Over five years have passed since the beginning of the most significant health challenge in the 21^st century has been the Sars-Cov-2. As of January 2025, monoclonal antibodies for treating immunocompromised patients with the Neus Variants of Sars-Cov-2 (especially those with comorbidities) have evolved significantly since the early pandemic stages. However, newer treatments may still be under investigation or regulatory review. The extensive research and the Global Cooperation response has been rapid and effective with  the profound understanding of fundamental biological and molecular characteristic of Covid-19 and many therapeutic monoclonal antibodies and small molecules developed for clinical use [1].

The effectiveness of monoclonal antibodies has been questioned because the virus and its variants have changed over time. This technical note highlights the need to assess the antiviral activity of these antibodies against new variants and adapt treatment strategies accordingly.

Pre-exposure prophylaxis using the latest monoclonal antibodies is one complementary preventative therapy to reduce severity of breakthrough Sars-Cov-2 in vulnerable persons with severe immunocompromise due organ transplant, cancer, HIV or use of certain medications experience diminished Covid-19 vaccine immune response and remain at higher risk for severe Sars-Cov-2 outcomes [2]; across many studies, Monoclonal Antibodies Pre-Exposure is associated with a 60% to 80% reduction in severe COVID-19 outcomes.

Covid-19 variants evolution, however, leads to viral mutations that can evade Monoclonal Antibodies due to the selective nature of their binding sites. Several Monoclonal Antibodies that received FDA emergency use authorization for prevention of Sars-Cov-2 have since had this authorization revoked once circulating variants demonstrated immune evasion [3].

Introduction

Sars-Cov-2 still represents a disproportionate risk for vulnerable patients, with infection often leading to serious and protracted illness. Vaccination against Sars-Cov-2 has reduced in the Word the burden Covid-19. The urgent need to find new therapeutic strategies to combat the Sars-Cov-2 pandemic led to the design of numerous anti-Covid 19 monoclonal antibody for Therapy and Pre-Exposure Prophylaxis for the Latest Variants [4]. The immunocompromised persons and those who cannot be vaccinated, remain at risk for severe Covid-19.

As the world deals with this evolving threat, the narrative extends to the realm of emerging variants, each displaying new mutations with implications that remain largely misunderstood. Notably, the JN.1 Omicron lineage is gaining global prevalence, and early findings suggest it stands among the immune-evading variants, a characteristic attributed to its mutation L455S. Moreover, the detrimental consequences of the novel emergence of SARS-CoV-2 lineages bear a particularly critical impact on immunocompromised individuals and older adults. Immunocompromised individuals face challenges such as suboptimal responses to COVID-19 vaccines, rendering them more susceptible to severe disease. Similarly, older adults have an increased risk of severe disease and the presence of comorbid conditions, find themselves at a heightened vulnerability to develop COVID-19 disease. Thus, recognizing these intricate factors is crucial for effectively tailoring public health strategies to protect these vulnerable populations. In this context, this review aims to describe, analyze, and discuss the current progress of the next-generation treatments encompassing   the latest monoclonal antibodies for Pre-Exposure Therapy immunotherapeutic approaches and advanced therapies emerging as complements that will offer solutions to counter the disadvantages of the existing options.

Although Monoclonal Antibodies as Prophilaxis and Therapy report efficacy as between 50-85% [5-6], global access is currently largely inequitable. Preliminary outcomes show that these strategies target the virus and address the immunomodulatory responses associated with COVID-19. Furthermore, the capacity to promote tissue repair has been demonstrated, which can be particularly noteworthy for immunocompromised individuals who stand as vulnerable actors in the global landscape of coronavirus infections [7-9].

Monoclonal antibodies, which protect against disease irrespective of immune system status and provide rapid protection, are potential options for Covid-19 immunoprophylaxis. Some combinations of monoclonal antibodies are already in use through emergency or temporary authorization for pre-exposure or post-exposure prophylaxis against Covid-19 or treatment of mild-to-moderate disease.

The emerging next-generation treatments possess broader potential, offering protection against a wide range of variants and enhancing the ability to counter the impact of the constant evolution of the virus. On the one hand, in vitro studies have suggested reduced susceptibility of the latest variants to monoclonal antibodies, whereas clinical data still show benefits in reducing severe illness and mortality, indicating that laboratory results do not always mirror real-world outcomes. As a result, although resistance to monoclonal antibodies can develop over time, they could still have an important role in COVID-19 treatment, especially when used in combination, and ongoing research aims to identify effective antibodies against new variants. The main purpose of this literature Review is to highlight the possible strategies to optimize and protect current and future therapeutic options Pre-Exposure to treat the most vulnerable patients [10-11].

New Variants: "Almost a New Pandemic"

Because of the fast-evolving nature of COVID-19 treatments and the emergence of new variants, the landscape for monoclonal antibody therapies may have shifted. It is critical for healthcare providers to stay updated on the most current guidance from agencies like the FDA and the WHO, and to choose therapies based on the latest variant prevalence, individual health conditions, and treatment availability.

With the emergence of this new variants, the researchers realized that vaccination offered less protection and that a third dose was needed to immunize the population. While previous variants had fewer than ten mutations on the spike protein compared with the original strain, Omicron had more than thirty. It was almost as if a new pandemic had begun. What the researchers were less aware of was that Omicron had a significant ability to evade monoclonal antibodies. This was demonstrated by several scientists in an article published in December 2021. In their research, the scientists showed that two thirds of the monoclonal antibodies used in clinical practice or currently under development lost all their antiviral activity against Omicron. The situation also became increasingly complex as several sub variants (BA.1, BA.2, etc.) emerged over the following weeks. So the scientists tried to determine whether the monoclonal antibodies were effective against the new strains that were co-circulating. In a study published in March 2022, they provided a number of answers. The casirivimab/imdevimab combination, which until then had offered a similar level of protection against severe forms of COVID-19 as vaccination, was no longer active against Omicron. The neutralizing activity of another antibody cocktail (tixagevimab/cilgavimab) was significantly reduced against BA.1 compared with the Delta variant, but its neutralizing activity was not reduced nearly as much against BA.2. This result, which showed that a monoclonal antibody could lose its neutralizing capability for a given variant before recovering it for a subsequent variant, emphasizes the importance of continuing with efficacy testing on all available antibodies (Figure 1).

The protective efficacy of monoclonal antibodies depends primarily, but not solely, on their neutralizing capability. Some monoclonal antibodies can also induce a key immune defense mechanism known as antibody-dependent cellular cytotoxicity (ADCC), which kills cells infected with SARS-CoV-2. In the case of COVID-19, natural killer (NK) cells in the immune system recognize the antibodies that bind to antigens on the surface of infected cells and then specifically lyse those cells. These antibodies are described as "polyfunctional." This characteristic is all the more interesting since the monoclonal antibodies with the highest neutralizing capability are not those that induce ADCC the most, as shown in a study published in December 2022. In short, to obtain protective antibody cocktails, it may be a good idea to include polyfunctional antibodies which combine a high neutralizing capability with a strong ability to induce immune defense mechanisms [12].

Key Variants of Concern in December 2024

Omicron Sublineages (XBB family)

XBB.1 and XBB.1.5: These sublineages of XBB have been circulating widely. XBB variants, including XBB.1 and its sublineages, continue to show high levels of immune escape, meaning they can evade immunity from previous infections or vaccinations to some extent. These variants have been associated with reinfections in individuals who had previously been exposed to COVID-19 or vaccinated.

XBB.2.75: This sublineage of XBB is also a major variant of concern, with continued reports of immune evasion and increased transmissibility compared to previous strains. The high number of mutations in the spike protein and other regions make this subvariant a key focus for both surveillance and vaccine updates [12,13].

BQ and BF Subvariants

BQ.1 and BQ.1.1: These are subvariants of Omicron that have demonstrated increased transmissibility and partial resistance to immunity from both previous infection and vaccines. They have been circulating in various regions and remain a concern due to their ability to evade neutralizing antibodies.

BF.7: Another important Omicron subvariant, which has been noted for its ability to potentially escape immunity, though vaccines still help protect against severe disease.

Monitoring of Emerging Variants

While Omicron remains the dominant lineage, there are always potential for new subvariants or entirely new variants to emerge, especially if mutations lead to more concerning traits, such as:

·       Increased transmissibility.

·       Higher resistance to immunity from vaccines or past infections.

·       Potential to cause more severe disease.

Health authorities like the WHO, CDC, and other global and regional bodies continuously monitor for any significant changes in the virus’s behavior. If new strains show signs of increased transmissibility or a higher risk of severe outcomes, they may be classified as Variants of Concern.

As of January 2025, monoclonal antibodies for COVID-19 treatment, particularly for immunocompromised patients and those with comorbidities, are still a key part of managing COVID-19 in high-risk groups. The emergence of new SARS-CoV-2 variants, especially Omicron subvariants, has impacted the effectiveness of some earlier treatments, and newer monoclonal antibody combinations are being investigated or deployed to counteract immune evasion and improve outcomes for vulnerable patients.

Latest Monoclonal Antibodies and Combinations (December 2024)

Evusheld (AstraZeneca):

·       Components: Tixagevimab and Cilgavimab.

·       Indication: Evusheld is still widely used for pre-exposure prophylaxis (PrEP) in immunocompromised individuals who are unable to mount an adequate immune response to vaccines. This includes people with conditions like cancer, autoimmune diseases, or those on immunosuppressive therapies.

·       Effectiveness: Though Evusheld has shown some diminished effectiveness against certain Omicron subvariants (e.g., XBB and BQ/BF subvariants), it is still considered a cornerstone in protecting vulnerable populations. Efforts to modify or enhance its effectiveness are ongoing.

Bebtelovimab (Lilly):

·       Indication: Bebtelovimab was used for treatment of mild to moderate COVID-19 in high-risk patients, including those who are immunocompromised, to prevent severe outcomes. However, due to the emergence of newer Omicron subvariants with mutations in the spike protein, Bebtelovimab has seen reduced effectiveness.

·       Status: It is becoming less favored due to its reduced efficacy against Omicron subvariants, but it may still be used in some contexts where other options are unavailable.

Combination of Monoclonal Antibodies (Emerging Treatments):

·       New combinations of monoclonal antibodies are being developed to provide broader protection against immune-evading variants. These combinations are designed to target multiple epitopes of the spike protein, reducing the chance of the virus escaping the therapy due to mutations. Examples include:

·       Dual or Triple Antibody Combinations: Research is ongoing to combine multiple monoclonal antibodies that can bind to different parts of the spike protein or other regions of the virus. These could provide better protection against the current circulating Omicron subvariants.

·       Bamlanivimab and Etesevimab (Eli Lilly): These were used as a combination treatment in the earlier stages of the pandemic but have shown limited effectiveness against recent Omicron variants, making them less commonly used today.

Long-Acting Antibodies for Prevention and Treatment:

·       Long-Acting Monoclonal Antibodies (LAMAs): These therapies are being investigated to offer longer-lasting protection against SARS-CoV-2, which is particularly beneficial for those who cannot mount an effective immune response. The concept behind these therapies is to provide extended immunity, which may be crucial for immunocompromised individuals who cannot rely on vaccines alone.

Key Considerations for Immunocompromised Patients

Variant-Specific Efficacy: The effectiveness of monoclonal antibodies has varied based on the circulating variant of SARS-CoV-2. Omicron subvariants like XBB and BQ have shown the potential to evade some antibodies designed for earlier strains. As a result, new monoclonal antibodies or combinations are being developed to enhance neutralizing activity against these newer variants.

Therapeutic vs. Prophylactic Use: Some monoclonal antibodies, such as Evusheld, are used prophylactically (to prevent infection), while others, like Bebtelovimab, have been used to treat COVID-19 in the early stages of infection. The choice of therapy will depend on the patient’s condition, the timing of infection, and the specific circulating variants [13].

Combination Therapies

In some cases, monoclonal antibodies are combined with antiviral medications (like Paxlovid) or other supportive therapies to improve outcomes in immunocompromised patients. These combinations may include:

·       Monoclonal antibodies + Antiviral treatments (e.g., Paxlovid): This combination can reduce viral load and prevent progression to severe disease, especially in high-risk individuals.

·       Monoclonal antibodies + Corticosteroids: For more severe cases, the combination of monoclonal antibodies with corticosteroids (which reduce inflammation) is sometimes used to manage severe COVID-19 infections.

Ongoing Research and Regulatory Approval

With the continuing evolution of SARS-CoV-2, pharmaceutical companies and researchers are focusing on:

·       Broader spectrum monoclonal antibodies: These would bind to various parts of the virus’s spike protein or other regions, reducing the likelihood of immune escape.

·       Updated monoclonal antibodies tailored to emerging Omicron subvariants like XBB and BQ/BF, as these strains continue to circulate globally.

Patients Immunocompromised with comorbidity and Sars-Cov-2 (Emerging Treatments)

Individuals with immunosuppressed conditions, including people with primary immunodeficiency’s and secondary immunodeficiencies, consisting of people with solid-organ trans-plants, metastatic cancers, hematologic malignancies, advanced or untreated HIV (human immunodeficiency virus) infection, those receiving cancer chemotherapy, and patients with autoimmune diseases receiving immunosuppressive biologics and medications.

Patients in this heterogeneous group had a higher risk of COVID-19-related hospitalization, severe COVID-19, or death and tend to have higher risk for opportunistic infections.  In addition, prolonged SARS-CoV-2 infection and persistent viral replication in ICP not only cause long duration of symptoms but also risk of emergence of antiviral-resistant or vaccine-escaped variants, prolonging the pandemic [14-20].

Although COVID-19 treatment guidelines had been proposed to manage patients with different severities and clinical cohorts, a consensus on COVID-19 patients in ICP was lacking and the information was limited. Immunocompromised individuals are at higher risk of severe COVID-19 outcomes. Vaccination remains a critical preventive mea-sure for this vulnerable population. Although some may have a reduced response to vaccines, receiving the recommended doses can still provide some level of protection and potentially mitigate severe disease.

Given the potential for diminished vaccine response, immunocompromised individuals should be considered for booster doses based on local guidelines and emerging data.   In cases of exposure to COVID-19, immunocompromised individuals may require specific isolation or quarantine measures, depending on their risk profile. The management of COVID-19 in ICP necessitates an individualized approach. Clinicians must carefully consider the patient's specific immunocompromised condition, medical history, and risk factors to determine the most appropriate treatment plan. In severe COVID-19 cases among ICP, antiviral therapies such as remdesivir may be considered.

The decision to use antiviral drugs should be based on clinical judgment and consultation with specialists from multidisciplinary areas. In severe COVID-19 cases with significant inflammatory responses, corticosteroids like dexamethasone may be used under close medical supervision. The use of CCP therapy in specific severe cases of COVID-19 among immunocompromised patients may be considered on a case-by-case basis early in the pandemic. Therapeutic recommendations for antiviral or immunomodulation therapy of adults with varying severities of COVID-19 are summarized in (Table 1).