Household transmission of the SARS-CoV-2 Omicron variant in Denmark

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Study design and participants

Delta VOC has been the dominant variant in Denmark since July 2021. The first Danish case infected with Omicron VOC was detected on November 22, 2021.18community transmission was present by early December 202119On 8 December, Danish authorities stopped intensive tracing of close contacts of cases specifically infected with Omicron VOC. Therefore, we have chosen a study period starting on December 9, 2021. At this time, cases of both variants were treated almost equally, reducing the bias from previous enhanced contact tracing and aggressive case-finding of his Omicron VOC.20The end of the primary case coverage period was set at 15 December, and family contacts were followed up to 7 days after the primary case, i.e. 22 December 2021. It often begins on 23 December and often involves extended family visits that disrupt typical patterns of transmission within the home. See the Appendix section for additional information on the number of new cases, Omicron ratio and number of tests conducted in Denmark during December 2021. 1.

Danish registry data were used for this study. Every Danish individual has a unique identification number, which allows reciprocal links between administrative registers. It is used to retrieve individual-level information on all residential addresses from the Central Personal Registry and complete data on all antigens and RT-PCR tests for SARS-CoV-2 from the Danish Microbiology Database (MiBa). data was obtained.twenty one), and all vaccination records from the Danish Immunization Registertwenty two.

A unique residential address was used to identify a Danish household, and all individuals registered at that address were assigned the same household identifier. This was used to define household size. We included only households with 2–6 members to exclude care homes and other locations where many individuals share the same address.

A primary case was defined as the first individual in a household who tested positive by RT-PCR test during the study period. All tests of other household members were followed for the duration of the study.Secondary cases were defined by either a positive RT-PCR test or a positive antigen testtwenty threeNearly all samples that tested positive by RT-PCR were then tested by variant PCR to determine VOCs.twenty four (Appendix table S1 and figure S1). We classified households associated with either Omicron VOC or Delta VOC based on the results of variant PCR testing of primary cases. Delta VOC has been the predominant variant in Denmark since early July 2021, accounting for almost all positive RT-PCR samples from August to November 2021.twenty fiveWe excluded households that had a positive RT-PCR test 60 days before the first case and households where the first case was ambiguous because two individuals tested positive on the same day.

We categorized individuals into three groups: (ii) is adequately vaccinated; or (iii) booster-vaccinated. The definition of a fully vaccinated person, which included individuals who had been infected ≥14 days earlier, was defined according to the vaccine used as: 15 days after the second dose of Vaxzevria (AstraZeneca). 14 days after his second dose of Spikevax (Moderna). Janssen (Johnson & Johnson) 14 days after his vaccination. For cross-vaccination, 14 days after the second dose.Booster vaccination was defined as 7 days after booster vaccination26, 27As of 22 December 2021, vaccine distribution in Denmark was Comirnaty 85%, Spikevax 14%, Janssen 1% and AstraZeneca about 0%.28All other individuals, including 59 partially vaccinated individuals, were considered unvaccinated.

statistical analysis

The causality of household exposure to Omicron VOCs rather than Delta VOCs to SARs can be confusing.This was evident from the different characteristics of households exposed to Omicron and Delta VOCs, with the latter being more widely dispersed at the beginning of the study period (Table 1 and appendix diagram S1b). These differences were likely caused by the transmission of spatiotemporal patterns when the omicron VOCs were first introduced. A causal interpretation of our findings is based on the assumption that all effects of non-random assignment of variants to households are blocked by the observed household characteristics.Causality assumptions are described in the Appendix section 2.

Secondary attack rate (SAR) was defined as the proportion of household contacts defined as secondary cases16Adjusted odds ratios (ORs) of infection were estimated using a multivariable logistic regression model, with the binary outcome of each household contact test result as the response variable, and the household variant (Omicron vs. Delta VOC) of interest. was used as the main explanatory variable with Additional explanatory variables to account for confounding factors included variables representing age and sex of primary cases, age and sex of household contacts, and household size (2–6 persons). To test whether vaccine status conferred differential protection against her Omicron and Delta VOCs, we included an interaction term between vaccination status and variants of primary cases and contacts. No evidence of interaction between primary case vaccination status and variant was found (P = 0.14). Specifically, we estimate the following expression:

$${{\log }}\left(\frac{{{\Pr }}({y}_{c,p}=1)}{1-{{\Pr }}({y}_{c ,p}=1)}\right)= {{{{{{\rm{constant}}}}}}}+{{{{{{\rm{variant}}}}}}}}_{ p }+{{{{{\rm{Vaccine Status}}}}}}}}{{{{{{\rm{s}}}}}}}_{c} \\ +{{{{{{ { \rm{Variant}}}}}}}_{p}\times {{{{{{\rm{VaccineStatu}}}}}}}{{{{{\rm{s}}}}} } }}_{c}+{{{{{{\rm{VaccineStatus}}}}}}}{{{{{{\rm{s}}}}}}}_{p} \\ +{ { {{{{\rm{Ag}}}}}}{{{{{{\rm{e}}}}}}}_{p}+{{{{{{\rm{gender} } }}}}}}_{p}+{{{{{{\rm{HouseholdSiz}}}}}}}{{{{{{\rm{e}}}}}}}_{p}+ {{{{{{\rm{Ag}}}}}}}{{{{{\rm{e}}}}}}}_{c}+{{{{{{\rm{gender }}}}}}}}_{c},$$

(1)

Where yc, p If your contact is 1 c Test positive 1–7 days after exposure to primary infected person p, otherwise zero.Mutantp Decide if it is a primary case p Infected with Omicron or Delta. VaccineStatus represents the fixed effects of primary case vaccination status (categorical variable) p and contact cAge represents the fixed effect of age at 10-year intervals (categorical variable), Sex the fixed effect of gender, and HouseholdSize the fixed effect of household size (categorical variable). To estimate the covariance matrix of the regression coefficients, the Taylor series linearization was used and cluster-robust standard errors were used for clustering at the household level.29.

We also performed a number of supplementary analyzes to support our primary analysis.To test the robustness of our findings, we compared different specifications of the main logistic regression models (Appendix section 4.4). To investigate the potential role mediated by viral load in primary cases infected with Omicron VOC compared to Delta VOC, we plotted the distribution of cycle threshold (Ct) values ​​for each variant (Appendix Fig. S3).We also examined to what extent Ct values ​​in primary cases could explain differences in transmission between variants (Appendix Table S21). Our study correctly distinguishes between primary and secondary cases and is based on the assumption that secondary cases at home are transmitted from the primary case and not from the outside community.To assess this potential misclassification of cases, we performed a series of robustness checks (Appendix section 4.2). First, to explore the potential role of differences in the incidence of tertiary cases across variants, we compared the relative SARs of two- and multi-person households, as tertiary cases are not possible in her two-person household. Did. Second, to explore the potential role of primary case misclassification, we took advantage of the fact that most of the contacts in the sample were tested multiple times. Untested contacts or secondary cases who test positive in the first test may be true primary cases, so all contacts after the primary case tests positive We restricted the sample to include only households that tested negative. Third, to explore potential misclassification of secondary cases infected from outside communities rather than households, we estimated the probability that a secondary case would be infected with the same variant as the primary case. Furthermore, to maximize the likelihood of identifying misclassifications, we focused on households infected with variants other than the most prevalent in the corresponding locations.

Our study also relied on Variant PCR testing to determine whether each primary case was infected with Omicron VOC or Delta VOC. To investigate whether there is any bias in the selection of samples for variant PCR testing, we examined the probability of sampling for variant PCR by sample Ct value and age (Appendix Figure 1). S1).In addition, we validated the variant PCR using whole-genome sequencing data (Appendix Table S5). Finally, we tested the robustness of tested-positive household contacts using only the RT-PCR test, which has greater sensitivity and specificity than the antigen test (Appendix Figure. S7).

ethics statement

This study was conducted using only data from national registries. According to Danish law, this type of research does not require ethics approval. All data management and analysis was performed on the restricted research server of the Danish Health Data Authority under project number FSEID-00004942. This survey contains only aggregate results and does not contain personal data.