key: cord-0915060-k3sn8gs5
authors: Ng, Oon Tek; Koh, Vanessa; Chiew, Calvin J; Marimuthu, Kalisvar; Thevasagayam, Natascha May; Mak, Tze Minn; Chua, Joon Kiat; Ong, Shannen Si Hui; Lim, Yong Kai; Ferdous, Zannatul; bte Johari, Alifa Khairunnisa; Cui, Lin; Lin, Raymond Tzer Pin; Tan, Kelvin Bryan; Cook, Alex R; Leo, Yee-Sin; Lee, Vernon J M
title: Impact of SARS-CoV-2 Vaccination and Paediatric Age on Delta Variant Household Transmission
date: 2022-03-22
journal: Clin Infect Dis
DOI: 10.1093/cid/ciac219
sha: 69bd7b9013c1a919350ec20f455aa60ac20612e3
doc_id: 915060
cord_uid: k3sn8gs5

BACKGROUND: The impact of SARS-CoV-2 vaccination status and paediatric age on transmission of the Delta variant is key to preventing COVID-19 spread. In Singapore, quarantine of all close-contacts, and quarantine-entry and exit PCR testing, enabled evaluation of these factors. METHODS: This retrospective cohort study included all household close-contacts between March 1, 2021 and August 31, 2021. Logistic regression using generalized estimating equations was used to determine risk factors associated with SARS-CoV-2 acquisition and symptomatic disease. FINDINGS: Among 8470 Delta variant-exposed household close-contacts linked to 2583 indices, full-vaccination of the index with BNT162b2 or mRNA-1273 was associated with significant reduction in SARS-CoV-2 acquisition by contacts (adjusted odds ratio [aOR]:0.56, 95% robust confidence interval [RCI]:0.44–0.71 and aOR:0.51, 95%RCI:0.27–0.96 respectively). Compared to young adults (18–29y), children (0–11y) were significantly more likely to transmit (aOR:2.37 [95%RCI:1.57–3.60]) and acquire (aOR:1.43 [95%RCI:1.07–1.93]) infection, taking into account vaccination status. Longer duration from completion of vaccination among contacts was associated with decline in protection against acquisition (first-month aOR:0.42, 95%RCI:0.33–0.55; fifth-month aOR:0.84, 95%RCI:0.55–0.98; p<0.0001 for trend) and symptomatic disease (first-month aOR:0.30, 95%RCI:0.23–0.41; fifth-month aOR;0.62, 95%RCI:0.38–1.02; p<0.0001 for trend). Contacts immunized with mRNA-1273 had significant reduction in acquisition (aOR:0.73, 95%RCI:0.58–0.91) compared to BNT162b2. CONCLUSIONS: Among household close-contacts, vaccination prevented onward SARS-CoV-2 transmission and there was increased risk of SARS-CoV-2 acquisition and transmission among children compared with young adults. Time after completion of vaccination and vaccine type affected SARS-CoV-2 acquisition.

SARS-CoV-2 Delta has spread rapidly even in settings with high vaccine coverage.

[1] Initial data suggests that vaccine protection against SARS-CoV-2 acquisition declined steadily after the first month of completing two doses. [2] To understand the role of vaccination on prevention of transmission, it is important to determine the separate and combined impact of index and closecontact vaccination on SARS-CoV-2 transmission.

While there is also considerable evidence that children are less susceptible to SARS-CoV-2 infections and the vast majority of infected children are asymptomatic to paucisymptomatic [3, 4] , it is unclear if they are less infectious than adults and how much they contribute to onward transmission. Some early household studies suggest that children are less likely to transmit SARS-CoV-2 compared to adults. Studies from Spain and Germany report significantly lower secondary attack rates (SAR) in households with paediatric compared to adult index cases [5, 6] , and an Israeli study estimated the infectivity of children as 63% (95% CI 37-88%) relative to adults. [7] In contrast, data from two large studies from India and China revealed that although children accounted for fewer overall infections than older age-groups, the former documented the highest rates of transmission from children aged 0-14 years and adults aged 65 years [8] , and the latter found no statistical evidence of differential transmissibility by age. [9] There is also evidence of efficient SARS-CoV-2 transmission from children to adult household members. [10, 11] Notably, current knowledge on the infectivity of paediatric age groups is limited to data from pre-Delta cohorts. The increase in number of paediatric cases due to global spread of the more infectious Delta variant and significant gains in adult immunization prompt an Determining SARS-CoV-2 acquisition rates is challenging as many settings rely on symptomatic testing of contacts, which would likely miss asymptomatic and mild infections, and underestimate the frequency of milder paediatric cases. [12] This limitation can be overcome in cohorts where routine SARS-CoV-2 testing regardless of symptoms is conducted. Household contacts are ideal for determining the impact of vaccination and age on transmission due to the high transmission-risk setting.

We studied household SARS-CoV-2 transmission in Singapore, where all close-contacts of known SARS-CoV-2 infected persons were contact-traced and quarantined for two weeks. As all close-contacts were tested routinely by PCR upon quarantine entry and exit, this cohort provided the opportunity to determine SARS-CoV-2 acquisition regardless of symptoms. As index-contact pairs are known, risks of onward transmission and acquisition could be estimated.

All close-contacts of confirmed COVID-19 index cases in Singapore issued quarantine orders by the Ministry of Health (MOH) between March 1, 2021 and August 31, 2021 were included in this retrospective cohort study. Since January 2, 2020, active surveillance for COVID-19 in Singapore has been conducted according to MOH COVID-19 guidelines (Supplementary Appendix), which are updated regularly, and all COVID-19 cases are legally required to be reported to MOH. A confirmed COVID-19 case was defined as positive detection of SARS-CoV-2 nucleic acid by real-time RT-PCR of respiratory specimens. [13] A c c e p t e d M a n u s c r i p t 8 Contact-tracing was performed by MOH for every diagnosed COVID-19 case. [14] Household close-contacts were defined as persons who shared the same residential address as the index case, regardless of duration or proximity of contact. All identified close-contacts underwent legallyenforced quarantine for 14 days and were not allowed to leave their residence or assigned location.

Quarantined individuals were monitored for symptoms daily and transferred to hospital for COVID-19 testing and clinical evaluation if significant symptoms developed. Regardless of symptoms, all quarantined close-contacts were tested for COVID-19 by PCR upon quarantine entry and exit. SAR was defined as the number of PCR-confirmed cases detected among all household close-contacts of the index case. All cases of possible COVID-19 reinfection were independently adjudicated by an expert panel comprising specialists in infectious diseases and laboratory medicine (Supplementary Appendix).

All SARS-CoV-2-positive cases with RT-PCR Ct<30 were subjected to WGS for variant identification (Supplementary Appendix).

Data on indices and close-contacts were obtained from MOH's contact-tracing database (Supplementary Appendix). Symptom information was collected via phone interview by the MOH contact-tracing team soon after diagnosis, while supplemental oxygen, intensive care requirements and COVID-19-related morbidity were ascertained during the period of inpatient care.

Contacts residing in worker dormitories (where the nature of spread is different from community households [15] ), those of overseas or imported cases, and those lacking index case information were excluded. If multiple indices were listed for a close-contact in the national records, the earliest-diagnosed index sharing the same residence as the contact was selected for analysis. It Table 1 ).

MOH investigated every new case for epidemiologically-linked transmission to prior cases and grouped cases into transmission clusters. [16] In this cohort, all cases with individually-assigned variant status in an epidemiologically-linked transmission cluster were found to have identical variant assignment. As such, cases with no individually-assigned variant status were also assigned the transmission cluster variant if available.

Risk-factors for acquisition of infection by household contacts of cases were assessed using logistic regression fitted using generalized estimating equations, to accommodate clustering.

Bivariate relationships between the outcome and all epidemiologically relevant and available covariates were assessed first, then all covariates, including those not significant on bivariate analysis, were included in a multivariable model. Significance was taken to be at the 5% level. 24 hypothesis tests were conducted in the multivariable model and another 24 across the bivariate models, so 2-3 false positives might be expected if no relationships existed. We adjusted for the age and gender of both index and contact, the vaccine status of the index, and the duration of exposure from symptom onset or notification of the index to his or her isolation in a healthcare facility as these co-variates have prior data supporting possible effects on SARS-CoV-2 acquisition and morbidity [17] [18] [19] [20] (Supplementary Table 2 ). The small number of cases of severe disease (i.e. need for supplemental oxygen and/or intensive care, and/or death) precluded risk-factor analysis for this endpoint.

To obtain estimates of waning of protection against infection or symptomatic infection of the contact, by time since the contact's vaccination, and of prevention of transmission by time since A c c e p t e d M a n u s c r i p t 10 vaccination of the index, we used logistic regression models fit using generalized estimating equations. We counted the months (30 days) since becoming fully-vaccinated, up to five or more months, as beyond six months the small numbers precluded analysis. Statistical analysis was conducted in R.

[21]

This work was performed as part of outbreak investigations approved under the Infectious Diseases Act of Singapore. [22] 

After adjusting for age, gender and vaccination status of both contact and index, as well as time exposure of the contact to the index, full-vaccination of the index with BNT162b2 or mRNA-1273 was associated with a significant reduction in contact SARS-CoV-2 acquisition (adjusted odds While reduction of SARS-CoV-2 acquisition following vaccination is well-described [23] , there is limited evidence of the effect of vaccination on onward transmission. Viral dynamics studies have measured comparable peak viral loads in fully-vaccinated individuals with breakthrough infections and unvaccinated cases, although viral load decline occurred at a faster rate in the former. [24] Vaccination of healthcare workers was associated with a reduction in reported cases of COVID-19 among their household members. [25] However, the study predated the emergence of the more infectious Delta variant in India and its subsequent global predominance.

[1] Our findings from this Delta-infected cohort underscore the importance of vaccination that extends beyond individual protection to protection of household contacts and suggests that vaccination would also help prevent transmission in the community.

Our results also affirm previous reports on waning immunity post-vaccination with mRNA vaccines [2, 26, 27] and support the need for booster doses in order to maintain initial high levels of protection against acquisition. As our analysis focuses on an exclusively Delta-infected cohort, we are able to show that the association with increased risk of SARS-CoV-2 infection is indeed dependent on time from full-vaccination and not simply inherent to the Delta variant.

Data from the United States CDC have suggested that there may be variation in vaccineinduced protection depending on vaccine type, with vaccine effectiveness against hospitalization A c c e p t e d M a n u s c r i p t 15 reportedly higher for the mRNA-1273 vaccine (93%) than the BNT162b2 vaccine (88%). [28] The CDC did not evaluate cases that did not result in hospitalization and did not stratify vaccine effectiveness by variant. Doing so in this study, we have similarly found that mRNA-1273 was associated with reduced risk of SARS-CoV-2 acquisition compared with BNT162b2, taking into account time since fullvaccination.

Paediatric household transmission is relatively understudied, with evidence limited to the pre-Delta era. The role of this age-group in driving onward transmission particularly during Delta predominance and in the context of varying rates of adult immunization is important. Results from early household studies have differing results, with some suggesting that children are less likely to transmit SARS-CoV-2 compared to adults [5] [6] [7] 29] , and others documenting comparable rates of transmission. [8] , [9] Our findings suggest that young children (0-11 years) are important drivers of onward transmission to their household contacts, and support paediatric vaccination where available [30] , especially in multigenerational households with high-risk elderly or immunocompromised family members.

Children are known to shed infectious SARS-CoV-2 [31] , and a few studies have detected higher or similar nasopharyngeal viral loads in children compared to adults [32, 33] .

Increasing use of physical-distancing and masks at home was associated with older age of indices 18 years old, suggesting that younger children may be less capable of adhering to strict hygiene practices[10], and/or are less able to self-isolate from caregivers when they are ill.

Since the completion of our study, the Omicron variant has largely replaced the Delta variant as the predominant strain. Preliminary findings from Denmark reported a higher household SAR for the Omicron variant than the Delta variant [34] . Reassuringly, vaccination appears to remain effective against the Omicron variant [34, 35] . The risk of household contacts acquiring infections outside of the household prior to quarantine cannot be excluded, but this would be minimized by the low number of community cases in Singapore during the study period (0.56 cases per 100,000 population per day over the study duration) and short lag-time between case notification and quarantine of household contacts. There is a possibility that the index (i.e. the first COVID-19-diagnosed person in the household) may not be the true primary case. However this scenario would likely be minimized by aggressive contacttracing and establishment of transmission chains in Singapore since the first diagnosed case, and where possible assignment of the index would be dependent on the earliest symptom onset or likely transmission source outside of the household. [36, 37] Contacts' symptom data was based on interview by MOH contact-tracers soon after index diagnosis and may have resulted in the misclassification of pre-symptomatic individuals (who were asymptomatic at time of interview) as asymptomatic, which could affect risk estimates of symptomatic infection. Chronic disease data is not routinely captured in the MOH contact-tracing database and hence chronic disease was not adjusted for in our analyses. As chronic diseases tend to be more common in older age, this could have been reflected by the increased risk estimates in older age-groups.

As the number of paediatric cases increases worldwide due to the spread of more infectious variants, the role of children in onward transmission will grow. Household members especially those who are primary caregivers of infected children recuperating at home should be aware of the potential risks and take necessary precautions. While breakthrough infections occur in fully- 

Individual-level participant data that underlie the results reported in this article, after deidentification (text, tables, figures, and appendices), is regarded as sensitive and will not be shared.

The study methods and statistical analyses are described in detail in the manuscript. 

The sponsor(s) of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. All authors were not precluded from accessing data in the study, and they accepted responsibility to submit for publication.

We declare no competing interests. M a n u s c r i p t 26 a Partially-vaccinated is defined to mean having received one vaccine dose or to be within 14 days of the second vaccine dose on the start date of quarantine. 24 b Fully-vaccinated is defined to mean having received both doses of vaccine more than 14 days prior to the start date of quarantine. 25 c One of 3955 (total) fully-vaccinated individuals was excluded as vaccine type information was not available. 

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A c c e p t e d M a n u s c r i p t 21 21.R Core Team. R: A language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing, 2020. Available at: https://www.Rproject.org/.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 24 group, rounded (SD) i Median days from symptom onset or notification of diagnosis (if asymptomatic) to hospital admission of index case (IQR) A c c e p t e d M a n u s c r i p t 25 c Fully-vaccinated is defined to mean having received both doses of vaccine more than 14 days prior to the start date of quarantine. 7 d Of 8470 contacts, age information was not available for one (0.01%). 8 e Of 2067 contacts, age information was not available for one (0.05%). 9 f Of 8470 contacts, gender information was not available for one (0.01%). 10 g Of 2067 contacts, gender information was not available for one (0.05%). 11 h Note that a unique index case may be linked to multiple contacts with different vaccination statuses. 12 I Contact group refers to a group consisting of an index case and their close-contacts. Note that a unique index case may be linked to multiple contacts with different 13 vaccination statuses. 14 j Refers to the number of contacts, excluding the linked index case(s).