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Summary

Background

The SARS-CoV-two delta (B.1.617.ii) variant is highly transmissible and spreading globally, including in populations with loftier vaccination rates. Nosotros aimed to investigate transmission and viral load kinetics in vaccinated and unvaccinated individuals with mild delta variant infection in the customs.

Methods

Between Sept 13, 2020, and Sept xv, 2021, 602 community contacts (identified via the United kingdom contract-tracing arrangement) of 471 UK COVID-19 index cases were recruited to the Assessment of Manual and Contagiousness of COVID-19 in Contacts accomplice study and contributed 8145 upper respiratory tract samples from daily sampling for up to twenty days. Household and non-household exposed contacts aged 5 years or older were eligible for recruitment if they could provide informed consent and hold to self-swabbing of the upper respiratory tract. We analysed transmission chance by vaccination status for 231 contacts exposed to 162 epidemiologically linked delta variant-infected alphabetize cases. We compared viral load trajectories from fully vaccinated individuals with delta infection (n=29) with unvaccinated individuals with delta (n=xvi), alpha (B.one.1.7; n=39), and pre-alpha (n=49) infections. Primary outcomes for the epidemiological analysis were to assess the secondary attack charge per unit (SAR) in household contacts stratified by contact vaccination condition and the index cases' vaccination status. Master outcomes for the viral load kinetics assay were to detect differences in the peak viral load, viral growth rate, and viral decline rate between participants according to SARS-CoV-2 variant and vaccination status.

Findings

The SAR in household contacts exposed to the delta variant was 25% (95% CI 18–33) for fully vaccinated individuals compared with 38% (24–53) in unvaccinated individuals. The median time between second vaccine dose and study recruitment in fully vaccinated contacts was longer for infected individuals (median 101 days [IQR 74–120]) than for uninfected individuals (64 days [32–97], p=0·001). SAR among household contacts exposed to fully vaccinated index cases was like to household contacts exposed to unvaccinated index cases (25% [95% CI 15–35] for vaccinated vs 23% [15–31] for unvaccinated). 12 (39%) of 31 infections in fully vaccinated household contacts arose from fully vaccinated epidemiologically linked index cases, further confirmed by genomic and virological assay in iii index case–contact pairs. Although peak viral load did non differ by vaccination condition or variant type, it increased modestly with age (difference of 0·39 [95% credible interval –0·03 to 0·79] in peak log₁₀ viral load per mL between those anile 10 years and 50 years). Fully vaccinated individuals with delta variant infection had a faster (posterior probability >0·84) mean rate of viral load turn down (0·95 log₁₀ copies per mL per 24-hour interval) than did unvaccinated individuals with pre-alpha (0·69), blastoff (0·82), or delta (0·79) variant infections. Within individuals, faster viral load growth was correlated with higher peak viral load (correlation 0·42 [95% credible interval 0·xiii to 0·65]) and slower decline (–0·44 [–0·67 to –0·18]).

Interpretation

Vaccination reduces the risk of delta variant infection and accelerates viral clearance. Nevertheless, fully vaccinated individuals with breakthrough infections have peak viral load similar to unvaccinated cases and can efficiently transmit infection in household settings, including to fully vaccinated contacts. Host–virus interactions early in infection may shape the unabridged viral trajectory.

Funding

National Institute for Wellness Research.

Introduction

While the master aim of vaccination is to protect individuals confronting severe COVID-nineteen disease and its consequences, the extent to which vaccines reduce onward transmission of SARS-CoV-two is key to containing the pandemic. This outcome depends on the ability of vaccines to protect against infection and the extent to which vaccination reduces the infectiousness of breakthrough infections.

Research in context

Evidence before this written report

The SARS-CoV-2 delta variant is spreading globally, including in populations with high vaccination coverage. While vaccination remains highly effective at attenuating disease severity and preventing death, vaccine effectiveness against infection is reduced for delta. Determining the extent of transmission from vaccinated delta-infected individuals to their vaccinated contacts is a public wellness priority. Comparison the upper respiratory tract (URT) viral load kinetics of delta infections with those of other variants gives insight into potential mechanisms for its increased transmissibility. We searched PubMed and medRxiv for articles published between database inception and Sept 20, 2021, using search terms describing "SARS-CoV-two, delta variant, viral load, and transmission". Two studies longitudinally sampled the URT in vaccinated and unvaccinated delta variant-infected individuals to compare viral load kinetics. In a retrospective study of a cohort of hospitalised patients in Singapore, more rapid viral load decline was found in vaccinated individuals than unvaccinated cases. However, the unvaccinated cases in this report had moderate-to-astringent infection, which is known to be associated with prolonged shedding. The second study longitudinally sampled professional USA sports players. Again, clearance of delta viral RNA in vaccinated cases was faster than in unvaccinated cases, but but 8% of unvaccinated cases had delta variant infection, complicating interpretation. Lastly, a report of a single-source nosocomial outbreak of a distinct delta sub-lineage in Vietnamese wellness-care workers plotted viral load kinetics (without comparing with unvaccinated delta infections) and demonstrated transmission betwixt fully vaccinated health-care workers in the nosocomial setting. The findings might therefore not exist generalisable beyond the particular setting and distinct viral sub-lineage investigated.

Added value of this study

The majority of SARS-CoV-2 transmission occurs in households, only manual betwixt fully vaccinated individuals in this setting has not been shown to engagement. To ascertain secondary manual with high sensitivity, nosotros longitudinally followed index cases and their contacts (regardless of symptoms) in the community early after exposure to the delta variant of SARS-CoV-2, performing daily quantitative RT-PCR on URT samples for 14–20 days. We constitute that the secondary assail rate in fully vaccinated household contacts was high at 25%, merely this value was lower than that of unvaccinated contacts (38%). Risk of infection increased with time in the ii–three months since the second dose of vaccine. The proportion of infected contacts was similar regardless of the index cases' vaccination status. Nosotros observed transmission of the delta variant betwixt fully vaccinated index cases and their fully vaccinated contacts in several households, confirmed by whole-genome sequencing. Peak viral load did not differ past vaccination status or variant blazon but did increment modestly with historic period. Vaccinated delta cases experienced faster viral load reject than did unvaccinated alpha or delta cases. Across study participants, faster viral load growth was correlated with college peak viral load and slower decline, suggesting that host–virus interactions early in infection shape the entire viral trajectory. Since our findings are derived from community household contacts in a existent-life setting, they are probably generalisable to the full general population.

Implications of all the bachelor testify

Although vaccines remain highly constructive at preventing severe disease and deaths from COVID-nineteen, our findings propose that vaccination is not sufficient to prevent transmission of the delta variant in household settings with prolonged exposures. Our findings highlight the importance of customs studies to characterise the epidemiological phenotype of new SARS-CoV-2 variants in increasingly highly vaccinated populations. Continued public health and social measures to curb transmission of the delta variant remain important, fifty-fifty in vaccinated individuals.

Vaccination was found to exist effective in reducing household transmission of the blastoff variant (B.1.1.vii) by 40–50%,

and infected, vaccinated individuals had lower viral load in the upper respiratory tract (URT) than infections in unvaccinated individuals,

which is indicative of reduced infectiousness.

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However, the delta variant (B.ane.617.ii), which is more than transmissible than the blastoff variant,

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is now the dominant strain worldwide. After a large outbreak in India, the UK was one of the first countries to study a sharp rise in delta variant infection. Current vaccines remain highly effective at preventing admission to infirmary and death from delta infection.

Nonetheless, vaccine effectiveness against infection is reduced for delta, compared with alpha,

^,

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and the delta variant continues to cause a high burden of cases fifty-fifty in countries with high vaccination coverage. Information are scarce on the risk of customs transmission of delta from vaccinated individuals with mild infections.

Here, we report data from a UK customs-based report, the Assessment of Transmission and Contagiousness of COVID-19 in Contacts (ATACCC) study, in which ambulatory close contacts of confirmed COVID-19 cases underwent daily, longitudinal URT sampling, with collection of associated clinical and epidemiological data. We aimed to quantify household manual of the delta variant and assess the effect of vaccination status on contacts' risk of infection and index cases' infectiousness, including (one) households with unvaccinated contacts and alphabetize cases and (2) households with fully vaccinated contacts and fully vaccinated index cases. We too compared sequentially sampled URT viral RNA trajectories from individuals with not-severe delta, alpha, and pre-alpha SARS-CoV-ii infections to infer the effects of SARS-CoV-2 variant condition—and, for delta infections, vaccination status—on transmission potential.

Methods

Study design and participants

ATACCC is an observational longitudinal accomplice study of community contacts of SARS-CoV-ii cases. Contacts of symptomatic PCR-confirmed index cases notified to the United kingdom contact-tracing system (National Wellness Service Test and Trace) were asked if they would be willing to be contacted by Public Health England to discuss participation in the study. All contacts notified inside 5 days of alphabetize case symptom onset were selected to be contacted within our recruitment capacity. Household and not-household contacts anile 5 years or older were eligible for recruitment if they could provide written informed consent and agree to self-swabbing of the URT. Farther details on URT sampling are given in the appendix (p thirteen).

The ATACCC study is separated into two report artillery, ATACCC1 and ATACCC2, which were designed to capture dissimilar waves of the SARS-CoV-2 pandemic. In ATACCC1, which investigated blastoff variant and pre-alpha cases in Greater London, only contacts were recruited betwixt Sept thirteen, 2020, and March xiii, 2021. ATACCC1 included a pre-alpha wave (September to November, 2020) and an alpha moving ridge (December, 2020, to March, 2021). In ATACCC2, the study was relaunched specifically to investigate delta variant cases in Greater London and Bolton, and both index cases and contacts were recruited between May 25, and Sept 15, 2021. Early recruitment was focused in West London and Bolton because UK incidence of the delta variant was highest in these areas.

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Based on national and regional surveillance data, community manual was moderate-to-high throughout most of our recruitment period.

This report was approved past the Wellness Research Authority. Written informed consent was obtained from all participants before enrolment. Parents and caregivers gave consent for children.

Information drove

Demographic information was nerveless past the study team on enrolment. The engagement of exposure for non-household contacts was obtained from Public Health England. COVID-nineteen vaccination history was determined from the UK National Immunisation Management Arrangement, general practitioner records, and self-reporting by written report participants. We defined a participant equally unvaccinated if they had not received a single dose of a COVID-nineteen vaccine at least 7 days earlier enrolment, partially vaccinated if they had received ane vaccine dose at to the lowest degree 7 days before study enrolment, and fully vaccinated if they had received ii doses of a COVID-19 vaccine at least 7 days before study enrolment. Previous literature was used to decide the seven-day threshold for defining vaccination status.

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^,

We besides did sensitivity analyses using a 14-mean solar day threshold. The time interval between vaccination and study recruitment was calculated. We used WHO criteria

to define symptomatic status upward to the mean solar day of study recruitment. Symptomatic status for incident cases—participants who were PCR-negative at enrolment and after tested positive—was divers from the day of the first PCR-positive result.

Laboratory procedures

SARS-CoV-2 quantitative RT-PCR, conversion of ORF1ab and envelope (Due east-gene) cycle threshold values to viral genome copies, whole-genome sequencing, and lineage assignments are described in the appendix (pp 13–fourteen).

Outcomes

Master outcomes for the epidemiological analysis were to appraise the secondary assault rate (SAR) in household contacts stratified past contact vaccination status and the index cases' vaccination condition. Primary outcomes for the viral load kinetics assay were to find differences in the peak viral load, viral growth rate, and viral decline rate betwixt participants infected with pre-alpha versus alpha versus delta variants and between unvaccinated delta-infected participants and vaccinated delta-infected participants.

We assessed vaccine effectiveness and susceptibility to SARS-CoV-ii infection stratified by time elapsed since receipt of second vaccination as exploratory analyses.

Statistical analysis

To model viral kinetics, we used a uncomplicated phenomenological model of viral titre

during disease pathogenesis. Viral kinetic parameters were estimated on a participant-specific ground using a Bayesian hierarchical model to fit this model to the entire dataset of sequential bicycle threshold values measured for all participants. For the 19 participants who were non-household contacts of index cases and had a unique date of exposure, the cycle threshold data were supplemented by a pseudo-absence data point (ie, undetectable virus) on the date of exposure. Test accuracy and model misspecification were modelled with a mixture model by assuming at that place was a probability p of a test giving an ascertainment drawn from a (normal) error distribution and probability 1 –p of it being fatigued from the true distribution.

The hierarchical structure was represented by grouping participants based on the infecting variant and their vaccination status. A unmarried-group model was fitted, which implicitly assumes that viral kinetic parameters vary by private merely non by variant or vaccination status. A four-group model was also explored, where groups 1, 2, three, and 4 correspond pre-alpha, alpha, unvaccinated delta, and fully vaccinated delta, respectively. Nosotros fitted a correlation matrix betwixt participant-specific kinetic parameters to allow us to examine whether there is within-group correlation between tiptop viral titre, viral growth charge per unit, and viral decline rate. Our initial model selection, using exit-one-out cross-validation, selected a 4-group hierarchical model with fitted correlation coefficients between individual-level parameters determining peak viral load and viral load growth and pass up rates (appendix p 5). However, resulting participant-specific estimates of peak viral load (but not growth and decline rates) showed a marked and meaning correlation with age in the exploratory analysis, which motivated examination of models where hateful peak viral load could vary with historic period. The most predictive model overall allowed hateful viral load growth and turn down rates to vary beyond the 4 groups, with hateful peak viral load common to all groups but assumed to vary linearly with the logarithm of historic period (appendix p v). We present peak viral loads for the reference age of fifty years with 95% credible intervals (95% CrIs). 50 years was called as the reference age as it is typical of the ages of the cases in the whole dataset and the choice of reference age fabricated no difference in the model fits or judgment of differences between the groups.

Nosotros computed group-level population means and within-sample group means of log peak viral titre, viral growth rate, and viral decline charge per unit. Since posterior estimates of each of these variables are correlated across groups, overlap in the apparent intervals of an gauge for 1 grouping with that for another group does not necessarily indicate no significant divergence between those groups. We, therefore, computed posterior probabilities, pp, that these variables were larger for i group than another. For our model, Bayes factors can be computed as pp/(1–pp). We only study population (group-level) posterior probabilities greater than 0·75 (respective to Bayes factors >3) as indicating at least moderate evidence of a difference.

For vaccine effectiveness, we divers the estimated effectiveness at preventing infection, regardless of symptoms, with delta in the household setting as 1 – SAR (fully vaccinated) / SAR (unvaccinated).

Role of the funding source

The funder of the report had no role in written report pattern, data collection, information analysis, data interpretation, or writing of the report.

Results

Between Sept xiii, 2020, and Sept fifteen, 2021, 621 community-based participants (602 contacts and 19 alphabetize cases) from 471 index notifications were prospectively enrolled in the ATACCC1 and ATACCC2 studies, and contributed 8145 URT samples. Of these, ATACCC1 enrolled 369 contacts (arising from 308 alphabetize notifications), and ATACCC2 enrolled 233 contacts (arising from 163 index notifications) and 19 index cases. SARS-CoV-2 RNA was detected in 163 (26%) of the 621 participants. Whole-genome sequencing of PCR-positive cases confirmed that 71 participants had delta variant infection (18 alphabetize cases and 53 contacts), 42 had alpha variant infection (one index case and 41 contacts), and 50 had pre-alpha variant infection (all contacts; figure 1A).

Figure one Recruitment, SARS-CoV-2 infection, variant condition, and vaccination history for ATACCC study participants

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(A) Study recruitment and variant condition confirmed past whole-genome sequencing (ATACCC1 and ATACCC2 combined). (B) ATACCC2: delta-exposed contacts included in secondary assault rate calculation (tabular array 1) and transmission assessment (table two). NHS=National Health Service. *All alphabetize cases were from ATACCC2. † All contacts. ‡The two earliest PCR-positive cases from the ATACCC2 cohort (one alphabetize case and one contact) were confirmed as having the alpha variant on whole-genome sequencing (recruited on May 28, 2021). This alpha variant-exposed, PCR-positive contact is excluded from effigy 1B. §Ane PCR-negative contact had no vaccination status data available and one PCR-negative contact's index case had no vaccination data available. ¶Vaccination data were available for 138 index cases of 163. ||The contacts of these 15 index cases are included within the 232 total contacts. **These iii index cases without contacts are only included in the viral load kinetics analysis (figure three) and are non included in tables one and ii.

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Of 163 PCR-positive participants, 89 (55%) were female and 133 (82%) were White. Median age was 36 years (IQR 26–50). Sex, age, ethnicity, body-mass index (BMI) distribution, and the frequency of comorbidities were like amongst those with delta, blastoff, and pre-alpha infection, and for vaccinated and unvaccinated delta-infected participants, except for age and sex (appendix pp two–iii). There were fewer unvaccinated females than males (p=0·04) and, as expected from the age-prioritisation of the United kingdom of great britain and northern ireland vaccine curl-out, unvaccinated participants infected with the delta variant were significantly younger (p<0·001; appendix p 3). Median fourth dimension between exposure to the index instance and study enrolment was 4 days (IQR 4–5). All participants had not-astringent ambulatory illness or were asymptomatic. The proportion of asymptomatic cases did not differ among fully vaccinated, partially vaccinated, and unvaccinated delta groups (appendix p iii).

No pre-alpha-infected and but one alpha-infected participant had received a COVID-19 vaccine before report enrolment. Of 71 delta-infected participants (of whom 18 were index cases), 23 (32%) were unvaccinated, ten (14%) were partially vaccinated, and 38 (54%) were fully vaccinated (figure 1A; appendix p 3). Of the 38 fully vaccinated delta-infected participants, 14 had received the BNT162b2 mRNA vaccine (Pfizer–BioNTech), 23 the ChAdOx1 nCoV-nineteen adenovirus vector vaccine (Oxford–AstraZeneca), and one the CoronaVac inactivated whole-virion vaccine (Sinovac).

It is highly probable that all but i of the 233 ATACCC2 contacts were exposed to the delta variant because they were recruited when the regional prevalence of delta was at to the lowest degree 90%, and mostly 95–99% (figure 1B).

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Of these, 206 (89%) were household contacts (in 127 households), and 26 (11%) were not-household contacts. Distributions of age, ethnicity, BMI, smoking condition, and comorbidities were similar betwixt PCR-positive and PCR-negative contacts (appendix p iv). The median time between second vaccine dose and study recruitment in fully vaccinated contacts with delta variant infection was 74 days (IQR 35–105; range 16–201), and this was significantly longer in PCR-positive contacts than in PCR-negative contacts (101 days [IQR 74–120] vs 64 days [32–97], respectively, p=0·001; appendix p 4). All 53 PCR-positive contacts were exposed in household settings and the SAR for all delta variant-exposed household contacts was 26% (95% CI twenty–32). SAR was not significantly college in unvaccinated (38%, 95% CI 24–53) than fully vaccinated (25%, xviii–33) household contacts (table 1). We estimated vaccine effectiveness at preventing infection (regardless of symptoms) with delta in the household setting to exist 34% (bootstrap 95% CI –15 to 60). Sensitivity analyses using a 14 day threshold for time since 2d vaccination to study recruitment to denote fully vaccinated did not materially touch our estimates of vaccine effectiveness or SAR (data not shown). Although precision is restricted past the pocket-size sample size, this estimate is broadly consistent with vaccine effectiveness estimates for delta variant infection based on larger datasets.

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Table 1 SAR in contacts of delta-exposed index cases recruited to the ATACCC2 report

	Full	PCR positive	PCR negative	SAR (95% CI)	p value
Contacts
All	231	53	178	23 (18–29)	NA
Fully vaccinated	140	31	109	22 (16–30)	0·16
Unvaccinated	44	15	29	34 (22–49)	..
Partially vaccinated	47	seven	40	15 (seven–28)	NA
Household contacts
All	205	53	152	26 (20–32)	NA
Fully vaccinated	126	31	95	25 (18–33)	0·17
Unvaccinated	twoscore	15	25	38 (24–53)	..
Partially vaccinated	39	7	32	xviii (9–33)	NA

χ² test was performed to calculate p values for differences in SAR betwixt fully vaccinated and unvaccinated cases. One PCR-negative contact who withdrew from the study without vaccination status data was excluded. NA=non applicative. SAR=secondary attack rate.

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The vaccination status of 138 epidemiologically linked alphabetize cases of 204 delta variant-exposed household contacts was available (figure 1B, table 2). The SAR in household contacts exposed to fully vaccinated index cases was 25% (95% CI fifteen–35; 17 of 69), which is similar to the SAR in household contacts exposed to unvaccinated alphabetize cases (23% [fifteen–31]; 23 of 100; tabular array 2). The 53 PCR-positive contacts arose from household exposure to 39 PCR-positive alphabetize cases. Of these index cases who gave rise to secondary transmission, the proportion who were fully vaccinated (15 [38%] of 39) was similar to the proportion who were unvaccinated (16 [41%] of 39). The median number of days from the index cases' second vaccination to the day of recruitment for their respective contacts was 73 days (IQR 38–116). Time interval did not differ between index cases who transmitted infection to their contacts and those who did not (94 days [IQR 62–112] and 63 days [35–117], respectively; p=0·43).

Table 2 Comparison of vaccination condition of the 138 epidemiologically linked PCR-positive index cases for 204 delta variant-exposed household contacts

	All household contacts (n=204) * The rows below show the number of contacts exposed to each category of index case.	Fully vaccinated contacts (due north=125)		Partially vaccinated contacts (n=39)		Unvaccinated contacts (due north=forty)
		PCR positive (northward=31)	PCR negative (n=94)	PCR positive (n=7)	PCR negative (due north=32)	PCR positive (due north=15)	PCR negative (n=25)
Fully vaccinated alphabetize cases (n=50)	69	12	31	ane	8	4	xiii
Partially vaccinated index cases (due north=25)	35	vii	12	iii	10	3	0
Unvaccinated alphabetize cases (n=63)	100	12	51	iii	fourteen	8	12

Non-household exposed contacts (n=24, all PCR negative) were excluded. One PCR-negative household contact who withdrew from the study without vaccination status information was excluded. 1 PCR-negative household contact who could not be linked to their index example was besides excluded.

* The rows beneath show the number of contacts exposed to each category of index case.

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eighteen of the 163 delta variant-infected index cases that led to contact enrolment were themselves recruited to ATACCC2 and serial URT samples were collected from them, allowing for more detailed virology and genome analyses. For 15 of these, their contacts were also recruited (xiii household contacts and two non-household contacts). A corresponding PCR-positive household contact was identified for four of these 15 index cases (figure 1B). Genomic analysis showed that index–contact pairs were infected with the same delta variant sub-lineage in these instances, with one exception (effigy 2A). In one household (number 4), an unvaccinated alphabetize case transmitted the delta variant to an unvaccinated contact, while another partially vaccinated contact was infected with a different delta sub-lineage (which was probably caused exterior the household). In the other three households (numbers 1–3), fully vaccinated index cases transmitted the delta variant to fully vaccinated household contacts, with high viral load in all cases, and temporal relationships between the viral load kinetics that were consistent with transmission from the index cases to their respective contacts (figure 2B).

Figure 2 Virological, epidemiological, and genomic evidence for transmission of the SARS-CoV-2 delta variant (B.i.617.2) in households

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(A) Genomic analysis of the 4 households with lineage-defining mutations for delta

and boosted mutations inside ORFs displayed to requite insight into whether strains from individuals within the household are closely related. Lineages AY.4 and AY.9 are sub-lineages of delta. (B) Viral trajectories and vaccination condition of the iv alphabetize cases infected with the delta variant for whom infection was detected in their epidemiologically linked household contacts. All individuals had non-severe disease. Each plot shows an index example and their household contacts. Undetectable viral load measurements are plotted at the limit of detection (10^one·49). C=contact. I=index case. FV=fully vaccinated. ORF=open up reading frame. PV=partially vaccinated. U=unvaccinated.

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Inclusion criteria for the modelling analysis selected 133 participant'due south viral load RNA trajectories from 163 PCR-positive participants (49 with the pre-blastoff variant, 39 blastoff, and 45 delta; appendix p fourteen). Of the 45 delta cases, 29 were fully vaccinated and xvi were unvaccinated; partially vaccinated cases were excluded. Of the 133 included cases, 29 (22%) were incident (ie, PCR negative at enrolment converting to PCR positive subsequently) and 104 (78%) were prevalent (ie, already PCR positive at enrolment). 15 of the prevalent cases had a clearly resolvable acme viral load. Effigy 3 shows modelled viral RNA (ORF1ab) trajectories together with the viral RNA re-create numbers measured for individual participants. The E-gene equivalent is shown in the appendix (p ii). Estimates derived from Due east-gene cycle threshold value data (appendix pp five, 7, 9, eleven) were like to those for ORF1ab.

Figure 3 ORF1ab viral load trajectories from 14 days before to 28 days afterwards tiptop for 133 participants infected with pre-alpha or alpha variants (uncaccinated), or the delta variant (vaccinated and unvaccinated) variants

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Black circles are measured values, with the first datapoint for each participant being taken to the solar day of enrolment. Plots are rooted on the day of elevation viral load for each participant, denoted every bit day 0 on the 10-axis. Curves show the model posterior median estimate, with a 95% credible interval shading. 133 infected participants, comprising 114 contacts and xix index cases. *Index cases.

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Figure three ORF1ab viral load trajectories from 14 days before to 28 days after meridian for 133 participants infected with pre-blastoff or alpha variants (uncaccinated), or the delta variant (vaccinated and unvaccinated) variants

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Black circles are measured values, with the first datapoint for each participant beingness taken to the day of enrolment. Plots are rooted on the day of superlative viral load for each participant, denoted equally day 0 on the 10-axis. Curves show the model posterior median estimate, with a 95% apparent interval shading. 133 infected participants, comprising 114 contacts and 19 index cases. *Index cases.

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Although viral kinetics appear visually similar for all iv groups of cases, we plant quantitative differences in estimated viral growth rates and pass up rates (Table 3, Tabular array 4). Population (grouping-level) estimates of mean viral load decline rates based on ORF1ab wheel threshold value data varied in the range of 0·69–0·95 log₁₀ units per mL per daxes four; appendix p x), indicating that a typical 10-mean solar day catamenia was required for viral load to decline from acme to undetectable. A faster decline was seen in the alpha (pp=0·93), unvaccinated delta (pp=0·79), and fully vaccinated delta (pp=0·99) groups than in the pre-alpha grouping. The mean viral load pass up charge per unit of the fully vaccinated delta group was also faster than those of the alpha group (pp=0·84) and the unvaccinated delta group (pp=0·85). The differences in decline rates translate into a difference of near 3 days in the hateful elapsing of the refuse phase between the pre-blastoff and delta vaccinated groups.

Table 3 Estimates of VL growth rates for pre-alpha, alpha, and delta (unvaccinated and fully vaccinated) cases, derived from ORF1ab bicycle threshold data

	VL growth rate (95% CrI), log 10 units per day	Posterior probability estimate is less than pre-alpha	Posterior probability estimate is less than alpha	Posterior probability estimate is less than delta (unvaccinated)	Posterior probability gauge is less than delta (fully vaccinated)
Pre-alpha (north=49)	three·24 (ane·78–6·fourteen)	..	0·44	0·27	0·21
Alpha (n=39)	3·13 (i·76–5·94)	0·56	..	0·32	0·25
Delta, unvaccinated (n=16)	two·81 (1·47–5·47)	0·73	0·68	..	0·44
Delta, fully vaccinated (n=29)	2·69 (ane·51–5·17)	0·79	0·75	0·56	..

VL growth rates are shown every bit inside-sample posterior mean estimates. Remaining columns show population (grouping-level) posterior probabilities that the gauge on that row is less than an estimate for a unlike group. Posterior probabilities are derived from 20 000 posterior samples and have sampling errors of <0·01. VL=viral load. CrI=credible interval.

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Table 4 Estimates of VL decline rates for pre-alpha, blastoff, and delta (unvaccinated and fully vaccinated) cases, derived from ORF1ab cycle threshold data

	VL turn down charge per unit (95% CrI), log 10 units per day	Posterior probability judge is larger than pre-alpha	Posterior probability judge is larger than blastoff	Posterior probability estimate is larger than delta (unvaccinated)	Posterior probability guess is larger than delta (fully vaccinated)
Pre-alpha (n=49)	0·69 (0·58–0·81)	..	0·07	0·21	0·01
Blastoff (north=39)	0·82 (0·67–1·01)	0·93	..	0·60	0·16
Delta, unvaccinated (n=sixteen)	0·79 (0·59–1·04)	0·79	0·40	..	0·xv
Delta, fully vaccinated (north=29)	0·95 (0·76–1·eighteen)	0·99	0·84	0·85	..

VL pass up rates are shown as within-sample posterior mean estimates. Remaining columns show population (group-level) posterior probabilities that the estimate on that row is less than an judge for a dissimilar group. Posterior probabilities are derived from xx 000 posterior samples and have sampling errors of <0·01. VL=viral load. CrI=credible interval.

• Open table in a new tab

Viral load growth rates were substantially faster than decline rates, varying in the range of 2·69–3·24 log_ten units per mL per day between groups, indicating that a typical three-mean solar day period was required for viral load to abound from undetectable to acme. Our ability to infer differences in growth rates betwixt groups was more restricted than for viral refuse, but there was moderate show (pp=0·79) that growth rates were lower for those in the vaccinated delta group than in the pre-alpha group.

We estimated mean peak viral load for l-yr-old adults to be viii·14 (95% CrI 7·95 to 8·32) log_ten copies per mL, simply peak viral load did not differ by variant or vaccination status. However, we estimated that peak viral load increases with historic period (pp=0·96 that the slope of peak viral load with log[age] was >0), with an estimated gradient of 0·24 (95% CrI –0·02 to 0·49) log₁₀ copies per mL per unit of measurement change in log(age). This approximate translates to a difference of 0·39 (–0·03 to 0·79) in mean acme log₁₀ copies per mL between those aged x years and 50 years.

Within-group individual participant estimates of viral load growth rate were positively correlated with peak viral load, with a correlation coefficient estimate of 0·42 (95% CrI 0·thirteen to 0·65; appendix p 8). Hence, individuals with faster viral load growth tend to have higher peak viral load. The refuse rate of viral load was as well negatively correlated with viral load growth rate, with a correlation coefficient estimate of –0·44 (95% CrI –0·67 to –0·18), illustrating that individuals with faster viral load growth tend to experience slower viral load refuse.

Discussion

Households are the site of most SARS-CoV-2 manual globally.

^nineteen

• Thompson HA
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• Crossref
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In our cohort of densely sampled household contacts exposed to the delta variant, SAR was 38% in unvaccinated contacts and 25% in fully vaccinated contacts. This finding is consistent with the known protective upshot of COVID-19 vaccination against infection.

^,

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Nevertheless, these findings point connected risk of infection in household contacts despite vaccination. Our estimate of SAR is higher than that reported in fully vaccinated household contacts exposed earlier the emergence of the delta variant.

^,

^twenty

• House T
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^,

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• de Gier B
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• Crossref
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The time interval between vaccination and report recruitment was significantly higher in fully vaccinated PCR-positive contacts than fully vaccinated PCR-negative contacts, suggesting that susceptibility to infection increases with time as before long as two–3 months after vaccination—consistent with waning protective immunity. This potentially important observation is consistent with recent big-scale data and requires further investigation.

¹⁷

• Pouwels Thou
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Affect of delta on viral burden and vaccine effectiveness against new SARS-CoV-ii infections in the Britain.

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Household SAR for delta infection, regardless of vaccination status, was 26% (95% CI xx–32), which is higher than estimates of UK national surveillance data (10·8% [x·7–x·nine]).

¹⁰

Public Health England
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Nonetheless, nosotros sampled contacts daily, regardless of symptomatology, to actively identify infection with high sensitivity. By contrast, symptom-based, unmarried-timepoint surveillance testing probably underestimates the true SAR, and potentially as well overestimates vaccine effectiveness against infection.

We identified like SAR (25%) in household contacts exposed to fully vaccinated index cases equally in those exposed to unvaccinated index cases (23%). This finding indicates that breakthrough infections in fully vaccinated people tin can efficiently transmit infection in the household setting. We identified 12 household transmission events betwixt fully vaccinated alphabetize case–contact pairs; for three of these, genomic sequencing confirmed that the index case and contact were infected by the same delta variant sub-lineage, thus substantiating epidemiological data and temporal relationships of viral load kinetics to provide definitive bear witness for secondary manual. To our cognition, one other written report has reported that transmission of the delta variant between fully vaccinated people was a point-source nosocomial outbreak—a single health-care worker with a particular delta variant sub-lineage in Vietnam.

²²

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Daily longitudinal sampling of cases from early (median iv days) afterwards exposure for up to 20 days allowed us to generate high-resolution trajectories of URT viral load over the course of infection. To engagement, ii studies have sequentially sampled customs cases of balmy SARS-CoV-2 infection, and these were from highly specific population groups identified through asymptomatic screening programmes (eg, for academy staff and students

²³

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and for professional person athletes

²⁴

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Densely sampled viral trajectories suggest longer elapsing of astute infection with B.1.1.seven variant relative to not-B.i.1.vii SARS-CoV-2.

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).

Our most predictive model of viral load kinetics estimated hateful acme log₁₀ viral load per mL of 8·14 (95% CrI 7·95–8·32) for adults aged fifty years, which is very similar to the approximate from a 2022 study using routine surveillance data.

Nosotros found no evidence of variation in meridian viral load past variant or vaccination status, but we study some evidence of modest but significant (pp=0·95) increases in peak viral load with age. Previous studies of viral load in children and adults

^iv

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Clan between SARS-CoV-2 transmissibility, viral load, and historic period in households.

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^,

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Nasopharyngeal SARS-CoV-2 viral loads in young children do not differ significantly from those in older children and adults.

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have not used such dense sequential sampling of viral load and have, therefore, been restricted in their power to resolve historic period-related differences; the largest such study

reported a similar deviation between children and adults to the one we estimated. We found the rate of viral load pass up was faster for vaccinated individuals with delta infection than all other groups, and was faster for individuals in the alpha and unvaccinated delta groups than those with pre-blastoff infection.

For all variant vaccination groups, the variation between participants seen in viral load kinetic parameter estimates was substantially larger than the variation in mean parameters estimated between groups. The pocket-size scale of differences in viral kinetics between fully vaccinated and unvaccinated individuals with delta infection might explain the relatively high rates of transmission seen from vaccinated delta alphabetize cases in our study. Nosotros found no evidence of lower SARs from fully vaccinated delta index cases than from unvaccinated ones. Nevertheless, given that index cases were identified through routine symptomatic surveillance, there might have been a selection bias towards identifying untypically symptomatic vaccine breakthrough index cases.

The differences in viral kinetics we found between the pre-alpha, blastoff, and delta variant groups suggest some incremental, simply potentially adaptive, changes in viral dynamics associated with the evolution of SARS-CoV-two towards more than rapid viral clearance. Our study provides the first testify that, within each variant or vaccination grouping, viral growth rate is positively correlated with peak viral load, but is negatively correlated with viral decline rate. This finding suggests that individual infections during which viral replication is initially fastest generate the highest height viral load and come across the slowest viral clearance, with the latter not only being due to the college peak. Mechanistically, these data propose that the host and viral factors determining the initial growth charge per unit of SARS-CoV-two have a central result on the trajectory throughout infection, with faster replication being more hard (in terms of both peak viral load and the subsequent turn down of viral load) for the immune response to control. Analysis of sequentially sampled immune markers during infection might requite insight into the immune correlates of these early differences in infection kinetics. It is also possible that individuals with the fastest viral load growth and highest peaks contribute disproportionately to community transmission, a hypothesis that should exist tested in futurity studies.

Several population-level, single-timepoint sampling studies using routinely available data accept found no major differences in cycle threshold values betwixt vaccinated and unvaccinated individuals with delta variant infection.

^x

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^,

²⁸

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However, as the timepoint of sampling in the viral trajectory is unknown, this restricts the interpretation of such results. Ii other studies longitudinally sampled vaccinated and unvaccinated individuals with delta variant infection.

²³

• Ke R
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• et al.

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• Google Scholar

^,

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• Google Scholar

A retrospective accomplice of hospitalised patients in Singapore

²⁹

• Chia PY
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• Google Scholar

also described a faster charge per unit of viral decline in vaccinated versus unvaccinated individuals with delta variant, reporting somewhat larger differences in decline rates than we estimated here. However, this disparity might be accounted for by the higher severity of affliction in unvaccinated individuals in the Singaporean report (almost two-thirds having pneumonia, ane-third requiring COVID-19 handling, and a fifth needing oxygen) than in our report, given that longer viral shedding has been reported in patients with more severe disease.

A longitudinal sampling report in the USA reported that pre-alpha, alpha, and delta variant infections had like viral trajectories.

²⁴

• Kissler SM
• Fauver JR
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• et al.

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The study besides compared trajectories in vaccinated and unvaccinated individuals, reporting like proliferation phases and summit cycle threshold values, only more than rapid clearance of virus in vaccinated individuals. However, this study in the USA stratified by vaccination status and variant separately, rather than jointly, pregnant vaccinated individuals with delta infection were being compared with, predominantly, unvaccinated individuals with pre-alpha and alpha infection. Moreover, sampling was done as office of a professional sports player occupational health screening plan, making the results not necessarily representative of typical community infections.

Our written report has limitations. First, nosotros recruited just contacts of symptomatic index cases every bit our study recruitment is derived from routine contact-tracing notifications. 2d, index cases were divers every bit the kickoff household member to have a PCR-positive swab, only we cannot exclude the possibility that another household fellow member might already have been infected and transmitted to the alphabetize instance. Tertiary, recording of viral load trajectories is subject to left censoring, where the growth stage in prevalent contacts (already PCR-positive at enrolment) was missed for a proportion of participants. However, we captured 29 incident cases and fifteen additional cases on the upslope of the viral trajectory, providing valuable, informative data on viral growth rates and meridian viral load in a subset of participants. Fourth, attributable to the age-stratified rollout of the Britain vaccination programme, the historic period of the unvaccinated, delta variant-infected participants was lower than that of vaccinated participants. Thus, age might be a misreckoning cistron in our results and, as discussed, top viral load was associated with historic period. However, it is unlikely that the higher SAR observed in the unvaccinated contacts would have been driven by younger age rather than the absenteeism of vaccination and, to our knowledge, at that place is no published prove showing increased susceptibility to SARS-CoV-2 infection with decreasing age.

³¹

• Viner RM
• Mytton OT
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Finally, although we did not perform viral civilisation here—which is a meliorate proxy for infectiousness than RT-PCR—2 other studies

²⁷

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have shown cultivable virus from around two-thirds of vaccinated individuals infected with the delta variant, consistent with our conclusions that vaccinated individuals still take the potential to infect others, particularly early after infection when viral loads are high and near transmission is idea to occur.

Our findings assist to explicate how and why the delta variant is beingness transmitted and then effectively in populations with high vaccine coverage. Although current vaccines remain effective at preventing severe disease and deaths from COVID-xix, our findings advise that vaccination lone is not sufficient to prevent all transmission of the delta variant in the household setting, where exposure is close and prolonged. Increasing population immunity via booster programmes and vaccination of teenagers will help to increase the currently limited result of vaccination on transmission, only our assay suggests that straight protection of individuals at risk of severe outcomes, via vaccination and non-pharmacological interventions, will remain central to containing the burden of illness caused by the delta variant.

This online publication has been corrected. The corrected version first appeared at thelancet.com/infection on November 2, 2021

Contributors

AS, JD, MZ, NMF, WB, and ALal conceptualised the study. AS, SH, JD, KJM, AK, JLB, MGW, ND-F, RV, RK, JF, CT, AVK, JC, VQ, EC, JSN, SH, EM, TP, HH, CL, JS, SB, JP, CA, SA, and NMF were responsible for data curation and investigation. AS, SH, KJM, JLB, AC, NMF, and ALal did the formal data analysis. MAC, AB, DJ, SM, JE, PSF, SD, and ALac did the laboratory work. RV, RK, JF, CT, AVK, JC, VQ, EC, JSN, SH, EM, and SE oversaw the project. Equally, SH, JD, KJM, JLB, NMF, and ALal accessed and verified the data. JD, MZ, and ALal acquired funding. NMF sourced and oversaw the software. As and ALal wrote the initial draft of the manuscript. AS, JD, GPT, MZ, NMF, SH, and ALal reviewed and edited the manuscript. The corresponding writer had full access to all the data in the study and had final responsibility for the determination to submit for publication.

The ATACCC Written report Investigators

Anjna Badhan, Simon Dustan, Chitra Tejpal, Anjeli V Ketkar, Janakan Sam Narean, Sarah Hammett, Eimear McDermott, Timesh Pillay, Hamish Houston, Constanta Luca, Jada Samuel, Samuel Bremang, Samuel Evetts, John Poh, Charlotte Anderson, David Jackson, Shahjahan Miah, Joanna Ellis, and Angie Lackenby.

Data sharing

An anonymised, de-identified version of the dataset tin can be fabricated available upon request to allow all results to be reproduced. Modelling code will also be made publicly bachelor on the GitHub repository.

Declaration of interests

NMF reports grants from United kingdom Medical Research Council, UK National Institute of Wellness Enquiry, United kingdom Research and Innovation, Community Jameel, Janssen Pharmaceuticals, the Bill & Melinda Gates Foundation, and Gavi, the Vaccine Alliance; consulting fees from the World Banking concern; payment or honoraria from the Wellcome Trust; travel expenses from WHO; advisory lath participation for Takeda; and is a senior editor of the eLife journal. All other authors declare no competing interests.

Acknowledgments

This work is supported past the National Constitute for Health Research (NIHR200927), a Section of Health and Social Care COVID-nineteen Fighting Fund honor, and the NIHR Wellness Protection Enquiry Units (HPRUs) in Respiratory Infections and in Modelling and Wellness Economic science. NMF acknowledges funding from the MRC Centre for Global Infectious Disease Analysis and the Jameel Constitute. PSF and MAC are supported past the UK Dementia Enquiry Establish. JD is supported by the NIHR HPRU in Emerging and Zoonotic Infections. MGW is supported by the NIHR HPRU in Healthcare Associated Infections and Antimicrobial Resistance. GPT is supported by the Imperial NIHR Biomedical Research Centre. We thank all the participants who were involved in the study, Public Health England staff for facilitating recruitment into the study, the staff of the Virus Reference Department for performing PCR and sequencing assays, and the Immunisations Section for assisting with analysis of vaccination data. We also thank Kristel Timcang, Mohammed Essoussi, Holly Grey, Guilia Miserocchi, Harriet Catchpole, Charlotte Williams, Niamh Nichols, Jessica Russell, Sean Nevin, Lulu Wang, Berenice Di Biase, Alice Panes, Esther Barrow, and Lauren Edmunds for their interest in logistics, conducting data entry, or quality control; and the Molecular Diagnostics Unit at Purple College London, in particular Lucy Mosscrop, Carolina Rosadas de Oliveira, and Patricia Watber, for performing RNA extraction, quantitative RT-PCR, and preparing samples for sequencing.

Supplementary Cloth

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Published: October 29, 2021

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• What is the vaccine effect on reducing transmission in the context of the SARS-CoV-2 delta variant?

  • COVID-19 vaccines that accept obtained WHO emergency use listing appear to have high efficacy against severe disease and death, merely lower efficacy confronting non-severe infections, and emerging show suggests that protection confronting not-severe illness declines faster following vaccination than that against astringent disease and death. What is less clear is whether vaccination non only directly protects individuals but reduces the chance of infection amongst the contacts of vaccinated people, specially with respect to the at present dominant delta variant.

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• Correction to Lancet Infect Dis 2021; published online October 28. https://doi.org/10.1016/S1473-3099(21)00648-iv

  • Singanayagam A, Hakki South, Dunning J, et al. Community transmission and viral load kinetics of the SARS-CoV-ii delta (B.1.617.two) variant in vaccinated and unvaccinated individuals in the UK: a prospective, longitudinal, cohort study. Lancet Infect Dis 2021; published online Oct 28. https://doi.org/ten.1016/S1473-3099(21)00648-four—In figure 2B of this Article, the alphabetize cases for households 1–3 were incorrectly labelled as unvaccinated. They have been corrected to "index (vaccinated)". This correction has been made to the online version every bit of Nov ii, 2021, and volition be made to the printed version.

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  • With involvement nosotros read the newspaper by Anika Singanayagam and colleagues¹ assessing the secondary set on rate (SAR) of SARS-CoV-2 in 204 vaccinated and unvaccinated household contacts exposed to 138 vaccinated and unvaccinated index cases. Here, we want to point out the importance of adjusting for age when comparing vaccinated and unvaccinated individuals.

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• Transmissibility of SARS-CoV-2 amongst fully vaccinated individuals – Authors' reply

  • We thank Carlos Franco-Peredes, Mirjam Knol and colleagues, and Humphrey Ko for their interest in our Article.¹ Nosotros reported that one in four household contacts exposed to fully vaccinated alphabetize cases with quantum delta (B.1.617.ii)-variant infections, and one in four fully vaccinated household contacts exposed to delta-infected alphabetize cases, become infected. These are observable risks, which led united states of america to conclude that fully vaccinated individuals remain susceptible to infection and, when breakthrough infection occurs, can efficiently transmit infection in household settings.

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• Transmissibility of SARS-CoV-2 among fully vaccinated individuals

  • Vaccine effectiveness studies have conclusively demonstrated the benefit of COVID-19 vaccines in reducing individual symptomatic and severe disease, resulting in reduced hospitalisations and intensive intendance unit admissions.^one Still, the impact of vaccination on transmissibility of SARS-CoV-2 needs to be elucidated. A prospective accomplice study in the United kingdom past Anika Singanayagam and colleagues² regarding community transmission of SARS-CoV-2 among unvaccinated and vaccinated individuals provides important data that needs to be considered in reassessing vaccination policies.

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Source: https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(21)00648-4/fulltext

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