RESUMEN
Although SARS-CoV-2 infects the upper respiratory tract, we know little about the amount, type, and kinetics of antibodies (Ab) generated at this site in response to intramuscular COVID-19 vaccination, and whether these Ab protect against subsequent "breakthrough" infections. We collected longitudinal serum and saliva samples from participants receiving two doses of mRNA COVID-19 vaccines over a 6-month period and measured the relative level of anti-Spike and anti-Receptor Binding Domain (RBD) Ab. We detected anti-Spike/RBD IgG and IgA and associated secretory component in the saliva of most participants receiving 1 dose of mRNA vaccine. Administration of a second dose of mRNA boosted the IgG but not the IgA response, with only 30% of participants remaining positive for IgA at this timepoint. At 6 months post-dose 2, these participants exhibited greatly diminished anti-Spike/RBD IgG and IgA levels concomitant with a reduction in neutralizing activity in the saliva, although the level of secretory component associated anti-Spike was less susceptible to decay. Examining two prospective cohorts of subjects that were monitored for infections post-vaccination, we found that participants who were subsequently infected with SARS-CoV-2 had lower levels of vaccine-induced serum anti-Spike/RBD IgA at 2-4 weeks post-dose 2 compared to participants who did not experience an infection, whereas IgG levels were comparable between groups. These data emphasize the importance of developing COVID-19 vaccines that elicit a durable IgA response. One-Sentence SummaryOur study delves into whether intra-muscular mRNA vaccination regimes confer a local IgA response in the oral cavity and whether the IgA response is associated with protection against breakthrough infection.
RESUMEN
BackgroundThere are currently no effective treatments for outpatients with coronavirus disease 2019 (COVID-19). Interferon-lambda-1 is a Type III interferon involved in the innate antiviral response with activity against respiratory pathogens. MethodsIn this double-blind, placebo-controlled trial, outpatients with laboratory-confirmed COVID-19 were randomized to a single subcutaneous injection of peginterferon-lambda 180g or placebo within 7 days of symptom onset or first positive swab if asymptomatic. The primary endpoint was proportion negative for SARS-CoV-2 RNA on Day 7 post-injection. FindingsThere were 30 patients per arm, with median baseline SARS-CoV-2 viral load of 6.71 (IQR 1.3-8.0) log copies/mL. The decline in SARS-CoV-2 RNA was greater in those treated with peginterferon-lambda than placebo (p=0.04). On Day 7, 24 participants (80%) in the peginterferon-lambda group had an undetectable viral load compared to 19 (63%) in the placebo arm (p=0.15). After controlling for baseline viral load, peginterferon lambda treatment resulted in a 4.12-fold (95CI 1.15-16.7, p=0.029) higher likelihood of viral clearance by Day 7. Of those with baseline viral load above 10E6 copies/mL, 15/19 (79%) in the peginterferon-lambda group were undetectable on Day 7 compared to 6/16 (38%) in the placebo group (p=0.012). Adverse events were similar between groups with only mild reversible transaminase elevations more frequently observed in the peginterferon-lambda group. InterpretationPeginterferon-lambda accelerated viral decline in outpatients with COVID-19 resulting in a greater proportion with viral clearance by Day 7, particularly in those with high baseline viral load. Peginterferon-lambda may have potential to prevent clinical deterioration and shorten duration of viral shedding. (NCT04354259) FundingThis study was supported by the Toronto COVID-19 Action Initiative, University of Toronto and the Ontario First COVID-19 Rapid Research Fund. Medication was supplied by Eiger BioPharma. Research in ContextTreatment trials for COVID-19 have largely focused on hospitalized patients and no treatments are approved for people with mild to moderate disease in the outpatient setting. A number of studies in ambulatory populations have been registered but no controlled studies in the outpatient setting have been reported to date (Pubmed Search October 20, 2020, COVID-19 treatment; controlled trials). Uncontrolled case series of hydroxychloroquine with or without azithromycin have been reported with mixed results but no clear signal of efficacy and some concerns raised about cardiac toxicity. Treamtent in the outpatient setting has potential to prevent infected individuals from deteriorating and perhaps more importantly, may shorten the duration of viral shedding, reducing the risk of transmission and the duration required for self-isolation, with significant public health and societal impact. Added value of this studyThis is the first study to show an antiviral effect in outpatients with COVID-19. After controlling for baseline viral load, those treated with peginterferon-lambda had a 4.12-fold (95%CI 1.15-16.7, p=0.029) higher odds of viral clearance by Day 7 compared to those who received placebo. The viral load decline was faster with pegterferon-lambda and the effect was most pronounced in those with high viral loads. In individuals with a baseline viral load of 10E6 copies/mL or higher, 15/19 (79%) in the peginterferon-lambda arm cleared by Day 7 compared to 6/16 (38%) (p=0.012) in the placebo arm (OR 6.25, 95%CI 1.49-31.1, p=0.012), translating to a median time to viral clearance of 7 days (95%CI 6.2-7.8 days) with peginterferon-lambda compared to 10 days (95%CI 7.8-12.2 days) with placebo (p=0.038). Those with low viral loads (<10E6 copies/mL) cleared quickly in both groups. Peginterferon-lambda was well-tolerated with a similar side effect profile to placebo and no concerning laboratory adverse events. Implications of all available evidenceThere is no currently approved therapy for outpatients with COVID-19. This study showed that peginterferon-lambda accelerated viral clearance, particularly in those with high baseline viral loads, highlighting the importance of quantitative viral load testing in the evaluation of antiviral agents for COVID-19. Treatment early in the course of disease may prevent clinical deterioration and shorenting of the duration of viral shedding may have important public health impact by limiting transmission and reducing the duration required for self-isolation. Additional trials of peginterferon-lambda and other antiviral strategies in the outpatient setting are required.