The public health impact of SARS-CoV-2 Omicron subvariant BA.5 versus BA.2 in Denmark

In a recent study published in The Lancet infectious diseasesresearchers conducted a nationwide study in Denmark to assess the public health impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron subvariant BA.5 versus BA.2.

Study: Risk of re-infection, vaccine protection and burden of infection with the BA.5 omicron subvariant: a nationwide population-based study in Denmark. Image credit: hyotographics/Shutterstock


Denmark is among the countries with the highest mRNA vaccination coverage. Approximately 9% of people over the age of 18 remain unvaccinated in Denmark. In addition, the reverse transcription and polymerase chain reaction (RT-PCR) test is free in Denmark.

Yet Denmark witnessed a massive Omicron wave between December 2021 and February 2022. During those three months, ~35% of their elderly population tested positive by RT-PCR initially due to the BA.1 subvariant. After January 2022, BA.2 became predominant until the rise of BA.5.

About the research

In the current study, the researchers first identified all Danish adults who ordered an RT-PCR test between April 10 and June 30, 2022. The National Surveillance System for the 2019 coronavirus disease (COVID-19) confirmed that these people had COVID-19 as main diagnosis. They used a case-control design to identify people infected with BA.5 or BA.2 during the study period.

First, the team calculated the immune protection afforded by RT-PCR-confirmed Omicron infection against breakthrough infection by BA.5 or BA.2 and hospitalization among triple-vaccinated individuals (Analysis 1).

They then compared their relative vaccination status to assess vaccine-induced immunity against the two variants (Analysis 2). Finally, they determined and compared hospitalizations due to COVID-19 in people infected with BA.5 and BA.2 (Analysis 3). The reference group in the sensitivity analyzes consisted of people who completed their primary series of vaccinations more than 4.5 months before June 30, 2022.

Finally, the researchers used a logistic regression model to estimate immune protection from previous infection with a 95% confidence interval (CI). They represented it as one minus the model-derived odds ratio (OR), similar to the method(s) estimating vaccine effectiveness. They adjusted this model for sex, age, geographic area, comorbidities, and time of RT-PCR sampling, the latter being a categorical variable.

Survey results

Of the 414,436 individuals tested by RT-PCR during the study period, analyzes 1, 2, and 3 covered 187,347, 42,150, and 48,119 individuals, respectively. Previous infection with Omicron provided adequate protection against subsequent breakthrough infection with BA.5. On the other hand, while previous Alpha or Delta infection offers protection against BA.5 and BA.2, it is relatively less so.

The analysis did not assess the effect of waning immunity as a function of time since vaccination or prior infection. Thus, the researchers did not attribute the weaker immune protection observed among those with prior Alpha/Delta infection versus Omicron infection to reduced cross-reactive immunity to different VOCs rather than to an attenuating effect.

Prior infection with SARS-CoV-2 conferred greater protection against BA.2 than BA.5 over the duration of the study. Results remained the same in sensitivity analyzes using a matched case-control design. Vaccine-induced immunity was almost similar for both BA.2 and BA.5. Although BA.5 showed slightly more attenuation of immunity in recipients of two doses of vaccine; however, more data could help arrive at more accurate estimates. Furthermore, the study results showed a higher rate of hospitalization among BA.5 cases compared to BA.2 cases (almost three times higher).

Yet evidence on the severity of BA.5 infection is scarce. Although Portugal reported increased mortality for several weeks, a preprint study from South Africa found that the risk of severe hospitalization and death was similar during the BA.4–BA.5 wave compared to the preceding BA.1 wave. The exceptionally high protection scores in the present study reflect the effect of hybrid immunity in the vaccinated Danish population. Even after accounting for outliers, the rate of immune protection remains high, about 85%, among people with a previous infection.


The present study found that prior Omicron infection in triple-vaccinated individuals provided significant protection against breakthrough BA.5 infection and subsequent hospitalization. Compared with BA.2, vaccine protection against breakthrough infection with BA.5 is slightly weaker.

Authorities identified the first case of Omicron BA.5 in Denmark on April 10, 2022. Since then, Denmark has subjected more than 83% of all positive cases to whole genome sequencing (WGS). Nearly 85% of these cases yield genomic data that help researchers identify causal VOCs. Indeed, this study highlights how WGS continues to be the mainstay of SARS-CoV-2 surveillance in Denmark.

Overall, the current BA.5 wave had minor adverse effects on the Danish population due to their high degree of hybrid immunity. Importantly, this effect was almost similar to that due to the previous waves driven by Omicron BA.1/BA.2. However, future studies should examine the burden of disease on BA.5, as it resulted in more hospitalizations than Omicron BA.2.

Journal reference:

  • Hansen, C., Friis, N., Bager, P., Stegger, M., Fonager, J., & Fomsgaard, A. et al. (2022). Risk of reinfection, vaccine protection and burden of infection with the BA.5 omicron subvariant: a nationwide population study in Denmark. Lancet Infectious Diseases. milking: 10.1016/s1473-3099(22)00595-3 text

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