ABSTRACT
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.
Subject(s)
COVID-19ABSTRACT
Background: Cases of reinfection with SARS-CoV-2 are reported in increasing numbers. Since the required molecular proof of reinfection is challenging to obtain, we aimed to provide serological evidence of reinfection in a cohort of potential reinfection cases.Methods: The study comprises 38 RT-PCR confirmed reinfection cases, with a COVID-19 symptom-free interval of at least 8 weeks (range 57-133 days) since their first RT-PCR confirmed episode. Specific disease symptoms were retrieved from 22 cases by contact tracing and compared between the two disease episodes. The oropharyngeal specimens from 13 cases enabled adequate genomic sequence comparisons. Seventeen cases provided a serum specimen, of which 12 within 7 days after onset of symptoms. Antibody determinations included SARS-CoV-2-specific total Ig, IgM, IgG, avidity, and virus neutralization. Antibody data were compared to that of a control group of primary cases (n=86) in relation to time since onset of disease symptoms.Findings: Reinfection cases generally experienced fewer or milder symptoms. Five of 8 cases which passed genomic comparison between both disease episodes showed reinfection with a different lineage. From 12 reinfection cases that provided a serum sample within 7 days after onset of symptoms, 11/12 (92%) and 12/12 (100%) showed high levels of specific total Ig and IgG antibodies, respectively, compared to 1/23 (4%) and 2/23 (9%) within the control group. Virus neutralizing antibodies were detected in 9/12 (75%) reinfection cases, 5 of which were above a titer of 30. Serological discrimination diminished after 7 days, except for IgG avidity; all 17 reinfection cases had antibodies of higher avidity when compared to control cases.Interpretation: IgG concentration and avidity can be used as an additional diagnostic marker to confirm reinfection with SARS-Cov-2. Reinfection cases that show a rapid and effective secondary immune response are expected to clear the infection more effectively, thereby reducing contagiousness and clinical severity. Understanding this reinfection response is also important for breakthrough infections following vaccination.Funding Statement: This work was supported by the National Institute for Public Health and the Environment, The Netherlands.Declaration of Interests: None of the authors have an association that poses a conflict of interest.Ethics Approval Statement: Approved by the Medical-Ethical Review Committee of the University Medical Center Utrecht.