Neutralizing activity and 3-month durability of tixagevimab and cilgavimab prophylaxis against Omicron sublineages in transplant recipients

Abstract

Neutralizing antibody (nAb) responses are attenuated in solid organ transplant recipients (SOTRs) despite severe acute respiratory syndrome-coronavirus-2 vaccination. Preexposure prophylaxis (PrEP) with the antibody combination tixagevimab and cilgavimab (T+C) might augment immunoprotection, yet in vitro activity and durability against Omicron sublineages BA.4/5 in fully vaccinated SOTRs have not been delineated. Vaccinated SOTRs, who received 300 + 300 mg T+C (ie, full dose), within a prospective observational cohort submitted pre and postinjection samples between January 31, 2022, and July 6, 2022. The peak live virus nAb was measured against Omicron sublineages (BA.1, BA.2, BA.2.12.1, and BA.4), and surrogate neutralization (percent inhibition of angiotensin-converting enzyme 2 receptor binding to full length spike, validated vs live virus) was measured out to 3 months against sublineages, including BA.4/5. With live virus testing, the proportion of SOTRs with any nAb increased against BA.2 (47%-100%; P < .01), BA.2.12.1 (27%-80%; P < .01), and BA.4 (27%-93%; P < .01), but not against BA.1 (40%-33%; P = .6). The proportion of SOTRs with surrogate neutralizing inhibition against BA.5, however, fell to 15% by 3 months. Two participants developed mild severe acute respiratory syndrome-coronavirus-2 infection during follow-up. The majority of fully vaccinated SOTRs receiving T+C PrEP achieved BA.4/5 neutralization, yet nAb activity commonly waned by 3 months postinjection. It is critical to assess the optimal dose and interval of T+C PrEP to maximize protection in a changing variant climate.

Keywords: COVID-19; Omicron variant; cilgavimab; monoclonal antibody; organ transplant; tixagevimab.

Figure 1

Live virus neutralizing antibody (nAb) against severe acute respiratory syndrome-coronavirus-2 variants pre and post tixagevimab and cilgavimab (T+C) injection among fully vaccinated solid organ transplant recipients (SOTRs). Live virus assays against the ancestral variant and Omicron sublineages BA.1, BA.2, BA.2.12.1, and BA.4 were performed in a subset of SOTRs (n = 15) before and 2 weeks following T+C injection. The Y axis denotes the area under the curve of the neutralization function (nAb AUC) on the log₁₀ scale, with AUC > 10 denoting a positive antibody test (above the dashed orange line). The proportion with detectable nAbs is displayed on the X axis pre- and post-T+C injection. nAb AUC significantly increased for ancestral, BA.1, BA.2, BA.2.12.1, and BA.4 variants (P < .001 by the Wilcoxon paired signed-rank test), but not for BA.1 (P = .8).

Figure 2

Longitudinal neutralizing inhibition against severe acute respiratory syndrome-coronavirus-2 variants following tixagevimab and cilgavimab (T+C) injection among fully vaccinated solid organ transplant recipients (SOTRs). Surrogate neutralization (%ACE2 inhibition) against the spike protein of the ancestral and Omicron BA.1, BA.2, BA.2.12.1, BA.4, and BA.5 sublineages was performed on all participant samples pre-T+C injection, and at 2 weeks, 1 month, and 3 months post-T+C injection. Each trajectory represents an individual SOTR, and those experiencing an infection following the first dose of T+C are highlighted with blue triangles. The Y axis represents %ACE2 inhibition (0%-100%). The proportion of participants demonstrating neutralizing inhibition at each timepoint (above the dashed orange line) is presented on the X axis; individuals developing incident COVID-19 infection prior to a given timepoint are excluded from the denominator. Neutralizing inhibition increased against the ancestral, BA.2, BA.2.12.1, BA.4, and BA.5 variants (P < .001 by the McNemar Exact test), but not against the BA.1 variant (P = .6), by 2 weeks. Neutralizing inhibition waned by 3 months post-T+C injection, as seen in <20% of participants against the BA.4/5 variant. %ACE2 inhibition, the inhibition of angiotensin-converting enzyme 2; COVID-19, coronavirus disease 2019.