Recipients of allogeneic hematopoietic cell transplantation (alloHCT) have a better danger of extreme COVID-19 and COVID-19-associated mortality in comparison with the final inhabitants [1, 2]. Vaccination towards SARS-CoV-2 stays the simplest intervention to cut back the danger of poor an infection final result [3]. Nonetheless, in alloHCT, the transplant process impairs immune reminiscence to beforehand administered vaccines and precludes efficient vaccine responses early after transplantation [4]. COVID-19 vaccines are subsequently beneficial earliest three months after alloHCT [5]. To bridge this time between HCT and efficient vaccination, pre-exposure prophylaxis (PrEP) for COVID-19 via administration of monoclonal antibodies (mAb) is beneficial in a number of nations since mid-2021 [6, 7]. Throughout the emergence of the Omicron BA.1 variant in winter 2021–2022, solely the mAbs sotrovimab and tixagevimab/cilgavimab [8] maintained sufficient neutralizing exercise in vitro and the PROVENT examine supplied promising medical outcomes with tixagevimab/cilgavimab as PrEP [9]. Current observational research reported breakthrough infections of three.8–4.4% and low charges of extreme illness in immunocompromised sufferers receiving PreP with tixagevimab/cilgavimab [10, 11]. Nonetheless, particular information in newly transplanted alloHCT recipients and correlations to neutralizing antibody responses are missing. As a result of tixagevimab/cilgavimab was not out there in Switzerland till 04/2022, our establishment used sotrovimab as PrEP for COVID-19 in newly transplanted alloHCT recipients. On this potential observational examine, we aimed to generate real-world information on dynamics of neutralization exercise and whole immunoglobulin (Ig) ranges towards SARS-CoV-2, security, and breakthrough infections within the first 3 months after sotrovimab administration in sufferers who lately underwent alloHCT.
We included alloHCT recipients who obtained at the least one dose of sotrovimab (500 mg intravenously) as PrEP throughout the first 3 months following alloHCT on the College Hospital Basel from January to March 2022. Sufferers had been routinely adopted twice weekly within the outpatient clinic. SARS-CoV-2 PCR from respiratory samples was carried out on day 30 and 60 after sotrovimab administration in addition to within the occasion of signs. Blood samples had been collected on day 0 earlier than and on days 7, 30 and 60 after administration. Affected person information had been collected till day 90. Outcomes had been censored earlier for SARS-CoV-2 vaccination or an infection or for administration of a second sotrovimab infusion. Anti-Spike/receptor binding area (anti-S/RBD) whole Ig ranges had been measured with a semi-quantitative Elecsys® Anti-SARS-CoV-2 immunoassay (Roche). Neutralizing antibody titers had been measured with a microneutralization assay utilizing wild-type Wuhan, Delta and BA.1 viruses and spike BA.2 pseudotype virus. Full strategies are described within the Supplemental Methods. The examine was permitted by Ethics Committee Northwest and Central Switzerland (Undertaking-ID 2020-00769).
Of the 41 sufferers who underwent alloHCT from 11/2021 to 03/2022, 36 (88%) had been included into the examine. 5 sufferers weren’t included due to loss of life (n = 1) or switch to a different hospital (n = 2) previous to sotrovimab administration, or sufferers want to not obtain sotrovimab (n = 2).
The 36 included sufferers obtained sotrovimab at a median of 29 days (vary 17–80) after alloHCT. Previous to HCT, 26 (72%) sufferers had obtained at the least one dose of vaccination towards SARS-CoV-2, 7 (19%) sufferers had a previous SARS-CoV-2 an infection, and solely 6 (17%) sufferers neither had prior vaccination nor an infection. No affected person was misplaced to follow-up. Baseline traits are in Supplemental Desk 1.
Earlier than sotrovimab administration, the median degree of anti-S/RBD whole Ig was 1016.5 U/ml (vary, 45.2–2500), 8 (22.2%) sufferers had absent or very low ranges (<256 U/ml). Solely 7 (19.4%) had ranges above the higher restrict of detection. After sotrovimab administration, anti-S/RBD whole Ig elevated and remained steady till day 60 with ranges above the higher restrict of detection in 31 (86.1%) sufferers (Fig. 1a).
a Spaghetti plot displaying the dynamics of anti-S/RBD whole Ig ranges (logarithmic scale) on day 0 earlier than and on day 7, 30 and 60 after sotrovimab administration. Inexperienced dots point out particular person samples of sufferers with out breakthrough SARS-CoV-2 an infection; yellow dots point out particular person samples of sufferers with breakthrough an infection. Traces join outcomes from particular person sufferers. Values above the higher restrict of detection (> 2500 U/ml) are offered scattered with the intention to enable a graphical illustration with out extreme overlap. Included are 3 sufferers who obtained a second dose of sotrovimab on day 30 due to persistent low degree of anti-S/RBD whole Ig. b, c Neutralizing antibody titers at baseline (earlier than administration of sotrovimab) sorted by SARS-CoV-2 standing pre-transplant and dynamic after pre-exposure prophylaxis with sotrovimab early after alloHCT. 50% neutralization titers (NT50) are offered on a logarithmic scale. Dots point out particular person samples. The horizontal dotted line alongside the x axis signifies the restrict of detection (LOD), which was set on the serum dilution of 1:10 (NT50, 14.142). The geometric imply values for the NT50 are offered graphically (horizontal black traces) and proven as absolute numbers on the prime of the plots. 
bars signify 95% confidence intervals.
Earlier than sotrovimab administration, 6 (19.4%) sufferers had no detectable neutralizing antibodies. SARS-CoV-2 vaccination and an infection previous to alloHCT had been related to a better neutralizing exercise towards BA.1 and BA.2 after alloHCT, however earlier than sotrovimab administration (p = 0.009) (Fig. 1b).
After sotrovimab administration, the geometric imply of neutralizing antibody titers throughout all sufferers elevated and peaked on day 7 with a imply fold enhance from baseline of 4.4 for Wuhan, 6.3 for Delta, 5.2 for BA.1 and a pair of.1 for BA.2 (Fig. 1c). Neutralizing antibodies towards BA.1 had been nonetheless detectable in 31/31 (100%) sufferers at day 30 and in 13/14 (92.9%) sufferers at day 60, and towards BA.2 in 30/31 (96.8%) sufferers and in 13/14 (92.9%) sufferers, respectively. Nonetheless, there was a decrease exercise of sotrovimab towards BA.1 and particularly BA.2, as beforehand proven in in vitro research [8]. Earlier than sotrovimab administration, the anti-S/RBD whole Ig and the neutralizing antibody titers confirmed a robust correlation (information not proven). After sotrovimab administration, most anti-S/RBD whole Ig ranges had been above the higher restrict of detection, and thus, the correlation couldn’t be assessed.
Just one hostile occasion involving transient fever and rash was reported in a single affected person (2.8%) after sotrovimab administration. All sufferers had been alive at day 90 after sotrovimab administration.
Breakthrough an infection with SARS-CoV-2 occurred in 7 sufferers (19.4%), on the median 42 days (vary 15–81) after sotrovimab administration. 4 sufferers had been asymptomatic and examined optimistic at day 30 or 60 within the routine PCRs. Three sufferers had a light course; two had been hospitalized for statement for 1 and 4 days, respectively, however none required supplemental oxygen. SARS-CoV-2 sequencing was carried out in 3 instances and BA.1 and BA.2 had been detected in 1 and a pair of sufferers, respectively. Sufferers with breakthrough infections had comparable neutralizing exercise towards BA.1 and BA.2 (information not proven) and comparable medical baseline traits in comparison with sufferers with out breakthrough an infection (Supplemental desk 1) except for the donor supply, which was extra usually a mismatched unrelated donor (5 [71%] vs. 7 [24%]).
Samples from 4 sufferers collected after breakthrough an infection confirmed a rise in neutralizing antibodies, suggesting that endogenous antibody manufacturing can develop early after alloHCT regardless of extreme immunosuppression.
The strengths of this examine are the real-world and longitudinal design, the inclusion of a cohort that’s each, extraordinarily susceptible to infections and underrepresented in research on COVID-19 prevention, the consecutive inclusion of all alloHCT recipients who obtained sotrovimab through the omicron wave in early 2022, and the usage of wild-type viruses for the microneutralization assays (aside from BA.2). Our examine has limitations together with the single-centre design, the comparatively small affected person quantity, the lack of awareness relating to the SARS-CoV-2 HCT donor standing, and the absence of a management group which limits conclusions on efficacy. Testing was restricted to humoral immunity as that is influenced by sotrovimab, nevertheless, mobile responses could also be even vital, particularly in breakthrough infections.
In conclusion, our information exhibit that sufferers with prior SARS-CoV2 vaccination or an infection had been extra more likely to have detectable neutralizing antibodies early after alloHCT. Administration of a PrEP with sotrovimab throughout the first 3 months after alloHCT was secure and resulted in related enhance in circulating anti-S/RBD whole Ig and efficient neutralizing exercise towards all viral strains. Regardless of detectable neutralizing exercise, SARS-CoV-2 breakthrough an infection occurred in 19.4% of sufferers, nevertheless, it’s reassuring that no affected person had a extreme course. It stays unclear whether or not the excessive price of breakthrough infections was because of restricted efficacy of sotrovimab towards the circulating BA.1 and BA.2 variants or the excessive omicron surge in Switzerland, which affected roughly 10% of the Swiss inhabitants per week through the examine interval. Efficacy information on PrEP adjusted for at the moment circulating variants and randomized trials on this inhabitants are wanted.
