COVID-19 is highly transmissible with potentially serious health outcomes, underscoring the need for effective prevention and treatment strategies. Vaccines are highly effective at preventing COVID-19 for the general population; however, efficacy is often impaired in immunocompromised patients given insufficient response to initial exposure and/or memory for secondary exposures. Risk factors for COVID-19 include older age, obesity, underlying medical conditions such as diabetes, inadequate vaccination, and/or being immunocompromised. People living with immunocompromising conditions including but not limited to active treatment for solid tumor and hematologic malignancies, solid organ transplant recipients, or people living with human immunodeficiency virus, even with appropriate vaccination, are at a greater risk for adverse outcomes from COVID-19 including hospitalization, time in the intensive care unit (ICU), and mechanical ventilation. Consequently, therapeutic monoclonal antibodies (mabs), developed rapidly as a part of the global response to COVID-19, have been crucial. Nevertheless, the evolving VOCs have reduced the effectiveness of current abs, necessitating the development of new ones effective against various sarbeco viruses. This Mini review explain the importance of Prophylaxis, Therapy with Monoclonal Antibodies as The First Major Therapeutic Opportunity to change the Clinical History in the Sars-Cov-2 Variants Era for elderly and immunocompromised persons.

COVID-19 is highly transmissible with potentially serious health outcomes, underscoring the need for effective prevention and treatment strategies. Vaccines are highly effective at preventing COVID-19 for the general population; however, efficacy is often impaired in immunocompromised patients given insufficient response to initial exposure and/or memory for secondary exposures. Risk factors for COVID-19 include older age, obesity, underlying medical conditions such as diabetes, inadequate vaccination, and/or being immunocompromised [1]. People living with immunocompromising conditions including but not limited to active treatment for solid tumour and hematologic malignancies, solid organ transplant recipients, or people living with human immunodeficiency virus, even with appropriate vaccination, are at a greater risk for adverse outcomes from COVID-19 including hospitalization, time in the intensive care unit (ICU), and mechanical ventilation [2]. Consequently, therapeutic monoclonal antibodies (mAbs), developed rapidly as a part of the global response to COVID-19, have been crucial. Nevertheless, the evolving VOCs have reduced the effectiveness of current mAbs, necessitating the development of new ones effective against various sarbecoviruses. This mini review explain the importance of Prophylaxis, Therapy with Monoclonal Antibodies as The First Major Therapeutic Opportunity to change the Clinical History in the Sars-Cov-2 Variants Era for elderly and immunocompromised persons.

Vaccination in elderly and in many immune-compromised persons is less effective where immunogenicity and clinical data show considerably impaired responses to vaccination. Thus Monoclonal antibodies targeting the anti-SARS-CoV-2 spike (S) protein are prescribed in high-income countries to prevent severe disease in at-risk patients. Although studies report efficacy as between 50–85% [3-4]. Global access is currently largely inequitable. Multivariate omicron (B.1.1.529) and sub variant (BA.2 followed by BA.4 and BA.5) dominance has challenged the treatment landscape for mild-to-moderate disease, introducing considerable certainty on the efficacy of monoclonal antibodies [5-7] and leading to changes to initial recommendations for some of them. Contemporaneously, oral, direct-acting antivirals with a reported efficacy ranging from 30% (molnupiravir) to 89–90% (nirmatrelvir/ritonavir) have recently received conditional or emergency approval in some countries and been recommended in international guidelines such as the World Health Organization guidelines [8-9].  S-217622, also known as ensitrelvir, a 3CL protease inhibitor that has been shown to significantly reduce the infectious viral load, is currently in phase 3 trials and waiting for emergency approval in Japan and should be submitted soon in China. The main purpose of this opinion paper is to highlight the possible strategies to optimize and protect current and future therapeutic options to treat the most vulnerable patients. [10].

Monoclonal Antibodies Aprovation as Prophylaxis-Therapy in the Ederly and Immonocompromised Sars-Cov-2 population at October 2023

Currently, most mAbs are ineffective at providing an immune response to Omicron strains post BA.2. Recently, the US Food and Drug Administration and provinces in Canada have found tixagevimab plus cilgavimab ineffective against Omicron variants [11]. Similar decisions in the US have been made previously for bamlanivimab monotherapy, which was revoked in April 2021 because of low efficacy against newer COVID-19 variants [12]. In the context of increasing prevalence of resistant SARS-CoV-2 subvariants, the decision to administer tixagevimab plus cilgavimab, or any other mAbs to a given patient should be based on regional prevalence of resistant variants, individual patient risks, available resources, and logistics. Further, patients who receive mAbs as a prophylactic for COVID-19 should continue taking precautions, including proper hand hygiene, physical distancing, and mask wearing to avoid exposure (Table 1). Although mAbs demonstrated effectiveness, concerns have been raised regarding the potential for creating spike protein resistance-associated viral mutations, particularly in immunocompromised patients. A study conducted from January to February 2022 investigated whether resistance-associated mutations developed after treatment with sotrovimab in high-risk patients. Out of the high-risk patients, specimens were collected at three time points from 14 of the 18 patients (78%). Genomic analysis revealed that all 18 (100%) patients were infected with the Omicron variant; 17 with BA.1 (94%) and one with BA.2 (6%). Ten patients (56%) developed receptor-binding domain mutations at spike position E340 or P337 within 3-31 days after treatment. The researchers identified six mutations in the spike protein S: E340K/A/V/D/G/Q and three in S: P337L/R/S. Mutations increased over time, exceeding 50% between days 5 and 28. Patients with mutations had significantly delayed time to viral clearance (mean, 32 [SD, 8.1] days vs 19.6 [SD, 11.1] days for those without mutations; HR, 0.11 [95% CI, 0.02-0.60]). No S: E340 or S: P337 mutations were found in the Omicron variant from sequences in the general population. The four patients with the sotrovimab resistance-associated S: E340K mutation were immunocompromised [13]. Evidence of how Fc-dependent antibody functions may impact infection consequences within immunocompromised populations is still limited, requiring a more robust framework for evaluation.

Sotrovimab is one of the few mabs that demonstrated retained favourable clinical outcomes against the Omicron variant and as such it is crucial to understand Fc-mediated effects in order to evaluate and improve application of antibody therapy. The Omicron variant presents a heightened risk to patients that are immunocompromised due to their inability to mount a sufficient antibody response, even when they are vaccinated and/or have previous COVID-19 infections. This reality places immunocompromised patients at risk of death and hospitalization due to increased likelihood of high viral load and their difficulty in eliminating the virus. There is a continued need for research supporting multiple COVID-19 prophylaxis. The medical and scientific community can best serve their immunocompromised patients by updating their understanding of COVID-19 prophylaxis and its utility in supporting immunocompromised patients. Moreover, there is an urgent need for new randomized controlled trials in vaccinated, immunocompromised subjects, during current strains of COVID-19 to support the development of more effective mAbs [Table 2]. Cowan J., Amson A., et al. Monoclonal antibodies as Covid-19 prophylaxis therapy in immunocompromised patient populations. International Journal of Infectiuos Diseases Vol.134:P228-238, (2023). AE, adverse event; ARD, absolute risk difference; CI, confidence interval; RCT, randomized control trial; RRD, relative risk difference; RRR, relative risk reduction; RR, relative risk^.. Amson A., et al. Monoclonal antibodies as Covid-19 prophylaxis therapy in immunocompromised patient populations. International Journal of Infectious Diseases Vol.134:P228-238, (2023). AE, adverse event; aOR, adjusted OR; BAU, binding antibody unit; CI, confidence interval; HR, hazard ratio; ICU, intensive care unit; IM, intramuscular; IQR, interquartile range; IV, intravenous; KTR, kidney transplant recipients; mAb, monoclonal antibody; MS, multiple sclerosis; NP, nasopharyngeal; OR, odds ratio; RRR, relative risk ration; SOTR, solid organ transplant recipients.

ECDC Variant Classification Criteria and Recommendations at October 2023

New evidence is regularly assessed on variants detected through epidemic intelligence, rules-based genomic variant screening, or other scientific sources. If a decision is made to add, remove, or change the category for any variant, the tables are updated to reflect this change. The tables are regularly sent for consultation to ECDC and WHO Regional Office for Europe’s joint virus characterisation working group.

Category

Variant of concern (VOC), variant of interest (VOI), or variant under monitoring (VU^M).

WHO label

 As of 31st May 2021, WHO proposed labels for global SARS-CoV-2 variants of concern and variants of interest (link is external) to be used alongside the scientific nomenclature in communications about variants to the public. This list includes variants on WHO’s global list of VOC and VOI, and is updated as WHO’s list changes

Lineage and additional mutations

 The variant designation specified by one or more Pango lineages and any additional characteristic spike protein changes. An alternate description may be used if the variant is not easy to describe using this nomenclature. For updated information on Pango lineages and definition of lineages and for instructions on how to suggest new lineages, visit the Pango lineages website (link is external). Each lineage in then table is linked to the respective lineage page on the Pango lineages website

Country first detected

 Only present if there is moderate confidence in the evidence relating to the first country of detection.

Spike mutations of interest

Not all spike protein amino acid changes are included – this is not a full reference for assignment of the variants. It includes changes to spike protein residues 319-541 (receptor binding domain) and 613-705 (the S1 part of the S1/S2 junction and a small stretch on the S2 side), and any additional unusual changes specific to the variant.

Year and month first detected

As reported in the GISAID EpiCoV database. This can be adjusted backwards in time if new retrospective detections are made.

Evidence 

Concerning properties in three different categories:

·         Transmissibility

·         Immunity

·         Infection severity

Each category is annotated as increased, reduced, similar, unclear, or no evidence depending on the currently available evidence. Increased or reduced means that there is evidence demonstrating that the property is different enough for the variant compared to previously circulating variants that it is likely to have an impact on the epidemiological situation in the EU/EEA. Similar means that there is evidence that demonstrates that the property is not different enough for this variant compared to previously circulating variants that it is unlikely to have an impact. Unclear means that the current evidence is preliminary or contradictory enough to make the assessment uncertain. No evidence means that no evidence has yet been evaluated for this category. The evidence is further annotated with v or m to indicate whether the evidence is available for the variant itself (v) or for mutations associated with the variant (m).

Transmission in the EU/EEA

Categorised as dominant, community, outbreak(s), and sporadic/travel. The categories are qualitative, and the assessment is based on surveillance data collected in TESSy, GISAID EpiCoV data, epidemic intelligence data, and direct communications with the affected countries.

Variants of Concern (VOC)

As of 3 March 2023, ECDC has de-escalated BA.2, BA.4 and BA.5 from its list of SARS-CoV-2 variants of concern (VOC), as these parental lineages are no longer circulating. ECDC will continue to categorise and report on specific SARS-CoV-2 sub-lineages in circulation that are relevant to the epidemiological situation.

There are currently no SARS-CoV-2 variants meeting the VOC criteria.

Variants of interest (VOI)

X: including its sub-lineages (BN, CH and others). Omicron-Omicron Recombinants XBF and XBK that share the same spike as BA.2.75 are monitored under BA.2.75 lineages

Y: W152R, F157L, I210V, G257S, D339H, G446S, N460K, Q493 (reversion)

A: Monitoring an umbrella of SARS-CoV-2 lineages that have similar Spike protein profiles and characterised by a specific set of mutations (S: Q183E, S: F486P and S: F490S). For the full list of lineages, please look at the table here.

Figure 1: Reported protection and antibody concentration from RCTs of monoclonal antibodies in preventing COVID-19.

Figure 2: Potential impact of SARS-CoV-2 antiviral drugs optimization in protecting available antivirals in the shifting landscape of new variants.

B: Monitoring an umbrella of SARS-CoV-2 lineages that have similar Spike protein profiles and characterised by a specific set of mutations (S: F456L, S: Q183E, S: F486P and S: F490S). For the full list of lineages, please look at the table here.

All sub-lineages of the listed lineages are also included in the variant

Reported protection and antibody concentration from RCTs of monoclonal antibodies in preventing COVID-19

Stadler et al. [14] searched MEDLINE, PubMed, Embase, and the Cochrane COVID-19 Study Register for randomized placebo-controlled trials of SARS-CoV-2-specific monoclonal antibodies (mAbs) used as pre-exposure and peri-exposure prophylaxis for COVID-19. They was included only studies where both protection from symptomatic infection and pharmacokinetic information of the monoclonal antibody were provided within the same study. They was identified six eligible studies assessing monoclonal antibodies as pre-exposure and peri-exposure prophylaxis for COVID-. The antibodies used in these studies were casirivimab/imdevimab (three studies), bamlanivimab, cilgavimab/tixagevimab, and adintrevimab.  Omicron variants were the dominant circulating variants. One study assessed protection in two time periods; firstly in a pre-Omicron period when the Delta variant was the dominant circulating variant, and separately later when Omicron variants BA.1 and BA.1.1 were the dominant variants13. The overall efficacies against pre-Omicron variants in the included studies ranged from 68.6% to 92.4%. Stadler et al.was identified a trend for lower efficacies with increasing time since administration and against the escaped variant, the latter being reported previously by Schmidt et al. [15] (Figure. 1). Stadler,E.et al. Monoclonal antibody levels and protection from COVID-19. Nature Communications volume 14:  4545 (2023).The efficacy at each time interval is shown in blue (points indicate observed efficacy, horizontal error bars indicate time interval and vertical error bars represent 95% CIs of efficacy). The antibody concentration is shown in black. an Antibody concentration (n?=?1776 individuals) and efficacy data (n?=?5172 individuals) for cilgavimab/tixagevimab was extracted from Levin et al.13 b Single administration of casirivimab/imdevimab data are a combination of data from O’Brien et al.14 and Herman et al.15 who report on the same clinical trial over different follow-up intervals. Efficacy data were reported weekly over the first four weeks in O’Brien et al. (diamonds) (n?=?1505), and monthly for eight months in Herman et al. (circles) (n?=?1683). Antibody concentration data was reported up to day 168 in O’Brien et al. (solid line, b n?=?12), and modelling of the pharmacokinetic profile of the antibody concentration, reported in Herman et al., was used to inform the antibody concentration between 168 and 240 days (dashed line, b). C Isa ET al.16 reported efficacy (n?=?969) and in vivo concentration after repeated administration of 1.2?g of casirivimab/imdevimab every 4 weeks (n?=?723). Hence, the antibody concentration did not decline as in the other studies. D The modeled concentration of adintrevimab after a single administration was extracted from the study by Schmidt ET al.12. The efficacy of adintrevimab was reported both when the delta variant was dominant (circles) (n?=?1267) and when Omicron variants BA.1 and BA.1.1 were dominant (triangles) (n?=?378).

Protecting Emerging Treatment Options

Several crucial issues warrant urgent attention to optimize the use of these emerging treatment options e (Figure 2). First, as proven to be transformational for HIV, rapid, affordable access to early antiviral treatment to slow the tide of new variants is critical to effective “test-and-treat” strategies to protect the most fragile patients and avoid a severe and/or persistent infection. After more than 2 years of pandemic, progress has been slow [17] and public health attention has recently been attracted by the low-profile agreement during the) in Geneva in May 2022. Together with vaccination, early diagnosis and treatment have the ability to reduce disease worsening, to reduce transmission and to constrain variability in viral sequences. Figure 2. Potential impact of SARS-CoV-2 antiviral drugs optimization in protecting available antivirals in the shifting landscape of new variants. Second, although the combined effect of omicron and increasing vaccine deployment in some regions has shifted the demand response from hospital to outpatient care, considerable uncertainty exists about who is now at risk for severe omicron disease [18]. While the risk/benefit ratio across at-risk subpopulations has unquestionably changed in vaccinated populations, gains made can only be preserved if those at highest risk are rapidly diagnosed and receive treatment in less than one week. Third, high levels of antiviral efficacy will be critically important, especially in immunocompromised patients who are grossly underrepresented in registration trials [19]. Causes of immunosuppression are diverse (including organ/stem cell transplants, cancer, immunosuppressive medications or uncontrolled HIV) and these patients represent a significant proportion of the population, e.g., 7 million adults in the USA [20] , but also in low- and middle-income countries due to the high prevalence of uncontrolled HIV. Overall, the mortality risk with omicron is still unclear, but protection of those who cannot be effectively vaccinated or protected by a prior SARS-CoV-2 infection remains imperative. Importantly, in regions where HIV is highly prevalent, there is a clear need and opportunity to reinforce HIV epidemic control by prompt diagnosis and sustained viral suppression with antiretroviral, key factors to also enable the control of SARS COV-2 spread in this group.

Although there are many other causes for variant emergence (host jump or adaptation, vaccine exposure, to name the most frequent), data confirm that immunocompromised patients with long-term SARS-CoV-2 replication are particularly susceptible to resistance and transmissible variant emergence. The emergence of resistance mutation thus impacting treatment efficacy is more likely if a patient has been exposed to specific antiviral drugs. In addition, it remains unclear if the small percent rebound occurrence (2%) observed with nirmatrelvir/r in the EPIC-HR (Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients) trial, performed in the delta variant era, is underestimating a risk that would be particularly of concern in patients harbouring an impaired immune system and in the omicron era. In one recent case series, one out of 7 patients who had a virologist rebound also had an immunosuppressing condition. Another recent case series revealed that all three patients with viral rebound were highly immunocompromised. This potentially raises concerns about the need of longer antiviral courses, especially in these patients. Preclinical data have clearly demonstrated that virological efficacy is higher for combinations of existing antiviral drugs than single agents. To achieve the goal of changing the treatment guidelines in SARS-CoV-2-infected immunocompromised individuals, independent and academic clinical trials for drug combinations should be considered as an urgent, unmet research priority. Today, collaboration with industry to allow early access to antiviral drugs to be combined has been an objective still to be achieved. Certain potent monoclonal antibodies, such as bebtelovimab, cannot even be accessed for research or for routine care outside of the USA [21].

Early Treatment Optimization

Treatment optimization has been truly transformational for other viral diseases [e.g., HIV/hepatitis C virus and was only achieved when antiviral drug combinations became the mainstay. With few drugs currently available, the opportunity must be seized prior to the emergence of resistance to drugs deployed widely as monotherapies. Combinations of polymerase inhibitors and polymerase/protease inhibitors have proven highly successful for other viruses and in animal models for SARS-CoV-2. Thus, as drugs that are appropriate to combine are available, there is no good reason not to study them clinically. In addition to the opportunities that combinations present for a more potent antiviral response (individual benefit), there can be no doubt that the rate at which resistance emerges will also be reduced (public health benefit). Higher potency will result in a lower variability in sequences through a lower degree of replication. In addition, the probability of the occurrence of multiple mutations to drive resistance to multiple antivirals simultaneously is much lower than for a single agent. This is particularly the case where concentrations achieved are close to the therapeutic efficacy threshold or in the case of low compliance. It is incumbent upon the international research community and the pharmaceutical industry to pool knowledge and provide the critical information that the World Health Organization and country-level authorities so urgently require, as well as early diagnosis and increased access to vaccines and antiviral therapy. The resistance risk for existing drugs has been woefully understudied throughout development, making it extremely challenging to rationalize during policy development. Looking beyond efficacy, drug combinations will unquestionably reduce the rate at which resistance and new variants impacting treatment options emerge and could be made available and accessible to those in need if timely efforts are made. In conclusion, we call for combination therapies to be tested in adequately powered clinical trials in the target population of immunocompromised patients, both in wealthy and in low-income countries where HIV-driven immunosuppression is prevalent. If higher efficacy is confirmed, the diversity of possible combinations will enable the tailoring of therapeutic options to individual patient needs (e.g., avoiding drug-drug interactions in transplant patients) as well as their specific regional context (e.g., oral-only combinations).

Does their use as a prophylactic or treatment potentially affect natural long-term immunity?

Considering the large doses used and the relative half-life of antibodies (~3 weeks for IgG molecules), there is a pertinent consideration whether the presence of circulating neutralizing mAbs could impact active immunity, whether through memory from infection or vaccination. From the collective clinical data with MAb114, REGN-EB3 and palivizumab, the general benefits and risks associated with neutralizing mAbs are similar to those observed with traditional passive immunization against infectious agents. The agents themselves are relatively tolerable for patients, efficacious during the early onset of disease symptoms and in certain cases as a prophylactic, but with limited efficacy once infections are severe. The distinctions between these therapies are largely logistical; CPT is more rapidly implemented during an emerging pandemic when few therapeutic options are yet available, while neutralizing mAbs take time to discover and it takes time for regulatory approval for their use to be obtained as well as to scale up manufacturing capacity. The use and promise of passive immunization during the coronavirus outbreaks of the twenty-first century (that is, with SARS-CoV, Middle East respiratory syndrome-related coronavirus and SARS-CoV-2) have re-emphasized these past lessons while also highlighting additional insights, as we discuss next [22]. Fortunatly today, the process to mass-produce recombinant mAbs has become scalable to meet demand and is cost-competitive with other treatments. Neutralizing mAbs overcome limitations intrinsic (for example, the risk of blood-borne diseases, time to development of detectable high-affinity antibodies and risk of low antibody titres, as well as variable epitope specificity. Furthermore, a high titre of neutralizing antibodies — which current evidence indicates is necessary for the efficacy— is inherent with neutralizing mAbs. As of April 2021, at least 20 neutralizing mAb therapies were being tested in late-stage clinical trials or had already been approved for use in nine infectious diseases, including RSV infection and Ebola.

Association with Several SARS-CoV-2 Neutralizing Monoclonal Antibodies Therapies with Adverse Outcomes of COVID-19

Table 1: Overview of randomized control trials of monoclonal antibodies as pre- and post-exposure prophylaxis for COVID-19 in immunocompromised populations.

Table 2: Overview of real-world evidence of monoclonal antibodies as pre- and post-exposure prophylactics for COVID-19 in immunocompromised populations.

Variants of Interest (VOI)

Variants under monitoring

The second lesson is that the magnitude of a treatment’s effectiveness may change over time if the disease evolves. As Ambrose et al. astutely comment, if severe disease and death decrease substantially between initial and later cases, treatments will have reduced effectiveness in preventing the same outcomes. For example, sotrovimab was associated with significant decreases in the odds of death within 30 days, but its NNT had increased to 666 by the Omicron era. Third, effective treatments are only effective if they can be readily administered to patients. Early in the pandemic, the outpatient infrastructure of US health care systems was not prepared or equipped to operationalize the rapid administration of intravenous infusions to highly contagious patients after diagnosis. Establishing processes to deliver mAb treatment was challenging, but the reward was great. Future investment in these therapies is even more important now that the infrastructure is in place to deliver them. Fourth, mAb therapies highlighted the importance of rapid diagnostic and/or point-of-care testing. Patients with symptoms needed quick access to SARS-CoV-2 testing with rapid turnaround times. Because real-time variant sequencing was not available in the clinical setting, clinicians had to make challenging decisions about whether to continue providing mAbs for treatment based on forecasting per geographic region. With point-of-care precision testing, more treatments could have been administered for longer periods, which is particularly important during times of scarce resources. While ethical allocation of scarce resources is challenging on many levels, it does bring into focus the fifth important lesson of mAb therapy: using risk-stratification strategies to optimize patient outcomes. These data from Ambrose et al further confirm that not all risk of COVID-19 progression is equal. Understanding this risk, ideally to the point of knowing patient-specific baseline immunity, would facilitate precision medicine and would be the gold standard for deploying optimal, equitable, and value-based care. Ambrose and colleagues found that mAb therapy allowed us to consistently keep patients out of the hospital and alive. Acknowledging that mAb development and implementation seems like a constant race against the clock, scientists and manufacturers will need incentives to produce safe and effective therapies that are at risk of becoming obsolete. Authorizations for use of these therapies should focus on the patients most likely to benefit. Systematic efforts should continue to focus on both clinical and implementation science to capture clinical practice results as expeditiously as possible, which will allow us to effectively adapt to an ever-changing landscape

Effectiveness of monoclonal antibodies against covid variants

The FDA has provisionally approved the following for the treatment and/or prevention of COVID-19:

Monoclonal antibodies that target the sars-cov-2 spike protein

• Casirivimab plus imdevimab (RONAPREVE)

• Regdanvimab (REGKIRONA)

• Sotrovimab (XEVUDY)

• Tixagevimab and cilgavimab (EVUSHELD)

Immune modulating monoclonal antibodies

• Tocilizumab (ACTEMRA)

Non monoclonal antibody antiviral agents used in the treatment of COVID 19

• Nirmatrelvir-ritonavir (PAXLOVID)

• Molnupiravir (LAGEVRIO)

• Remdesivir (VEKLURY)

Monoclonal antibodies targeting the SARS-CoV-2 spike protein had shown clinical benefits against COVID-19 caused by variants predominant during the earlier stages of the pandemic. These antibodies are designed to neutralise the virus by binding to the spike protein on its surface. However, emerging data show that anti-spike protein monoclonal antibodies demonstrate a significant decrease in their in-vitro neutralising activities against many newer circulating SARS-CoV-2 variants, particularly Omicron and its sub variants. While there are few published clinical trials on the effectiveness of these monoclonal antibodies against clinical disease caused by these newer variants, it is expected that these mAbs will not provide clinical benefit in those people infected with the newer variants. The activity of the monoclonal antibody tocilizumab is not reduced against variants as this antibody does not target the virus but acts as a modulator of the immune response. Non monoclonal antibody antiviral treatments such as nirmatrelvir/ritonavir (PAXLOVID), molnupiravir (LAGEVRIO) and remdesivir (VEKLURY), which have different mechanisms of action, are likely to retain their activity against the emerging strains. In the word, the situation continues to evolve, with the epidemiology of circulating variants changing regularly. The characteristics of the circulating SARS-CoV-2 viruses should be considered when prescribing monoclonal antibodies for prevention or treatment of COVID-19. Healthcare professionals will need to consider alternative treatments as appropriate. At this stage, the regulatory status of the products remain unchanged in the word. The FDA and its counterparts will continue to monitor the efficacy and safety of all COVID-19 medicines. Potential updates to the Product Information for individual monoclonal antibodies will be published (if required) as they become available

Vaccination has provided a high level of population immunity to COVID-19. However, there remain a number of subgroups in which vaccination is either not possible or ineffective (largely due to immunodeficiency).The use of monoclonal antibodies for prophylaxis in these cohorts has the potential to provide long-term protection from both symptomatic and severe COVID-19 for these vulnerable groups. However, the frequent observation of novel SARS-CoV-2 variants that escape antibody recognition has raised significant challenges in predicting monoclonal antibody protection against new variants. Several studies have investigated the efficacy of monoclonal antibodies as pre- and post-prophylaxis for COVID-19. Historical evidence is promising; however, new variants of concern are proving challenging for currently available regimens.

1. 1. Vardavas CI, Mathioudakis AG, Nikitara K, Stamatelopoulos K, Georgiopoulos G, Phalkey R, et al. Prognostic factors for mortality, intensive care unit and hospital admission due to SARS-CoV-2: a systematic review and meta-analysis of cohort studies in Europe. Eur Respir Rev. 2022.
   2. Ryan L. Vaccinated but not protected-living immunocompromised during the pandemic. JAMA. 2021; 325: 2443-2444.
   3. Gottlieb RL, Nirula A, Chen P, Boscia J, Heller B, Morris J,et al. Effect of bamlanivimab as monotherapy or in combination with etesevimab on viral load in patients with mild to moderate COVID-19: a randomized clinical trial. JAMA. 2021; 325: 632-644.
   4. Gupta A, Gonzalez-Rojas Y, Juarez E, Crespo Casal M, Moya J, Rodrigues Falci D, et al. Effect of sotrovimab on hospitalization or death among high-risk patients with mild to moderate COVID-19: a randomized clinical trial. JAMA.2022; 327: 1236-1246.
   5. Cao Y, Yisimayi A, Jian F, Song W, Xiao T, Wang L, et al. BA.2.12.1, BA.4 and BA.5 escape antibodies elicited by Omicron infection. Nature. 2022; 608: 593-602.
   6. Yamasoba D, Kosugi Y, Kimura I, Fujita S, Uriu K, Ito J, et al. Neutralisation sensitivity of SARS-CoV-2 omicron subvariants to therapeutic monoclonal antibodies. Lancet Infect Dis. 2022; 22: 942-943.
   7. United States Food Drug Administration FDA updates Sotrovimab emergency use authorization. FDA. 2022.
   8. Abdelnabi R, Foo CS, Kaptein SJF, Zhang X, Do TND, Langendries L, et al. The combined treatment of Molnupiravir and Favipiravir results in a potentiation of antiviral efficacy in a SARS-CoV-2 hamster infection model. eBioMedicine 2021; 72.
   9. Weinreich DM, Sivapalasingam S, Norton T, Ali S, GAO H, Bhore R, et al. REGEN-COV antibody combination and outcomes in outpatients with Covid-19. New Engl. J. Med. 2021; 385.
   10. World Health Organization. Therapeutics and COVID-19: living guideline. 2022.
   11. Miljanovic D, Cirkovic A, Lazarevic I, Knezevic A, Cupic M, Banko A. Clinical efficacy of anti-SARS-CoV-2 monoclonal antibodies in preventing hospitalisation and mortality among patients infected with Omicron variants: a systematic review and meta-analysis.Rev Med Virol. 2023.
   12. Cowan J, Amson A, Christofides A, Chagla Z.. Monoclonal antibodies as Covid-19 prophylaxis therapy in immunocompromised patient populations.Int J Infecti Dis. 2023; 134: 228-238.
   13. Stadler E, Burgess MT, Schlub TE, Khan SR, Chai KL,McQuilten ZK,  et al. Monoclonal antibody levels and protection from COVID-19. Nature Communications. 2023; 14.
   14. Schmidt P. Naryan K, Li Y, Kaku CI, Brown ME, Champney E, et al. Antibody-mediated protection against symptomatic COVID-19 can be achieved at low serum neutralizing titers. Sci. Transl. Med. 2023; 15.
   15. Levin MJ, Ustianowski A, De Wit S, Launay  O,Avila M, Templeton, et al. Intramuscular AZD7442 (tixagevimab-cilgavimab) for prevention of Covid-17. N. Engl. J. Med. 2022; 386: 2188-2200.
   16. O’Brien MP, Forleo-Neto E, Musser BJ, Isa F, Chan KC, Sarkar N,et al. Subcutaneous REGEN-COV antibody combination to prevent Covid-19. N. Engl. J. Med. 2021; 385: 1184-1195.
   17. Herman GA, O’Brien MP, Forleo-Neto E, Sarkar N, Isa F, Hou P,  et al. Efficacy and safety of a single dose of casirivimab and imdevimab for the prevention of COVID-19 over an 8-month period: a randomised, double-blind, placebo-controlled trial. Lancet Infect. Dis. 2022; 22: 1444-1454.
   18. Isa F, Forleo-neto E, Meyer J, Zheng W, Rasmussen S, Armas D, et al. Repeat subcutaneous administration of casirivimab and imdevimab in adults is well-tolerated and prevents the occurrence of COVID-19. Int. J. Infect. Dis. 2022; 122: 585-592.
   19. Hasan Q, Elfakki E, Fahmy K, Mere O, Ghoniem A, Langar, H, et al. Inequities in the deployment of COVID-19 vaccine in the WHO Eastern Mediterranean Region, 2020-2021. BMJ Glob Health. 2022; 7.
   20. Skarbinski J, Wood M S, Chervo TC, Schapiro JM, Elkin EP, Valice E.et al.Risk of severe clinical outcomes among persons with SARS-CoV-2 infection with differing levels of vaccination during widespread Omicron (B.1.1.529) and Delta (B.1.617.2) variant circulation in Northern California: A retrospective cohort study. Lancet Reg. Health Am. 2022; 12.
   21. John NA, John JE. Implications of COVID-19 infections in sickle cell disease. Pan. Afr. Med. J. 2020; 36: 81.
   22. Harpaz R, Dahl RM, Dooling KL. Prevalence of immunosuppression among US adults, 2013. JAMA 2016; 316: 2547-2548.
   23. Bloomberg (Europe Edition). Pfizer's Grip on Paxlovid Thwarts Research on Covid Treatment. Bloomberg.com. 2022.
   24. Pecetta S, Finco O. Seubert A. Quantum leap of monoclonal antibody (mAb) discovery and development in the COVID-19 era. Semin. Immunol. 2020; 50.
   25. Ambrose N, Amin A, Anderson B, et al. Neutralizing monoclonal antibody use and COVID-19 infection outcomes. JAMA Netw Open. 2023; 6.