Intradermal Fractional ChAdOx1 nCoV-19 Booster Vaccine Induces Memory T Cells: A Follow-Up Study.

The administration of viral vector and mRNA vaccine booster effectively induces humoral and cellular immune responses. Effector T cell responses after fractional intradermal (ID) vaccination are comparable to those after intramuscular (IM) boosters. Here, we quantified T cell responses after booster vaccination. ChAdOx1 nCoV-19 vaccination induced higher numbers of S1-specific CD8+ memory T cells, consistent with the antibody responses. Effector memory T cell phenotypes elicited by mRNA vaccination showed a similar trend to those elicited by the viral vector vaccine booster. Three months post-vaccination, cytokine responses remained detectable, confirming effector T cell responses induced by both vaccines. The ID fractional dose of ChAdOx1 nCoV-19 elicited higher effector CD8+ T cell responses than IM vaccination. This study confirmed that an ID dose-reduction vaccination strategy effectively stimulates effector memory T cell responses. ID injection could be an improved approach for effective vaccination programs.

Effectiveness of plant-based hand sanitizer incorporating Quercus infectoria gall extract.

AIMS: Quercus infectoria (Qi), a traditional herbal plant with a broad spectrum of activities on multidrug-resistant bacteria, has been developed for hand sanitizer applications. METHODS AND RESULTS: Antimicrobial activity was evaluated using agar-well diffusion and broth microdilution method. Bactericidal activity was determined following the European Standard 1276 antibacterial suspension test. Neutralization assay was performed to assess antirespiratory syncytial virus. Safety, stability, and skin permeation of Qi hand gel was investigated. Qi hand sanitizer gel inhibited microorganisms ranging from 99.9% to 99.999% against Enterococcus faecalis, Staphylococcus aureus, methicillin-resistant Staph. aureus, Staph. epidermidis, Staph. pseudintermedius, Staph. saprophyticus, Streptococcus pyogenes, Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Candida albicans. A significant reduction in main human dermatophytes including Microsporum canis, M. gypseum, and Talaromyces marneffei of ∼50% was observed (P < .05). Qi hand sanitizer gel inactivated >99% viral particles entering human laryngeal epidermoid carcinoma cells in a dose-dependent manner. Scanning electron micrographs further illustrated that Qi hand sanitizer gel disrupted microbial cell membrane after 1-min contact time resulting in cell death. Qi hand sanitizer gel delivered emollient compounds through simulated human skin layers and showed no cytotoxicity on fibroblast cells. Moreover, Qi hand sanitizer gel demonstrated stability under extreme conditions. CONCLUSIONS: Qi hand sanitizer gel was able to inhibit various microorganisms including bacteria, dermatophytes, and virus.

A five-antigen Esx-5a fusion delivered as a prime-boost regimen protects against M.tb challenge.

The development of tuberculosis (TB) vaccines has been hindered by the complex nature of Mycobacterium tuberculosis (M.tb) and the absence of clearly defined immune markers of protection. While Bacillus Calmette-Guerin (BCG) is currently the only licensed TB vaccine, its effectiveness diminishes in adulthood. In our previous research, we identified that boosting BCG with an intranasally administered chimpanzee adenovirus expressing the PPE15 antigen of M.tb (ChAdOx1.PPE15) improved its protection. To enhance the vaccine's efficacy, we combined PPE15 with the other three members of the Esx-5a secretion system and Ag85A into a multi-antigen construct (5Ag). Leveraging the mucosal administration safety of ChAdOx1, we targeted the site of M.tb infection to induce localized mucosal responses, while employing modified vaccinia virus (MVA) to boost systemic immune responses. The combination of these antigens resulted in enhanced BCG protection in both the lungs and spleens of vaccinated mice. These findings provide support for advancing ChAdOx1.5Ag and MVA.5Ag to the next stages of vaccine development.

Heterologous COVID-19 Vaccination and Booster with mRNA Vaccine Provide Enhanced Immune Response in Patients with Cirrhosis: A Prospective Observational Study.

This study aimed to evaluate the antibody and cellular responses to different coronavirus 2019 (COVID-19) vaccination regimens in patients with cirrhosis and to assess the antibody response after a vaccine booster. We conducted a prospective observational study of 89 patients with cirrhosis and 41 healthy volunteers who received two COVID-19 vaccine doses. Next, we prospectively evaluated 24 patients with cirrhosis who received a booster COVID-19 vaccine dose. In both studies, blood samples were collected before and 4 weeks after vaccination, and anti-spike receptor-binding domain protein IgG levels, T-cell phenotypes, and effector functions were assessed. The heterologous vaccine regimen (CoronaVac [SV]/AstraZeneca [AZ]) produced a better antibody response and CD4+IFNg+ T cell response compared to homogeneous vaccine regimens. The antibody response after the second dose of the vaccine was similar in patients with cirrhosis and healthy volunteers. Patients who received a booster dose of the mRNA vaccine had significantly increased antibody titers compared to those who received the AZ vaccine. In patients with cirrhosis, heterologous vaccination with SV/AZ resulted in a better immune response than the AZ/AZ and SV/SV regimens. Moreover, a booster dose of the mRNA vaccine led to a greater increase in antibody titers compared to the AZ vaccine.

Humoral Immunogenicity of mRNA Booster Vaccination after Heterologous CoronaVac-ChAdOx1 nCoV-19 or Homologous ChAdOx1 nCoV-19 Vaccination in Patients with Autoimmune Rheumatic Diseases: A Preliminary Report.

Immunogenicity data on the mRNA SARS-CoV-2 vaccine booster after completing a primary series vaccination, other than the mRNA vaccine, in patients with autoimmune rheumatic diseases (ARDs) is scarce. In this study, we reported the humoral immunogenicity of an mRNA booster 90-180 days after completing heterologous CoronaVac/ChAdOx1 nCoV-19 (n = 19) or homologous ChAdOx1 nCoV-19 (n = 14) vaccination by measuring the anti-SARS-CoV-2 receptor binding domain (RBD) IgG levels at one and three months after mRNA booster vaccination. This study included 33 patients with ARDs [78.8% women; mean (SD) age: 42.9 (10.6) years]. Most patients received prednisolone (75.8%, mean [IQR] daily dose: 7.5 [5, 7.5] mg) and azathioprine (45.5%). The seropositivity rates were 100% and 92.9% in CoronaVac/ChAdOx1 and ChAdOx1/ChAdOx1, respectively. The median (IQR) anti-RBD IgG level was lower in the ChAdOx1/ChAdOx1 group than in the CoronaVac/ChAdOx1 group (1867.8 [591.6, 2548.6] vs. 3735.8 [2347.9, 5014.0] BAU/mL, p = 0.061). A similar trend was significant in the third month [597.8 (735.5) vs. 1609.9 (828.4) BAU/mL, p = 0.003]. Minor disease flare-ups occurred in 18.2% of the patients. Our findings demonstrated satisfactory humoral immunogenicity of mRNA vaccine boosters after a primary series, with vaccine strategies other than the mRNA platform. Notably, the vaccine-induced immunity was lower in the ChAdOx1/ChAdOx1 primary series.

Characteristics, Outcomes, and Factors Affecting Mortality in Hospitalized Patients with CAP Due to Different Variants of SARS-CoV-2 and Non-COVID-19 CAP.

The study was conducted from October 2020 to March 2022 in a province in southern Thailand. The inpatients with community-acquired pneumonia (CAP) and more than 18 years old were enrolled. Of the 1511 inpatients with CAP, COVID-19 was the leading cause, accounting for 27%. Among the patients with COVID-19 CAP, mortalities, mechanical ventilators, ICU admissions, ICU stay, and hospital costs were significantly higher than of those with non-COVID-19 CAP. Household and workplace contact with COVID-19, co-morbidities, lymphocytopenia and peripheral infiltration in chest imaging were associated with CAP due to COVID-19. The delta variant yielded the most unfavorable clinical and non-clinical outcomes. While COVID-19 CAP due to B.1.113, Alpha and Omicron variants had relatively similar outcomes. Among those with CAP, COVID-19 infection as well as obesity, a higher Charlson comorbidity index (CCI) and APACHE II score were associated with in-hospital mortality. Among those with COVID-19 CAP, obesity, infection due to the Delta variant, a higher CCI and higher APACHE II score were associated with in-hospital mortality. COVID-19 had a great impact on the epidemiology and outcomes of CAP.

Immunogenicity of a fractional or full third dose of AZD1222 vaccine or BNT162b2 messenger RNA vaccine after two doses of CoronaVac vaccines against the Delta and Omicron variants.

OBJECTIVES: The study aimed to compare the immunogenicity and safety of fractional (half) third doses of heterologous COVID-19 vaccines (AZD1222 or BNT162b2) to full doses after the two-dose CoronaVac and when boosting after three different extended intervals. METHODS: At 60-<90, 90-<120, or 120-180 days intervals after the two-dose CoronaVac, participants were randomized to full-dose or half-dose AZD1222 or BNT162b2, followed up at day 28, 60, and 90. Vaccination-induced immune responses to Ancestral, Delta, and Omicron BA.1 strains were evaluated by antispike, pseudovirus, and microneutralization and T cell assays. Descriptive statistics and noninferiority cut-offs were reported as geometric mean concentration or titer and concentration or titer ratios comparing baseline to day 28 and day 90 and different intervals. RESULTS: No safety concerns were detected. All assays and intervals showed noninferior immunogenicity between full doses and half doses. However, full-dose vaccines and/or longer 120-180-day intervals substantially improved the immunogenicity (measured by antispike or measured by pseudotyped virus neutralizing titers 50; P <0.001). Seroconversion rates were over 90% against the SARS-CoV-2 strains by all assays. Immunogenicity waned more quickly with half doses than full doses but remained high against the Ancestral or Delta strains. Against Omicron, the day 28 immunogenicity increased with longer intervals than shorter intervals for full-dose vaccines. CONCLUSION: Immune responses after day 28 when boosting at longer intervals after the two-dose CoronaVac was optimal. Half doses met the noninferiority criteria compared with the full dose by all the immune assays assessed.

Humoral SARS-CoV-2 immunogenicity wanes 3 months after heterologous inactivated vaccine followed by ChAdOx1 nCoV-19 in autoimmune rheumatic diseases.

BACKGROUND: Alongside vaccine hesitancy, impaired and waning immunity in autoimmune rheumatic diseases (ARDs) are barriers to immunization. The timeframe of immunity waning in ARD remains unclear. OBJECTIVE: We aimed to examine the waning of humoral immunogenicity in a cohort of ARD patients who received the heterologous inactivated vaccine followed by the adenoviral vector SAR-CoV-2 vaccine at a 3-month follow-up. METHODS: The levels of SARS-CoV-2 anti-RBD IgG were evaluated at 1 and 3 months in adults with ARDs (n = 29) and age- and sex-matched healthy controls (HC) that received the heterologous prime-boost CoronaVac vaccine followed by the ChAdOx1 nCoV-19 vaccine. Seropositivity was defined as anti-receptor binding domain (RBD) IgG levels of ≥ 7.15 binding antibody units (BAU)/mL. The kinetic properties of the vaccines were evaluated based on the ratio of anti-RBD IgG values obtained at each follow-up. Disease activity was evaluated. RESULTS: The seropositivity rate was lower among patients with ARDs than among HCs (89.7% vs. 100%, p = 0.237). At 3 months, the median (IQR) anti-RBD IgG level was lower among patients with ARDs than among HCs (122.3 [30.6, 247.8] vs. 294.2 [127.4,605.7] BAU/mL, p = 0.006). Mean antibody levels in patients with ARDs decreased 3.5 (1.9)-fold within 3 months post-vaccination (122.3 [30.6, 247.8] vs. 279.9 [86,1076.5] BAU/mL, p < 0.001). Disease flare-ups occurred in three patients. CONCLUSIONS: Our findings included changes to anti-RBD IgG levels and may inform vaccination strategies. SAR-CoV2 vaccine-induced immunity was lower in patients with ARDs than in HCs and decreased within 3 months, suggesting a need for booster vaccinations.

Impaired neutralizing antibodies and preserved cellular immunogenicity against SARS-CoV-2 in systemic autoimmune rheumatic diseases.

Reports on vaccine immunogenicity in patients with systemic autoimmune rheumatic diseases (SARDs) have been inconclusive. Here, we report the immunogenicity of heterologous prime-boost with an inactivated vaccine followed by an adenoviral vector vaccine in patients with SARDs using anti-RBD antibodies, neutralizing capacity against Omicron BA.2 [plaque-reduction neutralization test (PRNT)], T cell phenotypes, and effector cytokine production at 4 weeks after vaccination. SARD patients had lower median (IQR) anti-RBD-IgG levels and neutralizing function against the Omicron BA.2 variant than the healthy group (p = 0.003, p = 0.004, respectively). T cell analysis revealed higher levels of IFN-γ- and TNF-α-secreting CD4 + T cells (p < 0.001, p = 0.0322, respectively) in SARD patients than in the healthy group. Effector cytokine production by CD8 + T cells was consistent with Th responses. These results suggest that this vaccine regimen revealed mildly impaired humoral response while preserving cellular immunogenicity and may be an alternative for individuals for whom mRNA vaccines are contraindicated.

T-Cell Responses Induced by an Intradermal BNT162b2 mRNA Vaccine Booster Following Primary Vaccination with Inactivated SARS-CoV-2 Vaccine.

A practical booster vaccine is urgently needed to control the coronavirus disease (COVID-19) pandemic. We have previously reported the safety and immunogenicity of a fractional intradermal booster, using the BNT162b2 mRNA vaccine in healthy volunteers who had completed two doses of inactivated SARS-CoV-2 vaccine. In this study, an intramuscular booster at full dosage was used as a control, and a half-dose vaccination was included for reciprocal comparison. Detailed T-cell studies are essential to understand cellular responses to vaccination. T-cell immunity was examined using S1 peptide restimulation and flow cytometry. The fractional dose (1:5) of the BNT162b2 mRNA vaccine enhanced antigen-specific effector T-cells, but the responses were less remarkable compared to the intramuscular booster at full dosage. However, the intradermal regimen was not inferior to the intramuscular booster a month after boosting. An intradermal booster using only one-fifth of the standard dosage could provide comparable T-cell responses with the fractional intramuscular booster. This work confirms the efficacy of intradermal and fractional vaccination in terms of T-cell immunogenicity in previously immunised populations.

Regulatory T Cells Decreased during Recovery from Mild COVID-19.

Depending on the intensity and duration of SARS-CoV-2 infection, the host immune response plays a significant role in immunological protection. Here, we studied the regulatory T-cell (Treg) response in relation to kinetic change and cytokine production in patients with mild COVID-19. Nineteen SARS-CoV-2-positive patients were recruited, and blood was collected at four time points, i.e., seven days after admission, after discharge, and one and three months after recovery. CD3+CD4+CD25+CD127low was marked as the Treg population, with IL-10 and TGF-ß used to study cytokine-producing Tregs. IFN-γ-producing CD8+ T cells were observed for an effector response. The Treg percentage in patients with mild COVID-19 increased during hospitalization compared to during the recovery period. Peripheral blood mononuclear cells (PBMCs) were quantified, and the T-cell response was characterized by re-stimulation with S1 and N peptides. IL-10 and TGF-ß were produced by CD25+CD127low T cells during the active infection phase, especially with N peptide stimulation. Compared to N peptide stimulation, S1 peptide stimulation provided superior IFN-γ-secreting CD8+ T-cell responses. Our results suggest that while IFN-γ+CD8+ T cells confer antiviral immunity, cytokine-producing Tregs may have a substantial role in regulating inflammatory responses in mild SARS-CoV-2 infection. Novel vaccine development may also consider enhancing T-cell repertoires.

Coronavirus Disease 2019 Vaccinations in Patients With Chronic Liver Disease and Liver Transplant Recipients: An Update.

Coronavirus disease 2019 (COVID-19) is a current global pandemic associated with an increased mortality, particularly in patients with comorbidities. Patients with chronic liver disease (CLD) and liver transplant (LT) recipients are at higher risk of morbidity and mortality after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Many liver societies have recommended that these patients should receive COVID-19 vaccinations, although there are limited studies assessing risks and benefits in this population. In addition, two doses of mRNA vaccines may not provide sufficient immune response, and booster dose(s) may be necessary, especially in LT recipients. Notably, variants of concern have recently emerged, and it remains unclear whether currently available vaccines provide adequate and durable protective immunity against these novel variants. This review focuses on the role of COVID-19 vaccinations in CLD and LT recipients.

Immunogenicity and safety of an intradermal ChAdOx1 nCoV-19 boost in a healthy population.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic. Two doses of an inactivated SARS-CoV-2 vaccine (CoronaVac) have been shown to be insufficient to protect against variants of concern (VOCs), while viral vector vaccines remain protective against the infection. Herein, we conducted a preliminary study to evaluate the safety and immunity in an adult population who received the conventional 2 dosage-regimen of inactivated SARS-CoV-2 vaccine; with an additional intradermal ChAdOx1 nCoV-19 reciprocal dosage (1:5). An Intramuscular ChAdOx1 nCoV-19 booster was also included as a control. Immediate and delayed local reactions were frequently observed in the fractional intradermal boost, but systemic side effects were significantly decreased compared to the conventional intramuscular boost. The anti-RBD-IgG levels, the neutralising function against delta variants, and T cell responses were significantly increased after boosting via both routes. Interestingly, the shorter interval elicited higher immunogenicity compared to the extended interval. Taken together, a reciprocal dosage of intradermal ChAdOx1 nCoV-19 booster reduces systemic adverse reactions and enhances non inferiority humoral and cellular immune responses compared to a full dose of intramuscular boosting. These findings provide for an effective vaccine management during the shortages of vaccine supply.

Immunogenicity and Safety of an Intradermal BNT162b2 mRNA Vaccine Booster after Two Doses of Inactivated SARS-CoV-2 Vaccine in Healthy Population.

Effective vaccine coverage is urgently needed to tackle the COVID-19 pandemic. Inactivated vaccines have been introduced in many countries for emergency usage, but have only provided limited protection. Heterologous vaccination is a promising strategy to maximise vaccine immunogenicity. Here, we conducted a phase I, randomised control trial to observe the safety and immunogenicity after an intradermal boost, using a fractional dosage (1:5) of BNT162b2 mRNA vaccine in healthy participants in Songkhla, Thailand. In total, 91 volunteers who had been administered with two doses of inactivated SARS-CoV-2 (CoronaVac) were recruited into the study, and then randomised (1:1:1) to received different regimens of the third dose. An intramuscular booster with a full dose of BNT162b2 was included as a conventional control, and a half dose group was included as reciprocal comparator. Both, immediate and delayed adverse events following immunisation (AEFI) were monitored. Humoral and cellular immune responses were examined to observe the booster effects. The intradermal booster provided significantly fewer systemic side effects, from 70% down to 19.4% (p < 0.001); however, they were comparable to local reactions with the conventional intramuscular booster. In the intradermal group after receiving only one fifth of the conventional dosage, serum Anti-RBD IgG was halved compared to the full dose of an intramuscular injection. However, the neutralising function against the Delta strain remained intact. T cell responses were also less effective in the intradermal group compared to the intramuscular booster. Together, the intradermal booster, using a fractional dose of BNT162b2, can reduce systemic reactions and provides a good level and function of antibody responses compared to the conventional booster. This favourable intradermal boosting strategy provides a suitable alternative for vaccines and effective vaccine management to increase the coverage during the vaccine shortage.

Using an effective TB vaccination regimen to identify immune responses associated with protection in the murine model.

A vaccine against tuberculosis (TB), a disease resulting from infection with Mycobacterium tuberculosis (M.tb), is urgently needed to prevent more than a million deaths per year. Bacillus Calmette-Guérin (BCG) is the only available vaccine against TB but its efficacy varies throughout the world. Subunit vaccine candidates, based on recombinant viral vectors expressing mycobacterial antigens, are one of the strategies being developed to boost BCG-primed host immune responses and efficacy. A promising vaccination regimen composed of intradermal (i.d.) BCG prime, followed by intranasally (i.n.) administered chimpanzee adenoviral vector (ChAdOx1) and i.n. or i.d. modified vaccinia Ankara virus (MVA), both expressing Ag85A, has been previously reported to significantly improve BCG efficacy in mice. Effector and memory immune responses induced by BCG-ChAdOx1.85A-MVA85A (B-C-M), were evaluated to identify immune correlates of protection in mice. This protective regime induced strong Ag85A-specific cytokine responses in CD4+ and CD8+ T cells, both in the systemic and pulmonary compartments. Lung parenchymal CXCR3+ KLRG1- Ag85A-specific memory CD4+ T cells were significantly increased in B-C-M compared to BCG immunised mice at 4, 8 and 20 weeks post vaccination, but the number of these cells decreased at the latter time point. This cell population was associated with the protective efficacy of this regime and may have an important protective role against M.tb infection.

MAVS Deficiency Is Associated With a Reduced T Cell Response Upon Secondary RSV Infection in Mice.

Infections with respiratory syncytial virus (RSV) occurs repeatedly throughout life because sustained, protective memory responses fail to develop. Why this occurs is not known. During RSV infection the recognition of the virus via the cytosolic RIG-I like receptors and signaling via the adaptor protein MAVS is crucial for mounting an innate immune response. However, if this signaling pathway is important for T cell responses during primary infection and during re-infection is not fully elucidated. We describe a second peak of pro-inflammatory mediators during the primary immune response to RSV that coincides with the arrival of T cells into the lung. This second peak of cytokines/chemokines is regulated differently than the early peak and is largely independent of signaling via MAVS. This was concurrent with Mavs-/- mice mounting a strong T cell response to primary RSV infection, with robust IFN-γ; and Granzyme B production. However, after RSV re-infection, Mavs-/- mice showed fewer CD4+ and CD8+ short term memory T cells and their capacity to produce IFN-γ; and Granzyme B, was decreased. In sum, cytosolic recognition of RSV is important not only for initiating innate anti-viral responses but also for generating or maintaining efficient, short term T cell memory responses.

Identification of antigens presented by MHC for vaccines against tuberculosis.

Mycobacterium tuberculosis (M.tb) is responsible for more deaths globally than any other pathogen. The only available vaccine, bacillus Calmette-Guérin (BCG), has variable efficacy throughout the world. A more effective vaccine is urgently needed. The immune response against tuberculosis relies, at least in part, on CD4+ T cells. Protective vaccines require the induction of antigen-specific CD4+ T cells via mycobacterial peptides presented by MHC class-II in infected macrophages. In order to identify mycobacterial antigens bound to MHC, we have immunoprecipitated MHC class-I and class-II complexes from THP-1 macrophages infected with BCG, purified MHC class-I and MHC class-II peptides and analysed them by liquid chromatography tandem mass spectrometry. We have successfully identified 94 mycobacterial peptides presented by MHC-II and 43 presented by MHC-I, from 76 and 41 antigens, respectively. These antigens were found to be highly expressed in infected macrophages. Gene ontology analysis suggests most of these antigens are associated with membranes and involved in lipid biosynthesis and transport. The sequences of selected peptides were confirmed by spectral match validation and immunogenicity evaluated by IFN-gamma ELISpot against peripheral blood mononuclear cell from volunteers vaccinated with BCG, M.tb latently infected subjects or patients with tuberculosis disease. Three antigens were expressed in viral vectors, and evaluated as vaccine candidates alone or in combination in a murine aerosol M.tb challenge model. When delivered in combination, the three candidate vaccines conferred significant protection in the lungs and spleen compared with BCG alone, demonstrating proof-of-concept for this unbiased approach to identifying new candidate antigens.

Identification and Evaluation of Novel Protective Antigens for the Development of a Candidate Tuberculosis Subunit Vaccine.

The development of a vaccine against tuberculosis (TB), a disease caused by Mycobacterium tuberculosis, is urgently needed. The only currently available vaccine, M. bovis BCG, has variable efficacy. One approach in the global vaccine development effort is focused on boosting BCG using subunit vaccines. The identification of novel antigens for inclusion in subunit vaccines is a critical step in the TB vaccine development pathway. We selected four novel mycobacterial antigens recognized during the course of human infection. A replication-deficient chimpanzee adenovirus (ChAdOx1) was constructed to express each antigen individually, and these vectors were evaluated for protective efficacy in murine M. tuberculosis challenge experiments. One antigen, PPE15 (Rv1039c), conferred significant and reproducible protection when administered alone and as a boost to BCG vaccination. We identified immunodominant epitopes to define the protective immune responses using tetramers and intravascular staining. Lung parenchymal CD4+ and CD8+ CXCR3+ KLRG1- T cells, previously associated with protection against M. tuberculosis, were enriched in the vaccinated groups compared to the control groups. Further work to evaluate the protective efficacy of PPE15 in more stringent preclinical animal models, together with the identification of further novel protective antigens using this selection strategy, is now merited.

Hepcidin deficiency and iron deficiency do not alter tuberculosis susceptibility in a murine M.tb infection model.

Tuberculosis (TB), caused by the macrophage-tropic pathogen Mycobacterium tuberculosis (M.tb) is a highly prevalent infectious disease. Since an immune correlate of protection or effective vaccine have yet to be found, continued research into host-pathogen interactions is important. Previous literature reports links between host iron status and disease outcome for many infections, including TB. For some extracellular bacteria, the iron regulatory hormone hepcidin is essential for protection against infection. Here, we investigated hepcidin (encoded by Hamp1) in the context of murine M.tb infection. Female C57BL/6 mice were infected with M.tb Erdman via aerosol. Hepatic expression of iron-responsive genes was measured by qRT-PCR and bacterial burden determined in organ homogenates. We found that hepatic Hamp1 mRNA levels decreased post-infection, and correlated with a marker of BMP/SMAD signalling pathways. Next, we tested the effect of Hamp1 deletion, and low iron diets, on M.tb infection. Hamp1 knockout mice did not have a significantly altered M.tb mycobacterial load in either the lungs or spleen. Up to 10 weeks of dietary iron restriction did not robustly affect disease outcome despite causing iron deficiency anaemia. Taken together, our data indicate that unlike with many other infections, hepcidin is decreased following M.tb infection, and show that hepcidin ablation does not influence M.tb growth in vivo. Furthermore, because even severe iron deficiency did not affect M.tb mycobacterial load, we suggest that the mechanisms M.tb uses to scavenge iron from the host must be extremely efficient, and may therefore represent potential targets for drugs and vaccines.