BackgroundTick-borne encephalitis virus (TBEV) is a flavivirus spread by ticks and can cause tick-borne encephalitis (TBE) in humans. Previously, TBE has been reported in returning travellers in the United Kingdom (UK), but in 2019 and 2020, two probable cases of TBE acquired in the UK were identified.AimThe aim of this study was to investigate TBE cases in the UK between 2015 and 2023, describing the incidence, place and mode of acquisition and diagnostic process.MethodsA retrospective review of possible, probable and confirmed cases of TBE diagnosed by the Rare and Imported Pathogens Laboratory (RIPL) between January 2015 and December 2023 was performed. For cases identified in 2022 and 2023, clinical data were collected for enhanced surveillance using structured case record forms. Laboratory diagnosis is reviewed and described.ResultsWe identified 21 cases: three possible, seven probable and 11 confirmed cases. Of these, 12 were between January 2022 and December 2023: three possible, three probable and six confirmed cases. Two confirmed TBE cases had definite or highly probable acquisition in the UK, in June and August 2022, respectively. One of the possible cases had definite UK acquisition. Cases typically have a biphasic presentation, with encephalitis in the second phase.ConclusionClinicians should be aware of the possibility of TBE when the cause for encephalitis is not identified, even in the absence of travel to previously identified endemic regions.

BACKGROUND:In May, 2022, the first global outbreak of mpox (formerly known as monkeypox) occurred. In response, public health agencies in the UK have made smallpox vaccines available to individuals at the highest risk of infection. With mpox cases still being detected globally, novel tools are required to aid with diagnosis, serosurveillance, and the evaluation of immune responses following infection and immunisation with current and new vaccine candidates. Here, we describe the development of a multiplexed immunoassay, MpoxPlex, able to measure IgG responses to 12 Orthopoxvirus antigens concurrently and distinguish between responses to infection and vaccination. METHODS:Using the Luminex (DiaSorin, Saluggia, Italy) platform, antibody responses to vaccinia virus (VACV) antigens B5, A27, and A33 and monkeypox virus (MPXV) antigens E8, B6, B2, M1, A27, A35, H3, A29, and A5 were assessed in serum from individuals after MPXV infection (n=24) and after vaccination (n=75) with modified VACV Ankara-Bavarian Nordic. Assay characteristics and cutoffs were calculated by fitting receiver operating characteristic curves to the median fluorescence intensities of these positive samples and negative samples that were run alongside (n=435). P values were calculated using non-parametric Mann-Whitney, Kruskal-Wallis, and Dunn's multiple comparisons tests. FINDINGS:Using the results from a combination of eight antigens, we were able to distinguish samples as either post-vaccination or post-infection from negative samples with a sensitivity of 98% and a specificity of 95%. IgG responses to MPXV antigen A27 were able to distinguish post-MPXV infection with a sensitivity of 88% and a specificity of 97%. VACV antigen A27 and MPXV antigens A29 and A5 provided little diagnostic advantage. INTERPRETATION:With additional benefits over current serological assays, we believe this assay will provide substantial insight into the current global outbreak of mpox. MpoxPlex shows use for both serosurveillance and immunological studies of vaccination and infection. FUNDING:Grant-in-aid funding to the Emerging Pathogen Serology Group at Porton Down, UK Health Security Agency.

OBJECTIVES:Yellow fever-associated viscerotropic disease (YEL-AVD) is a rare but serious complication arising from administration of live-attenuated yellow fever vaccine to individuals with risk factors such as thymectomy. At present there is no evidence-based treatment, and case fatality rates are high. Sofosbuvir, an NS5B nucleotide inhibitor, has activity against yellow fever virus in vitro and in vivo. PATIENT AND METHODS:Here we describe clinical and virological response to use of off-licence sofosbuvir as post-exposure prophylaxis for a patient inadvertently given yellow fever vaccine despite previous thymectomy. RESULTS:A 14-day course of oral sofosbuvir was administered in an outpatient setting with regular clinical and biochemical monitoring. The patient remained well without developing clinical features of YEL-AVD and did not experience adverse effects from the treatment. CONCLUSIONS:This supports the use of sofosbuvir as post-exposure prophylaxis in patients at high risk of developing YEL-AVD. Ongoing trials of efficacy of sofosbuvir in yellow fever infection may result in stronger support for this approach in the future.

Background: The 2022 Monkeypox virus (MPXV) global outbreak boosted development of multiple serological assays to aid understanding of Mpox immunology. Objectives: The study aimed to assess a multiplexed solid-phase electrochemiluminescence immunoassay (Meso Scale Discovery (MSD)) for simultaneous detection of antibodies against MPXV, including A35, E8 and M1 antigens, along with corresponding Vaccina Virus (VACV) homologues and demonstrate its accuracy in assessing antibody titres post-vaccination and infection. Methods: Assay performance was assessed for simultaneous detection of antibodies against MPXV and corresponding VACV antigens. Sensitivity and specificity were evaluated with paediatric negatives (n = 215), pre- and post-IMVANEX vaccinated (n = 80), and MPXV (Clade IIb, n = 39) infected serum samples. Results: The assay demonstrated high specificity (75.68 % (CI: 69.01-81.29) - 95.98 % (CI:92.54-97.87)) and sensitivity (62.11 % (CI:52.06-71.21) - 98.59 % (CI:92.44 %-99.93 %)) depending on the Orthopoxvirus antigen. Preferential binding was observed between MPXV-infected individuals and MPXV antigens, while vaccinated individuals exhibited increased binding to VACV antigens. These results highlight differential binding patterns between antigen homologues in related viruses. Conclusion: Overall, this assay demonstrates high sensitivities in detecting antibodies for multiple relevant MPXV and VACV antigens post-infection and post-vaccination, indicating its utility in understanding immune responses to Orthopoxviruses in current and future outbreaks and evaluating the immunogenicity of new-generation Mpoxspecific vaccinations.

In 2022, there were global reports of increased numbers of acute hepatitis not explained by hepatitis A-E virus infection in children. This manuscript summarises histopathology results from 20 patients in the United Kingdom who underwent liver transplant or had a liver biopsy as part of aetiological investigations. All available histopathological samples were reviewed centrally as part of the outbreak investigation. A working group comprised of infection specialists, hepatologists and histopathologists met virtually to review the cases, presentation, investigations and histopathology. All 20 liver samples had evidence of inflammation without significant interface activity, and submassive confluent pan-lobular or multilobular hepatocellular necrosis. Overall, the predominant histopathological findings were of acute nonspecific hepatitis with submassive hepatic necrosis and central vein perivenulitis and endothelitis. Histopathological findings were a poor indicator of aetiology. This review describes the centralised approach to histopathological examination and summarises the findings. Whilst adenovirus was frequently detected in blood or stool, histopathological examination could not support it as a causative factor. center dot center dot center dot What is Known image Adenovirus is implicated in the outbreak of acute hepatitis in children. Genomic studies have found high levels of adeno-associated virus 2 DNA in the blood and liver of a high proportion of cases. Of histopathology findings that have previously been published, there has not been evidence of adenovirus in hepatocytes.What is New Whilst adenovirus was frequently detected in blood or stool, histopathological examination could not confirm it as a causative factor. Histopathological findings were of acute nonspecific hepatitis with submassive hepatic necrosis and central vein perivenulitis and endothelitis. Immediate access to the relevant information about the histopathological features observed in this hepatitis outbreak.

Background To report on the implementation and outcomes of a virtual ward established for the management of mpox during the 2022 outbreak, we conducted a 2-center, observational, cross-sectional study over a 3-month period.Methods All patients aged >= 17 years with laboratory polymerase chain reaction-confirmed monkeypox virus managed between 14 May and 15 August 2022, at the Hospital for Tropical Diseases at University College London Hospitals National Health Service (NHS) Foundation Trust and sexual health services at Central North and West London NHS Foundation Trust, were included. Main outcomes included the proportion of patients managed exclusively on the virtual ward, proportion of patients requiring inpatient admission, proportion of patients with human immunodeficiency virus, and duration of lesion reepithelialization.Results Among confirmed cases (N = 221), 86% (191/221) were managed exclusively on the virtual ward, while 14% (30/221) required admission. Treatment for concomitant sexually transmitted infections was provided to 25% (55/221) of patients, antibiotics for other infective complications to 16% (35/221), and symptomatic relief to 27% (60/221). The median time from onset to complete lesion reepithelialization and de-isolation was 18 days (range, 8-56 days). Eleven percent (24/221) of individuals disengaged from services within 4 days of testing.Conclusions The virtual ward model facilitated safe and holistic outpatient management of mpox, while minimizing admissions. This approach could serve as a model for future outbreak responses. We assessed a mpox virtual outpatient model during the 2022 outbreak, when it was classified as a high consequence infectious disease (HCID). 86% patients were managed virtually, reducing admissions. This model could inform future HCID responses, enabling safe remote care.

In the summer of 2022, a large outbreak of Monkeypox virus (MPXV) cases occurred globally. By December 2022, a total of 3,582 Mpox cases had been confirmed within the UK. As a result, the Modified Vaccinia Ankara-Bavarian Nordic (IMVANEX) vaccine was offered to high-risk groups to protect against the spread of the virus. This outbreak led to the development of multiple serological assays to aid the current understanding of Mpox immunology. This study assessed the performance of a multiplexed solid-phase electrochemiluminescence (Meso Scale Discovery (MSD)) immunoassay for simultaneous detection of antibodies against MPXV A29, A35, B6, E8, and M1 antigens, along with the corresponding Vaccina Virus (VACV) homologues A27, A33, B5, D8, and L1. Sensitivity and specificity were evaluated with paediatric negatives (n=215), pre- and post-IMVANEX vaccinated (n=80) and MPXV (2022 Clade IIb outbreak, n=39) infected serum samples. The overall Orthopoxvirus multiplex assay demonstrated high specificity ranging from 75.68% (CI: 69.01&-81.29) - 95.98% (CI:92.54-97.87) and sensitivity from 62.11% (CI:52.06-71.21) - 98.59% (CI:92.44% - 99.93%) depending on the Orthopoxvirus antigen, either used singularly or combined. Additionally, preferential binding was observed between Mpox-infected individuals and MPXV antigens, whilst vaccinated individuals exhibited increased binding to VACV antigens. These results highlight the differential binding patterns between antigen homologues in closely related viruses. Using this assay, we show that the Orthopoxvirus MSD assay is highly sensitive in detecting IgG titres for vaccinated sera ≥24-days post dose one and ≥14-days post dose two for all antigens within the assay except for MPXV A29 and VACV A27. A similar trend was observed with convalescent sera, although differing antigens demonstrate stronger sensitivities. Overall, this assay has the capability to accurately assess antibody titres for multiple relevant MPXV and VACV antigens post infection and post vaccination, demonstrating its utility in understanding immune responses to Orthopox viruses in current and future outbreaks, and assessing the immunogenicity of new generation Orthopox and Mpox-specific vaccinations.### Competing Interest StatementThe authors have declared no competing interest.### Funding StatementThis study did not receive any funding### Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Mpox PCR-confirmed cases were granted approval for assay performance validation by the NHS Research Ethics Committee (reference 22/HRA/3321). IMVANEX Smallpox-vaccinated samples were obtained from individuals with written consent through UKHSA Research and Ethics Committee for assay validation. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.YesAll data produced in the present study are available upon reasonable request to the authors

The summer of 2022 saw the first global outbreak of Mpox disease (formerly monkeypox), primarily within gay, bisexual, and other men who have sex with men (GBMSM). In response, public health agencies in the UK have offered smallpox vaccines to those individuals deemed at highest risk of infection. With Mpox cases still being detected globally, novel tools are required to aid with diagnosis, serosurveillance and the evaluation of immune responses following infection and vaccination. Here, we describe the development of a multiplexed immunoassay that is able to measure IgG responses to twelve immunogenic Orthopoxvirus proteins concurrently and distinguish between responses to infection and vaccination. Using the Luminex platform, antibody responses to vaccinia virus (VACV) proteins B5, A27, A33 and Monkeypox virus (MPXV) proteins E8, B6, B2, M1, A27, A35, H3, A29, A5 were assessed in serum from individuals post-MPXV infection (n=24) and post-vaccination (n=75) with modified vaccinia virus Ankara-Bavarian Nordic (MVA-BN, IMVANEX). Negative sera (n=435) were run alongside to assess appropriate assay cut-offs and characteristics. Using the results from a combination of eight of the twelve proteins within the immunoassay we were able to classify samples as either post-vaccination or infection, from negative samples with a sensitivity of 98.39% (9.72-99.22%) and specificity of 95.24% (86.91-98.70%). IgG responses to VACV A27, MPXV A29 and MPXV A5 provided little diagnostic advantage. IgG responses to the MPXV protein A27 were able to distinguish post-MPXV infection from negative and post-vaccination samples with a sensitivity of 87.5% (69.00-95.66%) and specificity of 96.84% (94.84-98.07%). There is an ongoing need to utilise Mpox serology to conduct disease surveillance, assess the efficacy of current and new vaccine candidates, and further understand immune responses to Mpox infection. We believe this assay will provide substantial insight into the current global outbreak of Mpox, with additional benefits over current serological assays.### Competing Interest StatementThe authors have declared no competing interest.### Funding StatementThis study did not receive any funding### Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:The research ethics committee (Research and Public Health Practice Ethics and Governance Group, REGG) of the UK Health Security Agency (UKHA) granted ethical approval for sampling of individuals with written and informed consent. In addition, the NHS Research Ethics Committees (REC) granted approval for sampling from previous MPXV-infected individuals under reference 22/HRA/3321.I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.YesAll data produced in the present study are available upon reasonable request to the authors

Tularemia, caused by Francisella tularensis, is not known to occur in the United Kingdom. We report a case of tularemia diagnosed in July 2023 in a UK patient with no travel in the 6 weeks before symptom onset. We describe the subsequent multiagency investigation into possible routes of acquisition.

Background Lipid nanoparticle (LNP) encapsulated self-amplifying RNA (saRNA) is well tolerated and immunogenic in SARS-CoV-2 seronegative and seropositive individuals aged 18-75.Methods A phase 2a expanded safety and immunogenicity study of a saRNA SARS-CoV-2 vaccine candidate LNP-nCoVsaRNA, was conducted at participating centres in the UK between 10th August 2020 and 30th July 2021. Participants received 1 mu g then 10 mu g of LNP-nCoVsaRNA, similar to 14 weeks apart. Solicited adverse events (AEs) were collected for one week post-each vaccine, and unsolicited AEs throughout. Binding and neutralisating anti-SARS-CoV-2 antibody raised in participant sera was measured by means of an anti-Spike (S) IgG ELISA, and SARS-CoV-2 pseudoneutralisation assay. (The trial is registered: ISRCTN17072692, EudraCT 2020-001646-20).Findings 216 healthy individuals (median age 51 years) received 1.0 mu g followed by 10.0 mu g of the vaccine. 28/216 participants were either known to have previous SARS-CoV2 infection and/or were positive for anti-Spike (S) IgG at baseline. Reactogenicity was as expected based on the reactions following licensed COVID-19 vaccines, and there were no serious AEs related to vaccination. 80% of baseline SARS-CoV-2 naive individuals (147/183) seroconverted two weeks post second immunization, irrespective of age (18-75); 56% (102/183) had detectable neutralising antibodies. Almost all (28/31) SARS-CoV-2 positive individuals had increased S IgG binding antibodies following their first 1.0 mu g dose with a >= 0.5log10 increase in 71% (22/31).Interpretation Encapsulated saRNA was well tolerated and immunogenic in adults aged 18-75 years. Seroconversion rates in antigen naive were higher than those reported in our dose-ranging study. Further work is required to determine if this difference is related to a longer dosing interval (14 vs. 4 weeks) or dosing with 1.0 mu g followed by 10.0 mu g. Boosting of S IgG antibodies was observed with a single 1.0 mu g injection in those with pre-existing immune responses.Funding Grants and gifts from the Medical Research Council UKRI (MC_PC_19076), the National Institute for Health Research/Vaccine Task Force, Partners of Citadel and Citadel Securities, Sir Joseph Hotung Charitable Settlement, Jon Moulton Charity Trust, Pierre Andurand, and Restore the Earth. 2023;56: Published January https://doi.org/10. 1016/j.eclinm.2022. 101823Copyright (c) 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

A 48-year-old man with poorly controlled HIV presented with severe human monkeypox virus (hMPXV) infection, having completed 2 weeks of tecovirimat at another hospital. He had painful, ulcerating skin lesions on most of his body and oropharyngeal cavity, with subsequent Ludwig's angina requiring repeated surgical interventions. Despite commencing a second, prolonged course of tecovirimat, he did not objectively improve, and new lesions were still noted at day 24. Discussion at the UK National Health Service England High Consequence Infectious Diseases Network recommended the use of 3% topical and then intravenous cidofovir, which was given at 5 mg/kg; the patient made a noticeable improvement after the first intravenous dose. He received further intravenous doses at 7 days and 21 days after the dose and was discharged at day 52. Cidofovir is not licensed for use in treatment of hMPXV infection. Data for cidofovir use in hMPXV are restricted to studies in animals. Four other documented cases of cidofovir use against hMPXV have been reported in the USA in 2022, but we present its first use in the UK. The scarcity of studies into the use of cidofovir in this condition clearly shows the need for robust studies to assess efficacy, optimum dosage, timing, and route of administration.

Background: COV-BOOST is a multicentre, randomised, controlled, phase 2 trial of seven COVID-19 vaccines used as a third booster dose in June 2021. Monovalent messenger RNA (mRNA) COVID-19 vaccines were subsequently widely used for the third and fourth-dose vaccination campaigns in high-income countries. Real-world vaccine effectiveness against symptomatic infections following third doses declined during the Omicron wave. This report compares the immunogenicity and kinetics of responses to third doses of vac-cines from day (D) 28 to D242 following third doses in seven study arms. Methods: The trial initially included ten experimental vaccine arms (seven full-dose, three half-dose) de-livered at three groups of six sites. Participants in each site group were randomised to three or four ex-perimental vaccines, or MenACWY control. The trial was stratified such that half of participants had previously received two primary doses of ChAdOx1 nCov-19 (Oxford-AstraZeneca; hereafter referred to as ChAd) and half had received two doses of BNT162b2 (Pfizer-BioNtech, hereafter referred to as BNT). The D242 follow-up was done in seven arms (five full-dose, two half-dose). The BNT vaccine was used as the reference as it was the most commonly deployed third-dose vaccine in clinical practice in high-income countries. The primary analysis was conducted using all randomised and baseline seronegative participants who were SARS-CoV-2 naive during the study and who had not received a further COVID-19 vaccine for any reason since third dose randomisation.Results: Among the 817 participants included in this report, the median age was 72 years (IQR: 55-78) with 50.7% being female. The decay rates of anti-spike IgG between vaccines are different among both popula-tions who received initial doses of ChAd/ChAd and BNT/BNT. In the population that previously received ChAd/ChAd, mRNA vaccines had the highest titre at D242 following their vaccine dose although Ad26. COV2. S (Janssen; hereafter referred to as Ad26) showed slower decay. For people who received BNT/BNT as their initial doses, a slower decay was also seen in the Ad26 and ChAd arms. The anti-spike IgG became sig-nificantly higher in the Ad26 arm compared to the BNT arm as early as 3 months following vaccination. Similar decay rates were seen between BNT and half-BNT; the geometric mean ratios ranged from 0.76 to 0.94 at different time points. The difference in decay rates between vaccines was similar for wild-type live virus-neutralising antibodies and that seen for anti-spike IgG. For cellular responses, the persistence was similar between study arms.Conclusions: Heterologous third doses with viral vector vaccines following two doses of mRNA achieve more durable humoral responses compared with three doses of mRNA vaccines. Lower doses of mRNA vaccines could be considered for future booster campaigns.& COPY; 2023 The Authors. Published by Elsevier Ltd on behalf of The British Infection Association. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

IntroductionBetween 6 May 2022 and 19 December 2022 there were 3,404 confirmed cases of Mpox infection in England, predominantly among gay, bisexual, and other men who have sex with men (GBMSM). We measured the seroprevalence of Mpox-specific antibodies in sera collected before the first identified case to determine when infections first appeared in England, and from sera collected later in 2022, to measure the extent of undiagnosed Mpox infection.MethodsWe collected residual sera from men in London and Southeast England having confirmatory syphilis testing (as a proxy for high-risk for Mpox acquisition) January - May 2022 (before Mpox-outbreak), and from adults attending sexual health services (SHS) in London and Manchester between May and September 2022 (during Mpox-outbreak). A pooled antigen screening assay utilising four MPXV and one Vaccinia virus antigen was used to detect antibody responses to Mpox infection, or IMVANEX/past Smallpox vaccination. A differential assay using the MPXV A27 antigen (absent from the modified vaccinia Ankara strain within the IMVANEX vaccine) was also used, enabling differentiation between Mpox infection and IMVANEX vaccination.ResultsIn total, 3,482 samples from individuals were tested; 797 from men sampled before the Mpox outbreak was recognised and 2,685 from individuals attending SHS after. In total, 858 samples (24.65%) demonstrated poxvirus antigen reactivity, whilst 120 (3.45%) were also positive on the differential assay. All individuals testing positive before May were aged >51, suggesting antibody reactivity due to previous Smallpox vaccination.DiscussionWe did not find any evidence of Mpox-specific antibodies in this sample of high-risk men prior to identification of the Mpox outbreak in England. The low seroprevalence may reflect very little undiagnosed infection, or sampling bias. Linkage to national STI data surveillance is ongoing and will allow further analysis of the latter to determine seroprevalence within sub-populations of GBMSM.

Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK 1 . Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children.

Historically SARS-CoV-2 secondary attack rates (SAR) have been based on PCR positivity on screening symptomatic contacts; this misses transmission events and identifies only symptomatic contacts who are PCR positive at the time of sampling. We used serology to detect the relative transmissibility of Alpha Variant of Concern (VOC) to non-VOC SARS-CoV-2 to calculate household secondary attack rates. We identified index patients diagnosed with Alpha and non-VOC SARS-CoV-2 across two London Hospitals between November 2020 and January 2021 during a prolonged and well adhered national lockdown. We completed a household seroprevalence survey and found that 61.8% of non-VOC exposed household contacts were seropositive compared to 82.1% of Alpha exposed household contacts. The odds of infection doubled with exposure to an index diagnosed with Alpha. There was evidence of transmission events in almost all households. Our data strongly support that estimates of SAR should include serological data to improve accuracy and understanding.

OBJECTIVE:The burden of imported rickettsial infection in the UK is not previously described. This retrospective review identifies rickettsial cases diagnosed at the national reference laboratory between 2015 and 2022.METHODS:Samples testing positive for spotted fever group, typhus group, and scrub typhus IgG/IgM on acute and convalescent blood samples, and/or PCR on tissue/blood were categorized as suspected, confirmed or past infection.RESULTS:220 patients had rickettsioses, and the commonest import was acute spotted fever group infection (61%, 125/205), 54% (62/114) from South Africa. In acute typhus group cases, 60% (40/67) were from Southeast Asia. One patient with Rickettsia typhi bacteremia died. Scrub typhus group infections (5%, 10/205) were exclusively from Asia and the Western Pacific regions. Overall, 43% of confirmed cases (39/91) had not received doxycycline prior to results.CONCLUSIONS:Rickettsial infections are important and under-recognized causes of imported fever in the UK. Thorough history, examination, and timely treatment with doxycycline should be considered if there is suspicion of Rickettsia infection before testing.

In early 2022, a cluster of monkeypox virus (MPXV) infection (mpox) cases were identified within the UK with no prior travel history to MPXV-endemic regions. Subsequently, case numbers exceeding 80,000 were reported worldwide, primarily affecting gay, bisexual, and other men who have sex with men (GBMSM). Public health agencies worldwide have offered the IMVANEX Smallpox vaccination to these individuals at high-risk to provide protection and limit the spread of MPXV. We have developed a comprehensive array of ELISAs to study poxvirus-induced antibodies, utilising 24 MPXV and 3 Vaccinia virus (VACV) recombinant antigens. Panels of serum samples from individuals with differing Smallpox-vaccine doses and those with prior MPXV infection were tested on these assays, where we observed that one dose of Smallpox vaccination induces a low number of antibodies to a limited number of MPXV antigens but increasing with further vaccination doses. MPXV infection induced similar antibody responses to diverse poxvirus antigens observed in Smallpox-vaccinated individuals. We identify MPXV A27 as a serological marker of MPXV-infection, whilst MPXV M1 (VACV L1) is likely IMVANEX-specific. Here, we demonstrate analogous humoral antigen recognition between both MPXV-infected or Smallpox-vaccinated individuals, with binding to diverse yet core set of poxvirus antigens, providing opportunities for future vaccine (e.g., mRNA) and therapeutic (e.g., mAbs) design.

Background: An increase in acute severe hepatitis of unknown aetiology in previously healthy children in the UK in March, 2022, triggered global case-finding. We aimed to describe UK epidemiological investigations of cases and their possible causes.Methods: We actively surveilled unexplained paediatric acute hepatitis (transaminase >500 international units per litre) in children younger than 16 years presenting since Jan 1, 2022, through notifications from paediatricians, microbiologists, and paediatric liver units; we collected demographic, clinical, and exposure information. Then, we did a case-control study to investigate the association between adenoviraemia and other viruses and case-status using multivariable Firth penalised logistic regression. Cases aged 1-10 years and tested for adenovirus were included and compared with controls (ie, children admitted to hospital with an acute non-hepatitis illness who had residual blood samples collected between Jan 1 and May 28, 2022, and without known laboratory-confirmed diagnosis or previous adenovirus testing). Controls were frequency-matched on sex, age band, sample months, and nation or supra-region with randomised selection. We explored temporal associations between frequency of circulating viruses identified through routine laboratory pathogen surveillance and occurrence of cases by linear regression. SARS-CoV-2 seropositivity of cases was examined against residual serum from age-matched clinical comparison groups.Findings: Between Jan 1 and July 4, 2022, 274 cases were identified (median age 3 years [IQR 2-5]). 131 (48%) participants were male, 142 (52%) were female, and one (<1%) participant had sex data unknown. Jaundice (195 [83%] of 235) and gastrointestinal symptoms (202 [91%] of 222) were common. 15 (5%) children required liver transplantation and none died. Adenovirus was detected in 172 (68%) of 252 participants tested, regardless of sample type; 137 (63%) of 218 samples were positive for adenovirus in the blood. For cases that were successfully genotyped, 58 (81%) of 72 had Ad41F, and 57 were identified as positive via blood samples (six of these were among participants who had undergone a transplant). In the case-control analysis, adenoviraemia was associated with hepatitis case-status (adjusted OR 374 [95% CI 155-903]). Increases in the detection of adenovirus from faecal samples, but not other infectious agents, in routine laboratory pathogen surveillance correlated with hepatitis cases 4 weeks later, which independently suggested an association (beta 006 [95% CI 002-011]). No association was identified for SARS-CoV-2 antibody seropositivity.Interpretation: We observed an association between adenovirus 41F viraemia and paediatric acute hepatitis. These results can inform diagnostic testing recommendations, clinical management, and exploratory in vitro or clinical studies of paediatric acute hepatitis of unknown aetiology. The role of potential co-factors, including other viruses and host susceptibility, requires further investigation.