ABSTRACT
Background: Vaccines can be less immunogenic in people living with HIV (PLWH). So far, the immune response after SARS-CoV-2 vaccination of PLWH is not well-established. Methods: A prospective cohort study in 22 HIV treatment centres in the Netherlands examined the immunogenicity of SARS-CoV-2 vaccines in PLWH. Included were adult PLWH without prior COVID-19 infection, invited by the national vaccination programme to receive the BNT162b2, mRNA-1273, ChAdOx1-S or Ad26.COV2.S vaccine. Data from HIV-negative healthy controls were acquired from 2 concurrent prospective vaccination trials. The primary endpoint was the anti-SARS-CoV-2 IgG response (Liaison Trimeric Spike IgG in BAU/ml) measured 4-6 weeks after vaccination with one of the 2 mRNA vaccines in PLWH versus controls. Secondary endpoints included antibody response according to sex, CD4+ T-cell count, and vaccine reactogenicity. Results: Between February 14th and September 7th 2021, 1269 PLWH were enrolled and complete results were available for 1148 PLWH as well as for 440 healthy controls. 879 of the PLWH were vaccinated with BNT162b2 while 100, 150 and 19 had received mRNA-1273, ChAdOx1-S and 19 Ad26.COV2.S respectively. Their median age was 53 years [IQR 44-60], 85.5% was male, the median CD4+ T-cell count was 710/μ L [IQR 520-913]. 99% was on cART with HIV-RNA <50 copies/ml in 97.7%. The control group consisted of 440 healthy people;247 vaccinated with mRNA-1273, 94 with BNT162b2, 26 with ChAdOx1-S and 73 with Ad26.COV2.S. Their median age was 43 [IQR 33-53] and 28.6% was male. PLWH had a significantly lower anti-SARS-CoV-2 RBD IgG response compared to controls (mean value of 2171 BAU/mL (95% CI 1888-2453) versus 3586 BAU/ml (95% CI 3250-3922, p<0.001)). In the multivariable analysis, being HIV positive, age >65 years, being male and having received a non-mRNA vaccination were all independently associated with a lower antibody concentration (p<0.01 for all). In the PLWH vaccinated with BNT162b2 or mRNA-1273, mean antibody levels were significantly lower in those with a CD4+ T-cell counts <250/μ L (1617 BAU/mL, 95% CI 828-2407) compared to CD4 ≥250/μ L (2486 BAU/ml 95% CI 2149-2824, p=0.002). Reactogenicity occurred in 55 and 50% after the first and second vaccination respectively and were generally mild without vaccine-related SAE. Conclusion: After vaccination with BNT162b2 or mRNA-1273, Anti-Spike IgG levels were lower in PLWH compared to healthy controls. In PLWH, a CD4+ T cell count <250/μ L was associated with lower antibody concentration.
ABSTRACT
Background: Trials on convalescent plasma (CP) for hospitalized patients with COVID-19 have not demonstrated clear benefits. However, data on outpatients with early symptoms are limited. We studied if treatment with CP reduces disease burden of outpatients treated in the first 7 days of symptoms. Methods: Two double blind randomized trials (NCT04621123, NCT04589949) were merged. Pooling of data started when <20% of their predefined sample size had been recruited. A Bayesian adaptive individual patient data meta-analysis was implemented. Analyses were done with Bayesian proportional odds and logistic models, where odds ratios(OR)<1.0 indicate a favorable outcome for CP. A DSMB monitored the accumulating data for efficacy. Patients aged ≥50, diagnosed with COVID-19 and symptomatic for ≤7days were eligible for participation. The intervention was one unit (200-300mL) of CP with a predefined minimum level of antibodies. The two primary endpoints were (a) a 5-point disease severity scale (fully recovered by day 7 or not, hospital or ICU admission and death) and (b) a composite of hospitalization or death. Secondary endpoints were efficacy in patients with ≤5days of symptoms and time to full symptom resolution. Results: Of 797 patients included, 390 received CP and 392 placebo. They had a median age of 58, 1 comorbidity, symptoms for 5 days and 93% tested negative for SARS-CoV-2 S-protein IgG antibodies. 74 patients were hospitalized, 6 required mechanical ventilation and 3 died. The OR of CP for an improved disease severity scale was 0.936 (credible interval (CI) 0.667-1.311). The OR for hospitalization or death was 0.919 (CI 0.592-1.416). The effect of CP on hospital admission or death was largest in patients with ≤5days of symptoms (OR 0.658, 95% CI 0.394-1.085). CP did not decrease the time to full symptom resolution (p=0.62). Conclusion: Treatment with CP of outpatients in the first 7 days of symptoms did not improve outcome of COVID-19. The possible beneficial effect in patients with ≤5days of symptoms requires further study.
ABSTRACT
Background: Convalescent plasma could be an inexpensive and widely available drug for COVID-19 patients. Reports on its effectiveness are inconclusive. We collected convalescent plasma with high titers of neutralizing anti-SARS-CoV-2 antibodies effectively blocking SARS-CoV-2 infection and assessed their clinical and viro-immunological responses in COVID-19 patients with severe disease. Methods: In a multicentre open-label randomized clinical trial in 14 secondary and academic hospitals in the Netherlands, included patients were admitted for COVID-19 with SARS-CoV-2 detected by PCR and not on mechanical ventilation for >96hours. Convalescent plasma donors were selected based on SARS-CoV-2 plaque reduction neutralization test (PRNT50) result of ≥1:80. Primary outcome was day 60 mortality. Secondary outcomes were disease severity, inflammatory and virological markers. Results: Included patients were 72% male, median 63 years (IQR 56-74) and with median 10 days of symptoms (IQR 6-15) at inclusion when they were randomized to convalescent plasma or standard of care. We found no significant difference in mortality at day 60 by using 300mL of convalescent plasma (median PRNT50 1:640) between the arms after adjustment (OR: 0.95, 95%CI: 0.20-4.67). Improvements in WHO COVID-19 disease severity scores at day 15 (OR: 1.30, 95%CI 0.52-3.32) and time to discharge (HR: 0.88, 95%CI: 0.49-1.60) were also comparable. The vast majority of patients already had potent neutralizing anti-SARS-CoV-2 antibodies at hospital admission and at comparable titers as the carefully selected plasma donors. No effect of convalescent plasma on viral clearance in the respiratory tract, anti- SARS-CoV-2 antibody development or changes in serum pro-inflammatory cytokine levels were observed. After the inclusion of 86 patients and per DSMB recommendation, we decided to interrupt the study for futility. Conclusion: Convalescent plasma treatment in this patient group did not improve survival or disease course, nor did it alter relevant virological and immunological parameters. Together, these data indicate that the variable effectivity observed in trials on convalescent plasma for COVID-19 may be explained by the timing of treatment and varying levels of preexisting anti-SARS-CoV-2 immunity in patients. It also substantiates that convalescent plasma should be studied as early as possible in the disease course or at least preceding the start of an autologous humoral response. (Clinicaltrials.gov: NCT04342182).