In a recent study posted to the medRxiv* preprint server, researchers found prior exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron sub-variants BA.1/BA.2 reduced the risk of breakthrough infection by its sub-variant BA.5.

Background

The study evidenced that infection with Omicron sub-variants BA.1/BA.2 in the vaccinated population conferred more protection against BA.5 reinfection than prior exposure to other SARS-CoV-2 variants. Since all adapted coronavirus disease 2019 (COVID-19) vaccines under development are BA.1-based, the study data could be valuable for future vaccine research endeavors.

About the study

In the present study, researchers used data from Portugal’s national COVID-19 registry, which documents all reported cases regardless of clinical presentation, to calculate the absolute risk of BA.5 infection in naïve individuals and those with prior SARS-CoV-2 exposure in any time strata at least 90 days before June 1, 2022. Additionally, they computed the odds ratio (OR) and protective efficacy in percentage as (1-OR) x 100%, with 95% confidence intervals (CIs).

The team divided the Portuguese COVID-19 pandemic curve into time strata, each characterized by the dominance of one of the SARS-CoV-2 variants or subvariants, including Wuhan-Hu-1, Alpha, Delta, BA.1, BA.2, and BA.5. Given the slow transition between the period of dominance of BA.1 and BA.2, they pooled the BA.1 and BA.2 infections in one time strata. In this way, the researchers identified the first COVID-19 case in the dominance period(s) of each SARS-CoV-2 variant or sub-variant via nationwide genomic surveillance and a second case in the period of BA.5 dominance.

The national COVID-19 registry of Portugal had records of all Portugal residents over 12 years who were infected only once during the dominance of any one of the SARS-CoV-2 variants or subvariants. Notably, over 98% of these individuals had received a primary vaccination series before the beginning of the BA.5 dominance period, i.e., June 1, 2022, of which 82% had exclusively received messenger ribonucleic acid (mRNA) vaccines.

Results

Prior exposure to SARS-CoV-2 reduced the risk for BA.5 reinfection and the protective effectiveness of initial infection with Wuhan-Hu-1, Alpha, Delta, and BA.1/BA.2 was 52.9%, 54.9%, 62.3%, and 80.0%, respectively. However, prior infection with BA.1/BA.2 had a maximal protective effect against BA.5 reinfection in the highly vaccinated population of Portugal. Therefore, the study data either reflect the induction of a more effective immune protection towards BA.5 or the shorter time elapsed between infection and exposure to the Omicron BA.5 subvariant.

The study used such a large number of COVID-19 cases that it compensated for the lack of precision of a test-negative design. Therefore, the current study results aligned with another study from Qatar based on a test-negative design. The study showed a slightly higher estimate of the protective efficacy of BA.1/BA.2 infection against BA.4/BA.5 but not dissimilar (79.7% vs. 80%).

Like some other previous studies, the current study also showed that the Omicron sub-variants were superior to the pre-Omicron variants in conferring protection against emerging Omicron sub-variants. Also, for three to five months after BA.1/BA.2 infection, the protection conferred by the BA.1/BA.2-induced hybrid immunity remained significant. Future studies should, however, establish the effect of immune waning in this hybrid immunity.

The study sensitivity analyses used data from Portugal's national serologic survey. The results estimated the population with serologic evidence of SARS-CoV-2 infection that remained undetected by testing and undocumented in the COVID-19 registry was 29.2%. Thus, the researchers multiplied all SARS-CoV-2 infections (before June 1, 2020) by 0.292 to obtain the number of undetected cases, which was around 605,944, with the absolute risk of BA.5 reinfection of 0.020.

Considering a scenario where unreported cases comprised 20% to 40% of infected cases and redoing the calculations, the researchers observed an increase in the risk of primary BA.5 infections in the previously uninfected group and an increase in the relative protection conferred by the infection with a prior SARS-CoV-2 variant.

Since the researchers were considering BA.5 infections over the same time frame in all cases, any increase in the number of BA.5 cases (more because of unreported cases or not) would have affected all groups (uninfected and previously infected) in a similar proportion. It is noteworthy that Portugal changed its testing policy during the BA.5 dominance period, which could have increased the frequency of unreported cases.

Conclusion

Overall, the study findings altered the perception that BA.1/BA.2 infection cannot protect against BA.5 reinfection. More importantly, the study data could help better evaluate the current epidemiological situation to inform future public health policies.

*Important notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Written by

Neha Mathur

Neha is a digital marketing professional based in Gurugram, India. She has a Master’s degree from the University of Rajasthan with a specialization in Biotechnology in 2008. She has experience in pre-clinical research as part of her research project in The Department of Toxicology at the prestigious Central Drug Research Institute (CDRI), Lucknow, India. She also holds a certification in C++ programming.