Article Type : Research Article
Authors : Weimer LE, Cattari G, Fanales Belasio E, Cuccuru E and Vidili Gianpaolo
Keywords : SARS-CoV-2; Covid-19
The most significant health challenge in the 21st century has been the Sars-Cov-2. The Extensive research and the Global Cooperation have provided a profound understanding of the latest therapies, fundamental biological and molecular characteristics of SARS-CoV-2. Pre-exposure prophylaxis using monoclonal antibodies is one complementary preventative therapy to reduce severity of breakthrough Sars-Cov-2 in persons with severe immunocompromise due organ transplant, cancer, HIV or use of certain medications experience diminished SARS-CoV-2 vaccine immune response and remain at higher risk for severe COVID-19 outcomes; across many studies, Monoclonal Antibodies Pre-Exposure is associated with a 60% to 80% reduction in severe COVID-19 outcomes. Covid-19 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. This Review explain the Next –Generation of Pre-Exposure Prophylaxis, the recommendations for the Clinical Management for Persons with Risk factors for COVID-19, include obesity, older age, underlying medical conditions such as diabetes, inadequate vaccination, immunocompromised condition
The most significant health
challenge in the 21st century has been the Sars-Cov-2. The Extensive
research and the Global Cooperation have provided a profound understanding of
the lastest therapies, fundamental biological and molecular characteristics of
SARS-CoV-2 [1].
Pre-exposure prophylaxis using
monoclonal antibodies is one complementary preventative therapy to reduce
severity of breakthrough Sars-Cov-2 in persons with severe immunocompromise due
organ transplant, cancer, HIV or use of certain medications experience
diminished SARS-CoV-2 vaccine immune response and remain at higher risk for
severe COVID-19 outcomes [2]; across many studies, Monoclonal Antobodies
Pre-Exposure is associated with a 60% to 80% reduction in severe COVID-19
outcomes.
Covid-19 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].
This Review explain the Next –Generation of Pre-Exposure Prophylaxis, the
recommendations for the Clinical Mamagement for Persons with Risk factors for COVID-19 , include obesity,
older age, underlying medical conditions such as diabetes, inadequate
vaccination, immunocompromised condition.
Introduction
COVID-19 still represents a
significant and disproportionate risk for immunocompromised 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 [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 lastest 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 preexposure or postexposure 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. The main purpose of this leterature 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].
Omicron Variant: "Almost a new Pandemic"
With the emergence of this variant,
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 subvariants (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].
Lastest Monoclonal Antibodies for
Pre-Exposure Prophylaxis in Patients for the most vulnerable persons at June
2024
Pemivibart
(Pemgarda): The FDA issued an
emergency use authorization (EUA) for pemivibart (Pemgarda) opens in a new tab
or window as COVID-19 pre-exposure prophylaxis in immunocompromised individuals
who are unlikely to mount a sufficient immune response following vaccination. A
long-acting monoclonal antibody, pemivibart is specifically authorized for
people ages 12 years and older (and weighing 40 kg or more) with moderate-to-severe
immune compromise either because of a medical condition or due to
immunosuppressant medications. Pemivibart is given as a single intravenous
infusion and is not for use as post-exposure prophylaxis or in people currently
infected with SARS-CoV-2.
The EUA was based on immunobridging
data involving other human monoclonal antibodies against SARS-CoV-2
demonstrating that pemivibart may be effective for COVID prevention. Serum
neutralizing antibody titers of Pemgarda were consistent with the titer levels
associated with efficacy in prior clinical trials of adintrevimab and certain
other monoclonal antibody products.
According to the EUA, individuals
who would qualify for the antibody include those undergoing active treatment
for cancer (including those receiving CAR T-cell therapy or stem cell
transplant); patients with hematologic malignancies associated with poor
responses to COVID vaccines regardless of their treatment status; solid-organ
transplant recipients; those with moderate-or-severe primary immunodeficiency;
people with advanced or untreated HIV; and those on high-dose corticosteroids,
B-cell depleting agents, and other immunosuppressants.
No long-acting monoclonal antibody
has been available for preventing COVID infection in individuals with
moderate-to-severe immune compromise since the agency pulled the EUA opens in a
new tab or window for tixagevimab-cilgavimab (Evusheld) in January 2023 -- the
move followed data showing the combination was unlikely to be sufficiently
active against circulating SARS-CoV-2 variants. At the time, the CDC
recommended opens in a new tab or window that immunocompromised individuals
receive the latest COVID booster (if they had not already), wear a well-fitting
high-quality mask in public, maintain distance in crowded areas, and improve
indoor ventilation.
Pemivibart is administered at a
dose of 4,500 mg over a 60-minute infusion, with repeat dosing every 3 months
recommended if ongoing protection is needed. FDA cautioned that anaphylaxis
occurred in 0.6% of clinical trial participants who received pemivibart.
Therefore, patients should be monitored for 2 hours after the infusion is
finished, and pemivibart should be administered in settings where health
providers have immediate access to medications to reverse severe allergic
reactions and can alert EMS if necessary. Other potential side effects noted in
the labelingopens in a new tab or window include infusion-related reactions,
fatigue, nausea, and headache [13].
SUPERNOVA Phase III trial of
sipavibart long-acting antibody met primary endpoints in preventing COVID-19 in
immunocompromised patient population
SUPERNOVA is a large Phase III
global trial providing the only efficacy data in immunocompromised patients,
demonstrating the potential benefit of a COVID-19 antibody against recent
SARS-CoV-2 variants. Immunocompromised patients include those with blood
cancer, organ transplant recipients, patients with end-stage renal disease
requiring dialysis, patients receiving B-cell depleting therapy within the past
year, and those taking immunosuppressive medications. Despite accounting for
approximately 4% of the population, immunocompromised patients make up about
25% of COVID-19 hospitalisations, ICU admissions, and deaths, even after multiple
doses of COVID-19 vaccines [14].
The trial met both dual primary
endpoints; the first one being the relative risk reduction of symptomatic
COVID-19 caused by any SARS-CoV-2 variant and the second being the relative
risk reduction of infections caused by SARS-CoV-2 variants not containing the
F456L mutation. SUPERNOVA demonstrated the potential benefit of sipavibart in
an evolving variant landscape in which COVID-19 cases captured over the course
of the trial were caused by several different SARS-CoV-2 variants.
Primary efficacy endpoints. The
first evaluated the efficacy of sipavibart against any confirmed SARS-CoV-2
positive symptomatic illness occurring post dose prior to day 181 caused by any
variant (i.e., all cases regardless of if the variant has the F456L mutation or
not, which sipavibart is not expected to neutralise). The second dual primary
efficacy analysis was conducted using only the confirmed COVID-19 cases in the
trial where the variant causing the COVID-19 cases did not have the F456L
mutation, referred to as a “matched” variant analysis.
Participants were individuals 12
years of age and over who would benefit from prevention with the
investigational LAAB, defined as having increased risk for inadequate response
to active immunisation (predicted poor responders to vaccines or intolerant of
vaccine). Participants at the time of screening had a negative point-of-care
SARS-CoV-2 serology test. Participants will be followed for 15 months, with
SARS-CoV-2 neutralising antibodies assessed at one, three and six months.
All participants in the trial had
an immunocompromising condition and/or were on immunosuppressive treatments,
which put them at risk to mount an inadequate immune response to vaccination
and at high risk of developing severe COVID-19. This included patients with
hematologic malignancies, solid organ transplant recipients, hematopoietic stem
cell transplants, end stage kidney disease/dialysis and being within one year
of receipt of B cell depleting therapy, among others. Across the treatment
groups, demographic and baseline characteristics were generally well balanced.
Positive high-level results from
the SUPERNOVA Phase III COVID-19 pre-exposure prophylaxis (prevention) trial
showed AstraZeneca’s sipavibart (formerly AZD3152), an investigational
long-acting antibody (LAAB), demonstrated a statistically significant reduction
in the incidence of symptomatic COVID 19 compared to control
(tixagevimab/cilgavimab or placebo) in an immunocompromised patient population.
COVID-19 still represents a
significant and disproportionate risk for immunocompromised patients, with
infection often leading to serious and protracted illness.
Infection-fighting antibodies
directly to patients who often don’t respond adequately to vaccines, the data
support that sipavibart has the potential to provide much-needed protection
against COVID-19 in this highly vulnerable population [15,16].
Immunocompromised patients
currently have limited or no options for COVID-19 protection and continue to
face a significant burden of disease, despite often being fully vaccinated.
Sipavibart has the potential to prevent COVID-19 in the immunocompromised and
we will now work with regulatory authorities globally to bring sipavibart to
these vulnerable patients.
Sipavibart was well tolerated in
the trial and preliminary analyses show adverse events were balanced between
the control and sipavibart arms. The data will be presented at a forthcoming
medical meeting. AstraZeneca is in dialogue with regulatory authorities on
potential authorisation or approval pathways [17-19].
Sipavibart
Sipavibart (formerly AZD3152) is an
investigational long-acting monoclonal antibody (LAAB) against COVID-19.
Sipavibart was designed to provide broad and potent coverage across Omicron and
ancestral viral variants by neutralising spike protein interaction with the
host receptor ACE2.
Sipavibart was derived from B-cells
donated by convalescent patients after SARS-CoV-2 infection. Sipavibart has
been engineered using the same antibody scaffold as Evusheld and was optimized
with the same half-life extension and reduced Fc effector function and
complement C1q binding platform. The reduced Fc effector function aims to
minimise the risk of antibody-dependent enhancement of disease - a phenomenon
in which virus-specific antibodies promote, rather than inhibit, infection
and/or disease. Sipavibart was licensed by AstraZeneca in May 2022 from RQ
Biotechnology [20].
Patients Immunocompromysed and
Sars-Cov-2
Individuals with immunosuppressed
conditions, including people with primary immunodeficiencies 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 heterogenous 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 notonly cause long duration of symptoms
but also risk of emergence of antiviral-resistant or vaccine-escaped variants,
prolonging the pandemic.
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, corticoste-roids 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 immunomodulator therapy of adults with varying severities of
COVID-19 are summarized in (Table 1).
Effectiveness of Monoclonal Antibody-based
therapy Against Covid Variants (June 2024)
Monoclonal antibodies against the
SARS-CoV-2 S protein act through mechanisms related to their structure. First,
the antigen-binding fragments (Fab) prevent the virus from binding to the ACE2 receptors,
and second, the Fc fragment can activate the complement system and bind to the
Immunoglobulin Fc receptors (FcRs) on cytotoxic
cells that can eliminate virus-infected cells through Ab-dependent
cell-mediated cytotoxicity (ADCC). Unfortunately, some mAbs can bind to
macrophage FcRs and induce a hyperinflammatory response resulting from
Ab-dependent enhancement (ADE) of cytokine production.
The SARS-CoV-2 RBD has become the main target of mAbs
because of its crucial role in virus entry into host cells (Table 2). Analysis
of the structural relationship between RBD and anti-RBD NAbs has led to the
classification of these antibodies according to structural features and
mechanism of action. Class 1 NAbs, e.g., CT-P59 (regdanvimab), target the
receptor binding motif (RBM). They recognize the RBD in the up conformation,
thus blocking the interaction with the ACE2 receptor. Class 2 NAbs, e.g.
LY-CoV1404 (bebtelovimab), target the ACE2 binding site of the RBD in both up
and down conformations. Class 3 antibodies, e.g., S309 (sotrovimab), target the
conserved core domain of the RBD without altering interactions with the ACE2
receptor. Class 4 antibodies, e.g., S2X259, target epitopes in both the RBM and
the core domain of the RBD. Unfortunately, frequent mutations in the RBD have
modified the epitopes recognized by mAbs, resulting in the emergence of viral
variants resistant to mAbs. To address this issue, researchers are exploring
other SRS-CoV-2 regions as potential targets for therapeutic mAbs.
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 [21].
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 [22].
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 3).
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 [23].
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 favorable 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 4).
SARS-CoV-2 variants of concern as of 26 June 2024
Description of the tables
Category: variant of concern (VOC), variant of interest (VOI), or variant under
monitoring (VUM).
WHO
label: As of 31st May 2021, WHO proposed labels for
global SARS-CoV-2 variants of concern and variants of interest to be used
alongside the scientific nomenclature in communications about variants to the
public. This list includes variants on whose 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. 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.
Reported protection and antibody concentration from
RCTs of monoclonal antibodies in preventing COVID-19. 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. [24-27] (Figure 2).
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. a 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 modeling
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).
Conclusion
COVID-19 still represents a significant and
disproportionate risk for immunocompromised patients, with infection often
leading to serious and protracted illness. Infection-fighting antibodies
directly to patients who often don’t respond adequately to vaccines, the data
support that sipavibart has the potential to provide much-needed protection
against COVID-19 in this highly vulnerable population. Immunocompromised
patients currently have limited or no options for COVID-19 protection and
continue to face a significant burden of disease, despite often being fully
vaccinated. Sipavibart has the potential to prevent COVID-19 in the
immunocompromised and we will now work with regulatory authorities globally to
bring sipavibart to these vulnerable patients.
Studying the adaptation trajectory of SARS-CoV-2, it
is crucial to anticipate possible future events rooted in the molecular
mechanisms that underpin the evolutionary success of SARS-CoV-2 is essential. The
potential role of advanced Treatment as Pre-Exposure Prophylaxis against
SARS-CoV-2 has introduced it as a new platform to encourage the adaptation of
emerging medical technologies for infectious diseases.
The use of monoclonal antibodies for Pre-Exposure 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.
7. United States Food Drug
Administration. 2022.
10. World Health
Organization (2022). Therapeutics and COVID-19: living guideline. 2022.
13. Dube
S. Continued Increased Risk of COVID-19 Hospitalisation and Death in
Immunocompromised Individuals despite Receipt of ?4 Vaccine Doses: Updated 2023
Results from INFORM, a Retrospective Health Database Study in England.
14. Turtle
L. Individuals with Multiple Sclerosis Are at High Risk for COVID-19
Hospitalisation and Death Despite High Rates of Vaccination: Results from the
England INFORM Study. Oral Presentation at ECCMID 2024.
15. Meeraus
W. High Prevalence of Immunocompromising Conditions among Patients with Severe
Acute Respiratory Infection, Including SARS-CoV-2: Results from a Multicentre,
Test-Negative Case Control Study. Abstract #01796 at ECCMID 2024.
16. Meeraus
W. Immunocompromise, Cancer and Other Comorbidities in Patients with Severe
Acute Respiratory Infection Testing Positive versus Negative for SARS-CoV-2: A
Post Hoc Analysis of COVIDRIVE Data from May 2021 to May 2023. Abstract #01800
at ECCMID 2024.
19. https://www.cbc.ca/news/canada/calgary/alberta-covid-therapy-evusheld-1.6731381
22. 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:
4545.
23. Schmidt
P, Narayan 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. Science Translational Medicine. 2023; 15: 2783.
24. Levin
MJ, Ustianowski A, De Wit S, Launay O, Avila M, Templeton A, et al.
Intramuscular AZD7442 (tixagevimab–cilgavimab) for prevention of Covid-19. New
England J Med. 2022; 386: 2188-200.
25. 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. New England J Medicine.
2021; 385: 1184-1195.
27. COVID-19:
which monoclonal antibodies should be used for vulnerable individuals?.
Institut Pasteur/Olivier Schwartz & Félix Rey. 2024.