Breadth Of Responses Research Articles

The Immune Response to Respiratory Viruses: From Start to Memory.

Biomedical research has long strived to improve our understanding of the immune response to respiratory viral infections, an effort that has become all the more important as we live through the consequences of a pandemic. The disease course of these infections is shaped in large part by the actions of various cells of the innate and adaptive immune systems. While these cells are crucial in clearing viral pathogens and establishing long-term immunity, their effector mechanisms may also escalate into excessive, tissue-destructive inflammation detrimental to the host. In this review, we describe the breadth of the immune response to infection with respiratory viruses such as influenza and respiratory syncytial virus. Throughout, we focus on the host rather than the pathogen and try to describe shared patterns in the host response to different viruses. We start with the local cells of the airways, onto the recruitment and activation of innate and adaptive immune cells, followed by the establishment of local and systemic memory cells key in protection against reinfection. We end by exploring how respiratory viral infections can predispose to bacterial superinfection.

Characterization of Naturally Acquired Immunity to a Panel of Antigens Expressed in Mature P. falciparum Gametocytes.

IntroductionNaturally acquired immune responses against antigens expressed on the surface of mature gametocytes develop in individuals living in malaria-endemic areas. Evidence suggests that such anti-gametocyte immunity can block the development of the parasite in the mosquito, thus playing a role in interrupting transmission. A better comprehension of naturally acquired immunity to these gametocyte antigens can aid the development of transmission-blocking vaccines and improve our understanding of the human infectious reservoir.MethodsAntigens expressed on the surface of mature gametocytes that had not previously been widely studied for evidence of naturally acquired immunity were identified for protein expression alongside Pfs230-C using either the mammalian HEK293E or the wheat germ cell-free expression systems. Where there was sequence variation in the candidate antigens (3D7 vs a clinical isolate PfKE04), both variants were expressed. ELISA was used to assess antibody responses against these antigens, as well as against crude stage V gametocyte extract (GE) and AMA1 using archived plasma samples from individuals recruited to participate in malaria cohort studies. We analyzed antibody levels (estimated from optical density units using a standardized ELISA) and seroprevalence (defined as antibody levels greater than three standard deviations above the mean levels of a pool of malaria naïve sera). We described the dynamics of antibody responses to these antigens by identifying factors predictive of antibody levels using linear regression models.ResultsOf the 25 antigens selected, seven antigens were produced successfully as recombinant proteins, with one variant antigen, giving a total of eight proteins for evaluation. Antibodies to the candidate antigens were detectable in the study population (N = 216), with seroprevalence ranging from 37.0% (95% CI: 30.6%, 43.9%) for PSOP1 to 77.8% (95% CI: 71.6%, 83.1%) for G377 (3D7 variant). Responses to AMA1 and GE were more prevalent than those to the gametocyte proteins at 87.9% (95% CI: 82.8%, 91.9%) and 88.3% (95% CI: 83.1%, 92.4%), respectively. Additionally, both antibody levels and breadth of antibody responses were associated with age and concurrent parasitaemia.ConclusionAge and concurrent parasitaemia remain important determinants of naturally acquired immunity to gametocyte antigens. Furthermore, we identify novel candidates for transmission-blocking activity evaluation.

Complex Interactions Between Human Immunodeficiency Virus Type-1, Sex, and Osteopontin Influence Viral Replication and Leukocyte Proportions in Tissues

Evidence suggesting that HIV pathogenesis differs by sex, a variable known to influence the extent and breadth of immune responses in health and disease continues to accumulate. Host factors that promote or inhibit HIV replication may do so in a way that varies by sex. Prior studies using cultured human macrophages demonstrated that osteopontin (OPN)/secreted phosphoprotein-1 (SPP1) stimulates HIV replication. To test whether OPN has the same positive impact on virus replication at the level of tissues, we used a humanized mice model of low-level chronic HIV infection and in which OPN RNA and protein expression was inhibited with targeted aptamers. Interestingly, 4 months after infection when there were no significant differences in HIV viral load in plasma between groups however in contrast, in the spleen, lung, and liver the tissue burden of HIV RNA, as well as the proportion of leukocytes in female and male mice differed depending on whether OPN was expressed or not. The findings collectively demonstrate the potential for complex interactions between host factors like OPN and sex to influence different facets of HIV tissue-level pathogenesis.

Allotypic variation in antigen processing controls antigenic peptide generation from SARS-CoV-2 S1 spike glycoprotein

Population genetic variability in immune system genes can often underlie variability in immune responses to pathogens. Cytotoxic T-lymphocytes are emerging as critical determinants of both severe acute respiratory syndrome coronavirus 2 infection severity and long-term immunity, after either recovery or vaccination. A hallmark of coronavirus disease 2019 is its highly variable severity and breadth of immune responses between individuals. To address the underlying mechanisms behind this phenomenon, we analyzed the proteolytic processing of S1 spike glycoprotein precursor antigenic peptides across ten common allotypes of endoplasmic reticulum aminopeptidase 1 (ERAP1), a polymorphic intracellular enzyme that can regulate cytotoxic T-lymphocyte responses by generating or destroying antigenic peptides. We utilized a systematic proteomic approach that allows the concurrent analysis of hundreds of trimming reactions in parallel, thus better emulating antigen processing in the cell. While all ERAP1 allotypes were capable of producing optimal ligands for major histocompatibility complex class I molecules, including known severe acute respiratory syndrome coronavirus 2 epitopes, they presented significant differences in peptide sequences produced, suggesting allotype-dependent sequence biases. Allotype 10, previously suggested to be enzymatically deficient, was rather found to be functionally distinct from other allotypes. Our findings suggest that common ERAP1 allotypes can be a major source of heterogeneity in antigen processing and through this mechanism contribute to variable immune responses in coronavirus disease 2019.

A rapid review of practices to support people experiencing homelessness during COVID-19

Purpose People experiencing homelessness are uniquely vulnerable to the impacts of a pandemic, such as COVID-19. Therefore, governments across Canada have been implementing a patchwork of responses to address the needs of those who are homeless at this time. The purpose of this study is to both compile and assess the varying responses by exploring the breadth of actions presented in print and social media. Design/methodology/approach Rapid review methodology is a means of compiling a breadth of information to compare and contrast policy implementations. Herein, the authors provide a comprehensive rapid review of responses to homelessness considered through a health equity lens. Findings Based on policy implementations to date, the authors offer eight recommendations of potentially promising practices among these responses. Situated within a capabilities approach, the authors call upon governments to provide a full breadth of responses to ensure that both health and housing are better protected and obtained during the COVID-19 pandemic. Originality/value This paper presents the first comprehensive review of local government responses to homelessness in the context of COVID-19.

Monoreassortant Rotaviruses of Multiple G Types Are Differentially Neutralized by Sera From Infants Vaccinated With ROTARIX and RotaTeq.

Rotavirus is a leading cause of pediatric diarrheal mortality. The rotavirus outer capsid consists of VP7 and VP4 proteins, which, respectively, determine viral G and P type and are primary targets of neutralizing antibodies. To elucidate VP7-specific neutralizing antibody responses, we engineered monoreassortant rotaviruses each containing a human VP7 segment from a sequenced clinical specimen or a vaccine strain in an identical genetic background. We quantified replication and neutralization of engineered viruses using sera from infants vaccinated with monovalent ROTARIX or multivalent RotaTeq vaccines. Immunization with RotaTeq induced broader neutralizing antibody responses than ROTARIX. Inclusion of a single dose of RotaTeq in the schedule enhanced G-type neutralization breadth of vaccinated infant sera. Cell type-specific differences in infectivity, replication, and neutralization were detected for some monoreassortant viruses. These findings suggest that rotavirus VP7, independent of VP4, can contribute to cell tropism and the breadth of vaccine-elicited neutralizing antibody responses.

Introduction

Introduction Elizabeth Milroy (bio) and Randall F. Mason (bio) The essays in this issue, large and small, are all over the map—purposefully. Our intention in editing this volume of PMHB is to provoke fellow researchers and readers to look anew at and think deeply about the built environments all around us. Acts of building shape our everyday lives (collectively and individually) by creating location and a sense of place. The histories of these structures and places guide the creation of new environments, both inspiring and tempering contemporary building practice. By "built environment," we mean to invoke a broad set of places, professional fields, and ways of making, designing, thinking, and describing. We are not much concerned with covering the geography of Pennsylvania; rather, we emphasize a range of built environment histories, issues, subjects, and approaches. Individually, these pieces interrogate the uses, designs, and meanings of legacy environments. We also see each essay—and the group as a whole—as an invitation to find connections between environment-making in one place and period and the impulses still afield today in practices of design, preservation, and public history. We cast a wide net when drafting the call for papers for this issue to encourage authors to think creatively about how their work might resonate with the theme. The breadth of responses enabled us to bring together a lively variety of research articles and smaller "Hidden Gems," ranging from the commentaries of eighteenth-century Quaker diarists on the legacy of William Penn's agrarian capitalist landscapes to the history of public bath facilities in Philadelphia to the vexatious driving habits of Fiske and Marie Kimball. Readers have an opportunity to stroll through Germantown founder Francis Pastorius's garden, then delve into the meaning of Frank Furness's work for the great Philadelphia Modernist Louis Kahn. Each essay is a richly researched, carefully made, and deeply meaningful window onto the histories of thinking about and making the built environments that are Pennsylvania's legacy. Acknowledging the variety of subjects and approaches, we also sense some important linking themes. [End Page 188] First, rather than focusing on one structure or site, all of the authors take a contextual approach by interrogating the social and political milieux alongside the design conditions governing placemaking. A second theme involves the history of efforts to create as well as to critique peaceful and therapeutic places of refuge and improvement. A third concerns the tension between "official" and "vernacular" styles or ideologies. Relatedly, a fourth theme traces how the efforts of individual citizens—diarists, designers, administrators, and philanthropists—have informed the conception, construction, and use of public and private structures and spaces and how these efforts can both comply with and resist broader structures of sociopolitical and economic power. William Penn famously referred to the colony of Pennsylvania as "a holy experiment," envisioning the creation of an agrarian capitalist paradise built by the enterprising yeoman class. Jay Miller proposes that by projecting an idealized "official" vision of the colony in his promotional pamphlets, Penn fostered "a false set of expectations for what life in the new colony would be like, contributing to the acrimony that soon emerged between the proprietor and his putative subjects." It remained for Quaker authors of journals published in the 1770s, though they subscribed to Penn's reformist idealism, to confront the reality of the exploitative "vernacular" landscape created by settler colonialism. They produced a record of that landscape "attuned to precisely what Penn overlooked"—the actual shape of the agrarian capitalist economy created by colonists and the lives of the people it marginalized. In order to restore the imagined Arcadian past Penn had projected in his promotional works, these Quaker reformers recognized that direct action would be needed to alleviate the suffering of indentured servants and tenant farmers, enslaved Africans, and displaced Indigenous peoples. By the end of the nineteenth century, like their counterparts in other American cities, elite White Philadelphians led efforts to promote sanitary reform within the slum districts of Philadelphia. In her essay, Sarah Lerner describes how the Public Baths Association (PBA) used the construction of public bathhouses in targeted neighborhoods during the first quarter of the twentieth century both to...

Quadrivalent adjuvanted haemagglutinin nanoparticle influenza vaccine: a step towards better protection of older adults from the constantly mutating H3N2 influenza viruses

The H3N2 influenza subtype has been highly researched due to its rapid mutational variability, which allows it to escape a preexisting immune response, meaning that the effectiveness of the H3N2 vaccine component has been extremely low over the past few seasons, since the 2014–15 season. 1 Martin ET Cheng C Petrie JG et al. Low influenza vaccine effectiveness against A(H3N2)-associated hospitalizations in 2016–2017 and 2017–2018 of the hospitalized adult influenza vaccine effectiveness network (HAIVEN). J Infect Dis. 2020; 223: 2062-2071 Crossref Scopus (5) Google Scholar It is therefore not surprising that in seasons when the H3N2 virus predominates, many countries have markedly higher mortality rates than in other seasons, especially in older people, owing to their reduced immune functions. 2 Vestergaard LS Nielsen J Krause TG et al. Excess all-cause and influenza-attributable mortality in Europe, December 2016 to February 2017. Euro Surveill. 2017; 2230506 Crossref PubMed Scopus (79) Google Scholar In attempts to overcome the issue of immunosenescence in older adults, new enhanced influenza vaccines are being developed, such as high-dose vaccines or vaccines formulated with potent adjuvants. To some extent, these approaches have helped increase the breadth of antibody immune responses and to stimulate virus-specific T-cell responses, thus improving vaccine effectiveness in the older population. 3 Beran J Reynales H Poder A et al. Prevention of influenza during mismatched seasons in older adults with an MF59-adjuvanted quadrivalent influenza vaccine: a randomised, controlled, multicentre, phase 3 efficacy study. Lancet Infect Dis. 2021; 21: 1027-1037 Summary Full Text Full Text PDF PubMed Scopus (15) Google Scholar , 4 DiazGranados CA Dunning AJ Kimmel M et al. Efficacy of high-dose versus standard-dose influenza vaccine in older adults. N Engl J Med. 2014; 371: 635-645 Crossref PubMed Scopus (495) Google Scholar Comparison of the safety and immunogenicity of a novel Matrix-M-adjuvanted nanoparticle influenza vaccine with a quadrivalent seasonal influenza vaccine in older adults: a phase 3 randomised controlled trialqNIV was well tolerated and produced qualitatively and quantitatively enhanced humoral and cellular immune response in older adults compared with IIV4. qNIV might enhance the effectiveness of seasonal influenza vaccination, and future studies to show clinical efficacy are planned. Full-Text PDF

Repositioning TH cell polarization from single cytokines to complex help.

When helper T (TH) cell polarization was initially described three decades ago, the TH cell universe grew dramatically. New subsets were described based on their expression of few specific cytokines. Beyond TH1 and TH2 cells, this led to the coining of various TH17 and regulatory (Treg) cell subsets as well as TH22, TH25, follicular helper (TFH), TH3, TH5 and TH9 cells. High-dimensional single-cell analysis revealed that a categorization of TH cells into a single-cytokine-based nomenclature fails to capture the complexity and diversity of TH cells. Similar to the simple nomenclature used to describe innate lymphoid cells (ILCs), we propose that TH cell polarization should be categorized in terms of the help they provide to phagocytes (type 1), to B cells, eosinophils and mast cells (type 2) and to non-immune tissue cells, including the stroma and epithelium (type 3). Studying TH cells based on their helper function and the cells they help, rather than phenotypic features such as individual analyzed cytokines or transcription factors, better captures TH cell plasticity and conversion as well as the breadth of immune responses in vivo.

Ymir: A 3D structural affinity model for multi-epitope vaccine simulations

SummaryVaccine development is challenged by the hierarchy of immunodominance between target antigen epitopes and the emergence of antigenic variants by pathogen mutation. The strength and breadth of antibody responses relies on selection and mutation in the germinal center and on the structural similarity between antigens. Computational methods for assessing the breadth of germinal center responses to multivalent antigens are critical to speed up vaccine development. Yet, such methods have poorly reflected the 3D antigen structure and antibody breadth. Here, we present Ymir, a new 3D-lattice-based framework that calculates in silico antibody-antigen affinities. Key physiological properties naturally emerge from Ymir such as affinity jumps, cross-reactivity, and differential epitope accessibility. We validated Ymir by replicating known features of germinal center dynamics. We show that combining antigens with mutated but structurally related epitopes enhances vaccine breadth. Ymir opens a new avenue for understanding vaccine potency based on the structural relationship between vaccine antigens.

Enhancing influenza vaccine immunogenicity and efficacy through infection mimicry using silk microneedles

Traditional bolus vaccine administration leads to rapid clearance of vaccine from lymphoid tissue. However, there is increasing evidence suggesting that the kinetics of antigen delivery can impact immune responses to vaccines, particularly when tailored to mimic natural infections. Here, we present the specific enhancements sustained release immunization confers to seasonal influenza vaccine, including the magnitude, durability, and breadth of humoral responses. To achieve sustained vaccine delivery kinetics, we have developed a microneedle array patch (MIMIX), with silk fibroin-formulated vaccine tips designed to embed in the dermis after a short application to the skin and release antigen over 1–2 weeks, mimicking the time course of a natural influenza infection. In a preclinical murine model, a single influenza vaccine administration via MIMIX led to faster seroconversion, response-equivalence to prime-boost bolus immunization, higher HAI titers against drifted influenza strains, and improved protective efficacy upon lethal influenza challenge when compared with intramuscular injection. These results highlight infection mimicry, achieved through sustained release silk microneedles, as a powerful approach to improve existing seasonal influenza vaccines, while also suggesting the broader potential of this platform technology to enable more efficacious next-generation vaccines and vaccine combinations.

Electrically detected magnetic resonance and near-zero field magnetoresistance in 28Si/28SiO2

We report on electrically detected magnetic resonance (EDMR) and near-zero-field magnetoresistance (NZFMR) measurements observed through spin-dependent trap-assisted-tunneling on unpassivated Si/SiO2 metal–insulator–semiconductor capacitors comparing those containing silicon of natural isotopic abundance and silicon depleted of 29Si. Although our measurements involve monitoring the spin-dependence of the trap-assisted-tunneling current responsible for leakage across the oxide, the EDMR spectra resemble that of a combination of Pb0 and Pb1 silicon dangling bonds sites at the Si/SiO2 interface. Additionally, we observe a substantial narrowing of the NZFMR response with the removal of 29Si nuclei. The breadth of the NZFMR response is strongly influenced by hyperfine interactions. Since superhyerfine interactions between 29Si nuclei and silicon dangling bonds at the Si/SiO2 interface are a full order of magnitude stronger than such interactions involving silicon dangling bonds defects (E′ centers) within the oxide, the NZFMR results also strongly suggest a response dominated by Si/SiO2 interface trap defects. These results collectively suggest very strongly that the leakage currents that we observe involve tunneling from Si/SiO2 Pb dangling bonds to defects within the oxide. Our results thus offer fundamental insight into technologically important phenomena involving oxide leakage currents in metal–oxide–semiconductor devices such as stress induced leakage currents and time dependent dielectric breakdown.

Two doses of the SARS-CoV-2 BNT162b2 vaccine enhance antibody responses to variants in individuals with prior SARS-CoV-2 infection.

Understanding the impact of prior infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on the response to vaccination is a priority for responding to the coronavirus disease 2019 (COVID-19) pandemic. In particular, it is necessary to understand how prior infection plus vaccination can modulate immune responses against variants of concern. To address this, we sampled 20 individuals with and 25 individuals without confirmed previous SARS-CoV-2 infection from a large cohort of health care workers followed serologically since April 2020. All 45 individuals had received two doses of the Pfizer-BioNTech BNT162b2 vaccine with a delayed booster at 10 weeks. Absolute and neutralizing antibody titers against wild-type SARS-CoV-2 and variants were measured using enzyme immunoassays and pseudotype neutralization assays. We observed antibody reactivity against lineage A, B.1.351, and P.1 variants with increasing antigenic exposure, through either vaccination or natural infection. This improvement was further confirmed in neutralization assays using fixed dilutions of serum samples. The impact of antigenic exposure was more evident in enzyme immunoassays measuring SARS-CoV-2 spike protein–specific IgG antibody concentrations. Our data show that multiple exposures to SARS-CoV-2 spike protein in the context of a delayed booster expand the neutralizing breadth of the antibody response to neutralization-resistant SARS-CoV-2 variants. This suggests that additional vaccine boosts may be beneficial in improving immune responses against future SARS-CoV-2 variants of concern.

Natural influenza infection produces a greater diversity of humoral responses than vaccination in immunosuppressed transplant recipients

The humoral immune response to influenza virus infection is complex and may be different compared to the antibody response elicited by vaccination. We analyzed the breadth of IgG and IgA responses in solid organ transplant (SOT) recipients to a diverse collection of 86 influenza antigens elicited by natural influenza A virus (IAV) infection or by vaccination. Antibody levels were quantified using a custom antigen microarray. A total of 120 patients were included: 80 IAV infected (40 A/H1N1 and 40 A/H3N2) and 40 vaccinated. Based on hierarchical clustering analysis, infection with either H1N1 or H3N2 virus showed a more diverse antibody response compared to vaccination. Similarly, H1N1-infected individuals showed a significant IgG response to 27.9% of array antigens and H3N2-infected patients to 43.0% of antigens, whereas vaccination elicited a less broad immune response (7.0% of antigens). Immune responses were not exclusively targeting influenza hemagglutinin (HA) proteins but were also directed against conserved influenza antigens. Serum IgA responses followed a similar profile. This study provides novel data on the breadth of antibody responses to influenza. We also found that the diversity of response is greater in influenza-infected rather than vaccinated patients, providing a potential mechanistic rationale for suboptimal vaccine efficacy in this population.

Administration of Multivalent Influenza Virus Recombinant Hemagglutinin Vaccine in Combination-Adjuvant Elicits Broad Reactivity Beyond the Vaccine Components.

Combining variant antigens into a multivalent vaccine is a traditional approach used to provide broad coverage against antigenically variable pathogens, such as polio, human papilloma and influenza viruses. However, strategies for increasing the breadth of antibody coverage beyond the vaccine are not well understood, but may provide more anticipatory protection. Influenza virus hemagglutinin (HA) is a prototypic variant antigen. Vaccines that induce HA-specific neutralizing antibodies lose efficacy as amino acid substitutions accumulate in neutralizing epitopes during influenza virus evolution. Here we studied the effect of a potent combination adjuvant (CpG/MPLA/squalene-in-water emulsion) on the breadth and maturation of the antibody response to a representative variant of HA subtypes H1, H5 and H7. Using HA protein microarrays and antigen-specific B cell labelling, we show when administered individually, each HA elicits a cross-reactive antibody profile for multiple variants within the same subtype and other closely-related subtypes (homosubtypic and heterosubtypic cross-reactivity, respectively). Despite a capacity for each subtype to induce heterosubtypic cross-reactivity, broader coverage was elicited by simply combining the subtypes into a multivalent vaccine. Importantly, multiplexing did not compromise antibody avidity or affinity maturation to the individual HA constituents. The use of adjuvants to increase the breadth of antibody coverage beyond the vaccine antigens may help future-proof vaccines against newly-emerging variants.

EPIphany-A Platform for Analysis and Visualization of Peptide Immunoarray Data.

Antibodies are critical effector molecules of the humoral immune system. Upon infection or vaccination, populations of antibodies are generated which bind to various regions of the invading pathogen or exogenous agent. Defining the reactivity and breadth of this antibody response provides an understanding of the antigenic determinants and enables the rational development and assessment of vaccine candidates. High-resolution analysis of these populations typically requires advanced techniques such as B cell receptor repertoire sequencing, mass spectrometry of isolated immunoglobulins, or phage display libraries that are dependent upon equipment and expertise which are prohibitive for many labs. High-density peptide microarrays representing diverse populations of putative linear epitopes (immunoarrays) are an effective alternative for high-throughput examination of antibody reactivity and diversity. While a promising technology, widespread adoption of immunoarrays has been limited by the need for, and relative absence of, user-friendly tools for consideration and visualization of the emerging data. To address this limitation, we developed EPIphany, a software platform with a simple web-based user interface, aimed at biological users, that provides access to important analysis parameters, data normalization options, and a variety of unique data visualization options. This platform provides researchers the greatest opportunity to extract biologically meaningful information from the immunoarray data, thereby facilitating the discovery and development of novel immuno-therapeutics.

The host transcriptional response to Candidemia is dominated by neutrophil activation and heme biosynthesis and supports novel diagnostic approaches

BackgroundCandidemia is one of the most common nosocomial bloodstream infections in the United States, causing significant morbidity and mortality in hospitalized patients, but the breadth of the host response to Candida infections in human patients remains poorly defined.MethodsIn order to better define the host response to Candida infection at the transcriptional level, we performed RNA sequencing on serial peripheral blood samples from 48 hospitalized patients with blood cultures positive for Candida species and compared them to patients with other acute viral, bacterial, and non-infectious illnesses. Regularized multinomial regression was utilized to develop pathogen class-specific gene expression classifiers.ResultsCandidemia triggers a unique, robust, and conserved transcriptomic response in human hosts with 1641 genes differentially upregulated compared to healthy controls. Many of these genes corresponded to components of the immune response to fungal infection, heavily weighted toward neutrophil activation, heme biosynthesis, and T cell signaling. We developed pathogen class-specific classifiers from these unique signals capable of identifying and differentiating candidemia, viral, or bacterial infection across a variety of hosts with a high degree of accuracy (auROC 0.98 for candidemia, 0.99 for viral and bacterial infection). This classifier was validated on two separate human cohorts (auROC 0.88 for viral infection and 0.87 for bacterial infection in one cohort; auROC 0.97 in another cohort) and an in vitro model (auROC 0.94 for fungal infection, 0.96 for bacterial, and 0.90 for viral infection).ConclusionsTranscriptional analysis of circulating leukocytes in patients with acute Candida infections defines novel aspects of the breadth of the human immune response during candidemia and suggests promising diagnostic approaches for simultaneously differentiating multiple types of clinical illnesses in at-risk, acutely ill patients.

Dynamics of the Magnitude, Breadth and Depth of the Antibody Response at Epitope Level Following Dengue Infection.

Dengue is a major public health problem in tropical and sub-tropical regions worldwide. Since the Zika epidemic and the increased co-circulation of other arboviruses, the serology-based diagnosis of dengue has become more problematic due to the high antigenic resemblance, especially among the flavivirus family. Therefore, a more comprehensive understanding of the diversity, specificity and temporal evolution of the antibody response following dengue infection is needed. In order to close this knowledge gap, we used a high-density peptide microarray of 9,072 linear peptides covering the entire proteome diversity of dengue, Zika, yellow fever and chikungunya viruses. The IgM and IgG antibody responses were measured against the designed microarray in symptomatic dengue infected individuals from an arbovirus endemic area in Peru and in overseas travelers returning to Belgium, as representatives of multiple-exposed and primary infections, respectively. Serum samples were collected longitudinally across four time points over the period of six months in Peru and over two time points in travelers. We show that epitopes eliciting the strongest flavivirus cross-reactive antibodies, in both primary and secondary infections were concentrated in the capsid, E, NS1, NS3 and NS5 proteins. The IgG antibody responses against NS1 and NS3 followed a rise-and-fall pattern, with peak titers between two to four weeks after onset of illness. The response to the E and NS5 proteins increased rapidly in the acute phase and was maintained at stable levels until at least 6 months after illness. A more scattered IgM antibody reactivity across the viral proteome was observed in the acute phase of the disease and that persisted through the 6-month window. The magnitude, breadth (i.e. number of unique epitopes targeted) and depth (i.e. number of epitope variants recognized) of the IgG response was higher in secondary infections compared to primary infections. For IgM antibodies, the magnitude of the response was higher in primary infected individuals whereas the breadth and depth of the response was lower in this group compared with the endemic subjects. Finally, through this arboviral proteome-wide epitope mapping, we were able to identify IgM and IgG dengue-specific epitopes which can be useful serological markers for dengue diagnosis and serostatus determination.

AIDSVAX protein boost improves breadth and magnitude of vaccine-induced HIV-1 envelope-specific responses after a 7-year rest period

BackgroundEliciting durable humoral immunity with sufficient breadth and magnitude is important for HIV-1 vaccine design. The HVTN 114 vaccine trial evaluated different boost regimens administered after a 7-year rest period in participants previously enrolled in HVTN 205, who received either three MVA/HIV62B (MMM) or two DNA and two MVA/HIV62B (DDMM) injections; both vaccines expressed multiple HIV-1 antigens in non-infectious virus-like-particles. The primary objective of HVTN 114 was to assess the impact of a heterologous gp120 protein AIDSVAX B/E boost on the magnitude, breadth and durability of vaccine-induced immune responses. MethodsWe enrolled 27 participants from HVTN 205 into five groups. Eight participants who previously received MMM were randomized and boosted with either MVA/HIV62B alone (T1; n = 4) or MVA/HIV62B and AIDSVAX B/E (T2; n = 4). Nineteen participants who received DDMM were randomized and boosted with MVA/HIV62B alone (T3; n = 6), MVA/HIV62B and AIDSVAX B/E (T4; n = 6), or AIDSVAX B/E alone (T5; n = 7). Boosts were at months 0 and 4. Participants were followed for safety and immunogenicity for 10 months and were pooled for analysis based on the regimen: MVA-only (T1 + T3), MVA + AIDSVAX (T2 + T4), and AIDSVAX-only (T5). ResultsAll regimens were safe and well-tolerated. Prior to the boost vaccination, binding antibody and CD4+T-cell responses were observed 7 years after HVTN 205 vaccinations. Late boosting with AIDSVAX, with or without MVA, resulted in high binding antibody responses to gp120 and V1V2 epitopes, with increased magnitude and breadth compared to those observed in HVTN 205. Late boosting with MVA, with or without AIDSVAX, resulted in increased gp140 and gp41 antibody responses and higher CD4+T-cell responses to Env and Gag. ConclusionsLate boosting with AIDSVAX, alone or in combination with MVA, can broaden binding antibody responses and increase T-cell responses even years following the original MVA/HIV62B with or without DNA-priming vaccine.

HLA-A homozygosis is associated with susceptibility to COVID-19.

The purpose of this single center retrospective study was to investigate the relationship between HLA and ABO polymorphisms and COVID‐19 susceptibility and severity in kidney transplant recipients. It included 720 recipients who had COVID‐19 and 1680 controls composed by recipients in follow‐up who did not contact the transplantation center for COVID‐19 symptoms, up to the moment of their inclusion in the study. HLA‐A, ‐B, and ‐DRB1 allele groups and ABO frequencies were compared between recipients with COVID‐19 (all cases, or separately mild/moderate and severe disease) and controls. The HLA association study was conducted in two case–control series and only associations that showed a p‐value <0.05 in both series were considered. No HLA association regarding COVID‐19 occurrence or severity met this criterion. Homozygosity at HLA‐A locus was associated with COVID‐19 susceptibility (odds ratio 1.4) but not severity. Blood groups A and O were associated with susceptibility and resistance to COVID‐19, respectively. COVID‐19 severity was associated only with older age and cardiac disease, in a multivariate analysis. We conclude that an influence of HLA on COVID‐19 susceptibility is supported by the association with homozygosity at HLA‐A locus but that there is no evidence for a role of any particular HLA‐A, ‐B, or ‐DRB1 polymorphism. Thus, we suggest that what matters is the overall capability of an individual's HLA molecules to present SARS‐CoV‐2 peptides to T cells, a factor that might have a great influence on the breadth of the immune response.