Monkeypox Virus Infection in Humans across 16 Countries - April-June 2022.

BACKGROUND: Before April 2022, monkeypox virus infection in humans was seldom reported outside African regions where it is endemic. Currently, cases are occurring worldwide. Transmission, risk factors, clinical presentation, and outcomes of infection are poorly defined. METHODS: We formed an international collaborative group of clinicians who contributed to an international case series to describe the presentation, clinical course, and outcomes of polymerase-chain-reaction-confirmed monkeypox virus infections. RESULTS: We report 528 infections diagnosed between April 27 and June 24, 2022, at 43 sites in 16 countries. Overall, 98% of the persons with infection were gay or bisexual men, 75% were White, and 41% had human immunodeficiency virus infection; the median age was 38 years. Transmission was suspected to have occurred through sexual activity in 95% of the persons with infection. In this case series, 95% of the persons presented with a rash (with 64% having ≤10 lesions), 73% had anogenital lesions, and 41% had mucosal lesions (with 54 having a single genital lesion). Common systemic features preceding the rash included fever (62%), lethargy (41%), myalgia (31%), and headache (27%); lymphadenopathy was also common (reported in 56%). Concomitant sexually transmitted infections were reported in 109 of 377 persons (29%) who were tested. Among the 23 persons with a clear exposure history, the median incubation period was 7 days (range, 3 to 20). Monkeypox virus DNA was detected in 29 of the 32 persons in whom seminal fluid was analyzed. Antiviral treatment was given to 5% of the persons overall, and 70 (13%) were hospitalized; the reasons for hospitalization were pain management, mostly for severe anorectal pain (21 persons); soft-tissue superinfection (18); pharyngitis limiting oral intake (5); eye lesions (2); acute kidney injury (2); myocarditis (2); and infection-control purposes (13). No deaths were reported. CONCLUSIONS: In this case series, monkeypox manifested with a variety of dermatologic and systemic clinical findings. The simultaneous identification of cases outside areas where monkeypox has traditionally been endemic highlights the need for rapid identification and diagnosis of cases to contain further community spread.

Detection of respiratory syncytial virus defective genomes in nasal secretions is associated with distinct clinical outcomes.

Respiratory syncytial virus (RSV) causes respiratory illness in children, immunosuppressed individuals and the elderly. However, the viral factors influencing the clinical outcome of RSV infections remain poorly defined. Defective viral genomes (DVGs) can suppress virus replication by competing for viral proteins and by stimulating antiviral immunity. We studied the association between detection of DVGs of the copy-back type and disease severity in three RSV A-confirmed cohorts. In hospitalized children, detection of DVGs in respiratory samples at or around the time of admission associated strongly with more severe disease, higher viral load and a stronger pro-inflammatory response. Interestingly, in experimentally infected adults, the presence of DVGs in respiratory secretions differentially associated with RSV disease severity depending on when DVGs were detected. Detection of DVGs early after infection associated with low viral loads and mild disease, whereas detection of DVGs late after infection, especially if DVGs were present for prolonged periods, associated with high viral loads and severe disease. Taken together, we demonstrate that the kinetics of DVG accumulation and duration could predict clinical outcome of RSV A infection in humans, and thus could be used as a prognostic tool to identify patients at risk of worse clinical disease.

Neutrophilic inflammation in the respiratory mucosa predisposes to RSV infection.

The variable outcome of viral exposure is only partially explained by known factors. We administered respiratory syncytial virus (RSV) to 58 volunteers, of whom 57% became infected. Mucosal neutrophil activation before exposure was highly predictive of symptomatic RSV disease. This was associated with a rapid, presymptomatic decline in mucosal interleukin-17A (IL-17A) and other mediators. Conversely, those who resisted infection showed presymptomatic activation of IL-17- and tumor necrosis factor-related pathways. Vulnerability to infection was not associated with baseline microbiome but was reproduced in mice by preinfection chemokine-driven airway recruitment of neutrophils, which caused enhanced disease mediated by pulmonary CD8+ T cell infiltration. Thus, mucosal neutrophilic inflammation at the time of RSV exposure enhances susceptibility, revealing dynamic, time-dependent local immune responses before symptom onset and explaining the as-yet unpredictable outcomes of pathogen exposure.

Encephalomyelitis with Retinopathy in Common Variable Immunodeficiency (CVID).

Common variable immunodeficiency is the most common primary immunodeficiency and rarely causes neurological manifestations since the introduction of IVIg, but here, the authors present a case of a 31-year-old Afro-Caribbean man who after short non-adherence to his immunoglobulins, develops encephalomyelitis with retinopathy. To the authors' knowledge, this is the first case presented with retinal photographs, OCT, CT, MRI and brain biopsies.

Epitope-specific airway-resident CD4+ T cell dynamics during experimental human RSV infection.

BACKGROUNDRespiratory syncytial virus (RSV) is an important cause of acute pulmonary disease and one of the last remaining major infections of childhood for which there is no vaccine. CD4+ T cells play a key role in antiviral immunity, but they have been little studied in the human lung.METHODSHealthy adult volunteers were inoculated i.n. with RSV A Memphis 37. CD4+ T cells in blood and the lower airway were analyzed by flow cytometry and immunohistochemistry. Bronchial soluble mediators were measured using quantitative PCR and MesoScale Discovery. Epitope mapping was performed by IFN-γ ELISpot screening, confirmed by in vitro MHC binding.RESULTSActivated CD4+ T cell frequencies in bronchoalveolar lavage correlated strongly with local C-X-C motif chemokine 10 levels. Thirty-nine epitopes were identified, predominantly toward the 3' end of the viral genome. Five novel MHC II tetramers were made using an immunodominant EFYQSTCSAVSKGYL (F-EFY) epitope restricted to HLA-DR4, -DR9, and -DR11 (combined allelic frequency: 15% in Europeans) and G-DDF restricted to HLA-DPA1*01:03/DPB1*02:01 and -DPA1*01:03/DPB1*04:01 (allelic frequency: 55%). Tetramer labeling revealed enrichment of resident memory CD4+ T (Trm) cells in the lower airway; these Trm cells displayed progressive differentiation, downregulation of costimulatory molecules, and elevated CXCR3 expression as infection evolved.CONCLUSIONSHuman infection challenge provides a unique opportunity to study the breadth of specificity and dynamics of RSV-specific T-cell responses in the target organ, allowing the precise investigation of Trm recognizing novel viral antigens over time. The new tools that we describe enable precise tracking of RSV-specific CD4+ cells, potentially accelerating the development of effective vaccines.TRIAL REGISTRATIONClinicalTrials.gov NCT02755948.FUNDINGMedical Research Council, Wellcome Trust, National Institute for Health Research.

Controlled human infection with RSV: The opportunities of experimental challenge.

Despite the recent explosion in RSV vaccine development, there remain substantial hurdles to overcome before licensing of effective vaccines will allow widespread use, particularly in high-risk populations. Incomplete understanding of mechanisms and correlates of protection against RSV mean that, for the time being, successful RSV vaccines must directly demonstrate efficacy, which necessitates large and costly clinical trials in naturally infected patients. To mitigate the risks inherent in progressing to these late-stage trials, experimental human RSV infection studies have recently been re-established, representing the interface between pre-clinical models and observational studies of patients. Not only can they be used for early proof-of-concept clinical trials to test vaccine efficacy, but human challenge studies also offer the potential to better understand protective immunity against RSV infection to improve vaccine design and delivery. In the past, controlled human infection studies with RSV have been instrumental in elucidating the influence of factors such as route of infection and type of inoculum on the course of disease. Recently, efficacy trials of novel RSV antiviral drugs have also been successfully undertaken. Now, with advances in technology, detailed investigations of human mucosal immunity in the RSV-infected airway are possible. These have indicated defects in RSV-induced humoral and CD8+ T cell immunity that may contribute to the recurrent symptomatic infection that occurs throughout life and should be circumvented by optimal vaccines. Here, we discuss the insights derived from RSV human challenge models; the major impediments to their more widespread uptake; and their potential benefit in accelerating vaccine development, including future directions to further enhance the relevance of these models to at-risk patient populations.

RSV-specific airway resident memory CD8+ T cells and differential disease severity after experimental human infection.

In animal models, resident memory CD8+ T (Trm) cells assist in respiratory virus elimination but their importance in man has not been determined. Here, using experimental human respiratory syncytial virus (RSV) infection, we investigate systemic and local virus-specific CD8+ T-cell responses in adult volunteers. Having defined the immunodominance hierarchy, we analyse phenotype and function longitudinally in blood and by serial bronchoscopy. Despite rapid clinical recovery, we note surprisingly extensive lower airway inflammation with persistent viral antigen and cellular infiltrates. Pulmonary virus-specific CD8+ T cells display a CD69+CD103+ Trm phenotype and accumulate to strikingly high frequencies into convalescence without continued proliferation. While these have a more highly differentiated phenotype, they express fewer cytotoxicity markers than in blood. Nevertheless, their abundance before infection correlates with reduced symptoms and viral load, implying that CD8+ Trm cells in the human lung can confer protection against severe respiratory viral disease when humoral immunity is overcome.

A European single centre experience of management of hepatitis C virus genotype 4 infection with pegylated-interferon and ribavirin.

New direct acting antiviral agents are revolutionising hepatitis C virus (HCV) treatment. However, to date limited clinical trial data exists for outcomes in genotype 4 (GT4) HCV patients. GT4 HCV is more common in Africa, the Middle East, and Asia, and limited data exists to date for outcomes in Europe. We report the first "real-life" sustained virological response (SVR) outcomes using pegylated interferon and ribavirin for HCV GT4 in the UK, and the largest European single centre cohort. HCV GT4 patients treated at a London, UK centre between 2002 and 2014 were assessed for SVR outcomes. Patient age, sex, region of origin, co-infection with HIV, pre-treatment liver biopsy histological assessment, genotype subtyping, treatment duration, and dose reductions were compared against SVR outcomes on univariate analysis. Multivariate analysis was performed on results with P < 0.1. A total of 118 patients were treated with HCV GT4 during the study period, 57 achieved SVR (48%). On univariate analysis age ≥45 (P < 0.0001), high viral load (P < 0.0001), Ishak staging 5-6 (P < 0.0001), and non-Egyptian Africans (P = 0.0059) were all negatively associated with SVR. Eastern Europeans appeared to have higher SVR (P < 0.0001). Using multivariate correlation viral load (P = 0.0005); Ishak staging (P = 0.0031) and age (P = 0.0003) were associated with SVR but not country of origin (P = 0.0645). Outcomes with pegylated interferon and ribavirin for HCV GT4 in this "real-life" setting were sub-optimal especially in the context of newer regimens. Patients with older age, high viral loads, and advanced disease need prioritisation for alternative treatments.

Impaired Antibody-mediated Protection and Defective IgA B-Cell Memory in Experimental Infection of Adults with Respiratory Syncytial Virus.

RATIONALE: Despite relative antigenic stability, respiratory syncytial virus (RSV) reinfects throughout life. After more than 40 years of research, no effective human vaccine exists and correlates of protection remain poorly defined. Most current vaccine candidates seek to induce high levels of RSV-specific serum neutralizing antibodies, which are associated with reduced RSV-related hospitalization rates in observational studies but may not actually prevent infection. OBJECTIVES: To characterize correlates of protection from infection and the generation of RSV-specific humoral memory to promote effective vaccine development. METHODS: We inoculated 61 healthy adults with live RSV and studied protection from infection by serum and mucosal antibody. We analyzed RSV-specific peripheral blood plasmablast and memory B-cell frequencies and antibody longevity. MEASUREMENTS AND MAIN RESULTS: Despite moderately high levels of preexisting serum antibody, 34 (56%) became infected, of whom 23 (68%) developed symptomatic colds. Prior RSV-specific nasal IgA correlated significantly more strongly with protection from polymerase chain reaction-confirmed infection than serum neutralizing antibody. Increases in virus-specific antibody titers were variable and transient in infected subjects but correlated with plasmablasts that peaked around Day 10. During convalescence, only IgG (and no IgA) RSV-specific memory B cells were detectable in peripheral blood. This contrasted with natural influenza infection, in which virus-specific IgA memory B cells were readily recovered. CONCLUSIONS: This observed specific defect in IgA memory may partly explain the ability of RSV to cause recurrent symptomatic infections. If so, vaccines able to induce durable RSV-specific IgA responses may be more protective than those generating systemic antibody alone.

Benefit and harm from immunity to respiratory syncytial virus: implications for treatment.

PURPOSE OF REVIEW: Human respiratory syncytial virus (RSV) infection is a major cause of morbidity in children and of morbidity and mortality in elderly or immunocompromised adults. Given prophylactically, antibody can protect against infection, but natural levels are poorly protective. Vaccination may enhance disease, and there is no well tolerated and effective vaccine or antiviral treatment. Despite over 50 years of research, therapy remains nonspecific and supportive. RECENT FINDINGS: Experimental human challenge in adult volunteers is beginning to elucidate the dynamics of viral shedding and causes of disease, but investigations of naturally infected children remain logistically challenging. RSV was known to bind several surface ligands, but the recent demonstration that nucleolin acts as a receptor for the RSV fusion protein was unexpected. Recent studies increasingly emphasize the relevance of innate immune responses and the dysregulation of inflammation as key factors in causing the pathological effects of infection. Studies in both human infants and mice indicate that interleukin-17 plays a role in some forms of RSV disease and regulatory T cells may be important in controlling inflammation. SUMMARY: Improved understanding of the human immune response to RSV infection continues to be needed in order to accelerate the development of vaccines and new treatments for bronchiolitis.

Hot topics in the prevention of respiratory syncytial virus disease.

The 7th International Respiratory Syncytial Virus Symposium took place in Hotel Blijdorp, Rotterdam, The Netherlands. The series has been running since 1996; this meeting took place after a 3-year gap, and was attended by approximately 200 clinicians, scientists and industry representatives from all over the world. The conference covered all aspects of respiratory syncytial virus disease, including virology, cell biology, pathogenesis, clinical presentation, diagnosis, immunology, vaccines, antivirals and other therapeutic approaches. Reviews by invited keynote speakers were accompanied by oral and poster presentations, with ample opportunity for discussion of unpublished work. This article summarizes a small selection of hot topics from the meeting, focused on pathogenesis, therapeutics and vaccine development.