Evaluation of bivalent Omicron BA.1 booster vaccination after different priming regimens in healthcare workers (SWITCH ON): a randomized controlled trial (preprint)

Background Bivalent 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. Methods In 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. Findings No 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. Interpretation Bivalent 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.

Ad26.COV2.S priming provides a solid immunological base for mRNA-based COVID-19 booster vaccination (preprint)

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.

Immunogenicity and reactogenicity of booster vaccinations after Ad26.COV2.S priming (preprint)

Background In face of the developing COVID-19 pandemic with a need for rapid and practical vaccination strategies, Ad26.COV2.S was approved as single shot immunization regimen. While effective against severe COVID-19, Ad26.COV2.S vaccination induces lower SARS-CoV-2-specific antibody levels compared to its mRNA-based counterparts. To support decision making on the need for booster vaccinations in Ad26.COV2.S-primed individuals, we assessed the immunogenicity and reactogenicity of homologous and heterologous booster vaccinations in Ad26.COV2.S-primed health care workers (HCWs). Methods The SWITCH trial is a single-(participant)-blinded, multi-center, randomized controlled trial among 434 HCWs who received a single Ad26.COV2.S vaccination. HCWs were randomized to no boost, Ad26.COV2.S boost, mRNA-1273 boost, or BNT162b2 boost. We assessed the level of SARS-CoV-2-specific binding antibodies, neutralizing antibodies against infectious virus, SARS-CoV-2-specific T-cell responses, and reactogenicity. Results Homologous and heterologous booster vaccinations resulted in an increase in SARS-CoV-2-specific binding antibodies, neutralizing antibodies and T-cell responses when compared to single Ad26.COV.2.S vaccination. In comparison with the homologous boost, the increase was significantly larger in heterologous regimens with the mRNA-based vaccines. mRNA-1273 boosting was most immunogenic, associated with higher reactogenicity. Only mild to moderate local and systemic reactions were observed on the first two days following booster. Conclusions Boosting of Ad26.COV2.S-primed HCWs was well-tolerated and immunogenic. Strongest responses were detected after boosting with mRNA-based vaccines. Based on our data, efficacy on infection and transmission of boosters is expected. In addition to efficacy, decision making on boost vaccinations should include timing, target population, level of SARS CoV-2 circulation, and the global inequity in vaccine access. Trial registration. Funded by ZonMW (10430072110001); ClinicalTrials.gov number, NCT04927936.

Absence of rapid T cell control corresponds with delayed viral clearance in hospitalised COVID-19 patients (preprint)

SARS-CoV-2 viral load is associated with disease severity. A better understanding of immunological mechanisms involved in viral clearance is crucial to guide new therapeutic strategies. Here, we studied the timing of viral clearance in relation to 122 immune parameters in 150 hospitalized COVID-19 patients. Delayed viral clearance was associated with more severe disease, which occurred after the virus had been cleared in most cases. Paradoxically, delayed viral clearance was associated with over time higher maximum levels of SARS-CoV-2 specific IgG, IgA, and neutralizing antibodies, increased numbers of eosinophils, monocytes, and pro-inflammatory cyto-/chemokines. In contrast, early viral clearance and less critical illness correlated with higher levels of CD4 + and CD8 + T cells. Collectively, our data show that absence of rapid T cell control corresponds with delayed clearance and aberrant antibody and cytokine profiles. Viral clearance often precedes critical illness, which suggests immunopathology as underlying mechanism. These data can guide treatment strategies.

Tolerability, Safety and Immunogenicity of Intradermal Delivery of a Fractional Dose mRNA -1273 SARS-CoV-2 Vaccine in Healthy Adults as a Dose Sparing Strategy (preprint)

Background: There is an urgent need for fair and equitable access to safe and effective vaccines to end the COVID-19 pandemic. Shortages in reagents and vaccines are a major challenge, as well as limited knowledge on dose response relationship with mRNA COVID-19 vaccines. We explored intradermal fractional dose administration of a mRNA SARS-CoV-2/COVID-19 vaccine as a potential dose-sparing strategy. Methods: We conducted a proof-of-concept, dose-escalation, open-label, randomised-controlled vaccine trial (IDSCOVA) in healthy adults aged 18-30 years. To test initial safety, ten participants received 10 µg mRNA-1273 vaccine through intradermal injection at day 1 and 29. Following a favourable safety review, thirty participants were 1:1 randomised to receive 20 µg mRNA-1273 either intradermally or intramuscularly. The primary endpoint was tolerability and safety. The secondary endpoint was seroconversion and specific IgG concentration against SARS-CoV-2 spike S1 and Receptor Binding Domain (RBD) after the second dose at day 43. We compared results to two historical cohorts of non-hospitalised COVID-19 patients and vaccinated individuals. Findings: Thirty-eight of forty included participants (median age 25 years) completed the study. There were no serious adverse events. Self-reported local adverse reactions after intradermal delivery were mild, both in the 10 µg and the 20 µg group. In the higher dose group, systemic adverse reactions were more common , but still well tolerated. All 38 participants mounted substantially higher IgG-anti-S1 and IgG-anti-RBD concentrations at day 43 than COVID-19 controls. At day 43, anti-S1 (95% CI) was 1,696 (1,309-2,198) BAU/mL for the 10 µg intradermal group, 1,406 (953·5-2,074) BAU/mL for the 20 µg intramuscular group and 2,057 (1,421-2,975) BAU/mL for the 20 µg intradermal group. Anti-S1 was 107·2 (63-182·2) BAU/mL for the convalescent plasma control group and 1,558 (547·8-4,433) BAU/mL for the individuals vaccinated with 100 µg mRNA-1273.Interpretation: Intradermal administration of 10 µg and 20 µg mRNA-1273 vaccine was well tolerated and safe, and resulted in a robust antibody response. Intradermal vaccination has the potential to be deployed for vaccine dose-sparing.Clinical Trial Registration Details: registered in the Netherlands Trial Register (NTR) (https://www.trialregister.nl/trial/9275).Funding Information: The trial was supported by crowdfunding (Wake Up to Corona).Declaration of Interests: All authors declare no competing interests. Ethics Approval Statement: The trial was performed in accordance with the ethical principles of the Declaration of Helsinki and Good Clinical Practice guidelines developed by the International Harmonisation Task Force. The protocol was approved by the Medical Ethical Committee Leiden, Den Haag, Delft (NL 76702.058.21). All participants provided written informed consent. The vaccine manufacturer was not involved in this trial.