the HIV-1 envelope (Env), polyfunctional antibody, and Env-specific T-cell responses. In this review, we provide a brief overview of different HIV-1 vaccine approaches and discuss the current understanding of the cellular and humoral correlates of HIV-1 immunity