COVID-19 vaccine effectiveness against symptomatic infection with SARS-CoV-2 BA.1/BA.2 lineages among adults and adolescents in a multicentre primary care study, Europe, December 2021 to June 2022.

BackgroundScarce European data in early 2021 suggested lower vaccine effectiveness (VE) against SARS-CoV-2 Omicron lineages than previous variants.AimWe aimed to estimate primary series (PS) and first booster VE against symptomatic BA.1/BA.2 infection and investigate potential biases.MethodsThis European test-negative multicentre study tested primary care patients with acute respiratory symptoms for SARS-CoV-2 in the BA.1/BA.2-dominant period. We estimated PS and booster VE among adults and adolescents (PS only) for all products combined and for Comirnaty alone, by time since vaccination, age and chronic condition. We investigated potential bias due to correlation between COVID-19 and influenza vaccination and explored effect modification and confounding by prior SARS-CoV-2 infection.ResultsAmong adults, PS VE was 37% (95% CI: 24-47%) overall and 60% (95% CI: 44-72%), 43% (95% CI: 26-55%) and 29% (95% CI: 13-43%) < 90, 90-179 and ≥ 180 days post vaccination, respectively. Booster VE was 42% (95% CI: 32-51%) overall and 56% (95% CI: 47-64%), 22% (95% CI: 2-38%) and 3% (95% CI: -78% to 48%), respectively. Primary series VE was similar among adolescents. Restricting analyses to Comirnaty had little impact. Vaccine effectiveness was higher among older adults. There was no signal of bias due to correlation between COVID-19 and influenza vaccination. Confounding by previous infection was low, but sample size precluded definite assessment of effect modification.ConclusionPrimary series and booster VE against symptomatic infection with BA.1/BA.2 ranged from 37% to 42%, with similar waning post vaccination. Comprehensive data on previous SARS-CoV-2 infection would help disentangle vaccine- and infection-induced immunity.

A comparison of COVID-19 incidence rates across six European countries in 2021.

International comparisons of COVID-19 incidence rates have helped gain insights into the characteristics of the disease, benchmark disease impact, shape public health measures and inform potential travel restrictions and border control measures. However, these comparisons may be biased by differences in COVID-19 surveillance systems and approaches to reporting in each country. To better understand these differences and their impact on incidence comparisons, we collected data on surveillance systems from six European countries: Belgium, England, France, Italy, Romania and Sweden. Data collected included: target testing populations, access to testing, case definitions, data entry and management and statistical approaches to incidence calculation. Average testing, incidence and contextual data were also collected. Data represented the surveillance systems as they were in mid-May 2021. Overall, important differences between surveillance systems were detected. Results showed wide variations in testing rates, access to free testing and the types of tests recorded in national databases, which may substantially limit incidence comparability. By systematically including testing information when comparing incidence rates, these comparisons may be greatly improved. New indicators incorporating testing or existing indicators such as death or hospitalisation will be important to improving international comparisons.

Influenza vaccine effectiveness against influenza A subtypes in Europe: Results from the 2021-2022 I-MOVE primary care multicentre study.

BACKGROUND: In 2021-2022, influenza A viruses dominated in Europe. The I-MOVE primary care network conducted a multicentre test-negative study to measure influenza vaccine effectiveness (VE). METHODS: Primary care practitioners collected information on patients presenting with acute respiratory infection. Cases were influenza A(H3N2) or A(H1N1)pdm09 RT-PCR positive, and controls were influenza virus negative. We calculated VE using logistic regression, adjusting for study site, age, sex, onset date, and presence of chronic conditions. RESULTS: Between week 40 2021 and week 20 2022, we included over 11 000 patients of whom 253 and 1595 were positive for influenza A(H1N1)pdm09 and A(H3N2), respectively. Overall VE against influenza A(H1N1)pdm09 was 75% (95% CI: 43-89) and 81% (95% CI: 45-93) among those aged 15-64 years. Overall VE against influenza A(H3N2) was 29% (95% CI: 12-42) and 25% (95% CI: -41 to 61), 33% (95% CI: 14-49), and 26% (95% CI: -22 to 55) among those aged 0-14, 15-64, and over 65 years, respectively. The A(H3N2) VE among the influenza vaccination target group was 20% (95% CI: -6 to 39). All 53 sequenced A(H1N1)pdm09 viruses belonged to clade 6B.1A.5a.1. Among 410 sequenced influenza A(H3N2) viruses, all but eight belonged to clade 3C.2a1b.2a.2. DISCUSSION: Despite antigenic mismatch between vaccine and circulating strains for influenza A(H3N2) and A(H1N1)pdm09, 2021-2022 VE estimates against circulating influenza A(H1N1)pdm09 were the highest within the I-MOVE network since the 2009 influenza pandemic. VE against A(H3N2) was lower than A(H1N1)pdm09, but at least one in five individuals vaccinated against influenza were protected against presentation to primary care with laboratory-confirmed influenza.

Epidemiological and microbiological investigation of a large increase in vibriosis, northern Europe, 2018.

BackgroundVibriosis cases in Northern European countries and countries bordering the Baltic Sea increased during heatwaves in 2014 and 2018.AimWe describe the epidemiology of vibriosis and the genetic diversity of Vibrio spp. isolates from Norway, Sweden, Denmark, Finland, Poland and Estonia in 2018, a year with an exceptionally warm summer.MethodsIn a retrospective study, we analysed demographics, geographical distribution, seasonality, causative species and severity of non-travel-related vibriosis cases in 2018. Data sources included surveillance systems, national laboratory notification databases and/or nationwide surveys to public health microbiology laboratories. Moreover, we performed whole genome sequencing and multilocus sequence typing of available isolates from 2014 to 2018 to map their genetic diversity.ResultsIn 2018, we identified 445 non-travel-related vibriosis cases in the study countries, considerably more than the median of 126 cases between 2014 and 2017 (range: 87-272). The main reported mode of transmission was exposure to seawater. We observed a species-specific geographical disparity of vibriosis cases across the Nordic-Baltic region. Severe vibriosis was associated with infections caused by Vibrio vulnificus (adjOR: 17.2; 95% CI: 3.3-90.5) or Vibrio parahaemolyticus (adjOR: 2.1; 95% CI: 1.0-4.5), age ≥ 65 years (65-79 years: adjOR: 3.9; 95% CI: 1.7-8.7; ≥ 80 years: adjOR: 15.5; 95% CI: 4.4-54.3) or acquiring infections during summer (adjOR: 5.1; 95% CI: 2.4-10.9). Although phylogenetic analysis revealed diversity between Vibrio spp. isolates, two V. vulnificus clusters were identified.ConclusionShared sentinel surveillance for vibriosis during summer may be valuable to monitor this emerging public health issue.

Effectiveness of complete primary vaccination against COVID-19 at primary care and community level during predominant Delta circulation in Europe: multicentre analysis, I-MOVE-COVID-19 and ECDC networks, July to August 2021.

IntroductionIn July and August 2021, the SARS-CoV-2 Delta variant dominated in Europe.AimUsing a multicentre test-negative study, we measured COVID-19 vaccine effectiveness (VE) against symptomatic infection.MethodsIndividuals with COVID-19 or acute respiratory symptoms at primary care/community level in 10 European countries were tested for SARS-CoV-2. We measured complete primary course overall VE by vaccine brand and by time since vaccination.ResultsOverall VE was 74% (95% CI: 69-79), 76% (95% CI: 71-80), 63% (95% CI: 48-75) and 63% (95% CI: 16-83) among those aged 30-44, 45-59, 60-74 and ≥ 75 years, respectively. VE among those aged 30-59 years was 78% (95% CI: 75-81), 66% (95% CI: 58-73), 91% (95% CI: 87-94) and 52% (95% CI: 40-61), for Comirnaty, Vaxzevria, Spikevax and COVID-19 Vaccine Janssen, respectively. VE among people 60 years and older was 67% (95% CI: 52-77), 65% (95% CI: 48-76) and 83% (95% CI: 64-92) for Comirnaty, Vaxzevria and Spikevax, respectively. Comirnaty VE among those aged 30-59 years was 87% (95% CI: 83-89) at 14-29 days and 65% (95% CI: 56-71%) at ≥ 90 days between vaccination and onset of symptoms.ConclusionsVE against symptomatic infection with the SARS-CoV-2 Delta variant varied among brands, ranging from 52% to 91%. While some waning of the vaccine effect may be present (sample size limited this analysis to only Comirnaty), protection was 65% at 90 days or more between vaccination and onset.

Vaccine effectiveness against symptomatic SARS-CoV-2 infection in adults aged 65 years and older in primary care: I-MOVE-COVID-19 project, Europe, December 2020 to May 2021.

We measured COVID-19 vaccine effectiveness (VE) against symptomatic SARS-CoV-2 infection at primary care/outpatient level among adults ≥ 65 years old using a multicentre test-negative design in eight European countries. We included 592 SARS-CoV-2 cases and 4,372 test-negative controls in the main analysis. The VE was 62% (95% CI: 45-74) for one dose only and 89% (95% CI: 79-94) for complete vaccination. COVID-19 vaccines provide good protection against COVID-19 presentation at primary care/outpatient level, particularly among fully vaccinated individuals.

High impact of molecular surveillance on hepatitis A outbreak case detection in Sweden: a retrospective study, 2009 to 2018.

BackgroundSwedish hepatitis A surveillance includes sequence-based typing, but its contribution to outbreak detection in relation to epidemiological investigations has not been fully evaluated.AimTo evaluate the role of sequence-based typing in hepatitis A outbreak detection and to describe the hepatitis A epidemiology in Sweden to improve surveillance.MethodsWe retrospectively investigated hepatitis A virus sequences of 447 cases notified in Sweden 2009-18. We performed a phylogenetic analysis of evolutionary distances to identify cases with similar virus sequences (≥ 459/460 identical nt in the VP1/P2A junction). Unique sequences, dyads and sequence-based clusters (SBCs) were identified. We linked non-sequenced cases by epidemiological information and retrospectively assessed the value of typing for outbreak identification.ResultsFifty-five percent (n = 542/990) of the notified hepatitis A cases were referred to the Public Health Agency of Sweden for typing and 447 (45%) were sequenced successfully. Subgenotypes included IA (42.5%, n = 190), IB (42.7%, n = 191) and IIIA (14.8%, n = 66). Phylogenetic analysis identified 154 unique sequences, 33 dyads (66 cases) and 34 SBCs (227 cases). The combination of molecular and epidemiological data revealed 23 potential outbreaks comprising 201 cases. Cases were linked by sequence (59%, n = 118), epidemiological data (11%, n = 23) or both (30%, n = 60). Typing was needed to identify 15 of 23 potential outbreak signals.ConclusionSequence-based typing contributed substantially to detecting clustering cases and identifying outbreaks in Sweden. The results show routine sequence-based typing detects outbreaks, promotes timely outbreak investigations and facilitates international collaboration.

Hepatitis B Virus DNA is a Substrate for the cGAS/STING Pathway but is not Sensed in Infected Hepatocytes.

Hepatitis B virus (HBV) chronic infection is a critical risk factor for hepatocellular carcinoma. The innate immune response to HBV infection is a matter of debate. In particular, viral escape mechanisms are poorly understood. Our study reveals that HBV RNAs are not immunostimulatory in immunocompetent myeloid cells. In contrast, HBV DNA from viral particles and DNA replication intermediates are immunostimulatory and sensed by cyclic GMP-AMP Synthase (cGAS) and Stimulator of Interferon Genes (STING). We show that primary human hepatocytes express DNA sensors to reduced levels compared to myeloid cells. Nevertheless, hepatocytes can respond to HBV relaxed-circular DNA (rcDNA), when transfected in sufficient amounts, but not to HBV infection. Finally, our data suggest that HBV infection does not actively inhibit the DNA-sensing pathway. In conclusion, in infected hepatocytes, HBV passively evades recognition by cellular sensors of nucleic acids by (i) producing non-immunostimulatory RNAs, (ii) avoiding sensing of its DNAs by cGAS/STING without active inhibition of the pathway.

Insights into Innate Sensing of Prototype Foamy Viruses in Myeloid Cells.

Foamy viruses (FVs) belong to the Spumaretrovirinae subfamily of retroviruses and are characterized by unique features in their replication strategy. This includes a reverse transcription (RTr) step of the packaged RNA genome late in replication, resulting in the release of particles with a fraction of them already containing an infectious viral DNA (vDNA) genome. Little is known about the immune responses against FVs in their hosts, which control infection and may be responsible for their apparent apathogenic nature. We studied the interaction of FVs with the innate immune system in myeloid cells, and characterized the viral pathogen-associated molecular patterns (PAMPs) and the cellular pattern recognition receptors and sensing pathways involved. Upon cytoplasmic access, full-length but not minimal vector genome containing FVs with active reverse transcriptase, induced an efficient innate immune response in various myeloid cells. It was dependent on cellular cGAS and STING and largely unaffected by RTr inhibition during viral entry. This suggests that RTr products, which are generated during FV morphogenesis in infected cells, and are therefore already present in FV particles taken up by immune cells, are the main PAMPs of FVs with full-length genomes sensed in a cGAS and STING-dependent manner by the innate immune system in host cells of the myeloid lineage.

Cross-border outbreak of Yersinia enterocolitica O3 associated with imported fresh spinach, Sweden and Denmark, March 2019.

In April 2019, a cross-border outbreak of Yersinia entercolitica O3 was identified in Sweden and Denmark and confirmed using whole genome sequencing. Close cross-border collaboration with representatives from human and food authorities helped direct resources and investigations. Combined epidemiological and trace-back investigations pointed to imported fresh spinach as the outbreak vehicle and highlight that other vehicles of Y. enterocolitica outbreaks than pork should be considered.

Role of Innate Genes in HIV Replication.

Cells use an elaborate innate immune surveillance and defense system against virus infections. Here, we discuss recent studies that reveal how HIV-1 is sensed by the innate immune system. Furthermore, we present mechanisms on the counteraction of HIV-1. We will provide an overview how HIV-1 actively utilizes host cellular factors to avoid sensing. Additionally, we will summarize effectors of the innate response that provide an antiviral cellular state. HIV-1 has evolved passive mechanism to avoid restriction and to regulate the innate response. We review in detail two prominent examples of these cellular factors: (i) NLRX1, a negative regulator of the innate response that HIV-1 actively usurps to block cytosolic innate sensing; (ii) SAMHD1, a restriction factor blocking the virus at the reverse transcription step that HIV-1 passively avoids to escape sensing.

Interferons Induce Expression of SAMHD1 in Monocytes through Down-regulation of miR-181a and miR-30a.

SAMHD1 is a phosphohydrolase maintaining cellular dNTP homeostasis but also acts as a critical regulator in innate immune responses due to its antiviral activity and association with autoimmune disease, leading to aberrant activation of interferon. SAMHD1 expression is differentially regulated by interferon in certain primary cells, but the underlying mechanism is not understood. Here, we report a detailed characterization of the promotor region, the 5'- and 3'-untranslated region (UTR) of SAMHD1, and the mechanism responsible for the cell type-dependent up-regulation of SAMHD1 protein by interferon. We demonstrate that induction of SAMHD1 by type I and II interferons depends on 3'-UTR post-transcriptional regulation, whereas the promoter drives basal expression levels. We reveal novel functional target sites for the microRNAs miR-181a, miR-30a, and miR-155 in the SAMHD1 3'-UTR. Furthermore, we demonstrate that down-regulation of endogenous miR-181a and miR-30a levels inversely correlates with SAMHD1 protein up-regulation upon type I and II interferon stimulation in primary human monocytes. These miRNAs are not modulated by interferon in macrophages or dendritic cells, and consequently protein levels of SAMHD1 remain unchanged. These results suggest that SAMHD1 is a non-classical interferon-stimulated gene regulated through cell type-dependent down-regulation of miR-181a and miR-30a in innate sentinel cells.

Restrictive influence of SAMHD1 on Hepatitis B Virus life cycle.

Deoxynucleotide triphosphates (dNTPs) are essential for efficient hepatitis B virus (HBV) replication. Here, we investigated the influence of the restriction factor SAMHD1, a dNTP hydrolase (dNTPase) and RNase, on HBV replication. We demonstrated that silencing of SAMHD1 in hepatic cells increased HBV replication, while overexpression had the opposite effect. SAMHD1 significantly affected the levels of extracellular viral DNA as well as intracellular reverse transcription products, without affecting HBV RNAs or cccDNA. SAMHD1 mutations that interfere with the dNTPase activity (D137N) or in the catalytic center of the histidine-aspartate (HD) domain (D311A), and a phospho-mimetic mutation (T592E), abrogated the inhibitory activity. In contrast, a mutation diminishing the potential RNase but not dNTPase activity (Q548A) and a mutation disabling phosphorylation (T592A) did not affect antiviral activity. Moreover, HBV restriction by SAMHD1 was rescued by addition of deoxynucleosides. Although HBV infection did not directly affect protein level or phosphorylation of SAMHD1, the virus upregulated intracellular dATPs. Interestingly, SAMHD1 was dephosphorylated, thus in a potentially antiviral-active state, in primary human hepatocytes. Furthermore, SAMHD1 was upregulated by type I and II interferons in hepatic cells. These results suggest that SAMHD1 is a relevant restriction factor for HBV and restricts reverse transcription through its dNTPase activity.

NLRX1 Sequesters STING to Negatively Regulate the Interferon Response, Thereby Facilitating the Replication of HIV-1 and DNA Viruses.

Understanding the negative regulators of antiviral immune responses will be critical for advancing immune-modulated antiviral strategies. NLRX1, an NLR protein that negatively regulates innate immunity, was previously identified in an unbiased siRNA screen as required for HIV infection. We find that NLRX1 depletion results in impaired nuclear import of HIV-1 DNA in human monocytic cells. Additionally, NLRX1 was observed to reduce type-I interferon (IFN-I) and cytokines in response to HIV-1 reverse-transcribed DNA. NLRX1 sequesters the DNA-sensing adaptor STING from interaction with TANK-binding kinase 1 (TBK1), which is a requisite for IFN-1 induction in response to DNA. NLRX1-deficient cells generate an amplified STING-dependent host response to cytosolic DNA, c-di-GMP, cGAMP, HIV-1, and DNA viruses. Accordingly, Nlrx1(-/-) mice infected with DNA viruses exhibit enhanced innate immunity and reduced viral load. Thus, NLRX1 is a negative regulator of the host innate immune response to HIV-1 and DNA viruses.

Interferon but not MxB inhibits foamy retroviruses.

Foamy viruses (FV) are retroviruses that are widely distributed in primate and non-primate animal species. We tested here FV with capsids of simian and non-simian origin for sensitivity to interferon-ß (IFN-ß). Our data show significant inhibition of FV by IFN-ß early in infection of human HOS and THP-1 but not of HEK293T cells. The post-entry restriction of FV was not mediated by the interferon-induced MxB protein that was recently identified as a capsid-interacting restriction factor targeting Human immunodeficiency virus (HIV) before integration. Neither the ectopic expression of MxA or MxB in HEK293T cells nor the lack of MxB expression in CRISPR/CAS MxB THP-1 knockout cells impacted the infection of the tested FV. IFN-ß treated THP-1 and THP-1 KO MxB cells showed the same extend of restriction to FV. Together, the data demonstrate that IFN-ß inhibits FV early in infection and that MxB is not a restriction factor of FV.