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BACKGROUND: Early smallpox and Bacillus Calmette-Guérin (BCG) vaccinations have been associated with reduced risk of cutaneous malignant melanoma (CMM). We assessed the association between pre-school smallpox vaccination and early-school BCG vaccination and CMM in a young Danish population.METHODS: We conducted a register-based case-cohort study of individuals growing up during the phase-out period of smallpox and BCG vaccination in Denmark (born 1965-1976) utilising the decrease in vaccination during this period. Information on childhood vaccinations and potential confounders from Copenhagen school health records were linked with nationwide registers on cancer (CMM diagnoses), migrations and deaths by personal identification numbers.RESULTS: The individuals were followed from age 18 until 31/12/2014 (maximum age at end of follow-up, 49 years). 188 cases of CMM occurred in the background population of 46,239 individuals; 172 CMM cases (91%) had full information and were analysed. The adjusted hazard ratio (HR) for CMM by BCG and/or smallpox vaccination compared with neither vaccine was 1.29 (95% confidence interval (CI) 0.72-2.31). For smallpox vaccination only, HR = 1.23 (95% CI 0.53-2.86) for BCG vaccination only, HR = 1.13 (95% CI 0.61-2.09) and for both smallpox and BCG vaccination, HR = 1.75 (95% CI 0.87-3.48) compared with none of these. Vaccination below the age of one year gave similar results.CONCLUSIONS: We found no strong beneficial effect of smallpox and BCG vaccination against CMM among young adult Danes and with broad confidence intervals our data alone could be compatible with both modest preventive effects, no effects, and modest harmful effects. Our estimates do not contradict a potential modest beneficial effect of neonatal vaccination.

Host immune responses play an important role in the outcome of infection with hepatitis C virus (HCV). They can lead to viral clearance and a positive outcome, or progression and severity of chronic disease. Extensive research in the past &gt, 25 years into understanding the immune responses against HCV have still resulted in many unanswered questions implicating a role for unknown factors and events. In our earlier studies, we made a surprising discovery that peptides derived from structural and non-structural proteins of HCV have substantial amino acid sequence homologies with various proteins of adenoviruses and that immunizing mice with a non-replicating, non-recombinant adenovirus vector leads to induction of a robust cross-reactive cellular and humoral response against various HCV antigens. In this work, we further demonstrate antibody cross-reactivity between Ad and HCV in vivo. We also extend this observation to show that recombinant adenoviruses containing antigens from unrelated pathogens also possess the ability to induce cross-reactive immune responses against HCV antigens along with the induction of transgene antigen-specific immunity. This cross-reactive immunity can (a) accommodate the making of dual-pathogen vaccines, (b) play an important role in the natural course of HCV infection and (c) provide a plausible answer to many unexplained questions regarding immunity to HCV.

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.

Viral infections are agreat risk for successful transplantation. Surprisingly, also the immuneresponse against viruses can affect transplantation outcome, as T cells thatare trained to recognize self-HLA presenting a viral peptide, can make a“mistake” and recognize allogeneic (donor) HLA. This phenomenon is known tooccur frequently, but its clinical relevance remains unknown. In this thesis, we investigated and optimized the methods to detectcross-reactivity of virus-specific T cells in vitro. Illustrating the scope ofthe problem, we found that infection with a single virus induces a broadrepertoire of alloreactive T cells. Conversely, cross-reactivity may also boostanti-viral immunity in immunocompromised patients. Also, we found thatvirus-specific T cells of unrelated individuals can recognize the sameallogeneic HLA much more frequently than anticipated. This knowledge may helpto predict which patient-donor combinations induce alloreactivity.Addressing clinical relevance in transplantation, we showed that the immunepotential against the viral and allogeneic target can be equally strong,depending on the expression of the (allo)epitope. However, clinical relevanceonly truly be determined when the peptides presented by the cross-reactingallo-HLA molecules are identified. A promising allopeptide-defining strategy iscurrently under development at Monash University (Melbourne, Australia),described in the Discussion.

Background: It has been hypothesized that revaccination with live vaccines could be 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: A register-based nationwide cohort study including 295,559 children born in Denmark 1 April 2004 to 31 December 2010. The cohort were followed from age 47 months (1 month before turning age 4 years, 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 among children who had received no non-live vaccines with or after MMR.Results: 76.7% received MMR-2 before age 60 months. There was no association between MMR-2 and antibiotic prescriptions (aIRR, 1.01; 95% confidence interval (CI), 0.99 to1.02). The aIRR for the association between MMR-2 and admissions for any infection of any duration was 0.93 (95% CI, 0.88 to 0.98). For admissions for infection lasting 0 to 1 day, the aIRR was 0.97 (95% CI, 0.90 to1.03) compared with the aIRR of 0.84 (95% CI, 0.74 to 0.95) for admissions for infection lasting 2 days or longer (Test for equality of aIRRs, p=0.039).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 are needed of the possible association between revaccination with live attenuated vaccines and off-target infections.

Heterologous immunity of virus-specific T cells poses a potential barrier to transplantation tolerance. Cross-reactivity to HLA-A and -B molecules has broadly been described, whereas responses to allo-HLA-C have remained ill defined. In contrast to the transplant setting, HLA-C is the only polymorphic HLA molecule expressed by extravillous trophoblasts at the maternal-fetal interface during pregnancy. Uncontrolled placental viral infections, accompanied by a pro-inflammatory milieu, can alter the activation status and stability of effector T cells. Potential cross-reactivity of maternal decidual virus-specific T cells to fetal allo-HLA-C may thereby have detrimental consequences for the success of pregnancy. To explore the presence of cross-reactivity to HLA-C and the other non-classical HLA antigens expressed by trophoblasts, HLA-A and -B-restricted CD8+ T cells specific for Epstein-Barr virus, Cytomegalovirus, Varicella-Zoster virus, and Influenza virus were tested against target cells expressing HLA-C, -E, and -G molecules. An HLA-B*08:01-restricted EBV-specific T cell clone displayed cross-reactivity against HLA-C*01:02. Furthermore, cross-reactivity of HLA-C-restricted virus-specific CD8+ T cells was observed for HCMV HLA-C*06:02/TRA CD8+ T cell lines and clones against HLA-C*03:02. Collectively, these results demonstrate that cross-reactivity against HLA-C can occur and thereby may affect pregnancy outcome.

BACKGROUND: Bacillus Calmette-Guérin (BCG) vaccination may have beneficial non-specific effects on child survival, the effects being stronger for children developing a scar. In a prospective cohort study, we examined determinants for not developing a BCG scar within 6 months of vaccination.METHODS: Bandim Health Project (BHP) runs a Health and Demographic Surveillance System site in rural Guinea-Bissau. BHP provides BCG at monthly visits. We studied determinants for not developing a BCG scar using binomial regression models to obtain relative risks (RR).RESULTS: From May 2012 until October 2014, BHP nurses vaccinated 2415 infants with BCG. We assessed BCG scar between 6 and 12 months of age for 2156 (89%) of these children and 2115 (98%) had developed a scar. In comparison, among 785 children BCG vaccinated elsewhere, 622 (79%) had a scar, the RR of not having a scar being 10.91 (7.52-15.85) compared with children vaccinated by BHP. Among children vaccinated by BHP, those receiving the Russian BCG strain were more likely not to develop a scar (RR = 2.98 (1.52-5.81)) compared with children receiving Danish BCG strain. Children with no post-injection wheal or a wheal CONCLUSION: Vaccination technique and vaccine strain were associated with BCG scar development while nutritional status and socioeconomic status were not. Scarring rate may therefore be a better indicator of vaccination programme performance than coverage.

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.

Live measles vaccine (MV) may have beneficial off-target/non-specific effects (NSEs) reducing child mortality beyond prevention of measles infection. In contrast, the non-live pentavalent (Diphtheria-Tetanus-Pertussis- H. influenzae Type B-Hepatitis B) vaccine has no beneficial NSEs. The NSEs are strongest for the most recent vaccine. Hence, sequence of vaccination may affect survival. In Guinea-Bissau, we followed 7094 measles-vaccinated children prospectively from first home visit after 9 months (when MV is scheduled) to 5 years of age. We compared survival by sequence of MV and third Pentavalent vaccine (Penta3; scheduled at 3½ months) in Cox proportional-hazards models. Compared with being vaccinated in-sequence (Penta3-then-MV), having received out-of-sequence Penta3-after-MV before the visit was associated with an adjusted Hazard Ratio (aHR) of 1.19 (95%CI: 0.84–1.69); Receiving missing Penta doses on the visit date tended to be associated with higher mortality (aHR = 1.87 (0.96–3.65)) while not receiving missing doses of Penta was not (aHR = 0.93 (0.57–1.54)), test for interaction p = 0.09.

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 1940s, up-scaled in 1950s, succeeded in 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 pantropical regions since the 1950s, first in Southeast Asia in large-scale epidemics including severe dengue, though mostly sparing Sub-Saharan Africa. Globally, the WHO estimates 50 mio dengue infections every year, while others set estimate almost 400 mio cases, with 100 mio 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 haemorrhage. 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. The first person with concurrent malaria and dengue was reported in 2005 in a traveler to West Africa, and serological evidence of dengue is also high in sub-Saharan Africa. 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.

Despite the association between alloreactive T cells and poor graft survival, the mechanisms behind T-cell-mediated rejection are still under investigation. In this review, we will discuss the latest insights into the impact of T-cell alloreactivity on solid organ transplantation and hematopoietic stem cell transplantation (HSCT), with special emphasis on the potential impact of heterologous immunity.A large part of the memory T-cell repertoire is induced upon virus infections, and evidence for a role of T-cell receptor cross-reactivity of virus-induced memory T cells against allogeneic human leukocyte antigen (HLA) is accumulating in experimental and clinical solid organ transplantation studies. In HSCT, strong alloreactive potential of naïve T cells causes concerns for graft-versus-host disease while additional HLA-DP matching is suggested to prevent CD4 alloreactivity. Furthermore, virus-induced memory T cells hamper mixed chimerism induction, pointing once more towards a role for heterologous immunity.Both memory and naïve T cells contribute to the alloimmune response after transplantation. Monitoring for T-cell phenotypes could help predict rejection episodes and/or graft-versus-host disease, allowing timely intervention. Tailoring donor lymphocyte infusions and additional HLA matching could prevent strong alloreactivity in HSCT. Furthermore, the potential role of heterologous immunity in T-cell alloreactivity and transplantation is gaining interest.

Heterologous immunity refers to the phenomenon whereby a history of an immune response against one pathogen can provide a level of immunity to a second unrelated pathogen. Previous investigations have shown that heterologous immunity is not necessarily reciprocal, such as in the case of vaccinia virus (VACV). Replication of VACV is reduced in mice immune to a variety of pathogens, while VACV fails to induce immunity to several of the same pathogens, including lymphocytic choriomeningitis virus (LCMV). Here we examine the lack of reciprocity of heterologous immunity between VACV and LCMV and find that they induce qualitatively different memory CD8 T cells. However, depending on the repertoire of an individual host, VACV can provide protection against LCMV simply by experimentally amplifying the quantity of T cells cross-reactive with the two viruses. Thus, one cause for lack of reciprocity is differences in the frequencies of cross-reactive T cells in immune hosts.

Item does not contain fulltext INTRODUCTION: Bacille Calmette-Guerin (BCG) vaccine has beneficial non-specific effects on overall survival. After BCG vaccination, positive PPD response and scar formation are associated with increased survival. During a trial randomising low-birth-weight neonates to BCG at birth or the usual delayed BCG, the manufacturer of the BCG vaccine experienced a period with relatively slow growth rate of the BCG. We investigated the association between growth rate of BCG when manufacturing the vaccine and its capability to induce immune responses in vivo and in vitro. METHODS: 1633 neonates were randomised to BCG at birth and examined for scar at 12 months; a subgroup was tested for PPD response at 2 and 6 months. The BCG batches from the Slow growth period were compared with the precedent and subsequent Normal growth batches with regard to prevalence and size of BCG scar and PPD response. We also tested the effect of batches on in vitro cytokine responses. RESULTS: At 12 months, the Slow growth batches were associated with higher BCG scar prevalence (98.2%) than the precedent batches (92.3%, p=0.01) but the prevalence remained high after return to normal growth (98.8%, p=0.52). The Slow growth batches were associated with larger scar size (5.0mm) than precedent (4.4mm, p

Highlights • MMR vaccination is given to protect against measles, mumps and rubella. • RSV is an important cause of acute lower respiratory infections in young children. • MMR vaccination was associated with 22% lower rate of RSV hospital contacts. • MMR vaccination may reduce the rate or severity of RSV infection., Background The live measles vaccine has been associated with lower non-measles mortality and admissions in low-income countries. The live measles–mumps–rubella vaccine has also been associated with lower rate of admissions with any type of infection in Danish children; the association was strongest for admissions with lower respiratory infections. Objective To examine whether measles, mumps, and rubella (MMR) vaccination was associated with reduced rate of hospital contact related to respiratory syncytial virus (RSV) in a high-income country. Methods Nationwide cohort study of laboratory-confirmed RSV hospital contacts at age 14–23 months in all children born in Denmark 1997–2002 who had already received the vaccine against diphtheria, tetanus, pertussis (acellular), polio, and Haemophilus influenzae type b (DTaP-IPV-Hib) at the recommended ages of 3, 5, and 12 months. Results The study included 888 RSV hospital contacts in 128,588 person years of follow up (rate 6.8/1000 person years). Having MMR as the most recent vaccine was associated with a reduced rate of RSV hospital contacts compared with having DTaP-IPV-Hib as the most recent vaccine (Incidence rate ratio (IRR), 0.75; 95% confidence interval (CI), 0.63–0.89). After adjustment for potential confounders including exact age in days the IRR was 0.78 (95% CI, 0.66–0.93). The adjusted IRR was 0.74 (95% CI, 0.60–0.92) in males and 0.84 (95% CI, 0.66–1.06) in females (P Interaction, 0.42). There was no association in the first month after MMR vaccination (adjusted IRR, 0.97; 95% CI, 0.76–1.24) but the adjusted IRR was 0.70 (95% CI, 0.58–0.85) from one month after MMR vaccination. Conclusions MMR vaccination was associated with reduced rate of hospital contacts related to laboratory-confirmed RSV infection. Further research on the association between MMR vaccination and other unrelated pathogens are warranted.

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.

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.

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

Background Vaccination with Bacillus Calmette-Guerin (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 2012-2015 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 0.35 kUA/l) was found in 55/743 (7.4%) children in the BCG group and 50/627 (8.0%) of the control group (risk ratio 0.94 (0.65 to 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. This article is protected by copyright. All rights reserved.

While progress has been made in characterizing humoral immunity to Zika virus (ZIKV) in humans, little is known regarding the corresponding T cell responses to ZIKV. Here, we investigate the kinetics and viral epitopes targeted by T cells responding to ZIKV and address the critical question of whether preexisting dengue virus (DENV) T cell immunity modulates these responses. We find that memory T cell responses elicited by prior infection with DENV or vaccination with tetravalent dengue attenuated vaccines (TDLAV) recognize ZIKV-derived peptides. This cross-reactivity is explained by the sequence similarity of the two viruses, as the ZIKV peptides recognized by DENV-elicited memory T cells are identical or highly conserved in DENV and ZIKV. DENV exposure prior to ZIKV infection also influences the timing and magnitude of the T cell response. ZIKV-reactive T cells in the acute phase of infection are detected earlier and in greater magnitude in DENV-immune patients. Conversely, the frequency of ZIKV-reactive T cells continues to rise in the convalescent phase in DENV-naive donors but declines in DENV-preexposed donors, compatible with more efficient control of ZIKV replication and/or clearance of ZIKV antigen. The quality of responses is also influenced by previous DENV exposure, and ZIKV-specific CD8 T cells from DENV-preexposed donors selectively upregulated granzyme B and PD1, unlike DENV-naive donors. Finally, we discovered that ZIKV structural proteins (E, prM, and C) are major targets of both the CD4 and CD8 T cell responses, whereas DENV T cell epitopes are found primarily in nonstructural proteins. IMPORTANCE The issue of potential ZIKV and DENV cross-reactivity and how preexisting DENV T cell immunity modulates Zika T cell responses is of great relevance, as the two viruses often cocirculate and Zika virus has been spreading in geographical regions where DENV is endemic or hyperendemic. Our data show that memory T cell responses elicited by prior infection with DENV recognize ZIKV-derived peptides and that DENV exposure prior to ZIKV infection influences the timing, magnitude, and quality of the T cell response. Additionally, we show that ZIKV-specific responses target different proteins than DENV-specific responses, pointing toward important implications for vaccine design against this global threat.

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.

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.

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 46239 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.

Summary We conducted the present trial to test whether early BCG-Denmark reduces mortality rate in low-weight (LW) neonates. We found that early administration of BCG-Denmark in LW infants is associated with major reductions in mortality rate., 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 (

Contains fulltext : 169904.pdf (Publisher’s version ) (Open Access) INTRODUCTION: BCG vaccination has been associated with beneficial non-specific effects on child health. Some immunological studies have reported heterologous effects of vaccines on antibody responses to heterologous vaccines. Within a randomised clinical trial of Bacille Calmette-Guerin (BCG) vaccination at birth, The Danish Calmette Study, we investigated the effect of BCG at birth on the antibody response to the three routine vaccines against DiTeKiPol/Act-Hib and Prevenar 13 in a subgroup of participants. METHODS: Within 7days after birth, children were randomised 1:1 to BCG vaccination or to the control group (no intervention). After three routine vaccinations given at age 3, 5 and 12months, antibodies against DiTeKiPol/Act-Hib and Prevenar 13 (Streptococcus pneumoniae serotype type 4, 6B, 9V, 14, 18C, 19F and 23F) were measured 4weeks after the third vaccine dose. RESULTS: Among the 300 included children (178 BCG; 122 controls), almost all children (>96%) had antibody responses above the protective levels. Overall BCG vaccination at birth did not affect the antibody level. When stratifying by 'age at randomisation' we found a possible inducing effect of BCG on antibodies against B. pertussis and all pneumococcal serotypes, when BCG was given after the first day of life. Girls had significantly higher antibody levels for Haemophilus influenza type b and pneumococcus than boys. CONCLUSIONS AND RELEVANCE: Three routine vaccinations with DiTeKiPol/Act-Hib and Prevenar 13 induced sero-protective levels in almost all children. No overall effect of neonatal BCG vaccination was observed.

Background: Recurrent wheeze (RW) is frequent in childhood. Studies have suggested that BCG vaccination can have nonspecific effects, reducing general nontuberculosis morbidity, including respiratory tract infections and atopic diseases. The mechanisms behind these nonspecific effects of BCG are not fully understood, but a shift from a TH2 to a TH1 response has been suggested as a possible explanation. Objective: We hypothesized that BCG at birth would reduce the cumulative incidence of RW during the first year of life. Methods: The Danish Calmette Study is a multicenter randomized trial conducted from 2012-2015 at 3 Danish hospitals. The 4262 newborns of 4184 included mothers were randomized 1:1 to BCG (SSI strain 1331) or to a no-intervention control group within 7 days of birth; siblings were randomized together as one randomization unit. Exclusion criteria were gestational age of less than 32 weeks, birth weight of less than 1000 g, known immunodeficiency, or no Danish-speaking parent. Information was collected through telephone interviews and clinical examinations at 3 and 13 months of age; data collectors were blind to randomization group. RW was defined in several ways, with the main definition being physician-diagnosed and medically treated RW up to 13 months of age. Results: By 13 months, 211 (10.0%) of 2100 children in the BCG group and 195 (9.4%) of 2071 children in the control group had received a diagnosis of RW from a medical doctor and received antiasthma treatment (relative risk, 1.07; 95% CI, 0.89-1.28). Supplementary analyses were made, including an analysis of baseline risk factors for development of RW. Conclusion: Neonatal BCG had no effect on the development of RW before 13 months of age.

Background Vaccines may have non-specific effects. An observational study from Guinea-Bissau suggested that oral polio vaccine at birth (OPV0) provided with Bacillus Calmette–Guerin (BCG) vaccine was associated with down-regulation of the immune response to BCG vaccine 6 weeks later. Based on the previous finding, we wanted to test our a priori hypothesis that OPV would dampen the immune response to BCG, and secondarily to test immune responses to other antigens. Methods The study was conducted at the Bandim Health Project in Guinea-Bissau in 2009–2010. Infants were randomised to OPV0 + BCG versus BCG alone at birth, and subsequently randomised to have a blood sample taken at 2, 4 or 6 weeks post-randomisation. Excreted levels of cytokines (IL-2, IL-5, IL-10, TNF-α and IFN-γ) were measured from whole blood in vitro stimulations with a panel of recall vaccine antigens (BCG, PPD, OPV), mitogen (PHA) or innate agonists (LPS, Pam3cys, PolyI:C). Additionally, we measured the local reaction to BCG, white blood cell distribution, C-reactive protein (CRP) and retinol-binding protein (RBP). Cytokine production was analysed as the prevalence ratios of responders above the median. Results Blood samples from 430 infants (209 OPV0 + BCG; 221 BCG alone) were analysed. There were no strong differences in effects 2, 4 and 6 weeks post-randomisation and subsequent analyses were performed on the pooled data. As hypothesised, receiving OPV0 + BCG versus BCG alone was associated with significantly lower prevalence of IFN-γ responses to PPD (prevalence ratio (PR): 0.84 (0.72–0.98)) and reduced IL-5 to PPD (PR: 0.78 (0.64–0.96)). No effects were observed for CPR, RBP, white blood cell distribution, or BCG scar prevalence. Conclusion The results corroborate that OPV attenuates the immune response to co-administered BCG at birth.

The major burden of influenza morbidity resides within the elderly population. The challenge managing influenza-associated illness in the elderly is the decline of immune function, where mechanisms leading to immunological senescence have not been elucidated. To better represent the immune environment, we investigated clinical morbidity and immune function during sequential homologous and heterologous H1N1 influenza infection in an aged ferret model. Our findings demonstrated experimentally that aged ferrets had significant morbidity during monosubtypic heterologous 2° challenge with significant weight loss and respiratory symptoms. Furthermore, increased clinical morbidity was associated with slower and shorter hemagglutinin antibody generation and attenuated type 1 T-cell gene responses in peripheral blood. These results revealed dampened immune activation during sequential influenza infection in aged ferrets. With the presence of an aged model, dissecting clinical morbidity, viral dynamics and immune response during influenza infection will aid the development of future prophylactics such as age specific influenza vaccines.

Live-attenuated influenza virus (LAIV) prime-boost vaccination previously conferred protection against heterologous H3N2 swine influenza challenge, including in piglets with maternally derived antibodies (MDA). Conversely, a whole-inactivated virus (WIV) vaccine was associated with enhanced disease. This study was aimed at identifying immune correlates of cross-protection. Piglets with and without MDA received intramuscular adjuvanted WIV or intranasal LAIV, and were challenged with heterologous H3N2. WIV induced cross-reactive IgG, inhibited by MDA, and a moderate T cell response. LAIV elicited mucosal antibodies and T cells cross-reactive to the heterologous challenge strain. The presence of MDA at LAIV vaccination blocked lung and nasal antibody production, but did not interfere with T cell priming. Even without mucosal antibodies, MDA-positive LAIV vaccinates were protected, indicating a likely role for T cells. Based on the data, one LAIV dose can induce cell-mediated immunity against antigenically divergent H3N2 influenza virus despite passive antibody interference with humoral immune responses.

Having a history of infection with one pathogen may sometimes provide a level of T cell-dependent protective heterologous immunity to another pathogen. This immunity was initially thought due to cross-reactive T cell epitopes, but recent work has suggested that such protective immunity can be initiated nonspecifically by the action of cytokines on memory T cells. We retested this concept using two small and well-defined arenaviruses, lymphocytic choriomeningitis virus (LCMV) and Pichinde virus (PV), and found that heterologous immunity in these systems was indeed linked to T cell epitopes and the major histocompatibility complex.

(See the Major Article by Storgaard et al on pages 950–9.) Bacillus Calmette–Guerin (BCG) vaccine provides good protection against disseminated mycobacterial diseases such as miliary tuberculosis, tuberculous meningitis, and leprosy [1, 2] but weaker protection against pulmonary tuberculosis, especially in rural areas near the equator [3]. In high-mortality countries, until a different vaccine is given, BCG vaccine also provides nonspecific (heterologous) protection against diseases other than tuberculosis and leprosy (mainly respiratory infections and sepsis) [4]. In randomized trials in Guinea-Bissau, vaccination with BCG–Danish vaccine reduced neonatal mortality in low-birth-weight babies by 48% (95% confidence interval [CI], 18%–67%) [5, 6], and revaccination reduced all-cause mortality by 64% (95% CI, 1%–87%) in children aged 19 months who had received a booster dose of diphtheria–tetanus–pertussis vaccine [7]. BCG vaccine may also have important nonspecific effects in high-income countries. In a cohort study in Spain, BCG–Danish vaccine reduced nontuberculous hospital admissions in infants by 32% (95% CI, 31%–34%) for respiratory infections and by 53% (95% CI, 44%–61%) for sepsis [8]. In this issue of Clinical Infectious Diseases, Storgaard and colleagues report the results of a study based on a remarkable surveillance system that has prospectively monitored a representative sample of rural Guinea-Bissau since 1990. This is an extraordinary database. The study found a scar in only 52% of children given BCG–Moscow vaccine, the same rate as BCG–Moscow vaccine in Uganda [9] but much lower than the 72%–97% scar rate after BCG–Danish vaccine was given in urban Guinea-Bissau [10–13]. The low scar rate in rural Guinea-Bissau may be due to the fact that the BCG–Moscow vaccine is less likely to produce a scar than the BCG–Danish vaccine (as suggested by the similar result in Uganda), but it may also be due to disruption of the cold chain in rural areas or poor vaccination techniques. An important finding in the study in rural Guinea-Bissau was that among infants who had received BCG–Moscow vaccine, those with a scar had a 52% (95% CI, 10%–74%) lower mortality rate than those with no scar. The authors present evidence that the lower mortality was unlikely to be explained by healthier children being more likely to form a scar, and the results are consistent with previous studies showing a relationship between BCG–Danish vaccine scar and survival [10–13]. Clearly, it would be desirable to test whether revaccination with BCG vaccine reduces all-cause mortality in children who do not develop a scar after a single dose. In addition, in the randomized trial in Guinea-Bissau that showed reduced mortality after revaccination at age 19 months, 77% of the children had a scar [7]. Consequently, further randomized trials are needed to test the effects of revaccination on all-cause mortality in children who have a scar following BCG vaccination at birth, as well as those without a scar. Revaccination with BCG vaccine confers little or no extra protection against tuberculosis but it may improve protection against leprosy and increase the beneficial nonspecific effects of BCG vaccine [14]. Although the presence of a BCG vaccine scar is associated with reduced mortality from diseases other than tuberculosis, it does not predict susceptibility to tuberculosis [15]. Indeed, no laboratory test or clinical finding (such as BCG vaccine scar or Mantoux test) predicts susceptibility to tuberculosis after BCG vaccination, and animal models are not a reliable guide to the effectiveness of different strains of BCG [15]. Ninety-four years after it was first used in humans, we still have no way to determine which children are protected against tuberculosis following BCG vaccination, and we do not know how BCG vaccine protects against tuberculosis [16]. However, we do know that BCG vaccine protects against infections other than tuberculosis, at least in part, by an epigenetic effect mediated by methylation of histone that alters innate immunity in adults [17] and neonates [18]. It would be ironic if we were to discover that BCG vaccine protects against tuberculosis via a nonspecific effect mediated by innate immunity [16, 17]. We urgently need to know more about the mechanisms by which BCG vaccine protects against mycobacterial and nonmycobacterial infections. The Expanded Program on Immunization (EPI) recommends that BCG vaccine be given at birth to all neonates in countries with a high prevalence of tuberculosis; the World Health Organization-approved vaccines are BCG–Danish, BCG–Tokyo, and BCG–Moscow. Are different strains of BCG equivalent? A large randomized trial in 303 092 neonates in Hong Kong found that the risk of tuberculosis with BCG–Pasteur vaccine was 45% (95% CI, 22%–61%) less than with BCG–Glaxo [19]. In a cohort study in Kazakhstan, vaccination of neonates reduced the risk of clinically diagnosed tuberculosis by 69% (95% CI, 61%–75%) after BCG–Tokyo vaccination, by 43% (95% CI, 31%–53%) after BCG–Serbia, and only by 22% (95% CI, 7%–35%) after BCG–Moscow [20]. These findings suggest that there are very large differences in effectiveness against tuberculosis between BCG strains. In 2014, United Nations Children's Fund (UNICEF) supplied 86 million doses of BCG–Moscow vaccine (the least effective strain in Kazakhstan), only 31 million doses of BCG-Tokyo (the most effective strain in Kazakhstan), and only 5 million doses of BCG–Danish (the strain that reduced neonatal mortality by 48% in Guinea-Bissau) [21]. However, UNICEF's purchasing was constrained by limited supplies of BCG–Tokyo and BCG–Danish vaccines. The nonspecific effects of BCG vaccine are greater when there is a scar following BCG–Danish or BCG–Moscow vaccination, and different strains of BCG have very different scar rates (usually >90% for BCG–Danish and BCG–Tokyo vaccines, but only 52% for BCG–Moscow vaccine in Guinea-Bissau and Uganda) [9–13]. Consequently, different strains are likely to have different nonspecific effects. It is therefore highly desirable that we compare both the specific and nonspecific effects of different strains of BCG. Comstock has suggested that protection against tuberculosis could be tested easily with an ABAB observational study [19]. In such a study, all neonates in a defined region would be vaccinated with one strain (A) of BCG for a year and another strain (B) the next year, with the alternation continued for another 2 years (AB). Providing tuberculosis were recognized similarly in odd and even years, this ingenious design would approach true randomization but at much lower cost. In addition to the important genetic differences between the strains of BCG [22], there are genetic differences within some strains that can cause major differences in the characteristics of BCG vaccine produced from the same seed lot by different manufacturers [23] and between different batches from a single manufacturer [24]. BCG-Tokyo and BCG-Danish vaccines each contain at least 2 genotypes [25]. In 1983, Osborn suggested that BCG vaccines used for routine immunization should be prepared from seed lots derived from single colonies so that they have stable characteristics [23]. Unfortunately, this has not been done for BCG–Tokyo or BCG–Danish vaccines. This can lead to problems with the production of these vaccines [21] and the potential for large variations in clinical effects [24]. BCG–Danish vaccine and probably BCG–Tokyo vaccine have potent nonspecific effects that substantially reduce mortality from diseases other than tuberculosis; however, these beneficial effects are not properly exploited at present. Although it is EPI policy for BCG vaccine to be given to all infants at birth in high-prevalence regions, less than half actually receive BCG vaccine in the first month of life, partly because health workers are told not to open a multidose vial until enough infants need BCG vaccine. A 10- or 20-dose vial costs UNICEF only $0.75–$2.74, and BCG–Danish vaccine given soon after birth reduced neonatal mortality by 48% (95% CI, 18%–67%) in randomized trials in Guinea-Bissau [5, 6]. Policy should change so that as many infants as possible receive BCG vaccine as soon as possible after birth, and a multidose vial should be opened even if only 1 infant needs BCG vaccine. Over many years, substantial resources have been devoted to attempts to develop a new vaccine against tuberculosis, so far without success. This has distracted us from making optimal use of BCG vaccine, when some simple measures would almost certainly have improved both its specific and nonspecific effects. If a new vaccine against tuberculosis is developed, it will be important to test its effects on all-cause mortality as well as its effects on tuberculosis; we may need to continue to use BCG vaccine for its highly beneficial nonspecific effects. The BCG vaccine is not a single vaccine; the different strains have very different properties, and there are different genotypes within strains. It is likely that we could substantially improve protection against tuberculosis and lower child mortality from other infections by manufacturing each BCG vaccine from a single genotype, comparing these vaccines to find which genotype has the strongest effects against tuberculosis and against other infections, investigating the effect of revaccination on all-cause mortality, and ensuring that a high proportion of neonates are given BCG vaccine in the first few days of life. These measures are likely to yield very large benefits at minimal cost.