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In recent years, the century-old Mycobacterium bovis Bacillus Calmette-Guerin (BCG) vaccine against tuberculosis (TB) has been re-evaluated for its capacity to stem the global tide of TB. There is increasing evidence that the efficacy of BCG can be improved by the modified administration methods and schedules. Here, we first discuss recent approaches of vaccine administration, revaccination or boosting that have been used to try to improve the efficacy of BCG against TB. We then dive deeper into studies investigating the immune correlates of protection and describe studies that have investigated BCG-specific T-cell responses and the influence of environmental exposures. These studies all highlight that there is still a lot to learn about the immune response induced by BCG, both in terms of phenotype and specificity, which has been surprisingly understudied. We argue that several critical gaps in knowledge exist and must be addressed by future research to rationally improve the efficacy of BCG, including comprehensive, proteome-wide understanding of the epitopes derived from BCG recognized by BCG-vaccinated individuals, the phenotype of responding antigen-specific T cells and how previous exposure to environmental mycobacteria affect these parameters and thus influence vaccine efficacy. The development of modern techniques allows us to answer some of these questions to better understand how BCG works in terms of both protection against TB and the immune response that it triggers.

Severe coronavirus disease 2019 (COVID-19) pneumonia survivors often exhibit long-term pulmonary sequelae, but the underlying mechanisms or associated local and systemic immune correlates are not known. Here, we have performed high-dimensional characterization of the pathophysiological and immune traits of aged COVID-19 convalescents, and correlated the local and systemic immune profiles with pulmonary function and lung imaging. We found that chronic lung impairment was accompanied by persistent respiratory immune alterations. We showed that functional severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–specific memory T and B cells were enriched at the site of infection compared with those of blood. Detailed evaluation of the lung immune compartment revealed that dysregulated respiratory CD8(+) T cell responses were associated with the impaired lung function after acute COVID-19. Single-cell transcriptomic analysis identified the potential pathogenic subsets of respiratory CD8(+) T cells contributing to persistent tissue conditions after COVID-19. Our results have revealed pathophysiological and immune traits that may support the development of lung sequelae after SARS-CoV-2 pneumonia in older individuals, with implications for the treatment of chronic COVID-19 symptoms.

Background Development of a cytomegalovirus (CMV) vaccine is a high priority. However, the ability of antibodies to protect against CMV infection is not well characterized. Studies of maternal antibodies in infants offer the potential to identify humoral correlates of protection against postnatal acquisition. Methods This hypothesis-generating study analyzed 29 Ugandan mother-infant pairs that were followed weekly for CMV acquisition. Seventeen mothers and no infants were infected with human immunodeficiency virus (HIV). We evaluated the association between CMV-specific immunoglobulin G (IgG) responses in mothers at the time of delivery and their infants’ CMV status at 6 months of age. We also assessed levels of CMV-specific IgG in infants at 6 weeks of age. CMV-specific IgG responses in the mother-infant pairs were then analyzed on the basis of perinatal HIV exposure. Results We found similar levels of multiple CMV glycoprotein–specific IgG binding specificities and functions in mothers and infants, irrespective of perinatal HIV exposure or infant CMV status at 6 months of age. However, the glycoprotein B–specific IgG titer, measured by 2 distinct assays, was higher in infants without CMV infection and was moderately associated with delayed CMV acquisition. Conclusions These data suggest that high levels of glycoprotein B–specific IgG may contribute to the partial protection against postnatal CMV infection afforded by maternal antibodies, and they support the continued inclusion of glycoprotein B antigens in CMV vaccine candidates.

Introduction: Acute Ischemic Stroke (AIS) is one of the leading causes of disability and death in US. Although Endovascular Therapy (EVT) remains the mainstay therapy during acute phase for large vessel occlusions (LVOs), functional outcome varies among the treated patients. This ischemic injury results in an inflammatory response which plays an important role in the functional and neurological outcomes. We hypothesize that the early changes in the inflammatory response near the site of occlusion can be used as predictor of long-term neurofunctional decline Methods: AIS-LVO patients presenting to an academic comprehensive stroke center (CSC) within 24 hours from their last known well and undergoing EVT were included. Blood was collected proximal and distal to the thrombus during thrombectomy. Control samples were collected from the femoral artery and median cubital vein. Cytokine analysis and deep immune profiling was performed using a 20-parameter bead array and 13-parameter flow cytometer. Least Absolute Shrinkage and Selection Operator (LASSO) models were used for cell selection and correlation was evaluated for outcomes including mRS, NIHSS, MOCA and mortality, using R-software. Results: With 19 patients meeting the inclusion criteria, cytokine analysis revealed a significant increase in MMP and IFN-g, and decrease in GM-CSF, IL17, TNF-α, IL6, MIP-1a, and MIP-1b distal to clot. Flow cytometry analysis revealed a significant decrease in NK-T-cells, and CD8 T-cells counts and a relative increase in GM-CSF+ and IL17+ CD4 T-cells distal to clot. Immunological and neurological analysis revealed a correlation with CD4 + IFN-γ - IL10 + (r=0.7) & CD8 + IFN-γ - GMCSF + (0.6) with mRS, and CD4 + IFN-γ - IL10 + (r=0.7), CD4+ IFN-γ - IL17 + (r= -0.6), & CD8 + IFN-γ + IL17 + (r=0.7) cells with mortality. Conclusion: Our results indicate that local ischemia results in a hyperacute adaptive immune response at the site of occlusion. This immune response is predictive of functional outcome among AIS patients and is impactful in multiple ways, including the use of supportive therapy for patients with a poor functional trajectory and the use of immune-modulators at the site of ischemic injury.

Over the past decade, immunotherapies have revolutionized the treatment of cancer. Although the success of immunotherapy is remarkable, it is still limited to a subset of patients. More than 1500 clinical trials are currently ongoing with a goal of improving the efficacy of immunotherapy through co-administration of other agents. Preclinical, small-animal models are strongly desired to increase the pace of scientific discovery, while reducing the cost of combination drug testing in humans. Human immune system (HIS) mice are highly immune-deficient mouse recipients rtpeconstituted with human hematopoietic stem cells. These HIS-mice are capable of growing human tumor cell lines and patient-derived tumor xenografts. This model allows rapid testing of multiple, immune-related therapeutics for tumors originating from unique clinical samples. Using a cord blood-derived HIS-BALB/c-Rag2nullIl2rγnullSIRPαNOD (BRGS) mouse model, we summarize our experiments testing immune checkpoint blockade combinations in these mice bearing a variety of human tumors, including breast, colorectal, pancreatic, lung, adrenocortical, melanoma and hematological malignancies. We present in-depth characterization of the kinetics and subsets of the HIS in lymph and non-lymph organs and relate these to protocol development and immune-related treatment responses. Furthermore, we compare the phenotype of the HIS in lymph tissues and tumors. We show that the immunotype and amount of tumor infiltrating leukocytes are widely-variable and that this phenotype is tumor-dependent in the HIS-BRGS model. We further present flow cytometric analyses of immune cell subsets, activation state, cytokine production and inhibitory receptor expression in peripheral lymph organs and tumors. We show that responding tumors bear human infiltrating T cells with a more inflammatory signature compared to non-responding tumors, similar to reports of “responding” patients in human immunotherapy clinical trials. Collectively these data support the use of HIS mice as a preclinical model to test combination immunotherapies for human cancers, if careful attention is taken to both protocol details and data analysis.

Two proof of concept clinical trials with TB vaccines demonstrate that new approaches can prevent sustained TB infection in adolescents (BCG revaccination) and TB disease in adults (M72/ASO1E) (Nemes et al., 2018; Tait et al., 2019) [1,2]. Both approaches are in late stage development and provide motivation and rationale to invest into a global TB vaccine pipeline. This pipeline needs to be diverse to address TB-specific challenges including variation in target populations, uncertainties in animal model predictivity and lack of immune correlates of protection. It requires that individual vaccine candidates must be advanced rationally and that the global pipeline must be managed in the most nimble and resource-efficient way, especially in the current constrained funding environment. The TB Vaccine Development Pathway is a webtool which has been developed as an offer to the field to provide a source of information and guidance covering vaccine development from discovery to implementation. It is underpinned by generic and TB vaccine-specific guidelines, regulatory frameworks and best practice, and was compiled by a multi-disciplinary team of scientific and technical experts with the input of the TB vaccine community. The Pathway is a unique tool to guide and accelerate the development of TB vaccine candidates and may be useful for other vaccine development fields.

Background We examined cytokine immune response profiles among contacts to tuberculosis patients to identify immunologic and epidemiologic correlates of tuberculosis. Methods We prospectively enrolled 1272 contacts of culture-confirmed pulmonary tuberculosis patients at 9 United States and Canadian sites. Epidemiologic characteristics were recorded. Blood was collected and stimulated with Mycobacterium tuberculosis culture filtrate protein, and tumor necrosis factor (TNF-α), interferon gamma (IFN-γ), and interleukin 10 (IL-10) concentrations were determined using immunoassays. Results Of 1272 contacts, 41 (3.2%) were diagnosed with tuberculosis before or < 30 days after blood collection (co-prevalent tuberculosis) and 19 (1.5%) during subsequent four-year follow-up (incident tuberculosis). Compared with contacts without tuberculosis, those with co-prevalent tuberculosis had higher median baseline TNF-α and IFN-γ concentrations (in pg/mL, TNF-α 129 versus 71, P P P the median were associated with co-prevalent tuberculosis (P P = .03) and smoking (P Conclusions Cytokine concentrations and epidemiologic factors at the time of contact investigation may predict co-prevalent and incident tuberculosis.

Congenital cytomegalovirus (cCMV) might occur as a result of the human cytomegalovirus (HCMV) primary (PI) or nonprimary infection (NPI) in pregnant women. Immune correlates of protection against cCMV have been partly identified only for PI. Following either PI or NPI, HCMV strains undergo latency. From a diagnostic standpoint, while the serological criteria for the diagnosis of PI are well-established, those for the diagnosis of NPI are still incomplete. Thus far, a recombinant gB subunit vaccine has provided the best results in terms of partial protection. This partial efficacy was hypothetically attributed to the post-fusion instead of the pre-fusion conformation of the gB present in the vaccine. Future efforts should be addressed to verify whether a new recombinant gB pre-fusion vaccine would provide better results in terms of prevention of both PI and NPI. It is still a matter of debate whether human hyperimmune globulin are able to protect from HCMV vertical transmission. In conclusion, the development of an HCMV vaccine that would prevent a significant portion of PI would be a major step forward in the development of a vaccine for both PI and NPI.

Tuberculosis (TB) is one of the major global health concerns. There has been a lack of an effective vaccine strategy. The Bacillus Calmette-Guerin (BCG), the only licensed vaccine against TB, is not effective against adult pulmonary TB, the highly contagious form of TB. In the past two decades or so, many novel TB vaccines have been developed, and some of them were evaluated in clinical trials. However, the lack of validated immune correlates to assess the clinical relevance of novel TB vaccines before their entry into costly efficacy trials is a huge challenge to the field of TB vaccine development. Here we describe a general protocol for the procedure of a systematic immunological approach that can be utilized to better assess the clinical relevance of TB vaccine-activated T cells in early phases of clinical studies.

Introduction: It's been 20 years since the first report of a recombinant vaccine that protected against leptospirosis. Since then, numerous recombinant vaccines have been evaluated; however, no recombinant vaccine candidate has advanced to clinical trials. With the ever-increasing burden of leptospirosis, there is an urgent need for a universal vaccine against leptospirosis.Areas covered: This review covers the most promising vaccine candidates that induced significant, reproducible, protection and how advances in the field of bioinformatics has led to the discovery of hundreds of novel protein targets. The authors also discuss the most recent findings regarding the innate immune response and host-pathogen interactions and their impact on the discovery of novel vaccine candidates. In addition, the authors have identified what they believe are the most challenging problems for the discovery and development of a universal vaccine and their potential solutions.Expert opinion: A universal vaccine for leptospirosis will likely only be achieved using a recombinant vaccine as the bacterins are of limited use due to the lack of a cross-protective immune response. Although there are hundreds of novel targets, due to the lack of immune correlates and the need for more research into the basic microbiology of Leptospira spp., a universal vaccine is 10-15 years away.

e18043 Background: We aim to evaluate the efficacy and safety for single dose of preoperative D with or without T in patients with operable HNSCC with immune correlates. Methods: Patients with histologically confirmed, potentially resectable, stage II, III, and IVA HNSCC were eligible. Enrolled patients were randomized into D or D+T, stratified by primary site and human papilloma (HPV) infection status assessed by p16 expression. A single dose of preoperative D (1500mg) or D+T (1500mg+75mg) was administered and followed 2 to 8 weeks later by surgical tumor resection with curative intent. Postoperative (chemo) radiation (PO-CRT) was planned based on standard guidelines, followed by maintenance with D every 4 weeks for one year. Pathology response was quantified as the proportion of the resection bed with viable tumor, tumor necrosis, fibrosis, and inflammation. The primary objective was to determine the local recurrence rate. Secondary endpoints included pathologic response, safety and tolerability, disease-free survival, and immune dynamics incorporating multiple immunofluorescence and single cell transcriptomic analysis. A total 48 patients are planned to be enrolled. Results: As of Jan. 31, 2021, a total 36 patients were enrolled and received surgical resections with available data for pathologic response (D: 16 patients, D+T: 20 patients). Patient characteristics of both arms were well-balanced: hypopharynx/larynx/oral cavity as primary site (12.5%/12.5%/18.8%/56.3% in D, 20.0%/10.0%/10.0%/60.0% in D+T); HPV positivity (50.0% in D, 50.0% in D+T); cT1/T2/T3/T4 (6.3%/37.5%/31.3%/25.0% in D, 10.0%/25.0%/40.0%/25.0% in D+T); cN0/N1/N2/N3 (25.0%/18.8%/50.0%/6.3% in D, 30.0%/30.0%/40.0%/0% in D+T). Significant tumor shrinkage defined as more than 30% of size reduction was observed in 43.7% (7/16), including 2 patients with complete response in D and 20.0% (4/20) in D+T. During 128 days of median follow-ups, local recurrence was observed in 2 patients of D+T arm (5.6%). HPV positivity was numerically associated with favorable treatment response (average tumor shrinkage; -21.8% in p16-positive vs. -6.4% in p16-negative). Meaningful pathologic response was achieved in terms of tumor necrosis (average 10.3% in D, 5.5% in D+T), fibrosis (average 13.4% in D, 10.3% in D+T), and inflammation (average 15.0% in D, 5.8% in D+T), without significant differences according to HPV positivity. After preoperative D or D+T, serious adverse events and unexpected surgical complications did not occur. Conclusions: These early data suggested that preoperative D or D+T in patients with operable HNSCC was safe and feasible and had the potential to provide clinical benefits. The trial is ongoing and the updated outcomes with immune correlates including immunofluorescence and single cell transcriptomic analysis will be presented. Clinical trial information: NCT03737968.

Roles of human IL-37 in infections remain poorly characterized. Although plasma IL-37 is elevated in patients with tuberculosis (TB), IL-37 source and immune correlate in TB have not been investigated. It is also unknown whether and how TB can influence the ability of immune cells to mount innate responses of IL-37 and pre-inflammatory cytokines. Here, we demonstrated that IL-37b-producing monocytes coincided with a source of elevated plasma IL-37b in TB patients. While IL-37b production in TB was associated with prolonged/complicated TB, TB burdens and inflammatory reactions, it negatively correlated with immune responses of pro-inflammatory cytokines IL-1β, IL-6 and TNF-α or IL-10. Interestingly, mycobacterial re-infection of monocytes from TB patients, but not healthy BCG-vaccinated controls, enhanced or sustained IL-37b production by cultured monocytes. TB-sensitized monocytes from TB patients mounted more robust immune responses of IL-37b than those of pre-inflammatory cytokines during mycobacterial re-infection in culture. Our data represent new findings in terms of IL-37b responses, immune correlates and potential mechanisms in TB patients.

Summary The 4th Global Forum on TB Vaccines, convened in Shanghai, China, from 21 – 24 April 2015, brought together a wide and diverse community involved in tuberculosis vaccine research and development to discuss the current status of, and future directions for this critical effort. This paper summarizes the sessions on Immunopathogenesis of Tuberculosis, and Immunopathogenesis and Novel Mechanisms of Vaccine Activity. Summaries of all sessions from the 4th Global Forum are compiled in a special supplement of Tuberculosis .

Chagas disease is a major neglected tropical disease, transmitted predominantly by triatomine insect vectors, but also through congenital and oral routes. While endemic in the Americas, it has turned into a global disease. Because of the current drug treatment limitations, a vaccine would represent a major advancement for better control of the disease. Here, we review some of the rationale, advances, and challenges for the ongoing development of a vaccine against Chagas disease. Recent pre-clinical studies in murine models have further expanded (i) the range of vaccine platforms and formulations tested; (ii) our understanding of the immune correlates for protection; and (iii) the extent of vaccine effects on cardiac function, beyond survival and parasite burden. We further discuss outstanding issues and opportunities to move Chagas disease development forward in the near future.

Mycobacterium tuberculosis (Mtb) continues to be a global scourge with 10.4 million cases of TB and 1.7 million deaths each year. The burgeoning molecular biology is both clarifying Mtb-induced pathology, but also raising new questions with many major challenges remaining: Immune correlates of protection are still to be clarified. Clinical biomarkers that predict disease progression are needed. Non-sputum quantitative means to monitor treatment efficacy are needed. Herein, we briefly review the spectrum of Mtb infection and pathology and then discuss how novel studies in immunology, transcriptomics and epigenomics could be translated into clinical care.

Bordetella pertussis is the causative agent of whooping cough, commonly referred to as pertussis. Although the incidence of pertussis was reduced through vaccination, during the last thirty years it has returned to high levels in a number of countries. This resurgence has been linked to the switch from the use of whole-cell to acellular vaccines. Protection afforded by acellular vaccines appears to be short-lived compared to that afforded by whole cell vaccines. In order to inform future vaccine improvement by identifying immune correlates of protection, a human challenge model of B. pertussis colonisation has been developed. Accurate measurement of colonisation status in this model has required development of a qPCR-based assay to enumerate B. pertussis in samples that distinguishes between viable and dead bacteria. Here we report the development of this assay and its performance in the quantification of B. pertussis from human challenge model samples. This assay has future utility in diagnostic labs and in research where a quantitative measure of both B. pertussis number and viability is required.

Cancer vaccines are solely meant to amplify the pool of type 1 cytokine oriented CD4+ and CD8+ T cells that recognize tumor antigen and ultimately foster control and destruction of a growing tumor. They are not designed to deal with all aspects of immune ignorance, exclusion, suppression and escape that are generally in place in patients with cancer and may prevent the T cells to enter the tumor or to exert their effector function. This simple fact prompted for a reappraisal of the many recent trials in which therapeutic cancer vaccines have been examined as monotherapy. In this review, I focus on trials examining therapeutic cancer vaccines at different stages of existing disease. The analysis of vaccine-induced immune responses and clinical activity of therapeutic cancer vaccines revealed four levels of evidence for vaccine efficacy. The lowest levels, reflect the many trials in which the strength of the tumor-reactive T cell response of vaccinated patients is associated with better clinical outcome or change in tumor marker. The highest levels indicate occasional regressions of tumors and metastases after vaccination or reflect a stronger clinical impact of vaccine in a randomized trial. A whole series of trials in which vaccine-induced tumor immunity correlates with the clinical impact of cancer vaccines in premalignant diseases, settings of low tumor burden or tumor regressions in patients with cancer, form an attest to the fact that cancer vaccines work. While the current number of true clinical responders in each cancer trial is too low for firm conclusions on immune correlates of clinical reactivity in cancer, extrapolation of the results from vaccinated patients with pre-cancers suggest a requirement of broad type 1 T cell reactivity.

The quest for a licensed effective vaccine against malaria remains a global priority. Even though classical vaccine design strategies have been successful for some viral and bacterial pathogens, little success has been achieved for Plasmodium falciparum, which causes the deadliest form of malaria due to its diversity and ability to evade host immune responses. Nevertheless, recent advances in vaccinology through high throughput discovery of immune correlates of protection, lymphocyte repertoire sequencing and structural design of immunogens, provide a comprehensive approach to identifying and designing a highly efficacious vaccine for malaria. In this review, we discuss novel vaccine approaches that can be employed in malaria vaccine design.

The Bacille Calmette Guerin (BCG) vaccine can provide decades of protection against tuberculosis (TB) disease, and although imperfect, BCG is proof that vaccine mediated protection against TB is a possibility. A new TB vaccine is, therefore, an inevitability; the question is how long will it take us to get there? We have made substantial progress in the development of vaccine platforms, in the identification of antigens and of immune correlates of risk of TB disease. We have also standardized animal models to enable head-to-head comparison and selection of candidate TB vaccines for further development. To extend our understanding of the safety and immunogenicity of TB vaccines we have performed experimental medicine studies to explore route of administration and have begun to develop controlled human infection models. Driven by a desire to reduce the length and cost of human efficacy trials we have applied novel approaches to later stage clinical development, exploring alternative clinical endpoints to prevention of disease outcomes. Here, global leaders in TB vaccine development discuss the progress made and the challenges that remain. What emerges is that, despite scientific progress, few vaccine candidates have entered clinical trials in the last 5 years and few vaccines in clinical trials have progressed to efficacy trials. Crucially, we have undervalued the knowledge gained from our “failed” trials and fostered a culture of risk aversion that has limited new funding for clinical TB vaccine development. The unintended consequence of this abundance of caution is lack of diversity of new TB vaccine candidates and stagnation of the clinical pipeline. We have a variety of new vaccine platform technologies, mycobacterial antigens and animal and human models. However, we will not encourage progression of vaccine candidates into clinical trials unless we evaluate and embrace risk in pursuit of vaccine development.

Despite 70 years of research that has intensified in the past decade, a safe and efficacious dengue vaccine has yet to be available. In addition to the expected challenges such as identifying immune correlates of protection, the dengue vaccine field has faced additional hurdles including the necessity to design a tetravalent formulation and the risk of antibody-mediated disease enhancement. Nevertheless, tetravalent live attenuated vaccine candidates have reached efficacy trials and demonstrated some benefit, despite imbalanced immunogenicity and incomplete protection against the four serotypes. Meanwhile, the development of sub-unit dengue vaccines has gained momentum. As the target of most of the neutralizing antibodies so far reported, the virus envelope E protein has been the focus of much effort and represents the leading dengue sub-unit vaccine candidate. However, its notorious poor immunogenicity has prompted the development of innovative approaches to make E-derived constructs part of the second generation dengue vaccines portfolio.

Dengue viruses (DENV1-4) are mosquito-borne flaviviruses estimated to cause up to ∼400 million infections and ∼100 million dengue cases each year. Factors that contribute to protection from and risk of dengue and severe dengue disease have been studied extensively but are still not fully understood. Results from Phase 3 vaccine efficacy trials have recently become available for one vaccine candidate, now licensed for use in several countries, and more Phase 2 and 3 studies of additional vaccine candidates are ongoing, making these issues all the more urgent and timely. At the "Summit on Dengue Immune Correlates of Protection", held in Annecy, France, on March 8-9, 2016, dengue experts from diverse fields came together to discuss the current understanding of the immune response to and protection from DENV infection and disease, identify key unanswered questions, discuss data on immune correlates and plans for comparison of results across assays/consortia, and propose a research agenda for investigation of dengue immune correlates, all in the context of both natural infection studies and vaccine trials.

Human cytomegalovirus (HCMV) is the most common congenitally transmitted pathogen worldwide, impacting an estimated 1 million newborns annually. In a subset of infected infants, congenital HCMV causes severe, long-lasting sequelae, including deafness, microcephaly, neurodevelopmental delay, and even death. Accordingly, a maternal vaccine to prevent congenital HCMV infection continues to be a top public health priority. Nevertheless, all vaccines tested to date have failed to meet clinical trial endpoints. Maternal immunity provides partial protection against congenital HCMV transmission, as vertical transmission from seropositive mothers is relatively rare. Therefore, an understanding of the maternal immune correlates of protection against HCMV congenital infection will be critical to inform design of an efficacious maternal vaccine. This review summarizes our understanding of the innate and adaptive immune correlates of protection against congenital transmission of HCMV, and discusses the advantages and applications of a novel nonhuman primate model of congenital CMV transmission to aid in rational vaccine design and evaluation.

Background Mycobacterium tuberculosis (M.tb) is the leading infectious cause of mortality; however, there is no vaccine that confers lasting protection. To investigate the immune response to M.tb, we have developed an ultra-low dose (ULD) infection model in mice that better reflects the heterogeneous outcomes of human infection. Additionally, we have identified a blood transcriptional signature, taken at day 24, that predicts future bacterial burden after day 70. Methods Mice were infected with an ULD (1–3 CFU) of H37Rv M.tb. Control mice were infected with 50–100 CFU. Blood was drawn at day 24 for RNA signature. At early (day 34–35), and late (day 82–83) time points, mice were injected with an intravascular label. Individual lungs were then assessed for bacterial burden, phenotypic and spatial analysis of immune cells by flow cytometry, and histocytometry, a type of immunohistochemistry that allows for imaging of >12 colors Results At day 35, the following cell populations were correlated with an RNA signature score predicting disease progression: ESAT-6 tetramer+ CD4+ T cells (R2 = 0.35, P Conclusion This model replicates heterogeneity of TB seen in humans, while also providing a way to correlate differences in the immune response to future outcome. We have associated distinct immune cell subsets with the failure to control TB. With a larger sample size and data from histocytometry, we will have improved resolution to discern protective elements of the immune response to TB, which we can then test mechanistically in our model. Disclosures All authors: No reported disclosures.

Tuberculosis (TB) disease caused by Mycobacterium tuberculosis ( M. tb ) remains one of the leading infectious causes of death and disease throughout the world. The only licensed vaccine, Mycobacterium bovis bacille Calmette–Guérin (BCG) confers highly variable protection against pulmonary disease. An effective vaccination regimen would be the most efficient way to control the epidemic. However, BCG does confer consistent and reliable protection against disseminated disease in childhood, and most TB vaccine strategies being developed incorporate BCG to retain this protection. Cellular immunity is necessary for protection against TB and all the new vaccines in development are focused on inducing a strong and durable cellular immune response. There are two main strategies being pursued in TB vaccine development. The first is to replace BCG with an improved whole organism mycobacterial priming vaccine, which is either a recombinant BCG or an attenuated strain of M. tb . The second is to develop a subunit boosting vaccine, which is designed to be administered after BCG vaccination, and to enhance the protective efficacy of BCG. This article reviews the leading candidate vaccines in development and considers the current challenges in the field with regard to efficacy testing.

Since the identification of the Human Immunodeficiency Virus type 1 (HIV-1) as the etiologic agent of AIDS (Acquired Immunodeficiency Syndrome), many efforts have been made to stop the AIDS pandemic. A major success of medical research has been the development of the highly active antiretroviral therapy and its availability to an increasing number of people worldwide, with a considerable effect on survival. However, a safe and effective vaccine able to prevent and eradicate the HIV pandemic is still lacking. Clinical trials and preclinical proof-of-concept studies in nonhuman primate (NHP) models have provided insights into potential correlates of protection against the HIV-1 infection, which include broadly neutralizing antibodies (bnAbs), non-neutralizing antibodies targeting the variable loops 1 and 2 (V1V2) regions of the HIV-1 envelope (Env), polyfunctional antibody, and Env-specific T-cell responses. In this review, we provide a brief overview of different HIV-1 vaccine approaches and discuss the current understanding of the cellular and humoral correlates of HIV-1 immunity.

There has never been a greater need for a new protective tuberculosis vaccine. Bacille Calmette-Guerin remains the cornerstone of any vaccine strategy, but improving its immunogenicity and efficacy has now become an urgent global health priority. This review discusses the main vaccines currently in clinical development and other novel vaccine strategies in the pipeline. It addresses the key questions in vaccine design, including antigen selection, route of vaccine delivery and immune correlates of vaccine-induced protection. There is an opportunity to identify such correlates from ongoing and future Phase II/III trials and, as these emerge, they can be used to validate the most relevant and predictive animal models with which to develop the next generation of new vaccines.

In AIDS vaccine development the pendulum has swung towards a renewed emphasis on the potential role for neutralizing antibodies in a successful global vaccine. It is recognized that vaccine-induced antibody performance, as assessed in the available neutralization assays, may well serve as a “gatekeeper” for HIV-1 subunit vaccine prioritization and advancement. As a result, development of a standardized platform for reproducible measurement of neutralizing antibodies has received considerable attention. Here we review current advancements in our knowledge of the performance of different types of antibodies in a traditional primary cell neutralization assay and the newer, more standardized TZM-bl reporter cell line assay. In light of recently revealed differences (see accompanying article) in the results obtained in these two neutralization formats, parallel evaluation with both platforms should be contemplated as an interim solution until a better understanding of immune correlates of protection is achieved.

SummaryMycobacterium tuberculosis (Mtb) and the human immunodeficiency virus (HIV) are both life-threatening pathogens in their own right, but their synergic effects on the immune system during co-infection markedly enhance their effect on the host. This review focuses on the bidirectional interaction between HIV and Mtb and discusses the relevance of sputum smear examination, CD4+ counts, viral load at baseline and after initiation of anti-retroviral therapy, as well as additional existing and new potential immune correlates of disease progression and prognosis. These markers include β2-microglobulin, neopterin, tumor necrosis factor receptor II (TNFRII), CD8+/CD38+, soluble urokinase plasminogen activator receptor (suPAR) and CXCL10 (or IP-10).

Congenital cytomegalovirus (CMV) infection is a major cause of disability in newborns. In spite of knowledge that maternal immunity to CMV protects newborns against these disabilities, there is no licensed vaccine for CMV. The barriers to availability of a CMV vaccine include: (1) a lack of knowledge about the problem; (2) an incomplete understanding of the immune correlates of protection; and (3) uncertainty about what the proper target population is for vaccination. This review summarizes the current state of CMV vaccines and discusses the obstacles that must be overcome before the goal of a vaccine can be realized.

Recent studies suggest that immunologic containment of HIV-1 is possible and the immune correlates of this control are being defined. There have been significant advances in our ability to elicit virus-specific immune responses, which have led to viral control in animal models. Although viral escape from the immune system is an important challenge, new strategies for therapeutic and preventative HIV-1 vaccination are being vigorously pursued in human trials.

Because of the increasing incidence, geographic expansion and economic burden of dengue transmission, dengue poses major challenges to policy makers. A vaccine against dengue is urgently needed, but vaccine development has been hampered by the lack of an appropriate animal model, poor understanding of correlates of successful human immunity, the fear of immune enhancement, and viral interference in tetravalent combinations. The most suitable target epitopes for vaccines, as well as the role of nonstructural proteins remain elusive. The chimeric yellow fever bonebased live attenuated dengue vaccine is furthest in development, but initial efficacy results have been disappointing. Lessons learnt from this failure will affect the design of future trials, and increase the urgency to identify the best epitope and immune correlates. Dengue vaccine introduction will not be the only strategy to combat dengue, but needs to be “packaged” with novel vector control approaches, with community-based interventions to reduce the number of breeding sites, and reducing the case fatality rate by improving case management. Published version

At an international symposium**The Second International Workshop on ‘Immunology Correlates of Protection', specific clinical and preclinical settings were examined in order to increase our understanding of immunity to HIV. This data might help the design of more effective vaccine strategies for protection from HIV or the treatment of AIDS.

Tuberculosis continues to persist despite widespread use of BCG, the only licensed vaccine to prevent TB. BCG's limited efficacy coupled with the emergence of drug-resistant strains of Mycobacterium tuberculosis emphasizes the need for a more effective vaccine for combatting this disease. However, the development of a TB vaccine is hindered by the lack of immune correlates, suboptimal animal models, and limited funding. An adolescent/adult vaccine would have the greatest public health impact, but effective delivery of such a vaccine will require a better understanding of global TB epidemiology, improved infrastructure, and engagement of public health leaders and global manufacturers. Here we discuss the current state of tuberculosis vaccine research and development, including our understanding of the underlying immunology as well as the challenges and opportunities that may hinder or facilitate the development of a new and efficacious vaccine.

A review of the use of live attenuated varicella vaccine in immunocompromised children, particularly those with underlying leukemia in remission, is presented. Data concerning safety, immunogenicity, and efficacy of this vaccine in high-risk children are reviewed. The unique contributions toward our understanding of varicella vaccine, including spread of vaccine-type virus, incidence of zoster, and immune correlates provided by studies of immunocompromised patients are discussed. The importance of protecting high-risk children against severe varicella by the use of varicella vaccine is apparent.

Immunotherapy exploits the effector mechanisms of the immune system to combat cancer. A number of immunotherapeutic compounds are now firmly anchored in current treatment of cancer patients. For newly developed therapeutic entities, the study of the patient’s immune response to treatment remains an essential component of clinical trials. Under ideal circumstances, this analysis is accomplished by various laboratory assays that measure differences in wanted and unwanted immune parameters before, during, and after treatment, at both systemic and local levels, with the ultimate aim of identifying immune correlates of biological activity as well as clinical outcome. The biomarker identification process is assisted by a harmonization of assays and data reporting, because this enables a comparison of datasets obtained by testing similar therapeutic products in different trials. Moreover, a systematic use of the datasets to better understand the strengths, weaknesses and efficacy of various treatment modalities can guide decision making with regard to further clinical development, possibly encouraging investigators to move forward into larger trials or to further optimize immunotherapeutic compounds or approach. This chapter provides an overview of immunomonitoring principles to promote the clinical development of effective immunotherapeutics for cancer treatment.

3022Background: Preclinical models suggest systemic disease control with ipilimumab (IPI) and radiation. Here we conducted a phase I trial of IPI and high dose stereotactic body radiation therapy (...

This issue hosts diverse topics, from myeloid derived suppressor cells (MDSC) with their mechanism and role in cancer, the interplay between diet and emerging allergies studied in a genetically closed population, the pleiotropic anti-inflammatory effects of resveratrol, to the quest to achieve more reliable immune correlates of protection against the hepatitis C virus (HCV).

Non-human primates (NHPs) are used to model human disease owing to their remarkably similar genomes, physiology, and immune systems. Recently, there has been an increased interest in modeling tuberculosis (TB) in NHPs. Macaques are susceptible to infection with different strains of Mycobacterium tuberculosis (Mtb), producing the full spectrum of disease conditions, including latent infection, chronic progressive infection, and acute TB, depending on the route and dose of infection. Clearly, NHPs are an excellent model of human TB. While the initial aim of the NHP model was to allow preclinical testing of candidate vaccines and drugs, it is now also being used to study pathogenesis and immune correlates of protection. Recent advances in this field are discussed in this review. Key questions such as the effect of hypoxia on the biology of Mtb and the basis of reactivation of latent TB can now be investigated through the use of this model.

There is no licensed vaccine against any human parasitic disease and apicomplexan parasites cause enormous human suffering; the malaria parasite alone kills approximately one million people annually and is the cause of the majority of infection-related deaths in the young. A malaria vaccine is essential if the goal of malaria eradication is to be achieved. Decades ago it was shown that attenuated malaria parasites could induce sterile immunity to infection but progress towards efficacious vaccines for malaria has been slow. However, recent studies have begun to tease out the immune correlates of vaccine-induced sterile protection and essential research on animal models of disease continues to guide vaccine design. Whole parasite approaches to vaccine design through attenuation as well as subunit vaccine development continue to move forward to clinical trials and are showing promising results.

Meeting abstracts Varlilumab is a human IgG1 agonist anti-CD27 antibody designed to activate T cells through CD27 costimulation. Preclinical studies have shown that Varlilumab efficiently activates human T cells when combined with T cell receptor stimulation, enhances antigen specific CD8 T cell

The severity of the AIDS epidemic clearly emphasises the urgent need to expedite HIV vaccine candidates into clinical trials. Prophylactic HIV vaccine candidates have been evaluated in non-human primates. Based on specific proof of principle studies the first phase III clinical studies have recently begun in humans. However, a truly effective HIV vaccine is not yet at hand and many problems related to specific properties of the virus remain to be overcome. Previously proven empirical approaches have largely failed and now rational thinking based on an understanding of immunity to lentiviral infections is needed. This review addresses the scientific problems and complications facing the development of an HIV vaccine as well as the possible strategies currently available to overcome these problems. Recent attention has focussed on identifying the immune correlates and mechanisms of protection from either HIV infection or protection from disease progression. Based on these observations, the logic and rational behind the development of multiple component vaccine strategies are highlighted.

At an international workshop ∗ ∗The International Workshop on ‘Immunological Correlates of Protection from HIV Infection and Disease' was held at Montreux, Switzerland, on 27–30 May 1995., the immune responses observed in cases of protection from HIV infection or disease progression were discussed. An understanding of the immunological mechanisms associated with protection from lentivirus infection and disease is likely to have an important impact on vaccine design and new therapeutic strategies.

The advent of immunotherapies for cancer has resulted in robust clinical responses and confirmed that the immune system can significantly inhibit tumor progression. The recent success of adoptive cell therapy against melanoma suggests that endogenous T-cell responses have the potential to control cancer. However, the lack of responses in some patients receiving such therapy indicates a need for a better understanding of the host immune response to solid tumors. In this review, we summarize the current knowledge on the characteristics of adoptively transferred T cells associated with successful anti-melanoma immune responses in humans.

BACKGROUND: Heterogeneity in malaria exposure complicates survival analyses of vaccine efficacy trials and confounds the association between immune correlates of protection and malaria infection in longitudinal studies. Analysis may be facilitated by taking into account the variability in individual exposure levels, but it is unclear how exposure can be estimated at an individual level. METHOD AND FINDINGS: We studied three cohorts (Chonyi, Junju and Ngerenya) in Kilifi District, Kenya to assess measures of malaria exposure. Prospective data were available on malaria episodes, geospatial coordinates, proximity to infected and uninfected individuals and residence in predefined malaria hotspots for 2,425 individuals. Antibody levels to the malaria antigens AMA1 and MSP1(142) were available for 291 children from Junju. We calculated distance-weighted local prevalence of malaria infection within 1 km radius as a marker of individual's malaria exposure. We used multivariable modified Poisson regression model to assess the discriminatory power of these markers for malaria infection (i.e. asymptomatic parasitaemia or clinical malaria). The area under the receiver operating characteristic (ROC) curve was used to assess the discriminatory power of the models. Local malaria prevalence within 1 km radius and AMA1 and MSP1(142) antibodies levels were independently associated with malaria infection. Weighted local malaria prevalence had an area under ROC curve of 0.72 (95%CI: 0.66-0.73), 0.71 (95%CI: 0.69-0.73) and 0.82 (95%CI: 0.80-0.83) among cohorts in Chonyi, Junju and Ngerenya respectively. In a small subset of children from Junju, a model incorporating weighted local malaria prevalence with AMA1 and MSP1(142) antibody levels provided an AUC of 0.83 (95%CI: 0.79-0.88). CONCLUSION: We have proposed an approach to estimating the intensity of an individual's malaria exposure in the field. The weighted local malaria prevalence can be used as individual marker of malaria exposure in malaria vaccine trials and longitudinal studies of natural immunity to malaria.