Search

As the COVID‐19 pandemic has progressed, it has become apparent that COVID‐19 vaccination has limited impact on SAR‐CoV‐2 transmission and provides only short‐term protection against acquiring infection, but more robust protection against severe disease and death. As a result, vaccinated people remain susceptible to SARS‐CoV‐2 infection but are less likely to experience severe outcomes. Studies show that immunity derived from the combination of vaccination and natural infection, so‐called hybrid immunity, is superior to that provided by vaccination or natural infection alone. Since most Australian adults have received three or more doses of COVID‐19 vaccines and >70% have also been infected with SARS‐CoV‐2, we now have a population with high levels of hybrid immunity. This was mostly achieved by receiving original Wuhan strain vaccines and then experiencing Omicron strain infections. The original Wuhan strain of SARS‐CoV‐2 has now disappeared and been replaced with Omicron‐lineage variants globally. The predominance of the Omicron strain initially led to the development of bivalent vaccines containing both the Wuhan strain and Omicron variants. Currently, vaccines containing the original Wuhan strain of spike protein are being phased out, and new COVID‐19 vaccines based exclusively on the Omicron strain XBB have become available in Australia. This article explores the question of whether further doses will be required from 2024 onwards and, if so, who should receive them? [ABSTRACT FROM AUTHOR]

It is well established that vaccination does not affect males and females equally. For example, females generally mount greater antibody responses to vaccination than males, but also suffer more adverse events following vaccination, probably as a result of more robust immunity. Despite this, most researchers in the field of vaccinology do not take biological sex into account when conducting their studies. This omission is likely to lead to a loss of important information in terms of both reactogenicity and immunogenicity following vaccination as well as those suffering adverse events. It also suggests that the vaccine dose in males and females may need to be different in order to achieve the same outcome of protective immunity while minimising reactogenicity. [ABSTRACT FROM AUTHOR]

Both sex (i.e., biological differences) and gender (i.e., social or cultural influences) impact vaccine acceptance, responses, and outcomes. Clinical data illustrate that among children, young adults, and aged individuals, males and females differ in vaccine-induced immune responses, adverse events, and protection. Although males are more likely to receive vaccines, following vaccination, females typically develop higher antibody responses and report more adverse effects of vaccination than do males. Human, nonhuman animal, and in vitro studies reveal numerous immunological, genetic, hormonal, and environmental factors that differ between males and females and contribute to sex- and gender-specific vaccine responses and outcomes. Herein, we address the impact of sex and gender variables that should be considered in preclinical and clinical studies of vaccines. [ABSTRACT FROM AUTHOR]

Vaccines that do not take a comprehensive endpoint view of the pathogen population they want to tackle early in their developmental process, may find it financially prohibitive to redesign them once they have progressed down a costly regulatory and human trial pathway. Specifically, the lead malaria vaccine candidate RTS,S has limited ability to tackle parasite polymorphism and may induce sex-specific nonspecific effects (NSEs). [ABSTRACT FROM AUTHOR]

Abstract: Vaccines have non-specific effects (NSE) on subsequent morbidity and mortality from non-vaccine related infectious diseases. Thus NSE refers to any effect that cannot be accounted for by the induction of immunity against the vaccine-targeted disease. These effects are sex-differential, generally being more pronounced in females than males. Furthermore, the NSE are substantial causing greater than fifty percent changes in all cause mortality in certain settings, yet have never been systematically tested despite the fact that millions of children receive vaccines each year. As we strive to eliminate infectious diseases through vaccination programmes, the relative impact of NSE of vaccines on mortality is likely to increase, raising important questions regarding the future of certain vaccine schedules. A diverse group of scientists met in Copenhagen to discuss non-specific and sex-differential effects of vaccination, and explore plausible biological explanations. Herein we describe the contents of the meeting and the establishment of the ‘Optimmunize’ network aimed at raising awareness of this important issue among the wider scientific community. [Copyright &y& Elsevier]

Abstract: Parenteral quinine is the most frequently used first line treatment for severe Plasmodium falciparum malaria in the developed world. Quinine is known to have a number of toxic side effects including cardiotoxicity, ototoxicity and ocular toxicity. Many therefore advocate routine monitoring of quinine levels for patients receiving parenteral therapy. This paper reviews current evidence on the usefulness of quinine level monitoring in the context of 73 adult patients with severe P. falciparum malaria managed by the Hospital for Tropical Diseases in London. Combining data from these patients with a comprehensive literature review, we conclude that routine quinine level monitoring in all patients receiving parenteral therapy is seldom appropriate. [Copyright &y& Elsevier]

ABSTRACT Background Objective Methods Results Conclusions and Clinical Relevance The beneficial off‐target effects of Bacille Calmette–Guérin (BCG) vaccination potentially include protection against allergy.In the MIS BAIR trial, we aimed to determine whether neonatal BCG vaccination reduces atopic sensitisation and clinical food allergy in infants.In this randomised controlled trial, 1272 neonates were allocated to BCG‐Denmark vaccine (0.05 mL intradermal dose) or no BCG at birth. Randomisation was stratified by recruitment site, mode of delivery and plurality of birth. The primary outcome was the incidence of atopic sensitisation determined by skin prick test at 1 year of age. Food allergy was determined by 3‐monthly online questionnaires and oral food challenges. Data were analysed by intention‐to‐treat using binary regression. Clinicaltrials.gov (NCT01906853).Atopic sensitisation during the first year of life was 22.9% among infants in the BCG group and 18.9% in the control group (adjusted risk difference (aRD) 3.8% (95% CI −1.5 to 9.1) after multiple imputation). Clinical food allergy was similar between infants in the BCG and control groups (9.8% vs. 9.6%; aRD 0.2, 95% CI −3.4 to 3.8). An interaction was observed between the primary outcome and maternal history of BCG vaccination. No interaction was observed for the additional prespecified potential effect modifiers tested (sex, delivery mode, family history of any allergy, season of birth, hepatitis B vaccination at randomisation, BCG scar and age at BCG administration).Neonatal BCG‐Denmark vaccination does not protect against atopic sensitisation or clinical food allergy in the first year of life. [ABSTRACT FROM AUTHOR]

Focuses on the investigation and outcome of late complication of plasmodium falciparum malaria. Patients details; Treatments applied to the patient; Biphasic clinical course of the two patients; Complications associated with postmalaria neurological syndrome; Difference in the case of two patients studied.

The article discusses the study conducted by Woudenberg et al. on the effectiveness of early measles-mumps-rubella (MMR) vaccination. Also tackled is the research by Do et al. regarding the nonspecific protective effect against morbidity. Explored is the beneficial effect of MV on the sexual behavior of men.

Objective: To compare clinician documentation of sepsis for infective presentations in the ED against a formal sepsis pathway in the ED and to assess appropriateness of the initial parenteral antibiotic prescription for adult patients in ED. Methods: A retrospective, clinical audit of adult patients who received at least one parenteral antibiotic in ED over a 10‐week period in 2018. Documented initial clinical impression was compared with an approved sepsis pathway. Antibiotic appropriateness was assessed using National Antimicrobial Prescribing Survey definitions. Assessment was carried out by an infectious diseases pharmacist, with input from an infectious diseases physician. Results: Two hundred and nineteen infective presentations were included in the analysis. There was a discordance between the initial documented clinical impression compared with the classification when a sepsis pathway was applied. An initial documented clinical impression of sepsis and septic shock was present in 38 (60.3%) of the presentations compared to 63 presentations when a formal sepsis pathway was applied as a screening tool. There was a significant difference in the proportion of patients in each diagnostic group (infection, sepsis and septic shock) according to documented clinical impression versus sepsis pathway classification (P = 0.0002). There were 386 prescriptions for antibiotics as part of the initial management. Antibiotic appropriateness for the initial prescription was assessed as 63.7% appropriate, 27.2% inappropriate and 9.1% not assessable. Conclusion: Our observations demonstrate that use of a formal sepsis pathway may improve the screening and early diagnosis of sepsis and septic shock and that there is a need for antibiotic prescribing guidance in the ED. [ABSTRACT FROM AUTHOR]

The current framework for testing and regulating vaccines was established before the realization that vaccines, in addition to their effect against the vaccine-specific disease, may also have "non-specific effects" affecting the risk of unrelated diseases. Accumulating evidence from epidemiological studies shows that vaccines in some situations can affect all-cause mortality and morbidity in ways that are not explained by the prevention of the vaccine-targeted disease. Live attenuated vaccines have sometimes been associated with decreases in mortality and morbidity that are greater than anticipated. In contrast, some non-live vaccines have in certain contexts been associated with increases in all-cause mortality and morbidity. The non-specific effects are often greater for female than male individuals. Immunological studies have provided several mechanisms that explain how vaccines might modulate the immune response to unrelated pathogens, such as through trained innate immunity, emergency granulopoiesis, and heterologous T-cell immunity. These insights suggest that the framework for the testing, approving, and regulating vaccines needs to be updated to accommodate non-specific effects. Currently, non-specific effects are not routinely captured in phase I–III clinical trials or in the post-licensure safety surveillance. For instance, an infection with Streptococcus pneumoniae occurring months after a diphtheria-tetanus-pertussis vaccination would not be considered an effect of the vaccination, although evidence indicates it might well be for female individuals. Here, as a starting point for discussion, we propose a new framework that considers the non-specific effects of vaccines in both phase III trials and post-licensure. [ABSTRACT FROM AUTHOR]

Background: Bacille Calmette‐Guérin (BCG) vaccine could play a role in counteracting the rising prevalence of atopic diseases, through its beneficial off‐target effects. We aimed to determine whether neonatal BCG vaccination reduces the incidence of eczema in infants. Methods: Randomized controlled trial with 1272 infants allocated to receive BCG‐Denmark or no BCG at birth. The primary outcome was the 12‐month incidence of eczema based on 3‐monthly questionnaires. Eczema was also assessed at a 12‐month clinic visit. ClinicalTrial.gov: NCT01906853. Results: The 12‐month eczema incidence was 32.2% in the BCG group compared with 36.6% in the control group (adjusted risk difference (aRD) −4.3%, 95% CI −9.9% to 1.3%, multiple imputation model). In addition, comparing infants in the BCG group with the control group, 15.7% vs. 19.2% had eczema lesions at the 12‐month visit (aRD −3.5%, 95% CI −8.0% to 1.0%); 35.7% vs. 39.0% reported using topical steroids (aRD −3.3, 95% CI −9.2 to 2.7); and 7.3% vs. 10.2% had severe eczema scores (aRD −3.0%, 95% CI −8.8% to 2.7%). In 344 high‐risk infants (two atopic parents), the 12‐month eczema incidence was 35.3% in the BCG group compared with 46.8% in the control group (aRD −11.5%, 95% CI −21.9% to −1.2%; number needed to treat 8.7, 95% CI 4.6 to 83.3). Conclusion: There is insufficient evidence to recommend neonatal BCG vaccination in all infants for the prevention of eczema in the first year of life; however, a modest beneficial effect was observed among high‐risk infants. A single dose of BCG‐Denmark soon after birth could reduce the incidence of eczema in infants with two atopic parents. [ABSTRACT FROM AUTHOR]

• BCG vaccination reduced IFN-γ and MCP-1 responses to heterologous stimulants. • HBV vaccination alone did not alter heterologous cytokine responses. • Males overall produced more IFN-γ and TNF-α compared with females. • HBV co-administration influenced the heterologous effects of neonatal BCG vaccination in a sex-differential manner. Bacille Calmette-Guérin (BCG) and hepatitis B (HBV) vaccines are frequently given concomitantly at birth. Neonatal BCG vaccination induces off-target immunological effects. Whether HBV vaccine has immunomodulatory effects is unknown. As off-target effects might vary when vaccines are given simultaneously, this randomised controlled trial aimed to evaluate the influence of neonatal vaccination with BCG and/or HBV on heterologous immune responses. A total of 185 neonates in Australia were randomised to receive either neonatal BCG-Denmark vaccine, HBV vaccine, both (BCG + HBV group), or none (No vaccine group). In-vitro responses to heterologous stimulants were assessed 7 days after vaccination. The influence of (i) randomisation group and (ii) sex on interferon-gamma (IFN-γ), monocyte chemoattractant protein-1 (MCP-1), and tumour necrosis factor-alpha (TNF-α) responses was analysed using linear regression. Overall, BCG vaccination alone or with HBV co-administration reduced IFN-γ and MCP-1 responses to heterologous stimulants. HBV vaccination alone did not alter heterologous cytokine responses. In general, males produced more IFN-γ and TNF-α than females. We observed a sex-differential effect in relation to the influence of HBV co-administration on the effect of BCG on heterologous responses. Compared with males in the No vaccine group, males in the BCG + HBV group had lower IFN-γ and MCP-1 responses. In contrast, compared with females in the No vaccine group, females in the BCG group had higher IFN-γ response and lower MCP-1 responses. Neonatal BCG vaccination resulted in lower cytokine responses to unrelated pathogens. HBV co-administration did not have a significant impact on responses overall but influenced the heterologous effects of neonatal BCG vaccination in a sex-differential manner. [ABSTRACT FROM AUTHOR]

While first and foremost considered a respiratory infection, COVID-19 can result in complications affecting multiple organs. Immune responses in COVID-19 can both protect against the disease as well as drive it. Insights into these responses, and specifically the targets being recognised by the immune system, are of vital importance in understanding the side effects of COVID-19 and associated pathologies. The body's adaptive immunity recognises and responds against specific targets (antigens) expressed by foreign pathogens, but not usually to target self-antigens. However, if the immune system becomes dysfunctional, adaptive immune cells can react to self-antigens, which can result in autoimmune disease. Viral infections are well reported to be associated with, or exacerbate, autoimmune diseases such as multiple sclerosis (MS) and systemic lupus erythematosus (SLE). In COVID-19 patients, both new onset MS and SLE, as well as the occurrence of other autoimmune-like pathologies, have been reported. Additionally, the presence of autoantibodies, both with and without known associations to autoimmune diseases, have been found. Herein we describe the mechanisms of virally induced autoimmunity and summarise some of the emerging reports on the autoimmune-like diseases and autoreactivity that is reported to be associated with SARS-CoV-2 infection. [ABSTRACT FROM AUTHOR]

Morbidity and mortality rates from seasonal and pandemic influenza occur disproportionately in high-risk groups, including Indigenous people globally. Although vaccination against influenza is recommended for those most at risk, studies on immune responses elicited by seasonal vaccines in Indigenous populations are largely missing, with no data available for Indigenous Australians and only one report published on antibody responses in Indigenous Canadians. We recruited 78 Indigenous and 84 non-Indigenous Australians vaccinated with the quadrivalent influenza vaccine into the Looking into InFluenza T cell immunity - Vaccination cohort study and collected blood to define baseline, early (day 7), and memory (day 28) immune responses. We performed in-depth analyses of T and B cell activation, formation of memory B cells, and antibody profiles and investigated host factors that could contribute to vaccine responses. We found activation profiles of circulating T follicular helper type-1 cells at the early stage correlated strongly with the total change in antibody titers induced by vaccination. Formation of influenza-specific hemagglutinin-binding memory B cells was significantly higher in seroconverters compared with nonseroconverters. In-depth antibody characterization revealed a reduction in immunoglobulin G3 before and after vaccination in the Indigenous Australian population, potentially linked to the increased frequency of the G3m21* allotype. Overall, our data provide evidence that Indigenous populations elicit robust, broad, and prototypical immune responses following immunization with seasonal inactivated influenza vaccines. Our work strongly supports the recommendation of influenza vaccination to protect Indigenous populations from severe seasonal influenza virus infections and their subsequent complications. [ABSTRACT FROM AUTHOR]

Background: Bacille Calmette-Guérin (BCG) vaccination has beneficial off-target effects that may include protecting against non-mycobacterial infectious diseases. We aimed to determine whether neonatal BCG vaccination reduces lower respiratory tract infections (LRTI) in infants in the Melbourne Infant Study: BCG for Allergy and Infection Reduction (MIS BAIR) trial.Methods: In this investigator-blinded trial, neonates in Australia were randomized to receive BCG-Denmark vaccination or no BCG at birth. Episodes of LRTI were determined by symptoms reported in parent-completed, 3-month questionnaires over the first year of life. Data were analyzed by intention-to-treat using binary regression.Results: A total of 1272 neonates were randomized to the BCG vaccination (n = 637) or control (n = 635) group. The proportion of participants with an episode of LRTI in the first year of life among BCG-vaccinated infants was 54.8% compared to 58.0% in the control group, resulting in a risk difference of -3.2 (95% confidence interval, -9.0 to 2.6) after multiple imputation. There was no interaction observed between the primary outcome and sex, maternal BCG, or the other prespecified effect modifiers.Conclusions: Based on the findings of this trial, there is insufficient evidence to support the use of neonatal BCG vaccination to prevent LRTI in the first year of life in high-income settings. [ABSTRACT FROM AUTHOR]

Objective: CD4+ T cells are critical mediators of immunity to Plasmodium spp. infection, but their characteristics during malarial episodes and immunopathology in naturally infected adults are poorly defined. Flow cytometric analysis of PBMCs from patients with either P. falciparum or P. knowlesi malaria revealed a pronounced population of CD4+ T cells co‐expressing very high levels of CD4 and CD38 we have termed CD4hiCD38hi T cells. We set out to gain insight into the function of these novel cells. Methods: CD4+ T cells from 18 patients with P. falciparum or P. knowlesi malaria were assessed by flow cytometry and sorted into populations of CD4hiCD38hi or CD4norm T cells. Gene expression in the sorted populations was assessed by qPCR and NanoString. Results: CD4hiCD38hi T cells expressed high levels of CD4 mRNA and canonical type 1 regulatory T‐cell (TR1) genes including IL10, IFNG, LAG3 and HAVCR2 (TIM3), and other genes with relevance to cell migration and immunomodulation. These cells increased in proportion to malaria disease severity and were absent after parasite clearance with antimalarials. Conclusion: In naturally infected adults with acute malaria, a prominent population of type 1 regulatory T cells arises that can be defined by high co‐expression of CD4 and CD38 (CD4hiCD38hi) and that correlates with disease severity in patients with falciparum malaria. This study provides fundamental insights into T‐cell biology, including the first evidence that CD4 expression is modulated at the mRNA level. These findings have important implications for understanding the balance between immunity and immunopathology during malaria. [ABSTRACT FROM AUTHOR]

An improved understanding of human T cell-mediated immunity in COVID-19 is important for optimizing therapeutic and vaccine strategies. Experience with influenza shows that infection primes CD8+ T cell memory to peptides presented by common HLA types like HLA-A2, which enhances recovery and diminishes clinical severity upon reinfection. Stimulating peripheral blood mononuclear cells from COVID-19 convalescent patients with overlapping peptides from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to the clonal expansion of SARS-CoV-2−specific CD8+ and CD4+ T cells in vitro, with CD4+ T cells being robust. We identified two HLAA* 02:01-restricted SARS-CoV-2-specfic CD8+ T cell epitopes, A2/ S269–277 and A2/Orf1ab3183–3191. Using peptide−HLA tetramer enrichment, direct ex vivo assessment of A2/S269 +CD8+ and A2/ Orf1ab3183 +CD8+ populations indicated that A2/S269 +CD8+ T cellswere detected at comparable frequencies (∼1.3 × 10−5) in acute and convalescent HLA-A*02:01+ patients. These frequencies were higher than those found in uninfected HLA-A*02:01+ donors (∼2.5 × 10−6), but low when compared to frequencies for influenza-specific (A2/M158) and Epstein–Barr virus (EBV)-specific (A2/BMLF1280) (∼1.38 × 10−4) populations. Phenotyping A2/S269 +CD8+ T cells from COVID-19 convalescents ex vivo showed that A2/S269 +CD8+ T cells were predominantly negative for CD38, HLA-DR, PD-1, and CD71 activation markers, although the majority of total CD8+ T cells expressed granzymes and/or perforin. Furthermore, the bias toward naïve, stem cell memory and central memory A2/S269 +CD8+ T cells rather than effector memory populations suggests that SARS-CoV-2 infection may be compromising CD8+ T cell activation. Priming with appropriate vaccines may thus be beneficial for optimizing CD8+ T cell immunity in COVID-19. [ABSTRACT FROM AUTHOR]

Starting at birth, the immune system of newborns and children encounters and is influenced by environmental challenges. It is still not completely understood how γδ T cells emerge and adapt during early life. Studying the composition of T cell receptors (TCRs) using next-generation sequencing (NGS) in neonates, infants, and children can provide valuable insights into the adaptation of T cell subsets. To investigate how neonatal γδ T cell repertoires are shaped by microbial exposure after birth, we monitored the γ-chain (TRG) and δ-chain (TRD) repertoires of peripheral blood T cells in newborns, infants, and young children from Europe and sub-Saharan Africa. We identified a set of TRG and TRD sequences that were shared by all children from Europe and Africa. These were primarily public clones, characterized by simple rearrangements of Vγ9 and Vδ2 chains with low junctional diversity and usage of non-TRDJ1 gene segments, reminiscent of early ontogenetic subsets of γδ T cells. Further profiling revealed that these innate, public Vγ9Vδ2+ T cells underwent an immediate TCR-driven polyclonal proliferation within the first 4 wk of life. In contrast, γδ T cells using Vδ1+ and Vδ3+ TRD rearrangements did not significantly expand after birth. However, different environmental cues may lead to the observed increase of Vδ1+ and Vδ3+ TRD sequences in the majority of African children. In summary, we show how dynamic γδ TCR repertoires develop directly after birth and present important differences among γδ T cell subsets. [ABSTRACT FROM AUTHOR]

Malaria vaccines aim to induce long lasting protective immunity. Bejon and colleagues propose that levels of rapidly induced (effector memory) interleukin-2 and interferon gamma producing T-cells after vaccination with leading pre-erythrocytic stage vaccines predict the induction of resting memory responses (central memory). Herein we discuss Bejon''s findings in the context of current thinking on the generation and maintenance of T cell memory, with particular emphasis on the role of cytokines. [Copyright &y& Elsevier]

Background: BCG vaccination has beneficial nonspecific (heterologous) effects that protect against nonmycobacterial infections. We have previously reported that BCG vaccination at birth alters in vitro cytokine responses to heterologous stimulants in the neonatal period. This study investigated heterologous responses in 167 infants in the same trial 7 months after randomization.Methods: A whole-blood assay was used to interrogate in vitro cytokine responses to heterologous stimulants (killed pathogens) and Toll-like receptor (TLR) ligands.Results: Compared to BCG-naive infants, BCG-vaccinated infants had increased production of interferon gamma (IFN-γ) and monokine induced by gamma interferon (MIG) (CXCL9) in response to mycobacterial stimulation and decreased production of IFN-γ in response to heterologous stimulation and TLR ligands. Reduced IFN-γ responses were attributable to a decrease in the proportion of infants who mounted a detectable IFN-γ response. BCG-vaccinated infants also had increased production of MIG (CXCL9) and interleukin-8 (IL-8), and decreased production of IL-10, macrophage inflammatory protein-1α (MIP-1α), and MIP-1β, the pattern of which varied by stimulant. IL-1Ra responses following TLR1/2 (Pam3CYSK4) stimulation were increased in BCG-vaccinated infants. Both sex and maternal BCG vaccination status influenced the effect of neonatal BCG vaccination.Conclusions: BCG vaccination leads to changes in IFN-γ responsiveness to heterologous stimulation. BCG-induced changes in other cytokine responses to heterologous stimulation vary by pathogen. [ABSTRACT FROM AUTHOR]

Mucosal-associated invariant T (MAIT) cells are important for immune responses against microbial infections. Although known to undergo marked numerical changes with age in humans, our understanding of how MAIT cells are altered during different phases across the human life span is largely unknown. Although also abundant in the tissues, our study focuses on MAIT cell analyses in blood. Across the human life span, we show that naive-like MAIT cells in umbilical cord blood switch to a central/ effector memory-like profile that is sustained into older age. Whereas low-grade levels of plasma cytokine/chemokine were apparent in older donors (>65 y old), surprisingly, they did not correlate with the ex vivo MAIT hyperinflammatory cytokine profile observed in older adults. Removal of MAIT cells from older individuals and an aged environment resulted in the reversal of the baseline effector molecule profile comparable with MAIT cells from younger adults. An upregulated basal inflammatory profile accounted for reduced Escherichia coli-specific responses in aged MAIT cells compared with their young adult counterparts when fold change in expression levels of GzmB, CD107a, IFN-γ, and TNF was examined. However, the magnitude of antimicrobial MR1-dependent activation remained as potent and polyfunctional as with younger adults. Paired TCRab analyses of MAIT cells revealed large clonal expansions in older adults and tissues that rivalled, remarkably, the TCRαβ repertoire diversity of virus-specific CD8+ T cells. These data suggest that MAIT cells in older individuals, although associated with large clonal TCRαβ expansions and increased baseline inflammatory potential, demonstrate plasticity and provide potent antimicrobial immunity. [ABSTRACT FROM AUTHOR]

Aim: We investigated the effect of early-life factors, namely sex, delivery mode, feeding method and antibiotic exposure, on antibody responses to routine vaccinations administered during the first year of life.Methods: One and seven months after the primary course of routine vaccines and 1 month after routine vaccines at 12 months of age, antibodies against 26 vaccine antigens were measured in 398 healthy infants. The geometric mean concentration (GMC) of antibodies (adjusted for effect modifiers with multiple linear regression) and the seroprotection rate for each vaccine were compared for each early-life factor.Results: Sex had an influence on GMCs. Antibody concentrations were significantly lower at 7 months of age in females for tetanus and filamentous haemagglutinin and at 13 months of age for pertactin. In contrast, at 13 months of age, antibody concentrations were significantly higher in females for polio type 3, pneumococcal serotype 6A and measles. Sex did not have an influence on seroprotection rates. Delivery mode, feeding method and antibiotic exposure did not exert a substantial influence on vaccine antibody concentrations.Conclusion: There is a difference between males and females in the humoral response to routine vaccinations in the first year of life. [ABSTRACT FROM AUTHOR]

Chronic respiratory diseases are among the leading causes of mortality worldwide, with the major contributor, chronic obstructive pulmonary disease (COPD) accounting for approximately 3 million deaths annually. Frequent acute exacerbations (AEs) of COPD (AECOPD) drive clinical and functional decline in COPD and are associated with accelerated loss of lung function, increased mortality, decreased health-related quality of life and significant economic costs. Infections with a small subgroup of pathogens precipitate the majority of AEs and consequently constitute a significant comorbidity in COPD. However, current pharmacological interventions are ineffective in preventing infectious exacerbations and their treatment is compromised by the rapid development of antibiotic resistance. Thus, alternative preventative therapies need to be considered. Pathogen adherence to the pulmonary epithelium through host receptors is the prerequisite step for invasion and subsequent infection of surrounding structures. Thus, disruption of bacterial-host cell interactions with receptor antagonists or modulation of the ensuing inflammatory profile present attractive avenues for therapeutic development. This review explores key mediators of pathogen-host interactions that may offer new therapeutic targets with the potential to prevent viral/bacterial-mediated AECOPD. There are several conceptual and methodological hurdles hampering the development of new therapies that require further research and resolution. [ABSTRACT FROM AUTHOR]

Bacillus Calmette-Guérin vaccine (BCG), one of the most widely used vaccines, does not only provide protection against tuberculosis and other mycobacterial infections, but also has non-specific (heterologous) immunomodulatory effects. In participants in a randomised trial, we investigated the effect of neonatal BCG immunisation on antibody responses to routine infant vaccines given in the first year of life. Antibodies against antigens in the diphtheria, tetanus, pertussis, polio, Haemophilus influenzae type b (Hib), and the 13-valent pneumococcal conjugate vaccines were measured in 91 (45 BCG-vaccinated, 46 BCG-naïve) infants one month after, and in 310 (169 BCG-vaccinated, 141 BCG-naïve) infants seven months after immunisation at 6 weeks, 4 and 6 months of age. In addition, antibodies against meningococcus C, Hib , measles, mumps, and rubella were measured in 147 (78 BCG-vaccinated, 69 BCG-naïve) infants one month after immunisation at 12 months of age. The seroprotection rates for each vaccine and the geometric mean concentrations (GMC) of antibodies were compared in BCG-vaccinated and BCG-naïve infants. At 7 months of age, seroprotection rates were high in both BCG-vaccinated and BCG-naïve infants. At 13 months of age, seroprotection rates were lower than at 7 months of age, particularly for pertussis and a number of pneumococcal antigens, with generally higher rates for the latter in BCG-vaccinated infants. Although not statistically significant, antibody responses in BCG-vaccinated infants were consistently higher against diphtheria, tetanus, and pneumococcal antigens at both 7 and 13 months of age, and against measles and mumps at 13 months of age, but were lower against Hib one month after immunisation at both 7 and 13 months of age. The immunomodulatory effect of BCG on antibody responses to heterologous vaccines adds to the evidence that BCG immunisation at birth has broad heterologous effects on the infant immune system. [ABSTRACT FROM AUTHOR]

Sex differences in immunity are well described in the literature and thought to be mainly driven by sex hormones and sex-linked immune response genes. The gastrointestinal tract (GIT) is one of the largest immune organs in the body and contains multiple immune cells in the GIT-associated lymphoid tissue, Peyer's patches and elsewhere, which together have profound effects on local and systemic inflammation. The GIT is colonised with microbial communities composed of bacteria, fungi and viruses, collectively known as the GIT microbiota. The GIT microbiota drives multiple interactions locally with immune cells that regulate the homeostatic environment and systemically in diverse tissues. It is becoming evident that the microbiota differs between the sexes, both in animal models and in humans, and these sex differences often lead to sex-dependent changes in local GIT inflammation, systemic immunity and susceptibility to a range of inflammatory diseases. The sexually dimorphic microbiome has been termed the 'microgenderome'. Herein, we review the evidence for the microgenderome and contemplate the role it plays in driving sex differences in immunity and disease susceptibility. We further consider the impact that biological sex might play in the response to treatments aimed at manipulating the GIT microbiota, such as prebiotics, live biotherapeutics, (probiotics, synbiotics and bacteriotherapies) and faecal microbial transplant. These alternative therapies hold potential in the treatment of both psychological (e.g., anxiety, depression) and physiological (e.g., irritable bowel disease) disorders differentially affecting males and females. [ABSTRACT FROM AUTHOR]

Background: BCG vaccination is associated with a reduction in all-cause infant mortality in high-mortality settings. The underlying mechanisms remain uncertain, but long-term modulation of the innate immune response (trained immunity) may be involved.Methods: Whole-blood specimens, collected 7 days after randomization from 212 neonates enrolled in a randomized trial of neonatal BCG vaccination, were stimulated with killed pathogens and Toll-like receptor (TLR) ligands to interrogate cytokine responses.Results: BCG-vaccinated infants had increased production of interleukin 6 (IL-6) in unstimulated samples and decreased production of interleukin 1 receptor antagonist, IL-6, and IL-10 and the chemokines macrophage inflammatory protein 1α (MIP-1α), MIP-1β, and monocyte chemoattractant protein 1 (MCP-1) following stimulation with peptidoglycan (TLR2) and R848 (TLR7/8). BCG-vaccinated infants also had decreased MCP-1 responses following stimulation with heterologous pathogens. Sex and maternal BCG vaccination status interacted with neonatal BCG vaccination.Conclusions: Neonatal BCG vaccination influences cytokine responses to TLR ligands and heterologous pathogens. This effect is characterized by decreased antiinflammatory cytokine and chemokine responses in the context of higher levels of IL-6 in unstimulated samples. This supports the hypothesis that BCG vaccination modulates the innate immune system. Further research is warranted to determine whether there is an association between these findings and the beneficial nonspecific (heterologous) effects of BCG vaccine on all-cause mortality. [ABSTRACT FROM AUTHOR]

Vaccines can have nontargeted heterologous effects that manifest as increased protection against nonvaccine infections, as described for measles vaccine (MV), or increased susceptibility to infections and death, as described following diphtheria-tetanus-whole cell pertussis (DTP) vaccination. The mechanisms are unknown, and high-quality immunological studies are lacking. This study was designed to investigate the heterologous effects of MV and DTP in 302 Gambian infants. The results support a sex-differential immunosuppressive effect of DTP on innate proinflammatory responses and T-cell immunity. Males but not females receiving MV had enhanced proinflammatory innate responses. The results point to modified signaling via Toll-like receptor 4 (TLR4) as a possible mechanism for the effects on innate immunity.When both vaccines were administered together, purified protein derivative responses were enhanced in females but downregulated in males. Collectively, these data indicate immunological effects that could account for heterologous effects of MV and DTP, to take forward into prospective trials. [ABSTRACT FROM AUTHOR]

Background. Bacillus Calmette–Guérin (BCG) seems to have beneficial nonspecific effects; early BCG vaccination of low-birth-weight (LBW) newborns reduces neonatal mortality by >40% due to prevention of primarily septicemia and pneumonia.Methods. Within a randomized trial in LBW infants in Guinea-Bissau of early BCG vs the usual postponed BCG, a subgroup was bled 4 weeks after randomization. Levels of interleukin (IL)-1β, IL-5, IL-6, IL-10, IL-17, interferon (IFN)-γ and tumor necrosis factor (TNF)-α were measured from whole-blood assays stimulated with innate agonists to Toll-like receptor (TLR)-2, -4 or -7/8, or purified protein derivative (PPD).Results. Among 467 infants, BCG significantly increased the in vitro cytokine responses to purified protein derivative of Mycobacterium tuberculosis (PPD), as expected. BCG was also associated with increased responses to heterologous innate stimulation, particularly of the cytokines IL-1β, IL-6, TNF-α, and IFN-γ.Conclusion. Four weeks after immunization, BCG-vaccinated infants have a significantly increased production of cytokines upon heterologous challenge, particularly T helper cell type 1 polarizing and typically monocyte-derived pro-inflammatory cytokines. BCG may accelerate the development of the neonatal immune system, mediating comprehensive protection against infections and mortality. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus (EBV) infection often occurs in early childhood and is asymptomatic. However, if delayed until adolescence, primary infection may manifest as acute infectious mononucleosis (AIM), a febrile illness characterised by global CD8+ T-cell lymphocytosis, much of it reflecting a huge expansion of activated EBV-specific CD8+ T-cells. While the events of AIM have been intensely studied, little is known about how these relate to asymptomatic primary infection. Here Gambian children (14–18 months old, an age at which many acquire the virus) were followed for the ensuing six months, monitoring circulating EBV loads, antibody status against virus capsid antigen (VCA) and both total and virus-specific CD8+ T-cell numbers. Many children were IgG anti-VCA-positive and, though no longer IgM-positive, still retained high virus loads comparable to AIM patients and had detectable EBV-specific T-cells, some still expressing activation markers. Virus loads and the frequency/activation status of specific T-cells decreased over time, consistent with resolution of a relatively recent primary infection. Six children with similarly high EBV loads were IgM anti-VCA-positive, indicating very recent infection. In three of these donors with HLA types allowing MHC-tetramer analysis, highly activated EBV-specific T-cells were detectable in the blood with one individual epitope response reaching 15% of all CD8+ T-cells. That response was culled and the cells lost activation markers over time, just as seen in AIM. However, unlike AIM, these events occurred without marked expansion of total CD8+ numbers. Thus asymptomatic EBV infection in children elicits a virus-specific CD8+ T-cell response that can control the infection without over-expansion; conversely, in AIM it appears the CD8 over-expansion, rather than virus load per se, is the cause of disease symptoms. [ABSTRACT FROM AUTHOR]

Background. Many human immunodeficiency virus (HIV)–2-infected individuals remain aviremic and behave as long-term non-progressors but some progress to AIDS. We hypothesized that immune activation and T-cell turnover would be critical determinants of non-progressor/progressor status.Methods. We studied 37 subjects in The Gambia, West Africa: 10 HIV-negative controls, 10 HIV-2-infected subjects with low viral loads (HIV-2-LV), 7 HIV-2-infected subjects with high viral loads (HIV-2-HV), and 10 with HIV-1 infection. We measured in vivo T-cell turnover using deuterium-glucose labeling, and correlated results with T-cell phenotype (by flow cytometry) and T-cell receptor excision circle (TREC) abundance.Results. Immune activation (HLA-DR/CD38 coexpression) differed between groups with a significant trend: controls

Background: Many human immunodeficiency virus (HIV)-2-infected individuals remain aviremic and behave as long-term non-progressors but some progress to AIDS. We hypothesized that immune activation and T-cell turnover would be critical determinants of non-progressor/progressor status.Methods: We studied 37 subjects in The Gambia, West Africa: 10 HIV-negative controls, 10 HIV-2-infected subjects with low viral loads (HIV-2-LV), 7 HIV-2-infected subjects with high viral loads (HIV-2-HV), and 10 with HIV-1 infection. We measured in vivo T-cell turnover using deuterium-glucose labeling, and correlated results with T-cell phenotype (by flow cytometry) and T-cell receptor excision circle (TREC) abundance.Results: Immune activation (HLA-DR/CD38 coexpression) differed between groups with a significant trend: controls Conclusions: HIV-2 non-progressors have low rates of T-cell turnover (both CD4(+) and CD8(+)) and minimal immune activation; high viral load HIV-2 progressors had high values, similar to or exceeding those in HIV-1 infection. [ABSTRACT FROM AUTHOR]

Background BCG immunogenicity in infants differs between populations and these differences have been attributed to various factors. In this study, the influence of geographical location, season of birth, timing of vaccination, micronutrient status (zinc) and inflammatory status (C-reactive protein, CRP) were assessed. Methods Immunogenicity was assessed by cytokine signature in culture supernatants from diluted whole blood samples stimulated with M. tuberculosis PPD, using a multiplex bead assay. Results were correlated with the plasma zinc and CRP concentrations at the time of sampling, and with interview and household data. BCG vaccinated infants were recruited in Malawi, The Gambia and the UK. Results In Malawi, infants vaccinated within the first week after birth showed lower production of most cytokines measured than those vaccinated later. The number of cytokines showing significant differences between Malawian and Gambian infants decreased after adjusting for season of birth. In Malawi, a proportion of infants had zinc deficiency and elevated plasma CRP (>10 mg/L), but neither zinc deficiency nor high CRP was associated with production of any of the cytokines measured. Conclusions The cytokine/chemokine signatures observed in response to M. tuberculosis PPD in infants at 3 months post BCG vaccination were affected by geographical location, season of birth, and timing of vaccination but not associated with the concentration of plasma zinc or inflammatory status. These factors should be considered in future trials of new TB vaccines. [ABSTRACT FROM AUTHOR]

Objective To establish haematological and biological reference values for Gambian infants. Methods Basic haematological and biochemical indices were analysed in blood samples obtained from healthy infants from Sukuta in the Western Division of The Gambia. The 2.5 and the 97.5 centiles for these indices were estimated. Results Reference ranges for haematological and biochemical indices were determined. Haemoglobin, total white cell count ( WBC) and platelet levels decreased with age ( P < 0.001), whereas most of the white cell count subsets except monocytes did not vary with age. Potassium and alkaline phosphatase fell significantly with increasing age ( P < 0.001; P < 0.001), whereas urea and creatinine rose with increasing age ( P = 0.002; P < 0.001, respectively). Conclusion Our set of haematological and biochemical reference values for healthy infants in The Gambia differs from values in other settings, thus underscoring the importance of establishing region-specific paediatric reference ranges to ensure optimal patient management and evaluate the impact of interventions in clinical research. [ABSTRACT FROM AUTHOR]

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) emerged from Wuhan in China before it spread to the entire globe. It causes coronavirus disease of 2019 (COVID-19) where mostly individuals present mild symptoms, some remain asymptomatic and some show severe lung inflammation and pneumonia in the host through the induction of a marked inflammatory 'cytokine storm'. New and efficacious vaccines have been developed and put into clinical practice in record time, however, there is a still a need for effective treatments for those who are not vaccinated or remain susceptible to emerging SARS-CoV-2 variant strains. Despite this, effective therapeutic interventions against COVID-19 remain elusive. Here, we have reviewed potential drugs for COVID-19 classified on the basis of their mode of action. The mechanisms of action of each are discussed in detail to highlight the therapeutic targets that may help in reducing the global pandemic. The review was done up to July 2021 and the data was assessed through the official websites of WHO and CDC for collecting the information on the clinical trials. Moreover, the recent research papers were also assessed for the relevant data. The search was mainly based on keywords like Coronavirus, SARS-CoV-2, drugs (specific name of the drugs), COVID-19, clinical efficiency, safety profile, side-effects etc.This review outlines potential areas for future research into COVID-19 treatment strategies. • More than one year to the COVID-19 pandemic, still no effective drug treatment exists so far. • We have summarized the drugs showing both positive effect and negative effects for their future application. • Veklury (Remdesivir) is the only FDA-approved drug for adult and pediatric patients • Chloroquine, Hydroxychloroquine, Azithromycin, colchicine and Ivermectin has been removed from the list of potential drugs. • Tocilizumab and Sarilumab has been proven to work and are currently under trials. • Though, Remdesivir has been licensed for emergency and provisional use in different countries, it is not terribly effective. [ABSTRACT FROM AUTHOR]

Background: Chronic immune activation is a hallmark of HIV infection and has been associated with disease progression. Assessment of soluble biomarkers indicating immune activation provide clues into pathogenesis and hold promise for the development of point-of-care monitoring of HIV in resource-poor-settings. Their evaluation in cohort resources is therefore needed to further their development and use in HIV research. Methodology/Principal Findings: Longitudinal evaluation of βeta-2 microglobulin (β-2 m), neopterin and suPAR soluble urokinase-type plasminogen activator receptor (suPAR) was performed with archived plasma samples to predict disease progression and provided the first direct comparison of levels in HIV-1 and HIV-2 infections. At least 2095 samples from 137 HIV-1 and 198 HIV-2 subjects with starting CD4% of ≥28 and median follow up of 4 years were analysed. All biomarkers were correlated negatively to CD4% and positively to viral load and to each other. Analyses in subjects living for ≥5 years revealed increases in median β-2 m and neopterin and decreases in CD4% over this period and the odds of death within 5 years were positively associated with baseline levels of β-2 m and neopterin. ROC analyses strengthened the evidence of elevation of biomarkers in patients approaching death in both HIV-1 and HIV-2 infections. Regression models showed that rates of biomarker fold change accelerated from 6-8 years before death with no significant differences between biomarker levels in HIV-1 and HIV-2 at equal time points prior to death. An 'immune activation index' analysis indicative of biomarker levels at equivalent viral loads also showed no differences between the two infections. Conclusions/Significance: Our results suggest that β-2 m and neopterin are useful tools for disease monitoring in both HIV-1 and HIV-2 infections, whereas sUPAR performed less well. Levels of immune activation per amount of virus were comparable in HIV-1 and HIV-2 infected subjects. [ABSTRACT FROM AUTHOR]

T-cell immunity is important for controlling Kaposi sarcoma-associated herpesvirus (KSHV) diseases such as the endothelial cell malignancy Kaposi sarcoma, or the B-cell malignancy, primary effusion lymphoma (PEL). However, little is known about KSHV-specific T-cell immunity in healthy donors and immune control of disease. Using PBMCs from healthy KSHV-infected donors, we found weak ex vivo responses to the KSHV latent antigens LANA, vFLIP, vCyclin, and Kaposin, with LANA most frequently recognized. CD4+ T-cell clones specific to LANA, a protein expressed in all KSHV-infected cells and malignancies, were established to determine whether they could recognize LANA-expressing cells. B-cell targets expressing or fed LANA protein were consistently recognized by the clones; however, most PEL cell lines were not. PELs express the KSHV protein vlRF3 that inhibits promoter function of the HLA class II transactivator, decreasing expression of genes controlled by this transactivator. Re-expressing the class II transactivator in the PELs increased expression of downstream targets such as HLA class II and restored recognition but not killing by the LANA-specific clones. We suggest that PELs are poorly controlled in vivo because of inefficient recognition and killing by T cells. [ABSTRACT FROM AUTHOR]

The global burden of neonatal and infant mortality due to infection is staggering, particularly in resource-poor settings. Early childhood vaccination is one of the major interventions that can reduce this burden, but there are specific limitations to inducing effective immunity in early life, including impaired neonatal leukocyte production of Th1-polarizing cytokines to many stimuli. Characterizing the ontogeny of Toll-like receptor (TLR)-mediated innate immune responses in infants may shed light on susceptibility to infection in this vulnerable age group, and provide insights into TLR agonists as candidate adjuvants for improved neonatal vaccines. As little is known about the leukocyte responses of infants in resource-poor settings, we characterized production of Th1-, Th2-, and anti-inflammatory- cytokines in response to agonists of TLRs 1-9 in whole blood from 120 Gambian infants ranging from newborns (cord blood) to 12 months of age. Most of the TLR agonists induced TNFα, IL-1β, IL-6, and IL-10 in cord blood. The greatest TNFα responses were observed for TLR4, -5, and -8 agonists, the highest being the thiazoloquinoline CLO75 (TLR7/8) that also uniquely induced cord blood IFNγ production. For most agonists, TLR-mediated TNFα and IFNγ responses increased from birth to 1 month of age. TLR8 agonists also induced the greatest production of the Th1-polarizing cytokines TNFα and IFNγ throughout the first year of life, although the relative responses to the single TLR8 agonist and the combined TLR7/8 agonist changed with age. In contrast, IL-1β, IL-6, and IL-10 responses to most agonists were robust at birth and remained stable through 12 months of age. These observations provide fresh insights into the ontogeny of innate immunity in African children, and may inform development of agespecific adjuvanted vaccine formulations important for global health. [ABSTRACT FROM AUTHOR]

The tuberculin skin test (TST) is widely used in TB clinics to aid Mycobacterium tuberculosis (M.tb) diagnosis, but the definition and the significance of a positive test in very young children is still unclear. This study compared the TST in Gambian children at 4⅛ months of age who either received BCG vaccination at birth (Group 1) or were BCG naïve (Group 2) in order to examine the role of BCG vaccination and/or exposure to environmental mycobacteria in TST reactivity at this age. Nearly half of the BCG vaccinated children had a positive TST (⩾5 mm) whereas all the BCG naïve children were nonreactive, confirming that recent BCG vaccination affects TST reactivity. The BCG naïve children demonstrated in vitro PPD responses in peripheral blood in the absence of TST reactivity, supporting exposure to and priming by environmental mycobacterial antigens. Group 2 were then vaccinated at 4⅛ months of age and a repeat TST was performed at 20-28 months of age. Positive reactivity (⩾5 mm) was evident in 11.1% and 12.5% infants from Group 1 and Group 2 respectively suggesting that the timing of BCG vaccination had little effect by this age. We further assessed for immune correlates in peripheral blood at 4⅛ months of age. Mycobacterial specific IFNγ responses were greater in TST responders than in nonresponders, although the size of induration did not correlate with IFNγ. However the IFNγ: IL-10 ratio positively correlated with TST induration suggesting that the relationship between PPD induced IFNγ and IL-10 in the peripheral blood may be important in controlling TST reactivity. Collectively these data provide further insights into how the TST is regulated in early life, and how a positive response might be interpreted. [ABSTRACT FROM AUTHOR]

Background: Infection with Plasmodium falciparum during pregnancy contributes substantially to the disease burden in both mothers and offspring. Placental malaria may lead to intrauterine growth restriction or preterm delivery resulting in low birth weight (LBW), which, in general, is associated with increased infant morbidity and mortality. However, little is known about the possible direct impact of the specific disease processes occurring in PM on longer term outcomes such as subsequent retarded growth development independent of LBW. Methods: In an existing West-African cohort, 783 healthy infants with a birth weight of at least 2,000 g were followed up during their first year of life. The aim of the study was to investigate if Plasmodium falciparum infection of the placenta, assessed by placental histology, has an impact on several anthropometric parameters, measured at birth and after three, six and 12 months using generalized estimating equations models adjusting for moderate low birth weight. Results: Independent of LBW, first to third born infants who were exposed to either past, chronic or acute placental malaria during pregnancy had significantly lower weight-for-age (-0.43, 95% CI: -0.80;-0.07), weight-forlength (-0.47, 95% CI: -0.84; -0.10) and BMI-for-age z-scores (-0.57, 95% CI: -0.84; -0.10) compared to infants born to mothers who were not diagnosed with placental malaria (p = 0.019, 0.013, and 0.012, respectively). Interestingly, the longitudinal data on histology-based diagnosis of PM also document a sharp decline of PM prevalence in the Sukuta cohort from 16.5% in 2002 to 5.4% in 2004. Conclusions: It was demonstrated that PM has a negative impact on the infant's subsequent weight development that is independent of LBW, suggesting that the longer term effects of PM have been underestimated, even in areas where malaria transmission is declining. [ABSTRACT FROM AUTHOR]

Routine vaccination programmes have led to substantial declines in the incidence of most of the target diseases. In these circumstances, vaccine effects beyond those on the target diseases may become evident. Several studies have suggested that certain vaccines may influence mortality in low income settings in ways that cannot be attributed to effects on target diseases. Trials of such ‘non-specific’ effects are difficult if not impossible to organise; and observational studies of them are prone to serious confounding, because those who do or do not receive vaccines are likely to differ in many ways, some of which relate to their subsequent risk of early death, independent of vaccination. They are also prone to other biases, including the selective loss of vaccination records for children who die. We review these potential sources of bias and suggest what and how data may be collected to optimise the validity of such studies. [ABSTRACT FROM AUTHOR]

Routine vaccination programmes have led to substantial declines in the incidence of most of the target diseases. In these circumstances, vaccine effects beyond those on the target diseases may become evident. Several studies have suggested that certain vaccines may influence mortality in low income settings in ways that cannot be attributed to effects on target diseases. Trials of such 'non-specific' effects are difficult if not impossible to organise; and observational studies of them are prone to serious confounding, because those who do or do not receive vaccines are likely to differ in many ways, some of which relate to their subsequent risk of early death, independent of vaccination. They are also prone to other biases, including the selective loss of vaccination records for children who die. We review these potential sources of bias and suggest what and how data may be collected to optimise the validity of such studies. [ABSTRACT FROM AUTHOR]

Background: Multi-drug resistant tuberculosis (MDR-TB) is a major public health concern since diagnosis is often delayed, increasing the risk of spread to the community and health care workers. Treatment is prolonged, and the total cost of treating a single case is high. Diagnosis has traditionally relied upon clinical suspicion, based on risk factors and culture with sensitivity testing, a process that can take weeks or months. Rapid diagnostic molecular techniques have the potential to shorten the time to commencing appropriate therapy, but have not been put to the test under field conditions. Methodology/Principal Findings: This retrospective case-control study aimed to identify risk factors for MDR-TB, and analyse the impact of testing for rifampicin resistance using RNA polymerase B (rpoB) mutations as a surrogate for MDR-TB. Forty two MDR-TB cases and 84 fully sensitive TB controls were matched by date of diagnosis; and factors including demographics, clinical presentation, microbiology findings, management and outcome were analysed using their medical records. Conventionally recognised risk factors for MDR-TB were absent in almost half (43%) of the cases, and 15% of cases were asymptomatic. A significant number of MDR-TB cases were identified in new entrants to the country. Using rpoB mutation testing, the time to diagnosis of MDR-TB was dramatically shortened by a median of 6 weeks, allowing patients to be commenced on appropriate therapy a median of 51days earlier than those diagnosed by conventional culture and sensitivity testing. Conclusions/Significance: MDR-TB is frequently an unexpected finding, may be asymptomatic, and is particularly prevalent among TB infected new entrants to the country. Molecular resistance testing of all acid fast bacilli positive specimens has the potential to rapidly identify MDR-TB patients and commence them on appropriate therapy significantly earlier than by conventional methods. [ABSTRACT FROM AUTHOR]

Background: Immunity to malaria develops naturally in endemic regions, but the protective immune mechanisms are poorly understood. Many vaccination strategies aim to induce T cells against diverse pre-erythrocytic antigens, but correlates of protection in the field have been limited. The objective of this study was to investigate cell-mediated immune correlates of protection in natural malaria. Memory T cells reactive against thrombospondin-related adhesive protein (TRAP) and circumsporozoite (CS) protein, major vaccine candidate antigens, were measured, as were frequencies of CD4+ CD25high T cells, which may suppress immunity, and CD56+ NK cells and γδ T cells, which may be effectors or may modulate immunity. Methodology and Principal Findings: 112 healthy volunteers living in rural Kenya were entered in the study. Memory T cells reactive against TRAP and CS were measured using a cultured IFNc ELISPOT approach, whilst CD4+ CD25high T cells, CD56+ NK cells, and γδ T cells were measured by flow cytometry. We found that T cell responses against TRAP were established early in life (<5 years) in contrast to CS, and cultured ELISPOT memory T cell responses did not correlate with ex-vivo IFNγ ELISPOT effector responses. Data was examined for associations with risk of clinical malaria for a period of 300 days. Multivariate logistic analysis incorporating age and CS response showed that cultured memory T cell responses against TRAP were associated with a significantly reduced incidence of malaria (p = 0.028). This was not seen for CS responses. Higher numbers of CD4+ CD25high T cells, potentially regulatory T cells, were associated with a significantly increased risk of clinical malaria (p = 0.039). Conclusions: These data demonstrate a role for central memory T cells in natural malarial immunity and support current vaccination strategies aimed at inducing durable protective T cell responses against the TRAP antigen. They also suggest that CD4+ CD25high T cells may negatively affect naturally acquired malarial immunity. [ABSTRACT FROM AUTHOR]

Irradiated malaria sporozoites induce better protection than viable untreated sporozoites. We observed early differences between irradiated and viable untreated sporozoites in priming responsesin vivoto a protective CD8 T-cell epitope, pb9, of the circumsporozoite protein ofPlasmodium berghei. Sporozoites were processed for MHC class I presentation by dendritic cells (DC) to prime pb9-specific IFN-γ-producing CD8 T cells. DC pulsed with untreated and irradiated sporozoites were similarly capable of priming central memory T-cell responses, detectable by the IFN-γ cultured ELISPOT assay. However, irradiation significantly enhanced sporozoites’ ability to prime effector T-cell responses detectable by the IFN-γ ex vivoELISPOT assay. Irradiation also enhanced the ability of splenic APC to process and present sporozoites in order to re-stimulate pb9-specific polyclonal and clonal T-cell responses. Sporozoites did not stimulate T cells in the absence of APC. Over-irradiation decreased the sporozoites’ T-cell stimulating capacityin vitroat high parasite doses, which may indicate that an optimal irradiation dose is necessary to induce protective immunity by sporozoite inoculation. The induction of sporozoite-specific CD8 T-cell responses without the need for liver stage infection identifies a potentially important mechanism in the development of pre-erythrocytic immunity. [ABSTRACT FROM AUTHOR]

Variation in epitopes of infectious pathogens inhibits various effector functions of T lymphocytes through antagonism of the T-cell receptor. However, a more powerful strategy for immune evasion would be to prevent the induction of T-cell responses. We report here mutual 'interference' with the priming of human T-cell responses by a pair of naturally occurring variants of a malaria cytotoxic T-cell epitope. Interference with priming also occurs in vivo for a murine malaria T-cell epitope. Reshaping of the T-cell repertoire by such immune interference during naive T-cell induction may provide a general mechanism for observed patterns of immunodominance and persistence by many polymorphic pathogens. [ABSTRACT FROM AUTHOR]

Background: BCG immunogenicity in infants differs between populations and these differences have been attributed to various factors. In this study, the influence of geographical location, season of birth, timing of vaccination, micronutrient status (zinc) and inflammatory status (C-reactive protein, CRP) were assessed.Methods: Immunogenicity was assessed by cytokine signature in culture supernatants from diluted whole blood samples stimulated with M. tuberculosis PPD, using a multiplex bead assay. Results were correlated with the plasma zinc and CRP concentrations at the time of sampling, and with interview and household data. BCG vaccinated infants were recruited in Malawi, The Gambia and the UK.Results: In Malawi, infants vaccinated within the first week after birth showed lower production of most cytokines measured than those vaccinated later. The number of cytokines showing significant differences between Malawian and Gambian infants decreased after adjusting for season of birth. In Malawi, a proportion of infants had zinc deficiency and elevated plasma CRP (>10 mg/L), but neither zinc deficiency nor high CRP was associated with production of any of the cytokines measured.Conclusions: The cytokine/chemokine signatures observed in response to M. tuberculosis PPD in infants at 3 months post BCG vaccination were affected by geographical location, season of birth, and timing of vaccination but not associated with the concentration of plasma zinc or inflammatory status. These factors should be considered in future trials of new TB vaccines. [ABSTRACT FROM AUTHOR]

Background:A vaccine to decrease transmission of human immunodeficiency virus type 1 (HIV-1) during breast-feeding would complement efforts to eliminate infant HIV-1 infection by antiretroviral therapy. Relative to adults, infants have distinct immune development, potentially high-risk of transmission when exposed to HIV-1 and rapid progression to AIDS when infected. To date, there have been only three published HIV-1 vaccine trials in infants. Trial Design:We conducted a randomized phase I clinical trial PedVacc 001 assessing the feasibility, safety and immunogenicity of a single dose of candidate vaccine MVA.HIVA administered intramuscularly to 20-week-old infants born to HIV-1-negative mothers in The Gambia. Methods:Infants were followed to 9 months of age with assessment of safety, immunogenicity and interference with Expanded Program on Immunization (EPI) vaccines. The trial is the first stage of developing more complex prime-boost vaccination strategies against breast milk transmission of HIV-1. Results:From March to October 2010, 48 infants (24 vaccine and 24 no-treatment) were enrolled with 100% retention. The MVA.HIVA vaccine was safe with no difference in adverse events between vaccinees and untreated infants. Two vaccine recipients (9%) and no controls had positive exvivo interferon-γ ELISPOT assay responses. Antibody levels elicited to the EPI vaccines, which included diphtheria, tetanus, whole-cell pertussis, hepatitis B virus, Haemophilus influenzae type b and oral poliovirus, reached protective levels for the vast majority and were similar between the two arms. Conclusions:A single low-dose of MVA.HIVA administered to 20-week-old infants in The Gambia was found to be safe and without interference with the induction of protective antibody levels by EPI vaccines, but did not alone induce sufficient HIV-1-specific responses. These data support the use of MVA carrying other transgenes as a boosting vector within more complex prime-boost vaccine strategies against transmission of HIV-1 and/or other infections in this age group. Trial Registration: ClinicalTrials.gov NCT00982579 The Pan African Clinical Trials Registry PACTR2008120000904116 [ABSTRACT FROM AUTHOR]