In a recent study posted to the medRxiv* preprint server, researchers investigated the differences in vaccination- and previous infection-induced immunities against the Omicron BA.2 and BA.4/5 subvariants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Study: Higher risk of SARS-CoV-2 Omicron BA.4/5 infection than of BA.2 infection after previous BA.1 infection, the Netherlands, 2 May to 24 July 2022. Image Credit: Corona Borealis Studio/Shutterstock


Since November 2021, the SARS-CoV-2 Omicron subvariants have increased the number of coronavirus disease 2019 (COVID-19) cases due to their increased transmissibility and immune evasion capabilities. The Netherlands experienced a surge in cases during the dominance of the BA.1 Omicron subvariant during late 2021, followed by subsequent BA.2, BA.4, and BA.5 dominance periods from early- to mid-2022.  

The Omicron subvariants have mutations in the spike protein residues, resulting in increased humoral immunity evasion. Studies have shown that the BA.4 and BA.5 subvariants exhibit the highest degree of neutralization escape, raising concerns about the recurrence of severe COVID-19 outcomes.

About the study

The present study examined the effect of vaccination- and prior infection-induced immune status on the occurrence of BA.2 and BA.4/5 between May and July 2022 — the transition phase between BA.2 and BA.4/5 predominance.

The researchers used SARS-CoV-2-positive test results from national community testing performed between 2 May to 24 July 2022 and carried out spike (S)-gene target failure (SGTF). The pseudonymized demographic and vaccination status information was also procured from the national community testing register.

The SGTF test was performed using TaqPath COVID-19 real-time polymerase chain reaction (RT-PCR). Combined with quantification cycles less than or equal to 30 to amplify the open reading frame 1 a and b (ORF1ab) and nucleocapsid (N) genes, the inability to detect the S-gene is a proxy for variants containing S 69/70 deletion, such as the Omicron subvariants BA.4 and BA.5. Samples that were non-SGTF were considered to be BA.2 positive, while SGTF samples were BA.4/5 since SGTF cannot distinguish between BA.4 and BA.5.

Whole genome sequencing (WGS) of random SGTF samples was also carried out to see the proportion of BA.4 to BA.5 samples. A combination of WGS and SGTF results from previous infections was used to determine the variants of previous SARS-CoV-2 infections. The immune status groups were defined according to vaccination history and prior infections. The BA.2 and BA.4/5 infections were correlated to these immune status groups using various statistical analyses.


The results found that irrespective of vaccination status, the frequency of BA.4/5 cases was higher than BA.2 cases among individuals with previous infections, suggesting higher immune evasion by BA.4/5. BA.2 and BA.4/5 showed no association with vaccination status, implying that vaccines granted equal protection against all three subvariants.

Prior infection with the BA.1 subvariant presented lower and shorter protective effects against BA.4/5 than BA.2. The authors noted that a similar study from Denmark and other in vitro studies corroborated their results on BA.1 infection-induced immunity being ineffective against BA.4/5. They also discussed studies from the United Kingdom and Portugal, which substantiate their findings about similar vaccination-induced immunity against BA.2 and BA.4/5.

However, the authors believe that the evasion exhibited by BA.2 and BA.4/5 from prior infection-induced immunity is smaller than those seen for BA.1 or the Delta variant, which indicates high antibody escape between the earlier variants of concern than between Omicron subvariants.

The study had a few limitations. Based on the lack of confidence in the previous infection information, the authors believe some individuals might have been misclassified as not previously infected. Additionally, the BA.4 and BA.5 infections could not be separated for the entire dataset due to a lack of WGS data. Furthermore, the 90% threshold used for the TaqPath RT-PCR tests could have resulted in the misclassification of the subvariants. The authors believe, however, that these limitations are unlikely to change the results significantly.


To summarize, the study found that BA.4/5 exhibits higher antibody escape than BA.2 against immunity induced by previous infections from other subvariants such as BA.1, irrespective of vaccination status. Vaccination was seen to grant uniform protection against BA.2 and BA.4/5 infections.

The findings are significant as they suggest that vaccination provides better immunity against the Omicron subvariants than humoral immunity from previous infections. Therefore, vaccine updates and investigation of immune evasion by emergent subvariants should be prioritized.

*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.

Journal reference:
  • Andeweg, S. et al. (2022) "Higher risk of SARS-CoV-2 Omicron BA.4/5 infection than of BA.2 infection after previous BA.1 infection, the Netherlands, 2 May to 24 July 2022". medRxiv. doi: 10.1101/2022.09.21.22280189.

Posted in: Medical Science News | Medical Research News | Disease/Infection News

Tags: Antibody, Coronavirus, Coronavirus Disease COVID-19, covid-19, Frequency, Gene, Genes, Genome, immunity, in vitro, Omicron, Polymerase, Polymerase Chain Reaction, Protein, Respiratory, SARS, SARS-CoV-2, Severe Acute Respiratory, Severe Acute Respiratory Syndrome, Spike Protein, Syndrome, Vaccine, Whole Genome Sequencing

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Written by

Dr. Chinta Sidharthan

Chinta Sidharthan is a writer based in Bangalore, India. Her academic background is in evolutionary biology and genetics, and she has extensive experience in scientific research, teaching, science writing, and herpetology. Chinta holds a Ph.D. in evolutionary biology from the Indian Institute of Science and is passionate about science education, writing, animals, wildlife, and conservation. For her doctoral research, she explored the origins and diversification of blindsnakes in India, as a part of which she did extensive fieldwork in the jungles of southern India. She has received the Canadian Governor General’s bronze medal and Bangalore University gold medal for academic excellence and published her research in high-impact journals.

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