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Summary BackgroundBivalent mRNA-based COVID-19 vaccines encoding the ancestral and Omicron spike protein were developed as a countermeasure against antigenically distinct SARS-CoV-2 variants. We compared the (variant-specific) immunogenicity and reactogenicity of mRNA-based bivalent Omicron BA.1 vaccines in individuals who were primed with adenovirus- or mRNA-based vaccines. MethodsIn this open-label, multicenter, randomized, controlled trial, healthcare workers primed with Ad26.COV2.S or mRNA-based vaccines were boosted with mRNA-1273.214 or BNT162b2 OMI BA.1. The primary endpoint was the fold change in S1-specific IgG antibodies pre- and 28 days after booster vaccination. Secondary outcomes were fast response, (antibody levels on day 7), reactogenicity, neutralization of circulating variants and (cross-reactive) SARS-CoV-2-specific T-cell responses. FindingsNo effect of different priming regimens was observed on bivalent vaccination boosted S1-specific IgG antibodies. The largest increase in S1-specific IgG antibodies occurred between day 0 and 7 after bivalent booster. Neutralizing antibodies targeting the variants in the bivalent vaccine (ancestral SARS-CoV-2 and Omicron BA.1) were boosted. In addition, neutralizing antibodies against the circulating Omicron BA.5 variant increased after BA.1 bivalent booster. T-cell responses were boosted and retained reactivity with variants from the Omicron sub-lineage. InterpretationBivalent booster vaccination with mRNA-1273.214 or BNT162b2 OMI BA.1 resulted in a rapid recall of humoral and cellular immune responses independent of the initial priming regimen. Although no preferential boosting of variant-specific responses was observed, the induced antibodies and T-cells cross-reacted with Omicron BA.1 and BA.5. It remains crucial to monitor immunity at the population level, and simultaneously antigenic drift at the virus level, to determine the necessity (and timing) of COVID-19 booster vaccinations. FundingThe Netherlands Organization for Health Research and Development (ZonMw) grant agreement 10430072110001. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSVaccination against coronavirus disease-2019 (COVID-19) initially provided high levels of protection from both infection and severe disease. However, the emergence of antigenically distinct variants resulted in frequent breakthrough infections, especially with the emergence of variants from the Omicron sub-lineages. The frequent mutations in the Spike protein, and specifically the receptor binding domain (RBD), resulted in the recommendation by the WHO advisory group to update vaccines with novel antigens. Bivalent mRNA-based vaccines, encoding the Spike protein from both the ancestral SARS-CoV-2 and Omicron BA.1 (and later on BA.5) were subsequently introduced. Initial small comparative studies have been released on the evaluation of these bivalent vaccines, but it is essential is to evaluate the immunogenicity and reactogenicity of the vaccines against the background of different priming regimens. Added value of this studyThe SWITCH ON trial evaluated the bivalent booster vaccines BNT162b2 OMI BA.1 and mRNA-1273.214 vaccine in a cohort of Dutch healthcare workers. Study participants were primed with either Ad26.COV2.S, mRNA-1273, or BNT162b2. The study investigated three important topics: (1) immunogenicity of Omicron BA.1 bivalent vaccines after Ad26.COV2.S- or mRNA-based vaccine priming, (2) rapid immunological recall responses, indicative of preserved humoral and cellular immunological memory, and (3) cross-reactivity with relevant variants after booster vaccination. Implication of all the available evidenceVaccination with the bivalent booster mRNA-1273.214 or BNT162b2 OMI BA.1 resulted in a rapid recall of humoral and cellular immune responses independent of the initial priming regimen. The largest fraction of (neutralizing) antibodies and virus-specific T-cells was recalled within 7 days post booster vaccination. Although no preferential boosting of variant-specific responses was observed, the induced antibodies and T-cells cross-reacted with Omicron BA.1, which was included in the vaccine, but also the more antigenically distinct BA.5. It remains crucial to monitor immunity at the population level, and simultaneously antigenic drift at the virus level, to determine the necessity (and timing) of COVID-19 booster vaccinations.
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BackgroundThe 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. MethodsConsenting hyporesponders received an additional 100 {micro}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. ResultsOf 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). ConclusionAn 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.
ABSTRACT
A large proportion of the global population received a single dose of the Ad26.COV2.S coronavirus disease-2019 (COVID-19) vaccine as priming vaccination, which was shown to provide protection against moderate to severe COVID-19. However, the emergence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants that harbor immune-evasive mutations in the spike protein led to the recommendation of booster vaccinations after Ad26.COV2.S priming. Recent studies showed that heterologous booster vaccination with an mRNA-based vaccine following Ad26.COV2.S priming leads to high antibody levels. However, how heterologous booster vaccination affects other functional aspects of the immune response remains unknown. Here, we performed immunological profiling on samples obtained from Ad26.COV2.S-vaccinated individuals before and after a homologous (Ad26.COV2.S) or heterologous (mRNA-1273 or BNT162b2) booster vaccination. Both homologous and heterologous booster vaccination increased antibodies with multiple functionalities towards ancestral SARS-CoV-2, the Delta and Omicron BA.1 variants. Especially, mRNA-based booster vaccination induced high levels of neutralizing antibodies and antibodies with various Fc-mediated effector functions such as antibody-dependent cellular cytotoxicity and phagocytosis. In contrast, T cell responses were similar in magnitude following homologous or heterologous booster vaccination, and retained functionality towards Delta and Omicron BA.1. However, only heterologous booster vaccination with an mRNA-based vaccine led to the expansion of SARS-CoV-2-specific T cell clones, without an increase in the breadth of the T cell repertoire as assessed by T cell receptor sequencing. In conclusion, we show that Ad26.COV2.S priming vaccination provides a solid immunological base for heterologous boosting with an mRNA-based COVID-19 vaccine, increasing humoral and cellular responses targeting newly emerging variants of concern. One sentence summaryAd26.COV2.S priming provides a solid immunological base for extension of cellular and humoral immune responses following an mRNA-based booster.
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BackgroundSeverely immunocompromised patients are at risk for severe COVID-19. Benefit from convalescent plasma in these patients is suggested but data from randomised trials are lacking. The aim of this study is to determine efficacy of SARS-CoV-2 hyperimmune globulin ("COVIG") in treatment of severely immunocompromised, hospitalised COVID-19 patients. MethodsIn this randomised, controlled, double-blind, multicentre, phase 3 trial, severely immunocompromised patients who were hospitalised with symptomatic COVID-19 were randomly assigned (1:1) to receive 15 grams of COVIG or 15 grams of intravenous immunoglobulin without SARS-CoV-2 antibodies (IVIG, control). Patients included were solid organ transplant patients with three drugs from different immunosuppressive classes or patient with disease or treatment severely affecting B-cell function. Patients that required mechanical ventilation or high flow nasal oxygen were excluded. All investigators, research staff, and participants were masked to group allocation. The primary endpoint was occurrence of severe COVID-19 evaluated up until day 28 after treatment, defined as the need for mechanical ventilation, high-flow nasal oxygen, readmission for COVID-19 after hospital discharge or lack of clinical improvement on day seven or later. This trial is registered with Netherlands Trial Register (NL9436). FindingsFrom April, 2021, to July, 2021, 18 participants were enrolled at three sites in the Netherlands; 18 patients were analysed. Recruitment was halted prematurely when casirivimab/imdevimab became the recommended therapy in the Dutch COVID-19 treatment guideline for seronegative, hospitalised COVID-19 patients. Median age was 58 years and all but two were negative for SARS-CoV-2 spike IgG at baseline. Severe COVID-19 was observed in two out of ten (20%) patients treated with COVIG compared to seven of eight (88%) in the IVIG control group (p = 0{middle dot}015, Fishers exact test). InterpretationCOVIG reduced the incidence of severe COVID-19 in severely immunocompromised patients, hospitalised with COVID-19. COVIG may be a valuable treatment in this patient group and can be used when no monoclonal antibody therapies are available. FundingThe Netherlands Organisation for Health Research and Development, Sanquin Blood Supply Foundation.
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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.
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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.
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BackgroundSARS-CoV-2 vaccines are highly effective at preventing COVID-19-related morbidity and mortality. As no vaccine is 100% effective, breakthrough infections are expected to occur. MethodsWe analyzed the virological characteristics of 161 vaccine breakthrough infections in a population of 24,706 vaccinated healthcare workers (HCWs), using RT-PCR and virus culture. ResultsThe delta variant (B.1.617.2) was identified in the majority of cases. Despite similar Ct-values, we demonstrate lower probability of infectious virus detection in respiratory samples of vaccinated HCWs with breakthrough infections compared to unvaccinated HCWs with primary SARS-CoV-2 infections. Nevertheless, infectious virus was found in 68.6% of breakthrough infections and Ct-values decreased throughout the first 3 days of illness. ConclusionsWe conclude that rare vaccine breakthrough infections occur, but infectious virus shedding is reduced in these cases.
