Comparative neutralisation profile of SARS-CoV-2 omicron subvariants BA.2.75 and BA.5.

Following the emergence of the SARS-CoV-2 omicron variant in November, 2021, several omicron subvariants have been circulating globally, including BA.1, BA.2, BA.2.12.1, BA.2.75, BA.4, and BA.5. Unique spike mutations in omicron subvariants have resulted in the substantial ability of the virus to escape neutralising antibodies.1, 2, 3, 4 Within a few months after the emergence of BA.5, the most recent omicron subvariant, BA.2.75, was detected in June, 2022, in India and Japan (appendix p 4), carrying nine additional mutations in the spike protein that were not present in BA.2 (appendix p 5). These extra mutations have raised concern about an increased ability of the virus to escape neutralising antibodies, and WHO has classified BA.2.75 as a variant of concern to be monitored.

We evaluated the degree of neutralising antibody escape by omicron subvariants using serum panels derived from individuals who had received two doses (n=20) or three doses (n=19) of the BNT162b2 mRNA vaccine (Pfizer); had received two doses of BNT162b2 followed by an mRNA-1273 (Moderna) vaccine booster (n=20); had had omicron breakthrough infection after two doses (n=19) or three doses (n=9) of BNT162b2; and were unvaccinated and had recovered from omicron BA.1 (n=11) or BA.2 (n=8) infection. The details of each serum panel are listed in the appendix (p 6).

Individuals who had received two doses of BNT162b2 vaccine had low levels of neutralising antibodies cross-reactive against SARS-CoV-2 omicron subvariants, with geometric mean 50% pseudovirus neutralisation titres (pVNT50s) of 71 against BA.1, 95 against BA.2, 88 against BA.2.75, and 76 against BA.5—around 26–35 times lower than those against ancestral SARS-CoV-2 (2489; appendix p 5).

Despite an overall improvement in neutralising antibody titres following mRNA booster vaccination or an omicron breakthrough infection (appendix p 5), there was a significant loss of neutralising antibody potency against omicron subvariants compared with ancestral SARS-CoV-2, with BA.5 being the most effective subvariant at escaping neutralising antibodies. Relative to geometric mean pVNT50s against BA.2, titres against BA.2.75 were 1·1 to 1·4 times lower and those against BA.5 were 2·2 to 3·8 times lower in individuals who had received three doses of mRNA vaccine or recovered from an omicron breakthrough infection (appendix p 5).

Unvaccinated individuals who had recovered from omicron BA.1 or BA.2 infection had low levels of neutralising antibodies cross-reactive against ancestral SARS-CoV-2 or SARS-CoV-2 omicron BA.2.75 or BA.5. Geometric mean pVNT50s against BA.2.75 were 10 times lower (a pVNT50 of 52) and against BA.5 were 28 times lower (18) than those against BA.1 (500) in individuals recovered from BA.1 infection (appendix p 5). Geometric mean pVNT50s against BA.2.75 were 5 times lower (155) and against BA.5 were 7 times lower (103) than those against BA.2 (746) in individuals recovered from BA.2 infection (appendix p 5).

These data show that both BA.2.75 and BA.5 subvariants can substantially escape neutralising antibodies induced by vaccination or previous infection, or both. However, importantly, BA.2.75 showed less capacity for escape from neutralisation than did BA.5, despite BA.2.75 having emerged after BA.5 and having more mutations in the spike protein. Neutralising antibody titres against BA.5 and BA.2.75 being lower than those against BA.1 and BA.2 nevertheless suggests that omicron subvariants are continuing to evolve under selective immune pressure. These findings emphasise the importance of developing better vaccines with pan-sarbecovirus neutralising capability to counter future SARS-CoV-2 variants or yet-to-emerge zoonotic coronaviruses.

We declare no competing interests. This work was supported in part by grants from the Singapore National Research Foundation (NRF2016NRF-NSFC002-013, NRF2018NRF-NSFC003SB-002), the National Medical Research Council (STPRG-FY19-001, COVID19RF-003, COVID19RF-0008, COVID-19RF-018, COVID19RF-060, MOH-000535/MOH-OFYIRG19nov-0002 and OFLCG19May-0034), SingHealth Duke-NUS Academic Medicine COVID-19 Rapid Response Research Grant (AM/COV001/2020), and the National Public Health COVID program of the Government of Monaco.