Interventions addressing routine childhood immunization and its behavioral and social drivers.

Introduction: Despite the advances in vaccination, there are still several challenges in reaching millions of children in low- and middle-income countries (LMICs). In this review, we present an extensive summary of the various strategies used for improving routine immunization in LMICs to aid program implementers in designing vaccination interventions. Methods: Experimental and quasi-experimental impact evaluations conducted in LMICs evaluating the effectiveness of interventions in improving routine immunization of children aged 0-5 years or the intermediate outcomes were included from 3ie's review of systematic reviews. Some additional impact evaluation studies published in recent years in select LMICs with large number of unvaccinated children were also included. Studies were coded to identify interventions and the barriers in the study context using the intervention framework developed in 3ie's Evidence Gap Map and the WHO's Behavioral and Social Drivers (BeSD) of vaccination framework, respectively. Qualitative analysis of the content was conducted to analyze the intervention strategies and the vaccination barriers that they addressed. Results and conclusion: One hundred and forty-two impact evaluations were included to summarize the interventions. To address attitudinal and knowledge related barriers to vaccination and to motivate caregivers, sensitization and educational programs, media campaigns, and monetary or non-monetary incentives to caregivers, that may or may not be conditional upon certain health behaviors, have been used across contexts. To improve knowledge of vaccination, its place, time, and schedule, automated voice messages and written or pictorial messages have been used as standalone or multicomponent strategies. Interventions used to improve service quality included training and education of health workers and providing monetary or non-monetary perks to them or sending reminders to them on different aspects of provision of vaccination services. Interventions like effective planning or outreach activities, follow-up of children, tracking of children that have missed vaccinations, pay-for-performance schemes and health system strengthening have also been used to improve service access and quality. Interventions aimed at mobilizing and collaborating with the community to impact social norms, attitudes, and empower communities to make health decisions have also been widely implemented.

Service disruptions, trauma and burnout during the COVID-19 pandemic among healthcare providers delivering immunisation and maternal and child health services in Indonesia.

BACKGROUND: The COVID-19 pandemic resulted in extreme strain on health systems including the health workforce, essential health services and vaccination coverage. We examined disruptions to immunisation and maternal and child health (MCH) services, concerns of personal well-being and delivery of healthcare during the pandemic as well as factors associated with self-reported trauma or burnout among healthcare providers (HCPs). METHODS: In March-April 2022, we conducted a cross-sectional survey among HCPs in two provinces of Indonesia. HCPs involved in COVID-19 or routine immunisation and MCH services were randomly selected from district/city health office registration lists. We descriptively analysed service disruptions experienced by HCPs as well as trauma, burnout and concerns of personal well-being and delivery of healthcare during the pandemic. Multivariate logistic regression analyses were undertaken to identify factors associated with trauma or burnout. RESULTS: We recruited 604 HCPs. Mobilisation of staff from routine health services to COVID-19 response duties was a key reason for service disruptions (87.9%). Strategies such as community outreach and task shifting were implemented to overcome disruptions. Trauma or burnout during the pandemic was reported by 64.1% HCPs, with 23.5% reporting worse mental or emotional health.Factors associated with trauma or burnout included delivery of COVID-19 immunisation (adjusted OR (aOR) 2.54, 95% CI 1.08 to 5.94); and delivery of both COVID-19 immunisation and routine immunisation compared with no involvement in vaccination programmes (aOR 2.42, 95% CI 1.06 to 5.52); poor treatment in the workplace (aOR 2.26, 95% CI 1.51 to 3.38) and lower confidence to respond to patient queries on COVID-19 immunisation (aOR 1.51, 95% CI 1.03 to 2.22). CONCLUSION: HCPs experienced service disruptions, trauma and burnout and implemented strategies to minimise disruptions to service delivery and improve patient experiences. Our study highlights the need to ensure that workforce resilience and strategies to protect and support HCPs are considered for pandemic planning, preparedness and management.

IL-10 inhibition during immunization improves vaccine-induced protection against Staphylococcus aureus infection.

Staphylococcus aureus is a major human pathogen. An effective anti-S. aureus vaccine remains elusive as the correlates of protection are ill-defined. Targeting specific T cell populations is an important strategy for improving anti-S. aureus vaccine efficacy. Potential bottlenecks that remain are S. aureus-induced immunosuppression and the impact this might have on vaccine-induced immunity. S. aureus induces IL-10, which impedes effector T cell responses, facilitating persistence during both colonization and infection. Thus, it was hypothesized that transient targeting of IL-10 might represent an innovative way to improve vaccine efficacy. In this study, IL-10 expression was elevated in the nares of persistent carriers of S. aureus, and this was associated with reduced systemic S. aureus-specific Th1 responses. This suggests that systemic responses are remodeled because of commensal exposure to S. aureus, which negatively implicates vaccine function. To provide proof of concept that targeting immunosuppressive responses during immunization may be a useful approach to improve vaccine efficacy, we immunized mice with T cell-activating vaccines in combination with IL-10-neutralizing antibodies. Blocking IL-10 during vaccination enhanced effector T cell responses and improved bacterial clearance during subsequent systemic and subcutaneous infection. Taken together, these results reveal a potentially novel strategy for improving anti-S. aureus vaccine efficacy.

B Cell Receptor Transgenic Mice as Tools to Study Memory B Cells.

B cell receptor (BCR) transgenic mice allow the control of the initial target (antigen) specificity of naïve B cells and to investigate their properties following activation. Here, I describe how BCR transgenic B cells can be used in combination with adoptive cell transfer and immunization models to study memory B cell formation and reactivation.

Enhancing cross-protection against influenza by heterologous sequential immunization with mRNA LNP and protein nanoparticle vaccines.

Enhancing influenza vaccine cross-protection is imperative to alleviate the significant public health burden of influenza. Heterologous sequential immunization may synergize diverse vaccine formulations and routes to improve vaccine potency and breadth. Here we investigate the effects of immunization strategies on the generation of cross-protective immune responses in female Balb/c mice, utilizing mRNA lipid nanoparticle (LNP) and protein-based PHC nanoparticle vaccines targeting influenza hemagglutinin. Our findings emphasize the crucial role of priming vaccination in shaping Th bias and immunodominance hierarchies. mRNA LNP prime favors Th1-leaning responses, while PHC prime elicits Th2-skewing responses. We demonstrate that cellular and mucosal immune responses are pivotal correlates of cross-protection against influenza. Notably, intranasal PHC immunization outperforms its intramuscular counterpart in inducing mucosal immunity and conferring cross-protection. Sequential mRNA LNP prime and intranasal PHC boost demonstrate optimal cross-protection against antigenically drifted and shifted influenza strains. Our study offers valuable insights into tailoring immunization strategies to optimize influenza vaccine effectiveness.

Status of the national immunization technical advisory groups in the Americas: recommendations for improvement / Estado actual de los grupos técnicos asesores nacionales sobre inmunización en la Región de las Américas: recomendaciones para su mejora / Situação dos Grupos Técnicos Assessores Nacionais sobre Imunização na Região das Américas: recomendações para melhorias

[ABSTRACT]. Objectives. To evaluate the structure and operation of national immunization technical advisory groups (NITAGs) in Latin America and the Caribbean and to make recommendations for improvement. Methods. A convenience sample of six current and eight former NITAG members representing 12 countries in the region were invited in 2022 to answer a web-based questionnaire on NITAG structure, organization, and procedures. The questionnaire used indicators similar to those in the Joint Reporting Form on Immunization. Participants were also asked about the role their NITAGs played in coronavirus disease 2019 (COVID-19) immunization policies. Results. Brazil, Dominican Republic, and Venezuela (Bolivarian Republic of) reported not having an active NITAG. The nine active NITAGs are structured and organized according to World Health Organization and Pan American Health Organization recommendations, with variations between countries. Most NITAGs include representatives of the five recommended medical specialties with the participation of additional members possible. Only Bolivia (Plurinational State of) and Mexico have no explicit policy for managing members’ potential conflicts of interest. All NITAGs have an exclusively technical advisory role and generally meet once a quarter. Usually, NITAGs are asked by health ministries to analyze issues and make recommendations. All NITAGs, except for Peru’s, actively participated in supporting decision-making for immunization policy on COVID-19. Conclusions. NITAGs have successfully supported vaccine policy-making through evidence-based recommendations. However, improvement in their structure, operation, and transparency is needed to help them keep up with the rapidly evolving field of immunization. Research on the impact of NITAGs is important to support the development of recommendations for improvement.

[RESUMEN]. Objetivos. Evaluar la estructura y el funcionamiento de los grupos técnicos asesores nacionales sobre inmunización (NITAG, por su sigla en inglés) en América Latina y el Caribe y formular recomendaciones para su mejora. Métodos. En el 2022, se seleccionó una muestra por conveniencia, formada por seis miembros actuales y ocho antiguos miembros de NITAG que representaban a 12 países de la Región, y se les invitó a responder un cuestionario en línea sobre la estructura, la organización y los procedimientos de los NITAG. El cuestionario utilizaba indicadores similares a los del formulario de notificación conjunta de datos sobre inmunización. También se preguntó a los participantes sobre el papel que desempeñaron sus NITAG en las políticas de inmunización contra la COVID-19. Resultados. Brasil, República Dominicana y Venezuela (República Bolivariana de) informaron que no tenían un NITAG activo. Los nueve NITAG activos están estructurados y organizados según las recomendaciones de la Organización Mundial de la Salud y la Organización Panamericana de la Salud, con diferencias entre los países. La mayoría de los NITAG cuentan con representantes de las cinco especialidades médicas recomendadas, con la posibilidad de participación de miembros adicionales. Solo Bolivia (Estado Plurinacional de) y México carecen de una política explícita para gestionar los posibles conflictos de intereses de los miembros. Todos los NITAG tienen una función exclusivamente de asesoramiento técnico y suelen reunirse en forma trimestral. Por lo general, los ministerios de salud les solicitan el análisis de problemas y la formulación de recomendaciones. Salvo en el caso de Perú, todos los NITAG participaron activamente en la facilitación de la toma de decisiones sobre políticas de inmunización contra la COVID-19. Conclusiones. Los NITAG han brindado apoyo con éxito a la formulación de políticas de vacunación mediante recomendaciones basadas en la evidencia. Sin embargo, es necesario mejorar su estructura, funcionamiento y transparencia para que puedan mantenerse al día en el campo de la inmunización en constante evolución. La investigación sobre el impacto de los NITAG es importante para respaldar la formulación de recomendaciones para su mejora.

[RESUMO]. Objetivos. Avaliar a estrutura e o funcionamento dos Grupos Técnicos Assessores Nacionais sobre Imunização (NITAGs, na sigla em inglês) na América Latina e no Caribe e fazer recomendações para melhorá-los. Métodos. Em 2022, uma amostra de conveniência de seis membros atuais e oito ex-membros de NITAGs, representando 12 países da Região, foi convidada a responder a um questionário on-line sobre a estrutura, a organização e os procedimentos dos NITAGs. O questionário usou indicadores semelhantes aos do formulário de notificação conjunta sobre imunização. Também se perguntou aos participantes sobre o papel que seus NITAGs haviam desempenhado nas políticas de imunização contra a doença pelo coronavírus 2019 (COVID-19). Resultados. O Brasil, a República Dominicana e a Venezuela (República Bolivariana da) informaram não ter um NITAG ativo. Os nove NITAGs ativos são estruturados e organizados de acordo com as recomendações da Organização Mundial da Saúde e da Organização Pan-Americana da Saúde, com variações entre os países. A maioria dos NITAGs inclui representantes das cinco especialidades médicas recomendadas, sendo possível a participação de outros membros. Somente a Bolívia (Estado Plurinacional da) e o México não têm uma política explícita para gerenciar possíveis conflitos de interesse dos membros. Todos os NITAGs têm uma função exclusiva de assessoria técnica e geralmente se reúnem trimestralmente. Normalmente, os ministérios da Saúde solicitam aos NITAGs que analisem problemas e façam recomendações. Todos os NITAGs, exceto o do Peru, participaram ativamente no apoio ao processo decisório da política de imunização contra a COVID-19. Conclusões. Os NITAGs conseguiram apoiar a formulação de políticas de vacinação por meio de recomendações baseadas em evidências. Entretanto, é necessário melhorar a estrutura, o funcionamento e a transparência dos NITAGs para ajudá-los a se manter em dia com o campo da imunização, que está evoluindo rapidamente. A pesquisa sobre o impacto dos NITAGs é importante para apoiar a elaboração de recomendações de melhoria.

Educational interventions for the prevention and management of adverse events following immunisation: a systematic review. / Intervenções educativas para prevenção e conduta dos eventos adversos pós-vacinação: uma revisão sistemática.

This study investigated educational interventions for the prevention and management of adverse events following immunisation. This a systematic review was conducted by examining observational studies, with no restriction as to language or year, registered in PROSPERO with the identifier CRD42022313144 and by searching the MEDLINE, LILACS, Embase, CINAHL and Scopus databases. Two researchers selected the studies, extracted the data and assessed the risk of study bias; disagreements were resolved by a third researcher. A total of six articles met the inclusion criteria of the systematic review and the studies reported significant post-intervention improvements in staff conduct in relation to immunisation. It was concluded that educational strategies that lead to continued professional development in relation to vaccination in primary care were effective in reducing and/or eradicating immunisation errors and adverse events following immunisation.

O estudo tem como objetivo investigar as intervenções educativas para a prevenção e conduta dos eventos adversos pós-vacinação. Trata-se de uma revisão sistemática realizada por meio da análise de estudos observacionais sem restrição de idioma e ano com registro no PROSPERO pelo identificador CRD42022313144 e busca nas bases de dados MEDLINE, LILACS, Embase, CINAHL e Scopus. Dois pesquisadores selecionaram os estudos, extraíram os dados e avaliaram o risco de viés, as discordâncias foram resolvidas por um terceiro pesquisador. Atenderam os critérios de inclusão da revisão sistemática um total de seis artigos e os estudos apresentaram melhoras significativas pós-intervenção na conduta dos profissionais em relação à imunização. Conclui-se que o fornecimento de estratégias educativas de educação permanente no âmbito vacinal da atenção primária é eficaz para reduzir e/ou erradicar os erros de imunização e eventos adversos pós-vacinação.

Cyclic Peptide Conjugate Vaccines and Physically Mixed Cyclic Peptide Vaccines for Subcutaneous Immunization.

Immune stimulants (adjuvants) enhance immune system recognition to provide an effective and individualized immune response when delivered with an antigen. Synthetic cyclic deca-peptides, co-administered with a toll-like receptor targeting lipopeptide, have shown self-adjuvant properties, dramatically boosting the immune response in a murine model as a subunit peptide-based vaccine containing group A Streptococcus peptide antigens.Here, we designed a novel peptide and lipid adjuvant system for the delivery of group A Streptococcus peptide antigen and a T helper peptide epitope. Following linear peptide synthesis on 2-chlorotrityl chloride resin, the linear peptide was cleaved and head-to-tail cyclized in solution. The selective arrangement of amino acids in the deca-peptide allowed for selective conjugation of lipids and/or peptide antigens following cyclisation. Using both solution-phase peptide chemistry and copper-catalyzed azide-alkyne cycloaddition reaction were covalently (and selectively) ligated lipid and/or peptide antigens onto the cyclic deca-peptide core. Subcutaneous administration of the vaccine design to mice resulted in the generation of a large number of serum immunoglobulin (Ig) G antibodies.

Polyclonal Peptide Antisera.

Polyclonal antibodies are relatively easy to produce and may supplement monoclonal antibodies for some applications or even have some advantages.The choice of species for production of (peptide) antisera is based on practical considerations, including availability of immunogen (vaccine) and animals. Two major factors govern the production of antisera: the nature of adaptive immune responses, which take place over days/weeks and ethical guidelines for animal welfare.Here, simple procedures for immunization of mice, rabbits, sheep, goats, pigs, horses, and chickens are presented.

Single-cell analysis reveals lasting immunological consequences of influenza infection and respiratory immunization in the pig lung.

The pig is a natural host for influenza viruses and integrally involved in virus evolution through interspecies transmissions between humans and swine. Swine have many physiological, anatomical, and immunological similarities to humans, and are an excellent model for human influenza. Here, we employed single cell RNA-sequencing (scRNA-seq) and flow cytometry to characterize the major leukocyte subsets in bronchoalveolar lavage (BAL), twenty-one days after H1N1pdm09 infection or respiratory immunization with an adenoviral vector vaccine expressing hemagglutinin and nucleoprotein with or without IL-1ß. Mapping scRNA-seq clusters from BAL onto those previously described in peripheral blood facilitated annotation and highlighted differences between tissue resident and circulating immune cells. ScRNA-seq data and functional assays revealed lasting impacts of immune challenge on BAL populations. First, mucosal administration of IL-1ß reduced the number of functionally active Treg cells. Second, influenza infection upregulated IFI6 in BAL cells and decreased their susceptibility to virus replication in vitro. Our data provide a reference map of porcine BAL cells and reveal lasting immunological consequences of influenza infection and respiratory immunization in a highly relevant large animal model for respiratory virus infection.

Ionic Liquid-Based Immunization Patch for the Transdermal Delivery of Antigens.

Herein, we report a transdermal patch prepared using an ionic liquid-based solid in oil (IL-S/O) nanodispersion and a pressure-sensitive adhesive (PSA) to deliver the macromolecular antigenic protein, ovalbumin (OVA). The IL-S/O nanodispersion and a PSA were first mixed at an equal weight ratio, then coated onto a release liner, and covered with a support film. To evaluate the effect of the PSA, three types of PSAs, DURO-TAK 87-4098, DURO-TAK 87-4287, and DURO-TAK 87-235A, were used to obtain the corresponding IL-S/O patches SP-4098, SP-4287, and SP-235A, respectively. The prepared IL-S/O patches were characterized for surface morphology, viscoelasticity, and moisture content. In vitro skin penetration and in vivo immunization studies of the IL-S/O patches were performed using Yucatan micropig skin and the C57BL/6NJc1 mice model, respectively. The SP-4098 and SP-4287 delivered 5.49-fold and 5.47-fold higher amounts of drug compared with the aqueous formulation. Although both patches delivered a similar amount of drug, SP-4287 was not detached fully from the release liner after 30 days, indicating low stability. Mice immunized with the OVA-containing SP-4098 produced a 10-fold increase in anti-OVA IgG compared with those treated with an aqueous formulation. These findings suggested that the IL-S/O patch may be a good platform for the transdermal delivery of antigen molecules.

Intranasal Immunization for Zika in a Pre-Clinical Model.

Humans continue to be at risk from the Zika virus. Although there have been significant research advancements regarding Zika, the absence of a vaccine or approved treatment poses further challenges for healthcare providers. In this study, we developed a microparticulate Zika vaccine using an inactivated whole Zika virus as the antigen that can be administered pain-free via intranasal (IN) immunization. These microparticles (MP) were formulated using a double emulsion method developed by our lab. We explored a prime dose and two-booster-dose vaccination strategy using MPL-A® and Alhydrogel® as adjuvants to further stimulate the immune response. MPL-A® induces a Th1-mediated immune response and Alhydrogel® (alum) induces a Th2-mediated immune response. There was a high recovery yield of MPs, less than 5 µm in size, and particle charge of -19.42 ± 0.66 mV. IN immunization of Zika MP vaccine and the adjuvanted Zika MP vaccine showed a robust humoral response as indicated by several antibodies (IgA, IgM, and IgG) and several IgG subtypes (IgG1, IgG2a, and IgG3). Vaccine MP elicited a balance Th1- and Th2-mediated immune response. Immune organs, such as the spleen and lymph nodes, exhibited a significant increase in CD4+ helper and CD8+ cytotoxic T-cell cellular response in both vaccine groups. Zika MP vaccine and adjuvanted Zika MP vaccine displayed a robust memory response (CD27 and CD45R) in the spleen and lymph nodes. Adjuvanted vaccine-induced higher Zika-specific intracellular cytokines than the unadjuvanted vaccine. Our results suggest that more than one dose or multiple doses may be necessary to achieve necessary immunological responses. Compared to unvaccinated mice, the Zika vaccine MP and adjuvanted MP vaccine when administered via intranasal route demonstrated robust humoral, cellular, and memory responses. In this pre-clinical study, we established a pain-free microparticulate Zika vaccine that produced a significant immune response when administered intranasally.

Individualized neoantigen peptide immunization of a metastatic pancreatic cancer patient: a case report of combined tumor and liquid biopsy.

This report details a case of pancreatic cancer with liver metastasis that exhibited a positive immune response to personalized immunization therapy. Our study involved the identification of neoantigens and their corresponding immunogenic peptides using an in-house bioinformatic pipeline. This process included the identification of somatic mutations through DNA/RNA sequencing of solid tumor tissue and blood liquid biopsy. Computational prediction techniques were then employed to identify novel epitopes, followed by the design and manufacture of patient-specific immunization peptides. In combination with standard-of-care chemotherapy, the patient received a sequence of 5 biweekly prime injections followed by 2 boost injections 2 and 5 months later. The peptides were emulsified in Montanide and the injection-site was conditioned with nivolumab and imiquimod. The combined regimen of peptide immunization and chemotherapy resulted in a notable decline in CA19-9 tumor marker levels following both prime and boost applications. Subsequent MRI assessments revealed a reduction in the size of liver metastases several months post-immunization initiation. Importantly, the patient showed and improved overall survival and reported an improved quality of life without experiencing significant treatment-related adverse effects. This case underscores the potential benefits of personalized peptide-based immunization as an adjunctive therapy in the treatment of advanced pancreatic cancer, showcasing promising outcomes in tumor marker reduction, tumor shrinkage, and enhanced patient well-being.

Inflammatory Profiles Induced by Intranasal Immunization with Ricin Toxin-immune Complexes.

The underlying contribution of immune complexes in modulating adaptive immunity in mucosal tissues remains poorly understood. In this report, we examined, in mice, the proinflammatory response elicited by intranasal delivery of the biothreat agent ricin toxin (RT) in association with two toxin-neutralizing mAbs, SylH3 and PB10. We previously demonstrated that ricin-immune complexes (RICs) induce the rapid onset of high-titer toxin-neutralizing Abs that persist for months. We now demonstrate that such responses are dependent on CD4+ T cell help, because treatment of mice with an anti-CD4 mAb abrogated the onset of RT-specific Abs following intranasal RICs exposure. To define the inflammatory environment associated with RIC exposure, we collected bronchoalveolar lavage fluid (BALF) and sera from mice 6, 12, and 18 h after they had received RT or RICs by the intranasal route. A 32-plex cytometric bead array revealed an inflammatory profile elicited by RT that was dominated by IL-6 (>1500-fold increase in BALF) and secondarily by KC (CXCL1), G-CSF, GM-CSF, and MCP-1. RICs induced inflammatory profiles in both BALF and serum response that were similar to RT, albeit at markedly reduced levels. These results demonstrate that RICs retain the capacity to induce local and systemic inflammatory cytokines/chemokines that, in turn, may influence Ag sampling and presentation in the lung mucosa and draining lymph nodes. A better understanding of the fate of immune complexes following intranasal delivery has implications for the development of mucosal vaccines for biothreats and emerging infectious diseases.

Mucoadhesive chitosan-catechol as an efficient vaccine delivery system for intranasal immunization.

The mucosal barrier and scavenging effect of the mucosal layer are two main obstacles in inducing mucosal immunization. To overcome these obstacles, we synthesized a bio-inspired mucoadhesive material, chitosan-catechol (ChiC), for surface modification of inactive porcine epidemic diarrhea virus (PEDV). Studies have revealed that PEDV particles can be facilely and mildly modified by Chi-C forming Chi-C-PEDV nanoparticles (Chic-Ps) through the covalent and electrostatic bond, which effectively prolongs the retention time of PEDV in the nasal mucosa. The cell co-culture model demonstrated that Chic-Ps exhibit enhanced recruitment of dendritic cells via the secretion of stimulating chemokine CCL20 and improving antigen permeability by disruption the distribution of ZO-1 protein in epithelial cells. Additionally, the flow cytometry (FCM) analysis revealed that Chic-Ps facilitate trafficking to lymph nodes and induce stronger cellular and humoral immune responses compared to unmodified PEDV. Notably, Chic-Ps induced a higher level of PEDV neutralizing antibody was induced by Chic-Ps in the nasal washes, as confirmed by a plaque reduction neutralization test. These results demonstrate that Chi-C is a promising nasal delivery system for vaccines. Proof of principle was obtained for inactivated PEDV, but similar delivery mechanisms could be applied in other vaccines when intranasal administration is needed.

Distal Immunization and Systemic Cytokines Establish a Transient Immune Alert State in the Intestine.

Conventionally, immune responses are studied in the context of inflamed tissues and their corresponding draining lymph nodes (LNs). However, little is known about the effects of systemic inflammatory signals generated during local inflammation on distal tissues and nondraining LNs. Using a mouse model of cutaneous immunization, we found that systemic inflammatory stimuli triggered a rapid and selective distal response in the small intestine and the mesenteric LN (mesLN). This consisted of increased permeability of intestinal blood vessels and lymphatic drainage of bloodborne solutes into the mesLN, enhanced activation and migration of intestinal dendritic cells, as well as amplified T cell responses in the mesLNs to systemic but not orally derived Ags. Mechanistically, we found that the small intestine endothelial cells preferentially expressed molecules involved in TNF-α signaling and that TNF-α blockade markedly diminished distal intestinal responses to cutaneous immunization. Together, these findings reveal that the intestinal immune system is rapidly and selectively activated in response to inflammatory cues regardless of their origin, thus identifying an additional layer of defense and enhanced surveillance of a key barrier organ at constant risk of pathogen encounter.