COVID-19 Pre-Exposure Prophylaxis
July 30, 2022 3 minutes read
By Stan Deresinski, MD, FACP, FIDSA
Clinical Professor of Medicine, Stanford University
SYNOPSIS: The combination of tixagevimab and cilgavimab (Evusheld) was demonstrated to be effective in the prevention of symptomatic COVID-19, but much remains to be learned as SARS-CoV-2 continues to evolve.
SOURCE: Levin MJ, Ustianowski A, De Wit S, et al; PROVENT Study Group. Intramuscular AZD7442 (tixagevimab-cilgavimab) for prevention of COVID-19. N Engl J Med 2022;38:2188-2200.
Levin et al reported the results of an ongoing randomized trial evaluating the efficacy of a combination of monoclonal antibodies (tixagevimab and cilgavimab, marketed as Evusheld) in the prevention of symptomatic COVID-19 in adults. Subjects were judged to be at risk, either because of a likely inadequate response to vaccination or increased risk of exposure caused by location (e.g., nursing home) or circumstance. A total of 5,197 patients were randomized (2:1) to receive tixagevimab-cilgavimab, 300 mg of each component, as separate intramuscular injections at the same visit, or comparable placebo injections. The study took place between November 2020 and March 2021 (pre-omicron).
PCR-confirmed symptomatic illness occurred in eight of 3,441 tixagevimab-cilgavimab recipients and 17 of 1,731 who received placebo through day 183. The relative risk reduction was 76.7% (95% CI, 46.0-90.0; P < 0.001). With extended follow-up at a median of six months, the relative risk reduction was 82.8%. In addition, there were five cases of severe or critical COVID-19 and two COVID-19-related deaths, and all seven occurred in the placebo group. Adverse events, mostly mild, occurred in approximately one-third of subjects in each group.
Genotyping was performed on isolates from 20 patients, including from seven asymptomatic monoclonal recipients and 13 symptomatic placebo recipients. Among variants of concern, one was a beta (in a tixagevimab-cilgavimab subject). There were five alpha subvariants and five delta among placebo recipients.
A pharmacokinetic analysis revealed serum neutralization titers 29 days after administration were 16-22 times higher than reported in convalescent plasma in individuals recovering from COVID-19. Significant serum levels were seen at six months.
COMMENTARY
Tixagevimab and cilgavimab each bind to distinct sites within the receptor biding domain of the SARS-CoV-2 spike protein. This allows continued activity of the combination if resistance to only one of the epitopes emerges. The emergence of omicron led to the discarding of two available monoclonal combinations, bamlanivimab/etesevimab and casirivimab/imdevimab, because of markedly ineffective activity against the omicron BA.1 and BA.2 variants, and sotrovimab, because of less efficacy against BA.2. The emergence of mutants capable of escaping monoclonal antibodies became of concern regarding tixagevimab-cilgavimab when data indicated less activity of one of its components against BA.1. However, the combination of its components retains significant in vitro activity against BA.2, although BA.2 breakthrough infections have been identified. The reduced activity against BA.1 had led the FDA, in February 2022, to recommend a doubling of the doses of the components to 600 mg each, to overcome modest reductions in activity. This remains the current dose. Bebtelovimab, which has emergency use authorization for treatment but not prophylaxis, remains active against both BA.1 and BA.2.
Furthermore, with a half-life of 90 days, serum monoclonal antibody levels persisted after tixagevimab-cilgavimab administration for as long as nine months, with levels likely to be protective against susceptible variants for at least six months. The extended half-lives of the monoclonal components of tixagevimab-cilgavimab are the result of modifications that reduce binding to the Fc receptor and C1q. When repeat dosing is under discussion, the answer remains to be seen. This first depends on whether, in dealing with a constantly evolving virus, it remains efficacious when that time comes.
When tixagevimab-cilgavimab received emergency use authorization, it was in short supply. Thus, its use primarily was directed at patients with significant immunocompromise, such as those who were transplant recipients. However, in the clinical trial results presented here, there were only 198 patients with immunocompromise, with symptomatic infection occurring in 1/125 and 2/93 tixagevimab-cilgavimab and placebo recipients, respectively. Thus, we really do not know the degree of benefit that may be achieved in these patients, just as we do not know for certain its efficacy in an omicron world.
The combination of tixagevimab and cilgavimab (Evusheld) was demonstrated to be effective in the prevention of symptomatic COVID-19, but much remains to be learned as SARS-CoV-2 continues to evolve.
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