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

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

Background

Denmark is among those countries with the highest messenger ribonucleic acid (mRNA)-vaccination coverage. Approximately 9% of those older than 18 years remain unvaccinated in Denmark. Moreover, reverse transcription-polymerase chain reaction (RT-PCR) testing is free in Denmark. 

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

About the study 

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

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

Next, they compared their relative vaccination status to estimate the vaccine-induced immunity against both 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 sensitivity analyses comprised people who had completed their primary vaccination series more than 4.5 months before June 30, 2022.

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

Study findings

Of the 414,436 people RT-PCR tested during the study period, analyses 1, 2 & 3 comprised 187347, 42,150, and 48,119 individuals, respectively. A prior Omicron infection provided adequate protection against subsequent BA.5 breakthrough infection. On the other hand, while a prior Alpha or Delta infection offered protection against both BA.5 and BA.2, it was relatively less. 

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

A prior SARS-CoV-2 infection provided higher protection against BA.2 than BA.5 during the study duration. The results remained the same in sensitivity analyses employing a matched case-control design. Vaccine-induced immunity was almost similar for both BA.2 and BA.5. Although BA.5 showed slightly more immunity escape in recipients of two vaccine doses; however, more data could help arrive at more accurate estimates. Further, the study results evidenced higher hospitalization rates among BA.5 cases compared with BA.2 cases (nearly three times more).

Yet, the evidence of BA.5 infection severity is scarce. Although Portugal reported excess mortality for a few weeks, a pre-print study from South Africa found that the risk of severe hospitalization and death was similar during the BA.4–BA.5 wave compared with the preceding BA.1 wave. The markedly high estimates of protection in the current study reflect the hybrid immunity effect in the vaccinated population of Denmark. Even after accounting for biases, the extent of immune protection remained high, at around 85%, among people with the previous infection.

Conclusions

The current study found that a previous Omicron infection in triply vaccinated individuals conferred significant protection against BA.5 breakthrough infection and subsequent hospitalization. Relative to BA.2, vaccine protection against BA.5 breakthrough infection was slightly weaker.

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

Overall, the current BA.5 wave had negligible adverse effects on the Danish population due to their high degree of hybrid immunity. Importantly, this effect was nearly similar to that due to the previous Omicron BA.1/BA.2 driven wave(s). However, future studies should investigate the disease severity of BA.5 as it led to more hospitalizations than Omicron BA.2.