Monoclonal antibodies for the treatment of COVID-19 infection in children

ABSTRACT

Introduction

Monoclonal antibodies (mAbs) have been authorized for the treatment of COVID-19 in pediatric populations, however, there is a lack of evidence for their use in these populations.

Areas covered

We outline the evidence of mAbs for COVID-19, discuss their use in the treatment of COVID-19 infection for pediatric patients, and consider alternative treatment options and challenges to COVID-19 drug approvals.

Expert opinion

Limited evidence exists for the safety and efficacy of mAbs to treat COVID-19 in children as new variants emerge. In rare pediatric outpatient settings, such as profound immunodeficiency or severe pulmonary disease, the benefits of antiviral treatment for COVID-19 likely outweigh the relatively small risks. However, for the great majority of pediatric patients, mAb treatment is likely not indicated. Small molecule antiviral therapies are another potential treatment for COVID-19 in children in an outpatient setting, though neither mAb nor small molecule antiviral treatments have significant supporting evidence in children and developing a strong evidence base for these decisions will be challenging if not impractical. Ultimately, these decisions are likely to be made at the level of individual cases using expert opinion as the primary guiding principle.

KEYWORDS:

• Antiviral
• bebtelovimab
• children
• COVID-19
• mAbs
• monoclonal antibodies
• pediatric patients
• pediatric treatment
• SARS-COV-2

1. Introduction

Coronavirus disease (COVID-19) caused by the SARS-CoV-2 virus remains a threat to human health worldwide, with multiple variants evolving over recent years, most recently including the highly infectious Omicron variant and its sub-variants.

Vaccination is the most effective strategy to prevent infection and to slow transmission of COVID-19 [1–3]. In the United States, four COVID-19 vaccines have been approved or authorized by the Food and Drug Administration (FDA) for emergency use as of August 2022: Ad26.COV2, NVX-CoV2373, BNT162b2, and mRNA-1273 [4–10] . However, the efficacy of currently approved or authorized vaccines has waned since Omicron has emerged as the dominant variant, necessitating the development of therapies to treat infection [11,12].

Passive humoral immunotherapy with neutralizing monoclonal antibodies (mAbs) has emerged as a potential treatment option to prevent hospitalization and death related to COVID-19 [13,14]. In recognition of this, the mAb, bebtelovimab, remains authorized by the FDA for emergency use in children and adults to prevent severe disease [15,16]. Several additional mAbs that were authorized earlier in the pandemic have lost authorization due to the inability to bind the omicron variant [17–20]. For each of these antibodies, a paucity of evidence exists for use in pediatric populations.

In this review, we will outline the evidence of mAbs for COVID-19 treatment, examine their use in treating pediatric patients with COVID-19 infection, and discuss alternative treatment options and challenges to COVID-19 drug approvals.

2. Anti-Sars-CoV-2 monoclonal antibodies

2.1. Bamlanivimab-etesevimab

The FDA granted emergency use authorization (EUA) for bamlanivimab-etesevimab, administered together, in February 2021. The authorization was based on analysis of 1035 unvaccinated ambulatory patients with mild-to-moderate COVID-19 at risk for progression to severe disease enrolled from September – December 2020, when Alpha was the predominant variant of concern (VOC) [18]. The study includes 11 adolescents age 12–17 years. At day 29, 11/518 (2.1%) patients in the treatment arm vs 36/517 (7%) in the placebo arm had a COVID-19-related hospitalization or death, corresponding to a 70% relative risk reduction [18]. No deaths occurred in the treatment group, while 10 deaths occurred in the placebo group. All deaths occurred in adults. Serious adverse events (SAEs) were rare [18].

Bamlanivimab-etesevimab effectively neutralizes the Wuhan strain of SARS-CoV-2 and the alpha and delta variants but has reduced activity against gamma and lost activity against the Omicron variants [21,22]. Because the Omicron BA.5 subvariant is now the dominant circulating subvariant in the United States as of August 2022, the FDA has limited use of this combination.

2.2. Sotrovimab

In May 2021, the FDA granted emergency use authorization (EUA) for sotrovimab based on an interim analysis of 583 unvaccinated, non-hospitalized adults with mild-to-moderate COVID-19 enrolled between August 2020 – March 2021, when Alpha was the predominant VOC [20]. Hospitalization or death occurred in 21/292 (7%) patients who received placebo versus 3/291 (1%) patients treated with sotrovimab, an 85% relative risk reduction [20]. Adverse events (AEs) attributable to sotrovimab were rare [20,23].

Sotrovimab retains in-vitro activity against the Omicron BA.1 and BA.1.1 subvariants, but it has substantially decreased in-vitro activity against Omicron BA.2, BA.4 and BA.5 and is not expected to provide clinical benefit for patients infected with these variants. Because of this, the FDA has discontinued the authorization for sotrovimab.

2.3. Casirivimab-imdevimab (REGEN-COV)

The efficacy of casirivimab-imdevimab for COVID-19 treatment was evaluated in a phase 3 placebo-controlled study of 4057 unvaccinated participants [24]. The efficacy analysis included SARS-CoV-2 positive participants aged ≥18 years who had ≥1 risk factor for progression to severe COVID-19, enrolled between September 2020 – January 2021 when Alpha predominated [19]. For the participants who received 1200 mg, COVID-19 related hospitalization or death occurred in 7/736 (1%), compared to 24/748 (3.2%) of those who received placebo- a 70.4% relative risk reduction. For patients who received 2400 mg of casirivimab-imdevimab, hospitalization or death occurred in 18/1355 (1.3%) versus 62/1341 (4.6%) of patients in the placebo group [24].

Casirivimab-imdevimab also lost neutralizing activity against the omicron variant, and the FDA limited its use only to regions where there is likely a susceptible variant [21,25].

2.4. Bebtelovimab

As of August 2022, bebtelovimab is the only FDA-authorized mAb currently used in the United States for COVID-19 treatment as it is the only therapeutic antibody that retains full activity against the omicron variants in neutralization assays [15,16,26]. The data supporting the EUA are based on analysis of a portion of a phase 2 trial that enrolled 714 patients with mild-to-moderate COVID-19 between May and July 2021 when Alpha and Delta variants were predominant [15]. Those at low-risk for severe COVID-19 were unvaccinated and randomized 1:1:1 to placebo, bebtelovimab 175 mg, or bebtelovimab 175 mg + bamlanivimab 700 mg + etesevimab 1400 mg. High-risk adults and pediatric subjects (≥12 years weighing ≥40 kg), 31% of whom were vaccinated at baseline, received open-label active treatments of bebtelovimab or bebtelovimab + bamlanivimab + etesevimab. The primary endpoint was the proportion of subjects with persistently high viral load (PHVL) by Day 7. Of the low-risk patients, PHVL occurred in 25/126 subjects treated with placebo (19.8%), compared to 15/125 (12%) subjects treated with bebtelovimab alone, and 16/126 (12.7%) subjects treated with bebtelovimab + bamlanivimab + etesevimab. Although the rate of PHVL decreased, this finding did not reach a level of statistical significance (p = 0.097 BEB vs placebo; p = 0.132 bebtelovimab + bamlanivimab + etesevimab vs placebo) [15]. The key secondary endpoint of viral load area under the curve was reduced in low-risk patients treated with bebtelovimab compared to placebo (p = 0.006).

In the high-risk arm, the primary endpoint was safety. AEs occurred in 37/380 (9.7%) of low-risk and 48/326 (14.7%) of high-risk patients treated with bebtelovimab or bebtelovimab + bamlanivimab + etesevimab; the majority of AEs were considered mild or moderate in severity. SAEs were reported in 7/326 (2.1%) of high-risk patients, including one death (a cerebrovascular accident); 1 SAE was reported among low-risk patients [15].

2.5. Tixagevimab-cilgavimab (EVUSHELD)

In February 2022, The FDA granted EUA for Tixagevimab-cilgavimab for individuals ≥12 years weighing ≥40 kg who may not have an adequate response to COVID-19 vaccination or who cannot receive a full series of a COVID-19 vaccine [27]. Tixagevimab-cilgavimab has retained some activity against omicron subvariants and is authorized for the pre-exposure prophylaxis of COVID-19, but is not approved for COVID-19 treatment [25].

3. Small molecule antiviral therapies for SARS-CoV-2

Two of the three small molecule antiviral therapies that have been authorized or approved for use in treating COVID-19 are available to pediatric patients as of August 2022. Remdesivir, an inhibitor of viral RNA-dependent RNA polymerase with the ability to inhibit SARS-CoV-2 in vitro, is approved to treat pediatric patients ≥28 days of age weighing ≥3 kg [28–30]. Nirmatrelvir with Ritonavir (Paxlovid) is an oral protease inhibitor that has received EUA for adults and children age ≥12 years of age weighing ≥88 lbs [31]. Molnupiravir, a nucleoside analogue that inhibits viral replication, is only approved in adults [32].

4. Choice of antiviral therapies

Small molecule antivirals and anti-SARS-CoV-2 mAbs both show strong efficacy against COVID-19, but with different benefits and limitations. The small molecule antivirals described above target the active sites of highly conserved viral proteins that have proved resistant to mutation, allowing for use across multiple viral variants [33]. In vitro analysis shows that these antivirals have retained their activity against all variants of concern including Omicron [33]. The mAbs target the highly variable spike protein, recognizing a limited peptide sequence on its surface, and have lost efficacy with the emergence of new variants [21,25]. This is not surprising as the virus is under constant selective pressure to evade the human immune response in each productive infection, the same immune response that was leveraged to identify therapeutic antibodies. In all likelihood, future variants of concern will continue to evade mAb therapeutics while displaying relative sensitivity to the small molecule antivirals.

Although SARS-CoV-2 will likely continue to mutate to evade mAbs [21,25], generating antigen-specific mAbs for commercial use can be done rapidly [34]; bamlanivimab received EUA within 9 months of its initial discovery [35], a considerably shorter timeline than for de novo small molecule antivirals [36–38].

MAbs also have a very long duration of action, with half-lives of weeks [15,27]. Paxlovid and Remdesivir have half-lives of 6 and 0.89 hours, respectively [39,40]. In patients who are immunocompromised, the longer duration of action of mAbs may provide greater protection against severe COVID-19 over time. This is particularly important in comparison to Remdesivir which is also an IV infusion.

Small molecule antivirals are more likely than mAbs to have medication interactions and unintentional side effects due to off target binding and drug elimination. For example, Paxlovid is a strong CYP3A inhibitor, and is contraindicated for people taking medications that are either cleared by CYP3A, or strong CYP3A inducers that could reduce the plasma concentrations of Paxlovid [41,42]. If Paxlovid is being considered for use in high-risk pediatric populations, drug interactions for Paxlovid become an important consideration.

5. Indications for Covid-19 treatment in pediatric patients

The FDA has authorized mAb therapy for adolescents at high risk of severe COVID-19 despite limited data to support the use of mAbs in pediatric populations [18,43,44]. Although the safety profile of these agents in adult studies is deemed acceptable, the safety, efficacy, and pharmacokinetics of mAbs have not been studied systematically in pediatric groups [45,46]. Consequently, the American Academy of Pediatrics and a separate panel of pediatric experts has recommended that, for adolescents at moderate and high risk for severe COVID-19, an individual risk/benefit assessment should be performed when considering the use of mAbs [45,46]. The panel did not recommend routine mAb treatment for lower risk patients [46].

In general, children with COVID-19 are at low risk for hospitalization and progression to severe disease [46,47]. Conditions like obesity, medical complexity, and severe immunocompromising conditions may most strongly predispose children to severe COVID-19 [46]. Immunocompromising conditions that place children at probable high risk include severe combined immunodeficiency (SCID) phenotypes, B-cell deficiencies, bone marrow transplant, and immune suppression for organ transplant [48–55].

In rare cases, children with SARS-CoV-2 infection can develop Multisystem Inflammatory Syndrome in Children (MIS-C), a postinfectious complication of COVID-19 characterized by a severe shock-like illness [56–58]. Common clinical features include fever, and gastrointestinal, cardiorespiratory, and neurocognitive symptoms [59]. However, the disease presentation can have a wide spectrum and the risk factors for this condition are poorly understood [60,61].

Another complication of SARS-CoV-2 infection in children is ‘post-COVID-19 condition’ or ‘long-COVID.’ This is a broad range of physical and mental health symptoms that persist at least 4 weeks after the onset of symptoms [62]. The prevalence of long-COVID in children and adolescents is 25% in one study; the most prevalent clinical manifestations are mood symptoms (16.5%), fatigue (9.7%), sleep disorders (8.4%), headache (7.8%), and respiratory symptoms (7.6%) [63]. Whether antiviral treatments, including mAbs can modify the risk of Long-COVID in children remains unclear.

Severe COVID-19 is a public health concern for pediatric populations and disproportionately impacts Black, Hispanic, and American Indian/Alaska Native children in the United States [64–66]. In one study, children hospitalized for COVID-19 are 2.28, 1.38, and 2.95 times more likely to be Black, Hispanic, and multi- racial/ethnic, respectively, than they are to be White [67]. Children who died from COVID-19 are 2.96 and 3.33 times more likely to be Black or multiracial/ethnic than they are to be White [67]. In another study, American Indian and Alaska Native patients were more likely to die of COVID-19 than all other races [68]. MIS-C was also disproportionately high in Hispanic or Black children [56,69,70]. The racial disparities are likely driven by social determinants of health such as socioeconomic status and access to health care, which may affect COVID-19 infection outcome directly or through elevated risk of high-risk conditions. Therefore, increasing treatment access to these disproportionately affected groups is especially important to ensure equitable care.

6. Deciding when to use monoclonal antibody therapy in children

Without sufficient data, assessing the risk-benefit of mAb treatment in pediatric patients is based largely on inferences from adult data, our understanding of pediatric physiology, and data on the natural history of SARS-CoV-2 infection in children. First, the administration of mAb therapy may reduce endogenous antibody production compared to placebo [71,72]. For severely immunocompromised individuals unable to produce an endogenous antibody-mediated immune response against SARS-CoV-2, this influence on endogenous immunity is of limited importance. However, the reduction in endogenous antibody production could impact risk for reinfection after recovery, and may influence vaccine-induced antibody response, particularly in patients receiving lower doses of vaccine [73,74]. Currently, we have inadequate evidence to determine whether this effect on antibody production has any clinically meaningful impact on long-term reinfection risk.

Another challenge regarding the use of mAb treatment for pediatric patients involves the ease of treatment access. MAb treatments authorized by the FDA are administered as intravenous or intramuscular injections by a health care provider, usually within 7 days of symptom onset [15,18–20]. The limited healthcare capacity for ambulatory infusions, space, and staffing may partially explain the underutilization of mAbs by high-risk populations [75]. This barrier to treatment may be higher in children, as the limited available staff may also be less equipped to handle pediatric patients.

Compared to adults, pediatric patients are more likely to be asymptomatic or have mild symptoms when exposed to SARS-CoV-2. They are less likely to develop severe disease, be hospitalized, or die from COVID-19 [76,77]. Since children have less severe outcomes than adults with COVID-19 [78], the likely high number needed to treat makes the rare side effects from treatment more important, and amplifies the direct (nursing time, travel costs) and indirect (patient time) costs associated with each beneficial clinical outcome.

7. Expert opinion

In patients with severely compromised immune systems or severe pulmonary disease at baseline, the benefits of antiviral treatment for COVID-19 likely outweigh the relatively small risks. However, for the great majority of pediatric patients, mAb treatment is likely not indicated. Whether the convenience of oral therapies such as Paxlovid outweigh the uncertain effects of the drug during child growth and development is also not clear is this time [79]. The use of immunomodulators like convalescent plasma in pediatric populations also warrants more study [80,81].

7.1. Challenges to COVID-19 drug evaluation and approval

Numerous obstacles have influenced the rapid approval of mAb treatment for COVID-19. First, the SARS-CoV-2 virus has mutated over the course of the past year as it moves through hundreds of millions of people [82]. This poses a challenge because a typical clinical trial timeline for a new mAb treatment takes years to conduct, and during that time, the virus will likely evade neutralization by the mAb being tested. This has happened already for mAbs that previously received EUAs and will likely continue to occur for mAbs developed in the future [21,25].

Since the mAbs are most effective against COVID-19 when given within about 7 days of symptom onset, from a logistical standpoint, a rapid pipeline from SARS-CoV-2 infection diagnosis to referral to treatment needs to be established. Many healthcare settings lack the infrastructure to facilitate this turnaround time, although solutions such as mobile infusion units, home health nursing, and outreach from government and community-based organizations, have emerged as cost-effect ways to address this [83–86].

High recruitment for trials is another hurdle delaying new drug approvals. The risk of hospitalization for pediatric patients with SARS-CoV-2 infection is very low, and a majority of those hospitalized do not have severe disease [76]. Consequently, the COVID-19 mAb treatment trials would need to have very large enrollment targets to demonstrate that the treatment prevents severe illness without leading to unacceptable toxicities. The need for large studies may be partially obviated by using surrogate endpoints such as viral load, though no secondary endpoints for hospitalization and death from SARS-CoV-2 have been definitively established, particularly in pediatric patients.

Finally, challenges persist regarding the use of placebo controls in mAb trials. Since bebtelovimab’s EUA, testing new mAbs against placebo is not ethically acceptable. COVID-19 treatments under EUA have become frequently used in clinical settings, and many participants and enrolling physicians are likely to see placebo controls as inferior to the EUA treatments, as most of the medical community currently does. If new mAb treatments were compared against existing ones to demonstrate superiority or lack of inferiority, this would require higher recruitment numbers. On the other hand, if new mAb trial drugs were compared to placebo, prospective participants may choose not to opt in, if they are aware that a potentially effective treatment already exists under EUA. Indeed, we observed this trend first-hand participating in mAb phase 3 testing after the initial EUAs were granted based on phase 2 data [18]. In this case, many patients who were interested in enrolling in a trial for a new mAb were patients who did not meet the criteria to take a mAb with EUA but met inclusion criteria to enroll in the new mAb trial, or who otherwise did not have access to the EUA medication for logistical reasons. Both reasons introduce important biases into the final study data.

7.2. Conclusions

Vaccines are still the most effective strategy to stop and prevent the spread of COVID-19. However, in cases where vaccines are unable to prevent breakthrough infection, more treatments are needed. MAbs are an emerging therapy for COVID-19, however we have limited evidence for their safety and efficacy in children, and many have waning efficacy in the face of new variants. Small molecule antiviral therapies are another potential treatment for COVID-19 in children in an outpatient setting, though neither mAb nor small molecule antiviral treatments have significant supporting evidence in children. In rare circumstances, such as profound immunodeficiency, mAb treatments may still have an important role in treating children infected with SARS-CoV-2, though developing a strong evidence base for these decisions will be challenging if not impractical. Ultimately, these decisions are likely to be made at the level of individual cases using expert opinion as the primary guiding principle.

Article highlights

• Anti-SARS-CoV-2 monoclonal antibodies (mAbs) have emerged as a potential treatment option to prevent hospitalization and death related to COVID-19.

• Limited evidence exists for the use of monoclonal antibodies to treat COVID-19 in pediatric populations.

• Small molecule antivirals and mAbs both show strong efficacy against COVID-19, but with different benefits and limitations.

• In patients with severely compromised immune systems or severe pulmonary disease, the benefits of mAb treatment for COVID-19 likely outweigh the relatively small risks. However, for the great majority of pediatric patients, mAb treatment is likely not indicated.

• Numerous obstacles have influenced the approval of mAb treatment for COVID-19, thus developing a strong evidence base for use of antivirals in children will be challenging if not impractical.

Declaration of interest

M Dougan has research funding from Eli Lilly; he has received consulting fees from Tillotts Pharma, ORIC Pharmaceuticals, Partner Therapeutics, SQZ Biotech, AzurRx, Eli Lilly, Mallinckrodt Pharmaceuticals, Aditum, and Moderna; he is a member of the Scientific Advisory Board for Neoleukin Therapeutics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

K Ling and M Dougan would like to thank Keri Sullivan for the thoughtful insights and revision of the manuscript.

Additional information

Funding

This paper was not funded.