Pre-exposure anti-SARS-CoV-2 monoclonal antibodies in severely immunocompromised patients with immune-mediated inflammatory diseases.

Patients with immune-mediated inflammatory diseases are at a higher risk of severe COVID-19, in part, due to immune suppression induced by treatment.1, 2 France began vaccinations against COVID-19 in December, 2020, and patients with immune-mediated inflammatory diseases receiving immunosuppressive drugs were prioritised for vaccination. It has since been demonstrated that patients with immune-mediated inflammatory diseases—especially those receiving anti-CD20 agents—mount a suboptimal humoral response to COVID-19 vaccination.4, 5 These patients are thus candidates for additional strategies to protect them from COVID-19. Our objective was to determine whether pre-exposure prophylaxis with tixagevimab and cilgavimab—a monoclonal antibody combination with neutralising activity against alpha (B.1.1.7), beta (B.1.351), gamma (P.1), delta (B.1.617.2), and omicron (B.1.1.529) SARS-CoV-2 variants—might be of benefit to patients with immune-mediated inflammatory diseases who did not generate a humoral response to mRNA vaccination.

Tixagevimab plus cilgavimab was granted Emergency Use Authorisation by the Agence Nationale de Sécurité du Medicament in France in December, 2021, for pre-exposure prophylaxis against COVID-19 in individuals with severely compromised immune systems due to immunosuppressive medications who might not mount an adequate humoral response to COVID-19 vaccination. Immunosuppressive medications included anti-CD20 agents, Bruton's tyrosine kinase (BTK) inhibitor, azathioprine, cyclophosphamide, and mycophenolate mofetil. An inadequate humoral response to vaccine was defined by a serum SARS-CoV-2 anti-spike IgG (anti-S) titre of less than 264 binding antibody units (BAU)/mL 2–4 weeks after receiving a fourth vaccine dose.

We screened all outpatients with immune-mediated inflammatory disease (n=219) who were immunised via the vaccine task force set up between March and May, 2021, in our national centre for rare immune-mediated inflammatory diseases (Internal Medicine Department, Bichat Hospital, Paris, France). Of these patients, 165 were taking immunosuppressive drugs. 70 patients were treated with azathioprine, mycophenolate mofetil, anti-CD20 agents, or a combination thereof (no patients were receiving a BTK inhibitor or cyclophosphamide). All patients were fully vaccinated against SARS-CoV-2 (initial three-dose series with an mRNA-based COVID-19 vaccine and a fourth dose ≥6 months later), and were considered for pre-exposure prophylaxis. All 70 patients were contacted and invited for screening for SARS-CoV-2 anti-S titres in serum shortly after the fourth vaccine dose, and those patients with inadequate antibody titres were scheduled to receive an infusion with tixagevimab and cilgavimab. 44 (63%) of 70 patients were screened, and 17 (39%) had inadequate anti-S titres (0–256 BAU/mL [median 0·6]) and were eligible for pre-exposure prophylaxis. 12 (71%) of these eligible patients had received anti-CD20 agents. The absence of adequate humoral responses after vaccination was associated with age older than 60 years, obesity, and the use of anti-CD20 drugs (table ). Due to logistical constraints (appendix pp 1–2), only ten of the 17 eligible patients received anti-SARS-CoV-2 monoclonal antibodies at a median of 40·5 days (IQR 22–55) after the fourth vaccine dose and a median of 7·5 days (4–25) after antibody screening (appendix pp 3–6). All patients who received prophylactic monoclonal antibodies had a negative SARS-CoV-2 RT-PCR result on the day of infusion.

Table

patient characteristics

		All on immunosuppressants (n=165)	Severely immunocompromised*(n=70)	Screened for humoral response post vaccine (n=44)	Anti-S IgG† >264 BAU/mL (n=27)	Anti-S IgG <264 BAU/mL (n=17)	p value
Age, years		48 (37–62)	47 (37–61)	49 (37–63)	43 (35–57)	60 (43–69)	0·07
Gender
	Female	104 (63%)	45 (64%)	25 (57%)	14 (52%)	11 (65%)	ns
	Male	61 (37%)	25 (36%)	19 (43%)	13 (48%)	6 (35%)	ns
Autoimmune diseases		74 (45%)	41 (59%)	25 (57%)	16 (59%)	9 (53%)	ns
	Systemic lupus erythematosus	42	24	15	11	4	..
	Immune cytopenia	5	4	2	1	1	..
	Sjögren's syndrome	2	0	0	0	0	..
Systemic sclerosis		4	1	1	0	1	..
	Mixed connective tissue disease	5	3	1	1	0	..
	Immune encephalitis	3	2	2	0	2	..
	Myositis	13	7	4	3	1	..
Systemic vasculitis		49 (30%)	23 (33%)	15 (34%)	9 (33%)	6 (35%)	ns
	Small-vessels vasculitis	24	16	11	6	5	..
	Large-vessels vasculitis	10	1	1	1	0	..
	Behcet's disease	15	6	3	2	1	..
Other		42 (25%)	6 (9%)	4 (9%)	2 (7%)	2 (12%)	ns
	Sarcoidosis	14	0	0	0	0	..
	Autoinflammatory diseases	11	1	1	0	1	..
	IgG4-related diseases	8	3	1	1	0	..
	Relapsing polychondritis	3	0	0	0	0	..
	Unclassified	6	2	2	1	1	..
BMI >30 kg/m2		30 (18%)	10 (14%)	5 (11%)	1 (4%)	4 (24%)	0·06
Diabetes		22 (13%)	8 (11%)	5 (11%)	2 (7%)	3 (18%)	ns
COPD, pulmonary fibrosis		12 (7%)	6 (9%)	3 (7%)	2 (7%)	1 (6%)	ns
Treatment
	Mycophenolate mofetil	43 (26%)	29 (41%)	18 (41%)	11 (41%)	7 (41%)	ns
	Azathioprine	26 (16%)	18 (26%)	10 (23%)	7 (26%)	3 (18%)	ns
	Anti-CD20	39 (24%)	29 (41%)	21 (48%)	9 (33%)	12 (71%)	0·03
	Anti-CD20 plus mycophenolate mofetil	6	6	4	1	3	..
	Anti-CD20 plus azathioprine	6	5	3	1	2	..

Data are median (IQR), n (%), or n. Comparison was performed between patients with immune-mediated inflammatory diseases with (anti-S >264 BAU/mL) and without (anti-S <264 BAU/mL) adequate humoral responses after complete vaccination. The Mann-Whitney test was used to compare continuous variables. The Fisher's exact test was used to compare dichotomous variables. BAU=binding antibody units. BMI=body-mass index. COPD=chronic obstructive pulmonary disease. Anti-S=SARS-CoV-2-spike antibodies. ns=not significant (p>0·1).

Due to immunosuppressive medications included anti-CD20 agents, Bruton's tyrosine kinase inhibitor, azathioprine, cyclophosphamide, and mycophenolate mofetil.

Anti-S titres were measured 2–4 weeks after the vaccine booster administration, using the automated Abbott SARS-CoV-2 IgG kit (chemiluminescent microparticle immunoassay; Abbott, IL, USA) according to the manufacturer's instructions.

PCR-confirmed COVID-19 occurred in eight (47%) of the 17 patients who did not mount an adequate humoral response to vaccination, with infection occurring a median of 49 days (IQR 39–96) after the fourth vaccine dose (appendix p 7). All but one SARS-CoV-2 infection was due to the omicron variant. Among patients with COVID-19, five required hospitalisation, four of whom received supplemental oxygen; all eight patients received therapeutic anti-SARS-Cov-2 monoclonal antibodies, three received dexamethasone, and one received anakinra. One patient died (appendix p 7). Of the eight patients with PCR-confirmed COVID-19, seven did not receive prophylactic monoclonal antibodies. The patient who received tixagevimab and cilgavimab and developed COVID-19 had only mild disease and did not require admission to hospital. No serious adverse effects after administration of prophylactic SARS-CoV-2 monoclonal antibodies were reported. Of note, COVID-19 also occurred in one (4%) of the 27 patients who had adequate humoral responses after vaccination, and in one patient who was not screened for humoral response (appendix p 9).

Our study showed that more than a third of severely immunocompromised patients with immune-mediated inflammatory diseases did not mount an adequate antibody response to SARS-CoV-2 vaccination, and pre-exposure administration of tixagevimab and cilgavimab was associated with a lower risk of COVID-19. All patients with immune-mediated inflammatory diseases who are receiving immunosuppressive drugs should be screened for humoral response to vaccination based on anti-S titres. The absence of anti-SARS-Cov-2 antibodies after full vaccination identifies patients who are at high risk and are eligible for anti-COVID-19 monoclonal antibody prophylaxis. Successful administration of anti-SARS-CoV-2 monoclonal antibodies requires accurate identification of high-risk patients, rapid assessment of humoral responses to vaccination based on anti-S titres, and an easily accessible site for anti-SARS-CoV-2 monoclonal antibody administration.

The rate of COVID-19 was surprisingly high in our patients with immune-mediated inflammatory diseases who did not receive anti-SARS-CoV-2 monoclonal antibodies. A likely explanation for this is that patients in our cohort were highly exposed to SARS-CoV-2 during the omicron spread that occurred in France during the fifth wave of COVID-19 in January, 2022 (appendix p 10). The onset of a highly contagious variant that was spreading rapidly across the country and was dominant at the time of this study, along with the absence of adequate humoral response to vaccination, might explain the high infection rate. We did not observe differences in age, gender, immunosuppressive therapy, comorbidity, vaccine type, or timing of vaccinations between patients who received or did not receive anti-SARS-CoV-2 monoclonal antibodies (appendix pp 3–6). The median time from infusion to last follow-up (50 days, IQR 43–54) in the treatment group was longer than the time from humoral screening to development of COVID-19 (16·5 days, 5–22) in the control (untreated) group, suggesting that patients in both groups have had approximately the same exposure to SARS-CoV-2 (appendix pp 5–6). Conversely, the decrease in the incidence of COVID-19 observed over time (appendix p 10) might also have artificially inflated the benefit of prophylactic anti-SARS-CoV-2 monoclonal antibodies. It is also possible that patients who did not receive prophylactic antibodies were infected with SARS-CoV-2 before they were able to be treated. Although we have no evidence that our patients were in close contact with individuals infected with SARS-CoV-2, we cannot rule out the possibility that prophylactic treatment might have been given to patients after virus exposure. Three of the eight patients who developed COVID-19 were living in nursing homes and thus were at a higher risk of exposure to SARS-CoV-2. The threshold used to determine an adequate humoral response (264 BAU/mL) was consistent with a previously published study, and we observed a strong correlation between anti-S IgG titres and pseudoneutralisation activity (appendix p 11).

Our study had several limitations. The anti-S titres in response to vaccine were not available for all patients, but the characteristics of patients deemed eligible for pre-exposure monoclonal antibody therapy were not different from those who were not screened for vaccine response (appendix p 8). The sample size was small, and the study was done at a single centre. The findings of this study should thus be interpreted with caution, and future studies with larger sample sizes and more homogeneous follow-up times for treatment and control groups are necessary to confirm these results. Despite these limitations, our study is, to our knowledge, the first to report on the real-world clinical use of prophylactic anti-SARS-CoV-2 monoclonal antibodies in patients with immune-mediated inflammatory diseases, with initial evidence for clinical benefit.

In conclusion, our findings support the use of timely pre-exposure administration of prophylactic anti-SARS-CoV-2 monoclonal antibodies to prevent COVID-19 in patients with immune-mediated inflammatory diseases who are severely immunocompromised and do not generate an adequate humoral response to vaccination. Because it is unclear which SARS-CoV-2 variants will become dominant over the next few months, the benefits of pre-exposure prophylaxis will need to be updated over time.

TG and KS designed the study, directed the project, and wrote the Comment. TG and VMF did the analysis. LD, ND, CF, TP, and DD were involved in project development and edited the Comment. All authors reviewed and approved of the final Comment. DD received consulting fees from VIIV Heath Care, Gilead Sciences, Merck Sharp & Dohme, and Janssen Cilag; and support for attending meetings or travel, or both, from VIIV Heath Care and Gilead Sciences. TP received support for attending meetings or travel, or both, from Swedish Orphan Biovitrum. VMF received support for attending meetings or travel, or both, from Gilead Sciences. All other authors declare no competing interests. Patients and the public were not involved in the design, conduct, reporting, or dissemination plans of this research. Patient consent was not required for this study. The authors acknowledge Jean-Francois Alexandra, Marie-Paule Chauveheid, Julie Chezel, Antoine Dossier, Maureen Marie-Joseph, Julien Rohmer, Diane Rouzaud, and Celine Mendes from the Bichat Hospital Internal Medicine Department for their invaluable help. The study was supported by Agence Nationale pour la Recherche (grant number ANR-21-COVR-0034 COVALUS) and by the Agence Nationale de la Recherche sur le SIDA et les Maladies Infectieuses Emergentes, AC43 Medical Virology and Emergen Program.