South Asian dairy smallholders: A scoping review of practices and zoonoses

Objective: To identify and discuss on-farm management practices linked to bacterial zoonosis risk in smallholder dairy farmers in South Asia. Methods: This scoping review was conducted as per the PRISMA-ScR guidelines. Five hundred and two publications were retrieved from five online databases using a comprehensive search strategy. Studies were selected if they discussed a farm management practice which impacted human health within a South Asian country. Results: Twenty-two studies were included. Seven management practices relevant to farmers, livestock and their shared environment were identified including raw milk consumption, farm hygiene management, personal protective equipment uses, animal vaccination, cleaning udders, hand washing and disposal of afterbirth materials. Preventive practices were found to be utilized at lower frequencies compared to risk increasing practices. Awareness of bacterial zoonoses is particularly low within the region. Conclusions: Based on the results of this review, it was determined that improving farmer awareness of bacterial zoonotic diseases may favor several of the presented leverage points within the South Asian smallholder dairy system. Relying on formal school education to improve this awareness may not solve this problem, instead, more focus on accessible and affordable zoonoses education and farming programs is required.

Lessons from Vibrio Pathogen and the Comparative Study of Vaccines Developed

Cholera continues to be one of the most common causes of morbidity and mortality among children and adults in developing countries. Vaccine against cholera is an approach in the control of this epidemic and pandemic disease. From the development of very early oral cholera vaccine, advances in vaccine development documented due to a good illustration of the epidemiology, outbreak strategy, and pathophysiology of the disease causing pathogen. The newer-generation oral cholera vaccines are safe and guarantee a high level of protection during outbreak settings for several years. Yet infants and young children in developing countries are hyporesponsive to vaccines and show poor protection against cholera. In this review, we survey and analyse our current knowledge on the etiology of cholera, its clinical manifestation, global epidemiology and elaborate the vaccine candidates, which are effective against the pathogen and the corresponding immune responses to the available vaccines. These reviews comprehensively cover the salient features of recent discoveries related to Vibrio cholerae virulence, past and present vaccine candidates and their advantages and disadvantages with their development strategies. We believe that the advances that have been included in this review will give a comprehensive insight to the prevention and control of cholera outbreaks and development of effective cholera vaccines.

Unravelling the Functions of Regulatory T Cells during Infection

Accumulating evidences have suggested that Treg have an active role in the regulation of immunity to infection. Treg suppress not only autoimmune responses but also other immune responses for instance, during acute infections, against commensal microbes in inflammatory diseases or during chronic illness. Treg have been shown to limit exacerbated inflammation to avoid collateral tissue damage. Treg are also suggested to provide early protective responses in some viral infections as the permitting timely entry of effector cells in infected tissue. Furthermore, Treg have been shown to contribute to form memory pool after resolution of infection. In this review, we survey and analysis our current knowledge and relative dynamics of Treg in a wide range of infection settings and elaborate the examples in which these cells are of critical importance in conferring tolerance, suppressing pathogenesis, inducing protection and optimizing immunity to eliminate infection.

Dissecting Emerging Aspects of Regulatory Circuitry in Man and Mice: Regulatory T Cell Biology

Regulatory T cells (Treg), a component of adaptive immunity, are well known for their immunosuppressive roles and their ability to maintain the balance between the immunological and pathological reactions. Treg have been shown to provide protective responses and their depletion has resulted severe pathology in some pathogen infections. The work presented here has unravelled the potential of regulatory cells in the immune system including different repertoir of Treg cell subsets, markers to distinguish them, Treg suppression mechanisms in the pathogenesis of various infections and summarize different mouse models depleting Tregs. These findings would help set up future avenues of research to elucidate a key mechanism of action of these cells and provide new therapeutic insights for pathogenesis and also for broader antibacterial/antiviral/antiproliferative immunity.

Superior antibody and membrane protein‑specific T‑cell responses to CoronaVac by intradermal versus intramuscular routes in adolescents

Background Optimising the immunogenicity of COVID-19 vaccines to improve their protection against disease is necessary.Fractional dosing by intradermal(ID)administration has been shown to be equally immunogenic as intramuscular(IM)administration for several vaccines,but the immunogenicity of ID inactivated whole severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)at the full dose is unknown.This study(NCT04800133)investigated the superiority of antibody and T-cell responses of full-dose CoronaVac by ID over IM administration in adolescents.Methods Participants aged 11–17 years received two doses of IM or ID vaccine,followed by the 3rd dose 13–42 days later.Humoral and cellular immunogenicity outcomes were measured post-dose 2(IM-CC versus ID-CC)and post-dose 3(IMCCC versus ID-CCC).Doses 2 and 3 were administered to 173 and 104 adolescents,respectively.Results Spike protein(S)immunoglobulin G(IgG),S-receptor-binding domain(RBD)IgG,S IgG Fcγreceptor IIIa(FcγRIIIa)-binding,SNM[sum of individual(S),nucleocapsid protein(N),and membrane protein(M)peptide pool]-specific interleukin-2(IL-2)+CD4^(+),SNM-specific IL-2^(+)CD8^(+),S-specific IL-2^(+)CD8^(+),N-specific IL-2^(+)CD4^(+),N-specific IL-2^(+)CD8^(+)and M-specific IL-2^(+)CD4^(+)responses fulfilled the superior and non-inferior criteria for ID-CC compared to IM-CC,whereas IgG avidity was inferior.For ID-CCC,S-RBD IgG,surrogate virus neutralisation test,90%plaque reduction neutralisation titre(PRNT90),PRNT50,S IgG avidity,S IgG FcγRIIIa-binding,M-specific IL-2^(+)CD4^(+),interferon-γ+CD8^(+)and IL-2^(+)CD8^(+)responses were superior and non-inferior to IM-CCC.The estimated vaccine efficacies were 49%,52%,66%and 79%for IM-CC,ID-CC,IM-CCC and ID-CCC,respectively.The ID groups reported more local,mild adverse reactions.Conclusion This is the first study to demonstrate superior antibody and M-specific T-cell responses by ID inactivated SARSCoV-2 vaccination and serves as the basis for future research to improve the immunogenicity of inactivated vaccines.

Virology at the Lorne Infection and Immunity Conference 2019

The Lome Infection and Immunity Conference is one of five scientific meetings held during each month of February at the Cumberland resort in the picturesque seaside town of Lome,on the Great Ocean Road in Victoria(Australia).The specific aim of the meeting is to bring together basic,clinical and translational researchers-those who examine microbes and their impact on the innate or adaptive immune response,researchers who study the mechanisms that regulate immune responses,and those who apply this knowledge to preventing and treating infectious and in”ammatory diseases.The average number of attendees is 220,with registrants appreciative of the welcoming and relaxed atmosphere(Fig.1).

Infection-acquired versus vaccine-acquired immunity in an SIRWS model

In some disease systems,the process of waning immunity can be subtle,involving a complex relationship between the duration of immunitydacquired either through natural infection or vaccinationdand subsequent boosting of immunity through asymptomatic reexposure.We present and analyse a model of infectious disease transmission where primary and secondary infections are distinguished to examine the interplay between infection and immunity.Additionally we allow the duration of infection-acquired immunity to differ from that of vaccine-acquired immunity to explore the impact on long-term disease patterns and prevalence of infection in the presence of immune boosting.Our model demonstrates that vaccination may induce cyclic behaviour,and the ability of vaccinations to reduce primary infections may not lead to decreased transmission.Where the boosting of vaccine-acquired immunity delays a primary infection,the driver of transmission largely remains primary infections.In contrast,if the immune boosting bypasses a primary infection,secondary infections become the main driver of transmission under a sufficiently long duration of immunity.Our results show that the epidemiological patterns of an infectious disease may change considerably when the duration of vaccine-acquired immunity differs from that of infection-acquired immunity.Our study highlights that for any particular disease and associated vaccine,a detailed understanding of the waning and boosting of immunity and how the duration of protection is influenced by infection prevalence are important as we seek to optimise vaccination strategies.

Understanding the impact of disease and vaccine mechanisms on the importance of optimal vaccine allocation

Vaccination is an important epidemic intervention strategy.However,it is generally unclear how the outcomes of different vaccine strategies change depending on population characteristics,vaccine mechanisms and allocation objective.In this paper we develop a conceptual mathematical model to simulate strategies for pre-epidemic vaccination.We extend the SEIR model to incorporate a range of vaccine mechanisms and disease characteristics.We then compare the outcomes of optimal and suboptimal vaccination strategies for three public health objectives(total infections,total symptomatic infections and total deaths)using numerical optimisation.Our comparison shows that the difference in outcomes between vaccinating optimally and suboptimally depends on vaccine mechanisms,disease characteristics,and objective considered.Our modelling finds vaccines that impact transmission produce better outcomes as transmission is reduced for all strategies.For vaccines that impact the likelihood of symptomatic disease or dying due to infection,the improvement in outcome as we decrease these variables is dependent on the strategy implemented.Through a principled model-based process,this work highlights the importance of designing effective vaccine allocation strategies.We conclude that efficient allocation of resources can be just as crucial to the success of a vaccination strategy as the vaccine effectiveness and/or amount of vaccines available.

Innate and adaptive T cells in influenza disease

Influenza is a major global health problem, causing infections of the respiratory tract, often leading to acute pneumonia, life-threatening complications and even deaths. Over the last seven decades, vaccination strategies have been utilized to protect people from complications of influenza, especially groups at high risk of severe disease. While current vaccination regimens elicit strain-specific antibody responses, they fail to generate cross-protection against seasonal, pandemic and avian viruses. Moreover, vaccines designed to generate influenza- specific T-cell responses are yet to be optimized. During natural infection, viral replication is initially controlled by innate immunity before adaptive immune responses （T cells and antibody-producing B cells） achieve viral clearance and host recovery. Adaptive T and B cells maintain immunological memory and provide protection against subsequent infections with related influenza viruses. Recent studies also shed light on the role of innate T- cells （MAIT cells, y~ T cells, and NKT cells） in controlling influenza and linking innate and adaptive immune mechanisms, thus making them attractive targets for vaccination strategies. We summarize the current knowledge on influenza-specific innate MAIT and γδ T cells as well as adaptive CD8＋ and CD4＋ T cells, and discuss how these responses can be harnessed by novel vaccine strategies to elicit cross-protective immunity against different influenza strains and subtypes.

Local heroes or villains:tissue-resident memory T cells in human health and disease

Tissue-resident memory T(T_(RM))cells are increasingly associated with the outcomes of health and disease.T_(RM) cells can mediate local immune protection against infections and cancer,which has led to interest in T_(RM) cells as targets for vaccination and immunotherapies.However,these cells have also been implicated in mediating detrimental pro-inflammatory responses in autoimmune skin diseases such as psoriasis,alopecia areata,and vitiligo.Here,we summarize the biology of T_(RM) cells established in animal models and in translational human studies.We review the beneficial effects of T_(RM) cells in mediating protective responses against infection and cancer and the adverse role of T_(RM) cells in driving pathology in autoimmunity.A further understanding of the breadth and mechanisms of T_(RM) cell activity is essential for the safe design of strategies that manipulate T_(RM) cells,such that protective responses can be enhanced without unwanted tissue damage,and pathogenic T_(RM) cells can be eliminated without losing local immunity.

Resident and migratory adipose immune cells control systemic metabolism and thermogenesis

Glucose is a vital source of energy for all mammals.The balance between glucose uptake,metabolism and storage determines the energy status of an individual,and perturbations in this balance can lead to metabolic diseases.The maintenance of organismal glucose metabolism is a complex process that involves multiple tissues,including adipose tissue,which is an endocrine and energy storage organ that is critical for the regulation of systemic metabolism.Adipose tissue consists of an array of different cell types,including specialized adipocytes and stromal and endothelial cells.In addition,adipose tissue harbors a wide range of immune cells that play vital roles in adipose tissue homeostasis and function.These cells contribute to the regulation of systemic metabolism by modulating the inflammatory tone of adipose tissue,which is directly linked to insulin sensitivity and signaling.Furthermore,these cells affect the control of thermogenesis.While lean adipose tissue is rich in type 2 and anti-inflammatory cytokines such as IL-10,obesity tips the balance in favor of a proinflammatory milieu,leading to the development of insulin resistance and the dysregulation of systemic metabolism.Notably,anti-inflammatory immune cells,including regulatory T cells and innate lymphocytes,protect against insulin resistance and have the characteristics of tissue-resident cells,while proinflammatory immune cells are recruited from the circulation to obese adipose tissue.Here,we review the key findings that have shaped our understanding of how immune cells regulate adipose tissue homeostasis to control organismal metabolism.

CCR2 enhances CD25 expression by FoxP3^(+) regulatory T cells and regulates their abundance independently of chemotaxis and CCR2^(+) myeloid cells

A wide array of chemokine receptors,including CCR2,are known to control Treg migration.Here,we report that CCR2 regulates Tregs beyond chemotaxis.We found that CCR2 deficiency reduced CD25 expression by FoxP3^(+) Treg cells.Such a change was also consistently present in irradiation chimeras reconstituted with mixed bone marrow from wild-type(WT)and CCR2−/−strains.Thus,CCR2 deficiency resulted in profound loss of CD25 ^(hi) FoxP3^(+) Tregs in secondary lymphoid organs as well as in peripheral tissues.CCR2−/−Treg cells were also functionally inferior to WT cells.Interestingly,these changes to Treg cells did not depend on CCR2+monocytes/moDCs(the cells where CCR2 receptors are most abundant).Rather,we demonstrated that CCR2 was required for TLR-stimulated,but not TCR-or IL-2-stimulated,CD25 upregulation on Treg cells.Thus,we propose that CCR2 signaling can increase the fitness of FoxP3^(+) Treg cells and provide negative feedback to counter the proinflammatory effects of CCR2 on myeloid cells.

针对老年人群的疫苗

全球65岁以上的人口比重正在迅速增加。该年龄段人群发生的感染,比如最近的新型冠状病毒(SARS-CoV-2)感染,可导致大量并发症和死亡。通过添加新型佐剂(如新型重组带状疱疹疫苗和佐剂流感疫苗)或增加抗原浓度(如流感疫苗),老年人疫苗的开发已取得了重大进展。本文综述了3种最重要的可通过疫苗预防的老年疾病的免疫预防进展。重组带状疱疹疫苗的有效性为90%,很少受疫苗接种者年龄的影响,并且免疫效能可以持续4年以上。增加抗原剂量或加入佐剂已经改善了老年人流感疫苗的免疫原性,不过增强型流感疫苗的相对有效性和免疫反应持久性仍是正在进行的临床试验的焦点。在老年人中,肺炎球菌结合疫苗和多糖疫苗对于疫苗血清型引起的侵袭性肺炎球菌性疾病和肺炎球菌肺炎具有相似的功效。它们的相对价值受疫苗血清型的流行情况影响,主要与儿童结合疫苗的接种覆盖率有关。改善疫苗的效能可以增强公众对疫苗的信心并提高接种率。对老年人而言,联合接种这些疫苗切实可行并且至关重要。SARS-CoV-2的出现推动了新疫苗平台的开发,未来有望开发出针对其他病原体的新疫苗。