Role of tixagevimab/cilgavimab in preventing SARS-CoV-2 infection and severe COVID-19 among immunocompromised individuals

Fully vaccinated immunocompromised individuals (ICIs) are at higher risk of breakthrough SARS-CoV-2 infection and severe COVID-19 than people with normally functioning immune systems. This article explores latest data supporting the role of tixagevimab/cilgavimab, a combination of two long-acting monoclonal antibodies (mAbs), in providing additional protection against SARS-CoV-2 infection and minimizing the risk of severe COVID-19 among ICIs.

COVID-19 vaccination moderately effective in ICIs
While vaccination against COVID-19 reduces the risk of infection and severe disease (ie, hospitalization or death), its efficacy is lower among certain popula­tions, such as older people, those with multimorbidity, and ICIs.

For instance, a French cohort study of 28 million fully vaccinated (for ≥14 days as of 31 July 2021) individ­uals found that the risk of COVID-19– related hospitalization or death in­creased with increasing age, male gen­der and social deprivation. In addition, the risk of COVID-19 hospitalization and in-hospital death increased with the use of immunosuppressants (hos­pitalization: adjusted hazard ratio [aHR], 3.3; 95 percent confidence interval [CI], 2.8–3.8; death: aHR, 2.4; 95 percent CI, 1.7–3.5) and oral corticosteroids (hospitalization: aHR, 2.8; 95 percent CI, 2.5–3.1; death: aHR, 4.1; 95 per­cent CI, 3.3–5.1). The authors noted that while the 320,536 fully vaccinat­ed individuals on immunosuppressive treatment represented only 1 percent of their study’s population, they ac­counted for 9.5 percent of COVID-19– related hospitalizations. [Lancet Reg Health Eur 2022;19:100441]

Similarly, a pooled analysis of na­tional prospective cohort studies of 30 million individuals in England, Northern Ireland, Scotland, and Wales found that individuals receiving immunosuppres­sants remained at high risk of severe COVID-19 outcomes (adjusted rate ratio [aRR], 5.8; 95 percent CI, 5.53– 6.09) despite the initial booster vaccine dose (for ≥14 days as of 28 February 2022). [Lancet 2022;400:1305-1320]

An analysis of 34,220 hospitaliza­tions for COVID-19–like illness among adults with immunocompromising con­ditions in the US has found two doses of monovalent mRNA COVID-19 vac­cine to be 36 percent effective against COVID-19–associated hospitalization during a period of Omicron variant pre­dominance. Vaccine effectiveness in­creased to 67 percent with the addition of a third dose of monovalent vaccine during BA.1 predominance, but de­clined to 32 percent ≥90 days after the third dose and 43 percent ≥7 days after a monovalent fourth dose during com­bined BA.2/BA.2.12.1 and BA.4/BA.5 predominance. Authors of the study concluded that monovalent COVID-19 vaccination among ICIs conferred mod­erate protection against COVID-19–associated hospitalization during Omi­cron circulation, with lower protection during BA.2/BA.2.12.1 and BA.4/ BA.5 sublineage predominance peri­ods. [MMWR Morb Mortal Wkly Rep 2022;71:1335-1342]

Additional protection with tixagevimab/cilgavimab
The residual risk of severe COVID-19 outcomes in the fully vac­cinated elderly, immunocompromised and multimorbidity populations war­rants complementary preventive measures. [Lancet Reg Health Eur 2022;19:100441]

Tixagevimab/cilgavimab is a com­bination of two long-acting mAbs ap­proved for pre-exposure prophylaxis (PrEP) of COVID-19 in adults and ad­olescents ≥12 years of age weighing ≥40 kg. It is also indicated for treat­ment of COVID-19 in patients ≥12 years of age weighing ≥40 kg who do not require supplemental oxygen and who are at increased risk of progress­ing to severe COVID-19. [Evusheld Hong Kong Prescribing Information]

Tixagevimab and cilgavimab have a modified fragment crystallizable (Fc) receptor, which extends their half-life to approximately 90 days. [Viruses 2022;14:2278] The combination can thus be administered (as two separate consecutive intramuscular injections) every 6 months to patients at risk of inadequate response to immunization, and was shown to reduce the risk of symptomatic or severe COVID-19 or COVID-19–related death in a num­ber of clinical and real-world studies. [Evusheld Hong Kong Prescribing In­formation]

Clinical evidence
Between November 2020 and March 2021, the phase III, multi­centre, double-blind, parallel-group PROVENT trial randomized partici­pants at increased risk of inadequate response to COVID-19 vaccination, increased risk of exposure to SARS-CoV-2, or both, to receive one dose of tixagevimab/cilgavimab or placebo. Participants at increased risk of inad­equate response to COVID-19 vacci­nation were ≥60 years of age, obese (body mass index (≥30 kg/m²), immu­no-compromised, unable to receive vaccines without adverse effects, or had congestive heart failure, chronic obstructive pulmonary disease, chron­ic kidney disease, or chronic liver dis­ease. [N Engl J Med 2022;386:2188-2200]

At primary analysis, after approxi­mately 3 months of follow-up, symp­tomatic COVID-19 occurred in 8 of 3,441 participants (0.2 percent) in the tixagevimab/cilgavimab group vs 17 of 1,731 participants (1.0 percent) in the placebo group (relative risk reduc­tion [RRR], 76.7 percent; 95 percent CI, 46.0–90.0; p<0.001). Extended follow-up at a median of 6 months showed a RRR of 82.8 percent (95 percent CI, 65.8–91.4) in tixagevimab/cilgavimab recipients. Among partici­pants at increased risk of inadequate response to COVID-19 vaccination, the RRR was 80.7 percent. In partic­ipants receiving immunosuppressive treatment (n=173), the RRR was 71.7 percent.

In total, 1,221 of 3,461 participants (35.3 percent) in the tixagevimab/cil­gavimab group and 593 of 1,736 par­ticipants (34.2 percent) in the placebo group reported ≥1 adverse event (AE), most of which were mild or moder­ate in severity. Five cases of severe or critical COVID-19 and two COVID-19–related deaths occurred, all in the pla­cebo group.

Real-world evidence
As SARS-CoV-2 continued to evolve, sustained efficacy of tixa­gevimab/cilgavimab against emerging variants of concern, including Omicron, was brought into question. [Kidney Int 2022;102:442-444]

A recent retrospective observa­tional study evaluated the association between tixagevimab/cilgavimab ad­ministration and SARS-CoV-2 infec­tion and severe disease (ie, COVID-19 hospitalization and all-cause mortality) among selected ICIs during the fifth Omicron-dominated wave of COVID-19 (December 2021 – April 2022) in Israel. Since February 2022, tixagevimab/cil­gavimab was offered to all members of a large health maintenance organization aged ≥12 years and weighing ≥40 kg who had evidence of severe immuno­suppression and were not vaccinated against COVID-19 in the past 2 weeks. Among patients meeting the severe immunosuppression criteria (n=5,124), the most prevalent conditions were lymphoma (39.5 percent), solid organ transplant (33.0 percent), anti-CD20 treatment (19.1 percent), and multiple myeloma (13.3 percent). [Clin Infect Dis 2023;76:e126-e132]

Of the study population, 825 par­ticipants (16.1 percent) received tixa­gevimab/cilgavimab, 29 (3.5 percent) of whom were subsequently infected with SARS-CoV-2 (vs 308 of 4,299 participants [7.2 percent] who had not received tixagevimab/cilgavimab; p<0.001). This finding was consistent over the study period (23 February 2022 – 26 May 2022). After adjust­ment, the odds of infection for the tixa­gevimab/cilgavimab group were half vs the control group (odds ratio, 0.51; 95 percent CI, 0.30–0.84).

Only one person in the tixagevimab/ cilgavimab group (0.1 percent) was hospitalized for COVID-19 vs 27 peo­ple (0.6 percent) in the control group (p=0.05). No deaths occurred in the tix­agevimab/cilgavimab group during the study period vs 40 deaths (0.9 percent) in the control group (p=0.005). Evi­dence of severe disease was observed in only 0.1 percent of tixagevimab/ cilgavimab recipients vs 1.5 percent of participants in the control group (p=0.001). This finding remained con­sistent over the study period.

As the number of study participants with a severe disease outcome was small (n=64), a logistic regression anal­ysis was carried out, including only age group and cardiovascular disease. After adjustment, the odds of having severe disease in the tixagevimab/cilgavimab vs control group were 0.08 (95 percent CI, 0.01–0.54). (Table)

Another observational multicentre co­hort study evaluated PrEP efficacy of tix­agevimab/cilgavimab among 1,112 ICIs during the Omicron wave in France. After a median follow-up of 63 days, COVID-19 was confirmed in 4.4 percent of ICIs ≥5 days after tixagevimab/cilgavimab treat­ment. During the study period (28 De­cember 2021 – 31 March 2022), the mean weekly incidence rate of COVID-19 infection was 1,669 per 100,000 inhab­itants in the Ile-de-France area where ICIs were receiving treatment vs 530 per 100,000 among those given tixagevimab/ cilgavimab. (Figure) [Clin Microbiol Infect 2022;28:1654.e1-1654.e4]

In addition to efficacy in the gener­al population of ICIs, tixagevimab/cil­gavimab has also demonstrated a pro­tective effect against severe COVID-19 in subgroups of patients with haemato­logical malignancies, immune-mediated inflammatory disease undergoing B-cell depleting therapy, or errors of humoral immunity, and kidney transplant recip­ients. [Cancer 2022;128:3319-3329; RMD Open 2022;8:e002557; Kidney Int 2022;102:936-939]

Most recently, a real-world study eval­uated efficacy of tixagevimab/cilgavimab against breakthrough COVID-19 infection in fully vaccinated persons with neuroin­flammatory disease (pwNID) treated with potent immunosuppressives. Overall, 31 pwNID were given tixagevimab/cil­gavimab PrEP between January and July 2022, while 126 pwNID served as a vaccinated control group. PwNID treated with tixagevimab/cilgavimab had a sig­nificantly higher rate of comorbidities vs controls (54.8 percent vs 30.2 percent; p=0.02). In addition, pwNID who received tixagevimab/cilgavimab had a numerically lower rate of seroconversion vs controls (16.1 percent vs 30.2 percent; p=0.117). [Vaccines (Basel) 2023;11:350]

After 6 months of follow-up, break­through COVID-19 was significantly less frequent in tixagevimab/ cilgavimab-treated pwNID vs controls (6.5 percent vs 34.1 percent; p=0.002). Unlike in the control group where 20.9 percent of cases were moderate or severe, the two breakthrough infections in the tixagevimab/cilgavimab group were mild and did not require specific COVID-19 treatment. On the other hand, 20 of 43 (46.5 percent) patients with breakthrough infections in the control group received COVID-19–specific medication.

Summary
Vaccination against COVID-19 has been shown to be less effective in ICIs vs people with normally functioning im­mune systems. Based on clinical and real-world evidence, the long-acting tixagevimab/cilgavimab mAb com­bination offers additional protection against the infection and reduces the risk of symptomatic or severe COVID-19 or COVID-19–related death in ICIs.