ABSTRACT
The first 2 years of the COVID-19 pandemic were mainly characterized by convergent evolution of mutations of SARS-CoV-2 Spike protein at residues K417, L452, E484, N501 and P681 across different variants of concern (Alpha, Beta, Gamma, and Delta). Since Spring 2022 and the third year of the pandemic, with the advent of Omicron and its sublineages, convergent evolution has led to the observation of different lineages acquiring an additional group of mutations at different amino acid residues, namely R346, K444, N450, N460, F486, F490, Q493, and S494. Mutations at these residues have become increasingly prevalent during Summer and Autumn 2022, with combinations showing increased fitness. The most likely reason for this convergence is the selective pressure exerted by previous infection- or vaccine-elicited immunity. Such accelerated evolution has caused failure of all anti-Spike monoclonal antibodies, including bebtelovimab and cilgavimab. While we are learning how fast coronaviruses can mutate and recombine, we should reconsider opportunities for economically sustainable escape-proof combination therapies, and refocus antibody-mediated therapeutic efforts on polyclonal preparations that are less likely to allow for viral immune escape.
ABSTRACT
ObjectivesRecent 2022 SARS-CoV-2 Omicron variants, have acquired resistance to most neutralizing anti-Spike monoclonal antibodies authorized, and the BQ.1.* sublineages are notably resistant to all authorized monoclonal antibodies. Polyclonal antibodies from individuals both vaccinated and recently recovered from Omicron COVID-19 (VaxCCP) could retain new Omicron neutralizing activity. MethodsHere we reviewed BQ.1.* virus neutralization data from 920 individual patient samples from 43 separate cohorts defined by boosted vaccinations with or without recent Omicron COVID-19, as well as infection without vaccination. ResultsMore than 90% of the plasma samples from individuals in the recently (within 6 months) boosted VaxCCP study cohorts neutralized BQ.1.1, and BF.7 with 100% neutralization of WA-1, BA.4/5, BA.4.6 and BA.2.75. The geometric mean of the geometric mean 50% neutralizing titers (GM (GMT50) were 314, 78 and 204 for BQ.1.1, XBB.1 and BF.7, respectively. Compared to VaxCCP, plasma sampled from COVID-19 naive subjects who also recently within 6 months received at least a third vaccine dose had about half of the GM (GMT50) for all viral variants. ConclusionsBoosted VaxCCP characterized by either recent vaccine dose or infection event within 6 months represents a robust, variant-resilient, passive immunotherapy against the new Omicron BQ.1.1, XBB.1 and BF.7 variants.
ABSTRACT
Immunosuppressed patients have increased risk for morbidity and mortality from COVID-19 because they less frequently mount antibody responses to vaccines and often cannot tolerate small-molecule antivirals. The Omicron variant of concern of SARS-CoV-2 has progressively defeated anti-Spike mAbs authorized so far, paving the way to a return to COVID-19 convalescent plasma (CCP) therapy. In this systematic review we performed a metanalysis of 9 controlled studies (totaling 535 treated patients and 1365 controls and including 4 randomized controlled trials), an individual patient data analysis of 125 case reports/series (totaling 265 patients), and a descriptive analysis of 13 uncontrolled large case series without individual patient data available (totaling 358 patients). The metanalysis of controlled studies showed a risk ratio for mortality of 0.65 (risk difference -0.11) in treatment with CCP versus standard of care for immunosuppressed COVID-19 patients. On the basis of this evidence, we encourage initiation of high-titer CCP from vaccinees( hybrid plasma) in immunocompromised patients.
ABSTRACT
During pandemics, out-of-hospital treatments reduce the health system burden. Controversies persist regarding the best treatment options for COVID-19 outpatients at risk for hospitalization. We assembled data from 47 randomized controlled trials investigating 51 distinct interventions in more than 60,000 outpatients until October 2022 with the endpoint of hospitalization. These trials, largely performed in unvaccinated cohorts during pre-Omicron waves, mostly targeted populations with at least one risk factor for COVID-19 hospitalization. Grouping by class, the COVID-19 convalescent plasma (CCP) (OR=0.69 [95% CI=0.53 to 0.9]), anti-Spike monoclonal antibodies (OR=0.32 [95% CI=0.24-0.42]) and small molecule antivirals (OR=0.57 [95% CI=0.3-1.09]) each had comparable efficacy for hospital relative risk reduction dependent on intervention dose and timing. Repurposed drugs had lower efficacy. The recent Omicron sublineages (XBB and BQ.1.1) in vitro resistance to monoclonal antibodies suggests a pressing need to reevaluate CCP recommendations for COVID-19 outpatients at risk for hospitalization, especially in constrained medical resource settings.
ABSTRACT
The latest SARS-CoV-2 variant of concern Omicron, with its immune escape from therapeutic anti-Spike monoclonal antibodies and WA-1 vaccine-elicited sera, demonstrates the continued relevance of COVID- 19 convalescent plasma (CCP) therapies. Lessons learnt from previous usage of CCP suggests focusing on early outpatients and immunocompromised recipients, with high neutralizing antibody (nAb) titer units. In this analysis we systematically reviewed Omicron-neutralizing plasma activity data, and found that approximately 47% (424/902) of CCP from unvaccinated pre-Omicron donors neutralizes Omicron BA.1 with a very low geomean of geometric mean titers for 50% neutralization GM(GMT50) of about 13, representing a more than 20-fold reduction from WA-1 neutralization. Two doses of mRNA vaccines in nonconvalescent subjects had a similar 50% percent neutralization with Omicron BA.1 neutralization GM(GMT(50)) of about 27. However, plasma from vaccinees recovered from either previous pre-Omicron variants of concern infection, Omicron BA.1 infection, or third-dose uninfected vaccinees was nearly 100% neutralizing against Omicron BA.1, BA.2 and BA.4/5 with GM(GMT(50)) all over 189, 10 times higher than pre-Omicron CCP. Fully vaccinated and post-BA.1 plasma (Vax-CCP) had GM(GMT50) over 450 for BA.4/5 and over 1500 for BA.1 and BA.2. These findings have implications for both CCP stocks collected in prior pandemic periods and plans to restart CCP collections. Thus, Vax-CCP provides an effective tool to combat ongoing variants that defeat therapeutic monoclonal antibodies.
ABSTRACT
Accelerated SARS-CoV-2 evolution under selective pressure by massive deployment of neutralizing antibody-based therapeutics is a concern with potentially severe implications for public health. We review here reports of documented immune escape after treatment with monoclonal antibodies and COVID19 convalescent plasma (CCP). While the former is mainly associated with specific single amino acid mutations at residues within the receptor-binding domain (e.g., E484K/Q, Q493R, and S494P), the few cases of immune evasion after CCP were associated with recurrent deletions within the N-terminal domain of Spike protein (e.g, {Delta}HV69-70, {Delta}LGVY141-144 and {Delta}AL243-244). Continuous genomic monitoring of non-responders is needed to better understand immune escape frequencies and fitness of emerging variants.
ABSTRACT
Convalescent plasma (CP) recurs as a frontline treatment in epidemics because it is available as soon as there are survivors. The COVID-19 pandemic represented the first large-scale opportunity to shed light into mechanisms of action, safety and efficacy of CP using modern evidence-based medicine approaches. Studies ranging from observational case series to randomized controlled trials (RCT) have reported highly variable efficacy results for COVID-19 CP (CCP), resulting in uncertainty. Reasons for CCP success and failure may be hidden in study details, which are usually difficult to explain to physicians and the public but provide fertile ground for designing next-generation studies. We analyzed variables associated with efficacy such as clinical settings, disease severity, CCP SARS-CoV-2 antibody levels and function, dose, timing of administration (variously defined as time from onset of symptoms, molecular diagnosis, diagnosis of pneumonia, or hospitalization, or by serostatus), outcomes (defined as hospitalization, requirement for ventilation, clinical improvement or mortality), CCP provenance and time for collection, and criteria for efficacy. Focusing only on the results from the 30 available RCTs we noted that these were more likely to show signals of efficacy, including reductions in mortality, if the plasma neutralizing titer was [≥] 160 and the time to randomization was [≤] 9 days, consistent with passive antibody therapy efficacy requiring dosing with sufficient antibody. The fact that most studies revealed signals of efficacy despite variability in CCP and its use suggest likely therapeutic effects that become apparent despite the data noise. Despite the recent WHO guidelines discouraging CCP usage, the Omicron variant of concern is reminding us the superiority of polyclonal antibody therapies over monoclonal antibodies, and CCP from vaccinated convalescents is likely to be evaluated soon
