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Magnitude and determinants of SARS-CoV-2 household transmission: a longitudinal cohort study

Abstract Background Households have emerged as important venues for SARS-CoV-2 transmission. Little is known, however, regarding the magnitude and determinants of household transmission in increasingly vaccinated populations. Methods From September 2020 to January 2022, symptomatic non-hospitalized individuals with SARS-CoV-2 infection by RNA detection were identified within 5 days of symptom onset; all individuals resided with at least one other SARS-CoV-2-uninfected household member. These infected persons (cases) and their household members (contacts) were subsequently followed with questionnaire-based measurement and serial nasal specimen collection. The primary outcome was SARS-CoV-2 infection among contacts. Results We evaluated 42 cases and their 74 household contacts. Among the contacts, 32 (43%) became infected, of whom 5/32 (16%) were asymptomatic; 81% of transmissions occurred by 5 days after the case’s symptom onset. From 21 unvaccinated cases, 14-day cumulative incidence of SARS-CoV-2 infection among contacts was 18/40 (45%; 95% CI: 29, 62), most of whom were unvaccinated. From 21 vaccinated cases, 14-day cumulative incidence of SARS-CoV-2 infection was 14/34 (41%; 95% CI: 25, 59) among all contacts and 12/29 (41%; 95% CI: 24, 61) among vaccinated contacts. At least one co-morbid condition among cases and 10 or more days of RNA detection in cases were associated with increased risk of infection among contacts. Conclusions Among households including individuals with symptomatic SARS-CoV-2 infection, both vaccinated-to-vaccinated and unvaccinated-to-unvaccinated transmission of SARS-CoV-2 to household contacts was common. Because vaccination alone did not notably reduce risk of infection, household contacts will need to employ additional interventions to avoid infection.

The reported magnitude of SARS-CoV-2 transmission from index cases to household 2 members has varied, depending on multiple factors including viral variant, vaccination status of 3 both the index case and household contacts, and diagnostic procedures. [1] Prior to the 4 introduction of Delta variant, fully vaccinated index cases had a lower proportion of transmission 5 events (cumulative incidence, or secondary attack rates) to household members compared to 6 unvaccinated index cases. [2][3][4] Studies focused on Delta infections, however, found that there 7 was no difference in the proportion of transmission events between vaccinated and 8 unvaccinated index cases. [5][6][7] It should be noted that most of these Delta-focused transmission 9 studies did not perform longitudinal specimen collection more than weekly, and as a result, may 10 have missed cases in the household. Very few studies have taken the additional step of 11 generating qualitative and quantitative viral culture data from specimens to assess the effect of 12 infectious viral shedding of cases on infection of contacts. 13 Without rigorous descriptions of transmission events in households from and between 14 vaccinated and unvaccinated individuals, we have a limited understanding of the causal 15 determinants of SARS-CoV-2 transmission and host susceptibility of infection. We developed a 16 rigorous set of criteria, using viral, epidemiological, and genetic data, to identify primary cases. 17 Then, we sought to assess the host and viral determinants and magnitude of SARS-CoV-2 18 household transmission, stratifying cases and contacts by vaccination status. 19 20 Methods 21

Overall Design 22
This was a longitudinal cohort study enrolling vaccinated and unvaccinated individuals 23 (index cases) at the time of SARS-CoV-2 infection and their household contacts. The study was 24 reviewed by the UCSF Institutional Review Board and given a designation of public health 25 A C C E P T E D M A N U S C R I P T individuals in the household (see next section for more details). A household case was any 23 household contact infected by SARS-CoV-2 after the primary case and not considered a co-24 primary case. Serial interval was defined as the number of days between the symptom onsets 25 (or date of first positive test in asymptomatic cases) of the primary case and any household 26 A C C E P T E D M A N U S C R I P T case. Shared exposure was broadly defined as having had a high-risk exposure in the same 1 contextual setting (e.g., hospital, indoor dining, family gathering) within 14 days prior to 2 symptom onset of the index case. We created a decision algorithm with serial intervals, shared 3 exposures, and phylogenetic analyses to identify primary versus co-primary cases from index 4 cases. Details describing the decision algorithm can be found in the Supplemental Material. 5 6 Statistical analyses 7 We described the entire cohort and whether infected individuals self-reported the 8 presence or absence of any symptom over the infectious period. We restricted analyses to 9 households that had primary cases who were symptomatic. Our primary outcome was SARS-10 CoV-2 infection among household contacts, defined as the identification of SARS-CoV-2 RNA in 11 any nasal or oropharyngeal specimen longitudinally obtained over the infectious period. All 12 household contacts who developed SARS-CoV-2 infection during the study had positive testing 13 within 10 days of symptom onset of the primary case in the household; we assumed that all 14 infections identified in these households represented transmission from the primary case. 15 We estimated 14-day cumulative incidence of SARS-CoV-2 infection among household 16 contacts and determined which host and viral factors were associated with household 17 transmission. We stratified cumulative incidence by vaccination status and by variant of the 18 primary case. Participants were considered vaccinated if participants completed a primary 19 series of a COVID-19 vaccine >14 days prior to enrollment; those who had received booster 20 dose were also included as vaccinated. Partial vaccination was defined as having received the 21 first mRNA dose in a 2-dose series >14 days earlier but were either missing a second dose or 22 If no RNA or live virus was detected, we assigned that individual a duration of zero. In our 5 analyses of maximum RNA level or infectious viral load, we did not include individuals with a 6 value of zero because of the lack of a valid assumption for use of bins. 7 We used generalized estimating equations (GEE) with modified Poisson regression (log 8 link), clustering by household, to generate marginal estimates of risk ratios (cumulative 9 incidence ratios) and 95% confidence intervals (CIs). We performed a series of unadjusted 10 analyses examining each host and viral factor for primary cases and then each host factor for 11 household contacts. We performed a series of adjusted analyses that included factors for both 12 the primary cases and household contacts. To determine the relevant covariates, we created an 13 adjustment set of covariates in a Directed Acyclic Graph to assess potential confounders, 14 mediators, and colliders (Suppl. Figure 1). We considered the literature, expert consultation, 15 and the results of our unadjusted analyses in the determination of final covariate adjustment set. 16 We repeated this process in the assessment of each factor. Details of each model can be found 17 in the footnote of the tables. 18 Confidence intervals for cumulative incidence were calculated using Agresti-Coull 19 interval. We used GEE to compare cumulative incidence estimates and generated p-values, 20 considering any p-value of less than 0.05 as statistically significant. In the analyses involving 21 statistical modeling, we used confidence intervals to determine statistical significance and 22 considered intervals that did not include the null value to be significant. All analyses were 23 performed using STATA/BE 17.0 (StataCorp, College Station, Texas, USA). As a sensitivity 24 analysis of the cumulative incidence estimate, we repeated the analyses with the entire cohort, 25 inclusive of primary and co-primary cases (Suppl. Table 1). 26

Results 2
From September 2020 to January 2022, we enrolled 65 index cases and their 115 3 household contacts in the total study cohort (180 participants) (Figure 1). Among these 180 4 participants, 72 (57%) of 126 infected participants had sufficient RNA levels for viral sequencing 5 (Figure 2). There were 21 index cases that had no infected household contacts and were 6 classified as primary cases. Among the remaining 44 index cases, we assessed the serial 7 interval and shared exposures and identified 24 additional possible primary cases. From 8 phylogenetic analyses of available genomic data, 24 contacts had viral sequences that could be 9 paired to an index case and assessed as potentially related sequences. Based on these 10 phylogenetic analyses, we reclassified one of the 45 households thought to have a single 11 primary case as having co-primary cases (Figure 3). Among the remaining 44 single primary 12 cases, two were asymptomatic. We excluded asymptomatic primary cases to focus on an 13 analysis cohort of 42 symptomatic primary cases and their 74 household contacts (116 14 participants) (Figure 4). 15 16

Host and viral determinants of SARS-CoV-2 infection 9
In unadjusted analyses, household contacts had increased risk of infection when 10 exposed to primary cases who were female, or with at least one comorbidity, and 10 or more 11 days of RNA viral shedding. After adjustment, increased risk of infection among contacts 12 remained associated with primary cases who had at least one comorbidity and RNA viral 13 shedding for ≥10 days. Among these determinants, the greatest risk of infection was seen from 14 primary cases with at least one co-morbidity (adjusted risk ratio [aRR]: 2.1; 95% CI: 1.2, 3.8). 15 Although duration of infectious viral shedding was not statistically significant, household 16 contacts of primary cases with longer duration of infectious viral shedding had 1.05 times the 17 adjusted risk of infection than household contacts of primary cases with shorter duration of 18 shedding (95% CI: 0.96, 1.2) ( Table 5). 19 Host susceptibility factors associated with infection were assessed among household 20 contacts, and we found that after adjustment, household contacts of White race had higher risk 21 of infection than other races ( Table 6). We did not find any statistically significant associations 22 between risk of infection and the following characteristics of household contacts: age, sex, BMI, 23 vaccination status, or comorbidity status. 24 In this cohort longitudinally sampled for evidence of SARS-CoV-2, we identified a 2 significant amount of onward transmission from both vaccinated-to-vaccinated and 3 unvaccinated-to-unvaccinated individuals within households. When comparing vaccination 4 status of primary cases, we did not observe a difference in cumulative incidence among 5 household contacts. We used phylogenetic analyses to strengthen evidence of transmission 6 events from and between vaccinated individuals in a similar way as other studies, which have 7 described high-confidence events. [5,6] Although vaccination prevents severe illness [16], 8 SARS-CoV-2 transmission commonly occurs in vaccinated households, serving as a public 9 health reminder of the ongoing value in masking and other mitigating measures, particularly 10 when community transmission increases. 11 Although we did not detect associations between infection of household contacts and 12 most household contact characteristics, we did detect associations with host and viral 13 determinants of the primary case, despite small numbers. Increased risk of infection was 14 notably high among household contacts of primary cases with underlying conditions; this finding 15 may inform public health strategies, including targeted case and contact investigations. We also 16 identified an association between household contact infection and duration of viral RNA 17 shedding (10 or more days) in the primary case; we did not detect an association with maximum 18 viral RNA load, controlling for vaccination status, though previous studies have found maximum 19 viral RNA load was associated with the risk of onward transmission [6,17]. Our study extends 20 the literature with its inclusion of infectious viral data. We did not find that risk of infection was 21 associated with maximum infectious viral titer or maximum viral RNA load, though may have 22 been underpowered to detect such associations. These two virological parameters (maximum 23 loads) have been correlated in previous work.[18] It is possible that duration of RNA and 24 infectious viral shedding are also correlated and may be important virological parameters of 25 Our study has limitations. Although we attempted to reach infected participants as early as 1 possible, some of our primary cases were negative for infectious virus, meaning that we may 2 have missed the presence of viral shedding, which could have possibly left-censored our data. 3 Furthermore, we assessed maximum viral load available for each individual, but this may not 4 have reflected the true peak viral load in most primary cases. Low levels of RNA limited our 5 ability to sequence virus for some primary cases. Among the viruses sequenced, we had a 6 different distribution of variants among the vaccinated versus unvaccinated primary cases, 7 potentially biasing the difference in cumulative incidence among these groups to the null. Our 8 phylogenetic analyses depicted whether participants were from similar clades but were unable 9 to decipher the transmission chain with individual-level resolution. The magnitude of exposure 10 and mitigating factors during the isolation and quarantine periods likely varied and were not 11 considered in our analyses. We also lacked detailed symptom data for the characterization of 12 infected household contacts. This sample may have been enriched for characteristics specific to 13 non-hospitalized index cases who were symptomatic and diagnosed with rapid access to the 14 health system and thus limit the external validity or generalizability of the study. Our sample size 15 was small, however, so we may have been underpowered to detect some associations, such as 16 differences in cumulative incidence by variant or duration of infectious viral shedding. Because 17 of the small sample size, we also were not able to reliably assess the effects of time since 18 vaccination or booster vaccinations. 19 Although vaccination may reduce severity, it did not significantly reduce transmission from 20 June 2021 to January 2022, which was a period when household transmission was common 21 among vaccinated-to-vaccinated individuals. As new variants emerge and vaccines are 22 updated, we expect that the impact of vaccination on transmission may continue to change and 23 that there will be potential for unrecognized transmission despite widespread COVID-19 24 vaccination. It will be critical to characterize viral shedding and transmission dynamics through 25 ongoing active surveillance and natural history studies. 26 We thank the participants for making this study possible while acutely infected with SARS-CoV-2 2. We appreciate the input and support of Amy J. Markowitz, Elan L. Guterman, Thomas M. 3 Lietman, Will Brett, Eric Talbert, and others in the CDC COVID-19 response who contributed to 4 this study. Vero TMPRSS2 hAce2 cells were a kind gift from Barney Graham (NIH). 5

Supplement Sponsorship 6
This article appears as part of the supplement "Vaccines, Variants, and Vigilance: Strengthening

Conflicts of Interest 20
MBH reports funding support from the Centers for Disease Control and Prevention. All authors 21 submitted ICMJE forms and have no conflicts to report.      Annual household income reported from N=65 total index cases and N=42 primary cases.   NA: not applicable due to the inability of a statistical model to converge with a zero-value cell of 7 a strata.      excluded if index cases were determined to have co-primary cases criteria or if single primary 2 cases were asymptomatic. Note: We identified 42 households with single primary cases, also 3 referred to as primary cases. For analysis, we excluded 21 households with co-primary cases 4 and 2 households with asymptomatic primary cases. Determination of single primary or co-primary cases from 65 households (65 index cases). Note: 19 We identified 42 households with single primary cases, also referred to as primary cases.