AZD7442 (tixagevimab–cilgavimab) prevents COVID-19 in high-risk populations

Though most COVID-19 safe management measures have been lifted in Singapore, the pandemic continues to adversely impact the lives of immunocompromised patients at high risk of severe infection.

“It has been an absolute misery for these patients and their families,” said Dr Leong Hoe Nam, Infectious Disease Specialist at Mount Elizabeth Novena Hospital, Singapore. “The virus is an unseen enemy that may strike unexpectedly. The strike may kill, or if not, maim the individual. Patients isolate themselves for fear of getting infected while their family members fear bringing the illness back home.”

Immunocompromised patients are those with suppressed immunity resulting from health conditions, including solid organ and haematological cancers, end-stage kidney and liver disease, organ or bone marrow transplants, and immune-mediated inflammatory diseases such as rheumatoid arthritis, or those on active treatment with immunosuppressive medications. [Expert Rev Vaccines 2022;1-17; BMJ 2021;374:n2098]

COVID-19 vaccinations less effective in immunocompromised patients

While COVID-19 vaccinations are effective against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, symptomatic COVID-19 illness, and COVID-19-related hospitalization and death in the general population, evidence suggests they are less effective in immunocompromised populations. [Expert Rev Vaccines 2022;1-17]

Many of these patients are unable to mount an adequate response to the vaccine, leading to impaired vaccine effectiveness (VE). In an observational study, 40 percent of immunocompromised patients had lower responses to COVID-19 vaccines, with 11 percent failing to generate any antibodies after two vaccine shots. [BMJ 2021;374:n2098] Real-world studies reported lower effectiveness of mRNA vaccines against SARS-CoV-2 infection in immunocompromised populations (52–90 percent) than in the overall study populations (90–95 percent). [Expert Rev Vaccines 2022;1-17] VE is defined in the study as the percentage reduction in the risk of disease among vaccinated individuals relative to unvaccinated individuals.

In addition, immunocompromised individuals have a disproportionately higher risk of serious infection and hospitalization from COVID-19 than the general population. US data showed that up to 44 percent of vaccinated people hospitalized with breakthrough COVID-19 were immunocompromised, despite making up only 2.7 percent of the adult population. [Clin Infect Dis 2022;74:1515-1524]

Moreover, COVID-19 infections tend to last long in immunocompromised individuals, which leads to prolonged viral shedding and increased chances of transmitting the virus to others. The increased susceptibility to long infections, coupled with poor immune function, may also provide an environment for the virus to evolve and adapt into novel variants. [Expert Rev Vaccines 2022;1-17]

AZD7442 as COVID-19 prophylaxis

Monoclonal antibodies (mAbs) are potential options for COVID-19 immunoprophylaxis. AZD7442 is a combination of two fully human, SARS-CoV-2-neutralizing mAbs (tixagevimab and cilgavimab) that are derived from antibodies isolated from B cells obtained from individuals infected with SARS-CoV-2.

The Singapore Health Sciences Authority has granted an interim authorization to AZD7442 in August 2022 for the prevention of COVID-19 in adults. AZD7442, an antiviral mAb, is approved for use in those for whom COVID-19 vaccination is not recommended and who are unlikely to mount an adequate response to a COVID-19 vaccine due to immunodeficiencies. Recipients of AZD7442 for prevention of COVID-19 should not be currently infected with, or have had recent known exposure to a person infected with SARS-CoV-2.

The authorization was based on the efficacy and safety data from the phase III PROVENT pre-exposure prophylaxis trial, showing that a single dose of AZD7442 300 mg significantly reduced the risk of developing symptomatic COVID-19 by 76.7 percent (95 percent confidence interval [CI], 46–90; p<0.001) compared with placebo at the primary analysis. Extended follow-up at a median of 6 months showed a relative risk reduction of 82.8 percent (95 percent CI, 65.8–91.4), with protection from the virus lasting 6 months. [N Engl J Med 2022;386:2188-2200]

PROVENT population

The trial included adults 18 years or older who are at an increased risk of an inadequate response to COVID-19 vaccination (eg, those ≥60 years old, obese (BMI ≥30 kg/m²), immunocompromised, unable to receive vaccines without adverse effects, or have congestive heart failure, chronic obstructive pulmonary disease, chronic kidney disease, or chronic liver disease) or exposure to SARS-CoV-2 (eg, healthcare workers, industrial workers, military personnel, students living in dormitories, and people living in high-density proximity), or both, owing to location or circumstance.

AZD7442 was well‐tolerated, and the incidence of adverse events was generally low. Common adverse events reported were headache, throat pain, runny nose, nasal congestion, and myalgia, most of which were mild to moderate in severity.

“Although the PROVENT trial was conducted in unvaccinated patients, immunocompromised patients who were previously vaccinated would still benefit. AZD7442 is most helpful in providing an additional layer of defense against SARS-CoV-2,” assured Leong.

Q1. AZD7442 is not a substitute for patients in whom COVID-19 vaccination is recommended. Do you recommend COVID-19 vaccination for all your patients? In which situations are COVID-19 vaccines not advised?

See: We recommend that all eligible cancer patients within the age group of the approval of the vaccine clinical trials receive the COVID-19 vaccine. We also recommend the mRNA vaccines unless patients have demonstrated a prior allergic reaction, or severe reaction, to a similar vaccination. 

However, vaccination is not suitable for extremely sick patients with a performance status of 3 or 4, either on curative treatment for cancer, or palliative care, whereby any moderate-to-severe reaction to vaccination may compromise the timeline of their chemotherapy, or worse, accelerate their demise. We prioritize safety over immunity. Vaccination is also not advised in patients unlikely to mount an antibody reaction to the vaccine. Since the availability of AZD7442, this has been an easier decision. 

Khan: Patients with kidney disease can receive COVID-19 vaccines. In fact, it is highly recommended. However, caution is warranted in those who have had allergic reactions to a vaccine before, suffer from severe allergies to any medications, those undergoing chemotherapy for cancer, or have certain infections, for example, hepatitis, that require medication. 

Patients on immunosuppressive therapies may also need to delay vaccination in consultation with their doctor. If they had a complication from a previous dose of the COVID-19 vaccine, further doses should not be given. Lastly, if they had COVID recently, they may not need the vaccine for some time. 

Yoon: By and large, most patients with rheumatic diseases can receive the COVID-19 vaccine, except those with multiple drug allergies, those who had allergic or adverse reactions to the vaccines, or those on immunosuppressive therapy, for example, rituximab. Importantly, the timing of administration of immunosuppressive drugs should be rescheduled to maximize vaccine response. 

Additionally, patients with active diseases like arthritis should not receive the COVID-19 vaccine as up to 20 percent of patients experience a disease flare following receipt of an mRNA vaccine. What we do is postpone the vaccination until the condition stabilizes. Non-mRNA vaccines have minimal side effects and may be considered instead, although the efficacy is lower. Patients who have experienced moderate-to severe disease flares after vaccination or with vaccine-induced autoimmune diseases would not be suitable for further vaccinations or boosters. 

Q2. Which high-risk populations should be prioritized for additional protection using monoclonal antibodies like AZD7442?

Leong: Those with the greatest risk are organ or blood transplant individuals, followed by chemotherapy or cancer patients who are immunosuppressed from medications. Third in line are kidney and liver failure patients and those with poor control of diabetes. 

Interestingly, we have a large population of individuals on kidney dialysis and many of them have had four shots of the mRNA vaccines but had no demonstrable immune response to the vaccine. They are sitting ducks for the virus. 

Q3. What is the role of AZD7442 in cancer/kidney diseases/rheumatic diseases? Which subgroups of patients in your specialty would benefit the most from AZD7442? 

See: The 6-month follow-up of the PROVENT trial showed that AZD7442 300 mg, given intramuscularly, reduced the risk of symptomatic COVID-19 by 83 percent vs placebo, with no severe COVID-related illnesses or deaths. A separate trial (TACKLE) showed an 88 percent reduction in the risk of severe COVID-19 or death in patients treated within 3 days of symptom onset. [Lancet Respir Med 2022;S2213-2600(22)00180-1]

The chances of an inadequate response to antibody while on chemotherapy is inversely proportional to age. Hence, older cancer patients are likely to benefit the most. However, we do not limit AZD7442 only to older adults. All cancer patients with a performance status of 2 or better, or at high risk of adverse complications from the infection, are suitable for, and will benefit from, AZD7442. 

Khan: AZD7442 helps kidney disease patients who have not mounted an adequate antibody response to a COVID-19 vaccine. Those with advanced disease, poor kidney function, or already on dialysis, would theoretically benefit from AZD7442 as late-stage disease makes them immunodeficient. 

Yoon: AZD7442 would be beneficial as primary prophylaxis in patients who are unable to receive the COVID-19 vaccines due to various reasons (drug allergies, fear of side effects or disease flares, had experienced adverse reactions and are unable to continue their course of the vaccines, or with myocarditis), or have an inadequate immune response to vaccinations, as measured by antibody levels. 

In patients with rheumatic diseases and on immunosuppressants, vaccines have lower efficacy. Their antibody levels tend to be lower and reduce more rapidly with time. We have seen many breakthrough infections in our patients. Immunocompromised patients are more susceptible to complications of COVID-19, chronic disease flares, and long COVID syndrome. I would strongly recommend prophylaxis for this high-risk group. The TACKLE study, which is currently ongoing, has also demonstrated efficacy for AZD7442 in reducing severe COVID-19 or death when given early, with 50.5 percent relative risk reduction over placebo. [Lancet Respir Med 2022;S2213-2600(22)00180-1] 

Q4. What are the clinical implications of the PROVENT trial that are relevant to your practice? Could you share your experience with using AZD7442?

Yoon: PROVENT is a convincing study showing that AZD7442 can prevent infections in approximately 3 out of 4 patients. I have given AZD7442 to one of my patients who was hospitalized for severe COVID in 2021, probably the Delta strain, but still experienced symptoms after 10 months. She was unable to get COVID-19 jabs as she had multiple drug allergies. She received AZD7442 this year as a prophylaxis. The patient tolerated AZD7442 well and did not experience any side effects or adverse reactions from it. 

See: The PROVENT results are practice-changing. Now, we are not held ransom to the ineffectiveness of the mRNA or traditional vaccines in certain patients. With AZD7442, we also need not be concerned if our patients are unable to mount a response to vaccination. 

Additionally, findings from an independent study by investigators at the US FDA showed that long-acting antibody therapy retains neutralizing activity against the SARS-CoV-2 Omicron variant. [https://opendata.ncats.nih.gov/variant/activity] So, it can help tide our patients over until when Omicron-specific vaccinations are available. It is actually cheaper for our patients to prevent infection with COVID than be treated for COVID. I personally prefer to give AZD7442 to eligible patients for prophylaxis.  

Although there are potential side effects to AZD7442 injection, including hypersensitivity reactions (anaphylaxis), bleeding at the injection site, headache, fatigue, and cough, I have not seen this in my practice. I have referred to our ID physicians, as per MOH guidelines and regulations, on the use of AZD7442 and we continue to see the safety and effectiveness of AZD7442 in our patients in the pre-exposure setting, as well as in the infected and post-exposure settings. 

Khan: The PROVENT trial describes the benefit of giving mAbs to patients vulnerable to such disease states that cause them to be immunocompromised. The results are relevant to my practice, as I take care of kidney patients who are immunocompromised. As AZD7442 is now approved under the pandemic special access route, I look forward to having this useful tool available to help vulnerable patients in their fight against COVID-19. 

Leong: My use of AZD7442 has been mostly in patients with organ and bone marrow transplants. Soon after transplantation, patients’ immunity is at its lowest. We should think of AZD7442 as a double protection – the antibodies help in preventing or reducing the severity of COVID-19 infection. Even if breakthrough infections occur, the disease appears milder in those who received AZD7442 than those who did not. The injection is easy to administer into the buttocks and helps allay patient fears, giving them the confidence to go out again or travel overseas.