key: cord-0949535-ezi3yflg
authors: Heftdal, Line Dam; Schultz, Martin; Lange, Theis; Knudsen, Andreas Dehlbæk; Fogh, Kamille; Hasselbalch, Rasmus Bo; Linander, Christine Borgen; Kallemose, Thomas; Bundgaard, Henning; Grønbæk, Kirsten; Valentiner-Branth, Palle; Iversen, Kasper; Nielsen, Susanne Dam
title: Incidence of positive SARS-CoV-2 PCR after COVID-19 vaccination with up to eight months of follow-up: Real life data from the Capital Region of Denmark
date: 2022-01-07
journal: Clin Infect Dis
DOI: 10.1093/cid/ciac012
sha: 0c8a87129fdd0e184b53fe12601001afc8de0bdd
doc_id: 949535
cord_uid: ezi3yflg

BACKGROUND: COVID-19 vaccines are implemented worldwide in efforts to curb the pandemic. This study investigates the risk of a positive SARS-CoV-2 RT-PCR test following BNT162b2 vaccination in a large real-life population in Denmark. METHODS: Vaccination status and positive SARS-CoV-2 RT-PCR results from adults in the Capital Region of Denmark (n=1,549,488) were obtained from national registries. PCR testing was free and widely available. The number of positive PCR tests per individual at risk were calculated as weekly rates. Time to positive PCR test was modelled using Kaplan-Meier methods and hazard ratios (HR) were calculated using Cox regression. RESULTS: 1,119,574 individuals received first dose of BNT162b2 and 1,088,879 received a second dose of BNT162b2. Individuals were followed up to 8.7 months after first dose (median: 5.5 months, IQR:4.1-8.7). Rates of PCR-confirmed SARS-CoV-2 infection two to four months after the second dose were 0.21, 0.33 and 0.36 per 1000 individuals per week at risk for July, August and September, respectively. Four or more months after the second dose, the rates were 0.56, 0.76 and 0.53 per 1000 individuals per week at risk for July, August and September, respectively. HR of SARS-CoV-2 infection after the second dose was 0.2 (95% CI: 0.05-0.48, p=0.001) for individuals with eight months follow-up. CONCLUSION: Individuals who received two doses of the BNT162b2 COVID-19 vaccine had a low risk of breakthrough-infection after up to 8 months of follow-up. However, there was a tendency towards higher rates with longer follow-up.

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of corona virus disease 2019 . The virus has caused a global pandemic with more than 274 million cases and 5.4 million deaths 1 . Efforts to curb the pandemic are highly warranted, and vaccination is the mainstay of such efforts. At present, five vaccines have been approved in the European Union 2 . In Denmark mainly the two mRNA-based vaccines, BNT162b2 and mRNA-1273, are currently in use.

BNT162b2 and mRNA-1273, respectively. The main outcome was prevention of symptomatic COVID-19 defined as typical COVID-19 symptoms in combination with a positive PCR test within two months of follow-up 3, 4 . BNT162b2 had 52% efficacy in preventing symptomatic SARS-CoV-2 infection after the first dose, and 95% efficacy was found seven or more days after the second dose 3 . mRNA-1273 had 95% efficacy after the first dose and 94% efficacy after the second dose 4 . In a recent publication, the manufacturer reports that BNT162b2 is 91.3% effective six months following the second vaccine dose, with a gradual decline in vaccine efficacy over time. 5 Despite roll-out of the two mRNA vaccines in many countries, only few reports of real-life data have been published. Data from Israel including 4.7 million individuals of all ages vaccinated with BNT162b2 and a median follow-up of 7 weeks, found 95.3% efficacy of BNT162b2 in preventing symptomatic COVID-19 infection after the second dose and 91.5% on asymptomatic infection 6 . Waning immunity with increased risk of breakthrough infections has been observed in early vaccinated individuals compared to individuals vaccinated later [7] [8] [9] , and a recent study from Israel with one month follow-up after a third dose of BNT162b2 found lower rates of infection in individuals vaccinated thrice 10 . However, A c c e p t e d M a n u s c r i p t little is known about the incidence of SARS-CoV-2-infection including mild or asymptomatic disease in a vaccinated population 6, 7 .

In this large, observational study of all individuals in the Capital Region of Denmark between December 27, 2020 and September 14, 2021, and up to eight months of followup, we aimed to determine the rate of breakthrough infections following at least one dose of BNT162b2 COVID-19 vaccine. Furthermore, we present sensitivity analyses of presumed high-risk populations i.e. health care workers (HCW).

This is an observational study of all individuals vaccinated against SARS-CoV-2 infection with BNT162b2 between December 27, 2020 and September 14, 2021 in the Capital Region of Denmark.

The Danish health care system provides free health care to all Danish citizens, and the Danish vaccination program was organized by the Danish Health Authorities. HCW were prioritized for early vaccination in Denmark, along with the elderly population and patients belonging to groups with increased risk of severe COVID-19 [12] [13] [14] . Testing for SARS-CoV-2 is free-of-charge and widely available in Denmark. All RT-PCR test results for SARS-CoV-2 are registered in the Danish National Registries. week. The study population was defined by individuals from the first dataset, and follow-up throughout the time period of the second dataset. The vaccinated group was followed until positive SARS-CoV-2 RT-PCR test (the event) and censored in case of death. The unvaccinated group was followed until presenting a positive SARS-CoV-2 RT-PCR test (the event) and censored in case of death or vaccination. Hazard ratios were calculated using a Cox regression model and presented with 95% confidence intervals (95% CI); however, the proportional hazards assumption was not met for the models. Hazard ratios were calculated from day of vaccination and as a sensitivity analysis from 7 days after vaccination in which the risk time of unvaccinated controls was also postponed 7 days. Additionally, sub analysis using only HCW were performed. Statistical calculations were performed in R version 3.6.1 15 , using R-packages: survival 16 ,Epi 17 and dplyr 18 . week of administration of a second dose ( Figure 3B ). In HCW the corresponding HR was 0.2 (95% CI: 0.03-1.34, p=0.095) ( Figure 3B ). Similar trends were observed when performing sensitivity analyses 7 days after first and second vaccination respectively. All HRs are summarized in table 3.

We present data from a large observational study of all individuals in the Capital Region of Denmark, As vaccination coverage increases, the implementation of mandatory COVID-19 passports for vaccinated individuals has been suggested to allow for access to public facilities and traveling across borders. Thus, durability of the vaccine induced immunity has become an area of concern. In this study, the rates of RT-PCR-confirmed SARS-CoV-2 breakthrough infection showed a tendency towards increasing in individuals with more than four months since second vaccine dose, suggesting slightly decreasing protection of the vaccine 4 months after completed vaccination. A causal interpretation of the results will require time of vaccination not being dependent on risk of SARS-CoV-2-infection. However, individuals with high risk of severe COVID-19 were prioritized for early A c c e p t e d M a n u s c r i p t vaccination, and thus time of first vaccination was directly correlated with age and populations considered at increased risk of severe COVID-19. Thus, our results cannot assess the causal effects, and different study design or additional information associated with increased risk of SARS-CoV-2infection, would be necessary to determine causality.

In the weeks prior to initiation of the vaccine program, Denmark underwent the second nationwide lockdown due to increasing incidence of infection and COVID-19 related hospitalizations 19 . The effect of the lockdown was reflected in the nationwide percentage of positive PCR tests in the following weeks and coincided with the first part of the inclusion period for our study 19 . Thus, the percentage of positive tests also declined during the first three inclusion weeks 19 . In our study, the incidence of infection after completed vaccination on a population level with more than two months of followup 8, 9, [20] [21] [22] . The phase 2/3 study of BNT162b2 did not perform routine tests in asymptomatic A c c e p t e d M a n u s c r i p t individuals, and it is unknown to what extent BNT162b2 protects against asymptomatic disease 3 . In Denmark, the strongly encouraged, free and widely available testing for all residents, including HCW, provide a near ideal platform for studying the epidemiological effectiveness of COVID-19 vaccination regardless of symptom severity. However, we did not have access to clinical data, including comorbidities or hospitalization, and as such, we cannot provide information about the proportion with symptomatic disease. This may be further challenged by a varying tendency to get tested over the course of the study period. However, we found it reasonable to assume that individuals with symptoms consistent with COVID-19 would get tested regardless of vaccination status, although asymptomatic infections might not have been consistently detected throughout the study period.

The data presented suggest effective protection from virus transmission up to five months after completed vaccination with BNT162b2. However, we did find a tendency towards increasing rates of RT-PCR confirmed SARS-CoV-2 when exceeding 4 months since second vaccination, albeit we cannot draw conclusions on efficacy, as this study is strictly observational. Effects derived from public health interventions in the study environment might influence the result as seen by the decreasing positive percentage over time, but this would likely have affected both vaccinated and un-vaccinated individuals. Behavioral changes such as reduced testing frequency after vaccination or lack of testing due to absence from work are also possible confounders due to the observational nature of the study 6, 23 . Limitations to our study further include that pairing of our data with clinical data or information on comorbidities or hospitalization was not possible, and we cannot distinguish between severe or non-severe SARS-CoV-2 infections. Additionally, we do not have data on individual variants of concern, however we know from national inventories that the Alpha variant was the predominant strain in Denmark until the middle of June 2020 when the Delta variant took over 24 . SARS-CoV-2 testing in Denmark was free and encouraged as part of contact tracing efforts and for individuals who have symptoms consistent with COVID-19. Though HCW are more exposed, M a n u s c r i p t protection measurements are enforced. Hence, the overall risk is difficult to compare, and we cannot rule out that HCW and groups prioritized for vaccination may have had a higher propensity for testing than the control population.

In conclusion, our data estimates that individuals who received two doses of BNT162b2 had a minimal risk of breakthrough infection with SARS-CoV-2, however, there may be a tendency towards reduction in vaccine effectiveness over time. In the context of containing the current pandemic and preventing additional lockdowns, as winter, a season traditionally associated with higher infection rates, approaches, this is reassuring results. However, more evidence is needed on long term immunogenicity. Importantly, although our data support the findings in the original trials, it is essential to remain rigorous in maintaining transmission preventing precautions until the duration of the effect of the vaccine has been clarified. A c c e p t e d M a n u s c r i p t M a n u s c r i p t Tables: Table 1 M a n u s c r i p t A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t 

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