SARS-CoV-2 BA.4/5 variants escape vaccine and BA.1 infection induced antibodies

In a recent work published in the Cell journal, investigators examined the severe acute respiratory syndrome coronavirus (SARS-CoV-2) Omicron BA.5/4 variants escape from neutralizing antibodies induced by SARS-CoV-2 vaccines and natural infection.

Study: Antibody escape of SARS-CoV-2 Omicron BA.4 and BA.5 from vaccine and BA.1 serum

Study: Antibody escape of SARS-CoV-2 Omicron BA.4 and BA.5 from vaccine and BA.1 serum


SARS-CoV-2 that emerged at the end of 2019 in Wuhan quickly spread across the world with a succession of viral variants with enhanced fitness. To date, the coronavirus disease 2019 (COVID-19) pandemic has caused over 5325 million confirmed cases and 6.3 million deaths globally.

The SARS-CoV-2 Omicron lineage, initially discovered in late November 2021, has since branched into several sublineages and spread swiftly to become worldwide dominant. In many nations, the Omicron BA.1 variant dominated the first Omicron-linked COVID-19 wave, although it has now been superseded by BA.2. 

The availability of the SARS-CoV-2 vaccines did not control the COVID-19 pandemic, and the emergence of Omicron heightened the number of infected people. Existing COVID-19 vaccines are efficient at averting severe illness but not so much at limiting the spread, especially of the Omicron sublineages.

Two new Omicron sub-lineages (BA.5 and BA.4) have been discovered in the Gauteng region of South Africa via sequencing and are prevalent locally, triggering a new SARS-CoV-2 wave. Interestingly, BA.5 and BA.4 have similar spike (S) protein sequences and, despite being closely associated with BA.2, have additional mutations in the S protein's receptor-binding domain (RBD).

About the study

In the present work, the researchers investigated the neutralization of Omicron BA.4/5 variants utilizing naturally immune serum, multiple COVID-19 vaccines, and monoclonal antibody (mAbs) panels. The team reported the antigenic characterization of BA.5/4 relative to the other Omicron subvariants, including BA.3, although it was less concerning. 

The authors used a biophysical investigation of binding to confirm the findings on neutralization. They combined surface plasmon resonance (SPR) data with earlier mapping using bio-layer interferometry (BLI) competition matrices and thorough structural details to examine the influence of F486V and L452R mutations on BA.5/4 neutralization escape capacity.

The scientists quantified the BA.5/4 RBD's affinity for angiotensin-converting enzyme 2 (ACE2) receptors in the host. Further, the study's panel of powerful mAbs was derived from BA.1-infected people who had been vaccinated. 


The study results demonstrated that COVID-19 Pfizer or AstraZeneca triple vaccinated serum showed approximately two- to three-fold drop in SARS-CoV-2 Omicron BA.5/4 mutant neutralization compared to BA.2 and BA.1. Likewise, serum from BA.1 vaccine breakthrough infections exhibited a nearly two- to three-fold decrease in the BA.5/4 neutralization, boosting the probability of recurrent Omicron infections. Indeed, these reductions were consistent with reductions in BA.5 and BA.4 neutralization titers described in previous literature after BA.1 vaccination breakthrough infection.

The team discovered that the SARS-CoV-2 therapeutic antibodies, such as S309, had diminished efficacy against the Omicron BA.5/4 variants. They found that of the 28 mAbs, 10 were entirely knocked out against the BA.5/4 mutants, and the remaining had a drastic reduction in BA.5/4 neutralization capacity versus the other Omicron subvariants.

The authors inferred the contribution of F486V and L452R mutations from the neutralization data on BA.4/5 compared to the Delta variant. They illustrated structure-function reasons for mAb failure towards BA.5/4 owing to modifications at residues 486 and 452. The scientists noted that the F486V and L452R mutations contributed significantly to BA.5/4 neutralization escape characteristic. Besides, the BA.5/4 had a stronger ACE2 affinity than previous BA.2 and BA.1 Omicron strains.


Overall, the study findings reported that the SARS-CoV-2 Omicron BA.5/4 variants were more resistant to neutralization than BA.2 and BA.1. Compared to BA.2 and BA.1, the SARS-CoV-2 Omicron BA.5/4 mutants show lower neutralization by serum from individuals vaccinated with three doses of COVID-19 Pfizer or AstraZeneca vaccines. BA.1 vaccine breakthrough infection sera samples also depicted a substantial decline in the BA.5/4 neutralization. 

The team noted that compared to prior Omicron sublineages, several mAbs were either wiped out or highly reduced in their activity against BA.4/5. The Omicron lineage, notably BA.5/4, had reduced or escaped the effect of COVID-19 mAbs designed for clinical usage.

Furthermore, although there was no indication of increased COVID-19 severity, the data from the current study and prior investigations imply that a new wave of Omicron infection, fueled by BA.5/4, was probable, partially because of a breakthrough of naturally- and vaccine-acquired immunity.

Journal reference:
  • Tuekprakhon, A., Huo, J., Nutalai, R., Dijokaite-Guraliuc, A., Zhou, D., Ginn, H.M., Selvaraj, M., Liu, C., Mentzer, A.J., Supasa, P., Duyvesteyn, H.M.E., Das, R., Skelly, D., Ritter, T.G., Amini, A., Bibi, S., Adele, S., Johnson, S.A., Constantinides, B., Webster, H., Temperton, N., Klenerman, P., Barnes, E., Dunachie, S.J., Crook, D., Pollard, A.J, Lambe, T., Goulder, P., Paterson, N.G., Williams, M.A., Hall, D.R., OPTIC consortium, ISARIC4C consortium, Fry, E.E., Mongkolsapaya, J., Ren, J., Stuart, D.I., Screaton, G.R, Antibody escape of SARS-CoV-2 Omicron BA.4 and BA.5 from vaccine and BA.1 serum. Cell (2022), DOI:,
Shanet Susan Alex

Written by

Shanet Susan Alex

Shanet Susan Alex, a medical writer, based in Kerala, India, is a Doctor of Pharmacy graduate from Kerala University of Health Sciences. Her academic background is in clinical pharmacy and research, and she is passionate about medical writing. Shanet has published papers in the International Journal of Medical Science and Current Research (IJMSCR), the International Journal of Pharmacy (IJP), and the International Journal of Medical Science and Applied Research (IJMSAR). Apart from work, she enjoys listening to music and watching movies.


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