ABSTRACT
ImportanceWaning immunity against COVID-19 in parallel with an increased incidence during the Omicron outbreak led the Israeli Ministry of Health to recommend a second booster dose of BNT162b2 (Pfizer) to high-risk individuals. Israel was the first country to recommend this, allowing evaluation of the added protection of a fourth vaccine dose to hospitalized patients with severe diseases. ObjectiveTo assess the effect of a fourth dose for hospitalized patients with severe/critical breakthrough COVID-19. DesignA cohort study of hospitalized adults from 01/15/2022-01/31/2022. SettingsA multi-center study of 14 medical centers in Israel. ParticipantsHospitalized adult patients with PCR-confirmed severe/critical COVID-19. Excluded were patients lacking data on vaccination status. ExposureCases were divided according to the total number of vaccine doses received up to 7 days before diagnosis. Unvaccinated adults and single-dose recipients were grouped into an unvaccinated group. Main OutcomeA composite of mechanical-ventilation or in-hospital death was defined as poor outcome. Outcomes were compared between 3- and 4-dose vaccinees. ResultsIncluded were 1,049 patients with severe/critical COVID-19, median age 80 (IQR 69-87), 51% males. Among them, 360 unvaccinated, 34, 172, 386 and 88 were after 1, 2, 3 or 4 doses, respectively. Patients after 3 doses were older, had more males and immunosuppression, but with similar outcomes, 49% vs. 51% compared to unvaccinated patients (p=0.72). Patients after 4 doses were similarly older and immunosuppressed, but had improved outcomes compared to unvaccinated patients, 34% vs. 51% (p<0.01). We proceeded to examine independent predictors for poor outcome in fully-vaccinated patients with either 3 doses given a median of 161 (IQR 147-168) days earlier, or 4 doses given a median of 14 (IQR 10-18) days before diagnoses. Receipt of the fourth dose conferred significant protection: OR 0.51 (95%CI 0.30.87). Conclusion and RelevanceWithin a population of hospitalized patients with severe/critical breakthrough COVID-19, a recent fourth dose was associated with significant protection against mechanical ventilation or death, compared to fully vaccinated single-boosted individuals. Key pointsO_ST_ABSQuestionC_ST_ABSWhat is the benefit of a fourth vaccine dose (second booster) for hospitalized patients with severe COVID-19? FindingsIn this multicenter cohort study in Israel during the Omicron wave, hospitalized severe COVID-19 patients that received a recent fourth dose had a 49% lower odds for a poor outcome (mechanical ventilation or death) compared with those who received 3 doses approximately 5 months before diagnosis, a significant difference. MeaningA vaccine booster given at the onset of a COVID-19 wave can benefit vulnerable individuals.
ABSTRACT
A wide range of SARS-CoV-2 neutralizing monoclonal antibodies (mAbs) were reported to date, most of which target the spike glycoprotein and in particular its receptor binding domain (RBD) and N-terminal domain (NTD) of the S1 subunit. The therapeutic implementation of these antibodies has been recently challenged by emerging SARS-CoV-2 variants that harbor extensively mutated spike versions. Consequently, the re-assessment of mAbs, previously reported to neutralize the original early-version of the virus, is of high priority. Four previously selected mAbs targeting non-overlapping epitopes, were evaluated for their binding potency to RBD versions harboring individual mutations at spike positions 417, 439, 453, 477, 484 and 501. Mutations at these positions represent the prevailing worldwide distributed modifications of the RBD, previously reported to mediate escape from antibody neutralization. Additionally, the in vitro neutralization potencies of the four RBD-specific mAbs, as well as two NTD-specific mAbs, were evaluated against two frequent SARS-CoV-2 variants of concern (VOCs): (i) the B.1.1.7 variant, emerged in the UK and (ii) the B.1.351 variant, emerged in South Africa. Variant B.1.351 was previously suggested to escape many therapeutic mAbs, including those authorized for clinical use. The possible impact of RBD mutations on recognition by mAbs is addressed by comparative structural modelling. Finally, we demonstrate the therapeutic potential of three selected mAbs by treatment of K18-hACE2 transgenic mice two days post infection with each of the virus strains. Our results clearly indicate that despite the accumulation of spike mutations, some neutralizing mAbs preserve their potency against SARS-CoV-2. In particular, the highly potent MD65 and BL6 mAbs are shown to retain their ability to bind the prevalent novel viral mutations and to effectively protect against B.1.1.7 and B.1.351 variants of high clinical concern.
ABSTRACT
The interactions between antibodies, SARS-CoV-2 and immune cells contribute to the pathogenesis of COVID-19 and protective immunity. To understand the differences between antibody responses in mild versus severe cases of COVID-19, we analyzed the B cell responses in patients 1.5 months post SARS-CoV-2 infection. Severe and not mild infection correlated with high titers of IgG against Spike receptor binding domain (RBD) that were capable of viral inhibition. B cell receptor (BCR) sequencing revealed two VH genes, VH3-38 and VH3-53, that were enriched during severe infection. Of the 22 antibodies cloned from two severe donors, six exhibited potent neutralization against live SARS-CoV-2, and inhibited syncytia formation. Using peptide libraries, competition ELISA and RBD mutagenesis, we mapped the epitopes of the neutralizing antibodies (nAbs) to three different sites on the Spike. Finally, we used combinations of nAbs targeting different immune-sites to efficiently block SARS-CoV-2 infection. Analysis of 49 healthy BCR repertoires revealed that the nAbs germline VHJH precursors comprise up to 2.7% of all VHJHs. We demonstrate that severe COVID-19 is associated with unique BCR signatures and multi-clonal neutralizing responses that are relatively frequent in the population. Moreover, our data support the use of combination antibody therapy to prevent and treat COVID-19.