Dosing of convalescent plasma and hyperimmune anti-SARS-CoV-2 1 immunoglobulins: a phase I/II dose finding study (preprint)

Background: During the COVID-19 pandemic, trials on convalescent plasma (ConvP) were performed without preceding dose-finding studies. This study aimed to assess potential protective dosing regimens by constructing a population pharmacokinetic (popPK) model describing neutralizing antibody (Nab) titers following the administration of ConvP or hyperimmune globulins(COVIg). Methods: Immunocompromised patients, testing negative for anti-SARS-CoV-2 spike antibodies despite vaccination received a range of anti-SARS-CoV-2 antibodies in the form of COVIg or ConvP infusion. The popPK analysis was performed using NONMEM v7.4. Monte Carlo simulations were performed to assess potential COVIg and ConvP dosing regimens for prevention of COVID-19. Results: 44 patients were enrolled, and data from 42 were used for constructing the popPK model. A two-compartment elimination model with mixed residual error best described the Nab-titers after administration. Inter individual variation was associated to CL (44.3%), V1 (27.3%), and V2 (29.2%). Lean body weight and type of treatment (ConvP/COVIg) were associated with V1 and V2, respectively. Median elimination half-life was 20 days (interquartile-range: 17-25 days). Simulations demonstrated that even monthly infusions of 600ml of the ConvP or COVIg used in this trial would not achieve potentially protective serum antibody levels for >90% of the time. However, as a result of hybrid immunity and/or repeated vaccination plasma donors with extremely high Nab-titers are now readily available, and a >90% target attainment should be possible. Conclusion: The results of this study may inform future intervention studies on the prophylactic and therapeutic use of antiviral antibodies in the form of ConvP or COVIg.

Immunogenicity of an additional mRNA-1273 SARS-CoV-2 vaccination in people living with HIV with hyporesponse after primary vaccination (preprint)

Background The COVIH study is a prospective SARS-CoV-2 vaccination study in people living with HIV (PLWH). Of the 1154 PLWH enrolled, 14% showed a reduced or absent antibody response after a primary vaccination regimen. As the response to an additional vaccination in PLWH with hyporesponse is unknown, we evaluated whether an additional vaccination boosts immune responses in these hyporesponders. Methods Consenting hyporesponders received an additional 100 g of mRNA-1273. Hyporesponse was defined as [≤]300 spike(S)-specific binding antibody units [BAU]/mL. The primary endpoint was the increase in antibodies 28 days after the additional vaccination. Secondary endpoints were the correlation between patient characteristics and antibody response, levels of neutralizing antibodies, S-specific T-cell and B-cell responses, and reactogenicity. Results Of the 75 PLWH enrolled, five were excluded as their antibody level had increased to >300 BAU/mL at baseline, two for a SARS-CoV-2 infection before the primary endpoint evaluation and two were lost to follow-up. Of the 66 remaining participants, 40 previously received ChAdOx1-S, 22 BNT162b2, and four Ad26.COV2.S. The median age was 63[IQR:60-66], 86% were male, pre-vaccination and nadir CD4+ T-cell counts were 650/L[IQR:423-941] and 230/L[IQR:145-345] and 96% had HIV-RNA <50 copies/mL. The mean antibody level before the additional vaccination was 35 BAU/mL (SEM 5.4) and 45/66 (68%) were antibody negative. After the additional mRNA-1273 vaccination, antibodies were >300 BAU/mL in 64/66 (97%) with a mean increase of 4282 BAU/mL (95%CI:3241-5323). No patient characteristics correlated with the magnitude of the antibody response, nor did the primary vaccination regimen. The additional vaccination significantly increased the proportion of participants with detectable ancestral S-specific B-cells (p=0.016) and CD4+ T-cells (p=0.037). Conclusion An additional mRNA-1273 vaccination induced a robust serological response in 97% of the PLWH with a hyporesponse after a primary vaccination regimen. This response was observed regardless of the primary vaccination regimen or patient characteristics.

Clinical characteristics and outcome of immunocompromised patients with COVID-19 caused by the Omicron variant: a prospective observational study (preprint)

Summary Background In the general population, illness after infection with the SARS-CoV-2 Omicron variant is less severe compared with previous variants. Data on the disease burden of Omicron in immunocompromised patients are lacking. We investigated the clinical characteristics and outcome of a cohort of immunocompromised patients with COVID-19 caused by Omicron. Methods Solid organ transplant recipients, patients on anti-CD20 therapy, and allogenic hematopoietic stem cell transplantation recipients on immunosuppressive therapy infected with the Omicron variant, were included. Patients were contacted regularly until symptom resolution. Clinical characteristics of consenting patients were collected through their electronic patient files. To identify possible risk factors for hospitalization, a univariate logistic analysis was performed. Findings A total of 114 consecutive immunocompromised patients(88% after a solid organ transplant) were enrolled. Eighty-nine percent had previously received three mRNA vaccinations. While only one patient died, 23(20%) required hospital admission for a median of 11 days. A low SARS-CoV-2 IgG antibody response(<300 BAU/mL) at diagnosis, higher age, being a lung transplant recipient, more comorbidities and a higher frailty were associated with hospital admission(all p<0.01). At the end of follow-up, 25% had still not fully recovered. Of the 23 hospitalized patients, 70% had a negative and 92% a low IgG (<300 BAU/mL) antibody response at admission. Sotrovimab was administered to 17 of them, of which one died. Interpretation While the mortality in immunocompromised patients infected with Omicron was low, hospital admission was frequent and the duration of symptoms often prolonged. Besides vaccination, other interventions are needed to limit the morbidity from COVID-19 in immunocompromised patients. Funding None.

Immunogenicity and reactogenicity of SARS-CoV-2 vaccines in people living with HIV: a nationwide prospective cohort study in the Netherlands (preprint)

BackgroundVaccines can be less immunogenic in people living with HIV (PLWH), but for SARS-CoV-2 vaccinations this is unknown. Methods and FindingsA prospective cohort study to examine the immunogenicity of BNT162b2, mRNA-1273, ChAdOx1-S and Ad26.COV2.S vaccines in adult PLWH, without prior COVID-19, compared to HIV-negative controls. The primary endpoint was the anti-spike SARS-CoV-2 IgG response after mRNA vaccination. Secondary endpoints included the serological response after vector vaccination, anti-SARS-CoV-2 T-cell response and reactogenicity. Between February-September 2021, 1154 PLWH (median age 53 [IQR 44-60], 86% male) and 440 controls (median age 43 [IQR 33-53], 29% male) were included. 884 PLWH received BNT162b2, 100 mRNA-1273, 150 ChAdOx1-S, and 20 Ad26.COV2.S. 99% were on antiretroviral therapy, 98% virally suppressed, and the median CD4+T-cell count was 710 cells/{micro}L [IQR 520-913]. 247 controls received mRNA-1273, 94 BNT162b2, 26 ChAdOx1-S and 73 Ad26.COV2.S. After mRNA vaccination, geometric mean concentration was 1418 BAU/mL in PLWH (95%CI 1322-1523), and after adjustment for age, sex, and vaccine type, HIV-status remained associated with a decreased response (0.607, 95%CI 0.508-0.725). In PLWH vaccinated with mRNA-based vaccines, higher antibody responses were predicted by CD4+T-cell counts 250-500 cells/{micro}L (2.845, 95%CI 1.876-4.314) or >500 cells/{micro}L (2.936, 95%CI 1.961-4.394), whilst a viral load >50 copies/mL was associated with a reduced response (0.454, 95%CI 0.286-0.720). Increased IFN-{gamma}, CD4+, and CD8+T-cell responses were observed after stimulation with SARS-CoV-2 spike peptides in ELISpot and activation induced marker assays, comparable to controls. Reactogenicity was generally mild without vaccine-related SAE. ConclusionAfter vaccination with BNT162b2 or mRNA-1273, anti-spike SARS-CoV-2 antibody levels were reduced in PLWH. To reach and maintain the same serological responses and vaccine efficacy as HIV-negative controls, additional vaccinations are probably required.

Divergent SARS CoV-2 Omicron-specific T- and B-cell responses in COVID-19 vaccine recipients (preprint)

The severe acute respiratory distress syndrome coronavirus-2 (SARS-CoV-2) Omicron variant (B.1.1.529) is spreading rapidly, even in vaccinated individuals, raising concerns about immune escape. Here, we studied neutralizing antibodies and T-cell responses to SARS-CoV-2 D614G (wildtype, WT), and the B.1.351 (Beta), B.1.617.2 (Delta), and B.1.1.529 (Omicron) variants of concern (VOC) in a cohort of 60 health care workers (HCW) after immunization with ChAdOx-1 S, Ad26.COV2.S, mRNA-1273 or BNT162b2. High binding antibody levels against WT SARS-CoV-2 spike (S) were detected 28 days after vaccination with both mRNA vaccines (mRNA-1273 or BNT162b2), which significantly decreased after 6 months. In contrast, antibody levels were lower after Ad26.COV2.S vaccination but did not wane. Neutralization assays with authentic virus showed consistent cross-neutralization of the Beta and Delta variants in study participants, but Omicron-specific responses were significantly lower or absent (up to a 34-fold decrease compared to D614G). Notably, BNT162b2 booster vaccination after either two mRNA-1273 immunizations or Ad26.COV.2 priming partially restored neutralization of the Omicron variant, but responses were still up to-17-fold decreased compared to D614G. CD4+ T-cell responses were detected up to 6 months after all vaccination regimens; S-specific T-cell responses were highest after mRNA-1273 vaccination. No significant differences were detected between D614G- and variant-specific T-cell responses, including Omicron, indicating minimal escape at the T-cell level. This study shows that vaccinated individuals retain T-cell immunity to the SARS-CoV-2 Omicron variant, potentially balancing the lack of neutralizing antibodies in preventing or limiting severe COVID-19. Booster vaccinations may be needed to further restore Omicron cross-neutralization by antibodies.

Interferon-α Auto-Antibodies in Convalescent Plasma Therapy for COVID-19 (preprint)

Purpose:  To study the effect of Interferon-α auto-antibodies (IFN-α Abs) on clinical and virological outcomes in critically ill COVID-19 patients and the risk of IFN-α Abs transfer during convalescent plasma treatment. Methods: : Sera from cases of COVID-19 and other respiratory illness were tested for IFN-αAbs by ELISA and bioassay. IFN-α Abslevels were compared between critically, severely and moderately ill groups in both acute and convalescent stages. Longitudinal analyses were performed to determine whether IFN-α Abs levels change after convalescent plasma transfusion. Results: : Critically ill COVID-19 caseshad significantly higher IFN-α Abs detection rate and levels compared tonon-COVID-19 controls.Neutralizing IFN-α Abs levels were found in 1 out of 118plasma donors.Plasma from 2 positive donors was administered to 5 patients, with no subsequent elevation of IFN-α Abs levels in the recipients. Neutralizing levels of IFN-α Abswere associated with delayed viral clearance from the respiratory tract. Conclusions: : IFN-α Abs can be detected by ELISA in critical, severe, moderate and mild COVID-19 cases in both the acute and convalescent stages of disease. The presence of neutralizing IFN-α Abs in critically ill COVID-19 is associated with delayed viral clearance. Levels of IFN-α Abs inCOVID-19 convalescent plasma donorsare likely too low to be clinically relevant to the recipients.

Immunophenotyping and machine learning identify distinct immunotypes that predict COVID-19 clinical severity (preprint)

Quantitative or qualitative differences in immunity may drive and predict clinical severity in COVID-19. We therefore measured modules of serum pro-inflammatory, anti-inflammatory and anti-viral cytokines in combination with the anti-SARS-CoV-2 antibody response in COVID-19 patients admitted to tertiary care. Using machine learning and employing unsupervised hierarchical clustering, agnostic to severity, we identified three distinct immunotypes that were shown post-clustering to predict very different clinical courses such as clinical improvement or clinical deterioration. Immunotypes did not associate chronologically with disease duration but rather reflect variations in the nature and kinetics of individual patient’s immune response. Here we demonstrate that immunophenotyping can stratify patients to high and low risk clinical subtypes, with distinct cytokine and antibody profiles, that can predict severity progression and guide personalized therapy.