The SARS-CoV-2 variants BA.4 and BA.5 were first discovered in South Africa in January and February 2022, respectively. They became the dominant variants in that country in May 2022  and a parallel upward trend in epidemiological indicators, such as the number of cases reported and the percentage of test positivity suggested that these two variants were responsible for the increase in the number of cases seen in South Africa in April-May 2022. Effective May 12, 2022, ECDC has reclassified the Omicron sublines 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 having different sets of mutations in their remaining genome. The defining mutations in the spike protein of BA.4 and BA.5 compared to BA.2 include Δ69-70, L452R, F486V and R493Q (reversion). Given the current epidemiological background in which BA.2 is the dominant variant in the EU/EEA, laboratories can exploit the presence of the peak changes L452R or F486V or failure of the S gene target  as preliminary research into the variants. Distinguishing between BA.4 and BA.5 requires assays targeting discordant parts outside the spike gene or whole genome sequencing (WGS). Because BA.4 and BA.5 were only recently introduced to the market, it was not yet possible to include the variants in an evaluation study with a rapid antigen detection test (RADT).
There is currently no indication of any change in severity for BA.4 or BA.5 compared to previous Omicron lines. Portugal’s severity indicators (hospitalization, ICU admissions and deaths) are below the level reached in the previous Omicron peak on June 1, but weekly increases are still seen. Over the past six weeks, both hospital admissions and ICU admissions were mainly among people aged 60 and older †
The current growth advantage for the BA.4 and BA.5 variants of care (observed mainly in South Africa)  and Portugal ) compared to the dominant variant BA.2 is probably due to their ability to evade immune protection against infection caused by previous infection and/or vaccination, especially if it has declined over time. Based on preliminary in vitro data from preprints, BA.4 and BA.5 antigen have been removed from the ancestral virus [7,8] and compared to BA.1 and BA.2, they are neutralized less efficiently by sera from individuals vaccinated with three doses of COVID-19 vaccine (Vaxzevria or Comirnaty), or by sera from breakthrough infections in the BA.1 vaccine [8,9]† In addition, there is an increased number of reinfections in Portugal † Overall, this raises concerns about more frequent BA.4/BA.5 vaccine breakthrough infections than for BA.1/BA.2 and for Omicron reinfections. Nevertheless, as of the end of week 22, 2022, total transmission continues to decline in most EU/EEA countries, as evidenced by both overall reporting rates and case rates among people aged 65 and over †
More evidence is needed to elucidate the efficiency of monoclonal antibodies (mAb) against the BA.4 and BA.5 variants, but so far there is evidence to suggest that BA.4 and BA.5 have a reduced or largely similar pattern of mAb sensitivity to that of BA.2 [7,11,12]†
At present, no data are available on vaccine efficacy against different clinical outcomes for Omicron sublines BA.4 and BA.5. Vaccine efficacy data against Omicron variants BA.1 and BA.2 are described in a recently published ECDC technical report on the second mRNA COVID-19 vaccine booster dose †
BA.4 and BA.5 in the EU/EEA: update as of June 13, 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 observe a significant increase in the number and proportion of one of these two variants ( BA.5). As of May 30, 2022, BA.5 is the dominant SARS-CoV-2 variant in Portugal, with an estimated share of approximately 87% [6,14]† Between week 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. In recent weeks (weeks 17-21 of 2022), an increase in the proportion of BA.4 and BA.5 infections was observed in many EU/EEA countries, including Austria, Belgium, Denmark, France, Germany, Ireland, Italy, Netherlands, Spain and Sweden [15,16]†
Particularly in Belgium, BA.5 reached an estimated share of 19% and BA.4 accounted for 7.5% of the genomes sequenced 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 10 autonomous communities during weeks 21-22, with large inter-community variation. In the Netherlands, BA.5 reached a percentage of 8% at week 20, while BA.4 was detected at a percentage of almost 5%.
The reported growth advantage for BA.4 and BA.5 suggests that these variants will become dominant across the EU/EEA, likely resulting in an increase in COVID-19 cases in the coming weeks. The magnitude of the increase will depend on several factors, including immune protection against infection affected by the timing and coverage of COVID-19 vaccination regimens and the magnitude, timing and variant landscape of previous SARS-CoV-2 pandemic waves. Based on limited data, there is no evidence that BA.4 and BA.5 are associated with increased infection severity compared to the circulating variants BA.1 and BA.2. However, as in previous waves, an increase in COVID-19 cases could lead to an increase in hospitalizations, ICU admissions and deaths.
Monitoring and reporting
ECDC encourages countries to remain vigilant for signs of the emergence of BA.4 and BA.5. Sensitive and representative testing policies and genomic surveillance are needed to accurately determine the extent to which these variants may contribute to an observed increase in serious outcomes in the population (eg, increase in hospital or ICU admissions).
Countries should therefore strengthen sentinel stations (primary care ILI/ARI and SARI) and continue to collect data on laboratory-confirmed cases (from non-testing stations) and on hospital admissions/ICU admissions and hospital bed occupancy † Countries should remain vigilant and scale up testing and sequencing as needed. 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 data of SARS-CoV-2 sequences should be deposited in the COVID-19 data portal via the European Nucleotide Archive (ENA) † If possible, antigenic characterization should be performed as this will contribute to a better understanding of the properties of these variants and samples/isolates for characterization can also be shared with the WHO reference laboratories †
Minimal metadata should be reported to TESSy case record type NCOV or in aggregated form to NCOVVariant and, if possible, GISAID accession numbers of sequenced cases should be reported. ECDC has invited nominated users from countries to participate in the EpiPulse event on BA.4 and BA.5 to informally discuss and share information on these two variants, especially on virus characterization and evidence on changes in disease severity, virus transmissibility, immune evasion, and effects on diagnostics and therapy.
Improving primary course and first booster dose COVID-19 vaccine uptake in populations remains a priority for all age groups to reduce hospitalization and death from COVID-19. Detailed information on the COVID-19 vaccine doses administered and the vaccine absorption rate is provided on the: ECDC Vaccine Tracker †
Depending on evolving epidemiology, data on vaccine effectiveness over time, and other factors such as seasonality, it will be necessary to reassess recommendations on timing and populations that may benefit from additional booster doses.
The public health benefit of administering a second mRNA COVID-19 booster dose was recently assessed by ECDC to be most apparent in subjects 80 years of age 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 rollout, including those aged 60-79 who are immunocompetent in the EU/EEA, is likely to be beneficial in terms of avoided deaths, although the best timing for the rollout is uncertain is and will depend on future waves †
Rapid deployment in those groups most at risk of serious disease (e.g., adults 60 years of age and older and medically vulnerable populations) is expected to require additional booster doses in anticipation of future waves, or prior to the fall/winter season. These additional doses will have the greatest impact if administered closer to the expected periods of increased viral circulation, but before it reaches high levels.
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