Rapid investigation of BA.4/BA.5 cases in France

Aim We aimed to describe the characteristics of individuals infected by BA.4 or BA.5 in France in comparison to BA.1, and analyze the factors associated with hospitalization among BA.4 and BA.5 cases. Methods A standardized questionnaire was used to collect information on confirmed and probable Omicron cases. Hospitalization risk factors among BA.4/BA.5 cases were analyzed using Poisson regression. Variables with a p-value below 0.2 in the univariate analysis and a priori confounders were included in the multivariable regression model. Results The median age of the 301 cases investigated was 47 years and 97% of cases were symptomatic. The most common clinical signs were asthenia/fatigue (75.7%), cough (58.3%), fever (58.3%), headache (52.1%) and rhinorrhea (50.7%). Twelve cases were hospitalized, and 27.1% reported risk factors. No admissions to intensive care and no deaths were reported. Vaccination status was available for 292 cases, 20.9% were unvaccinated, 1.4% had received one dose, 38.3% two doses and 39.4% three doses. Cases presenting at least one risk factor were almost seventeen times more likely to be hospitalized than those with no risk factors (aRR = 16.72 [95% CI2.59–326.86]). Conclusion Despite the longer duration of and the differences in symptoms and their possible immune escape, BA.4/BA.5 Omicron sub-lineages globally showed no severe clinical presentation. The presence of at least one risk factor for severe disease significantly increased the risk of hospitalization for those infected with BA.4 or BA.5.


Results:
The median age of the cases investigated was years and % of cases were symptomatic. The most common clinical signs were asthenia/fatigue ( . %), cough ( . %), fever ( . %), headache ( . %) and rhinorrhea ( . %). Twelve cases were hospitalized, and . % reported risk factors. No admissions to intensive care and no deaths were reported. Vaccination status was available for cases, . % were unvaccinated, . % had received one dose, . % two doses and . % three doses. Cases presenting at least one risk factor were almost seventeen times more likely to be hospitalized than those with no risk factors (aRR = .
Conclusion: Despite the longer duration of and the di erences in symptoms and their possible immune escape, BA. /BA. Omicron sub-lineages globally showed no severe clinical presentation. The presence of at least one risk factor for severe disease significantly increased the risk of hospitalization for those infected with BA. or BA. .

Introduction
At the end of 2021, the SARS-CoV-2 Delta variant was replaced by Omicron (B.1.1.529), which was classified as a variant of concern by the World Health Organization (1). Omicron showed major differences compared to previous variants, including increased transmissibility, high immune escape, different clinical presentation (less anosmia and ageusia) and lower severity (2). Omicron's BA.1 sub-lineage became predominant in France in December 2021 and later gave way to new Omicron sub-lineages, such as BA.2, BA.4 and BA.5. Since April 2022, the number of BA.4 and BA.5 cases has been increasing, coinciding with an increased incidence rate, and by mid-June, these two sub-lineages combined represented more than half of all cases.
We aimed to describe the characteristics of individuals infected by BA.4 or BA.5 in France in comparison to BA.1, and analyze the factors associated with hospitalization among BA.4 and BA.5 cases. The purpose of these investigations was to produce early data that could inform public health decisions regarding these emerging variants.

Methods
Between 6 April and 10 June 2022, 277 confirmed cases (by sequencing) and 24 possible cases (linked to a confirmed case) of BA.4 or BA.5 (designated BA.4/BA.5 for the following text) were investigated by epidemiologists from the regional offices of Santé publique France in collaboration with the Regional Health Agencies. A standardized questionnaire was used as for the previously investigated 468 Omicron cases between November 2021 and January 2022 (>99% BA.1) (3). Hospitalization risk factors among BA.4/BA.5 cases were analyzed using Poisson regression. Predictors with a p-value below 0.2 in the univariate analysis ( Table 2) and age and sex as a priori confounders were included in the multivariable regression model.

Results
Characteristics of BA. /BA. cases compared to BA.

Discussion
In comparison to BA.1, our investigation shows that the first BA.4/BA.5 cases in France were significantly older, less likely to have traveled during the 14 days preceding the positive test, more likely to be related to a cluster, and more likely to have risk factors. BA.4/BA.5 cases had significantly longer median duration of symptoms, and were significantly more likely to develop rhinorrhea, nausea/vomiting, diarrhea, ageusia and anosmia. The hospitalization rate was not significantly different compared to BA.1.
The current increase of cases in France coincides with a spread of mostly BA.5 (4), as previously observed in other countries (5). The replacement of BA.2 by BA.4/BA.5 illustrates a growth advantage, which could be due to higher transmissibility and/or immune evasion (6). Increased case numbers might have been due to BA.4/BA.5, as well as changes in population behavior, waning immunity (7,8) and relaxation of prevention measures (9). In addition, elderly have been vaccinated earlier with a third dose than younger individuals, hence waning immunity in this population is expected (10) and may have contributed to more infections in higher age groups during the BA.4/BA.5 wave.
The investigation periods for BA.1 and BA.4/BA.5 differ by the increase of vaccination coverage for the third dose and an easing of preventive measures, which may have led to different infection patterns regarding clusters and vaccinated individuals.
The hospitalization rate among BA.4/BA.5 cases was only significantly related to risk factors for severe COVID-19, as reported previously (5,11). A higher proportion of BA.4/BA.5 cases were symptomatic with different clinical signs and a longer median duration of symptoms than observed for BA.1.
Most cases investigated were symptomatic, which could be due to changes in testing behaviors (lower adherence to testing recommendations); hence, the proportion of hospitalizations for BA.4/BA.5 infections might be overestimated compared to hospitalizations for BA.1. Small numbers of hospitalized cases in both groups also lowered the statistical power of the analysis. Nevertheless, our study found similar disease severity between BA.4/BA.5 and BA.1 as reported recently from South Africa (12). These investigations included as a reference only individuals infected by BA.1 and not BA.2, which had followed and overtaken BA.1. However, while Omicron sub-lineages have shown varying competitiveness, no major differences in vaccine effectiveness, severity and clinical presentation have been identified so far.

Conclusion
Despite the longer duration of and the differences in symptoms and their possible immune escape, BA.4/BA.5 Omicron sub-lineages globally showed no severe clinical presentation. This is similar to other Omicron sub-lineages, and their impact on public health could remain limited. However, an increase in case numbers of these more transmissible sublineages may still lead to a high burden of absenteeism and hospitalizations.
Caution is required and continued vaccination efforts and adhesion to prevention measures are necessary to reduce the spread and impact of these variants. The French public health system through the EMERGEN Consortium, local, regional and national authorities, maintains its ability to quickly detect, react and adapt to the emergence of a new variant.

Data availability statement
The original contributions presented in the study are included in the article, further inquiries can be directed to the corresponding author.

Ethics statement
Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.