Infectiousness of SARS-CoV-2 breakthrough infections and reinfections during the Omicron wave - Nature.com

Transmission dynamics of terrible acute respiratory syndrome coronavirus 2 (SARS-CoV-2) person shifted implicit the people of the pandemic owed to wide vaccination, earthy corruption and emergence of caller variants¹. Although the aboriginal pandemic was characterized by infections successful afloat susceptible individuals, SARS-CoV-2 breakthrough infections among vaccinated individuals and reinfections among antecedently infected individuals are present progressively frequent^2,3,4. After the emergence of the highly infectious Omicron variant successful December 2021, the United States observed the largest surge successful Coronavirus Disease 2019 (COVID-19) cases to date⁵. Determining the interaction of vaccination, including booster doses, and anterior corruption connected the infectiousness of individuals with Omicron variant infections remains indispensable to recognize transmission dynamics of these variants.

There are constricted information connected the infectiousness of breakthrough SARS-CoV-2 infections successful vaccinated individuals and reinfections with the Omicron variant, particularly successful high-risk transmission settings, specified arsenic prisons. Before the Omicron variant, disposable information connected the infectiousness of SARS-CoV-2 breakthrough infections successful vaccinated individuals was mixed; determination was grounds to enactment reduced infectiousness of breakthrough infections successful household studies and done survey of viral kinetics^6,7,8, though different studies person recovered nary quality successful the infectiousness of superior and breakthrough SARS-CoV-2 infections^9,10. These information were predominately among individuals immunized lone with superior bid doses^6,7,8,9,10. More caller information from household studies of Omicron variant transmission enactment that vaccination whitethorn trim infectiousness, though they are often constricted successful capturing elaborate aspects of the transmission situation and accounting for enactment with anterior infection^11,12,13.

Studying the transmission dynamics of the SARS-CoV-2 Omicron variant and the interaction of vaccination and anterior corruption is particularly important successful vulnerable, high-risk populations with aggravated ongoing transmission, specified arsenic the incarcerated population. The COVID-19 pandemic has disproportionately affected incarcerated individuals^14,15, arsenic transmission of SARS-CoV-2 remains precocious successful situation settings, fueled, successful part, by overcrowding, mediocre oregon deficiency of ventilation and instauration from assemblage sources contempt precocious vaccination rates among residents^{14,16,17,18,19,20,21}. In this study, we study connected the infectiousness of SARS-CoV-2 infections occurring successful vaccinated individuals and/or those with anterior corruption comparative to unvaccinated and antecedently uninfected individuals who were incarcerated successful a US authorities situation strategy during the archetypal 5 months of the Omicron question (subvariants BA.1 and BA.2). Our findings person wide implications for nationalist wellness policy, with peculiar relevance to incarcerated populations and different high-density congregate surviving environments.

SARS-CoV-2 infections and investigating wrong the survey population

We analyzed elaborate records of SARS-CoV-2 corruption and lodging information from each 35 big institutions successful California’s authorities situation strategy during periods of high-volume testing, assessing hazard of transmission betwixt individuals sharing a compartment with coagulated doors and walls. We aimed to measure the infectiousness of Omicron variant SARS-CoV-2 infections successful confirmed scale cases, stratified by their vaccine presumption and anterior corruption history. We analyzed information during a 5-month interval (15 December 2021 to 23 May 2022) of wide circulation of Omicron variants (subvariants BA.1 and BA.2), during periods of some systematic and reactive SARS-CoV-2 testing. In total, determination were 22,334 confirmed SARS-CoV-2 infections and 31 hospitalizations owed to COVID-19 successful the survey colonisation (n = 111,687) during the survey play (Figs. 1 and 2 and Supplementary Fig. 1). The survey colonisation was 97% antheral based connected the colonisation incarcerated successful these institutions. Residents were tested connected mean 8.1 times (interquartile scope (IQR): 4–11) for SARS-CoV-2 implicit the 5-month period. The mean clip betwixt tests successful the survey colonisation was 11.7 days (IQR: 4–10) (Supplementary Fig. 2). Most scale cases were moved into quarantine oregon isolation wrong 3 days of their archetypal affirmative test. Additional details connected testing, quarantine and isolation successful California authorities prisons are included successful Supplementary Notes.

Fig. 1: SARS-CoV-2 infections and vaccination implicit clip successful the survey colonisation successful California authorities prisons.

We obtained information connected SARS-CoV-2 infections, vaccination and interaction past for residents incarcerated successful the California authorities situation strategy from 1 March 2020 to 20 May 2022. a, Number of SARS-CoV-2 infections implicit clip successful the California authorities situation system. b, Number of COVID-19 scale cases included successful the investigation implicit time, stratified by past of anterior earthy corruption and vaccination. c, Number of COVID-19 scale cases by instauration during the Omicron question (15 December 2021 to 20 May 2022) included successful the analysis. d, COVID-19 vaccine sum implicit clip for residents successful the California authorities situation strategy by superior bid and booster dose. The shaded portion successful a and d corresponds with the Omicron variant wave.

Fig. 2: Study colonisation travel chart.

We obtained information connected residents incarcerated successful the California authorities situation strategy from 1 March 2020 to 20 May 2022 who were diagnosed with COVID-19 based connected a affirmative test. We applied the inclusion and exclusion criteria to Omicron scale cases of COVID-19 and adjacent contacts who shared a compartment for astatine slightest 1 night. The illustration size astatine each measurement is plotted successful the figure.

We identified 1,226 scale cases implicit the survey play based connected the inclusion criteria of having a affirmative SARS-CoV-2 diagnostic trial (without a anterior affirmative trial successful the preceding 90 days), continuous incarceration opening earlier 1 April 2020 (to guarantee reliable reporting of anterior SARS-CoV-2 infection) and a valid adjacent interaction successful a shared, closed-door compartment (Figs. 1 and 2 and Supplementary Fig. 1). We defined adjacent contacts of the scale lawsuit arsenic residents who shared a compartment with an scale lawsuit for astatine slightest 1 nighttime portion the scale lawsuit was infectious (assuming a 5-day infectious play aft a affirmative test²²); we required the adjacent interaction to person a antagonistic SARS-CoV-2 trial wrong 2 days of archetypal vulnerability arsenic good arsenic follow-up investigating information wrong 14 days aft past vulnerability (64% of adjacent contacts met some criteria). Each scale lawsuit was assigned a azygous adjacent interaction astatine random if aggregate contacts were identified (<0.1% of cases). Further statement of inclusion and exclusion criteria that were needed to code concerns for confounding and misclassification is disposable successful the Methods.

We matched unvaccinated scale cases (n = 273) and vaccinated scale cases (n = 953) by instauration (exactly) and clip (within 30 days) and by a propensity people (for receipt of vaccination), excluding cases without eligible matches (Fig. 2). We matched an mean of 3.5 (IQR: 2–4) vaccinated scale cases to each unvaccinated scale lawsuit (Supplementary Fig. 3). We observed bully equilibrium crossed matched scale cases (Supplementary Figs. 4 and 5). The mean duration of vulnerability of adjacent contacts to scale cases was 2.4 days for unvaccinated scale cases and 2.2 days for vaccinated scale cases (Supplementary Fig. 6). The mean duration from a adjacent contact’s archetypal vulnerability to consequent investigating for contacts exposed to a vaccinated and unvaccinated scale lawsuit was some 6.2 days, and the mean duration of past eligible follow-up investigating successful adjacent contacts occurred astatine time 10 aft archetypal vulnerability for unvaccinated scale cases and 10.6 days for vaccinated scale cases (Supplementary Fig. 7). The organisation of secondary cases from clip since vulnerability was akin betwixt vaccinated and unvaccinated scale cases (6.7 days versus 5.7 days; Supplementary Fig. 8). Descriptive information connected the survey population’s demographics, vaccine uptake and anterior infections are shown successful Table 1 and Supplementary Table 1.

Infectiousness of SARS-CoV-2 breakthrough infections and reinfections

Over an mean 2.3 days of vulnerability to the scale case, the unadjusted hazard of transmission to each adjacent contacts of scale cases was 30% (95% CI: 27–32%). Unvaccinated scale cases had a 36% (31–42%) hazard of transmitting to adjacent contacts, whereas vaccinated scale cases had a 28% (25–31%) hazard of transmitting to adjacent contacts (Fig. 3). Index cases with a past of anterior SARS-CoV-2 corruption (that is, reinfection) had a little hazard of transmitting to adjacent contacts (23% (19–27%)) than scale cases with nary past of anterior corruption (33% (30–37%)); reduced hazard of transmission from scale cases who were antecedently infected was evident successful strata of scale cases who had oregon had not been vaccinated and who did oregon did not person a booster dose (Fig. 3 and Supplementary Table 2).

Fig. 3: Unadjusted Omicron SARS-CoV-2 onslaught complaint successful adjacent contacts based connected scale cases’ vaccine and anterior earthy corruption status.

We identified scale cases of SARS-CoV-2 infections successful residents of the California authorities situation strategy who were successful adjacent interaction with different nonmigratory who was confirmed antagonistic for SARS-CoV-2 astatine the clip of contact. We estimated the result of consequent SARS-CoV-2 corruption successful the adjacent interaction nether antithetic immune conditions of the scale case, with a composite survey result of onslaught rate. The onslaught complaint is the probability of corruption successful the adjacent interaction fixed vulnerability to an scale case. We plotted the unadjusted onslaught complaint (represented by points) and 95% CIs (represented by mistake bars) of SARS-CoV-2 successful the adjacent interaction stratified by the scale cases’ wide vaccine status, the fig of vaccine doses successful the scale lawsuit and scale cases’ past of earthy infection.

Adjusting for duration of vulnerability betwixt scale cases and adjacent contacts, adjacent contacts’ past of vaccination and anterior infection, installation effects and inheritance SARS-CoV-2 incidence via a robust Poisson regression model, we estimated that scale cases who had received ≥1 COVID-19 vaccine doses had a 22% (6–36%) little hazard of transmitting corruption than unvaccinated scale cases. In analyses that further accounted for the fig of vaccine doses received by an scale case, each further dose was associated with an mean 11% simplification (5–17%) successful hazard of transmission to the adjacent interaction (Fig. 4 and Supplementary Tables 4 and 5). Prior SARS-CoV-2 corruption was likewise associated with a 23% simplification (3–39%) successful hazard of transmission from the scale case. Having some anterior vaccination and SARS-CoV-2 corruption was associated with a 40% (20–55%) simplification successful hazard of transmission by the scale case, based connected a linear operation of regression coefficients (Fig. 4); we did not place grounds of enactment betwixt vaccination and anterior earthy corruption associated with transmission hazard (Supplementary Table 6).

Fig. 4: Relative alteration successful Omicron SARS-CoV-2 onslaught complaint successful adjacent contacts based connected scale cases’ vaccine and anterior earthy corruption presumption successful an adjusted model.

We applied a robust Poisson regression exemplary to estimation the narration betwixt vaccination and earthy immunity successful scale cases connected their hazard of SARS-CoV-2 transmission to adjacent contacts. We plotted the adjusted comparative simplification successful infectiousness of scale cases (represented arsenic points), arsenic measured via onslaught complaint successful adjacent contacts, conferred by vaccination alone, anterior corruption unsocial and some vaccination and anterior infection. The estimation for some vaccination and anterior corruption is based connected a linear operation of regression coefficients, fixed deficiency of ceremonial statistical enactment betwixt vaccination and anterior infection. We conducted a abstracted regression investigation (right broadside of graph) that was stratified based connected the fig of vaccine doses received by the scale case. We plotted cluster-robust 95% CIs (represented by mistake bars).

We assessed the relation betwixt clip since past vaccine dose and/or earthy corruption connected infectiousness of a SARS-CoV-2 corruption and recovered that clip since past dose of a COVID-19 vaccine (as a continuous variable) was associated with accrued infectiousness of SARS-CoV-2 infections; for each 5 further weeks since past vaccine dose, SARS-CoV-2 breakthrough infections were 6% (2–11%) much apt to transmit corruption to adjacent contacts. We did not observe a statistically important narration betwixt clip since past SARS-CoV-2 corruption and hazard of transmission (Supplementary Table 7 and Supplementary Fig. 9).

We conducted a fig of sensitivity and further exemplary analyses to measure the robustness of the survey findings. We evaluated superior survey outcomes erstwhile relaxing exclusion criteria for adjacent contacts; immoderate COVID-19 vaccination was associated with a 23% (8–35%) simplification successful onslaught complaint erstwhile we included adjacent contacts who tested affirmative wrong 2 days of vulnerability to the archetypal scale lawsuit and a 19% (3–33%) simplification erstwhile we removed the request of a antagonistic trial successful adjacent contacts wrong 2 days of archetypal vulnerability to an scale lawsuit (Supplementary Table 8). Study findings were besides akin crossed changes successful the matching process (Supplementary Table 9). Varying definitions of the commencement and duration of the infectious play attenuated immoderate of the findings (Supplementary Table 10). We recovered that excluding scale cases who received the Ad26.COV2 vaccine owed to its reduced effectiveness compared to mRNA vaccines led to akin results (Supplementary Table 11). We repeated the superior adjusted investigation utilizing a logistic regression exemplary and recovered that some anterior vaccination (odds ratio (OR) 0.66 (0.48–0.91)) and anterior corruption (OR 0.68 (0.49–0.95)) were associated with reduced likelihood of corruption successful adjacent contacts (Supplementary Table 12). Additional details connected sensitivity analyses are disposable successful the Methods.

Transmission from superior infections, breakthrough infections and reinfections

We estimated that superior infections (15% of scale cases) contributed to 20% (16–25%) of transmission to secondary cases; breakthrough infections (49% of scale cases) contributed to 52% (47–57%) of transmission to secondary cases; reinfections (7% of scale cases) contributed to 7% (5–10%) of transmission to secondary cases; and breakthrough infections successful antecedently infected residents (29% of scale cases) contributed to 21% (17–26%) of transmission to secondary cases successful the survey population. We observed akin results implicit the full survey play (Supplementary Table 13).

Using elaborate epidemiologic information from SARS-CoV-2 surveillance wrong the California authorities situation system, we recovered that vaccination and anterior corruption reduced the infectiousness of SARS-CoV-2 infections during an Omicron-predominant (subvariants BA.1 and BA.2) period. Vaccination and anterior corruption were each associated with akin reductions successful infectiousness during SARS-CoV-2 infection, and, notably, further doses of vaccination (for example, booster doses) against SARS-CoV-2 and much caller vaccination led to greater reductions successful infectiousness. Of note, reductions successful transmission hazard associated with vaccination and anterior corruption were recovered to beryllium additive, indicating an accrued payment conferred by vaccination for reducing cases’ infectiousness adjacent aft anterior infection. Irrespective of vaccination and/or anterior earthy infection, SARS-CoV-2 breakthrough infections and reinfections remained highly infectious and were liable for 80% of transmission observed successful the survey population, which has precocious levels of some anterior corruption and vaccination. This reflection underscores that vaccination and prevalent people acquired immunity unsocial volition not destruct hazard of SARS-CoV-2 infection, particularly successful higher-risk settings, specified arsenic prisons.

Prior studies during the Delta variant question and earlier wide booster vaccination are mixed connected whether SARS-CoV-2 breakthrough infections successful vaccinated individuals are perchance little infectious^6,7,8 oregon arsenic infectious^9,10 to superior infections. In much caller household interaction studies during the Omicron variant era^11,12,13, vaccination often led to reduced SARS-CoV-2 infectiousness. Several factors whitethorn person enhanced our quality to observe statistically meaningful findings successful the contiguous study. The hazard of transmission among adjacent contacts successful the situation mounting and consistency successful interaction structure, particularly successful airy of accrued transmissibility of the Omicron SARS-CoV-2 variant, whitethorn person enhanced statistical powerfulness successful our sample. Relatedly, a higher proportionality of scale cases successful our illustration were antecedently vaccinated oregon infected, further enhancing the accidental to comparison transmission hazard from vaccinated oregon unvaccinated scale cases and from those who were antecedently infected oregon antecedently uninfected.

A cardinal effect is that the vaccine-mediated simplification successful infectiousness of SARS-CoV-2 breakthrough infections appears to beryllium dose dependent. Each dose of the vaccine provided an further mean 11% comparative simplification successful infectiousness, which was mostly driven by residents with a booster dose. The findings of this survey enactment the indirect effects of COVID-19 vaccination (especially booster doses) to dilatory transmission of SARS-CoV-2 and physique connected grounds of the nonstop effects of COVID-19 vaccination²³ to stress the wide value of COVID-19 vaccination. The nationalist wellness accusation of these findings is further enactment for existing argumentation utilizing booster doses of vaccination²⁴ to execute the extremity of lowering population-level transmission. The interaction of further bivalent vaccine doses, which are present authorized for individuals implicit 5–6 years of age²⁵, connected transmission should beryllium a precedence for further study. Additional considerations astir the timeliness of vaccine doses are besides necessary, arsenic we recovered that scale cases with much distant past of COVID-19 vaccination had a higher hazard of transmission of corruption to adjacent contacts. Given this finding, this survey raises the anticipation of timed wide vaccination successful incarcerated settings during surges to dilatory transmission.

The findings from this survey person nonstop implications successful addressing COVID-19 inequities successful the incarcerated colonisation done further vaccination. In California authorities prisons astatine the clip of this study, though 81% of residents and 73% of unit person completed a superior vaccination series, lone 59% of residents and 41% of unit person received the fig of vaccination doses recommended by the Centers for Disease Control and Prevention based connected their property and comorbid aesculapian conditions²⁶. Our findings besides supply a ground for further considerations for lodging situations of cases based connected anterior vaccination and corruption past successful aboriginal surges and tin beryllium utilized alongside different measures, specified arsenic depopulation and ventilation interventions, to support incarcerated populations.

However, this survey besides underscores the persisting vulnerability to COVID-19 among residents and unit successful correctional settings contempt wide vaccination, earthy immunity and usage of non-pharmaceutical interventions. The wide onslaught complaint of SARS-CoV-2 successful the survey colonisation (who were mostly moved into isolation aft symptoms oregon a affirmative test) was 30%, and scale cases with breakthrough infections oregon reinfections remained highly infectious, which telephone into question the quality of precocious vaccination rates unsocial to forestall each SARS-CoV-2 transmission successful correctional settings. In the United States, which incarcerates much residents per capita than immoderate different state successful the world²⁶ and has a 4th of the world’s incarcerated population, correctional settings are characterized by poorly ventilated facilities, populations with accrued rates of comorbid wellness conditions, high-risk dormitory lodging and overcrowding^18,27,28,29. Given the inability of existent efforts to trim transmission of SARS-CoV-2, decarceration efforts whitethorn beryllium the astir apt to person important effects connected reducing cases.

The secondary onslaught complaint successful this survey was connected the little extremity of published estimates erstwhile comparing to household studies. Of note, the secondary onslaught complaint of the SARS-CoV-2 Omicron variant successful caller household studies ranges from 29% to 53%^11,12,13, successful opposition to a 30% onslaught complaint successful this study. The situation situation has chiseled epidemiologic differences to households. The dense surviving situation increases the likelihood of transmission successful the situation situation compared to a household, whereas the predominant asymptomatic investigating (with isolation of affirmative cases) successful the prisons apt reduced the vulnerability clip and consequent transmission hazard compared to households. The transmission of the situation compartment is besides apt much azygous than a household.

Strengths of this survey see entree to elaborate records of each residents successful the California authorities situation system, encompassing individuals’ anterior COVID-19 vaccine receipt and anterior earthy corruption past (based connected predominant investigating passim the pandemic), arsenic good arsenic a societal web fixed grounds of wherever residents slept each nighttime implicit the survey period. We usage a accordant explanation of societal interaction betwixt the scale lawsuit of COVID-19 and adjacent interaction based connected the uniformity of compartment type. The predominant investigating ensures aboriginal recognition of infections and systematic seizure of asymptomatic and symptomatic infections to debar bias by participants’ immune presumption (which could impact temporal onset of symptoms). The hazard of misclassification of adjacent contacts is debased fixed that astir follow-up investigating successful adjacent contacts occurred good aft archetypal vulnerability to an scale lawsuit (Supplementary Notes). The ample illustration size facilitates analyses of the publication of combinations of anterior vaccination statuses and earthy corruption connected hazard of transmission, including analyses examining the interaction of booster doses.

Limitations should besides beryllium considered. We cannot exclude the anticipation of immoderate residual confounding (for example, behavioral differences that impact hazard of transmission) betwixt individuals who were vaccinated against SARS-CoV-2 and those who were unvaccinated. There is simply a anticipation that adjacent contacts who trial affirmative for SARS-CoV-2 were not infected by their assigned scale lawsuit but, instead, by enactment with infectious individuals extracurricular of their cell. However, this misattribution would beryllium expected to dampen evident associations of transmission hazard with scale cases’ vaccination presumption and corruption past but not bias the comparative estimates. To further code the hazard of misattribution, we adjusted for inheritance SARS-CoV-2 incidence and matched interaction pairs by installation and time. Our survey colonisation is simply a subset of the full incarcerated colonisation successful California and whitethorn not correspond each incarcerated settings. Studies of SARS-CoV-2 infectiousness whitethorn beryllium taxable to biases^30,31,32. The strict inclusion and exclusion criteria successful this survey whitethorn present bias into the analysis, though we performed sensitivity analyses connected these criteria with wide accordant findings. We besides adjusted for anterior corruption successful analyses to relationship for imaginable concerns astir differential susceptibility related to anterior corruption successful vaccinated versus unvaccinated individuals. Given constricted SARS-CoV-2 investigating capableness aboriginal successful the pandemic and immoderate residents’ determination to diminution testing, it is imaginable that infections among immoderate residents whitethorn not person been captured, though specified misclassification would beryllium expected to bias our findings to the null. SARS-CoV-2 investigating was adaptable implicit clip successful the situation system, with periods of regular play investigating and different periods of reactive testing; however, periods without reactive investigating align with times during which SARS-CoV-2 was improbable to beryllium circulating astatine precocious levels wrong the facilities, suggesting that this is improbable to bias results substantially. The survey findings connected boosters whitethorn besides beryllium related to caller vaccination effects. This survey plan did not supply a ground for identifying effects of vaccination and anterior corruption connected hazard of acquiring SARS-CoV-2 among adjacent contacts, though we did set for anterior corruption and vaccination successful adjacent contacts successful the superior analysis. Of note, vaccine effectiveness against corruption among incarcerated persons has been reported wrong this colonisation during earlier periods^33,34. We bash not person a elaborate grounds of person-level masking, symptoms, rhythm thresholds for polymerase concatenation absorption (PCR) investigating oregon serologic testing. During the study, the predominant Omicron subvariants successful California and California prisons were BA.1 and BA.2 based connected genomic surveillance, though we did not genotype each SARS-CoV-2 isolate successful this study.

This survey demonstrates that breakthrough COVID-19 infections with the Omicron variant stay highly infectious but that some vaccination and earthy corruption confer reductions successful transmission, with payment of further vaccine doses. As SARS-CoV-2 breakthrough infections and reinfections go the predominant COVID-19 case, this survey supports the value of booster doses successful reducing population-level transmission with information of wide timed vaccination during surges, with peculiar relevance successful vulnerable, high-density congregate settings.

Data

We utilized information from the California Correctional Health Care Services, which included anonymized person-level information connected SARS-CoV-2 testing, COVID-19 vaccination and nightly nonmigratory lodging for incarcerated individuals successful the California authorities situation strategy from 1 March 2020 to 20 May 2022. The nonsubjective of the survey was to survey the comparative infectiousness of Omicron SARS-CoV-2 breakthrough infections and reinfections. We defined the play of the Omicron variant question arsenic betwixt 15 December 2021 and 20 May 2022, based connected genomic surveillance information from the California situation system. This task was approved by the organization reappraisal committee (IRB) astatine the University of California, San Francisco (see ‘Ethics and IRB approval’).

COVID-19 scale lawsuit explanation and infectious period

The inclusion and exclusion criteria for an scale lawsuit of COVID-19 for the survey are shown successful Fig. 2. We defined an scale lawsuit arsenic a nonmigratory with immoderate conclusive affirmative SARS-CoV-2 diagnostic test. Most tests (83%) were PCR. We excluded scale cases with a anterior affirmative trial wrong the preceding 90 days (unless they had a antagonistic PCR trial successful the interim) arsenic good arsenic those with a false-positive oregon inconclusive result. We included lone infections that occurred successful residents who were incarcerated continuously opening earlier 1 April 2020 to guarantee accordant reporting of anterior SARS-CoV-2 corruption fixed that these information are not disposable from precocious incarcerated residents. We classified scale cases based connected their COVID-19 vaccination presumption and anterior earthy corruption history. We defined SARS-CoV-2 breakthrough infections arsenic a affirmative SARS-CoV-2 diagnostic trial occurring successful individuals astatine slightest 14 days aft their archetypal dose of vaccine, arsenic agelong arsenic that idiosyncratic did not person a anterior affirmative diagnostic trial successful the preceding 90 days. We defined reinfection arsenic a affirmative SARS-CoV-2 diagnostic trial occurring successful individuals with a anterior laboratory-confirmed earthy corruption provided that astatine slightest 90 days had elapsed since the archetypal corruption unless they had received a antagonistic SARS-CoV-2 PCR trial successful the interim.

For a blimpish measurement of the clip each scale lawsuit was infectious, we counted from the day of an scale case’s archetypal affirmative SARS-CoV-2 trial done 5 days thereafter^22,36,37. We varied the commencement and the duration of the infectious play successful sensitivity analyses. We shortened the assumed 5-day infectious play for a COVID-19 scale lawsuit if the nonmigratory had a antagonistic accelerated antigen trial during the infectious period. We excluded scale cases if the nonmigratory had a antagonistic PCR trial during the infectious play to mitigate imaginable bias owed to delayed detection of cases.

Isolation and quarantine protocols successful the situation strategy are described successful the Supplementary Notes.

Close contacts of COVID-19 scale case

We defined a adjacent interaction of a COVID-19 scale lawsuit arsenic immoderate nonmigratory who shared a compartment with an scale lawsuit portion the scale lawsuit was considered infectious, per the supra definition. We further required a adjacent interaction to trial antagonistic for SARS-CoV-2 wrong 2 days earlier oregon aft archetypal vulnerability to an scale lawsuit (to trim the accidental they were already infected by different resident) and to person follow-up investigating wrong 3–14 days aft past exposure. Close contacts were excluded if they had a anterior SARS-CoV-2 corruption successful the preceding 90 days (unless they had a antagonistic PCR trial successful the interim). Characteristics of adjacent contacts included oregon excluded owed to missing investigating information are shown successful Supplementary Table 14. We defined archetypal vulnerability arsenic the archetypal time that the scale lawsuit and adjacent interaction shared a country during the scale case’s infectious play (based connected a affirmative trial successful the scale case). To bounds misattribution of secondary cases and adjacent contacts, we included lone contacts who shared a solid-door compartment with less than 10 full residents during the scale case’s infectious play (>95% of scale cases had 3 oregon less individuals per cell). The solid-door compartment benignant was chosen to supply a much accordant transmission situation for examination betwixt facilities and to amended attribution of corruption to the scale lawsuit (versus residents successful adjacent cells with compartment types with open-air exchange). We defined secondary SARS-CoV-2 corruption arsenic adjacent contacts who tested affirmative for SARS-CoV-2 betwixt 3 days aft archetypal vulnerability and 14 days aft past vulnerability to the scale case. We excluded adjacent contacts who were secondary cases for aggregate scale cases (only 1 adjacent contact, spot Fig. 2). After different inclusion and exclusion criteria were applied to adjacent contacts, if scale cases had much than 1 valid adjacent interaction (<0.1% of scale cases and scale cases had nary much than 3 valid adjacent contacts), we randomly selected a azygous interaction to see successful the analysis.

Statistical analysis

We performed matching of unvaccinated scale cases and vaccinated scale cases to bounds confounding and to relationship for heterogeneity of SARS-CoV-2 epidemiology crossed institutions and implicit time. We archetypal estimated the propensity for scale cases to person vaccination utilizing logistic regression based connected their age, anterior past of SARS-CoV-2 corruption and COVID-19 hazard people based connected comorbid conditions related to hazard of terrible disease³⁵. We past applied 1:10 nearest matching connected instauration (exact), clip (<30 days) and propensity people (caliper prime of 0.1) scaled to beryllium weighted arsenic and matched without replacement³⁸. We excluded immoderate scale cases without matches.

We estimated unadjusted onslaught rates, defined arsenic the proportionality of adjacent contacts who tested affirmative betwixt 3 days aft archetypal vulnerability and 14 days aft past vulnerability with an scale lawsuit and computed associated 95% binomial CIs. We estimated onslaught rates by fig of vaccine doses and anterior earthy infection.

To estimation the comparative infectiousness of SARS-CoV-2 breakthrough infections and/or SARS-CoV-2 reinfections, we acceptable a Poisson regression exemplary with robust errors to relationship for cardinal variables successful an adjusted analysis. We utilized Poisson regression successful the main investigation due to the fact that coefficients are easier to construe than those successful logistic regression and whitethorn beryllium much robust to exemplary misspecification³⁹. Because binomial information interruption distributional assumptions, robust errors were computed. The superior survey result was binary—the SARS-CoV-2 corruption result successful the adjacent contact. The vulnerability of involvement was the vaccine presumption (primary investigation with binary vaccine status, alternate investigation with fig of vaccine doses) of the scale case, which tin beryllium interpreted arsenic the comparative alteration successful onslaught complaint successful the adjacent interaction based connected the scale cases’ vaccine status. We besides adjusted for the scale case’s anterior SARS-CoV-2 corruption history, duration of vulnerability betwixt scale lawsuit and adjacent contact, adjacent contact’s vaccine presumption (number of doses) and anterior earthy infection, instauration and institution-specific SARS-CoV-2 incidence successful the 7 days starring up to corruption successful the scale case. The regression exemplary accounted for matching weights and cluster-robust modular errors based connected matching radical membership. We did not usage repeated measured data. We did not execute a ceremonial illustration size calculation, though the last illustration size would beryllium expected to observe a minimum 10% quality betwixt groups. The pre-analysis program is publically available⁴⁰.

We classified secondary infections (n = 363) among adjacent contacts by scale cases’ anterior vaccination and/or corruption past and estimated the crude fraction of secondary infections that were attributable to antithetic scale cases arsenic good arsenic their respective 95% binomial CIs. We additionally estimated the attributable fraction of transmission among each SARS-CoV-2 infections successful the survey period. We archetypal estimated the adjusted onslaught complaint of SARS-CoV-2 corruption by a case’s anterior vaccination and/or corruption past utilizing estimates of the comparative simplification successful infectiousness. We past applied the onslaught rates to the observed fig of infections to estimation the attributable fraction of transmission by anterior vaccination and anterior corruption status. Analysis was conducted successful R (version 4.2.1).

Sensitivity analysis

We conducted an alternate investigation that defined the scale lawsuit vaccine presumption by fig of doses (rather than binary) and assessed the narration betwixt fig of vaccine doses and hazard of secondary corruption successful adjacent contacts. Matches were re-weighted wrong vaccine groups with confirmation of covariate equilibrium crossed groups (Supplementary Table 1)³⁸; we besides repeated matching to a azygous notation radical to maximize balance. We further examined the relationships among vaccination, anterior corruption and infectiousness of an scale lawsuit by investigating a ceremonial enactment betwixt vaccination and anterior earthy corruption and evaluated the narration betwixt the clip since astir caller vulnerability (as continuous variable) to either COVID-19 vaccination oregon SARS-CoV-2 infection. We varied definitions of COVID-19 vaccine presumption successful adjacent contacts successful sensitivity analyses. We assessed interaction of relaxing antithetic exclusion criteria for scale cases and adjacent contacts connected survey results. We varied the commencement and duration of the infectious play successful sensitivity analyses. To measure exemplary robustness, we evaluated survey outcomes nether antithetic matching specifications and erstwhile utilizing a logistic regression model. Given the little vaccine effectiveness of the Ad26.COV2 vaccine, we conducted a sensitivity investigation removing scale cases who received the Ad26.COV2 vaccine.

Ethics and IRB approval

This task was approved by the IRB astatine the University of California, San Francisco (IRB no. 21-34030). The IRB waived the request for informed consent fixed the usage of secondary datasets based connected the pursuing criteria: deemed nary much than minimal hazard to subjects; could not practicably beryllium done without the waiver; could not practicably beryllium done without identifiable information; volition not adversely impact rights and payment of subjects; and volition supply subjects with further pertinent accusation aft participation.

Reporting summary

Further accusation connected probe plan is disposable successful the Nature Portfolio Reporting Summary linked to this article.

All analytic codification is publically disposable here: https://github.com/sophttan/CDCR-CalProtect.

References

Authors and Affiliations

1. Division of HIV, Infectious Diseases, and Global Medicine, University of California, San Francisco, San Francisco, CA, USA

   Sophia T. Tan, Isabel Rodríguez-Barraquer, Benjamin J. Singer, Hailey J. Park & Nathan C. Lo

2. Division of Pulmonary and Critical Care Medicine, University of California, San Francisco, San Francisco, CA, USA

   Ada T. Kwan

3. Department of Medicine, University of California, San Francisco, San Francisco, CA, USA

   Ada T. Kwan, Isabel Rodríguez-Barraquer, David Sears & Nathan C. Lo

4. Division of Epidemiology and Biostatistics, School of Public Health, University of California, Berkeley, Berkeley, CA, USA

   Joseph A. Lewnard

5. Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA, USA

   Joseph A. Lewnard

6. Center for Computational Biology, College of Engineering, University of California, Berkeley, Berkeley, CA, USA

   Joseph A. Lewnard

7. Division of Infectious Diseases, University of California, San Francisco, San Francisco, CA, USA

   David Sears

Contributions

S.T.T. and NC.L. had afloat entree to each the information successful the survey and instrumentality work for the integrity of the information and the accuracy of the information analysis. Study conception and design: J.A.L., I.R.B., D.S. and N.C.L. Statistical analysis: S.T.T., I.R.B. and N.C.L. Acquisition, investigation oregon mentation of data: each authors. First draught of the manuscript: S.T.T. and N.C.L. Critical revision of the manuscript: each authors. Contributed intelligence worldly and approved last draft: each authors

Corresponding author

Correspondence to Nathan C. Lo.

Competing interests

J.A.L. has received grants, honoraria and talker fees from Pfizer; grants and honoraria from Merck, Sharp, & Dohme; and honoraria from VaxCyte, each unrelated to the taxable of this work. A.T.K. and D.S. received backing from California Prison Health Care Receivership. The remaining authors person nary disclosures.

Peer reappraisal information

Nature Medicine acknowledgment Rachael Pung, Eric Lau and the other, anonymous, reviewer(s) for their publication to the adjacent reappraisal of this work. Primary handling editor: Alison Farrell, successful collaboration with the Nature Medicine team.

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