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

Study: Risk of reinfection, vaccine protection, and severity of infection with the BA.5 omicron subvariant: a nation-wide population-based study in Denmark. Image Credit: hyotographics/Shutterstock

Background

Denmark is amongst those countries with the best messenger ribonucleic acid (mRNA)-vaccination coverage. Roughly 9% of those older than 18 years remain unvaccinated in Denmark. Furthermore, reverse transcription-polymerase chain response (RT-PCR) testing is free in Denmark. 

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

Concerning the study 

In the current 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 discover BA.5 or BA.2-infected people throughout 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 amongst triple-vaccinated individuals (Evaluation 1). 

Next, they compared their relative vaccination status to estimate the vaccine-induced immunity against each variants (Evaluation 2). Finally, they determined and compared hospitalizations attributable to COVID-19 in people infected with BA.5 and BA.2 (Evaluation 3). The reference group in sensitivity analyses comprised individuals who had accomplished their primary vaccination series greater 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), just like the strategy(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 throughout the study period, analyses 1, 2 & 3 comprised 187347, 42,150, and 48,119 individuals, respectively. A previous Omicron infection provided adequate protection against subsequent BA.5 breakthrough infection. Then again, while a previous Alpha or Delta infection offered protection against each BA.5 and BA.2, it was relatively less. 

The evaluation didn’t assess the effect of waning immunity as a function of time from vaccination or prior infection. Thus, the researchers didn’t attribute weaker immune protection observed amongst those with a previous Alpha/Delta infection relative to Omicron infection to reduced cross-reactive immunity against different VOCs fairly than a waning effect.

A previous SARS-CoV-2 infection provided higher protection against BA.2 than BA.5 throughout the study duration. The outcomes remained the identical in sensitivity analyses employing a matched case-control design. Vaccine-induced immunity was almost similar for each BA.2 and BA.5. Although BA.5 showed barely more immunity escape in recipients of two vaccine doses; nevertheless, more data could help arrive at more accurate estimates. Further, the study results evidenced higher hospitalization rates amongst BA.5 cases compared with BA.2 cases (nearly 3 times more).

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

Conclusions

The present 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 barely weaker.

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

Overall, the present BA.5 wave had negligible adversarial effects on the Danish population attributable to their high degree of hybrid immunity. Importantly, this effect was nearly just like that attributable to the previous Omicron BA.1/BA.2 driven wave(s). Nonetheless, future studies should investigate the disease severity of BA.5 because it led to 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 severity of infection with the BA.5 omicron subvariant: a nation-wide population-based study in Denmark. The Lancet Infectious Diseases. doi: 10.1016/s1473-3099(22)00595-3 https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(22)00595-3/fulltext