European Centre for Disease Prevention and Control
An agency of the European Union
In 2023, after several months of very low rates of infection, coronavirus disease 2019 (COVID-19) transmission has started to increase in some EU/EEA countries. Although this has coincided with increasing detections of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) XBB.1.5-like lineages carrying the F456L mutation, there are other drivers that can contribute to the increasing transmission rates. This includes large gatherings during seasonal holidays and lower levels of immunological protection against infection after several months of very low disease incidence. There is currently no sign of increased hospitalisations or pressures on healthcare systems.
ECDC classified XBB.1.5-like lineages with the additional amino acid change F456L as variants of interest (VOI) due to a rapid increase in the proportion of these variants presently in circulation, which may have immune-escape properties compared to the variants which were previously in circulation.
Based on what is observed in countries outside the EU/EEA, it is likely that F456L variants will contribute to increased transmission in the coming weeks. However, it is unlikely that the resultant levels of severe disease will reach those of similar peaks previously observed during the COVID-19 pandemic. It is also unlikely that F456L variants are associated with any increase in infection severity compared to the previously circulating variants, or reduction in vaccine effectiveness against severe disease. However, as for other SARS-CoV-2 variants, older individuals and those with underlying conditions could develop severe symptoms if infected.
The completeness and timeliness of epidemiological and virological COVID-19 surveillance data has decreased in the last year, which affects the ability to make an assessment for all EU/EEA countries. Member States are encouraged to expand their use of, and report data from well-designed, representative population-based surveillance in primary and secondary care to monitor trends in transmission and severe disease by time, place, and person, in a timely manner. Where possible, all SARS-CoV-2-positive specimens from representative surveillance systems should be sequenced and reported to the Global Initiative on Sharing All Influenza Data (GISAID) and/or The European Surveillance System (TESSy) to facilitate the assessment of circulating variants.
Adherence to national vaccination schedules is essential to protect people at high risk for severe disease and death. Countries should assess their readiness to identify target groups and conduct timely COVID-19 vaccination campaigns. In addition, communication campaigns aimed at the public and healthcare professionals are deemed necessary to reach high-risk groups and inform them of the importance to stay up to date with vaccination.
As of 10 August 2023, ECDC classified all XBB.1.5-like lineages with the additional spike protein change F456L as SARS-CoV-2 variants of interest (VOI). The reasons for this classification are: a) the rapid increase in the proportion of this mutation in the positive samples from EU/EEA countries, b) a slight increase in the epidemiological indicators of community transmission, and c) the mutation is predicted and verified by a preliminary in-vitro study to contribute to immune escape, compared to the previously circulating variants [1].
So far there is no evidence that F456L variants meet any of the criteria for variants of concern (VOC), i.e. moderate to high evidence of the variant being associated with an increase in infection severity, a risk for compromising the healthcare capacity in the EU/EEA, or a reduction in vaccine effectiveness (Figure 1). ECDC SARS-CoV-2 variant classification criteria and recommended actions for EU/EEA Member States are outlined on the ECDC variant webpage [2,3].
ECDC criteria as of 29 June 2023
VUM
VOI
VOC
(Weak)
(Low-Mod)
(Mod-High)
Predicted growth advantage in the EU/EEA
Yes
Yes
Yes
Predicted EU/EEA epi impact (increases in cases or other measure)
Unclear
Possible
Likely
ECDC risk assessment to be undertaken
No
Yes
Yes
Risk assessment confirms with moderate/high certainty any of
– increased severity
– risk of healthcare system compromise
– reduced vaccine effectiveness
N/A
No
Yes
VUM: variants under monitoring; VOI: variants of interest; VOC: variants of concern
The mutation is also increasing globally, with the World Health Organization (WHO) classifying EG.5, which is the most prevalent lineage with this mutation, as a VOI as of 9 August 2023 [4] and the United Kingdom Health Security Agency (UKHSA) classifying EG.5.1 as a variant as of 31 July 2023 [5]. ECDC classifies EG.5 within the group of lineages carrying F456L, since all 456L-lineages exhibit elevated growth rates, and the likely source of the elevated growth rate is mainly the F456L change itself.
The XBB.1.5-like lineages with F456L are characterised by spike protein receptor-binding domain changes F456L, N460K, S486P, and F490S. The XBB.1.5-like umbrella already comprises several distinct lineages which are all descendants from the recombinant lineage XBB that emerged and became successful in late 2022. Among these, there are XBB.1.5, XBB.1.9.1, XBB.1.9.2, XBB.1.16, and XBB.2.3. Several different sub-lineages within these have now acquired the additional spike protein change F456L which currently seems to confer a selective advantage over the previously circulating variants. Among these lineages, there is FE.1, which rose to high proportions close to dominance in Brazil in May 2023, but did not have wider success globally. There is also EG.5, which is now the most common lineage within the F456L group, both globally and in the EU/EEA (Figure 2).
Source: GISAID EpiCoV (Note, that the assignment of novel lineages in GISAID EpiCoV is associated with some delay. For this reason, some sequences are assigned to more parental lineages. Reporting delays affect the number of sequences from the last three to four weeks shown in the figure.)
The CoV-spectrum tool provides estimates of the weekly growth advantage of variants over the currently circulating variants using a logistic regression model fitted to data from GISAID EpiCoV. These estimates are associated with significant uncertainty due to potential biases in the underlying data.
As of 14 August 2023, the EG.5 lineage is estimated to have a weekly growth advantage relative to the previously circulating lineages in the United States – US (1.38), the UK (1.51), and Europe (1.59) [6].
Among the other lineages within the F456L group that are circulating in lower proportions (e.g. FL.1.5.1, XBB.1.16.6, and XBB.1.5.59), the FL.1.5.1 lineage is also currently estimated to have a large growth advantage relative to the previously circulating lineages in the US (1.67) and the UK (1.47) [7]. This variant is also currently the dominant lineage in the Dominican Republic (61% proportion),and is circulating in low proportions in EU/EEA countries.
The lineage XBB.1.16.6 has also been estimated to have growth advantage in the US (1.39), the UK (1.57), and Europe (1.44) [8]. The growth advantage observed for 456L-lineages is most likely caused by increased immune escape conferred by the F456L change [1], combined with waning immunity to infection in the population.
The latest epidemiological bulletin of WHO reports that cases of COVID-19 globally remain at low levels in August 2023, compared with the last peak of cases in November to December 2022. Cases of COVID-19 decreased between December 2022 and June 2023, when the cases reached the lowest levels observed in 2023 [9].
Between 10 July and 6 August 2023, 1.5 million new cases of COVID-19 and over 2 500 deaths have been reported. This constitutes an increase of 80% in cases of COVID-19 compared to the previous reporting period. The number of deaths, however, decreased by 57%. During this period, 103 countries reported COVID-19 data to WHO. However, due to the global reduction in testing and reporting, number of reported cases do not reflect infection rates adequately. All the WHO Regions reported a decrease in cases of COVID-19 during this period, except the Western Pacific Region which showed an increase of 137% compared with the previous reporting period. This was mostly driven by a large increase in the number of cases in South Korea.
Outside of the EU/EEA, the following countries reported an increase in cases of COVID-19 during this period in 2023:
In addition, the ECDC Epidemic Intelligence team has identified signals of increases in cases of COVID-19 through open media sources in the following countries:
Source: GISAID EpiCoV
The nine EU/EEA countries reporting at least 10 sequences to GISAID EpiCoV for week 29 (17 July to 23 July 2023) showed the following proportions of XBB.1.5-like + F456L lineages: Denmark (41%), France (42%), Germany (10%), Iceland (59%), Ireland (47%), Italy (10%), Portugal (60%), Spain (34%), and Sweden (24%). The overall trend for the variant proportion is increasing (Figure 4). The most common lineage within XBB.1.5-like + F456L is EG.5 and its sub-lineages (Figure 5).
Source: GISAID EpiCoV
Source: GISAID EpiCoV
Sequences that are not part of the XBB.1.5-like + F456L umbrella are mainly from other XBB.1.5-like lineages, and there are also some BA.2.75-descendant lineages still in circulation, such as CH.1.1.
Data reported to ECDC by the end of week 31 (ending 6 August 2023) suggest that transmission of SARS-CoV-2 is increasing in many countries across the EU/EEA from the low levels observed during the summer [19]. Increasing levels of respiratory illness among patients presenting to sentinel general practitioners were reported in some countries, together with an elevated proportion of positive tests for SARS-CoV-2 in this setting. Additionally, among 18 countries which are still able to report age-specific counts of cases testing positive for COVID-19, half of them observed increases in COVID-19 case rates among people aged 65 years.
The availability of data on severe COVID-19 disease is more limited, but suggests minimal impact on severity to date. None of the four countries reporting data from severe acute respiratory infections (SARI) surveillance up to week 31 observed increasing or elevated rates of SARI hospitalisations. One additional country without a SARI surveillance system reported an increasing trend in COVID-19 hospital admissions compared to the last week. Four countries observed increasing death rates in the 65–79 years and 80 years and above age groups. These trends in reported deaths and hospital admissions are recent (of one to three weeks’ duration) and current levels remain very low relative to peaks reported during the pandemic.
Current data availability makes it challenging to assess the COVID-19 epidemiological situation in the EU/EEA. Although some countries have continued with primary care syndromic surveillance this summer, the low levels of testing of symptomatic patients in these settings add substantial uncertainty to estimates of SARS-CoV-2 positivity. SARI surveillance has been expanded in the EU/EEA but is still limited to relatively few countries. As of week 31, around two-thirds of countries reported data on counts of cases testing positive for COVID-19, a third reported data on admissions to hospital or ICU, and half reported data on COVID-19 deaths. These can still be a useful complement to data from sentinel systems, but must be treated with some caution. The lack of a proper case definition and potential for changes in underlying strategies for testing and reporting can introduce bias or artefact. The reduction in PCR testing and low levels of transmission over the summer has also led to very limited volumes of sequencing, which limits ECDC’s ability to assess variants.
As outlined in the guidance document, ‘Operational considerations for respiratory virus surveillance in Europe’ [19], EU/EEA Member States are encouraged to expand their use of, and report data from well-designed, representative population-based surveillance in primary and secondary care to monitor trends in transmission and severe disease. Where possible, all SARS-CoV-2-positive specimens from representative surveillance systems should be sequenced and reported to GISAID and/or TESSy to facilitate the assessment of circulating variants.
ECDC has provided interim public health considerations for COVID-19 vaccination roll-out during 2023 [20]. Since then, National Technical Immunisation Groups (NITAGs) in several EU/EEA countries have issued recommendations regarding the COVID-19 vaccination campaigns in autumn 2023. For most of the countries, target groups include: older adults (different age cut-offs, i.e. 50, 60, 65 years), individuals with underlying medical conditions regardless of age (including the immunocompromised), pregnant women, and healthcare workers. Recently, the WHO Regional Office for Europe (WHO/Europe) issued a guidance document on the development of national COVID-19 vaccination policies and planning, implementing, and monitoring integration of COVID-19 vaccination into national immunisation programmes (NIPs) [21].
Due to the evolving COVID-19 epidemiology, adherence to vaccination schedule is essential to protect people at high risk for severe disease and death. Countries should assess their readiness to identify target groups and conduct timely COVID-19 vaccination campaigns. Decisions made at the country level depend on several key evolving factors, such as the specific national epidemiological situation, availability of vaccines, projected vaccine uptake in different target groups, the capacity of healthcare systems to deliver vaccinations, and other factors. Communication campaigns aimed at the public and healthcare professionals are deemed necessary in an effort to reach high-risk groups and inform them of the importance to stay up to date with vaccination.
Erik Alm, Jon Bilbatua, Kim Brolin, Nick Bundle, Priyanka Nannapaneni, Ajibola Omokanye, Giulia Perego, Adriana Romani, Theodora Stavrou
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ECDC regularly assesses new evidence on variants detected through epidemic intelligence, rules-based genomic variant screening or other scientific sources.
Well-designed, representative sentinel surveillance systems in primary and secondary care remain the core surveillance method for acute viral respiratory infections.