PREPRINT: SARS-CoV-2 Omicron has extensive but incomplete escape of Pfizer BNT162b2 elicited neutralization and requires ACE2 for infection

The emergence of the Omicron variant (1) of SARS-CoV-2 in November 2021 in South Africa has
raised concerns that, based on the large number of mutations in the spike protein and elsewhere on
the virus (https://covdb.stanford.edu/page/mutation-viewer/#sec_b-1-351), this variant will have
considerable escape from vaccine elicited immunity. Furthermore, several mutations in the receptor
binding domain and S2 are predicted to impact transmissibility and affinity for ACE-2.

Here we investigated whether Omicron escapes antibody neutralization elicited by the Pfizer
BNT162b2 mRNA vaccine and whether the virus still requires binding to the ACE2 receptor to infect
cells. We used an early passage of isolated and sequence confirmed live Omicron virus isolated in
South Africa. We used a human lung cell line clone (H1299-ACE2) engineered to express the ACE2
receptor (2) to both isolate the virus and test neutralization. We also tested growth in the parental
H1299 which do not overexpress ACE2 and are not appreciably infectable with SARS-CoV-2 (Fig S1).
The H1299-ACE2 cells were similar to Vero-E6 in titer dependent focus formation, but were
considerably more sensitive (Fig S2).

We observed that Omicron infected the ACE2-expressing cells in a concentration dependent manner
but did not infect the parental H1299 cells, indicating that ACE2 is required for Omicron entry (Fig.
1A). We then tested the ability of plasma from BNT162b2 vaccinated study participants to neutralize
Omicron versus ancestral D614G virus in a live virus neutralization assay. We tested 14 plasma
samples from 12 participants (Table S1), with 6 having no previous record of SARS-CoV-2 infection
nor detectable nucleocapsid antibodies indicative of previous infection. For two of these
participants, we used samples from two timepoints. The remaining 6 participants had a record of
previous infection in the first SARS-CoV-2 infection wave in South Africa where infection was with
ancestral D614G virus (Table S1). Geometric mean titer (GMT) FRNT50 (inverse of the plasma
dilution required for 50% reduction in infection foci number) was 1321 for D614G. These samples
therefore had very strong neutralization of D614G virus, consistent with sampling soon after
vaccination. GMT FRNT50 for the same samples was 32 for Omicron, a 41-fold decline (Fig 1B).
However, the escape was incomplete, with 5 of the participants, all previously infected, showing
relatively high neutralization titers with Omicron.

Beta variant escape from BNT162b2 in a live virus neutralization assay has been reported to be
substantial (3) and our own data confirmed these results (4), with about 3-fold reduction in FRNT50.
The results we present here with Omicron show much more extensive escape. However, escape was
incomplete in participants with higher FRNT50 due to previous infection. Previous infection,
followed by vaccination or booster is likely to increase the neutralization level and likely confer
protection from severe disease in Omicron infection.

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