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Summary
Background
The SARS-CoV-2 delta (B.1.617.ii) variant is highly transmissible and spreading globally, including in populations with high vaccination rates. We aimed to investigate transmission and viral load kinetics in vaccinated and unvaccinated individuals with mild delta variant infection in the community.
Methods
Betwixt Sept thirteen, 2020, and Sept 15, 2021, 602 community contacts (identified via the United kingdom of great britain and northern ireland contract-tracing organisation) of 471 UK COVID-xix alphabetize cases were recruited to the Assessment of Transmission and Contagiousness of COVID-19 in Contacts cohort study and contributed 8145 upper respiratory tract samples from daily sampling for up to xx days. Household and non-household exposed contacts aged 5 years or older were eligible for recruitment if they could provide informed consent and concur to self-swabbing of the upper respiratory tract. We analysed transmission risk past vaccination status for 231 contacts exposed to 162 epidemiologically linked delta variant-infected index cases. We compared viral load trajectories from fully vaccinated individuals with delta infection (n=29) with unvaccinated individuals with delta (n=16), alpha (B.1.1.7; northward=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 status and the index cases' vaccination status. Primary outcomes for the viral load kinetics analysis were to discover differences in the peak viral load, viral growth charge per unit, and viral decline charge per unit 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 fourth dimension 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 similar to household contacts exposed to unvaccinated index cases (25% [95% CI xv–35] for vaccinated vs 23% [xv–31] for unvaccinated). 12 (39%) of 31 infections in fully vaccinated household contacts arose from fully vaccinated epidemiologically linked alphabetize cases, farther confirmed by genomic and virological analysis in three index instance–contact pairs. Although peak viral load did not differ by vaccination condition or variant type, information technology increased modestly with age (difference of 0·39 [95% credible interval –0·03 to 0·79] in peak logx viral load per mL between those aged x years and 50 years). Fully vaccinated individuals with delta variant infection had a faster (posterior probability >0·84) mean rate of viral load decline (0·95 log10 copies per mL per day) than did unvaccinated individuals with pre-alpha (0·69), alpha (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 0·13 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. However, fully vaccinated individuals with breakthrough infections have meridian viral load like 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 entire viral trajectory.
Funding
National Institute for Health Research.
Introduction
While the primary aim of vaccination is to protect individuals against severe COVID-19 disease and its consequences, the extent to which vaccines reduce onward manual of SARS-CoV-2 is central to containing the pandemic. This outcome depends on the power of vaccines to protect confronting infection and the extent to which vaccination reduces the infectiousness of breakthrough infections.
Research in context
Evidence before this study
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 manual from vaccinated delta-infected individuals to their vaccinated contacts is a public health 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 twenty, 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 report of a cohort of hospitalised patients in Singapore, more rapid viral load turn down was found in vaccinated individuals than unvaccinated cases. However, the unvaccinated cases in this study had moderate-to-severe infection, which is known to be associated with prolonged shedding. The second report longitudinally sampled professional USA sports players. Once again, clearance of delta viral RNA in vaccinated cases was faster than in unvaccinated cases, but simply 8% of unvaccinated cases had delta variant infection, complicating interpretation. Lastly, a written report of a single-source nosocomial outbreak of a distinct delta sub-lineage in Vietnamese health-care workers plotted viral load kinetics (without comparison with unvaccinated delta infections) and demonstrated transmission between fully vaccinated wellness-care workers in the nosocomial setting. The findings might therefore not be generalisable beyond the particular setting and distinct viral sub-lineage investigated.
Added value of this written report
The bulk of SARS-CoV-2 manual occurs in households, but transmission between fully vaccinated individuals in this setting has non been shown to date. To ascertain secondary transmission 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–xx days. We found that the secondary attack charge per unit in fully vaccinated household contacts was high at 25%, merely this value was lower than that of unvaccinated contacts (38%). Hazard of infection increased with time in the 2–3 months since the second dose of vaccine. The proportion of infected contacts was similar regardless of the index cases' vaccination status. We observed transmission of the delta variant between fully vaccinated index cases and their fully vaccinated contacts in several households, confirmed past whole-genome sequencing. Peak viral load did non differ by vaccination status or variant type but did increase modestly with historic period. Vaccinated delta cases experienced faster viral load decline than did unvaccinated blastoff or delta cases. Across report participants, faster viral load growth was correlated with higher peak viral load and slower decline, suggesting that host–virus interactions early in infection shape the unabridged viral trajectory. Since our findings are derived from community household contacts in a real-life setting, they are probably generalisable to the full general population.
Implications of all the available bear witness
Although vaccines remain highly effective at preventing severe affliction and deaths from COVID-19, our findings suggest that vaccination is not sufficient to prevent transmission of the delta variant in household settings with prolonged exposures. Our findings highlight the importance of community studies to characterise the epidemiological phenotype of new SARS-CoV-2 variants in increasingly highly vaccinated populations. Continued public health and social measures to adjourn transmission of the delta variant remain of import, even in vaccinated individuals.
Vaccination was institute to be effective in reducing household transmission of the alpha variant (B.1.1.7) by xl–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.1.617.2), which is more than transmissible than the blastoff variant,
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is now the dominant strain worldwide. After a large outbreak in Republic of india, the UK was one of the get-go countries to report a sharp rise in delta variant infection. Electric current vaccines remain highly effective at preventing admission to hospital and death from delta infection.
However, vaccine effectiveness against infection is reduced for delta, compared with blastoff,
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and the delta variant continues to crusade a high burden of cases fifty-fifty in countries with loftier vaccination coverage. Data are scarce on the gamble of community transmission of delta from vaccinated individuals with balmy infections.
Hither, nosotros report data from a UK customs-based study, the Assessment of Manual 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 information. Nosotros aimed to quantify household manual of the delta variant and appraise the effect of vaccination condition on contacts' run a risk of infection and alphabetize cases' infectiousness, including (1) households with unvaccinated contacts and alphabetize cases and (2) households with fully vaccinated contacts and fully vaccinated index cases. We also compared sequentially sampled URT viral RNA trajectories from individuals with non-severe delta, alpha, and pre-alpha SARS-CoV-2 infections to infer the furnishings of SARS-CoV-2 variant condition—and, for delta infections, vaccination status—on manual potential.
Methods
Report pattern and participants
ATACCC is an observational longitudinal cohort study of community contacts of SARS-CoV-2 cases. Contacts of symptomatic PCR-confirmed index cases notified to the UK contact-tracing system (National Health Service Examination 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 within five days of alphabetize example symptom onset were selected to be contacted within our recruitment capacity. Household and not-household contacts anile five years or older were eligible for recruitment if they could provide written informed consent and agree to self-swabbing of the URT. Further details on URT sampling are given in the appendix (p 13).
The ATACCC study is separated into two study artillery, ATACCC1 and ATACCC2, which were designed to capture different waves of the SARS-CoV-2 pandemic. In ATACCC1, which investigated blastoff variant and pre-alpha cases in Greater London, only contacts were recruited between Sept thirteen, 2020, and March thirteen, 2021. ATACCC1 included a pre-blastoff wave (September to November, 2020) and an alpha wave (Dec, 2020, to March, 2021). In ATACCC2, the report 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 xv, 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 transmission was moderate-to-high throughout almost of our recruitment catamenia.
This study was canonical by the Health Research Authorization. Written informed consent was obtained from all participants before enrolment. Parents and caregivers gave consent for children.
Data collection
Demographic information was collected by the study squad on enrolment. The date of exposure for non-household contacts was obtained from Public Health England. COVID-19 vaccination history was determined from the United kingdom of great britain and northern ireland National Immunisation Management Arrangement, general practitioner records, and self-reporting by report participants. We defined a participant as 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 one vaccine dose at least 7 days earlier study enrolment, and fully vaccinated if they had received two doses of a COVID-19 vaccine at least vii days before study enrolment. Previous literature was used to make up one's mind the 7-solar day threshold for defining vaccination condition.
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We besides did sensitivity analyses using a 14-day threshold. The time interval between vaccination and study recruitment was calculated. We used WHO criteria
to define symptomatic status up to the day of study recruitment. Symptomatic status for incident cases—participants who were PCR-negative at enrolment and afterwards tested positive—was defined from the day of the kickoff PCR-positive result.
Laboratory procedures
SARS-CoV-ii quantitative RT-PCR, conversion of ORF1ab and envelope (E-gene) cycle threshold values to viral genome copies, whole-genome sequencing, and lineage assignments are described in the appendix (pp 13–xiv).
Outcomes
Primary outcomes for the epidemiological analysis were to assess the secondary assault charge per unit (SAR) in household contacts stratified past contact vaccination status and the index cases' vaccination status. Primary outcomes for the viral load kinetics analysis were to detect differences in the peak viral load, viral growth rate, and viral decline rate between participants infected with pre-alpha versus blastoff versus delta variants and betwixt unvaccinated delta-infected participants and vaccinated delta-infected participants.
We assessed vaccine effectiveness and susceptibility to SARS-CoV-two infection stratified past time elapsed since receipt of second vaccination equally exploratory analyses.
Statistical analysis
To model viral kinetics, we used a unproblematic phenomenological model of viral titre
during disease pathogenesis. Viral kinetic parameters were estimated on a participant-specific basis using a Bayesian hierarchical model to fit this model to the entire dataset of sequential cycle 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 bike 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 past assuming there was a probability p of a test giving an observation drawn from a (normal) mistake distribution and probability 1 –p of it being drawn from the truthful distribution.
The hierarchical structure was represented by group participants based on the infecting variant and their vaccination status. A single-group model was fitted, which implicitly assumes that viral kinetic parameters vary by private but not by variant or vaccination status. A iv-group model was also explored, where groups i, 2, iii, and iv represent pre-alpha, alpha, unvaccinated delta, and fully vaccinated delta, respectively. We fitted a correlation matrix between participant-specific kinetic parameters to allow u.s. to examine whether at that place is inside-group correlation between top viral titre, viral growth rate, and viral decline rate. Our initial model selection, using leave-1-out cantankerous-validation, selected a four-group hierarchical model with fitted correlation coefficients betwixt private-level parameters determining peak viral load and viral load growth and pass up rates (appendix p v). However, resulting participant-specific estimates of elevation viral load (simply non growth and refuse rates) showed a marked and significant correlation with age in the exploratory analysis, which motivated examination of models where mean peak viral load could vary with historic period. The near predictive model overall allowed mean viral load growth and pass up rates to vary beyond the four groups, with mean peak viral load mutual to all groups but assumed to vary linearly with the logarithm of age (appendix p 5). We present superlative viral loads for the reference age of 50 years with 95% credible intervals (95% CrIs). 50 years was chosen as the reference age equally information technology 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 grouping-level population means and within-sample grouping means of log peak viral titre, viral growth rate, and viral refuse rate. Since posterior estimates of each of these variables are correlated across groups, overlap in the credible intervals of an approximate for one group with that for another group does not necessarily signal no significant departure between those groups. Nosotros, therefore, computed posterior probabilities, pp, that these variables were larger for one grouping than another. For our model, Bayes factors can be computed every bit pp/(i–pp). We only report population (group-level) posterior probabilities greater than 0·75 (corresponding to Bayes factors >3) as indicating at least moderate testify of a departure.
For vaccine effectiveness, nosotros divers the estimated effectiveness at preventing infection, regardless of symptoms, with delta in the household setting as one – SAR (fully vaccinated) / SAR (unvaccinated).
Role of the funding source
The funder of the study had no office in study pattern, data drove, information assay, data interpretation, or writing of the report.
Results
Between Sept thirteen, 2020, and Sept 15, 2021, 621 community-based participants (602 contacts and 19 index 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 index 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 index cases and 53 contacts), 42 had alpha variant infection (one index case and 41 contacts), and 50 had pre-alpha variant infection (all contacts; effigy 1A).
Effigy 1 Recruitment, SARS-CoV-ii infection, variant condition, and vaccination history for ATACCC study participants
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(A) Study recruitment and variant condition confirmed by whole-genome sequencing (ATACCC1 and ATACCC2 combined). (B) ATACCC2: delta-exposed contacts included in secondary attack rate calculation (table 1) and manual assessment (table 2). NHS=National Health Service. *All index cases were from ATACCC2. † All contacts. ‡The 2 earliest PCR-positive cases from the ATACCC2 cohort (one index instance 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 figure 1B. §One PCR-negative contact had no vaccination condition information available and i PCR-negative contact'south index case had no vaccination information available. ¶Vaccination data were bachelor for 138 alphabetize cases of 163. ||The contacts of these 15 alphabetize cases are included inside the 232 total contacts. **These three alphabetize cases without contacts are merely included in the viral load kinetics analysis (figure 3) and are not included in tables 1 and two.
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Of 163 PCR-positive participants, 89 (55%) were female person and 133 (82%) were White. Median age was 36 years (IQR 26–50). Sex, historic period, ethnicity, torso-mass index (BMI) distribution, and the frequency of comorbidities were similar amid those with delta, alpha, and pre-blastoff infection, and for vaccinated and unvaccinated delta-infected participants, except for historic period and sex (appendix pp ii–3). At that place were fewer unvaccinated females than males (p=0·04) and, as expected from the historic period-prioritisation of the Great britain vaccine roll-out, unvaccinated participants infected with the delta variant were significantly younger (p<0·001; appendix p 3). Median time between exposure to the index case and study enrolment was iv days (IQR four–5). All participants had non-severe ambulatory illness or were asymptomatic. The proportion of asymptomatic cases did not differ among fully vaccinated, partially vaccinated, and unvaccinated delta groups (appendix p 3).
No pre-blastoff-infected and merely one alpha-infected participant had received a COVID-nineteen vaccine before study enrolment. Of 71 delta-infected participants (of whom 18 were alphabetize cases), 23 (32%) were unvaccinated, x (14%) were partially vaccinated, and 38 (54%) were fully vaccinated (figure 1A; appendix p 3). Of the 38 fully vaccinated delta-infected participants, fourteen had received the BNT162b2 mRNA vaccine (Pfizer–BioNTech), 23 the ChAdOx1 nCoV-19 adenovirus vector vaccine (Oxford–AstraZeneca), and one the CoronaVac inactivated whole-virion vaccine (Sinovac).
It is highly likely that all merely one of the 233 ATACCC2 contacts were exposed to the delta variant considering they were recruited when the regional prevalence of delta was at least 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 status, and comorbidities were similar between PCR-positive and PCR-negative contacts (appendix p iv). The median time betwixt 2d vaccine dose and study recruitment in fully vaccinated contacts with delta variant infection was 74 days (IQR 35–105; range sixteen–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 20–32). SAR was not significantly higher in unvaccinated (38%, 95% CI 24–53) than fully vaccinated (25%, 18–33) household contacts (tabular array one). Nosotros estimated vaccine effectiveness at preventing infection (regardless of symptoms) with delta in the household setting to exist 34% (bootstrap 95% CI –15 to lx). Sensitivity analyses using a 14 day threshold for time since 2nd vaccination to study recruitment to announce fully vaccinated did not materially bear on our estimates of vaccine effectiveness or SAR (data not shown). Although precision is restricted by the small 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 study
| Full | PCR positive | PCR negative | SAR (95% CI) | p value | |
|---|---|---|---|---|---|
| Contacts | |||||
| All | 231 | 53 | 178 | 23 (xviii–29) | NA |
| Fully vaccinated | 140 | 31 | 109 | 22 (xvi–30) | 0·16 |
| Unvaccinated | 44 | 15 | 29 | 34 (22–49) | .. |
| Partially vaccinated | 47 | 7 | 40 | fifteen (7–28) | NA |
| Household contacts | |||||
| All | 205 | 53 | 152 | 26 (20–32) | NA |
| Fully vaccinated | 126 | 31 | 95 | 25 (18–33) | 0·17 |
| Unvaccinated | forty | fifteen | 25 | 38 (24–53) | .. |
| Partially vaccinated | 39 | 7 | 32 | 18 (ix–33) | NA |
χii test was performed to calculate p values for differences in SAR between fully vaccinated and unvaccinated cases. One PCR-negative contact who withdrew from the study without vaccination status information was excluded. NA=not applicable. SAR=secondary assault rate.
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The vaccination status of 138 epidemiologically linked index cases of 204 delta variant-exposed household contacts was available (figure 1B, tabular array ii). The SAR in household contacts exposed to fully vaccinated alphabetize 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% [15–31]; 23 of 100; table 2). The 53 PCR-positive contacts arose from household exposure to 39 PCR-positive index cases. Of these index cases who gave rise to secondary transmission, the proportion who were fully vaccinated (15 [38%] of 39) was like 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). Fourth dimension interval did not differ between alphabetize 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).
Tabular array 2 Comparison of vaccination condition of the 138 epidemiologically linked PCR-positive index cases for 204 delta variant-exposed household contacts
| All household contacts (due north=204) * The rows below prove the number of contacts exposed to each category of index case. | Fully vaccinated contacts (n=125) | Partially vaccinated contacts (n=39) | Unvaccinated contacts (n=40) | ||||
|---|---|---|---|---|---|---|---|
| PCR positive (n=31) | PCR negative (n=94) | PCR positive (n=7) | PCR negative (north=32) | PCR positive (n=15) | PCR negative (northward=25) | ||
| Fully vaccinated alphabetize cases (north=50) | 69 | 12 | 31 | 1 | 8 | 4 | 13 |
| Partially vaccinated index cases (n=25) | 35 | 7 | 12 | 3 | 10 | 3 | 0 |
| Unvaccinated index cases (n=63) | 100 | 12 | 51 | 3 | fourteen | viii | 12 |
Not-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 non exist linked to their index case was besides excluded.
* The rows below show the number of contacts exposed to each category of alphabetize case.
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18 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 fifteen of these, their contacts were likewise recruited (13 household contacts and two non-household contacts). A corresponding PCR-positive household contact was identified for four of these 15 alphabetize cases (figure 1B). Genomic analysis showed that index–contact pairs were infected with the same delta variant sub-lineage in these instances, with 1 exception (figure 2A). In ane household (number four), an unvaccinated index 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 outside 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 betwixt the viral load kinetics that were consistent with transmission from the alphabetize cases to their corresponding contacts (figure 2B).
Figure 2 Virological, epidemiological, and genomic evidence for manual of the SARS-CoV-two delta variant (B.1.617.2) in households
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(A) Genomic analysis of the 4 households with lineage-defining mutations for delta
and additional mutations within ORFs displayed to give insight into whether strains from individuals within the household are closely related. Lineages AY.iv and AY.9 are sub-lineages of delta. (B) Viral trajectories and vaccination status of the four index 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 case and their household contacts. Undetectable viral load measurements are plotted at the limit of detection (10one·49). C=contact. I=index case. FV=fully vaccinated. ORF=open reading frame. PV=partially vaccinated. U=unvaccinated.
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Inclusion criteria for the modelling analysis selected 133 participant's viral load RNA trajectories from 163 PCR-positive participants (49 with the pre-alpha variant, 39 alpha, and 45 delta; appendix p 14). Of the 45 delta cases, 29 were fully vaccinated and 16 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 afterwards) and 104 (78%) were prevalent (ie, already PCR positive at enrolment). 15 of the prevalent cases had a clearly resolvable peak viral load. Figure 3 shows modelled viral RNA (ORF1ab) trajectories together with the viral RNA re-create numbers measured for individual participants. The E-factor equivalent is shown in the appendix (p 2). Estimates derived from E-factor cycle threshold value data (appendix pp 5, 7, 9, xi) were similar to those for ORF1ab.
Figure iii ORF1ab viral load trajectories from 14 days before to 28 days later peak for 133 participants infected with pre-blastoff or blastoff 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 24-hour interval of enrolment. Plots are rooted on the day of top viral load for each participant, denoted every bit 24-hour interval 0 on the x-centrality. Curves show the model posterior median estimate, with a 95% credible interval shading. 133 infected participants, comprising 114 contacts and xix index cases. *Alphabetize cases.
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Figure 3 ORF1ab viral load trajectories from xiv days before to 28 days after peak for 133 participants infected with pre-blastoff or alpha variants (uncaccinated), or the delta variant (vaccinated and unvaccinated) variants
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Blackness circles are measured values, with the kickoff datapoint for each participant being taken to the day of enrolment. Plots are rooted on the day of peak viral load for each participant, denoted as day 0 on the x-centrality. Curves evidence the model posterior median approximate, with a 95% credible interval shading. 133 infected participants, comprising 114 contacts and 19 alphabetize cases. *Alphabetize cases.
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Although viral kinetics appear visually similar for all four groups of cases, nosotros establish quantitative differences in estimated viral growth rates and decline rates (Table 3, Tabular array 4). Population (group-level) estimates of mean viral load decline rates based on ORF1ab cycle threshold value information varied in the range of 0·69–0·95 log10 units per mL per daxes 4; appendix p x), indicating that a typical ten-day period was required for viral load to turn down from superlative 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 decline charge per unit of the fully vaccinated delta group was too 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 mean elapsing of the decline phase between the pre-alpha and delta vaccinated groups.
Table three Estimates of VL growth rates for pre-alpha, alpha, and delta (unvaccinated and fully vaccinated) cases, derived from ORF1ab cycle threshold data
| VL growth charge per unit (95% CrI), log 10 units per day | Posterior probability approximate is less than pre-alpha | Posterior probability estimate is less than alpha | Posterior probability estimate is less than delta (unvaccinated) | Posterior probability estimate is less than delta (fully vaccinated) | |
|---|---|---|---|---|---|
| Pre-alpha (n=49) | three·24 (i·78–half-dozen·fourteen) | .. | 0·44 | 0·27 | 0·21 |
| Alpha (n=39) | 3·13 (1·76–5·94) | 0·56 | .. | 0·32 | 0·25 |
| Delta, unvaccinated (due north=16) | 2·81 (one·47–5·47) | 0·73 | 0·68 | .. | 0·44 |
| Delta, fully vaccinated (n=29) | 2·69 (1·51–5·17) | 0·79 | 0·75 | 0·56 | .. |
VL growth rates are shown as within-sample posterior mean estimates. Remaining columns testify population (group-level) posterior probabilities that the gauge on that row is less than an estimate for a different 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 four Estimates of VL turn down rates for pre-alpha, alpha, and delta (unvaccinated and fully vaccinated) cases, derived from ORF1ab cycle threshold data
| VL turn down rate (95% CrI), log ten units per twenty-four hours | Posterior probability guess is larger than pre-blastoff | Posterior probability gauge is larger than alpha | Posterior probability estimate is larger than delta (unvaccinated) | Posterior probability approximate is larger than delta (fully vaccinated) | |
|---|---|---|---|---|---|
| Pre-alpha (n=49) | 0·69 (0·58–0·81) | .. | 0·07 | 0·21 | 0·01 |
| Alpha (n=39) | 0·82 (0·67–1·01) | 0·93 | .. | 0·60 | 0·16 |
| Delta, unvaccinated (due north=16) | 0·79 (0·59–one·04) | 0·79 | 0·40 | .. | 0·15 |
| Delta, fully vaccinated (n=29) | 0·95 (0·76–ane·18) | 0·99 | 0·84 | 0·85 | .. |
VL decline rates are shown every bit within-sample posterior mean estimates. Remaining columns show population (group-level) posterior probabilities that the estimate on that row is less than an gauge for a different grouping. Posterior probabilities are derived from xx 000 posterior samples and have sampling errors of <0·01. VL=viral load. CrI=credible interval.
- Open up table in a new tab
Viral load growth rates were substantially faster than pass up rates, varying in the range of ii·69–three·24 log10 units per mL per day betwixt groups, indicating that a typical three-mean solar day period was required for viral load to grow from undetectable to peak. Our power to infer differences in growth rates between groups was more restricted than for viral pass up, but there was moderate evidence (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-twelvemonth-old adults to be 8·14 (95% CrI 7·95 to viii·32) logten copies per mL, but peak viral load did not differ by variant or vaccination status. Yet, nosotros estimated that pinnacle viral load increases with age (pp=0·96 that the slope of elevation viral load with log[age] was >0), with an estimated slope of 0·24 (95% CrI –0·02 to 0·49) log10 copies per mL per unit change in log(age). This guess translates to a departure of 0·39 (–0·03 to 0·79) in mean peak logten copies per mL betwixt those anile 10 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 0·13 to 0·65; appendix p viii). Hence, individuals with faster viral load growth tend to accept higher acme viral load. The decline rate of viral load was besides 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 decline.
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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 consequent with the known protective event of COVID-xix vaccination confronting infection.
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Withal, these findings signal continued 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.
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The fourth dimension interval between vaccination and study recruitment was significantly higher in fully vaccinated PCR-positive contacts than fully vaccinated PCR-negative contacts, suggesting that susceptibility to infection increases with time equally soon equally 2–iii months after vaccination—consistent with waning protective immunity. This potentially of import observation is consistent with recent large-scale information and requires further investigation.
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However, we sampled contacts daily, regardless of symptomatology, to actively identify infection with high sensitivity. Past dissimilarity, symptom-based, single-timepoint surveillance testing probably underestimates the true SAR, and potentially also overestimates vaccine effectiveness against infection.
Nosotros identified similar SAR (25%) in household contacts exposed to fully vaccinated index cases equally in those exposed to unvaccinated alphabetize 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 manual events between fully vaccinated index instance–contact pairs; for iii of these, genomic sequencing confirmed that the alphabetize instance and contact were infected by the aforementioned delta variant sub-lineage, thus substantiating epidemiological information and temporal relationships of viral load kinetics to provide definitive prove for secondary transmission. To our knowledge, i other study has reported that transmission of the delta variant between fully vaccinated people was a point-source nosocomial outbreak—a single wellness-care worker with a particular delta variant sub-lineage in Vietnam.
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Our most predictive model of viral load kinetics estimated mean superlative log10 viral load per mL of 8·14 (95% CrI seven·95–8·32) for adults aged 50 years, which is very similar to the estimate from a 2021 report using routine surveillance data.
We found no evidence of variation in meridian viral load past variant or vaccination condition, but we written report some testify of small-scale but significant (pp=0·95) increases in meridian viral load with age. Previous studies of viral load in children and adults
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reported a like difference between children and adults to the ane we estimated. We constitute the rate of viral load decline was faster for vaccinated individuals with delta infection than all other groups, and was faster for individuals in the blastoff 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 modest scale of differences in viral kinetics between fully vaccinated and unvaccinated individuals with delta infection might explain the relatively loftier rates of transmission seen from vaccinated delta index cases in our study. We constitute no evidence of lower SARs from fully vaccinated delta index cases than from unvaccinated ones. However, given that index cases were identified through routine symptomatic surveillance, there might have been a option bias towards identifying untypically symptomatic vaccine breakthrough index cases.
The differences in viral kinetics we establish betwixt the pre-alpha, alpha, and delta variant groups advise some incremental, but potentially adaptive, changes in viral dynamics associated with the evolution of SARS-CoV-2 towards more rapid viral clearance. Our report provides the first evidence that, within each variant or vaccination group, viral growth rate is positively correlated with peak viral load, but is negatively correlated with viral refuse rate. This finding suggests that private infections during which viral replication is initially fastest generate the highest superlative viral load and see the slowest viral clearance, with the latter not just being due to the higher height. Mechanistically, these data suggest that the host and viral factors determining the initial growth rate of SARS-CoV-2 have a central consequence on the trajectory throughout infection, with faster replication being more difficult (in terms of both peak viral load and the subsequent refuse of viral load) for the immune response to command. Analysis of sequentially sampled immune markers during infection might requite insight into the allowed 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 be tested in time to come studies.
Several population-level, unmarried-timepoint sampling studies using routinely bachelor data take constitute no major differences in cycle threshold values betwixt vaccinated and unvaccinated individuals with delta variant infection.
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A longitudinal sampling study in the Usa reported that pre-blastoff, blastoff, and delta variant infections had similar viral trajectories.
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The study also compared trajectories in vaccinated and unvaccinated individuals, reporting similar proliferation phases and superlative cycle threshold values, simply more rapid clearance of virus in vaccinated individuals. All the same, this study in the USA stratified by vaccination status and variant separately, rather than jointly, meaning vaccinated individuals with delta infection were beingness compared with, predominantly, unvaccinated individuals with pre-alpha and alpha infection. Moreover, sampling was washed equally part of a professional sports role player occupational wellness screening programme, making the results not necessarily representative of typical community infections.
Our report has limitations. First, nosotros recruited only contacts of symptomatic index cases equally our report recruitment is derived from routine contact-tracing notifications. Second, alphabetize cases were defined as the kickoff household member to take a PCR-positive swab, but we cannot exclude the possibility that another household member might already take been infected and transmitted to the index case. Third, recording of viral load trajectories is subject to left censoring, where the growth phase in prevalent contacts (already PCR-positive at enrolment) was missed for a proportion of participants. However, we captured 29 incident cases and xv additional cases on the upslope of the viral trajectory, providing valuable, informative information on viral growth rates and tiptop viral load in a subset of participants. 4th, owing to the age-stratified rollout of the Britain vaccination program, the age of the unvaccinated, delta variant-infected participants was lower than that of vaccinated participants. Thus, age might exist a confounding cistron in our results and, as discussed, height viral load was associated with historic period. Still, information technology is unlikely that the higher SAR observed in the unvaccinated contacts would have been driven by younger age rather than the absence of vaccination and, to our noesis, in that location is no published evidence showing increased susceptibility to SARS-CoV-ii infection with decreasing historic period.
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Our findings help to explain how and why the delta variant is being transmitted then finer in populations with high vaccine coverage. Although current vaccines remain constructive at preventing severe disease and deaths from COVID-19, our findings advise that vaccination solitary is not sufficient to prevent all transmission of the delta variant in the household setting, where exposure is shut and prolonged. Increasing population immunity via booster programmes and vaccination of teenagers will help to increase the currently limited effect of vaccination on manual, but our analysis suggests that direct protection of individuals at risk of severe outcomes, via vaccination and non-pharmacological interventions, will remain central to containing the burden of disease caused by the delta variant.
This online publication has been corrected. The corrected version first appeared at thelancet.com/infection on Nov 2, 2021
Contributors
AS, JD, MZ, NMF, WB, and ALal conceptualised the written report. 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 information curation and investigation. Equally, 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. AS, SH, JD, KJM, JLB, NMF, and ALal accessed and verified the data. JD, MZ, and ALal caused funding. NMF sourced and oversaw the software. Every bit and ALal wrote the initial draft of the manuscript. As, JD, GPT, MZ, NMF, SH, and ALal reviewed and edited the manuscript. The respective writer had full access to all the data in the study and had concluding responsibility for the decision to submit for publication.
The ATACCC Study 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 can be fabricated available upon request to permit all results to be reproduced. Modelling lawmaking volition also exist made publicly available on the GitHub repository.
Proclamation of interests
NMF reports grants from United kingdom of great britain and northern ireland Medical Research Quango, UK National Plant of Health Research, UK Inquiry and Innovation, Customs Jameel, Janssen Pharmaceuticals, the Beak & Melinda Gates Foundation, and Gavi, the Vaccine Brotherhood; consulting fees from the Globe Bank; payment or honoraria from the Wellcome Trust; travel expenses from WHO; advisory board participation for Takeda; and is a senior editor of the eLife journal. All other authors declare no competing interests.
Acknowledgments
This work is supported by the National Establish for Health Research (NIHR200927), a Department of Health and Social Care COVID-nineteen Fighting Fund award, and the NIHR Health Protection Research Units (HPRUs) in Respiratory Infections and in Modelling and Health Economics. NMF acknowledges funding from the MRC Middle for Global Infectious disease Analysis and the Jameel Constitute. PSF and MAC are supported by the UK Dementia Research Institute. JD is supported by the NIHR HPRU in Emerging and Zoonotic Infections. MGW is supported past the NIHR HPRU in Healthcare Associated Infections and Antimicrobial Resistance. GPT is supported by the Purple NIHR Biomedical Research Centre. We thank all the participants who were involved in the study, Public Health England staff for facilitating recruitment into the written report, the staff of the Virus Reference Department for performing PCR and sequencing assays, and the Immunisations Department for profitable 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 involvement in logistics, conducting data entry, or quality control; and the Molecular Diagnostics Unit at Imperial College London, in detail Lucy Mosscrop, Carolina Rosadas de Oliveira, and Patricia Watber, for performing RNA extraction, quantitative RT-PCR, and preparing samples for sequencing.
Supplementary Fabric
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Published: October 29, 2021
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DOI: https://doi.org/ten.1016/S1473-3099(21)00648-four
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Nosotros give thanks Carlos Franco-Peredes, Mirjam Knol and colleagues, and Humphrey Ko for their interest in our Commodity.1 We reported that i in iv household contacts exposed to fully vaccinated index cases with breakthrough delta (B.1.617.2)-variant infections, and 1 in four fully vaccinated household contacts exposed to delta-infected alphabetize cases, become infected. These are appreciable risks, which led us to conclude that fully vaccinated individuals remain susceptible to infection and, when breakthrough infection occurs, tin can efficiently transmit infection in household settings.
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Source: https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(21)00648-4/fulltext
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