Heterologous Infection Research Articles

Effect of E-cigarette use on lung immunity to influenza infection

Abstract Use of E-cigarettes, also called vaping, has been significantly increasing, with over 10 million adults and 3 million adolescents reported to actively vape. Of particular concern recently is the association of vaping with increased risk of respiratory infection, including influenza and COVID-19. Despite the claims of safety, lung immunological development appears to be impacted by vaping, with associated pulmonary toxicity and potential to impair immunity against respiratory infections. Immunity against respiratory pathogens, particularly viral pathogens is dependent on a robust CD4 and CD8 T cell responses responsible for viral clearance. CD4 and CD8 T cells then develop memory responses to protect against reinfection. T cell memory also provides protection against infection after vaccination. We asked whether vaping exposure affects T cell responses to influenza infection. We exposed animals for 8 weeks to base components of vape devices, including propylene glycol (PG), vegetable glycerin (VG), and a novel cutting agent, phytol, then assessed immune responses to influenza. We find that PGVG and phytol exposure alters pulmonary function, promotes proteomic changes to the lung, and modify immune cell subsets in the lung. We also find that PGVG and phytol exposure alters T cell responses to influenza infection, particularly T cell memory protection against heterologous infection. These results suggest that vaping affects immune responses to respiratory influenza infection, including T cell memory responses. Effects of vaping on T cell memory may have wide ranging consequences for T cell mediated protection against other respiratory disease including SARS-CoV-2 and protection after vaccination. Supported by NIH (P20 GM121176; P20GM130422)

Alveolar macrophages act as an early viral sponge inducing long-lived functional enhancement

Abstract Alveolar macrophages (AM) are one of the first immune cells to encounter pathogens in the lung. However, the role of AMs early after infection remains to be completely defined. To track virally infected cells, mice were infected with a panel of fluorescent reporter-expressing respiratory viruses. By 6 hr post-infection (p.i.), AM numbers significantly declined. The remaining AMs accounted for the majority of infected cells at early time points, surpassing the epithelium, but did not support significant viral replication. Strikingly, AMs represented over 80% of all respiratory syncytial virus (RSV)-infected cells which was confirmed by intravital microscopy and ImageStream flow cytometry. To track cells that survive infection, we utilized a novel cre recombinase-expressing RSV in a floxed-reporter mouse in which infected cells are indelibly marked. Cre-mediated reporter activation required direct infection, and reporter-positive AM numbers remained constant up to 30 days p.i., long after viral clearance. Reporter-positive and -negative AMs were isolated at 30 days p.i., and their functional capacity was assessed ex vivo. Both reporter-positive and -negative AMs exhibited increased basal levels of pro-inflammatory cytokines as compared to naïve AMs which was further increased upon heterologous infection. Reporter-positive AMs displayed an enhanced inflammatory response as compared to reporter-negative AMs from the same lung, indicating innate immunity can be further increased post-direct infection. Our results confirm that AMs play an essential role in limiting early viral access to the respiratory epithelium by serving as a reservoir for non-productive infection resulting in long-lived functional enhancement. Supported by grants from NIH (R01AI124093-01A1, T32AI007485) and fellowships from NASA (Iowa Space Grant Consortium) and the University of Iowa Graduate College.

An inactivated SARS-CoV-2 vaccine causes enhanced type 2 inflammation in mice during coronavirus challenge.

Abstract Inactivated vaccines administered with the adjuvant aluminum hydroxide (Alum) are currently the most widely used COVID-19 vaccines in the world and have been critical to responding to the SARS-CoV-2 pandemic. Although these vaccines are efficacious against homologous virus infection in healthy young adults, the emergence of novel SARS-CoV-2 variants has resulted in significant vaccine breakthrough. Pre-clinical studies with inactivated SARS-CoV-1 and MERS-CoV vaccines have reported enhanced immunopathology upon breakthrough infection, characterized by pulmonary eosinophilia and upregulation of type 2 cytokines. These previous reports therefore raise the concern that inactivated COVID-19 vaccines may cause enhanced immunopathology upon vaccine breakthrough. To investigate this possibility, we vaccinated female BALB/c mice with inactivated SARS-CoV-2 (iCoV2) prior to coronavirus challenge. Although iCoV2 protected mice from severe clinical disease and pulmonary pathology upon homologous challenge with pathogenic SARS-CoV-2, we observed increased pulmonary pathology and pulmonary eosinophilia upon challenge in mice vaccinated with iCoV2 and Alum (iCoV2 + Alum) compared to mice vaccinated with iCoV2 alone. Furthermore, to model vaccine breakthrough upon heterologous coronavirus infection, we challenged iCoV2-vaccinated mice with a zoonotic SARS-like coronavirus (SHC014). Upon SHC014 challenge, iCoV2 + Alum vaccination failed to control virus replication and caused enhanced pulmonary pathology, pulmonary eosinophilia and upregulation of pulmonary type 2 cytokines. Ongoing studies are investigating the mechanism of iCoV2-related immunopathology, including the role of specific iCoV2 antigens. Supported by grants from NIH (K01 OD026529, U19 AI100625, U19 AI109680, and MSTP T32 GM008719), Infectious Disease Drug Discovery Program (ID3), Rapidly Emerging Antiviral Drug Development Initiative (READDI), NCTraCS and Emerging Challenges in Biomedical Research COVID Pilot Award, SOM Junior Investigator Development Award, Department of Pathology and Laboratory Medicine.

Functional tuning of commensal-specific lymphocytes by nociceptive sensory neurons

Abstract The somatosensory nervous system surveils external stimuli at barrier tissues, regulating innate immune cells under infection and inflammation. The roles of nociceptive nerves in homeostatic adaptive immunity to the microbiota, however, remain elusive. Here, we identified a novel mechanism for direct neuro-immune interaction between commensal-specific T lymphocytes and skin-innervating nociceptive neurons through secretion of calcitonin gene-related peptide (CGRP). We observed upregulation of the CGRP co-receptor, receptor activity modifying protein 1 (RAMP1), in T lymphocytes induced by topical colonization of the human skin commensal Staphylococcus epidermidis, but not in T cell populations elicited by cutaneous infection or inflammation. Utilizing intravital imaging, we observed that commensal-specific T cells interact intimately and dynamically with skin nociceptive nerves in a CGRP-dependent manner. Importantly, CGRP secreted from nociceptors acts directly on commensal-specific T cells via RAMP1 to regulate their accumulation in the tissues, cytokine production and motility in vivo. Activation or inhibition of nociceptive neurons functionally tune commensal-specific T cells and optimize their responses to ensuing heterologous infections or damaging challenges in the skin. The ability of the somatosensory neurons to participate in the highly specific and potentially long-lasting adaptive immune response to the microbiota underscores the functional versatility and plasticity of commensal-specific T lymphocytes that can be swiftly tuned to diverse arrays of sensory modalities ranging from thermosensation to noxious pain under steady state and pathology. Supported by Damon Runyon Cancer Research Foundation

Chronic Vaccine Boost Prolongs Malaria Vaccine Immunity and CD4 Effector and Memory T cells

Abstract Vaccines to persistent parasite infections have been challenging to develop, and current iterations lack long-term protection. Persistent infection generates effector and effector memory T cells (Teff, Tem), and both contribute to protection, as we recently showed for Plasmodium infection. Sterilizing immunity from live P. chabaudi vaccination lasts less than 200 days. While specific antibody levels remain stable after the acute phase of infection, the decay of T cells corresponds with loss of protection from re-infection. Chronic vaccination with CMV has been shown to generate Tem and Teff, and so we tested MCMV for the ability to prolong protection to P. chabaudi. We generated MCMV encoding P. chabaudi MSP-1 epitope B5 (MCMV-B5), and used B5 TCR Transgenic CD4 T cells to follow the MCMV-B5 response. We showed that boosting the live malaria vaccine with MCMV-B5: i) prolonged vaccine protection to heterologous infection at day 200, ii) increased parasite-specific T cells and promoted a highly-differentiated Teff phenotype, including iii) IFN-γ+ and TNF+ T cells. Importantly, chronic MCMV infection itself improved protection from P. chabaudi infection and promoted generation of a T cell phenotype similar to P. chabaudi infection. Investigating the mechanisms of MCMV in prolonged vaccine-induced protection, we found an impressive role for IFN-γ, as its neutralization in vivo during MCMV latency is associated with loss of protection to P. chabaudi challenge. Blocking IFN-γ before challenge induced fewer Teff and less plasma IL-12 upon P. chabaudi challenge. Our findings suggest a mechanism to boost CD4 T cell immunity using chronic vaccines, which may be broadly applicable to infections that require T cell based immunity. Supported by R01AI135061

Airway epithelial interferon response to SARS-CoV-2 is inferior to rhinovirus and heterologous rhinovirus infection suppresses SARS-CoV-2 replication

Common alphacoronaviruses and human rhinoviruses (HRV) induce type I and III interferon (IFN) responses important to limiting viral replication in the airway epithelium. In contrast, highly pathogenic betacoronaviruses including SARS-CoV-2 may evade or antagonize RNA-induced IFN I/III responses. In airway epithelial cells (AECs) from children and older adults we compared IFN I/III responses to SARS-CoV-2 and HRV-16, and assessed whether pre-infection with HRV-16, or pretreatment with recombinant IFN-β or IFN-λ, modified SARS-CoV-2 replication. Bronchial AECs from children (ages 6–18 years) and older adults (ages 60–75 years) were differentiated ex vivo to generate organotypic cultures. In a biosafety level 3 (BSL-3) facility, cultures were infected with SARS-CoV-2 or HRV-16, and RNA and protein was harvested from cell lysates 96 h. following infection and supernatant was collected 48 and 96 h. following infection. In additional experiments cultures were pre-infected with HRV-16, or pre-treated with recombinant IFN-β1 or IFN-λ2 before SARS-CoV-2 infection. In a subset of experiments a range of infectious concentrations of HRV-16, SARS-CoV-2 WA-01, SARS-CoV-2 Delta variant, and SARS-CoV-2 Omicron variant were studied. Despite significant between-donor heterogeneity SARS-CoV-2 replicated 100 times more efficiently than HRV-16. IFNB1, INFL2, and CXCL10 gene expression and protein production following HRV-16 infection was significantly greater than following SARS-CoV-2. IFN gene expression and protein production were inversely correlated with SARS-CoV-2 replication. Treatment of cultures with recombinant IFNβ1 or IFNλ2, or pre-infection of cultures with HRV-16, markedly reduced SARS-CoV-2 replication. In addition to marked between-donor heterogeneity in IFN responses and viral replication, SARS-CoV-2 (WA-01, Delta, and Omicron variants) elicits a less robust IFN response in primary AEC cultures than does rhinovirus, and heterologous rhinovirus infection, or treatment with recombinant IFN-β1 or IFN-λ2, reduces SARS-CoV-2 replication, although to a lesser degree for the Delta and Omicron variants.

A Murine Model of Waning Scrub Typhus Cross-Protection between Heterologous Strains of Orientia tsutsugamushi.

Orientia tsutsugamushi, the etiologic agent of the life-threatening febrile disease scrub typhus, is an obligately intracellular small coccobacillary bacterium belonging to the family Rickettsiaceae and is transmitted by the parasitic larval stage of trombiculid mites. Progress towards a vaccine for protection against scrub typhus has been impeded by characteristics of the pathogen and the infection. There are numerous strains of O. tsutsugamushi in the Asia-Pacific region with geographical overlap. In human cases immunity has been described as poor against heterologous strains of the pathogen, as well as short-lived against the homologous strain, with a mean antibody reversion rate of less than one year. Animal models of cross-protection as well as of deterioration of this cross-protection are needed to enhance understanding of transient immunity to scrub typhus. To build upon current understanding of this ineffective protection we sought to utilize our recently developed models, sublethal intradermal infection followed by challenge via ordinarily lethal hematogenous dissemination. Mice that were initially infected sublethally with O. tsutsugamushi Gilliam strain and were challenged with an ordinarily lethal dose of heterologous Karp strain were protected from death by a robust immune response at one month after the primary infection as evidenced by an abundance of mononuclear cellular infiltrates in target organs such as lung, liver, and kidney; maintenance of body weight; and low bacterial loads in the organs. Waning protection from lethal Karp strain challenge indicated by weight loss mirroring that observed in naïve mice was observed as early as 9 months after primary Gilliam strain infection, and higher bacterial loads, severe disease, and eventual death in some mice was observed after challenge with Karp strain at 14 months post-initial heterologous infection.

Cross Strain Protection against Cytomegalovirus Reduces DISC Vaccine Efficacy against CMV in the Guinea Pig Model.

Congenital cytomegalovirus (CMV) is a leading cause of disease in newborns and a vaccine is a high priority. The guinea pig is the only small animal model for congenital CMV but requires guinea pig cytomegalovirus (GPCMV). Previously, a disabled infectious single cycle (DISC) vaccine strategy demonstrated complete protection against congenital GPCMV (22122 strain) and required neutralizing antibodies to various viral glycoprotein complexes. This included gB, essential for all cell types, and the pentamer complex (PC) for infection of non-fibroblast cells. All GPCMV research has utilized prototype strain 22122 limiting the translational impact, as numerous human CMV strains exist allowing re-infection and congenital CMV despite convalescent immunity. A novel GPCMV strain isolate (designated TAMYC) enabled vaccine cross strain protection studies. A GPCMV DISC (PC+) vaccine (22122 strain) induced a comprehensive immune response in animals, but vaccinated animals challenged with the TAMYC strain virus resulted in sustained viremia and the virus spread to target organs (liver, lung and spleen) with a significant viral load in the salivary glands. Protection was better than natural convalescent immunity, but the results fell short of previous DISC vaccine sterilizing immunity against the homologous 22122 virus challenge, despite a similarity in viral glycoprotein sequences between strains. The outcome suggests a limitation of the current DISC vaccine design against heterologous infection.

A mathematical model to describe antibody-dependent enhancement and assess the effect of limiting cloning for plasma cells in heterologous secondary dengue infection.

We propose a mathematical model to study the antibody-dependent enhancement (ADE) phenomenon. Here, we explore the interaction between macrophages, dengue virus and plasma cells, especially the effect of a limitation on plasma cell proliferation, which occurs due to immunological memory. The model has up to three equilibrium points: one virus-free equilibrium and two virus-presence equilibrium, depending on the value of two thresholds. We determine the existence regions for the model equilibrium points and their stability, a sensitivity analysis was performed in the model thresholds. Numerical simulations illustrate that ADE can occur even when the basic reproduction number is less than one.

Transcriptomic Analysis of Liver Indicates Novel Vaccine to Porcine Reproductive and Respiratory Virus Promotes Homeostasis in T-Cell and Inflammatory Immune Responses Compared to a Commercial Vaccine in Pigs.

One of the largest impediments for commercial swine production is the presence of Porcine Reproductive and Respiratory Syndrome Virus (PRRSV), a devastating RNA viral infection that is responsible for over $1 billion in loss in the U.S. annually. The challenge with combating PRRSV is a combination of the effect of an extraordinary rate of mutation, the ability to infect macrophages, and subversion of host immune response through a series of actions leading to both immunomodulation and immune evasion. Currently there are a handful of commercial vaccines on the market that have been shown to be effective against homologous infections, but struggle against heterologous or mixed strain infections. However, vaccination is the current best strategy for combating PRRSV, making research into new vaccine technology key. To address these issues with PRRSV and host antiviral functions a novel modified-live vaccine (MLV) able to stimulate known antiviral interferons was created and examined for its ability to potentiate effective immunity and better protection. Here, we examine gene expression in the liver of pigs vaccinated with our novel vaccine, given the liver's large role in antiviral responses and vaccine metabolism. Our study indicated that pigs administered the novel vaccine experience homeostatic gene expression consistent with less inflammation and T-cell depletion risk than pigs administered the commercial vaccine.

Vaccine-Induced, High-Magnitude HIV Env-Specific Antibodies with Fc-Mediated Effector Functions Are Insufficient to Protect Infant Rhesus Macaques against Oral SHIV Infection.

ABSTRACTImproved access to antiretroviral therapy (ART) and antenatal care has significantly reduced in utero and peripartum mother-to-child human immunodeficiency virus (HIV) transmission. However, as breast milk transmission of HIV still occurs at an unacceptable rate, there remains a need to develop an effective vaccine for the pediatric population. Previously, we compared different HIV vaccine strategies, intervals, and adjuvants in infant rhesus macaques to optimize the induction of HIV envelope (Env)-specific antibodies with Fc-mediated effector function. In this study, we tested the efficacy of an optimized vaccine regimen against oral simian-human immunodeficiency virus (SHIV) acquisition in infant macaques. Twelve animals were immunized with 1086.c gp120 protein adjuvanted with 3M-052 in stable emulsion and modified vaccinia Ankara (MVA) virus expressing 1086.c HIV Env. Twelve control animals were immunized with empty MVA. The vaccine prime was given within 10 days of birth, with booster doses being administered at weeks 6 and 12. The vaccine regimen induced Env-specific plasma IgG antibodies capable of antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP). Beginning at week 15, infants were exposed orally to escalating doses of heterologous SHIV-1157(QNE)Y173H once a week until infected. Despite the induction of strong Fc-mediated antibody responses, the vaccine regimen did not reduce the risk of infection or time to acquisition compared to controls. However, among vaccinated animals, ADCC postvaccination and postinfection was associated with reduced peak viremia. Thus, nonneutralizing Env-specific antibodies with Fc effector function elicited by this vaccine regimen were insufficient for protection against heterologous oral SHIV infection shortly after the final immunization but may have contributed to control of viremia.IMPORTANCE Women of childbearing age are three times more likely to contract HIV infection than their male counterparts. Poor HIV testing rates coupled with low adherence to antiretroviral therapy (ART) result in a high risk of mother-to-infant HIV transmission, especially during the breastfeeding period. A preventative vaccine could curb pediatric HIV infections, reduce potential health sequalae, and prevent the need for lifelong ART in this population. The results of the current study imply that the HIV Env-specific IgG antibodies elicited by this candidate vaccine regimen, despite a high magnitude of Fc-mediated effector function but a lack of neutralizing antibodies and polyfunctional T cell responses, were insufficient to protect infant rhesus macaques against oral virus acquisition.

BCG-induced trained immunity enhances acellular pertussis vaccination responses in an explorative randomized clinical trial

Acellular pertussis (aP) booster vaccines are central to pertussis immunization programs, although their effectiveness varies. The Bacille Calmette-Guérin (BCG) vaccine is a prototype inducer of trained immunity, which enhances immune responses to subsequent infections or vaccinations. While previous clinical studies have demonstrated that trained immunity can protect against heterologous infections, its effect on aP vaccines in humans is unknown. We conducted a clinical study in order to determine the immunological effects of trained immunity on pertussis vaccination. Healthy female volunteers were randomly assigned to either receive BCG followed by a booster dose of tetanus-diphteria-pertussis inactivated polio vaccine (Tdap-IPV) 3 months later (BCG-trained), BCG + Tdap-IPV concurrently, or Tdap-IPV followed by BCG 3 months later. Primary outcomes were pertussis-specific humoral, T- and B-cell responses and were quantified at baseline of Tdap-IPV vaccination and 2 weeks thereafter. As a secondary outcome in the BCG-trained cohort, ex vivo leukocyte responses were measured in response to unrelated stimuli before and after BCG vaccination. BCG vaccination 3 months prior to, but not concurrent with, Tdap-IPV improves pertussis-specific Th1-cell and humoral responses, and also increases total memory B cell responses. These responses were correlated with enhanced IL-6 and IL-1β production at the baseline of Tdap-IPV vaccination in the BCG-trained cohort. Our study demonstrates that prior BCG vaccination potentiates immune responses to pertussis vaccines and that biomarkers of trained immunity are the most reliable correlates of those responses.

Convergent clonal selection of donor- and recipient-derived CMV-specific T cells in hematopoietic stem cell transplant patients

Competition between antigen-specific T cells for peptide:MHC complexes shapes the ensuing T cell response. Mouse model studies provided compelling evidence that competition is a highly effective mechanism controlling the activation of naïve T cells. However, assessing the effect of T cell competition in the context of a human infection requires defined pathogen kinetics and trackable naïve and memory T cell populations of defined specificity. A unique cohort of nonmyeloablative hematopoietic stem cell transplant patients allowed us to assess T cell competition in response to cytomegalovirus (CMV) reactivation, which was documented with detailed virology data. In our cohort, hematopoietic stem cell transplant donors and recipients were CMV seronegative and positive, respectively, thus providing genetically distinct memory and naïve T cell populations. We used single-cell transcriptomics to track donor versus recipient-derived T cell clones over the course of 90 d. We found that donor-derived T cell clones proliferated and expanded substantially following CMV reactivation. However, for immunodominant CMV epitopes, recipient-derived memory T cells remained the overall dominant population. This dominance was maintained despite more robust clonal expansion of donor-derived T cells in response to CMV reactivation. Interestingly, the donor-derived T cells that were recruited into these immunodominant memory populations shared strikingly similar TCR properties with the recipient-derived memory T cells. This selective recruitment of identical and nearly identical clones from the naïve into the immunodominant memory T cell pool suggests that competition is in place but does not interfere with rejuvenating a memory T cell population. Instead, it results in selection of convergent clones to the memory T cell pool.

Respiratory Syncytial Virus Provides Protection against a Subsequent Influenza A Virus Infection.

Respiratory infections are a leading cause of morbidity and mortality. The presence of multiple heterologous virus infections is routinely observed in a subset of individuals screened for the presence of respiratory viruses. However, the impact overlapping infections has on disease severity and the host immune response is not well understood. Respiratory syncytial virus (RSV) and influenza A virus (IAV) are two of the most common respiratory infections observed in hospitalized patients, particularly in the very young and aged populations. In this study, we examined how the order in which BALB/c mice were infected with both RSV and IAV impacts disease severity. RSV infection prior to an IAV infection was associated with decreased weight loss and increased survival as compared with IAV infection alone. In contrast, IAV infection prior to an RSV infection was associated with similar morbidity and mortality as compared with an IAV infection alone. Our results suggest that the order in which viral infections are acquired plays a critical role in the outcome of disease severity and the host immune response.

Cross-Reactive Antibody Responses against Nonpoliovirus Enteroviruses.

ABSTRACTEnteroviruses are among the most common human viral pathogens. Infection with members of a subgroup of viruses within this genus, the nonpoliovirus enteroviruses (NPEVs), can result in a broad spectrum of serious illnesses, including acute flaccid myelitis (AFM), a polio-like childhood paralysis; neonatal sepsis; aseptic meningitis; myocarditis; and hand-foot-mouth disease. Despite the diverse primary sites of virus infection, including the respiratory and alimentary tracts, and an array of diseases associated with these infections, there is significant genetic and antigenic similarity among NPEVs. This conservation results in the induction of cross-reactive antibodies that are either able to bind and neutralize or bind but not neutralize multiple NPEVs. Using plaque reduction and enzyme-linked immunosorbent assay (ELISA)-based binding assays, we define the antigenic relationship among poliovirus and NPEVs, including multiple isolates of EV-D68, EV-A71, EV-D70, EV-94, EV-111, Coxsackievirus A24v, and rhinovirus. The results reveal extensive cross-reactivity among EVs that cannot be predicted from phylogenetic analysis. Determining the immunologic relationship among EVs is critical to understanding the humoral response elicited during homologous and heterologous virus infections.

Heterologous infection and vaccination shapes immunity against SARS-CoV-2 variants.

The impact of the initial severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infecting strain on downstream immunity to heterologous variants of concern (VOCs) is unknown. Studying a longitudinal healthcare worker cohort, we found that after three antigen exposures (infection plus two vaccine doses), S1 antibody, memory B cells, and heterologous neutralization of B.1.351, P.1, and B.1.617.2 plateaued, whereas B.1.1.7 neutralization and spike T cell responses increased. Serology using the Wuhan Hu-1 spike receptor binding domain poorly predicted neutralizing immunity against VOCs. Neutralization potency against VOCs changed with heterologous virus encounter and number of antigen exposures. Neutralization potency fell differentially depending on targeted VOCs over the 5 months from the second vaccine dose. Heterologous combinations of spike encountered during infection and vaccination shape subsequent cross-protection against VOC, with implications for future-proof next-generation vaccines.

Gammaherpesvirus Alters Alveolar Macrophages According to the Host Genetic Background and Promotes Beneficial Inflammatory Control over Pneumovirus Infection.

Human respiratory syncytial virus (hRSV) infection brings a wide spectrum of clinical outcomes, from a mild cold to severe bronchiolitis or even acute interstitial pneumonia. Among the known factors influencing this clinical diversity, genetic background has often been mentioned. In parallel, recent evidence has also pointed out that an early infectious experience affects heterologous infections severity. Here, we analyzed the importance of these two host-related factors in shaping the immune response in pneumoviral disease. We show that a prior gammaherpesvirus infection improves, in a genetic background-dependent manner, the immune system response against a subsequent lethal dose of pneumovirus primary infection notably by inducing a systematic expansion of the CD8+ bystander cell pool and by modifying the resident alveolar macrophages (AMs) phenotype to induce immediate cyto/chemokinic responses upon pneumovirus exposure, thereby drastically attenuating the host inflammatory response without affecting viral replication. Moreover, we show that these AMs present similar rapid and increased production of neutrophil chemokines both in front of pneumoviral or bacterial challenge, confirming recent studies attributing a critical antibacterial role of primed AMs. These results corroborate other recent studies suggesting that the innate immunity cells are themselves capable of memory, a capacity hitherto reserved for acquired immunity.

Virus-Like Particles Containing the E2 Core Domain of Hepatitis C Virus Generate Broadly Neutralizing Antibodies in Guinea Pigs.

ABSTRACTA vaccine to prevent hepatitis C virus (HCV) infection is urgently needed for use alongside direct-acting antiviral drugs to achieve elimination targets. We have previously shown that a soluble recombinant form of the glycoprotein E2 ectodomain (residues 384 to 661) that lacks three variable regions (Δ123) is able to elicit a higher titer of broadly neutralizing antibodies (bNAbs) than the parental form (receptor-binding domain [RBD]). In this study, we engineered a viral nanoparticle that displays HCV glycoprotein E2 on a duck hepatitis B virus (DHBV) small surface antigen (S) scaffold. Four variants of E2-S virus-like particles (VLPs) were constructed: Δ123-S, RBD-S, Δ123A7-S, and RBDA7-S; in the last two, 7 cysteines were replaced with alanines. While all four E2-S variant VLPs display E2 as a surface antigen, the Δ123A7-S and RBDA7-S VLPs were the most efficiently secreted from transfected mammalian cells and displayed epitopes recognized by cross-genotype broadly neutralizing monoclonal antibodies (bNMAbs). Both Δ123A7-S and RBDA7-S VLPs were immunogenic in guinea pigs, generating high titers of antibodies reactive to native E2 and able to prevent the interaction between E2 and the cellular receptor CD81. Four out of eight animals immunized with Δ123A7-S elicited neutralizing antibodies (NAbs), with three of those animals generating bNAbs against 7 genotypes. Immune serum generated by animals with NAbs mapped to major neutralization epitopes located at residues 412 to 420 (epitope I) and antigenic region 3. VLPs that display E2 glycoproteins represent a promising vaccine platform for HCV and could be adapted to large-scale manufacturing in yeast systems.IMPORTANCE There is currently no vaccine to prevent hepatitis C virus infection, which affects more than 71 million people globally and is a leading cause of progressive liver disease, including cirrhosis and cancer. Broadly neutralizing antibodies that recognize the E2 envelope glycoprotein can protect against heterologous viral infection and correlate with viral clearance in humans. However, broadly neutralizing antibodies are difficult to generate due to conformational flexibility of the E2 protein and epitope occlusion. Here, we show that a VLP vaccine using the duck hepatitis B virus S antigen fused to HCV glycoprotein E2 assembles into virus-like particles that display epitopes recognized by broadly neutralizing antibodies and elicit such antibodies in guinea pigs. This platform represents a novel HCV vaccine candidate amenable to large-scale manufacture at low cost.

BBIBP-CorV Vaccination Reduces COVID-19 Severity Rate and Accelerates Anti-Viral Antibody Responses in Heterologous Omicron Infection

BBIBP-CorV Vaccination Reduces COVID-19 Severity Rate and Accelerates Anti-Viral Antibody Responses in Heterologous Omicron Infection

Recombinant Adjuvanted Zoster Vaccine and Reduced Risk of Coronavirus Disease 2019 Diagnosis and Hospitalization in Older Adults.

BackgroundSome vaccines elicit nonspecific immune responses that may protect against heterologous infections. We evaluated the association between recombinant adjuvanted zoster vaccine (RZV) and coronavirus disease 2019 (COVID-19) outcomes at Kaiser Permanente Southern California.MethodsIn a cohort design, adults aged ≥50 years who received ≥1 RZV dose before 1 March 2020 were matched 1:2 to unvaccinated individuals and followed until 31 December 2020. Adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for COVID-19 outcomes were estimated using Cox proportional hazards regression. In a test-negative design, cases had a positive severe acute respiratory syndrome coronavirus 2 test and controls had only negative tests, during 1 March–31 December 2020. Adjusted odds ratios (aORs) and 95% CIs for RZV receipt were estimated using logistic regression.ResultsIn the cohort design, 149 244 RZV recipients were matched to 298 488 unvaccinated individuals. The aHRs for COVID-19 diagnosis and hospitalization were 0.84 (95% CI, .81–.87) and 0.68 (95% CI, .64–.74), respectively. In the test-negative design, 8.4% of 75 726 test-positive cases and 13.1% of 340 898 test-negative controls had received ≥1 RZV dose (aOR, 0.84 [95% CI, .81–.86]).ConclusionsRZV vaccination was associated with a 16% lower risk of COVID-19 diagnosis and 32% lower risk of hospitalization. Further study of vaccine-induced nonspecific immunity for potential attenuation of future pandemics is warranted.