SARS-CoV-2 variants BA.4 and BA.5 were first detected in South Africa in January and February 2022. They became the dominant variants in this country in May 2022.  and a parallel growing trend in epidemiological indicators such as the number of reported cases and the positivity rate of tests suggested that these two options were responsible for the increase in cases observed in South Africa between April and May 2022. As of May 12, 2022, the ECDC reclassified Omicron BA.4 and BA.5 from variants of interest to variants of concern. .
BA.4 and BA.5 are two sublines of the Omicron clade (B.1.1.529). They share the same mutation profile in the spike gene, while in the remaining genome they have different sets of mutations. Defining mutations in the spike protein BA.4 and BA.5 compared to BA.2 include A69-70, L452R, F486V and R493Q (reverse). Due to the current epidemiological background, where BA.2 is the dominant variant in the EU / EEA, laboratories may take advantage of the presence of peak changes in L452R or F486V or the failure of the S-gene target  as a preliminary examination of variants. In order to distinguish between BA.4 and BA.5, tests targeting mismatched parts outside the spike gene or whole genome sequencing (WGS) are required. Due to the recent emergence of BA.4 and BA.5, it has not yet been possible to include variants in the evaluation study of the Rapid Antigen Detection Test (RADT).
There is currently no indication of any change in severity with BA.4 or BA.5 compared to previous Omicron lines. Severity indicators in Portugal (hospitalizations, ICU admissions and deaths) are below the levels reached in the previous Omicron peak as of 1 June, but week-on-week increases can still be observed. During the last six weeks, there has been an increase in the number of hospitalizations and admissions in the ICU, mainly among people aged 60 and over .
The current growth advantage of variants BA.4 and BA.5, which is of interest (observed mainly in South Africa  and Portugal ) compared to the dominant variant BA.2 is probably due to their ability to avoid immune protection against infection caused by a previous infection and / or vaccination, especially if it has disappeared over time. Based on preliminary in-vitro data from the preprints, BA.4 and BA.5 are antigenically distant from the original virus [7,8] and compared to BA.1 and BA.2, sera from individuals vaccinated with three doses of COVID-19 (Vaxzevria or Comirnaty) or sera from breakthrough BA.1 infections are less effectively neutralized [8,9]. In addition, there has been an increased rate of re-infection in Portugal . Overall, this raises concerns about the more frequent breakthrough infections of BA.4 / BA.5 than BA.1 / BA.2 and Omicron reinfections. However, since the end of Week 22, 2022, overall transmission has continued to decline in most EU / EEA countries, as shown by both the overall case reporting rate and the case rate between people aged 65 and over. .
More evidence is needed to elucidate the efficacy of monoclonal antibodies (mAbs) against BA.4 and BA.5 variants, but evidence so far suggests that BA.4 and BA.5 have shown a reduced or substantially similar pattern of mAb sensitivity to BA.2. [7,11,12].
There are currently no data available on the efficacy of the vaccine against the different clinical outcomes for Omicron BA.4 and BA.5. Vaccine efficacy data against Omicron BA.1 and BA.2 are described in the recently published ECDC Technical Report on the second booster dose of COVID-19 mRNA .
BA.4 and BA.5 in EU / EEA: update as of 13 June 2022
BA.4 and BA.5 were first detected in the EU / EEA in March 2022. Portugal was the first country in the EU / EEA to record a significant increase in cases and the share of one of these two options (BA.5). As of May 30, 2022, BA.5 is the dominant variant of SARS-CoV-2 in Portugal with an estimated share of approximately 87% [6,14]. Between weeks 19 and 20, 2022, the number of cases in Portugal decreased and stabilized, suggesting that the peak of the BA.5 wave may have been reached in Portugal. In recent weeks (weeks 17-21 of 2022), an increase in the proportion of BA.4 and BA.5 infections has been observed in many EU / EEA countries, including Austria, Belgium, Denmark, France, Germany, Ireland, Italy, the Netherlands. , Spain and Sweden [15,16].
Specifically, in Belgium, BA.5 reached an estimated 19% and BA.4 represented 7.5% of the sequenced genomes during weeks 21-22. In Spain, BA.4 and BA.5 accounted for more than 10% of the samples analyzed by variant specific PCR in the 10 Autonomous Communities during weeks 21-22, with large differences between communities. In the Netherlands, BA.5 reached 8% at week 20, while BA.4 was detected at close to 5%.
The growth advantage reported for BA.4 and BA.5 suggests that these options will become dominant across the EU / EEA, which is likely to increase the number of COVID-19 cases in the coming weeks. The extent of the increase will depend on various factors, including immune protection against infection affected by the timing and coverage of the COVID-19 vaccination regimens and the extent, timing and variant environment of previous SARS-CoV-2 pandemic waves. Based on limited data, there is no evidence that BA.4 and BA.5 are associated with an increased severity of infection compared to circulating variants BA.1 and BA.2. However, as in previous waves, an increase in COVID-19 cases may lead to an increase in hospitalizations, ICU admissions and deaths.
Monitoring and reporting
ECDC calls on countries to remain vigilant with regard to signals of the emergence of BA.4 and BA.5. Sensitive and representative testing procedures and genomic surveillance are required to accurately determine the extent to which these variants may contribute to any observed increase in severe outcomes in the population (eg increase in hospitalizations or ICU hospitalizations).
Countries should therefore strengthen sentinel systems (ILI / ARI and SARI primary care) and continue to collect data on laboratory-confirmed cases (from non-sentinel workplaces) and on ICU hospitalizations / incomes and occupancy. . Countries should remain vigilant and expand testing and sequencing if necessary. Countries should continue to sequence positive samples and share sequence data in a timely manner [18,19]. SARS-CoV-2 consensus sequences should be stored in the GISAID database and, if available, raw SARS-CoV-2 sequence data should be stored on the COVID-19 data portal via the European Nucleotide Archive (ENA). . If possible, antigenic characterization should be performed as this will help to understand the properties of these variants and samples / isolates could also be shared for characterization with WHO reference laboratories. .
Minimum metadata should be reported in the TOV type of the NCOV-based record type or in aggregated form in the NCOVVariant, and if possible, the GISAID increment numbers of the sequenced cases should be reported. ECDC invited nominated users from countries to use the EpiPulse event at BA.4 and BA.5 to informally discuss and share information on the two options, namely on virus characterization and evidence of changes in disease severity, virus transmission, immune avoidance and effects on diagnosis and therapy.
Improving the absorption of COVID-19 in the primary course and the first revaccination in the population remains a priority for all age groups to reduce hospitalization and mortality of COVID-19. Detailed information on COVID-19 doses administered and vaccine absorption rates are provided on the ECDC Vaccine Tracker .
Depending on the evolving epidemiology, vaccine efficacy data over time, and other factors such as seasonality, it will be necessary to reconsider the timing and population recommendations that may benefit from additional booster doses.
The ECDC recently assessed that the public health benefit of administering a second booster dose of COVID-19 mRNA is most evident in individuals 80 years of age and older, and immediate administration of a second booster dose to this population was found to be optimal in situations where viral circulation was high or rising. . Mathematical modeling also suggests that the introduction of second revaccinations, including those aged 60-79 who are immunocompetent in the EU / EEA, is likely to be beneficial in terms of averted deaths, although the best timing of introduction is uncertain and will depend on future waves. .
Additional booster doses in anticipation of future waves or before the autumn / winter season are expected to be needed for rapid deployment in those groups most at risk of serious illness (eg adults aged 60 and over and vulnerable populations). These additional doses will have the greatest impact if administered closer to the expected period of increased viral circulation, but before it reaches high levels.
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