The emerging SARS-CoV-2 Omicron (B. 1.1. 529) variant has caused considerable concern about the future of containing the ongoing COVID-19 pandemic (World Health Organization, 2021). First isolated in late November of 2021, the Omicron variant harbors a staggering 30–40 mutations in the viral spike (S) protein, including substantial changes to the S-receptor-binding domain, that have produced significant concern about the potentially high immune evasion of this variant (World Health Organization, 2021). Additionally, the rapid increase in COVID-19 cases attributed to the Omicron variant (Karim and Karim, 2021) has caused major public health concern about its increased transmissibility. We recently reported that the Omicron variant exhibits drastic resistance to neutralizing antibodies (nAbs) in healthy recipients of two-dose mRNA-1273 or BNT162b2 mRNA vaccines, as well as in COVID-19 patients (Zeng et al., 2021a). However, healthy individuals who received an additional third mRNA booster vaccine dose exhibit much stronger protection against the Omicron variant, comparable to their protection against other SARS-CoV-2 variants of concern (VOCs)(Zeng et al., 2021a). Our results indicate that not only does booster vaccination enhances nAb levels, but it also broadens the nAb response against these VOCs, including the Omicron variant. However, it remains unclear how booster vaccination impacts immunity against the Omicron variant in immunocompromised groups, especially in patients with cancer who are on active therapy. A report from our group has recently shown that patients with cancer are a key group of immunocompromised individuals with reduced responsiveness to two-dose mRNA vaccination(Zeng et al., 2021b). This reduced vaccine responsiveness can be somewhat overcome by the administration of booster vaccine doses (Greenberger et al., 2021; Shapiro et al., 2021). However, the breadth of the nAb response in these boosted patients, in particular their immunity against the Omicron variant, remains unclear. This is a critical question to resolve in order to determine future vaccination strategies, especially the administration of additional booster doses, for immunocompromised groups. To address this urgent need, we utilized our previously reported, highly sensitive, pseudotyped-lentivirus neutralization assay (Zeng et al., 2020) to examine the nAb response to Omicron compared to Delta and the ancestral D614G variants in patients with cancer (n= 50) following two mRNA vaccine doses (n= 23) and three doses including a third booster vaccine (n= 27). Samples were collected between 31 and 121 days (median 95 days) after the second mRNA vaccine dose for 15 lung cancer patients vaccinated with mRNA-1273 (n= 10) or BNT162b2 (n= 5) and 8 breast cancer patients vaccinated with mRNA-1273 (n= 2) or

BNT162b2 (n= 6). For booster vaccine recipients, samples were collected between 2 and 112 days (median 47 days) after the third mRNA vaccine dose for patient with solid tumors, including 12 breast cancer patients vaccinated with mRNA-1273 (n= 4) or BNT162b2 (n= 8) and a mix of patients with 15 other types of solid tumor (such as melanoma, genitourinary, gastrointestinal, etc.) who were vaccinated with either mRNA-1273 (n= 5) or BNT162b2 (n= 10)(Table S1). Neutralizing Ab titers (NT50) were measured against the Omicron variant, along with the ancestral D614G SARS-CoV-2 and the Delta variant, the latter being responsible for the most recent wave of infections. We found that, for recipients of two mRNA vaccine doses, the Delta and Omicron variants exhibited a 4.2-fold (p< 0.01) and 21.3-fold (p< 0.01 …