Omicron sub-lineages BA.4/BA.5 escape BA.1 infection elicited neutralizing immunity

The SARS-CoV-2 Omicron (B.1.1.529) variant first emerged as the BA.1 sub-lineage, with extensive escape from neutralizing immunity elicited by previous infection with other variants, vaccines, or combinations of both[1][1],[2][2]. Two new sub-lineages, BA.4 and BA.5, are now emerging in South Africa with changes relative to BA.1, including L452R and F486V mutations in the spike receptor binding domain. We isolated live BA.4 and BA.5 viruses and tested them against neutralizing immunity elicited to BA.1 infection in participants who were Omicron/BA.1 infected but unvaccinated (n=24) and participants vaccinated with Pfizer BNT162b2 or Johnson and Johnson Ad26.CoV.2S with breakthrough Omicron/BA.1 infection (n=15). In unvaccinated individuals, FRNT50, the inverse of the dilution for 50% neutralization, declined from 275 for BA.1 to 36 for BA.4 and 37 for BA.5, a 7.6 and 7.5-fold drop, respectively. In vaccinated BA.1 breakthroughs, FRNT50 declined from 507 for BA.1 to 158 for BA.4 (3.2-fold) and 198 for BA.5 (2.6-fold). Absolute BA.4 and BA.5 neutralization levels were about 5-fold higher in this group versus unvaccinated BA.1 infected participants. The observed escape of BA.4 and BA.5 from BA.1 elicited immunity is more moderate than of BA.1 against previous immunity[1][1],[3][3]. However, the low absolute neutralization levels for BA.4 and BA.5, particularly in the unvaccinated group, are unlikely to protect well against symptomatic infection[4][4].This may indicate that, based on neutralization escape, BA.4 and BA.5 have potential to result in a new infection wave. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was supported by the Bill and Melinda Gates award INV-018944 (AS), National Institutes of Health award R01 AI138546 (AS), and South African Medical Research Council Award 6084COAP2020 (AS) ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Blood samples were obtained after written informed consent from adults with PCR-confirmed SARS-CoV-2 infection who were enrolled in a prospective cohort study at the Africa Health Research Institute approved by the Biomedical Research Ethics Committee at the University of KwaZulu-Natal (reference BREC/00001275/2020). The Omicron/BA.1 and BA.4 was isolated from a residual swab sample with SARS-CoV-2 isolation from the sample approved by the University of the Witwatersrand Human Research Ethics Committee (HREC) (ref. M210752). The sample to isolate Omicron/BA.5 was collected after written informed consent as part of the COVID-19 transmission and natural history in KwaZulu-Natal, South Africa: Epidemiological Investigation to Guide Prevention and Clinical Care Centre for the AIDS Programme of Research in South Africa (CAPRISA) study and approved by the Biomedical Research Ethics Committee at the University of KwaZulu-Natal (reference BREC/00001195/2020, BREC/00003106/2021). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Sequences of outgrown Omicron sub-lineages have been deposited in GISAID with accession EPI\_ISL\_7886688 (Omicron/BA.1), EPI\_ISL\_12268495.2 (Omicron/BA.4), EPI\_ISL\_12268493.2 (Omicron/BA.5). Raw images of the data are available upon reasonable request. [1]: #ref-1 [2]: #ref-2 [3]: #ref-3 [4]: #ref-4