Context of the event
SARS-CoV-2 variants BA.4 and BA.5 were first detected in South Africa in January and February 2022, respectively. They became the dominant variants in this country in May 2022  and a parallel upward trend in epidemiological indicators, such as case notification rates and test positivity rates suggested that these two variants were responsible for the spike in cases seen in South Africa in April–May 2022. As of 12 May 2022, the ECDC reclassified the Omicron BA.4 and BA.5 sublines from the interest in variants of concern .
BA.4 and BA.5 are two sublineages of the Omicron clade (B.1.1.529). They share the same mutation profile in the spike gene, while they have different sets of mutations in their remaining genome. Defining mutations in the spike protein of BA.4 and BA.5 relative to BA.2 include Δ69-70, L452R, F486V and R493Q (reversion). Given the current epidemiological context where BA.2 is the dominant variant in the EU/EEA, laboratories can use the presence of the spike changes L452R or F486V or the failure of the S gene target  as a pre-selection of variants. To be able to differentiate BA.4 and BA.5, tests targeting discordant parts outside of the spike gene or whole genome sequencing (WGS) are needed. Since BA.4 and BA.5 have only recently emerged, it has not yet been possible to include the variants in a study evaluating the rapid antigen detection test (RADT).
There is currently no indication of a change in severity for BA.4 or BA.5 compared to previous Omicron lines. Severity indicators in Portugal (hospitalizations, intensive care admissions and deaths) as of June 1 are below the levels reached during the previous Omicron peak, however, weekly increases continue to be observed. Over the past six weeks, hospitalizations and increases in intensive care admissions have mostly been among people aged 60 and over .
The current growth advantage for the BA.4 and BA.5 variants of concern (mostly seen in South Africa  and Portugal ) compared to the dominant BA.2 variant, is likely due to their ability to evade immune protection against infection induced by previous infection and/or vaccination, particularly if this has diminished over time. Based on preliminary in vitro data from preprints, BA.4 and BA.5 are antigenically distant from the ancestral virus [7,8] and, compared to BA.1 and BA.2, they are less effectively neutralized by sera from individuals vaccinated with three doses of COVID-19 vaccine (Vaxzevria or Comirnaty), or by sera from BA breakthrough infections .1 [8,9]. In addition, there has been an increase in the rate of reinfection in Portugal . Overall, this raises concerns about more frequent BA.4/BA.5 breakthrough infections than BA.1/BA.2, and Omicron reinfections. Nevertheless, as of the end of week 22 2022, overall transmission continues to decline in most EU/EEA countries, as shown by both overall case notification rates and case rates in people aged 65 and over. .
More evidence is needed to elucidate the efficacy of monoclonal antibodies (mAb) against BA.4 and BA.5 variants, but evidence so far suggests that BA.4 and BA.5 showed a reduced or largely similar in sensitivity of mAbs to that of BA.2 [7,11,12].
At present, there are no data available on the efficacy of the vaccine against different clinical outcomes for the Omicron BA.4 and BA.5 sublines. Vaccine efficacy data against Omicron BA.1 and BA.2 variants are described in a recently published ECDC technical report on the second booster dose of the COVID-19 mRNA vaccine .
BA.4 and BA.5 in the EU/EEA: updated to June 13, 2022
BA.4 and BA.5 were first detected in the EU/EEA in March 2022. Portugal was the first EU/EEA country to observe a significant increase in cases and the proportion of one of these two variants (BA.5 ). As of May 30, 2022, BA.5 is the dominant variant of SARS-CoV-2 in Portugal, with an estimated proportion of around 87% [6,14]. Between weeks 19 and 20 2022, the number of cases in Portugal decreased and stabilized, indicating that the peak of a BA.5 wave in Portugal may have been reached. Over the past few weeks (week 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 and the Netherlands. , Spain and Sweden [15,16].
In particular, in Belgium, BA.5 reached an estimated proportion of 19% and BA.4 represented 7.5% of the genomes sequenced during weeks 21 to 22. In Spain, BA.4 and BA.5 represented more than 10% of samples analyzed by variant-specific PCR in 10 autonomous communities during weeks 21 to 22, with a large variation between communities. In the Netherlands, BA.5 reached a proportion of 8% at week 20, while BA.4 was detected in a proportion close to 5%.
The growth advantage reported for BA.4 and BA.5 suggests that these variants will become dominant across the EU/EEA, likely leading to an increase in COVID-19 cases in the coming weeks. The magnitude of the increase will depend on a variety of factors, including immune protection against infection influenced by the timing and coverage of COVID-19 vaccination regimens and the extent, timing and landscape of variants from previous waves. SARS-CoV-2 pandemics. Based on limited data, there is no evidence that BA.4 and BA.5 are associated with increased severity of infection compared to circulating variants BA.1 and BA.2. However, as in previous waves, an increase in COVID-19 cases can lead to an increase in hospitalizations, ICU admissions and deaths.
Monitoring and Reporting
ECDC encourages countries to remain vigilant for emerging signs of BA.4 and BA.5. Sensitive and representative testing policies and genomic monitoring are needed to accurately determine the extent to which these variants may contribute to any observed increases in serious outcomes in the population (eg, increased hospital or ICU admissions) .
Countries should therefore strengthen sentinel systems (primary care ILI/ARI and SARI) and continue to collect data on laboratory-confirmed cases (from non-sentinel sites) and hospitalizations/ICU admissions and occupancy. hospital beds. . Countries should remain vigilant and step up 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 deposited in the GISAID database and, if available, raw SARS-CoV-2 sequence data should be deposited in the COVID-19 Data Portal via the European Nucleotide Archive (ENA) . If possible, antigenic characterization should be undertaken as this will help in understanding the properties of these variants and samples/isolates could also be shared for characterization with WHO reference laboratories. .
Minimum metadata should be reported to the TESSy NCOV case record type or in aggregate form to the NCOVVariant and, if possible, GISAID accession numbers of sequenced cases should be reported. ECDC has invited Designated Users in countries to use the EpiPulse event on BA.4 and BA.5 informally discuss and share information about these two variants, particularly virus characterization and evidence for changes in disease severity, virus transmissibility, immune evasion, and effects on diagnosis and therapy .
Improving uptake of the COVID-19 vaccine as part of primary treatment and the first booster dose in populations remains a priority for all age groups to reduce the number of hospitalizations and related deaths. to COVID-19. Detailed information on COVID-19 vaccine doses administered and vaccination rates are reported on the ECDC Vaccine Tracking .
Depending on changing epidemiology, data on vaccine effectiveness over time, and other factors such as seasonality, it will be necessary to reevaluate recommendations on timing and populations likely to benefit from additional booster doses.
The public health benefit of administering a second COVID-19 mRNA booster dose was recently assessed by the ECDC as clearest in people aged 80 years and older and immediate administration of a second booster dose in this population has been shown to be optimal in situations where viral circulation was high or increasing. Mathematical modeling also suggests that a second booster deployment including people aged 60-79 who are immunocompetent in the EU/EEA is likely to be beneficial in terms of deaths averted, although the best timing for deployment is uncertain and will depend on future waves .
Additional booster doses in anticipation of future waves, or prior to the fall/winter season, should be required for rapid deployment in groups most at risk for severe disease (e.g., adults aged 60 and over and medically vulnerable populations). These additional doses will have the greatest impact if given closer to expected periods of increased viral circulation, but before it reaches high levels.
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