The imprinting effect of COVID-19 vaccines: an expected selection bias in observational studies (preprint)

Findings of recent observational studies have been interpreted as supporting immune imprinting of COVID-19 vaccines. In this work, we clarify that the current discussion can be mapped to an attempt to estimate the direct effect of vaccine boosters on SARS-CoV-2 reinfections, and that such direct effect cannot be correctly estimated with observational data. We conclude that recent observational estimates regarding immune imprinting are fundamentally biased, and that the increased risk of reinfection in individuals vaccinated with a vaccine booster compared to no booster is expected even if the immune imprinting hypothesis is false. We use graphical methods (directed acyclic graphs), data simulations and analysis of real-life data to illustrate the mechanism and magnitude of this bias.

Effectiveness of non-pharmaceutical interventions in nine fields of activity to decrease SARS-CoV-2 transmission (Spain, September 2020 - May 2021) (preprint)

Background We estimated the association between the level of restriction in nine different fields of activity and SARS-CoV-2 transmissibility in Spain, from 15 September 2020 to 9 May 2021.Methods A stringency index (0 to 1) was created for mobility, social distancing, commerce, indoor and outdoor bars and restaurants, culture and leisure, worship and ceremonies, indoor and outdoor sports, for each Spanish province (n = 50) daily. The logarithmic return (LR) of the weekly percentage variation of the 7-days COVID-19 cumulative incidence was used to measure COVID-19 transmission, lagged 12 days behind the stringency index. A hierarchical multiplicative model was fitted, and the median of coefficients across provinces (with 95% bootstrap confidence intervals) was used to quantify the effect of increasing one standard deviation (1SD) in the stringency index in each field.Results Highest levels of restriction were seen in mobility, sports and restaurants, particularly indoors. The increase in restrictions overall reduced SARS-CoV-2 transmission by 22% (RR = 0.78; one-sided 95%CI: 0,0.82) in one week, with highest effects for culture and leisure 14% (0.86; 0,0.98), social distancing 13% (0.87; 0,0.95), indoor restaurants 10% (0.90; 0,0.95) and indoor sports 6% (0.94; 0,0.98). In a reduced model with seven fields, culture and leisure no longer had a significant effect while ceremonies decreased transmission by 5% (0.95; 0,0.96). Models R2 was around 70%.Conclusion Increased restrictions decreased COVID-19 transmission. Limitations include remaining collinearity between fields, and somewhat artificial quantification of qualitative restrictions, so the exact attribution of the effect to specific areas must be done with caution.

COVID-19 vaccine effectiveness against hospitalization due to SARS-CoV-2: A test negative design study based on SARI sentinel surveillance in Spain (preprint)

Background: With the emergence of SARS-CoV-2, influenza surveillance systems in Spain were transformed into a new syndromic sentinel surveillance system. The Acute Respiratory Infection Surveillance System (SiVIRA in Spanish) is based on a sentinel network for Acute Respiratory Infection (ARI) surveillance in Primary care, and a network of sentinel hospitals for Severe ARI (SARI) surveillance in hospitals. Methods: Using a test-negative design and data from SARI admissions notified to SiVIRA between January 1 and October 3, 2021, we estimated COVID-19 VE against hospitalization, by age group, vaccine type, time since vaccination and SARS-CoV-2 variant. Results: VE was 89% (95% CI: 83-93) against COVID-19 hospitalization overall in persons aged 20 years and older. VE was higher for mRNA vaccines, and lower for those aged 80 years and older, with a decrease in protection beyond 3 months of completing vaccination, and a further decrease after 5 months. We found no differences between periods with circulation of Alpha or Delta SARS-CoV-2 variants, although variant-specific VE was slightly higher against Alpha. Conclusions: The SiVIRA surveillance system, with a network of sentinel hospitals in Spain was able to describe clinical and epidemiological characteristics of SARI hospitalizations, monitor the circulation of SARS-CoV-2 and other respiratory viruses, and provide data to measure the effectiveness of COVID-19 vaccination in the population under surveillance. Our results add to evidence of high VE of mRNA vaccines against severe COVID-19 and waning protection with time since vaccination.

Direct and indirect effectiveness of mRNA vaccination against SARS-CoV-2 infection in long-term care facilities in Spain (preprint)

Objectives: To estimate indirect and total (direct plus indirect) effects of COVID-19 vaccination in residents in long-term care facilities (LTCF). Design: Registries-based cohort study including all residents in LTCF 65 years or older offered vaccination between 27 December 2020 and 10 March 2021. Risk of SARS-CoV-2 infection following vaccination was compared with the risk in the same individuals in a period before vaccination. Risk in non-vaccinated was also compared to a period before the vaccination programme to estimate indirect protection. Standardized cumulative risk was computed adjusted by previous documented infection (before the start of follow-up) and daily-varying SARS-CoV-2 incidence and reproductive number. Participants: 573,533 records of 299,209 individuals in the National vaccination registry were selected; 99.0% had received at least 1 vaccine-dos, 99.8% was Pfizer/BioNTech (BNT162b2). Residents mean age was 85.9, 70.9% were females. A previous SARS-CoV-2 infection was found in around 25% and 13% of participants, respectively, at the time of vaccine offer and in the reference period. Main outcome measures: Documented SARS-CoV-2 infection identified in the National COVID-19 laboratory registry. Results: Total VE was 57.2% (95% Confidence Interval: 56.1%-58.3%), and was highest starting 28 days after the first vaccine-dose (proxy of more than 7 days after the second dose) and for individuals naive to SARS-CoV-2 [81.8% (81.0%-82.7%)] compared to those with previous infection [56.8% (47.1%-67.7%)]. Vaccination prevented up to 9.6 (9.3-9.9) cases per 10.000 vaccinated per day; 11.6 (11.3-11.9) if naive vs. 0.8 (0.5-1.0) if previous infection. Indirect protection in the non-vaccinated could only be estimated for naive individuals, at 81.4% (73.3%-90.3%) and up to 12.8 (9.4-16.2) infections prevented per 10.000 indirectly protected per day. Conclusions: Our results confirm the effectiveness of mRNA vaccination in institutionalized elderly population, endorse the policy of universal vaccination in this setting, including in people with previous infection, and suggest that even non-vaccinated individuals benefit from indirect protection.