Introduction Immunosuppression is associated with an increased risk of delayed SARS-CoV-2 viral clearance, severe COVID-19 and related death. This heterogeneous group of affected patients includes but is not limited to those with a haematological malignancy, people on immunosuppressive therapy for the treatment of autoimmune/inflammatory diseases and those following bone marrow transplantation (BMT). Immunosuppression is associated with decreased rates of anti-spike IgG seroconversion following COVID-19 vaccination. While clinical guidelines have been established to guide vaccination pre-splenectomy and post-BMT, there are limited data to guide timing of COVID-19 or other booster vaccines in adults commencing new or intensified moderate to severe immunosuppression. The comparison of immunity-boosting regimens for COVID-19 upon initiation of immunosuppressive therapy (CIRCUIT) study was designed to address this knowledge gap. CIRCUIT investigates whether administration of a third (or subsequent) COVID-19 booster vaccine ≤2 weeks prior to immunosuppression provides greater anti-spike IgG-mediated immunity than a booster given 24 weeks after new or intensified immunosuppression, that is, week 24 timepoint (Group 1; n=280). Additionally, the research will investigate whether giving a fourth post-BMT COVID-19 booster vaccine at 9 months post-transplant provides greater anti-spike IgG-mediated immunity than a booster given 15 months post-transplant (Group 2; n=40).Methods and analysis The CIRCUIT study is an open-label, multicentre randomised clinical trial. Participants will be randomised 1:1 to receive either an additional COVID-19 booster ≤2 weeks pre-immunosuppression and a diphtheria/tetanus toxoids (DT) booster at 24 weeks following new or intensified immunosuppression (week 24 timepoint) or receive a DT booster ≤2 weeks pre-immunosuppression and an additional COVID-19 booster at week 24 (Group 1). Group 2 participants who underwent autologous or allogenic BMT in the last 9 months will be randomised 1:1 to either receive a fourth post-BMT COVID-19 booster at 9 or 15 months post-transplant. The primary outcome will be the integrated time-weighted area under the curve anti-SARS-CoV-2 neutralising antibody (NAb) response over 12 months from a SARS-CoV-2 booster as assessed by a high-throughput SARS-CoV-2 NAb platform assay. Key secondary outcomes of the CIRCUIT randomised control trial will include safety and generation of SARS-CoV-2 antigen specific T and B cell responses.Ethics and dissemination The research protocol was approved by the Western Sydney Local Health District Human Research Ethics Committee on 25 August 2022 (Ref no. 2022/PID00782 – 20022/ETH0069). Study results will be published in peer-reviewed medical journals and presented at local and international conferences. All findings regardless of the outcome will be reported.Trial registration number NCT05415267.

Dendritic cells (DCs) are potent antigen-presenting cells and play a key role in facilitating the sexual transmission of HIV, functioning as a delivery system responsible for trafficking the virus from exposed barrier sites to their key target cells, CD4 T cells. Although the role of DCs in HIV transmission is well established, the recent advent of high-parameter, single-cell detection technologies, coupled with improved cell isolation techniques, has led to the rapid reclassification of the DC landscape, particularly within human barrier tissues. The identification of new subsets introduces the challenge of incorporating previously understood transmission principles with new, cell-specific, functional nuances to identify the key DCs responsible for facilitating HIV infection. This review explores the history of research linking DCs with HIV transmission as well as our understanding of how HIV manipulates DC biology to achieve this purpose. Furthermore, it provides an up-to-date understanding of the antigen-presenting cell landscape within human anogenital tissues and how each subset contributes to sexual transmission. Uncovering the cells and biological processes responsible for the sexual transmission of HIV is a fundamental step in the pursuit of an HIV vaccine and better prophylaxis to block infection.

Herpes zoster (HZ) is increasingly common in the aging and is experienced by approximately one in three people in their lifetime. It is also relatively common in immune-compromised people. Acute HZ causes severe pain, reduced quality of life and severe complications, including prolonged pain, or postherpetic neuralgia (PHN), and ocular zoster, which may rarely progress to blindness. In severely immune-compromised people disseminated zoster may affect the brain and liver. A second-generation vaccine, the Recombinant Zoster Vaccine, consisting of recombinant viral glycoprotein E and the Adjuvant System 01 (AS01B), now offers >90% efficacy against HZ and associated complications in immune-competent people. Efficacy persists above 80% for 11 years. In severely immune-compromised patients, the vaccine is safe with efficacy and/or immunogenicity of 68-87%. There is also excellent immunogenicity for those on JAK inhibitors and corticosteroid therapy. The vaccine offers a paradigm for successful and durable immunization in the aging and immune-compromised.

Objective To evaluate the immunogenicity of adjuvanted recombinant zoster vaccine (RZV) in patients with rheumatoid arthritis receiving upadacitinib 15 mg once daily (QD) with background methotrexate.Methods Eligible patients in SELECT-COMPARE (NCT02629159) receiving upadacitinib 15 mg QD and background methotrexate received RZV at weeks 0 and 12. Antibody titres were collected at weeks 0, 4, 16 and 60 (prevaccination, 4 weeks after first dose, and 4 and 48 weeks after second dose). The primary endpoint was the proportion of patients achieving a satisfactory humoral response to RZV at week 16 (≥ 4-fold increase in prevaccination anti-glycoprotein E (gE) antibody titres). Cell-mediated immune (CMI) response to RZV (≥ 2-fold increase in prevaccination gE-specific CD4+ [2+] T-cell frequency) was assessed at each time point in a subcohort of 38 patients. Safety was assessed for 30 days after each vaccination.Results Overall, 93 patients received both RZV doses (78.5% female; mean age, 62.4 years). At baseline, 49.5% used concomitant corticosteroids (median daily dose, 5.0 mg). Satisfactory humoral responses to RZV were observed in 87.8% (95% CI 81.0 to 94.5) of patients at week 16. Age and concomitant corticosteroid use did not affect RZV antibody response. Over 60% of patients achieved a CMI response to RZV at all time points. No serious adverse events were reported. One patient developed herpes zoster 4 months after the second RZV dose.Conclusions Most patients receiving upadacitinib 15 mg QD with background methotrexate achieved satisfactory humoral and CMI responses 4 weeks after the second RZV vaccination (week 16).

Herpes Keratitis (HK) is a debilitating infection of the cornea that remains the leading cause of infectious blindness in developed countries. Caused primarily by herpes simplex virus type 1 (HSV-1), it is associated with recurrent inflammation, leading to corneal scarring. This study investigated the initial events during acute HSV-1 infection in the cornea by adapting our human anogenital mucosal explant model to a HSV-1 infected porcine corneal explant model. We infected these corneas topically via high-density microarray patches (HD-MAPs) dipped in GFP-labelled HSV-1. Virus infection and spread was detected by both GFP protein and RNAscope, adapted for HSV-1 DNA. The punctures were consistent, usually in the epithelium but some extended into the underlying stroma. However, HSV-1 was restricted to the corneal epithelium, without spread through the anterior limiting membrane (ALM) or Bowman's layer into the stroma nor to the uppermost epithelial layer. This layer expressed SPRR1A similarly to the stratum granulosum of skin which is refractory to HSV-1 infection. In corneas where infected epithelial cells extended to the ALM, SPRR1A was also observed in this layer, suggesting it may contribute to its barrier function. Such studies of HSV-1 infection and spread will help improve therapy for HK and vaccine design to prevent it.

Anogenital inflammation is a critical risk factor for HIV acquisition. The primary preventative HIV intervention, pre-exposure prophylaxis (PrEP), is ineffective in blocking transmission in anogenital inflammation. Pre-existing sexually transmitted diseases (STIs) and anogenital microbiota dysbiosis are the leading causes of inflammation, where inflammation is extensive and often asymptomatic and undiagnosed. Dendritic cells (DCs), as potent antigen-presenting cells, are among the first to capture HIV upon its entry into the mucosa, and they subsequently transport the virus to CD4 T cells, the primary HIV target cells. This increased HIV susceptibility in inflamed tissue likely stems from a disrupted epithelial barrier integrity, phenotypic changes in resident DCs and an influx of inflammatory HIV target cells, including DCs and CD4 T cells. Gaining insight into how HIV interacts with specific inflammatory DC subsets could inform the development of new therapeutic strategies to block HIV transmission. However, little is known about the early stages of HIV capture and transmission in inflammatory environments. Here, we review the currently characterised inflammatory-tissue DCs and their interactions with HIV.

HIV infection implicates a spectrum of tissues in the human body starting with viral transmission in the anogenital tract and subsequently persisting in lymphoid tissues and brain. Though studies using isolated cells have contributed significantly towards our understanding of HIV infection, the tissue microenvironment is characterised by a complex interplay of a range of factors, all of which can influence the course of infection but are otherwise missed in ex vivo studies. To address this knowledge gap, it is necessary to investigate the dynamics of infection and the host immune response in situ using imaging-based approaches. Over the last decade, emerging imaging techniques have continually redefined the limits of detection, both in terms of the scope and the scale of the targets. In doing so, this has opened up new questions that can be answered by in situ studies. This review discusses the high-dimensional imaging modalities that are now available and their application towards understanding the spatial biology of HIV infection.

Herpes zoster (HZ, Shingles) is a vaccine-preventable viral disease impacting patients’ quality of life owing to pain and rash. An estimated 15 million HZ cases occur annually in individuals aged ≥ 50 years worldwide. Recombinant zoster vaccine (RZV) is effective in protecting against HZ. This is the first study evaluating the potential incremental public health benefits in terms of HZ cases averted worldwide by vaccinating adults aged ≥ 50 years with RZV. A previously published static multi-cohort Markov model with an annual cycle length and lifetime horizon was used for all analyses. Demographic data depicting populations on 31 December 2023, and age–sex specific mortality rates by region were sourced from United Nations (2022). HZ incidence rates were informed from a recent meta-regression analysis of global HZ burden (Asia, Europe, Northern America, Oceania, and worldwide). RZV efficacy and waning modelling was based on 11-year clinical trial follow-up data [NCT02723773]. Assuming 70

Background Herpes zoster (HZ) vaccines should provide durable protection against HZ and HZ-related complications. We report the final analysis of a long-term follow-up (LTFU) study (ZOE-LTFU) including 11 years of follow-up after primary vaccination with recombinant zoster vaccine (RZV). Methods ZOE-LTFU (NCT02723773) was an open-label, phase 3b study following participants of two phase 3 trials, ZOE-50 and ZOE-70. ZOE-LTFU started approximately 5 years post-vaccination in ZOE-50/70 and participants were followed for 6 years. The primary objective was to assess vaccine efficacy (VE) against HZ during ZOE-LTFU. Secondary objectives included VE against HZ from 1 month post-dose 2 in ZOE-50/70 until end of ZOE-LTFU, VE against post-herpetic neuralgia (PHN) and non-PHN complications, immunogenicity, and long-term safety. The VE calculation used a historical control constructed with ZOE-50/70 placebo data. Findings VE was assessed in the modified total vaccinated cohort (n = 7273 [mean age 67·3 years at first vaccination]). During ZOE-LTFU, VE was 79·8% (95% confidence interval [CI]: 73·7, 84·6) and 73·2% (95% CI: 62·9, 80·9) against HZ in participants ≥50 and ≥70 years at first vaccination, respectively, and was 87·5% (95% CI: 64·8, 96·8) against PHN and 91·7% (95% CI: 43·7, 99·8) against other HZ-related complications in participants ≥50 years. From 1 month post-dose 2 in ZOE-50/70 to the end of ZOE-LTFU, VE against HZ was 87·7% (95% CI: 84·9, 90·1) in participants ≥50 years and sustained at 82·0% (95% CI: 63·0, 92·2) in the eleventh year post-vaccination. Humoural and cell-mediated immune responses plateaued at over 5-fold and ∼7-fold, respectively, above pre-vaccination levels in ZOE-50/70. No RZV-related serious adverse events occurred. Interpretation Efficacy of RZV against HZ and associated complications remained high through 11 years post-vaccination, indicating sustained clinical benefit. Funding The funder of the study was GSK who was involved in study design, data collection, data analysis, data interpretation, writing of the report, and the decision to submit for publication.

Herpes zoster (HZ) is caused by reactivation of latent infection of varicella zoster virus (VZV) in sensory (cranial, dorsal root) ganglia. Major risk factors for HZ are increasing age and immunosuppression. HZ ophthalmicus (HZO) is a subset of HZ with involvement of the ophthalmic division of the fifth cranial trigeminal nerve. Approximately 4–20

AXL+ Siglec-6+ dendritic cells (ASDC) are novel myeloid DCs which can be subdivided into CD11c+ and CD123+ expressing subsets. We showed for the first time that these two ASDC subsets are present in inflamed human anogenital tissues where HIV transmission occurs. Their presence in inflamed tissues was supported by single cell RNA analysis of public databases of such tissues including psoriasis diseased skin and colorectal cancer. Almost all previous studies have examined ASDCs as a combined population. Our data revealed that the two ASDC subsets differ markedly in their functions when compared with each other and to pDCs. Relative to their cell functions, both subsets of blood ASDCs but not pDCs expressed co-stimulatory and maturation markers which were more prevalent on CD11c+ ASDCs, thus inducing more T cell proliferation and activation than their CD123+ counterparts. There was also a significant polarisation of naïve T cells by both ASDC subsets toward Th2, Th9, Th22, Th17 and Treg but less toward a Th1 phenotype. Furthermore, we investigated the expression of chemokine receptors that facilitate ASDCs and pDCs migration from blood to inflamed tissues, their HIV binding receptors, and their interactions with HIV and CD4 T cells. For HIV infection, within 2 hours of HIV exposure, CD11c+ ASDCs showed a trend in more viral transfer to T cells than CD123+ ASDCs and pDCs for first phase transfer. However, for second phase transfer, CD123+ ASDCs showed a trend in transferring more HIV than CD11c+ ASDCs and there was no viral transfer from pDCs. As anogenital inflammation is a prerequisite for HIV transmission, strategies to inhibit ASDC recruitment into inflamed tissues and their ability to transmit HIV to CD4 T cells should be considered.

Herpes simplex virus (HSV) is sexually transmitted via the anogenital mucosa where it initially infects epidermal keratinocytes and mononuclear phagocytes (MNPs). It then spreads to the dorsal root ganglion via sensory nerve endings, to remain latent for life with periodic reactivation. Currently, there is no cure or vaccine. Initial or recurrent HSV infection can produce serious complications and mediate acquisition of HIV. This review outlines the initial events after the HSV infection of human anogenital mucosa to determine the optimal window to target the virus before it becomes latent. After infection, HSV spreads rapidly within the mid-layers of epidermal keratinocytes in the explanted human inner foreskin. Infected cells produce chemokines, which modulate nectin-1 distribution on the surface of adjacent keratinocytes, facilitating viral spread. Epidermal Langerhans cells and dendritic cells become infected with HSV followed by a “viral relay” to dermal MNPs, which then present viral antigen to T cells in the dermis or lymph nodes. These data indicate the need for interruption of spread within 24 h by diffusible vaccine-induced mediators such as antiviral cytokines from resident immune cells or antibodies. Intradermal/mucosal vaccines would need to target the relevant dermal MNPs to induce HSV-specific CD4+ and CD8+ T cells.

BACKGROUND:Current literature informs us that bivalent vaccines will generate a broader serum neutralizing antibody response to multiple SARS-CoV-2 variants, but studies on how this breadth relates to the memory B cell (MBC) and T cell responses are sparse. This study compared breadth of neutralising antibody, and memory B and T cell responses to monovalent or a bivalent ancestral/Omicron BA.1 COVID-19 booster vaccine. METHODS:At baseline and 1-month post-booster, neutralisation activity and frequencies of receptor binding domain (RBD)-specific MBCs and Spike-specific memory T cells were measured against a panel of variants. FINDINGS:Both vaccines boosted neutralising antibodies to 5 variants - Wuhan-Hu-1, Delta, BA.1, BA.5 and JN.1, the latter of which had not yet emerged at the time of sample collection. The bivalent vaccine induced a significantly larger increase in nAb against BA.1 and JN.1. Both vaccines boosted RBD-specific MBC responses to Wuhan-Hu-1, Delta, BA.1 and BA.5 variants with a significantly greater increase for BA.1 in the bivalent group. The breadth of MBCs was significantly higher in those who received the bivalent boost and correlated with nAb breadth. Both vaccines significantly boosted Spike-specific T cell responses to the Wuhan-Hu-1 and BA.5 variants, but only the bivalent vaccine boosted BA.1 responses. INTERPRETATION:These results suggest that the bivalent vaccine confers an advantage against future novel variants due to increased frequency of broadly reactive RBD-specific B cells. FUNDING:Work supported by NSW Health for the NSW Vaccine, Infection and Immunology Collaborative (VIIM).

Most individuals are latently infected with herpes simplex virus type 1 (HSV-1) and it is well-established that HSV-1 establishes latency in sensory neurons of peripheral ganglia. However, it was recently proposed that latent virus is also present in immune cells recovered from ganglia in a mouse model used for studying latency. Here, we reanalyzed the single-cell RNA sequencing (scRNA-Seq) data that formed the basis for this conclusion. Unexpectedly, off-target priming in 3' scRNA-Seq experiments enabled the detection of non-polyadenylated HSV-1 latency-associated transcript (LAT) intronic RNAs. However, LAT reads were nearexclusively detected in a mixed population of cells undergoing cell death. Specific loss of HSV1 LAT and neuronal transcripts during quality control filtering indicated widespread destruction of neurons, supporting the presence of contaminating cell-free RNA in other cells following tissue processing. In conclusion, the reported detection of latent HSV-1 in non-neuronal cells is best explained by inaccuracies in the data analyses.

In this article, we discuss a recently published article that demonstrated a novel way of identifying viral pathogens reactivating in human cells to be used as cellular therapy, in this instance chimeric antigen receptor (CAR) T cells. The authors used search engines and databases to identify viruses able to reactivate in T cells and then tested this initially in T-cell cultures, specifically human herpesvirus 6. This virus was then shown to reactivate infrequently in vitro and in vivo in CAR T cells as a consequence of T-cell activation. The methodology may be most clinically useful for more frequently reactivating viruses in other types of cellular therapy such as allogenic CAR T cells or induced pluripotent stem cells.

Vaccine adjuvants are thought to work by stimulating innate immunity in the draining lymph node (LN), although this has not been proven in humans. To bridge the data obtained in animals to humans, we have developed an in situ human LN explant model to investigate how adjuvants initiate immunity. Slices of explanted LNs were exposed to vaccine adjuvants and revealed responses that were not detectable in LN cell suspensions. We used this model to compare the liposome-based AS01 with its components, monophosphoryl lipid A (MPL) and QS-21, and TLR ligands. Liposomes were predominantly taken up by subcapsular sinus-lining macrophages, monocytes, and DCs. AS01 induced DC maturation and a strong proinflammatory cytokine response in intact LN slices but not in dissociated cell cultures, in contrast to R848. This suggests that the onset of the immune response to AS01 required a coordinated activation of LN cells in time and space. Consistent with the robust immune response observed in older adults with AS01-adjuvanted vaccines, the AS01 response in human LNs was independent of age, unlike the response to R848. This human LN explant model is a valuable tool for studying the mechanism of action of adjuvants in humans and for screening new formulations to streamline vaccine development.

Summary:The coronavirus disease 2019 (COVID-19) pandemic has highlighted that preparedness for and responsiveness to pandemics requires public health platforms and processes which are nimble and evidence-based and a research ecosystem which is rapidly responsive to the evolving needs of society and decision-makers. The national BEAT COVID-19 research consortium was funded in 2020 by the Snow Medical Research Foundation (Snow Medical). Its Expert Advisory Committee met with the consortium post-pandemic to summarise the research undertaken and to consider lessons learned through the research response to COVID-19 in Australia. The panel observed that philanthropy offered an important 'kick-starter' funding mechanism for urgent research, which facilitated leveraging of additional funds. It further agreed that research requirements for strengthening Australia's pandemic preparedness and response include: (1) development of a national health and medical research strategy for pandemic research; (2) long-term investment in pre-established research partnerships and networks; (3) systemic procedural improvements, e.g. in ethics, governance and resource allocation; (4) responsive funding mechanisms including philanthropy; and (5) integration of research outputs into health practice and decision-making, as illustrated in Figure 1.

Next-generation vaccines may be delivered via the skin and mucosa. The stratified squamous epithelium (SSE) represents the outermost layer of the skin (epidermis) and type II mucosa (epithelium). Langerhans cells (LCs) have been considered the sole antigen-presenting cells (APCs) to inhabit the SSE; however, it is now clear that dendritic cells (DCs) are also present. Importantly, there are functional differences in how LCs and DCs take up and process pathogens as well as their ability to activate and polarize T cells, though whether DCs participate in neuroimmune interactions like LCs is yet to be elucidated. A correct definition and functional characterization of APCs in the skin and anogenital tissues are of utmost importance for the design of better vaccines and blocking pathogen transmission. Here, we provide a historical perspective on the evolution of our understanding of the APCs that inhabit the SSE, including a detailed review of the most recent literature.