Real-world efficacy, roll-out and uptake of intramuscular tixagevimab/cilgavimab as COVID-19 pre-exposure prophylaxis in people with multiple sclerosis and neuroimmunological conditions during the COVID-19 pandemic

Introduction

In Australia, available COVID-19 vaccines are highly effective and widely accessible. As of mid-August 2022, over 95% of the adult Australian population have received at least two doses of a COVID-19 vaccine, 72% of those eligible for a third dose have received at least three doses, and 38% of those eligible for a fourth dose have received four doses.1 However, people with multiple sclerosis (pwMS) and people with other neuroimmunological conditions (pwNIc) on anti-CD20 and anti-CD52 monoclonal antibody therapies or sphingosine-1-phosphate receptor modulators exhibit attenuated humoral responses to COVID-19 vaccines and may be at increased risk of severe COVID-19.2–7

These observations support the eligibility of these people for tixagevimab/cilgavimab.

Tixagevimab/cilgavimab is a combination of two human monoclonal antibodies which target the surface spike protein of SARS-CoV-2. It is the first non-vaccine medication in Australia for the prevention of COVID-19 in people who are at risk of infection but have not been exposed to the virus. Data from clinical trials indicate that a single dose of tixagevimab/cilgavimab 150/150 mg reduces the risk of COVID-19 for up to 6 months.8–10

The first delivery of tixagevimab/cilgavimab to the National Medical Stockpile in Australia was on 22 March 2022, with the state of Victoria receiving its allocated stockpile shortly after. The Victorian eligibility criteria to access tixagevimab/cilgavimab was expanded on 27 May 2022, to include pwMS and pwNIc who had received in the last 12 months one of the following medications: anti-CD20 antibodies (rituximab, obinutuzumab, ocrelizumab, ofatumumab), sphingosine-1-phosphate receptor modulators (fingolimod, siponimod, ozanimod) or anti-CD52 antibodies (alemtuzumab).11

Tixagevimab/cilgavimab for eligible pwMS and pwNIc was fully funded by the government, with no costs to eligible people. Treatment was available at different hospital and community locations from mid-2022. Here, we report the roll-out, uptake, real-world efficacy of tixagevimab/cilgavimab in pwMS and pwNIc during the COVID-19 pandemic in the second half of 2022.

Methods

This was a retrospective analysis of pwMS and pwNIc who were eligible for tixagevimab/cilgavimab attending a single academic tertiary multiple sclerosis (MS) and neuroimmunology (NI) service in Victoria, Australia. The study was conducted as an MSBase Registry substudy.12 Three administration sites became available to eligible people at our service. The hospital infusion centre became active on 14 June 2022. The infusion centre is a 22-chair centre within the hospital where people receive a wide range of infusible treatments. The hospital vaccination hub became active on 21 June 2022. This was an initiative by the hospital to provide a space in a non-clinical area of the hospital for people to receive tixagevimab/cilgavimab. The site, while staffed by the hospital, was not physically within the hospital building. Local supercare pharmacies were metropolitan or rural pharmacies that had a nurse available and private areas for administration 7 days a week from 18:00 to 22:00 hours became active on 15 July 2022.13

Results

At our site, 46.7% (440/942) of people met the local eligibility criteria for tixagevimab/cilgavimab and received an alert of their eligibility. All eligible people were offered a neurologist consultation for further discussion of tixagevimab/cilgavimab. A total of 53.0% (233/440) pwMS and pwNIc responded and received tixagevimab/cilgavimab information during their scheduled consultation to discuss risks and benefits of administration. Demographics of the cohort are described in table 1.

Following consultation, 13 people were excluded due to either a contraindication to the drug (cardiac risk factors (n=5, 38.5) or declined due to personal choice. (n=8, 615%). The remaining 220 people consented to receive tixagevimab/cilgavimab and were given a choice of location for administration. Of those who consented, 167 people received tixagevimab/cilgavimab, and 47 people confirmed did not, 6 people unable to be contacted. The roll-out of tixagevimab/cilgavimab administration at site from initial eligibility to administration at three available locations is described in figure 1.

Request permission

Discussion

The COVID-19 pandemic has required MS and NI services to be highly adaptable and dedicate substantial resources to implement changes in local treatment and preventative guidelines. Vulnerable people such as those pwMS and pwNIc exposed to certain DMTs require specific and rapidly disseminated information to ensure their safety. Our results demonstrate the resources required to implement policy changes and the complexities of securing compliance in real-world health settings.

Just under half of the eligible peoples contacted did not respond to our offer to receive further consultation on the benefits of receiving pre-exposure prophylaxis. Our initial messaging was in English only and may have contributed to this. As Leask et al and Lewandowsky et al17 18 have emphasised with vaccine communication, we prioritised the key groups of eligible people for targeted communication and utilised key senior neurologists as signatures of communication. Consultation was available in the persons’ language of choice using the hospital interpreter service. A response rate of just over 50% may also suggest health literacy or language barriers.19 20 Moreover, information was exclusively provided through specialist centres and hospitals with no specific involvement from primary healthcare providers such as general practitioners. A wider and more consistent information campaign is essential when communicating risk and needs to be considered in future health strategies during pandemics.

Our results demonstrate the highest compliance with tixagevimab/cilgavimab administration occurred when the treatment was offered while the person was already on-site, for instance, receiving their usual DMT in the hospital infusion centre. In contrast, the lowest compliance was seen in people who opted to receive treatment through the hospital vaccination hub. Scheduling this additional appointment required several person-driven steps and, for some, significant travel time. People cited a change of risk perception to COVID-19 and logistical reasons, as reasons for not obtaining a booking. These observations are important as they suggest that preprophylaxis treatment for any future pandemics may be more successful at opportunistic moments such as in hospital infusion centre or outpatient consultations.

Our results demonstrate that at least one in five people who received tixagevimab/cilgavimab developed symptomatic COVID-19 during the 6-month observation period. This breakthrough infection rate is substantially higher than the published efficacy rate in the PROVENT study on unvaccinated participants. In this pivotal trial, symptomatic COVID-19 occurred in 8 of 3441 participants (0.2%) in the AZD7442 group and 17 of 1731 participants (1.0%) in the placebo group. Severe infections occurred (0.1%) in the placebo group in contrast to our study where none were observed. Our study, in contrast, demonstrates high levels of COVID-19 vaccination among eligible people. Our breakthrough COVID-19 positive incidence of 19.16% at the end of 2022 supports other recent studies that tixagevimab/cilgavimab had weakening neutralising effectiveness against Omicron BA.5, BR.2, BA2.75, BQ.1 and XBB.21–24 The severity of COVID-19 in both treated and untreated groups was mild, with no hospitalisation required.

Completion of tixagevimab/cilgavimab administration did not decrease the risk of COVID-19 in the observational period when compared with those who did not receive the treatment. However, we observed that people with higher disability levels were less likely to develop COVID-19, which suggests that these people may have been more compliant with social distancing and other precautions than those with less disability. This observation gives important significance to the social behaviours of vulnerable groups during health emergencies.

Vaccination is one of the most effective strategies in reducing severity of COVID-19. Tixagevimab/cilgavimab was approved in Australia to provide additional protection against COVID-19 for vulnerable/immunocompromised people who may not mount adequate vaccine responses. However, at the time when access to tixagevimab/cilgavimab was granted, the Australian population, including pwMS and pwNIc, were already highly vaccinated. Australia’s variant of concern had changed from Delta to Omicron with the first known Omicron sub lineages BA.1, BA.2 and BA.5 being reported in Australia in November 2021. In Victoria mid-April 2022, the BA.2 sublineage was the dominant strain in Victoria comprised at 97% of all COVID-19 variants, BA.4 was detected at 3% and BA.2.12.1 less than 1%.25 The dominant variant BA.2 at the time of roll-out supported the use of tixagevimab/cilgavimab as an effective neutralising treatment. Victoria did not see a change in variants till July 2022, when BA.5 and sublineages became dominant, however were, still neutralised by tixagevimab/cilgavimab. By December 2022, variants in Victoria were polyclonal mix including XBF, BA.2.75 sublineages and BQ.1 and BQ.1.1. The USA FDA warned on 1 June 2022 that tixagevimab/cilgavimab 150 mg/150 mg might not be effective at neutralising new emerging variants of concern and by December 2022, the effectiveness of tixagevimab/cilgavimab administration against these variants was shown to be reduced to less than 25%.26 In addition, infections from the new variants were reported to result in less severe infections.27–29 This information was widely available through online resources and may be one of the reasons 53% of eligible pwMS and pwNIc did not respond to our message to discuss securing tixagevimab/cilgavimab administration. It also is plausible that by late 2022 pandemic fatigue had caused our poor response rate. Eligible people now had not only complex individual health-related messaging, but competing community economic, social and educational aspects to consider and prioritise.30

This study has several limitations to generalisability, as it took place in only one tertiary centre, and the numbers although high for a single centre, may be not reflective of the wider population and health sector. It was not possible to follow up on eligible people who did not seek tixagevimab/cilgavimab consultation and their reasons for not contacting the service. Further research to explore optimal pre-exposure prophylaxis uptake and social behaviours during a pandemic is warranted to ensure healthcare services communicate important health information effectively and plan administration locations based on minimal steps required from patients.

Conclusion

MS and NI services need to have strategies and resources to rapidly disseminate crucial health information during a pandemic to vulnerable/immune-compromised people. Information needs to be multilingual, targeted and at a health literacy level that the majority would understand to make meaningful decisions. While a shared decision-making framework was followed during consultation, pwMS and pwNIc who consented to tixagevimab/cilgavimab still had poor compliance when responsible for booking and receiving the treatment. Compliance tended to be highest in the hospital infusion centre compared with hospital vaccination hub and pharmacy, suggesting preprophylaxis treatments may have greater uptake if people can access the therapy at DMT infusions or outpatient clinics. We demonstrate that in second half of 2022 one dose of tixagevimab/cilgavimab had limited efficacy in the prevention of COVID-19 in a highly vaccinated cohort of pwMS and pwNIc.