Investing in health preparedness, response and resilience: a genomics costing tool focused on next generation sequencing.

The world has seen unprecedented gains in the global genomic surveillance capacities for pathogens with pandemic and epidemic potential within the last 4 years. To strengthen and sustain the gains made, WHO is working with countries and partners to implement the Global Genomic Surveillance Strategy for Pathogens with Pandemic and Epidemic Potential 2022-2032. A key technical product developed through these multi-agency collaborative efforts is a genomics costing tool (GCT), as sought by many countries. This tool was developed by five institutions - Association of Public Health Laboratories, FIND, The Global Fund to Fight AIDS, Tuberculosis and Malaria, UK Health Security Agency, and the World Health Organization. These institutions developed the GCT to support financial planning and budgeting for SARS-CoV-2 next-generation sequencing activities, including bioinformatic analysis. The tool costs infrastructure, consumables and reagents, human resources, facility and quality management. It is being used by countries to (1) obtain costs of routine sequencing and bioinformatics activities, (2) optimize available resources, and (3) build an investment case for the scale-up or establishment of sequencing and bioinformatics activities. The tool has been validated and is available in English and Russian at https://www.who.int/publications/i/item/9789240090866. This paper aims to highlight the rationale for developing the tool, describe the process of the collaborative effort in developing the tool, and describe the utility of the tool to countries.

Strengthening pathogen genomic surveillance for health emergencies: insights from the World Health Organization's regional initiatives.

The onset of the COVID-19 pandemic triggered a rapid scale-up in the use of genomic surveillance as a pandemic preparedness and response tool. As a result, the number of countries with in-country SARS-CoV-2 genomic sequencing capability increased by 40% from February 2021 to July 2022. The Global Genomic Surveillance Strategy for Pathogens with Pandemic and Epidemic Potential 2022-2032 was launched by the World Health Organization (WHO) in March 2022 to bring greater coherence to ongoing work to strengthen genomic surveillance. This paper describes how WHO's tailored regional approaches contribute to expanding and further institutionalizing the use of genomic surveillance to guide pandemic preparedness and response measures as part of a harmonized global undertaking. Challenges to achieving this vision include difficulties obtaining sequencing equipment and supplies, shortages of skilled staff, and obstacles to maximizing the utility of genomic data to inform risk assessment and public health action. WHO is helping to overcome these challenges in collaboration with partners. Through its global headquarters, six regional offices, and 153 country offices, WHO is providing support for country-driven efforts to strengthen genomic surveillance in its 194 Member States, with activities reflecting regional specificities. WHO's regional offices serve as platforms for those countries in their respective regions to share resources and knowledge, engage stakeholders in ways that reflect national and regional priorities, and develop regionally aligned approaches to implementing and sustaining genomic surveillance within public health systems.

Global update on the susceptibilities of human influenza viruses to neuraminidase inhibitors and the cap-dependent endonuclease inhibitor baloxavir, 2018-2020.

Global analysis of the susceptibility of influenza viruses to neuraminidase (NA) inhibitors (NAIs) and the polymerase acidic (PA) inhibitor (PAI) baloxavir was conducted by five World Health Organization Collaborating Centres for Reference and Research on Influenza during two periods (May 2018-May 2019 and May 2019-May 2020). Combined phenotypic and NA sequence-based analysis revealed that the global frequency of viruses displaying reduced or highly reduced inhibition (RI or HRI) or potential to show RI/HRI by NAIs remained low, 0.5% (165/35045) and 0.6% (159/26010) for the 2018-2019 and 2019-2020 periods, respectively. The most common amino acid substitution was NA-H275Y (N1 numbering) conferring HRI by oseltamivir and peramivir in A(H1N1)pdm09 viruses. Combined phenotypic and PA sequence-based analysis showed that the global frequency of viruses showing reduced susceptibility to baloxavir or carrying substitutions associated with reduced susceptibility was low, 0.5% (72/15906) and 0.1% (18/15692) for the 2018-2019 and 2019-2020 periods, respectively. Most (n = 61) of these viruses had I38→T/F/M/S/L/V PA amino acid substitutions. In Japan, where baloxavir use was highest, the rate was 4.5% (41/919) in the 2018-2019 period and most of the viruses (n = 32) had PA-I38T. Zoonotic viruses isolated from humans (n = 32) in different countries did not contain substitutions in NA associated with NAI RI/HRI phenotypes. One A(H5N6) virus had a dual substitution PA-I38V + PA-E199G, which may reduce susceptibility to baloxavir. Therefore, NAIs and baloxavir remain appropriate choices for the treatment of influenza virus infections, but close monitoring of antiviral susceptibility is warranted.

Virological surveillance of influenza viruses in the WHO European Region in 2019/20 - impact of the COVID-19 pandemic.

The COVID-19 pandemic negatively impacted the 2019/20 WHO European Region influenza surveillance. Compared with previous 4-year averages, antigenic and genetic characterisations decreased by 17% (3,140 vs 2,601) and 24% (4,474 vs 3,403). Of subtyped influenza A viruses, 56% (26,477/47,357) were A(H1)pdm09, 44% (20,880/47,357) A(H3). Of characterised B viruses, 98% (4,585/4,679) were B/Victoria. Considerable numbers of viruses antigenically differed from northern hemisphere vaccine components. In 2020/21, maintaining influenza virological surveillance, while supporting SARS-CoV-2 surveillance is crucial.

Geographical and temporal distribution of SARS-CoV-2 clades in the WHO European Region, January to June 2020.

We show the distribution of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) genetic clades over time and between countries and outline potential genomic surveillance objectives. We applied three genomic nomenclature systems to all sequence data from the World Health Organization European Region available until 10 July 2020. We highlight the importance of real-time sequencing and data dissemination in a pandemic situation, compare the nomenclatures and lay a foundation for future European genomic surveillance of SARS-CoV-2.

Predominance of influenza virus A(H3N2) 3C.2a1b and A(H1N1)pdm09 6B.1A5A genetic subclades in the WHO European Region, 2018-2019.

BACKGROUND: The 2018/2019 influenza season in the WHO European Region was dominated by influenza A (H1N1)pdm09 and (H3N2) viruses, with very few influenza B viruses detected. METHODS: Countries in the European Region reported virus characterization data to The European Surveillance System for weeks 40/2018 to 20/2019. These virus antigenic and genetic characterization and haemagglutinin (HA) sequence data were analysed to describe and assess circulating viruses relative to the 2018/2019 vaccine virus components for the northern hemisphere. RESULTS: Thirty countries reported 4776 viruses characterized genetically and 3311 viruses antigenically. All genetically characterized A(H1N1)pdm09 viruses fell in subclade 6B.1A, of which 90% carried the amino acid substitution S183P in the HA gene. Antigenic data indicated that circulating A(H1N1)pdm09 viruses were similar to the 2018/2019 vaccine virus. Genetic data showed that A(H3N2) viruses mostly fell in clade 3C.2a (75%) and 90% of which were subclade 3C.2a1b. A lower proportion fell in clade 3C.3a (23%) and were antigenically distinct from the vaccine virus. All B/Victoria viruses belonged to clade 1A; 30% carried a double amino acid deletion in HA and were genetically and antigenically similar to the vaccine virus component, while 55% carried a triple amino acid deletion or no deletion in HA; these were antigenically distinct from each other and from the vaccine component. All B/Yamagata viruses belonged to clade 3 and were antigenically similar to the virus component in the quadrivalent vaccine for 2018/2019. CONCLUSIONS: A simultaneous circulation of genetically and antigenically diverse A(H3N2) and B/Victoria viruses was observed and represented a challenge to vaccine strain selection.

First cases of coronavirus disease 2019 (COVID-19) in the WHO European Region, 24 January to 21 February 2020.

In the WHO European Region, COVID-19 surveillance was implemented 27 January 2020. We detail the first European cases. As at 21 February, nine European countries reported 47 cases. Among 38 cases studied, 21 were linked to two clusters in Germany and France, 14 were infected in China. Median case age was 42 years; 25 were male. Late detection of the clusters' index cases delayed isolation of further local cases. As at 5 March, there were 4,250 cases.

Global update on the susceptibilities of human influenza viruses to neuraminidase inhibitors and the cap-dependent endonuclease inhibitor baloxavir, 2017-2018.

The global analysis of neuraminidase inhibitor (NAI) susceptibility of influenza viruses has been conducted since the 2012-13 period. In 2018 a novel cap-dependent endonuclease inhibitor, baloxavir, that targets polymerase acidic subunit (PA) was approved for the treatment of influenza virus infection in Japan and the United States. For this annual report, the susceptibilities of influenza viruses to NAIs and baloxavir were analyzed. A total of 15409 viruses, collected by World Health Organization (WHO) recognized National Influenza Centers and other laboratories between May 2017 and May 2018, were assessed for phenotypic NAI susceptibility by five WHO Collaborating Centers (CCs). The 50% inhibitory concentration (IC50) was determined for oseltamivir, zanamivir, peramivir and laninamivir. Reduced inhibition (RI) or highly reduced inhibition (HRI) by one or more NAIs was exhibited by 0.8% of viruses tested (n = 122). The frequency of viruses with RI or HRI has remained low since this global analysis began (2012-13: 0.6%; 2013-14: 1.9%; 2014-15: 0.5%; 2015-16: 0.8%; 2016-17: 0.2%). PA gene sequence data, available from public databases (n = 13523), were screened for amino acid substitutions associated with reduced susceptibility to baloxavir (PA E23G/K/R, PA A36V, PA A37T, PA I38F/M/T/L, PA E119D, PA E199G): 11 (0.08%) viruses possessed such substitutions. Five of them were included in phenotypic baloxavir susceptibility analysis by two WHO CCs and IC50 values were determined. The PA variant viruses showed 6-17-fold reduced susceptibility to baloxavir. Overall, in the 2017-18 period the frequency of circulating influenza viruses with reduced susceptibility to NAIs or baloxavir was low, but continued monitoring is important.

Alternating patterns of seasonal influenza activity in the WHO European Region following the 2009 pandemic, 2010-2018.

BACKGROUND: Influenza virus infections are common and lead to substantial morbidity and mortality worldwide. We characterized the first eight influenza epidemics since the 2009 influenza pandemic by describing the distribution of viruses and epidemics temporally and geographically across the WHO European Region. METHODS: We retrospectively analyzed laboratory-confirmed influenza detections in ambulatory patients from sentinel sites. Data were aggregated by reporting entity and season (weeks 40-20) for 2010-2011 to 2017-2018. We explored geographical spread using correlation coefficients. RESULTS: There was variation in the regional influenza epidemics during the study period. Influenza A virus subtypes alternated in dominance, except for 2013-2014 during which both cocirculated, and only one season (2017-2018) was B virus dominant. The median start week for epidemics in the Region was week 50, the time to the peak ranged between four and 13 weeks, and the duration of the epidemic ranged between 19 and 25 weeks. There was evidence of a west-to-east spread across the Region during epidemics in 2010-2011 (r = .365; P = .019), 2012-2013 (r = .484; P = .001), 2014-2015 (r = .423; P = .006), and 2017-2018 (r = .566; P < .001) seasons. Variation in virus distribution and timing existed within reporting entities across seasons and across reporting entities for a given season. CONCLUSIONS: Aggregated influenza detection data from sentinel surveillance sites by season between 2010 and 2018 have been presented for the European Region for the first time. Substantial diversity exists between influenza epidemics. These data can inform prevention and control efforts at national, sub-national, and international levels. Aggregated, regional surveillance data from early affected reporting entities may provide an early warning function and be helpful for early season forecasting efforts.

Co-circulation of influenza A(H1N1)pdm09 and influenza A(H3N2) viruses, World Health Organization (WHO) European Region, October 2018 to February 2019.

In the World Health Organization European Region, the 2018/19 influenza season started in week 49 2018, crossing 10% virus-positivity in sentinel surveillance specimens. At week 5 2019, activity remained elevated with positivity rates at 55%. Both A(H1N1)pdm09 and A(H3N2) viruses circulated widely and detection levels in primary care and hospital settings were similar to past seasons. Hospitalisation data may suggest an increased susceptibility to A(H1N1)pdm09 virus in older age groups.

Global update on the susceptibility of human influenza viruses to neuraminidase inhibitors and status of novel antivirals, 2016-2017.

A total of 13672 viruses, collected by World Health Organization recognised National Influenza Centres between May 2016 and May 2017, were assessed for neuraminidase inhibitor susceptibility by four WHO Collaborating Centres for Reference and Research on Influenza and one WHO Collaborating Centre for the Surveillance Epidemiology and Control of Influenza. The 50% inhibitory concentration (IC50) was determined for oseltamivir and zanamivir for all viruses, and for peramivir and laninamivir in a subset (n = 8457). Of the viruses tested, 94% were obtained from the Western Pacific, Americas and European WHO regions, while limited viruses were available from the Eastern Mediterranean, African and South East Asian regions. Reduced inhibition (RI) by one or more neuraminidase inhibitor was exhibited by 0.2% of viruses tested (n = 32). The frequency of viruses with RI has remained low since this global analysis began (2015/16: 0.8%, 2014/15: 0.5%; 2013/14: 1.9%; 2012/13: 0.6%) but 2016/17 has the lowest frequency observed to date. Analysis of 13581 neuraminidase sequences retrieved from public databases, of which 5243 sequences were from viruses not included in the phenotypic analyses, identified 58 further viruses (29 without phenotypic analyses) with amino acid substitutions associated with RI by at least one neuraminidase inhibitor. Bringing the total proportion to 0.5% (90/18915). This 2016/17 analysis demonstrates that neuraminidase inhibitors remain suitable for treatment and prophylaxis of influenza virus infections, but continued monitoring is important. An expansion of surveillance testing is paramount since several novel influenza antivirals are in late stage clinical trials with some resistance already having been identified.

Global update on the susceptibility of human influenza viruses to neuraminidase inhibitors, 2015-2016.

Four World Health Organization (WHO) Collaborating Centres for Reference and Research on Influenza and one WHO Collaborating Centre for the Surveillance, Epidemiology and Control of Influenza (WHO CCs) assessed antiviral susceptibility of 14,330 influenza A and B viruses collected by WHO-recognized National Influenza Centres (NICs) between May 2015 and May 2016. Neuraminidase (NA) inhibition assay was used to determine 50% inhibitory concentration (IC50) data for NA inhibitors (NAIs) oseltamivir, zanamivir, peramivir and laninamivir. Furthermore, NA sequences from 13,484 influenza viruses were retrieved from public sequence databases and screened for amino acid substitutions (AAS) associated with reduced inhibition (RI) or highly reduced inhibition (HRI) by NAIs. Of the viruses tested by WHO CCs 93% were from three WHO regions: Western Pacific, the Americas and Europe. Approximately 0.8% (n = 113) exhibited either RI or HRI by at least one of four NAIs. As in previous seasons, the most common NA AAS was H275Y in A(H1N1)pdm09 viruses, which confers HRI by oseltamivir and peramivir. Two A(H1N1)pdm09 viruses carried a rare NA AAS, S247R, shown in this study to confer RI/HRI by the four NAIs. The overall frequency of A(H1N1)pdm09 viruses containing NA AAS associated with RI/HRI was approximately 1.8% (125/6915), which is slightly higher than in the previous 2014-15 season (0.5%). Three B/Victoria-lineage viruses contained a new AAS, NA H134N, which conferred HRI by zanamivir and laninamivir, and borderline HRI by peramivir. A single B/Victoria-lineage virus harboured NA G104E, which was associated with HRI by all four NAIs. The overall frequency of RI/HRI phenotype among type B viruses was approximately 0.6% (43/7677), which is lower than that in the previous season. Overall, the vast majority (>99%) of the viruses tested by WHO CCs were susceptible to all four NAIs, showing normal inhibition (NI). Hence, NAIs remain the recommended antivirals for treatment of influenza virus infections. Nevertheless, our data indicate that it is prudent to continue drug susceptibility monitoring using both NAI assay and sequence analysis.

Global update on the susceptibility of human influenza viruses to neuraminidase inhibitors, 2014-2015.

The World Health Organization (WHO) Collaborating Centres for Reference and Research on Influenza (WHO CCs) tested 13,312 viruses collected by WHO recognized National Influenza Centres between May 2014 and May 2015 to determine 50% inhibitory concentration (IC50) data for neuraminidase inhibitors (NAIs) oseltamivir, zanamivir, peramivir and laninamivir. Ninety-four per cent of the viruses tested by the WHO CCs were from three WHO regions: Western Pacific, the Americas and Europe. Approximately 0.5% (n = 68) of viruses showed either highly reduced inhibition (HRI) or reduced inhibition (RI) (n = 56) against at least one of the four NAIs. Of the twelve viruses with HRI, six were A(H1N1)pdm09 viruses, three were A(H3N2) viruses and three were B/Yamagata-lineage viruses. The overall frequency of viruses with RI or HRI by the NAIs was lower than that observed in 2013-14 (1.9%), but similar to the 2012-13 period (0.6%). Based on the current analysis, the NAIs remain an appropriate choice for the treatment and prophylaxis of influenza virus infections.

The potential risks and impact of the start of the 2015-2016 influenza season in the WHO European Region: a rapid risk assessment.

BACKGROUND: Countries in the World Health Organization (WHO) European Region are reporting more severe influenza activity in the 2015-2016 season compared to previous seasons. OBJECTIVES: To conduct a rapid risk assessment to provide interim information on the severity of the current influenza season METHODS: Using the WHO manual for rapid risk assessment of acute public health events and surveillance data available from Flu News Europe, an assessment of the current influenza season from 28 September 2015 (week 40/2015) up to 31 January 2016 (week 04/2016) was made compared with the 4 previous seasons. RESULTS: The current influenza season started around week 51/2015 with higher influenza activity reported in eastern Europe compared to Western Europe. There is a strong predominance of influenza A(H1N1)pdm09 compared to previous seasons, but the virus is antigenically similar to the strain included in the seasonal influenza vaccine. Compared to the 2014/2015 season, there was a rapid increase in the number of severe cases in eastern European countries with the majority of such cases occurring among adults aged <65 years. CONCLUSIONS: The current influenza season is characterised by an early start in eastern European countries, with indications of a more severe season. Currently circulating influenza A(H1N1)pdm09 viruses are similar antigenically to those included in the seasonal influenza vaccine and the vaccine is expected to be effective. Authorities should provide information to the public and health providers about the current influenza season, recommendations for treatment of severe disease and effective public health measures to prevent influenza transmission. This article is protected by copyright. All rights reserved.

Improving the representativeness of influenza viruses shared within the WHO Global Influenza Surveillance and Response System.

BACKGROUND: Sharing influenza viruses within the WHO Global Influenza Surveillance and Response System is crucial for monitoring evolution of influenza viruses. OBJECTIVES: Analysis of timeliness and geographic representativeness of viruses shared by National Influenza Centres (NICs) in the WHO European Region with the London WHO Collaborating Centre for Reference and Research on Influenza for the Northern Hemisphere's 2010-2011 and 2011-2012 influenza seasons. MATERIALS AND METHODS: Data from NICs on influenza-positive specimens shared with WHO CC London for the above-mentioned influenza seasons were analyzed for timeliness of sharing with respect to the February deadline (31 January) for inclusion in the WHO consultations on the composition of influenza virus vaccines for the Northern Hemisphere and geographic representativeness. RESULTS: The 2010-2011 and 2011-2012 seasons were different in terms of the seasonal pattern, the timing of the epidemic, and the dominant virus. Consistent patterns of virus sharing across the seasons were observed. Approximately half the viruses collected before the deadline were not shared within the deadline; the average delay between date of specimen collection and shipment receipt was 3 and 1·5 months for the first and second season, respectively. CONCLUSION: A baseline was provided for future work on enhancement of specimen sharing in the WHO European Region and improving the vaccine virus selection process. Greater insight into virus selection criteria applied by countries and the causes of delays in shipment are needed to understand the representativeness of viruses shared and to assess the importance of this for vaccine strain selection.