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Herpes simplex virus 2 (HSV2) causes genital herpes in >400 million persons worldwide. We conducted a randomized, double-blinded, placebo-controlled trial of a replication-defective HSV2 vaccine, HSV529. Twenty adults were enrolled in each of 3 serogroups of individuals: those negative for both HSV1 and HSV2 (HSV1-/HSV2-), those positive or negative for HSV1 and positive for HSV2 (HSV1±/HSV2+), and those positive for HSV1 and negative for HSV2 (HSV1+/HSV2-). Sixty participants received vaccine or placebo at 0, 1, and 6 months. The primary end point was the frequency of solicited local and systemic reactions to vaccination. Eighty-nine percent of vaccinees experienced mild-to-moderate solicited injection site reactions, compared with 47% of placebo recipients (95% confidence interval [CI], 12.9%-67.6%; P = .006). Sixty-four percent of vaccinees experienced systemic reactions, compared with 53% of placebo recipients (95% CI, -17.9% to 40.2%; P = .44). Seventy-eight percent of HSV1-/HSV2- vaccine recipients had a ≥4-fold increase in neutralizing antibody titer after 3 doses of vaccine, whereas none of the participants in the other serogroups had such responses. HSV2-specific CD4+ T-cell responses were detected in 36%, 46%, and 27% of HSV1-/HSV2-, HSV1±/HSV2+, and HSV1+/HSV2- participants, respectively, 1 month after the third dose of vaccine, and CD8+ T-cell responses were detected in 14%, 8%, and 18% of participants, respectively. HSV529 vaccine was safe and elicited neutralizing antibody and modest CD4+ T-cell responses in HSV-seronegative vaccinees. NCT01915212.

Purpose Talimogene laherparepvec (T-VEC) is an oncolytic immunotherapy designed to induce tumor regression of injected lesions through direct lytic effects, and of uninjected lesions through induction of systemic antitumor immunity. In this study, we describe the patterns and time course of response to T-VEC from the phase III OPTiM trial of 436 patients with unresected stages IIIB–IV melanoma. Methods Lesion-level response analyses were performed based on the type of lesion (injected or uninjected cutaneous, subcutaneous, or nodal lesions; or visceral lesions [uninjected]), and the best percentage change from baseline of the sum of products of the longest diameters was calculated. Patients randomized to T-VEC ( n  = 295) who experienced a durable response (continuous partial or complete response for ≥6 months) were evaluated for progression prior to response (PPR), defined as the appearance of a new lesion or >25 % increase in total baseline tumor area. Results T-VEC resulted in a decrease in size by ≥50 % in 64 % of injected lesions ( N  = 2116), 34 % of uninjected non-visceral lesions ( N  = 981), and 15 % of visceral lesions ( N  = 177). Complete resolution of lesions occurred in 47 % of injected lesions, 22 % of uninjected non-visceral lesions, and 9 % of visceral lesions. Of 48 patients with durable responses, 23 (48 %) experienced PPR, including 14 who developed new lesions only. No difference in overall survival was observed, and median duration of response was not reached in patients with PPR versus those without PPR. Conclusions Responses in uninjected lesions provide validation of T-VEC-induced systemic immunotherapeutic effects against melanoma. PPR did not negatively impact the clinical effectiveness of T-VEC.

In the HIV-1 vaccine trial RV144, ALVAC-HIV prime with an AIDSVAX® B/E boost reduced HIV-1 acquisition by 31% at 42 months post first vaccination. The bivalent AIDSVAX® B/E vaccine contains two gp120 envelope glycoproteins, one from the subtype B HIV-1 MN isolate and one from the subtype CRF01_AE A244 isolate. Each envelope glycoprotein harbors a highly conserved 27-amino acid HSV-1 glycoprotein D (gD) tag sequence that shares 93% sequence identity with the HSV-2 gD sequence. We assessed whether vaccine-induced anti-gD antibodies protected females against HSV-2 acquisition in RV144. Of the women enrolled in RV144, 777 vaccine and 807 placebo recipients were eligible and randomly selected according to their pre-vaccination HSV-1 and HSV-2 serostatus for analysis. Immunoglobulin G (IgG) and IgA responses to gD were determined by a binding antibody multiplex assay and HSV-2 serostatus was determined by Western blot analysis. Ninety-three percent and 75% of the vaccine recipients had anti-gD IgG and IgA responses two weeks post last vaccination, respectively. There was no evidence of reduction in HSV-2 infection by vaccination compared to placebo recipients over 78 weeks of follow-up. The annual incidence of HSV-2 infection in individuals who were HSV-2 negative at baseline or HSV-1 positive and HSV-2 indeterminate at baseline were 4.38/100 person-years (py) and 3.28/100 py in the vaccine and placebo groups, respectively. Baseline HSV-1 status did not affect subsequent HSV-2 acquisition. Specifically, the estimated odds ratio of HSV-2 infection by Week 78 for female placebo recipients who were baseline HSV-1 positive (n = 422) vs. negative (n = 1120) was 1.14 [95% confidence interval 0.66 to 1.94, p = 0.64)]. No evidence of reduction in the incidence of HSV-2 infection by vaccination was detected. AIDSVAX® B/E containing gD did not confer protection from HSV-2 acquisition in HSV-2 seronegative women, despite eliciting anti-gD serum antibodies.

Background. Previously we conducted a double-blind controlled, randomized efficacy field trial of gD-2 HSV vaccine adjuvanted with ASO4 in 8323 women. Subjects had been previously selected to be seronegative for HSV-1 and HSV-2. We found that vaccine was 82% protective against HSV-1 genital disease, but offered no significant protection against HSV-2 genital disease. Methods. To better understand the results of the efficacy study, post-vaccination anti-gD-2 antibody concentrations from all HSV infected subjects and matched uninfected controls were measured. Three models were used to determine whether these responses correlated with protection against HSV infection or disease. Similarly, cellular immune responses from a subset of subjects and matched controls were evaluated for a correlation with HSV protection. Results. Antibodies to gD-2 correlated with protection against HSV-1 infection with higher antibody concentration associated with higher efficacy. Cellular immune responses to gD-2 did not correlate with protection. Conclusions. The protection against HSV-1 infection observed in the Herpevac Trial for Women was associated with antibodies directed against the vaccine. Clinical Trials Registration. NCT00057330.

Few studies have evaluated the relationship between condom use and herpes simplex virus type 2 (HSV-2) and HSV type 1 (HSV-1) acquisition. To assess the relationship between condom use and acquisition of HSV-2 and HSV-1 among men and women. Analysis of data collected as part of a clinical trial of an ineffective candidate vaccine for HSV-2. Sexually transmitted disease clinics. Men and women at risk for HSV-2 acquisition, defined as having 4 or more sexual partners or having a sexually transmitted disease in the past year. Acquisition of HSV-2 and HSV-1 as measured by viral culture or change to positive HSV serostatus. Of 1843 participants, 118 (6.4%) became infected with HSV-2. In multivariate analyses, participants reporting more frequent use of condoms were at lower risk for acquiring HSV-2 than participants who used condoms less frequently (hazard ratio, 0.74 [95% CI, 0.59 to 0.95]); categories of increasing condom use were 0% to 25%, 25% to 75%, and greater than 75% of sexual acts. Nineteen (2.9%) of 659 participants at risk for infection with HSV-1 became infected. No statistically significant association between condom use and infection with HSV-1 was found (hazard ratio, 0.79 [CI, 0.48 to 1.31]). Use of condoms was measured by self-report, and persons who used condoms may have differed from those who did not. Consistent use of condoms is associated with lower rates of infection with HSV-2 and should be routinely recommended.

Immunotherapy failures can result from the highly suppressive tumour microenvironment that characterizes aggressive forms of cancer such as recurrent glioblastoma (rGBM) 1 , 2 . Here we report the results of a first-in-human phase I trial in 41 patients with rGBM who were injected with CAN-3110—an oncolytic herpes virus (oHSV) 3 . In contrast to other clinical oHSVs, CAN-3110 retains the viral neurovirulence ICP34.5  gene transcribed by a nestin promoter; nestin is overexpressed in GBM and other invasive tumours, but not in the adult brain or healthy differentiated tissue 4 . These modifications confer CAN-3110 with preferential tumour replication. No dose-limiting toxicities were encountered. Positive HSV1 serology was significantly associated with both improved survival and clearance of CAN-3110 from injected tumours. Survival after treatment, particularly in individuals seropositive for HSV1, was significantly associated with (1) changes in tumour/PBMC T cell counts and clonal diversity, (2) peripheral expansion/contraction of specific T cell clonotypes; and (3) tumour transcriptomic signatures of immune activation. These results provide human validation that intralesional oHSV treatment enhances anticancer immune responses even in immunosuppressive tumour microenvironments, particularly in individuals with cognate serology to the injected virus. This provides a biological rationale for use of this oncolytic modality in cancers that are otherwise unresponsive to immunotherapy (ClinicalTrials.gov: NCT03152318 ). Treatment with the oncolytic herpes virus CAN-3110 is associated with improved survival responses in patients with recurrent glioblastoma, particularly in individuals who are seropositive for HSV1.

Most cases of herpes simplex virus 1 (HSV-1) encephalitis (HSE) remain unexplained 1 , 2 . Here, we report on two unrelated people who had HSE as children and are homozygous for rare deleterious variants of TMEFF1 , which encodes a cell membrane protein that is preferentially expressed by brain cortical neurons. TMEFF1 interacts with the cell-surface HSV-1 receptor NECTIN-1, impairing HSV-1 glycoprotein D- and NECTIN-1-mediated fusion of the virus and the cell membrane, blocking viral entry. Genetic TMEFF1 deficiency allows HSV-1 to rapidly enter cortical neurons that are either patient specific or derived from CRISPR–Cas9-engineered human pluripotent stem cells, thereby enhancing HSV-1 translocation to the nucleus and subsequent replication. This cellular phenotype can be rescued by pretreatment with type I interferon (IFN) or the expression of exogenous wild-type TMEFF1 . Moreover, ectopic expression of full-length TMEFF1 or its amino-terminal extracellular domain, but not its carboxy-terminal intracellular domain, impairs HSV-1 entry into NECTIN-1-expressing cells other than neurons, increasing their resistance to HSV-1 infection. Human TMEFF1 is therefore a host restriction factor for HSV-1 entry into cortical neurons. Its constitutively high abundance in cortical neurons protects these cells from HSV-1 infection, whereas inherited TMEFF1 deficiency renders them susceptible to this virus and can therefore underlie HSE. A study of two childhood cases of herpes simplex encephalitis shows that TMEFF1 interacts with the HSV-1 cell-surface receptor NECTIN-1, preventing HSV-1 from fusing with the cell membrane and entering cortical neurons.

Herpes simplex virus type 1 (HSV-1) commonly causes orolabial ulcers, while HSV-2 commonly causes genital ulcers. However, HSV-1 is an increasing cause of genital infection. Previously, the World Health Organization estimated the global burden of HSV-2 for 2003 and for 2012. The global burden of HSV-1 has not been estimated. We fitted a constant-incidence model to pooled HSV-1 prevalence data from literature searches for 6 World Health Organization regions and used 2012 population data to derive global numbers of 0-49-year-olds with prevalent and incident HSV-1 infection. To estimate genital HSV-1, we applied values for the proportion of incident infections that are genital. We estimated that 3709 million people (range: 3440-3878 million) aged 0-49 years had prevalent HSV-1 infection in 2012 (67%), with highest prevalence in Africa, South-East Asia and Western Pacific. Assuming 50% of incident infections among 15-49-year-olds are genital, an estimated 140 million (range: 67-212 million) people had prevalent genital HSV-1 infection, most of which occurred in the Americas, Europe and Western Pacific. The global burden of HSV-1 infection is huge. Genital HSV-1 burden can be substantial but varies widely by region. Future control efforts, including development of HSV vaccines, should consider the epidemiology of HSV-1 in addition to HSV-2, and especially the relative contribution of HSV-1 to genital infection.

Stimulator of interferon genes (STING) is essential for the type I interferon response against DNA pathogens. In response to the presence of DNA and/or cyclic dinucleotides, STING translocates from the endoplasmic reticulum to perinuclear compartments. However, the role of this subcellular translocation remains poorly defined. Here we show that palmitoylation of STING at the Golgi is essential for activation of STING. Treatment with palmitoylation inhibitor 2-bromopalmitate (2-BP) suppresses palmitoylation of STING and abolishes the type I interferon response. Mutation of two membrane-proximal Cys residues (Cys88/91) suppresses palmitoylation, and this STING mutant cannot induce STING-dependent host defense genes. STING variants that constitutively induce the type I interferon response were found in patients with autoimmune diseases. The response elicited by these STING variants is effectively inhibited by 2-BP or an introduction of Cys88/91Ser mutation. Our results may lead to new treatments for cytosolic DNA-triggered autoinflammatory diseases. STING is essential for the type I interferon immune response to foreign DNA. Here, the authors show that palmitoylation of STING at the Golgi is required for activating downstream signalling, and increased Golgi localization of certain STING variants may cause autoimmune disease in some cases.

Long-lived tissue-resident memory T cells (T RM cells) confer fast, robust protection after pathogen rechallenge. Gebhardt and colleagues show that skin T RM cells arise from KLRG1 – cells that differentiate in situ in response to IL-15 and TGF-β. Tissue-resident memory T cells (T RM cells) provide superior protection against infection in extralymphoid tissues. Here we found that CD103 + CD8 + T RM cells developed in the skin from epithelium-infiltrating precursor cells that lacked expression of the effector-cell marker KLRG1. A combination of entry into the epithelium plus local signaling by interleukin 15 (IL-15) and transforming growth factor-β (TGF-β) was required for the formation of these long-lived memory cells. Notably, differentiation into T RM cells resulted in the progressive acquisition of a unique transcriptional profile that differed from that of circulating memory cells and other types of T cells that permanently reside in skin epithelium. We provide a comprehensive molecular framework for the local differentiation of a distinct peripheral population of memory cells that forms a first-line immunological defense system in barrier tissues.