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The US National Institute of Allergy and Infectious Diseases (NIAID) convened a virtual workshop in July 2022 to address the research landscape and identify gaps and opportunities in the understanding of durable vaccine protection.

A June 2007 meeting of immunologists in Crete focused on the intricate interconnections between the innate and adaptive immune systems and their implications for host defense against pathogens.

The worlds of innate and adaptive immunity collided pleasantly and productively as investigators from each field met in Mykonos for the 4^th Aegean Conference on the Crossroads Between Innate and Adaptive Immunity.

Bali Pulendran provides a historical overview of the development of the successful yellow fever vaccine. He describes recent advancements in our understanding of its mechanisms of action resulting from the use of systems biological approaches and how this knowledge might be applicable to vaccine development in general.

Longitudinal metatranscriptomics in a prospective cohort of 1,164 adults hospitalized for COVID-19 reveals that azithromycin offered no apparent anti-inflammatory benefit but enriched the respiratory microbiome with potential pathogens and antimicrobial resistance genes.

Bali Pulendran and his colleagues explore ways that signaling through different pathogen receptors can program dendritic cells (DCs) to orchestrate inflammatory or tolerogenic immune responses. The yeast component zymosan triggers signaling through both Toll-like receptor 2 (TLR2) and the C-type lectin dectin-1. In the absence of TLR2, zymosan induces proinflammatory responses through dectin-1. But TLR2 triggering induces DCs to form the vitamin A–metabolizing enzyme Raldh2. The DCs can then form retinoic acid that acts in an autocrine manner on the DCs, programming them for the induction of regulatory T cell responses.

Pulendran and colleagues define a molecular signature that can be used to predict the durability of antibody responses to vaccination and reveal important insights into the mechanisms by which vaccines induce durable immunity.

Pulendran and colleagues perform a comparative analysis of transcriptional responses of healthy young adults across 13 different vaccines. They find that while a common transcriptional program is shared across many vaccines, there is significant heterogeneity especially in the kinetics of immune responses.

Pulendran and colleagues delineated the mechanisms underlying the nonspecific antiviral effects exerted by the BCG vaccine against SARS-CoV-2 and reveal a pivotal role for BCG-specific CD4⁺ T cells that produce interferon-γ in imprinting a persistent antiviral innate program in the lung, mediating heterologous viral protection.

Here it is shown that nanoparticles containing two Toll-like receptor ligands can boost the magnitude and persistence of vaccine-elicited antibody responses in primates, improving vaccine-mediated protection against influenza virus.

The mammalian target of rapamycin pathway regulates many essential cellular responses. Pulendran and colleagues show that this pathway is required for Toll-like receptor–mediated production of type I interferon by plasmacytoid dendritic cells.

The mechanisms that initiate T helper type 2 responses are poorly understood. Pulendran and colleagues now show that such responses to cysteine proteases require dendritic cell–basophil cooperation via signaling mediated by reactive oxygen species.

The search is on for for vaccine adjuvants that boost the innate immune response and complement existing adjuvants. Mast cell activators may be one option (pages 536–541).

Regulatory T cells that express the transcription factor Foxp3 are pivotal in suppressing autoimmune responses. A report in this issue describes a key role for interleukin 10 produced by lamina propria macrophages in maintaining Foxp3 expression during inflammatory responses in the intestine.

Cross-presentation of antigens is essential for the responses of cytotoxic T cells to tumors and viruses. Two new papers offer insights into the subcellular compartment and types of dendritic cells that mediate cross-presentation.

A major challenge for vaccinologists is to understand vaccine immunogenicity. Pulendran and colleagues use systems biology to determine gene 'signatures' that predict CD8⁺ T cell and antibody responses to the yellow fever vaccine.

Identifying molecular predictors of effective vaccination is an important clinical and technical goal. Pulendran and colleagues use a systems biology approach to study human responses to vaccination against influenza and determine the correlates of immunogenicity.

Pulendran and colleagues use a systems biology analysis to reveal distinct transcriptional signatures of antibody responses to different classes of human vaccines.

Antibiotic exposure in early life disrupts the infant microbiome, dampens vaccine responses and alters immune programming. Restoring Bifidobacterium may offer a microbiota-targeted strategy to enhance vaccine efficacy in vulnerable populations.

An HIV vaccine that elicits both antibodies and cellular immune responses confers long-lasting protection against viral challenge in nonhuman primates.

Post-acute sequelae of SARS-CoV-2 (PASC) is still not well understood. Here the authors provide patient reported outcomes from 590 hospitalized COVID-19 patients and show association of PASC with higher respiratory SARS-CoV-2 load and circulating antibody titers, and in some an elevation in circulating fibroblast growth factor 21.

Here the authors develop a ferritin-based protein nanoparticle vaccine candidate for SARS-CoV-2, and show induction of neutralizing antibodies to variants of concern, including Omicron BQ.1, in non-human primates after initial immunization and a booster dose.

Profiling the immune responses of 56 volunteers vaccinated with BNT162b2 reveals how this mRNA vaccine primes the innate immune system to mount a potent response to SARS-CoV-2 after booster immunization.

Adjuvants provide additional impetus for the immune response to vaccination regimens, however their modes of activity and impact on particular compartments of the immune response are currently not well understood. Here the authors perform high resolution assessment of the immune response to a well-established vaccination model and show innate immune transcriptomic and epigenomic alterations of innate cells in the lymph nodes following vaccination.

Trials in rhesus macaques show that a subunit vaccine against SARS-CoV-2, comprising the spike protein receptor-binding domain displayed on a nanoparticle protein scaffold, produces a robust protective response against the virus.

A new design for vaccines consisting of reorienting the viral glycoprotein in an ‘upside-down’ configuration broadens immune responses to diverse influenza subtypes and serves as a proof of concept for designing a universal flu vaccine.

Here I propose the ‘Creation Game’, inspired by the Turing test, to assess the capacity of artificial intelligence for human-like creativity, focusing on its potential for scientific discovery about the human immune system in the field of systems vaccinology.

The route of vaccine administration is known to effect the induction of immune response and the quality of such immunity. Here the authors show that intradermal but not intramuscular vaccination using live-attenuated vaccinia-based SHIV vaccine confers protection in the SHIV model in female macaques and characterise the induced immune response.

The regulatory protein SREBP is required for CD8⁺ T cell metabolic reprogramming after activation. Luo et al. demonstrate that stimulated B cells require SCAP, a regulator of SREBP, for metabolic reprogramming and the formation and maintenance of germinal center B cells.

A nanoparticle-based adjuvant incorporating a Toll-like receptor 7 agonist elicits cross-reactive antibodies for both dominant and subdominant epitopes and enhances immune responses against multiple variants of influenza and SARS-CoV-2.

How mRNA-based coronavirus disease 2019 vaccines drive immune responses is not clear. Here the authors characterize immune responses to the BNT162b2 vaccine in mice, and show how it stimulates innate immunity, with antigen-specific CD8⁺ T cell responses dependent on the RNA sensor MDA5.

B lymphocytes can regulate dendritic cell (DC) functions, but the extent of this regulation and the functional outcomes have not been fully established. Here, the authors show that direct interaction with activated B cells induces maturation of DCs, driving the differentiation of T cells towards the Th2 subset.

Considering immune responses through the framework of ‘integrated organ immunity’ could enable the design of a new class of universal vaccines.

Solid organ transplant recipients are at increased risk of infectious disease and have unique molecular pathophysiology. Here the authors use host-microbe profiling to assess SARS-CoV-2 infection and immunity in solid organ transplant recipients, showing enhanced viral abundance, impaired clearance, and increased expression of innate immunity genes.

The role of IgG glycosylation in the immune response has been studied, but less is known about IgM glycosylation. Here the authors characterize glycosylation of SARS-CoV-2 spike specific IgM and show that it correlates with COVID-19 severity and affects complement deposition.

Jayavelu, Samaha et al., apply machine learning models on hospital admission data, including antibody titers and viral load, to identify patients at high risk for Long COVID. Low antibody levels, high viral loads, chronic diseases, and female sex are key predictors, supporting early, targeted interventions.

Cooperation between dendritic cell subtypes and a newly identified function for interleukin 15 demonstrate the complexity surrounding the initial events required for effective antipathogen immunity.