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Background: Routine childhood vaccination, e.g., for diphtheria, tetanus, and pertussis (DTP), might provide additional protection against SARS-CoV-2 infection. This concept of heterologous immunity was explored in healthy children receiving both DTP and inactivated SARS-CoV-2 vaccines. Methods: A cross-sectional study was performed on 154 healthy children aged 6–8 years old in Jakarta, Indonesia. Their vaccination status for the DTP (including a diphtheria–tetanus booster vaccine at 5 years old) and CoronaVac (from 6 years old) vaccines were recorded. Peripheral blood samples were collected from all participants, in which anti-diphtheria toxoid IgG and anti-SARS-CoV-2 S-RBD antibodies and T cell-derived IFN-γ were measured. Results: The study participants with complete DTP vaccination had significantly higher titers of anti-diphtheria toxoid IgG than the ones without (median = 0.9349 versus 0.2113 IU/mL; p < 0.0001). Upon stratification based on DTP and CoronaVac vaccination statuses, the participants with complete DTP and CoronaVac vaccinations had the highest titer of anti-SARS-CoV-2 S-RBD antibodies (median = 1196 U/mL) and the highest concentration of SARS-CoV-2-specific T cell-derived IFN-γ (median = 560.9 mIU/mL) among all the groups. Conclusions: Healthy children aged 6–8 years old with complete DTP and CoronaVac vaccinations exhibited stronger SARS-CoV-2-specific T cell immune responses. This might suggest an additional benefit of routine childhood vaccination in generating protection against novel pathogens, presumably via heterologous immunity. [ABSTRACT FROM AUTHOR]

Background: To combat coronavirus disease 2019 (COVID-19), booster vaccination strategies are important. However, the optimal administration of booster vaccine platforms remains unclear. Herein, we aimed to assess the benefits and harms of three or four heterologous versus homologous booster regimens. Methods: From November 3 2022 to December 21, 2023, we searched five databases for randomised clinical trials (RCT). Reviewers screened, extracted data, and assessed bias risks independently with the Cochrane risk-of-bias 2 tool. We conducted meta-analyses and trial sequential analyses (TSA) on our primary (all-cause mortality; laboratory confirmed symptomatic and severe COVID-19; serious adverse events [SAE]) and secondary outcomes (quality of life [QoL]; adverse events [AE] considered non-serious). We assessed the evidence with the GRADE approach. Subgroup analyses were stratified for trials before and after 2023, three or four boosters, immunocompromised status, follow-up, risk of bias, heterologous booster vaccine platforms, and valency of booster. Results: We included 29 RCTs with 43 comparisons (12,538 participants). Heterologous booster regimens may not reduce the relative risk (RR) of all-cause mortality (11 trials; RR 0.86; 95% CI 0.33 to 2.26; I2 0%; very low certainty evidence); laboratory-confirmed symptomatic COVID-19 (14 trials; RR 0.95; 95% CI 0.72 to 1.25; I2 0%; very low certainty); or severe COVID-19 (10 trials; RR 0.51; 95% CI 0.20 to 1.33; I2 0%; very low certainty). For safety outcomes, heterologous booster regimens may have no effect on SAE (27 trials; RR 1.15; 95% CI 0.68 to 1.95; I2 0%; very low certainty) but may raise AE considered non-serious (20 trials; RR 1.19; 95% CI 1.08 to 1.32; I2 64.4%; very low certainty). No data on QoL was available. Our TSAs showed that the cumulative Z curves did not reach futility for any outcome. Conclusions: With our current sample sizes, we were not able to infer differences of effects for any outcomes, but heterologous booster regimens seem to cause more non-serious AE. Furthermore, more robust data are instrumental to update this review. [ABSTRACT FROM AUTHOR]

Memory T cells form from the adaptive immune response to historic infections or vaccinations. Some memory T cells have the potential to recognise unrelated pathogens like severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and generate cross-reactive immune responses. Notably, such T cell cross-reactivity has been observed between SARS-CoV-2 and other human coronaviruses. T cell cross-reactivity has also been observed between SARS-CoV-2 variants from unrelated microbes and unrelated vaccinations against influenza A, tuberculosis and measles, mumps and rubella. Extensive research and debate is underway to understand the mechanism and role of T cell cross-reactivity and how it relates to Coronavirus disease 2019 (COVID-19) outcomes. Here, we review the evidence for the ability of pre-existing memory T cells to cross-react with SARS-CoV-2. We discuss the latest findings on the impact of T cell cross-reactivity and the extent to which it can cross-protect from COVID-19. [ABSTRACT FROM AUTHOR]

Mycobacterium bovis Bacillus Calmette-Guérin (BCG) protects against childhood tuberculosis; and unlike most vaccines, BCG broadly impacts immunity to other pathogens and even some cancers. Early in the COVID-19 pandemic, epidemiological studies identified a protective association between BCG vaccination and outcomes of SARS-CoV-2, but the associations in later studies were inconsistent. We sought possible reasons and noticed the study populations often lived in the same country. Since individuals from the same regions can share common ancestors, we hypothesized that genetic background could influence associations between BCG and SARS-CoV-2. To explore this hypothesis in a controlled environment, we performed a pilot study using Diversity Outbred mice. First, we identified amino acid sequences shared by BCG and SARS-CoV-2 spike protein. Next, we tested for IgG reactive to spike protein from BCG-vaccinated mice. Sera from some, but not all, BCG-vaccinated Diversity Outbred mice contained higher levels of IgG cross-reactive to SARS-CoV-2 spike protein than sera from BCG-vaccinated C57BL/6J inbred mice and unvaccinated mice. Although larger experimental studies are needed to obtain mechanistic insight, these findings suggest that genetic background may be an important variable contributing to different associations observed in human randomized clinical trials evaluating BCG vaccination on SARS-CoV-2 and COVID-19. [ABSTRACT FROM AUTHOR]

HLA antigen presentation and T‐cell mediated immunity are critical to control acute viral infection such as COVID‐19 caused by SARS‐CoV‐2. Recent data suggest that both the depth of peptide presentation and the breadth of the T‐cell repertoire are associated with disease outcome. It has also been shown that unexposed subjects can develop strong T‐cell responses against SARS‐CoV‐2 due to heterologous immunity. In this study, we explored the anti‐SARS‐CoV‐2 T‐cell repertoire by analyzing previously published T‐cell receptor (TCR) CDR3β immunosequencing data in a cohort of 116 healthy donors and in the context of immune reconstitution after allogeneic hematopoietic stem cell transplantation in 116 recipients collected during the pre‐COVID‐19 era. For this, 143,310 publicly available SARS‐CoV‐2 specific T‐cell sequences were investigated among the 3.5 million clonotypes in the cohort. We also performed HLA class I peptide binding predictions using the reference proteome of the virus and high resolution genotyping data in these patients. We could demonstrate that individuals are fully equipped at the genetic level to recognize SARS‐CoV‐2. This is evidenced by the 5% median cumulative frequency of clonotypes having their sequence matched to a SARS‐CoV‐2 specific T‐cell. In addition, any combination of HLA class I variants in this cohort is associated with a broad capacity of presenting hundreds of SARS‐CoV‐2 derived peptides. These results could be explained by heterologous immunity and random somatic TCR recombination. We speculate that these observations could explain the efficacy of the specific immune response against SARS‐CoV‐2 in individuals without risk factors of immunodeficiency and infected prior to vaccination. [ABSTRACT FROM AUTHOR]

Mucosal vaccination appears to be suitable to protect against SARS-CoV-2 infection. In this study, we tested an intranasal mucosal vaccine candidate for COVID-19 that consisted of a cationic liposome containing a trimeric SARS-CoV-2 spike protein and CpG-ODNs, a Toll-like receptor 9 agonist, as an adjuvant. In vitro and in vivo experiments indicated the absence of toxicity following the intranasal administration of this vaccine formulation. First, we found that subcutaneous or intranasal vaccination protected hACE-2 transgenic mice from infection with the wild-type (Wuhan) SARS-CoV-2 strain, as shown by weight loss and mortality indicators. However, when compared with subcutaneous administration, the intranasal route was more effective in the pulmonary clearance of the virus and induced higher neutralizing antibodies and anti-S IgA titers. In addition, the intranasal vaccination afforded protection against gamma, delta, and omicron virus variants of concern. Furthermore, the intranasal vaccine formulation was superior to intramuscular vaccination with a recombinant, replication-deficient chimpanzee adenovirus vector encoding the SARS-CoV-2 spike glycoprotein (Oxford/AstraZeneca) in terms of virus lung clearance and production of neutralizing antibodies in serum and bronchial alveolar lavage (BAL). Finally, the intranasal liposomal formulation boosted heterologous immunity induced by previous intramuscular vaccination with the Oxford/AstraZeneca vaccine, which was more robust than homologous immunity. [ABSTRACT FROM AUTHOR]

Background: Clinical and immunological studies in humans show that the live attenuated Bacillus Calmette-Gue'rin (BCG) vaccine has beneficial non-specific effects, increasing resistance against diseases other than tuberculosis. The underlying mechanisms are currently being explored. The pig exhibits considerable physiological similarity to humans in anatomy and physiology, suggesting that similar responses to BCG could be expected. Studies of the non-specific effects of BCG in pigs are scarce. We investigated the feasibility of using pigs as a large animal model to investigate the non-specific immunological effects of BCG. Methods: In a series of experiments, we randomized newborn or young piglets from conventional farms to receiving BCG or placebo and investigated the persistence of live BCG bacteria in various tissues, the immunogenicity of BCG in ex vivo blood and in vitro stimulation assays, and the acute phase protein and clinical responses to heterologous infectious challenge with influenza A virus or Actinobacillus pleuropneumoniae. Results: The BCG vaccine was generally well tolerated. In contrast to humans, no skin reaction in the form of abscesses, ulcers, or scars was observed. Live BCG was recovered from draining lymph nodes in 2/13 animals 20 weeks after vaccination. Specific in vitro responses of IFN-g to antigen-specific restimulation with mycobacterial antigen were increased but not TNF-responses to TLR2 or TLR4 agonists. A few genes were differentially expressed in blood after vaccination, including the antiviral genes RIG-I and CSF1, although the effect disappeared after correction for multiple testing. Clinical symptoms after heterologous bacterial or viral respiratory infections did not differ, nor did virus copies in nasopharyngeal samples after the challenge. However, the acute phase protein response was significantly reduced in BCG-vaccinated animals after influenza challenge but not after A. pleuropneumoniae challenge. Discussion: BCG was safe in pigs, inducing specific immunological responses, but our model did not corroborate the innate immunological responsiveness to BCG seen in humans. The dose of BCG or the bacterial and viral challenges may have been sub-optimal. Even so, the acute phase protein response to influenza infection was significantly reduced in BCG-vaccinated animals. [ABSTRACT FROM AUTHOR]

Tissue‐resident memory CD4 T (TRM) cells induced by infection with Bordetella pertussis persist in respiratory tissues and confer long‐term protective immunity against reinfection. However, it is not clear how they are maintained in respiratory tissues. Here, we demonstrate that B. pertussis‐specific CD4 TRM cells produce IL‐17A in response to in vitro stimulation with LPS or heat‐killed Klebsiella pneumoniae (HKKP) in the presence of dendritic cells. Furthermore, IL‐17A‐secreting CD4 TRM cells expand in the lung and nasal tissue of B. pertussis convalescent mice following in vivo administration of LPS or HKKP. Bystander activation of CD4 TRM cells was suppressed by anti‐IL‐12p40 but not by anti‐MHCII antibodies. Furthermore, purified respiratory tissue‐resident, but not circulating, CD4 T cells from convalescent mice produced IL‐17A following direct stimulation with IL‐23 and IL‐1β or IL‐18. Intranasal immunization of mice with a whole‐cell pertussis vaccine induced respiratory CD4 TRM cells that were reactivated following stimulation with K. pneumoniae. Furthermore, the nasal pertussis vaccine conferred protective immunity against B. pertussis but also attenuated infection with K. pneumoniae. Our findings demonstrate that CD4 TRM cells induced by respiratory infection or vaccination can undergo bystander activation and confer heterologous immunity to an unrelated respiratory pathogen. [ABSTRACT FROM AUTHOR]

Immunological memory to a previously encountered pathogen can influence the outcome of a sequential infection, which is called heterologous immunity. Lymphocytic choriomeningitis virus (LCMV) immune mice develop a NP205-specific T cell response that is cross-reactive to Pichinde virus infection (PICV). So far, limited data are available if cross-reactive T cell responses appear also during chronic infections with exhausted T cell responses. Exhaustion in chronic viral infections can be treated with checkpoint inhibitors, which might affect heterologous outcomes unexpectedly. The aim of this study was to investigate the cross-reactive immune response in chronic LCMV clone 13 (LCMVcl13) infection during primary PICV infection at phenotypic, functional, and T cell receptor (TCR) level. Moreover, the influence of checkpoint inhibitor therapy with αPD-L1 was investigated. Cross-reactive NP205-specific responses were present and functional in the chronic environment. Additionally, chronically infected mice were also protected from PICV mediated weight loss compared to naive PICV mice. An altered phenotype of NP205-specific T cells was detectable, but no major differences in the clonality and diversity of their TCR repertoire were observed. Checkpoint inhibitor treatment with αPD-L1 did alter chronic LCMV infection but had no major effect on heterologous immunity to PICV. Our study demonstrated that cross-reactive CD8+ T cells also exist in the setting of chronic infection, indicating a clinically relevant role of cross-reactive T cells in chronic infections. [ABSTRACT FROM AUTHOR]

Severe acute respiratory syndrome virus-2 (SARS-CoV-2), the causative infectious agent of the COVID-19 pandemic, has led to multiple (4-6) waves of infections worldwide during the past two years. The development of vaccines against SARS-CoV-2 has led to successful mass immunizations worldwide, mitigating the worldwide mortality due the pandemic to a great extent. Yet the evolution of new variants highlights a need to develop a universal vaccine which can prevent infections from all virulent SARS-CoV-2. Most of the current first generation COVID-19 vaccines are based on the Spike protein from the original Wuhan-hu-1 virus strain. It is encouraging that they still protect from serious illnesses, hospitalizations and mortality against a number of mutated viral strains, to varying degrees. Understanding the mechanisms by which these vaccines provide heterologous protection against multiple highly mutated variants can reveal strategies to develop a universal vaccine. In addition, many unexposed individuals have been found to harbor T cells that are cross-reactive against SARS-CoV-2 antigens, with a possible protective role. In this review, we will discuss various aspects of natural or vaccine-induced heterologous (cross-reactive) adaptive immunity against SARS-CoV-2 and other coronaviruses, and their role in achieving the concept of a pan-coronavirus vaccine. [ABSTRACT FROM AUTHOR]

While an increased risk of active and latent tuberculosis infection (LTBI) in people with type-2 diabetes (DM) has been demonstrated, it is less well characterized whether LTBI is associated with an increased risk of developing DM. We investigated the link between LTBI and DM in people living with HIV in the Swiss HIV Cohort Study via time-dependent Cox proportional hazards models. We found that LTBI significantly increased the risk of developing DM (HR = 1.47), which was robust across different adjustment and censoring techniques. Our results thus suggest that LTBI may be associated with an increased risk of developing DM. [ABSTRACT FROM AUTHOR]

Live vaccines use attenuated microbes to acquire immunity against pathogens in a safe way. As live attenuated vaccines (LAVs) still maintain infectivity, the vaccination stimulates diverse immune responses by mimicking natural infection. Induction of pathogen-specific antibodies or cell-mediated cytotoxicity provides means of specific protection, but LAV can also elicit unintended off-target effects, termed non-specific effects. Such mechanisms as short-lived genetic interference and non-specific innate immune response or long-lasting trained immunity and heterologous immunity allow LAVs to develop resistance to subsequent microbial infections. Based on their safety and potential for interference, LAVs may be considered as an alternative for immediate mitigation and control of unexpected pandemic outbreaks before pathogen-specific therapeutic and prophylactic measures are deployed. [ABSTRACT FROM AUTHOR]

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Drug hypersensitivity reactions (DHR) are heterogeneous and unusual immune reactions with rather unique clinical presentations. Accumulating evidence indicates that certain non‐covalent drug‐protein interactions are able to elicit exclusively effector functions of antibody reactions or complete T‐cell reactions which contribute substantially to DHR. Here, we discuss three key interactions; (a) mimicry: whereby soluble, non‐covalent drug‐protein complexes ("fake antigens") mimic covalent drug‐protein adducts; (b) increased antibody affinity: for example, in quinine‐type immune thrombocytopenia where the drug gets trapped between antibody and membrane‐bound glycoprotein; and (c) p‐i‐stimulation: where naïve and memory T cells are activated by direct binding of drugs to the human leukocyte antigen and/or T‐cell receptors. This transient drug‐immune receptor interaction initiates a polyclonal T‐cell response with mild‐to‐severe DHR symptoms. Notable complications arising from p‐i DHR can include viral reactivations, autoimmunity, and multiple drug hypersensitivity. In conclusion, DHR is characterized by abnormal immune stimulation driven by non‐covalent drug‐protein interactions. This contrasts DHR from "normal" immunity, which relies on antigen‐formation by covalent hapten‐protein adducts and predominantly results in asymptomatic immunity. [ABSTRACT FROM AUTHOR]

Heterologous immunity, when the memory T cell response elicited by one pathogen recognizes another pathogen, has been offered as a contributing factor for the high variability in coronavirus disease 2019 (COVID-19) severity outcomes. Here we demonstrate that sensitization with bacterial peptides can induce heterologous immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) derived peptides and that vaccination with the SARS-CoV-2 spike protein can induce heterologous immunity to bacterial peptides. Using in silico prediction methods, we identified 6 bacterial peptides with sequence homology to either the spike protein or non-structural protein 3 (NSP3) of SARS-CoV-2. Notwithstanding the effects of bystander activation, in vitro co-cultures showed that all individuals tested (n =18) developed heterologous immunity to SARS-CoV-2 peptides when sensitized with the identified bacterial peptides. T cell recall responses measured included cytokine production (IFN-γ, TNF, IL-2), activation (CD69) and proliferation (CellTrace). As an extension of the principle of heterologous immunity between bacterial pathogens and COVID-19, we tracked donor responses before and after SARS-CoV-2 vaccination and measured the cross-reactive T cell responses to bacterial peptides with similar sequence homology to the spike protein. We found that SARS-CoV-2 vaccination could induce heterologous immunity to bacterial peptides. These findings provide a mechanism for heterologous T cell immunity between common bacterial pathogens and SARS-CoV-2, which may explain the high variance in COVID-19 outcomes from asymptomatic to severe. We also demonstrate proof-of-concept that SARS-CoV-2 vaccination can induce heterologous immunity to pathogenic bacteria derived peptides. [ABSTRACT FROM AUTHOR]

Though SARS-CoV-2 infections are yet to be completely characterised in a host-pathogen interaction context, some of the mechanisms governing the interaction between the novel betacoronavirus and the human host, have been brought to light in satisfactory detail. Among the emerging evidence, postulates regarding potential benefits of innate immune memory and heterologous immunity have been put under discussion. Innate immune memory entails epigenetic reprogramming of innate immune cells caused by vaccination or infections, whereas heterologous immunity denotes cross-reactivity of T cells with unrelated epitopes and bystander CD8+ activation. Familiarization of the host immune system with a certain pathogen, educates monocytes, macrophages and other innate cells into phenotypes competent for combating unrelated pathogens. Indeed, the resolution at which non-specific innate immune memory occurs, is predominant at the level of enhanced cytokine secretion as a result of epigenetic alterations. One vaccine whose non-specific effects have been documented and harnessed in treating infections, cancer and autoimmunity, is the Bacillus Calmette-Guérin (BCG) vaccine currently used for immunization against pulmonary tuberculosis (TB). The BCG vaccine induces a diverse cytokine secretion profile in immunized subjects, which in turn may stimulate epigenetic changes mediated by immunoreceptor signalling. Herein, we provide a concise summarization of previous findings regarding the effects of the BCG vaccine on innate immune memory and heterolo gous immunity, supplemented with clinical evidence of the non-specific effects of this vaccine on non-mycobacterial infections, cancer and autoimmunity. This interpretative synthesis aims at providing a plausible immunological and immunogenetic model by which BCG vaccination may, in fact, be beneficial for the current efforts in combating COVID-19. [ABSTRACT FROM AUTHOR]

Arthritogenic alphaviruses are globally distributed, mosquitotransmitted viruses that cause rheumatological disease in humans and include Chikungunya virus (CHIKV), Mayaro virus (MAYV), and others. Although serological evidence suggests that some antibodymediated heterologous immunity may be afforded by alphavirus infection, the extent to which broadly neutralizing antibodies that protect against multiple arthritogenic alphaviruses are elicited during natural infection remains unknown. Here, we describe the isolation and characterization of MAYV-reactive alphavirus monoclonal antibodies (mAbs) from a CHIKV-convalescent donor. We characterized 33 human mAbs that cross-reacted with CHIKV and MAYV and engaged multiple epitopes on the E1 and E2 glycoproteins. We identified five mAbs that target distinct regions of the B domain of E2 and potently neutralize multiple alphaviruses with differential breadth of inhibition. These broadly neutralizing mAbs (bNAbs) contain few somatic mutations and inferred germline-revertants retained neutralizing capacity. Two bNAbs, DC2.M16 and DC2.M357, protected against both CHIKV- and MAYV-induced musculoskeletal disease in mice. These findings enhance our understanding of the crossreactive and cross-protective antibody response to human alphavirus infections. [ABSTRACT FROM AUTHOR]

Epidemiological studies and clinical trials suggest Bacillus Calmette-Guérin (BCG) vaccine has protective effects against coronavirus disease 2019 (COVID-19). There are now over 30 clinical trials evaluating if BCG vaccination can prevent or reduce the severity of COVID-19. However, the mechanism by which BCG vaccination can induce severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cell responses is unknown. Here, we identify 8 novel BCG-derived peptides with significant sequence homology to either SARS-CoV-2 NSP3 or NSP13-derived peptides. Using an in vitro co-culture system, we show that human CD4+ and CD8+ T cells primed with a BCG-derived peptide developed enhanced reactivity to its corresponding homologous SARS-CoV-2-derived peptide. As expected, HLA differences between individuals meant that not all persons developed immunogenic responses to all 8 BCG-derived peptides. Nevertheless, all of the 20 individuals that were primed with BCG-derived peptides developed enhanced T cell reactivity to at least 7 of 8 SARS-CoV-2-derived peptides. These findings provide an in vitro mechanism that may account, in part, for the epidemiologic observation that BCG vaccination confers some protection from COVID-19. [ABSTRACT FROM AUTHOR]

Schistosomiasis is a neglected tropical parasitic disease which has been controlled by praziquantel for many decades; however, reemergence of praziquantel resistant strains has been a continuous threat. Therefore, the development of reliable antischistosomal vaccine is significantly demanded for optimal control. In the present study, comparison among Schistosoma haematobium, Schsitosoma mansoni and Pygidiopsis genata crude antigens was carried out by Sodium dodecyl sulphate polyacrylamide gel electrophoresis. Hyperimmunization of rabbits with tested parasites' crude antigens was done to obtain hyperimmune sera. Western blotting was applied to show cross reactivity between parasites' crude antigens and either homologous or heterologous sera. Although there was no cross reaction between P. genata crude antigens and sera of both Schistosoma species and vice versa; it is supposed that the immunogenic band at 79 kDa might develop cross reactivity with Schistosma spp. SEA fractionation if used in future studies. [ABSTRACT FROM AUTHOR]

Neoantigens are tumor‐specific mutated proteins that are exempt from central tolerance and are therefore capable of efficiently eliciting effective T‐cell responses. The identification of immunogenic neoantigens in tumor‐specific mutated proteins has promising clinical implications for cancer immunotherapy. However, the factors that may contribute to neoantigen immunogenicity are not yet fully understood. Through molecular mimicry of antigens arising during cancer progression, the gut microbiota and previously encountered pathogens potentially have profound impacts on T‐cell responses to previously unencountered tumor neoantigens. Here, we review the characteristics of immunogenic neoantigens and how host exposure to microbes may affect T‐cell responses to neoantigens. We address the hypothesis that pre‐existing heterologous memory T‐cell immunity is a major factor that influences neoantigen immunogenicity in individual cancer patients. Accumulating data suggest that differences in individual histories of microbial exposure should be taken into account during the optimisation of algorithms that predict neoantigen immunogenicity. [ABSTRACT FROM AUTHOR]

Background Certain vaccines, such as Bacille Calmette-Guérin (BCG), have nonspecific effects, which modulate innate immune responses and lead to protection against mortality from unrelated infections (trained immunity). In contrast, in spite of the disease-specific effects, an enhanced overall mortality has been described after diphtheria-tetanus-pertussis (DTP) vaccination in females. This randomized trial aimed to investigate the nonspecific immunological effects of BCG and DTP-containing vaccines on the immune response to unrelated pathogens. Methods We randomized 75 healthy, female, adult volunteers to receive either BCG, followed by a booster dose of tetanus-diphtheria-pertussis inactivated polio vaccine (Tdap) 3 months later; BCG and Tdap combined; or Tdap followed by BCG 3 months later. Blood was collected before vaccination, as well as at 1 day, 4 days, 2 weeks, and 3 months after the first vaccination(s), plus 2 weeks after the second vaccination. Ex vivo leukocyte responses to unrelated stimuli and pathogens were assessed. Results Tdap vaccination led to short-term potentiation and long-term repression of monocyte-derived cytokine responses, and short-term as well as long-term repression of T-cell reactivity to unrelated pathogens. BCG led to short-term and long-term potentiation of monocyte-derived cytokine responses. When given together with Tdap or after Tdap, BCG abrogated the immunosuppressive effects of Tdap vaccination. Conclusions Tdap induces immunotolerance to unrelated antigens, which is partially restored by concurrent or subsequent BCG vaccination. These data indicate that the modulation of heterologous immune responses is induced by vaccination with Tdap and BCG, and more studies are warranted to investigate whether this is involved in the nonspecific effects of vaccines on mortality. Clinical Trials Registration NCT02771782. [ABSTRACT FROM AUTHOR]

Cytomegalovirus (CMV) infection is associated with allograft rejection but the mechanisms behind are poorly defined yet. Although cross-reactivity of T cells to alloantigen and CMV has been hypothesized, direct evidence in patients is lacking. In this observational cohort study, we tested the pre-transplant effector/memory T cell response to CMV peptide pools and alloantigen in 78 living donor/recipient pairs using the interferon-gamma Enzyme-Linked ImmunoSpot (ELISPOT) assay. To prove the hypothesis of cross-reactivity, we analyzed by applying next-generation sequencing the T cell receptor ß (TCR- ß) repertoire of CMV- and alloantigen-reactive T cells enriched from peripheral pre-transplant blood of 11 CMV-seropositive and HLA class I mismatched patients. Moreover, the TCR-repertoire was also analyzed in the allograft biopsies of those patients. There was a significant association between the presence of pre-transplant CMV immediate-early protein 1 (IE-1)-specific effector/memory T cells and acute renal allograft rejection and function (p = 0.01). Most importantly, we revealed shared TCR-ß sequences between CMV-IE1 and donor alloantigen-reactive T cells in all pre-transplant peripheral blood samples analyzed in CMV-seropositive patients who received HLA class I mismatched grafts. Identical TCR sequences were also found in particular in post-transplant allograft biopsies of patients with concomitant CMV infection and rejection. Our data show the presence of functional, cross-reactive T cells and their clonotypes in peripheral blood and in kidney allograft tissue. It is therefore likely that CMV-donor cross-reactivity as well as CMV specific T cell elicited inflammation is involved in the processes that affect allograft outcomes. [ABSTRACT FROM AUTHOR]

Background: Vaccines may have non-specific effects, affecting resistance to heterologous pathogens. Veterinary vaccines have seldom been investigated for their non-specific effects. However, recent observational studies suggest that an inactivated paratuberculosis vaccine reduced all-cause mortality in goats and cattle. Aim: We tested if vaccination with a killed mycobacterial vaccine may have heterologous effects in swine (Sus domesticus), specifically on the pathogenic and clinical effects of a heterologous challenge with Actinobacillus pleuropneumoniae in young pigs. Methods: Newborn piglets were randomized to vaccination s.c. with the inactivated paratuberculosis vaccine Gudair (Zoetis Inc.) (n = 17) or no vaccine (n = 16). At 4–5 weeks after vaccination, all piglets were challenged intra-nasally with a high (Gudair: n = 8; control: n = 8) or a low (Gudair: n = 9; control: n = 8) dose of the gram-negative bacterium A. pleuropneumoniae causing acute porcine pleuropneumonia. The effect and severity of pathogen challenge was evaluated by measuring acute phase proteins C-reactive protein, haptoglobin and Porcine α1-acid glycoprotein, and by gross pathology 1 day post challenge. Specific and non-specific in vitro cytokine responses to vaccination were evaluated in whole blood before bacterial challenge. Results: The vaccine was immunogenic in the pigs as evidenced by increased IFN-γ responses to purified protein derivative of Mycobacterium paratuberculosis. However, Gudair vaccine did not affect IL-6 responses. The gross pathology of the lungs as well as the acute phase protein responses after the high A. pleuropneumoniae dose challenge was slightly increased in the vaccinated animals compared with controls, whereas this was not seen in the animals receiving the low-dose bacterial challenge. Conclusion: The inactivated paratuberculosis vaccine exacerbated the pathological and inflammatory effects of an experimental A. pleuropneumoniae infection in young pigs. [ABSTRACT FROM AUTHOR]

Most of the world is at risk of being infected with a flavivirus such as dengue virus, West Nile virus, yellow fever virus, Japanese encephalitis virus, tick-borne encephalitis virus, and Zika virus, significantly impacting millions of lives. Importantly, many of these genetically similar viruses co-circulate within the same geographic regions, making it likely for individuals living in areas of high flavivirus endemicity to be infected with multiple flaviviruses during their lifetime. Following a flavivirus infection, a robust virus-specific T cell response is generated and the memory recall of this response has been demonstrated to provide long-lasting immunity, protecting against reinfection with the same pathogen. However, multiple studies have shown that this flavivirus specific T cell response can be cross-reactive and active during heterologous flavivirus infection, leading to the question: How does immunity to one flavivirus shape immunity to the next, and how does this impact disease? It has been proposed that in some cases unfavorable disease outcomes may be caused by lower avidity cross-reactive memory T cells generated during a primary flavivirus infection that preferentially expand during a secondary heterologous infection and function sub optimally against the new pathogen. While in other cases, these cross-reactive cells still have the potential to facilitate cross-protection. In this review, we focus on cross-reactive T cell responses to flaviviruses and the concepts and consequences of T cell cross-reactivity, with particular emphasis linking data generated using murine models to our new understanding of disease outcomes following heterologous flavivirus infection. [ABSTRACT FROM AUTHOR]

Background It has been hypothesized that revaccination with live vaccines is associated with reductions in off-target morbidity and mortality. We examined if revaccination with the live measles, mumps, and rubella vaccine (MMR) is associated with a lower rate of off-target infections. Methods We performed a register-based nationwide cohort study that included 295559 children born in Denmark from April 2004 to December 2010. The cohort were followed from age 47 months (1 month before turning age 4 years, which is the recommended age of the second MMR [MMR-2]) until age 60 months. In Cox regression, we estimated adjusted incidence rate ratios (aIRRs) of antibiotic prescriptions and hospital admissions for any infection comparing MMR-2 as most recent vaccine with not having MMR-2 as the most recent vaccine. Results There was no association between MMR-2 and antibiotic prescriptions (aIRR, 1.01; 95% confidence interval [CI], 0.99–1.02). The aIRR for the association between MMR-2 and admissions for infection of any duration was 0.93 (95% CI, 0.88–0.98). For admissions for infection lasting 0 to 1 day, the aIRR was 0.97 (95% CI, 0.90–1.03) compared with the aIRR of 0.84 (95% CI, 0.74–0.95) for admissions for infection lasting 2 days or longer (test for equality of aIRRs, P =.039). Conclusions In this study, revaccination with MMR appeared safe in relation to off-target infections and was associated with a lower rate of severe off-target infections. More studies of the possible association between revaccination with live attenuated vaccines and off-target infections are needed. [ABSTRACT FROM AUTHOR]

In the article, the author discusses issues on the use of both live vaccines like measles vaccine and bacille Calmette-Guerin (BCG) and nonlive vaccines such as diphtheria-tetanus-pertussis (DTP). Other topics include why live vaccines reduce mortality from other infections like sepsis while nonlive vaccines increase all-cause mortality, as well as a study on the interaction between DTP and measles vaccines.

Heterologous immunity, trained immunity, vaccines, immunotherapies, autoimmunity. [Extracted from the article]

Zika virus (ZIKV), a flavivirus with homology to dengue virus (DENV), is spreading to areas of DENV hyper-endemicity. Heterologous T cell immunity, whereby virus-specific memory T cells are activated by variant peptides derived from a different virus, can lead to enhanced viral clearance or diminished protective immunity and altered immunopathology. In mice, CD8+ T cells specific for DENV provide in vivo protective efficacy against subsequent ZIKV infection. In humans, contrasting studies report complete absence or varying degrees of DENV/ZIKV T cell cross-reactivity. Moreover, the impact of cross-reactive T cell recognition on the anti-viral capacity of T cells remains unclear. Here, we show that DENV-specific memory T cells display robust cross-reactive recognition of ZIKV NS3 ex vivo and after in vitro expansion in respectively n = 7/10 and n = 9/9 dengue-immune individuals tested. In contrast, cross-reactivity toward ZIKV capsid is low or absent. Cross-reactive recognition of DENV or ZIKV NS3 peptides elicits similar production of the anti-viral effector mediators IFN-γ, TNF-α, and CD107a. We identify 9 DENV/ZIKV cross-reactive epitopes, 7 of which are CD4+ and 2 are CD8+ T cell epitopes. We also show that cross-reactive CD4+ and CD8+ T cells targeting novel NS3 epitopes display anti-viral effector potential toward ZIKV-infected cells, with CD8+ T cells mediating direct lyses of these cells. Our results demonstrate that DENV NS3-specific memory T cells display anti-viral effector capacity toward ZIKV, suggesting a potential beneficial effect in humans of pre-existing T cell immunity to DENV upon ZIKV infection. [ABSTRACT FROM AUTHOR]

The global malaria burden, including falciparum malaria, has been reduced by 50% since 2000, though less so in Sub-Saharan Africa. Regional malaria elimination campaigns beginning in the 1940s, up-scaled in the 1950s, succeeded in the 1970s in eliminating malaria from Europe, North America, the Caribbean (except Haiti), and parts of Asia and South- and Central America. Dengue has grown dramatically throughout the pantropical regions since the 1950s, first in Southeast Asia in the form of large-scale epidemics including severe dengue, though mostly sparing Sub-Saharan Africa. Globally, the WHO estimates 50 million dengue infections every year, while others estimate almost 400 million infections, including 100 million clinical cases. Curiously, despite wide geographic overlap between malaria and dengue-endemic areas, published reports of co-infections have been scarce until recently. Superimposed acute dengue infection might be expected to result in more severe combined disease because both pathogens can induce shock and hemorrhage. However, a recent review found no reports on more severe morbidity or higher mortality associated with co-infections. Cases of severe dual infections have almost exclusively been reported from South America, and predominantly in persons infected by Plasmodium vivax. We hypothesize that malaria infection may partially protect against dengue -- in particular falciparum malaria against severe dengue -- and that this inter-species cross-protection may explain the near absence of severe dengue from the Sub-Saharan region and parts of South Asia until recently. We speculate that malaria infection elicits cross-reactive antibodies or other immune responses that infer cross-protection, or at least partial cross-protection, against symptomatic and severe dengue. Plasmodia have been shown to give rise to polyclonal B-cell activation and to heterophilic antibodies, while some anti-dengue IgM tests have high degree of cross-reactivity with sera from malaria patients. In the following, the historical evolution of falciparum malaria and dengue is briefly reviewed, and we explore early evidence of subclinical dengue in high-transmission malaria areas as well as conflicting reports on severity of co-morbidity. We also discuss examples of other interspecies interactions. [ABSTRACT FROM AUTHOR]

Background: Three randomized trials (RCTs) in low-weight (<2.5 kg) infants have shown that Bacille Calmette-Guérin (BCG) vaccine nonspecifically reduces all-cause mortality in the neonatal period.Methods: Using data from 3 RCTs of early BCG (n = 6583) we examined potential sex differences in the timing of the mortality reduction in the neonatal period, presenting metaestimates of the main outcome mortality rate ratios (MRR) for BCG-vaccinated and controls.Results: Among controls, boys had a particularly high mortality during the first week after randomization: male-female MRR 2.71 (95% CI, 1.70-4.50). During the first week, BCG had a marked beneficial effect for boys, reducing mortality 3-fold (MRR [BCG/no BCG] = 0.36 [0.20-0.67]). In weeks 2-4 the effect waned for boys (MRR = 0.91 [0.51-1.69]). In girls, the pattern was opposite with a limited effect in the first week (MRR = 0.85 [0.46-1.54]), but a significant reduction in weeks 2-4 (MRR = 0.56 [0.31-1.00]). This was consistent in all 3 trials. Verbal autopsies linked early benefit to fewer sepsis-related deaths among BCG-vaccinated boys.Discussion: The marked reduction in mortality in the days after BCG vaccination in boys emphasizes the importance of providing BCG soon after birth.Trial registration numbers: ClinicalTrials.gov (NCT00146302) and ClinicalTrials.gov (NCT00625482). [ABSTRACT FROM AUTHOR]

Abstract: Background: Studies have suggested that Bacillus Calmette‐Guérin (BCG) vaccination may reduce the risk of allergic diseases, including atopic dermatitis. Methods: The Danish Calmette Study was conducted 2012‐2015. Within 7 days of birth new‐borns were randomised 1:1 to BCG or no BCG. Exclusion criteria were gestational age <32 weeks, birth weight <1000 g, known immunodeficiency or no Danish‐speaking parent. Data were collected through telephone interviews and clinical examinations until 13 months. Results: Clinical atopic dermatitis was diagnosed in 466/2,052 (22.7%) children in the BCG group and 495/1,952 (25.4%) children in the control group (RR = 0.90 [95% confidence intervals 0.80‐1.00]). The effect of neonatal BCG vaccination differed significantly between children with atopic predisposition (RR 0.84 (0.74‐0.95)) and children without atopic predisposition (RR 1.09 [0.88‐1.37]) (test of no interaction, P = .04). Conclusion: Among children with atopic predisposition, the number‐needed‐to‐treat with BCG to prevent one case of atopic dermatitis was 21 (12‐76). [ABSTRACT FROM AUTHOR]

The yearly, cyclic impact of viruses like influenza on human health and the economy is due to the high rates of mutation of traditional antibody targets, which negate any preexisting humoral immunity. However, the seasonality of influenza infections can equally be attributed to an absent or defective memory CD8 T cell response since the epitopes recognized by these cells are derived from essential virus proteins that mutate infrequently. Experiments in mouse models show that protection from heterologous influenza infection is temporally limited and conferred by a population of tissue-resident memory (TRM) cells residing in the lung and lung airways. TRM are elicited by a diverse set of pathogens penetrating mucosal barriers and broadly identified by extravascular staining and expression of the activation and adhesion molecules CD69 and CD103. Interestingly, lung TRM fail to express these molecules, which could limit tissue retention, resulting in airway expulsion or death with concomitant loss of heterologous protection. Here, we make the case that respiratory infections uniquely evoke a form of natural immunosuppression whereby specific cytokines and cell-cell interactions negatively impact memory cell programming and differentiation. Respiratory memory is not only short-lived but most of the memory cells in the lung parenchyma may not be bona fide TRM. Given the quantity of microbes humans inhale over a lifetime, limiting cellular residence could be a mechanism employed by the respiratory tract to preserve organismal vitality. Therefore, successful efforts to improve respiratory immunity must carefully and selectively breach these inherent tissue barriers. [ABSTRACT FROM AUTHOR]

Influenza epidemics occur annually, and estimated 5-10% of the adult population and 20-30% of children will become ill from influenza infection. Seasonal vaccines primarily work through the induction of neutralizing antibodies against the principal surface antigen hemagglutinin (HA). This important role of HA-specific antibodies explains why previous pandemics have emerged when new HAs have appeared in circulating human viruses. It has long been recognized that influenza virus-specific CD4(+) T cells are important in protection from infection through direct effector mechanisms or by providing help to B cells and CD8(+) T cells. However, the seasonal influenza vaccine is poor at inducing CD4(+) T-cell responses and needs to be combined with an adjuvant facilitating this response. In this study, we applied the ferret model to investigate the cross-protective efficacy of a heterologous trivalent influenza split-virion (TIV) vaccine adjuvanted with the CAF01 adjuvant, with proven ability to induce CD4(+) T-cell and antibody responses in mice, ferrets, pigs, primates, and humans. Our results indicate that CAF01-adjuvanted vaccine induces HA inhibition (HAI)-independent protection after heterologous challenge, manifested as reduced viral load and fever. On the other hand, we observe increased inflammation in the airways and more neutrophil and mononuclear cell infiltration in these ferrets when compared with optimally protected animals, i.e., ferrets receiving the same vaccine but a homologous challenge. This suggest that HAI-independent immunity induced by TIV + CAF01 can reduce viral shedding and systemic disease symptoms, but does not reduce local inflammation in the nasal cavity. [ABSTRACT FROM AUTHOR]

High-dose vitamin A supplementation (VAS) may affect mortality to infectious diseases in a sex-differential manner. Here, we analysed the long-term immunological effects of neonatal vitamin A supplementation (NVAS) in 247 children, who had been randomly allocated to 50 000 or 25 000 IU vitamin A (15mg and 7·5mg retinol equivalents, respectively) or placebo at birth. At 4–6 months of age, we assessed bacille Calmette–Guérin (BCG) scarification, and we analysed in vitro responses of TNF-α, IL-5, IL-10, IL-13 and IFN-γ in whole blood stimulations to phytohaemagglutinin (PHA), purified protein derivative (PPD), tetanus toxoid and lipopolysaccharide. There were no differences between the two doses of NVAS, and thus they were analysed combined as NVAS (any dose) v. placebo. All analyses were performed unstratified and by sex. NVAS increased the chance of having a scar after BCG vaccination in females (NVAS v. placebo: 96 v. 71 %, proportion ratio: 1·24; 95 % CI 1·09, 1·42), but not in males (Pfor interaction=0·012). NVAS was associated with significant sex-differential effects on the pro- to anti-inflammatory cytokine ratios (TNF-α:IL-10) to PPD, tetanus toxoid and medium alone, which were increased in females but decreased in males. In addition, IL-17 responses tended to be increased in NVAS v. placebo recipients in males but not in females, significantly so for the PHA stimulation. The study corroborates sex-differential effects of VAS on the immune system, emphasising the importance of analysing VAS effects by sex. [ABSTRACT FROM PUBLISHER]

Background: Vaccination is used worldwide to prevent infectious diseases. However, vaccination programmes in western countries face challenges in sustaining high coverage rates. The aim of this study was to explore how parents in Denmark make a decision about whether to allow their child to receive a Bacille Calmette Guerin vaccine at birth for the purpose of achieving non-specific effects on the immune system.Methods: A total of five focus groups were conducted with expectant mothers and fathers. Written information about the vaccine and information about the hypothesis of non-specific effects of the vaccine were delivered in order to discuss considerations and determinants of parents' decisions.Results: Heritable factors and the possibility of stimulating the immune system of the child to achieve less atopic diseases and fewer infections were identified as arguments in favour of receiving the BCG vaccine. Arguments against receiving BCG mainly focused on concerns about its described and non-described side effects. Both arguments for and arguments against the vaccine were seen as parents attempt to make an individual risk evaluation for their child. Attitudes and beliefs in the local network were identified as important for parents' decisions.Discussion: It is discussed how "lay epidemiology" characterizes parents' risk evaluation as an individual addition to the population-based risk declaration. It is furthermore discussed how health professionals should engage with both the empirical element and the value element of "Lay epidemiology".Conclusion: "Lay epidemiology" forms the basis for the parental decision of whether to allow their child to receive a BCG vaccination. Attitudes and beliefs about the causes and distribution of illnesses in the family or local network influence parents' risk evaluations. It would be ideal for parents if health professionals focused their communication about the BCG vaccine on individual risk evaluations. [ABSTRACT FROM AUTHOR]

Background. BCG vaccine may reduce overall mortality by increasing resistance to nontuberculosis infections. In 2 randomized trials in Guinea-Bissau of early BCG-Denmark (Statens Serum Institut) given to low-weight (LW) neonates (<2500 g at inclusion) to reduce infant mortality rates, we observed a very beneficial effect in the neonatal period. We therefore conducted the present trial to test whether early BCG-Denmark reduces neonatal mortality by 45%. We also conducted a meta-analysis of the 3 BCG-Denmark trials. Methods. In 2008-2013, we randomized LW neonates to "early BCG-Denmark" (intervention group; n = 2083) or "control" (local policy for LW and no BCG-Denmark; n = 2089) at discharge from the maternity ward or at first contact with the health center. The infants were randomized (1:1) without blinding in blocks of 24. Data was analyzed in Cox hazards models providing mortality rate ratios (MRRs). We had prespecified an analysis censoring follow-up at oral poliovirus vaccine campaigns. Results. Early administration of BCG-Denmark was associated with a nonsignificant reduction in neonatal mortality rate (MRR, 0.70; 95% confidence interval [CI], .47-1.04) and a 34% reduction (0.66; .44-1.00) when censoring for oral poliovirus vaccine campaigns. There was no reduction in mortality rate for noninfectious diseases, but a 43% reduction in infectious disease mortality rate (MRR, 0.57; 95% CI, .35-.93). A meta-analysis of 3 BCG trials showed that early BCG-Denmark reduced mortality by 38% (MRR, 0.62; 95% CI, .46-.83) within the neonatal period and 16% (0.84; .71-1.00) by age 12 months. Conclusion. Early administration of BCG-Denmark in LW infants is associated with major reductions in mortality rate. It is important that all LW infants receive early BCG in areas with high neonatal mortality rates. [ABSTRACT FROM AUTHOR]

Background. Recent studies have shown that some vaccines have beneficial effects that cannot be explained solely by the prevention of their respective targeted disease(s). Methods. We used the MarketScan US Commercial Claims Databases for 2005 to 2014 to assess the risk of hospital admission for nontargeted infectious (NTI) diseases in children aged 16 through 24 months according to the last vaccine type (live and/or inactivated). We included children continuously enrolled within a month of birth through 15 months who received at least 3 doses of diphtheria-tetanus-acellular pertussis vaccine by the end of 15 months of age. We used Cox regression to estimate hazard ratios (HRs), stratifying by birthdate to control for age, year, and seasonality and adjusting for sex, chronic diseases, prior hospitalizations, number of outpatient visits, region of residence, urban/rural area of domicile, prematurity, low birth weight, and mother's age. Results. 311 663 children were included. In adjusted analyses, risk of hospitalization for NTI from ages 16 through 24 months was reduced for those who received live vaccine alone compared with inactivated alone or concurrent live and inactivated vaccines (HR, 0.50; 95% confidence interval [CI], 0.43, 0.57 and HR, 0.78; 95% CI, 0.67, 0.91, respectively) and for those who received live and inactivated vaccines concurrently compared with inactivated-only (HR, 0.64; 95% CI, 0.58, 0.70). Conclusions. We found lower risk of NTI disease hospitalizations from age 16 through 24 months among children whose last vaccine received was live compared with inactivated vaccine, as well as concurrent receipt compared with inactivated vaccine. [ABSTRACT FROM AUTHOR]

Background Vaccination with Bacillus Calmette-Guérin ( BCG) is used in many countries as protection against tuberculosis. Studies have suggested that BCG may also have non-specific effects, reducing non-tuberculosis mortality, morbidity, and atopic manifestations. In this study, we evaluated the effect of neonatal BCG vaccination on allergic sensitization and suspected food allergy at 13 months of age. Methods The Danish Calmette Study was conducted from 2012 to 2015 at three Danish hospitals. Within 7 days of birth, the 4262 newborns of 4184 included mothers were randomized 1:1 to BCG or to a no-intervention control group. Exclusion criteria were gestational age <32 weeks, birth weight <1000 g, known immunodeficiency, or no Danish-speaking parent. Follow-up information was collected through telephone interviews at 3 and 13 months of age. Subgroups of participants were offered blood sampling at 13 months of age. Results By 13 months of age, the parents and/or general practitioners of 5.6% (117/2089) of the children in the BCG group and 6.1% (126/2061) of the control group suspected food allergy, resulting in a risk ratio comparing BCG-vaccinated children with control children of 0.91 (95% CI 0.71-1.16). Among 1370 blood samples, sensitization (Phadiatop Infant >0.35 kUA/L) was found in 55 of 743 (7.4%) children in the BCG group and 50 of 627 (8.0%) of the control group (risk ratio 0.94 [0.65-1.36]). Conclusion In this randomized clinical trial, neonatal BCG had no significant effect on suspected food allergy or on sensitization at 13 months of age. [ABSTRACT FROM AUTHOR]

Chronic infection with hepatitis C virus (HCV) afflicts 3% of the world's population and can lead to serious and late-stage liver diseases. Developing a vaccine for HCV is challenging because the correlates of protection are uncertain and traditional vaccine approaches do not work. Studies of natural immunity to HCV in humans have resulted in many enigmas. Human beings are not immunologically naïve because they are continually exposed to various environmental microbes and antigens, creating large populations of memory T cells. Heterologous immunity occurs when this pool of memory T cells cross-react against a new pathogen in an individual. Such heterologous immunity could influence the outcome when an individual is infected by a pathogen. We have recently made an unexpected finding that adenoviruses, a common environmental pathogen and an experimental vaccine vector, can induce robust cross-reactive immune responses against multiple antigens of HCV. Our unique finding of previously uncharacterized heterologous immunity against HCV opens new avenues to understand HCV pathogenesis and develop effective vaccines. [ABSTRACT FROM AUTHOR]

Transplant recipients can be sensitized against allo-HLA antigens by previous transplantation, blood transfusion, or pregnancy. While there is growing awareness that multiple components of the immune system can act as effectors of the alloresponse, the role of infectious pathogen exposure in triggering sensitization and allograft rejection has remained a matter of much debate. Here, we describe that exposure to pathogens may enhance the immune response to allogeneic HLA antigens via different pathways. The potential role of allo-HLA cross-reactivity of virus-specific memory T cells, activation of innate immunity leading to a more efficient induction of the adaptive alloimmune response by antigen-presenting cells, and bystander activation of existing memory B cell activation will be discussed in this review. [ABSTRACT FROM AUTHOR]

Background. The live smallpox and Bacillus Calmette-Guérin (BCG) vaccinations have been associated with better adult survival in both Guinea-Bissau and Denmark. In Guinea-Bissau, human immunodeficiency virus (HIV)-1 became an important cause of death after smallpox vaccination was phased out globally in 1980. We hypothesised that smallpox and BCG vaccinations were associated with a lower prevalence of HIV-1 infection, and we tested this hypothesis in both Guinea-Bissau and Denmark. Methods. We conducted 2 studies: (1) a cross-sectional study of HIV infection and vaccination scars in Guinea-Bissau including 1751 individuals and (2) a case-base study with a background population of 46 239 individuals in Denmark. In Guinea-Bissau, HIV-1 transmission was almost exclusively sexually transmitted. In Denmark, we excluded intravenous drug users. Data were analyzed using logistic regression. Results. Bacillus Calmette-Guérin and/or smallpox vaccination compared with neither of these vaccines was associated with an adjusted odds ratio (aOR) for HIV-1 of 0.62 (95% confidence interval [CI], 0.36-1.07) in Guinea-Bissau and 0.70 (95% CI, 0.43-1.15) in Denmark. We combined the results from both settings in a meta-analysis (aOR = 0.66; 95% CI, 0.46-0.96). Data from Guinea-Bissau indicated a stronger effect of multiple smallpox vaccination scars (aOR = 0.27; 95% CI, 0.10-0.75) as follows: women, aOR = 0.18 (95% CI, 0.05-0.64); men, aOR = 0.52 (95% CI, 0.12-2.33); sex-differential effect, P = .29. Conclusions. The studies from Guinea-Bissau and Denmark, 2 very different settings, both suggest that the BCG and smallpox vaccines could be associated with a decreased risk of sexually transmitted HIV-1. It might be informative to pursue this observation and explore possible protective mechanisms as part of the search for an HIV-1 vaccine. [ABSTRACT FROM AUTHOR]

Background: Children in Guinea-Bissau receive measles vaccine (MV) at 9 months of age, but studies have shown that an additional dose before 9 months of age might have beneficial nonspecific effects. Within a randomized trial designed to examine nonspecific effects of early MV receipt on mortality, we conducted a substudy to investigate the effect of early MV receipt on morbidity.Methods: Children were randomly assigned at a ratio of 2:1 to receive 2 doses of MV at 18 weeks and age 9 months (intervention group) or 1 dose of MV at age 9 months, in accordance with current practice (control group). Children were visited weekly from enrollment to age 9 months; the mother reported morbidity, and the field assistants examined the children. Using Cox and binomial regression models, we compared the 2 randomization groups.Results: Among the 1592 children, early measles vaccination was not associated with a higher risk of the well-known adverse events of fever, rash, and convulsions within the first 14 days. From 15 days after randomization to age 9 months, early measles vaccination was associated with reductions in maternally reported diarrhea (hazard ratio [HR], 0.89; 95% confidence interval [CI], .82-.97), vomiting (HR, 0.86; 95% CI, .75-.98), and fever (HR, 0.93; 95% CI, .87-1.00).Conclusion: Early MV receipt was associated with reduced general morbidity in the following months, supporting that early MV receipt may improve the general health of children. [ABSTRACT FROM AUTHOR]

Background: When vaccinations with vaccinia against smallpox and Bacillus Calmette-Guérin (BCG) against tuberculosis were phased out in some high-income countries around 1980, the impact on overall mortality was not examined. Recent studies from low-income countries have suggested that these vaccines are associated with mortality reductions, not explained by specific disease protection. We examined whether vaccinia and BCG administered in childhood were associated with long-term mortality reductions in a high-income population.Methods: In this case-cohort study, we followed 47 622 schoolchildren from Copenhagen, Denmark, born 1965 to 1976, from their first health examination to 2010. This cohort experienced the phase-out of vaccinia and BCG vaccination programmes.Results: A sub-cohort of 5 316 individuals (699 excluded) was followed for 164 450 person-years (0.2% were lost to follow-up), and 401 deaths due to natural causes (841 deaths in total) occurred in the full cohort. Compared with individuals who had not received vaccinia or BCG, those who had received both vaccinia and BCG had an adjusted hazard ratio (aHR) of 0.54 [95% confidence interval (CI): 0.36-0.81] for mortality due to natural causes of death; those who only received BCG had an aHR of 0.58 (95% CI: 0.39-0.85). Vaccinia and BCG were not associated with any protection against deaths by accidents, suicide or murder, the combined aHR being 0.94 (95% CI: 0.62-1.42).Conclusions: Vaccinia and BCG vaccinations were associated with better long-term survival, which was not explained by specific protection. Vaccines with beneficial non-specific effects may reduce overall mortality even after the target diseases are eradicated. [ABSTRACT FROM AUTHOR]

Preventive influenza vaccines must be reformulated annually because of antigen shift and drift of circulating influenza viral strains. However, seasonal vaccines do not always match the circulating strains, and there is the ever-present threat that avian influenza viruses may adapt to humans. Hence, a universal influenza vaccine is needed to provide protective immunity against a broad range of influenza viruses. We designed an influenza antigen consisting of three tandem M2e repeats plus HA2, in combination with a detoxified anthrax oedema toxin delivery system ( EFn plus PA) to enhance immune responses. The EFn-3×M2e- HA2 plus PA vaccine formulation elicited robust, antigen-specific, IgG responses; and was protective against heterologous influenza viral challenge when intranasally delivered to mice three times. Moreover, use of the detoxified anthrax toxin system as an adjuvant had the additional benefit of generating protective immunity against anthrax. Hence, this novel vaccine strategy could potentially address two major emerging public health and biodefence threats. [ABSTRACT FROM AUTHOR]

Memory T cells are characterized by their low activation threshold, robust effector functions, and resistance to conventional immunosuppression and costimulation blockade. Unlike their naïve counterparts, memory T cells reside in and recirculate through peripheral non-lymphoid tissues. Alloreactive memory T cells are subdivided into different categories based on their origins, phenotypes, and functions. Recipients whose immune systems have been directly exposed to allogeneic major histocompatibility complex (MHC) molecules display high affinity alloreactive memory T cells. In the absence of any prior exposure to allogeneic MHC molecules, endogenous alloreactive memory T cells are regularly generated through microbial infections (heterologous immunity). Regardless of their origin, alloreactive memory T cells represent an essential element of the allograft rejection process and a major barrier to tolerance induction in clinical transplantation. This article describes the different subsets of alloreactive memory T cells involved in transplant rejection and examine their generation, functional properties, and mechanisms of action. In addition, we discuss strategies developed to target deleterious allospecific memory T cells in experimental animal models and clinical settings. [ABSTRACT FROM AUTHOR]

Background: Problems of live and inactivated influenza vaccines such as, increasing emerge and re-emerge viruses with high human mortality, current epidemics of influenza and direct transmission of avian viruses to human, affect the vaccination program. DNA vaccines as third generation of vaccines is specially considered for control of influenza in human and poultry. The main advantage of these vaccines is humoral and cellular immune responses and broad spectrum of using these vaccines for control of circulating strains of influenza. In this study the conserved fragment of HA2 to form of DNA vaccine was designed to induce immunity against influenza viruses and its heterologous protective immunity against these viruses was evaluated. Methods: The experimental study was performed in Razi Vaccine and Serum Research Institute from December 2014 to July 2015 in Iran. The HA2 was cloned into pcDNA3.1 to assess the HA2 DNA vaccine and mice were immunized with the generated constructs in a DNA prime-DNA boost regimen in 4 groups. The humoral immune responses were analyzed at defined intervals by VN tests. The safety of the vaccine was evaluated by daily inspection and histopathological examination. For evaluation of cellular immunity, proliferation assay was used. Results: The antibody titre and cellular immunity of immunized mice was significantly higher than control group for two serotypes and the highest responses was in the group with two-time boosting (P<0.01). There were no any local, general and histopathology reactions in immunized mice. Conclusion: The HA2 DNA vaccine significantly enhanced circulatory antibody responses and cellular immunity against influenza current serotypes. This study showed the highest immune responses were in the group that immunized with HA2 in prime and two boosts. Besides that, this construct did not have any local and general reaction and any side effects in treated mice. So, this construct was introduced as candidate for control of influenza virus serotypes. [ABSTRACT FROM AUTHOR]

Background: Oral vaccination with live-attenuated Salmonella Typhi strain Ty21a is modestly efficacious, but the mechanisms of protection are currently unknown. While humoral and cellular immune responses are well described in peripheral blood, the cellular response at the intestinal mucosa has never been directly assessed.Methods: We vaccinated healthy adults with Ty21a and assessed humoral and cellular immunity in vaccinated volunteers and controls after 18 days. Immunoglobulin levels were assessed in peripheral blood by an enzyme-linked immunosorbent assay. Cellular responses were assessed in peripheral blood and at the duodenal and colonic mucosa by flow cytometry.Results: We demonstrate the generation of Ty21a-responsive and heterologous influenza virus-responsive CD4(+) and CD8(+) T cells at the duodenal mucosa. All duodenal responses were consistently correlated, and no responses were observed at the colonic mucosa. Peripheral anti-lipopolysaccharide immunoglobulin G and immunoglobulin A responses were significantly correlated with duodenal responses. The assessment of integrin β7 expression intensity among peripheral and duodenal T-cell subsets revealed varied capacities for mucosal homing and residence.Conclusions: The breadth of duodenal cellular responses was not reflected peripherally. The direct evaluation of mucosal immune defense may yield functional correlates of protection and could provide insight into mechanisms that may be manipulated to enhance vaccine immunogenicity. [ABSTRACT FROM AUTHOR]

As WHO recommends vitamin A supplementation (VAS) at vaccination contacts after age 6 months, many children receive VAS together with measles vaccine (MV). We aimed to investigate the immunological effect of VAS given with MV. Within a randomised placebo-controlled trial investigating the effect on overall mortality of providing VAS with vaccines in Guinea-Bissau, we conducted an immunological sub-study of VAS v. placebo with MV, analysing leucocyte counts, whole blood in vitro cytokine production, vitamin A status and concentration of C-reactive protein (CRP). VAS compared with placebo was associated with an increased frequency of CRP≥5 mg/l (28 v. 12 %; P=0·005). Six weeks after supplementation, VAS had significant sex-differential effects on leucocyte, lymphocyte, monocyte and basophil cell counts, decreasing them in males but increasing them in females. Mainly in females, the effect of VAS on cytokine responses differed by previous VAS: in previous VAS recipients, VAS increased the pro-inflammatory and T helper cell type 1 (Th1) cytokine responses, whereas VAS decreased these responses in previously unsupplemented children. In previous VAS recipients, VAS was associated with increased IFN-γ responses to phytohaemagglutinin in females (geometric mean ratio (GMR): 3·97; 95 % CI 1·44, 10·90) but not in males (GMR 0·44; 95 % CI 0·14, 1·42); the opposite was observed in previously unsupplemented children. Our results corroborate that VAS provided with MV has immunological effects, which may depend on sex and previous VAS. VAS may increase the number of leucocytes, but also repress both the innate and lymphocyte-derived cytokine responses in females, whereas this repression may be opposite if the females have previously received VAS. [ABSTRACT FROM AUTHOR]

Acquired immunity against infectious disease (AIID) has long been considered as strictly dependent on the B and T lymphocytes of the adaptive immune system. Consequently, AIID has been viewed as highly specific to the antigens expressed by pathogens. However, a growing body of data motivates revision of this central paradigm of immunology. Unrelated past infection, vaccination, and chronic infection have been found to induce cross-protection against numerous pathogens. These observations can be partially explained by the poly-specificity of antigenic T and B receptors, the Mackaness effect and trained immunity. In addition, numerous studies highlight the importance of microbiota composition on resistance to infectious disease via direct competition or modulation of the immune response. All of these data support the idea that a non-negligible part of AIID in nature can be nonspecific to the pathogens encountered and even of the antigens expressed by pathogens. As this protection may be dependent on the private T and B repertoires produced by the random rearrangement of genes, past immune history, chronic infection, and microbiota composition, it is largely unpredictable at the individual level. However, we can reasonably expect that a better understanding of the underlying mechanisms will allow us to statistically predict cross-protection at the population level. From an evolutionary perspective, selection of immune mechanisms allowing for partially nonspecific AIID would appear to be advantageous against highly polymorphic and rapidly evolving pathogens. This new emerging paradigm may have several important consequences on our understanding of individual infectious disease susceptibility and our conception of tolerance, vaccination and therapeutic strategies against infection and cancer. It also underscores the importance of viewing the microbiota and persisting infectious agents as integral parts of the immune system. [ABSTRACT FROM AUTHOR]

Background: Influenza-related morbidity and mortality remain high. Seasonal vaccination is the backbone of influenza management but does not always result in protective antibody titers. Nonspecific effects of BCG vaccination related to enhanced function of myeloid antigen-presenting cells have been reported. We hypothesized that BCG vaccination could also enhance immune responses to influenza vaccination.Methods: Healthy volunteers received either live attenuated BCG vaccine (n = 20) or placebo (n = 20) in a randomized fashion, followed by intramuscular injection of trivalent influenza vaccine 14 days later. Hemagglutination-inhibiting (HI) antibodies and cellular immunity measured by ex vivo leukocyte responses were assessed.Results: In BCG-vaccinated subjects, HI antibody responses against the 2009 pandemic influenza A(H1N1) vaccine strain were significantly enhanced, compared with the placebo group, and there was a trend toward more-rapid seroconversion. Additionally, apart from enhanced proinflammatory leukocyte responses following BCG vaccination, nonspecific effects of influenza vaccination were also observed, with modulation of cytokine responses against unrelated pathogens.Conclusions: BCG vaccination prior to influenza vaccination results in a more pronounced increase and accelerated induction of functional antibody responses against the 2009 pandemic influenza A(H1N1) vaccine strain. These results may have implications for the design of vaccination strategies and could lead to improvement of vaccination efficacy. [ABSTRACT FROM AUTHOR]