key: cord-0767444-snmnilm9
authors: Egunsola, O.; Mastikhina, L.; Dowsett, L.; Farkas, B.; Hofmeister, M.; Saxinger, L.; Clement, F.
title: Transmissibility of COVID-19 among Vaccinated Individuals: A Rapid Literature Review
date: 2021-07-02
journal: nan
DOI: 10.1101/2021.06.29.21255526
sha: ac22fe6b0aa81cebb3fbef17e25a91a4eb2737e6
doc_id: 767444
cord_uid: snmnilm9

Objectives: This is an update of a previous report that examined literature published up to March 11th, 2021. Sixteen additional studies have been included in this update. The objective of this report is to identify comparative observational studies and randomized controlled trials (RCTs) evaluating the efficacy and effectiveness of COVID-19 vaccination in reducing forward transmission from vaccinated people, and studies examining the biological plausibility of vaccination-induced transmission reduction. Method: A search of databases, MEDLINE, Embase, L-OVE and the Cochrane Central Register of Controlled Trials was conducted to identify RCTs or comparative observational studies evaluating the efficacy and effectiveness of COVID-19 vaccination in the prevention of transmission, asymptomatic infections and transmissibility of COVID-19 among vaccinated persons. An additional search of grey literature was conducted. This search is current to May 4th, 2021. Results: In this update, 16 additional studies, including 9 human and 7 animal studies, were included. Therefore, this review examines a total of 33 included studies: 21 human studies and 12 preclinical animal studies. Evidence from two large household surveillance studies from the UK suggests that a single or full dose of AstraZeneca (AZ) and Pfizer-BioNtech (PfBnT) vaccines may prevent household transmission of COVID-19 after 14 days of vaccination by up to 54%. The AZ vaccine trials in the general population suggest that an initial low dose followed by a standard dose may provide up to 59% protection against asymptomatic or unknown infection, although efficacy against these outcomes was not demonstrated following two standard doses. PfBnT vaccine observational studies in the general population suggest up to 90% effectiveness against asymptomatic infection after seven or more days of full dose vaccination. Up to 75% effectiveness against asymptomatic infection was reported after full-dose in healthcare workers. Across RCTs examining asymptomatic infection in the general population, one dose of Moderna was shown to provide an efficacy of 61.4% against asymptomatic infection 21 days after the first dose; in another trial, the J&J vaccine had an efficacy of 74% 28 days after the first dose. Lastly, seven of eight studies found significantly increased cycle threshold, suggestive of lower viral load, in PfBnT or AZ vaccinated individuals compared with those who were unvaccinated. Conclusion: The AZ and PfBnT vaccines may prevent household transmission of COVID-19 after 14 days of vaccination. More studies have found the vaccines to significantly reduce the risk of asymptomatic infection and significantly increase cycle threshold, suggestive of lower viral load. Further research is needed to evaluate post-vaccination infectivity and transmission of both the wild type COVID-19 virus and the variants of concern from other jurisdictions.

Results: In this update, 16 additional studies, including 9 human and 7 animal studies, were included. Therefore, this review examines a total of 33 included studies: 21 human studies and 12 preclinical animal studies. Evidence from two large household surveillance studies from the UK suggests that a single or full dose of AstraZeneca (AZ) and Pfizer-BioNtech (PfBnT) vaccines may prevent household transmission of COVID-19 after 14 days of vaccination by up to 54%. The AZ vaccine trials in the general population suggest that an initial low dose followed by a standard dose may provide up to 59% protection against asymptomatic or unknown infection, although efficacy against these outcomes was not demonstrated following two standard doses. PfBnT vaccine observational studies in the general population suggest up to 90% effectiveness against asymptomatic infection after seven or more days of full dose vaccination. Up to 75% effectiveness against asymptomatic infection was reported after fulldose in healthcare workers. Across RCTs examining asymptomatic infection in the general population, one dose of Moderna was shown to provide an efficacy of 61.4% against asymptomatic infection 21 days after the first dose; in another trial, the J&J vaccine had an efficacy of 74% 28 days after the first dose. Lastly, seven of eight studies found significantly increased cycle threshold, suggestive of lower viral load, in PfBnT or AZ vaccinated individuals compared with those who were unvaccinated.

Conclusion: The AZ and PfBnT vaccines may prevent household transmission of COVID-19 after 14 days of vaccination. More studies have found the vaccines to significantly reduce the risk of asymptomatic infection and significantly increase cycle threshold, suggestive of lower viral load. Further research is needed to evaluate post-vaccination infectivity and transmission of both the wild type COVID-19 virus and the variants of concern from other jurisdictions.

3

Coronavirus disease is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). As of May 2021, there have been more than 164,000,000 confirmed cases of COVID-19, which have resulted in more than 3,400,000 confirmed deaths worldwide. 23 Since the start of the pandemic, several clinical trials have been underway to examine the safety and effectiveness of different vaccines to prevent COVID-19. Many of these have found the vaccines to be generally effective against symptomatic COVID-19 infection, with an average efficacy of 85% (95% CI: 71 -93%) after a full course of vaccination. 24 People who have started or finished the COVID19 vaccine series have been documented to have detectable SARSCoV2 by RT-PCR at various time points after vaccination, 4 although demonstration of cultivatable virus and definitive evidence of transmission post vaccination has not been assessed. It is not yet clear whether the current COVID-19 vaccines are as effective at reducing transmission as they are at reducing disease. Moreover, evaluating the ability of vaccinated individuals to transmit the virus after infection is challenging. Therefore, virologic surrogates of possible transmissibility may be a helpful way around this challenge.

Monoclonal antibody studies may provide useful insights into the pathophysiologic plausibility of vaccine induced transmission reduction, since they have been shown to result in circulating neutralizing antibody, with a significant decrease in quantitative viral load. 25 In one study, following quantitative reverse-transcriptase-polymerase-chain-reaction (RT-PCR) testing of nasopharyngeal swabs, an antibody cocktail was found to significantly reduce viral load compared with placebo. 25 The time-weighted average change in viral load in the first 7 days was −0.56 log10 copies per milliliter (95% CI, −1.02 to −0.11) among those who were serum antibody-negative at baseline. 25 Another study reported an elimination of more than 99.97% of viral RNA on day 11 after monoclonal antibody treatment. 26 There is evolving data around the frequency of asymptomatic COVID-19 and if the viral load, and therefore infectiousness, is lower among people who develop COVID-19 post-vaccination compared with those who have not been vaccinated. Viral presence is an imperfect proxy of transmissibility although the quantity of virus present does appear to influence risk, as studies document transmission risk is higher with a higher viral load or lower Ct value. 27, 28 Marks et al. found index viral load to be a major driver of transmission in a Spanish cohort, 28 with only 32% of index cases responsible for transmission, and an attack rate of 12% in contacts of index cases with a viral load <10 6 and 25% in contacts of index cases with a viral load of 10 10 . Similarly, Bjorkman et al. found that higher viral load increased SARS-CoV-2 transmission between asymptomatic residence hall roommates. 29 The index cases who transmitted infection had an average viral load 6.5 log higher than those who did not. Transmission from asymptomatic students to roommates occurred in 20% of rooms with an infected student, with a lower mean Ct (E gene) of 26.2 in transmission index cases versus 28.9, (median 26.11 in transmission index cases versus 29.32).

However, the risks related to viral presence by RT-PCR may be modulated by individual's immune status, as viral persistence after natural infection has been observed in individuals with neutralizing antibody responses after natural infection, without transmission to close contacts. 30 Although asymptomatic and especially pre-symptomatic transmission of SARSCoV-2 has been well documented, existing studies suggest that transmission risk is lower from asymptomatic individuals than symptomatic individuals. 31 The evidence for the transmissibility and transmission of COVID-19 infections in vaccinated individuals is rapidly evolving; therefore, the objective of this rapid review was to identify comparative observational studies and randomized controlled trials (RCTs) evaluating the effectiveness or efficacy of COVID-19 vaccination in reducing infection transmission, asymptomatic viral carriage and other proxies of possible transmission, such as cycle threshold (Ct) values and viral load. This is an update of a previous report with a literature search that ended 11 March 2021. 1

An experienced medical information specialist developed and tested the search strategies through an iterative process in consultation with the review team. The MEDLINE strategy was peer reviewed by another senior information specialist prior to execution using the PRESS Checklist. 32 Using the multifile option and deduplication tool available on the OVID platform, we searched Ovid MEDLINE®, including Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Embase, and EBM Reviews -Cochrane Central Register of Controlled Trials. We also searched for primary studies on the Living Overviews of Evidence (L-OVE) platform. We performed all searches on May 4, 2021.

The strategies utilized a combination of controlled vocabulary (e.g., "COVID-19 Vaccines", "COVID-19/tm [Transmission]", "Disease Transmission, Infectious") and keywords (e.g., "mRNA vaccine", "unvaccinated", "infectiousness"). Vocabulary and syntax were adjusted across the databases. The search strategies are in Appendix 1. No language or date limits were applied. Results were downloaded and deduplicated using EndNote version 9.3.3 (Clarivate Analytics) and uploaded to word.

A grey literature search was also conducted, including: Clinicaltrials.gov, McMaster Health Forum (CoVID-END), MedRxiv, Google, regulatory submissions, and websites of the Center for Disease Control and Prevention (CDC) and World Health Organization (WHO). This search was limited to studies conducted in 2020 and 2021 and current to May 4th, 2021. There were no language limitations.

A screening form based on the eligibility criteria was prepared. Citations identified as potentially relevant from the literature search were screened by a reviewer, and subsequently read in full text by two reviewers and assessed for eligibility based on the criteria outlined below (Table 1 ). Discrepancies were resolved by discussion or by a third reviewer. Reference lists of included studies were hand searched to ensure all relevant literature is captured. 

Comparative observational studies and RCTs evaluating the efficacy and effectiveness of COVID-19 vaccination in the prevention of asymptomatic viral infections as a proxy of a possible transmission will be included. Studies eligible for inclusion must have a control group of unvaccinated people.

A standardized data extraction sheet was used to extract the year of publication, country, study design, patient characteristics including sex, gender and age, variants of COVID-19, whether infection was symptomatic or asymptomatic, and all the reported outcomes. All reviewers completed a calibration exercise whereby data from two sample studies were extracted by all four reviewers and areas of disagreement were discussed. Data were extracted by one reviewer and verified by another reviewer.

Quality assessment was conducted based on study design: Cochrane risk of bias for nonrandomized studies (ROBINS-I) for non-randomized studies, 33 Cochrane Risk of Bias (version 5.1.0) for human-subject RCTs, 34 and the Systematic Review Centre for Laboratory animal Experimentation's (SYRCLE) risk of bias for animal studies. 35 Quality assessment was conducted by one reviewer and verified by a second reviewer.

This updated search yielded 4993 unique citations, 4749 of which were excluded after abstract review ( Figure 1 ). Fifty studies identified from the database search proceeded to full-text review. An additional 82 studies identified through grey literature search were also reviewed. In total, ninety-nine studies were excluded for the following reasons: outcomes not of interest (n=54), study design not of interest (n=10), comparator not of interest (n=4), intervention not of interest (n=1) and duplicate (n=30).

A total of 33 studies were included in this review ( Figure 1 ). Twenty-one were human studies ( Table 2 and Table 3), 2-17,19,29,36-38 and 12 were preclinical animal studies, with viral challenge 1-17 weeks post vaccination (Table 4) . [20] [21] [22] [39] [40] [41] [42] [43] [44] [45] [46] [47] In the previous report, a targeted literature  search was conducted and 17 studies included. Thus, an additional 16 studies have been  included since the last update on 11 March 2011, including two studies evaluating household  transmission. Five of the human studies were randomized controlled trials, 4-6,18,19 eight were  prospective cohort studies, 8,11 seven were retrospective cohort studies, 2,10,12,13,36-38 and one was  a case control study. 15 . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted July 2, 2021. Included . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted July 2, 2021. *tPA.S: tPA leader sequence with full-length S; tPA.S.PP: tPA leader sequence with full-length S with mutation of the furin cleavage site and two proline stabilizing mutations; S: wild-type leader sequence with native full-length S; S.dCT: wild-type leader sequence with S with deletion of the cytoplasmic tail; tPA.WT.S: tandem tPA and wild-type leader sequences with full-length S as a strategy to enhance expression; S.dTM.PP: wild-type leader sequence with S with deletion of the transmembrane region and cytoplasmic tail, reflecting the soluble ectodomain, with mutation of the furin cleavage site, proline stabilizing mutations and a foldon trimerization domain **S.dCT: full-length deletion of the cytoplasmic tail; S.dTM: deletion of the transmembrane domain and cytoplasmic tail reflecting the soluble ectodomain; S1: S1 domain with a foldon trimerization tag; RBD: receptor-binding domain with a foldon trimerization tag; S.dTM.PP: prefusion-stabilized soluble ectodomain with deletion of the furin cleavage site, two proline mutations, and a foldon trimerization tag

The five included RCTs [4] [5] [6] 18, 19 were assessed with the Cochrane Risk of Bias Assessment Tool. 34 Two studies had some concerns regarding randomization, 6,19 two were of low risk 5, 18 and one study had no sufficient information for assessment. 4 All but one low risk study 18 was assessed to have some concerns regarding deviation from intended intervention. Four studies were of some concerns for missing outcome data, 4, 5, 18, 19 one was assessed to be of high risk of bias. 6 All the studies were of low risk of bias for the measurement of outcomes. All but one study with some concern 6 were of low risk for the selection of reported results. [4] [5] [6] 18, 19 Overall, four of the RCTs were of some concerns for bias 4, 5, 18, 19 and one had a high risk of bias 6 ( Table  5 ).

The sixteen non-RCTs were assessed using the ROBINS-I tool. 33 Overall, all but one low risk study 15 were of moderate risk of bias; while one study did not have enough information for risk assessment 12 (Table 6 ). Table 7 describes the results of the SYRCLE risk of bias assessment for the animal studies. 35 The majority of the studies were assessed as having unclear risks of bias for all domains.

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The copyright holder for this preprint this version posted July 2, 2021. 3 The baseline serology and PCR of household contacts were not reported (Table 8) .

Ten studies reported vaccine efficacy or effectiveness against asymptomatic COVID-19 infection (Table 9 and Table 10 ). Three of these involved AZ vaccine, 4-6 another four examined . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted July 2, 2021. ; https://doi.org/10.1101/2021.06.29.21255526 doi: medRxiv preprint PfBnT vaccine 8, 11, 12, 38 and one study each evaluated mRNA-1273 18 and J and J 19 vaccines and one evaluated both mRNA-1273 and BNT162b2. 10 The methods of assessing efficacy or effectiveness against asymptomatic infection used in some of these studies include RT-PCR nasopharyngeal swabs at time intervals.

Asymptomatic infection data were presented for only the UK component of the AZ vaccine studies. Two AZ vaccine studies reported vaccine efficacy against asymptomatic or unknown infection of 7.8% (-46.7-42.1) 5 and 16% (-88-62) 4 respectively, after more than 21 days and 22 to 90 days of the first dose. However, vaccine efficacy among participants with positive results, irrespective of symptoms, were 46.3% (31.8-57.8) 5 and 67% 4 , respectively over the same period (Table 9 ). These trials implemented weekly self-administered nose and throat swabs for testing on baseline seronegative participants. The PCR status of these participants was not established at baseline.

After 14 days of the second dose, two AZ vaccine studies did not demonstrate efficacy against asymptomatic or unknown infection with the wild type virus 22.2% (-9.9-45) and 27.3% (95% CI: -17-54.9)) respectively. 4,5 A third study did not show efficacy against asymptomatic infection with the B.1.1.7 variant (26.5% (95% CI: -112-74.5)), following low or standard dose vaccination. 6 All three studies involved baseline seronegative participants. The baseline PCR results of the participants were not reported, therefore, persistent carriage after previous infection was not ruled out. In the subgroup of participants with an initial low dose of the vaccine, followed by a standard dose, two studies reported 49.3%(95% CI: 7.4-72.2) 4 and 58.9%(95% CI: 1-82.9) 5 respective efficacies against asymptomatic and unknown infection 14 days after the second dose (Table 10) .

However, when participants who were PCR positive irrespective of symptoms were considered, two doses of AZ vaccine showed efficacies of 55.7% (41.1-66.7) 5 and 54.1% (44.7%, 61.9%) 4 after 14 days of second dose vaccination.

In a large UK household survey with longitudinal follow-up among seronegative or seropositive individuals, Pritchard et al. reported significant reductions in the odds of asymptomatic infections following AZ vaccine 0-7 days, 8-20 days and 21 or more days after the first dose (ORs: 0.45 (95% CI: 0.35-0.57), 0.47 (95% CI: 0.37-0.6) and 0.39 (95% CI: 0.3 -0.51), respectively). 7 Nose and throat self-swabs were conducted every week for a month, and subsequently monthly for 12 months from enrolment. 7 . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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An Israeli observational study by Dagan et al., which did not establish baseline seronegativity, showed that one dose of BNT162b2 significantly reduced asymptomatic infection by 29% (95% CI: 17-39) and 52% (95% CI: 41-60) after 14 to 20 days and 21 to 27 days of follow-up respectively, as assessed by confirmed positive PCR SARS-CoV-2 test without documented symptoms. No routine swabbing was documented for the participants (Table 9 ).

In a large UK household survey with longitudinal follow-up involving participants with unknown baseline serology status, Pritchard et al. reported significant reductions in the odds of asymptomatic infections following PfBnT vaccine 0-7 days, 8-20 days and 21 or more days after the first dose, ORs: 0.48 (95% CI: 0.39-0.6) and 0.54 (95% CI: 0.45-0.65) respectively, compared with unvaccinated previously PCR negative individuals. 7 Nose and throat self-swabs were conducted every week for a month, and subsequently monthly for 12 months from enrolment. 7

Dagan et al. also demonstrated 90% effectiveness (95% CI: 83-94) against asymptomatic infection seven days after the second dose. 8 A press release by the vaccine manufacturer reported two weeks post-second dose effectiveness of 94% against asymptomatic infection in Israel. 38 The study utilized de-identified aggregate Israel Ministry of Health public health surveillance data. The analysis was conducted when more than 80% of tested specimens in Israel were variant B.1.1.7. 38 In another Israeli study, which utilized the national public health surveillance data, Haas et al. reported significantly higher vaccine effectiveness seven or more days after full dose PfBnT vaccination, 90.4% (95% CI: 89.1-91.5). 9 The incidence rate per 100 000 person-days among unvaccinated individuals was 54.6 compared with 3.2 in those vaccinated. Vaccine effectiveness after 14 or more days was 93.8% (95% CI: 93.3-94.2). 9 Pritchard et al. also found full dose vaccination with PfBnT vaccine to significantly reduce the odds of asymptomatic infection compared with unvaccinated previously PCR negative UK residents, 0.48 (95% CI: 0.36-0.66). 7

Tande et al. evaluated the effectiveness of at least one dose of either mRNA-1273 or PfBnT vaccine among people who underwent molecular tests prior to a procedure or surgery. 10 The relative risk for a positive test during asymptomatic pre-procedure screening in vaccinated compared with unvaccinated was significantly lower (0.44 (95% CI: 0.33-0.60)). Ten or more days after the 1st dose, the risk of a positive test was also significantly lower among the vaccinated (0.28 (95% CI: 0.16-0.49; p<.0001)). The risk of test positivity was similarly lower among the vaccinated, after the second dose 0.27 (95% CI: 0.12-0.60). 10 . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted July 2, 2021. ; https://doi.org/10.1101/2021.06.29.21255526 doi: medRxiv preprint

A study of the mRNA-1273 reported that 0.1% of the participants receiving the first dose developed asymptomatic infection, assessed at second dose with nasal swabs, compared with 0.27% of the unvaccinated group, 21 days after the first dose; which is suggestive of 61.4% efficacy against asymptomatic carriage. Participants in this trial were negative for COVID-19 by RT-PCR or antibody testing at baseline. 18 There was no data on asymptomatic infection after full dose (Table 9 ).

This is a single dose vaccine. The J&J vaccine did not show statistically significant efficacy against asymptomatic infection in the first 29 days of follow-up. However, after 29 days postvaccination, asymptomatic infection, assessed via surveillance swabs at unspecified intervals among baseline seronegative participants, was significantly lower among vaccinated participants (74%, 95% CI: 46.8-88.4%). 19 Asymptomatic infection in this trial was assessed by lack of symptoms on the day preceding, the day of, or any time after a positive PCR test. Furthermore, efficacy as demonstrated by seroconversion in previously asymptomatic participants was 74.2% compared with placebo (95% CI: 47.1; 88.6). 19 

Hall et al. in a surveillance study of HCWs with documented baseline PCR and antibody in the UK, reported a higher incidence density of asymptomatic or unknown test positivity in unvaccinated HCWs than PfBnT or AZ vaccine recipients. In this biweekly surveillance of vaccine status, symptoms, and nasal or nasal plus oral swabs, the vaccine recipients were followed up for 396,318 person-days compared with 710,587 person days in unvaccinated group, with 35 and 218 asymptomatic or unknown infections reported, translating to 0.88 and 3 infections per 10,000 person-days respectively. 11 The vaccine effectiveness overall was 72% from 21 days after dose one and 86% after two. Protection was noted from day 10 post first dose in these data. The study took place over two months and involved 23,320 HCWs in 104 hospitals, of whom 35% were previously documented SARS-CoV-2 positive. Also, of practical relevance in those testing positive, the unvaccinated group had a higher proportion with "classic" symptoms at 63%: 14% had other symptoms, 5% were asymptomatic and 17% unknown. In the vaccinated group only 40% had classic symptoms, 13% had other symptoms, 13% were asymptomatic, and 31% had unknowntherefore asymptomatic or non-classic symptoms comprised 26% of the post vaccine test positive. In a second observational HCW study in Israel by Amit et al., 12 asymptomatic test positive data was limited, and reasons for tests done without documented symptoms was not reported. The baseline RT-PCR status was not assessed; therefore, prolonged RT-PCR positivity after prior infection was not ruled out. Estimated asymptomatic infection prevalence in the vaccinated group was 1.7 per 10,000person years between 15 and 28 days after vaccination, compared with 2.4 per 10,000 personyears in the unvaccinated group (VE: 29%). 12 The overall infection rate in the whole cohort for . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted July 2, 2021. ; https://doi.org/10.1101/2021.06.29.21255526 doi: medRxiv preprint the 2-month study was 1.9%. Matheson et al. in an asymptomatic weekly screening study among HCWs who were vaccinated with one dose of PfBnT vaccine compared with unvaccinated HCWs, showed that 0.8% of tests from unvaccinated HCWs were positive compared with 0.37% and 0.2% from vaccinated ones at <12 days and >12 days postvaccination respectively (p=0.023 and p=0.004, respectively). 13 In another large Israeli cohort study of HCWs who were either seropositive or negative at baseline, Regev-Yochay et al. 14 reported a prevalence of PCR positive asymptomatic (at first testing) infection following exposure to COVID-19 of 5.2% among unvaccinated HCW compared with 1.8% among fully PfBNT vaccinated HCW (VE:65%, 95%CI: 45-79%). The prevalence of infection among true asymptomatic (who never became symptomatic) was 3.3% among unvaccinated and 0.9% among vaccinated individuals. The vaccine effectiveness was 72% (95% CI: 48-86%). 14 Furthermore, the vaccine was 70% effective (95% CI: 43-84%) in preventing all presumably infectious cases (with Ct values <30) and 83% effective (95% CI: 51-94%) against presumably infectious asymptomatic cases. 14 Bouton et al. however did not find any significant difference in asymptomatic cases (assessed following workplace exposure, out of state travel or upon request) at any time from the first dose of vaccination with either Moderna or PfBnT vaccines compared with unvaccinated HCWs at a tertiary health centre. 15 . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted July 2, 2021. Table 11 to Table 13 utilized estimates from the current HCW specific literature on likelihood of asymptomatic, symptomatic or any infection over a range of attack rates (to encompass a range of exposure risk) to describe the risk of vaccinated HCW developing COVID-19 after a potential exposure to support decision makers in policy design. The risk reduction values used are from an evolving body of literature and a range of study designs, with reduction of risk noted by weeks from first dose as extracted from the studies. Vaccine related risk reduction ranges are based on available HCW study data, from the following time points: 3 weeks post dose 1 mRNA; 3 weeks to 12 weeks post dose 1 nonreplicating adenovirus. Vaccination protection following first dose was selected both based on available data and because this is relevant as the dosing schedules are currently based on an extended interval for many vaccinees. These data should be considered within the context of current uncertainties including long-term follow up data beyond three months after vaccination.

As an example, the risk of a HCW developing an asymptomatic COVID-19 infection (estimated to be 20% of all infections) following a low-risk exposure (0.5%) after receiving first dose of vaccine would be between 1/757 (3 weeks post vaccination) and 1/1,136 (12 weeks post vaccination) for adenovirus vector vaccines and 1/833 to 1/5,000 3 weeks post vaccination for mRNA vaccines.

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The copyright holder for this preprint this version posted July 2, 2021. ; https://doi.org/10.1101/2021.06.29.21255526 doi: medRxiv preprint 

Eight studies reported on Ct, an inverse proxy for viral load. Five of these are new to the updated version of this report.

Results from Phase 2/3 vaccine efficacy studies of AZ vaccine compared with a comparator meningococcal vaccine in the United Kingdom, showed that the Ct values in infected vaccinated participants were statistically significantly higher than the comparator (p<0.0001), after 14 days of the second dose in baseline seronegative efficacy cohorts. 6 Furthermore, the vaccine recipients were PCR-positive for a significantly shorter period of time (p<0.0001). The Ct values in asymptomatic cases were also significantly higher among vaccine recipients than control (p=0.0040); however, this difference was not significant for primary symptomatic cases (p=0.1534). Vaccine recipients infected with the B. 16 However, after 28 days, there was a statistically significant decrease in the mean Ct between vaccinated and unvaccinated persons (mean Ct 26.6 (95% CI: 26-27.1) vs 31·3 (95% CI: 29.6-32.9), p<0·001). 16 Monthly routine PCR testing was conducted in these patients; however, the baseline serology was not reported. 16 In a longitudinal cohort study of HCWs who were offered voluntary nasal and oropharyngeal swab PCR testing every two weeks as well as serological testing, Lumley et al., found vaccination with either PfBnT or AZ to nonsignificantly increase Ct value by a mean of 2.7. 17 A retrospective study of PfBnT mRNA vaccine recipients compared with demographically matched control group of unvaccinated individuals in Israel, found no significant differences in the Ct values for any of the 3 genes (RdRp, N and E) measured less than 12 days after the first dose in infected persons. However, between 12 and 28 days after the first dose, the Ct values for the 3 genes were significantly higher among infected vaccinated persons than controls (p<10 -8 ). 36 

All the animal studies estimated viral load by using viral genomic RNA (gRNA) and subgenomic RNA (sgRNA), from nasal or bronchoalveolar lavage (BAL) samples. The vaccines have either been approved or have progressed to human trials.

van Doremalen et al. found that the AZ vaccine significantly reduced viral load in the bronchoalveolar lavage fluid of vaccinated rhesus macaques on the third, fifth and seventh day post viral challenge, compared with control animals. 20 In the BAL fluid obtained from control animals, viral genomic and subgenomic RNA were detected on all days; while two of the vaccinated animals had detectable viral gRNA three days after challenge. Viral gRNA was detected in nose swabs from all animals and no difference was found on any day between vaccinated and control animals. Mercado et al. reported that all or almost all macaques vaccinated with Ad26-S.PP, an adenovirus serotype 26 (Ad26) vector-based vaccines expressing tPA leader sequence by J&J, had no detectable virus in BAL or nasal samples respectively, compared with sham controls, which showed high titres of viral sgRNA (p<0.0001 and p<0.0001, respectively). 41 

Patel et al. found that peak viral sgmRNA and RNA loads in the BAL were significantly lower in INO-4800 vaccinated macaques (two doses) at day 7 post-challenge (peak: p=0.048, day 7: p=0.024). 42 However, viral sgmRNA was still detectable in the nasal swabs of both the control and INO-4800 vaccinated animals. Viral mRNA levels trended downwards in INO-4800 vaccinated animals. 42 mRNA Vaccines

The mRNA-1273 vaccine showed significantly lower RNA and subgenomic RNA, in BAL and nasal swabs, in the 100-μg dose group compared with the control group. 21 Only one of the eight vaccinated had detectable subgenomic RNA in BAL fluid two days after challenge, while all the control animals had detectable RNA. Similarly, none of the eight animals administered the 100-μg dose had detectable subgenomic RNA detected in nasal swab compared with six of eight in the control. Ji et al. found no viral RNA in the lung tissues of mice 42 days after a second dose of BNT162b2-vaccination, compared with a mean of 10 6 copies/mL in control animals (p<0.001). 40 A study by Vogel et al. showed BNT162b2-immunized, SARS-CoV-2 challenged macaques cleared all viral RNA by day 3 after challenge; while viral RNA was detected in bronchoalveolar lavage fluid from seven of nine control macaques. One day post challenge, 4 of 9 control animals had detectable viral RNA. In subsequent nasal swabs, viral RNA was detected from some of the control macaques at each sampling time point (5 of 9 on . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted July 2, 2021. ; https://doi.org/10.1101/2021.06.29.21255526 doi: medRxiv preprint day 3; 4 of 9 on day 6; and 2 of 9 on days 7-23), but none of the BNT162b2-immunized macaques at any sampling time point. 44 

In the Novavax's NVX-CoV2373 vaccine study, macaques administered placebo had elevated viral load two and four days post viral challenge, while all but one of the vaccinated animals had no detectable sgRNA in their BAL fluid. 22 Similarly, half of the placebo group had elevated viral RNA in their nasal swabs, while none was detectable in vaccinated animals. 22 

In this update, 16 additional studies, including 9 human and 7 animal studies, were included. Therefore, this review has a total of 33 included studies, twenty-one of which were in humans and 12 were preclinical animal studies. Two new studies from Scotland and England evaluated household transmission following vaccination and found PfBnT and AZ to significantly reduce the risk of household transmission. 2, 3 The majority of the vaccines included in this review demonstrated efficacy and effectiveness against asymptomatic wild-type COVID-19 infections.

. CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted July 2, 2021. ; https://doi.org/10.1101/2021.06.29.21255526 doi: medRxiv preprint

The AZ and PfBnT vaccines were found to be significantly associated with higher Ct values than their respective comparators, suggesting that these vaccines may potentially reduce viral load and consequently lower the risk of transmission. It is however noteworthy that the relationship between viral load, viral shedding, infectivity and the duration of infectivity are not well understood. Ct values are also subject to error. 50 Preclinical primate studies showed that vaccinated animals receiving the Moderna mRNA (8 weeks prior), 21 PfBnT, or Novavax protein vaccine (35 days prior), 22 were less likely to have the virus recovered from nasal or lower respiratory samples than unvaccinated animals. The AZ vaccine was more protective against lower respiratory replication, while showing no difference in nasal virus replication. 20 Studies suggesting the plausibility of vaccine-induced reduction of transmission, including monoclonal antibody therapeutics trials and epidemiologic evidence of transmission from individuals who were persistently RT-PCR positive after natural infection, with evidence of an immunologic response, indicated that viral load can be reduced by circulating antibodies, and that a lower viral load or higher Ct on RT-PCR was associated with a reduced risk of transmission. 25, 26 However, RT-PCR positivity in the presence of neutralizing antibody and or correlates of cell mediated immunity should not be considered to necessarily represent transmissible infection.

There were significant limitations to many of the included studies. The primary endpoint of the vaccine randomized controlled trials were detection of test positive symptomatic COVID-19, however some studies presented data, which suggest a reduction in the likelihood of testing positive for SARS-CoV-2 RT-PCR in the absence of documented symptoms after vaccination. Furthermore, it was not possible to directly compare findings across studies owing to variations in the assessment of symptom status, and the testing used and timing of these assessments. Also, the possibility of persistent PCR positivity after COVID-19 infection 51 could not be excluded in some of the studies without baseline PCR assessment. Few studies included surveillance nasal swabs for PCR positivity. Most of the current data were around viral detection, rather than evidence of cultivatable virus. Therefore, there was limited data to evaluate the efficacy or effectiveness of COVID-19 vaccines in decreasing viral loads. In addition, there are only a limited number of epidemiologic data addressing evidence of forward transmission after vaccination.

Based on the current evidence, we suggest the following: 1) all vaccinees should self-isolate and seek testing after the development of COVID-19 compatible symptoms 2) Following exposure, the risk of contracting COVID-19 and subsequent forward transmission from asymptomatic or pauci symptomatic viral carriage should be considered in light of whether the exposed individual was vaccinated the time elapsed since immunization and the consequent expected degree of protection on, a case-by-case basis for those in vulnerable setting. When possible, a case-by-case consideration for whether exposed persons are . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted July 2, 2021. ; https://doi.org/10.1101/2021.06.29.21255526 doi: medRxiv preprint immunized, is necessary. Low-moderate risk exposures could potentially be managed with careful use of personal protective equipment (PPE), and self-monitoring.

3) If a vaccinated HCW is assessed as having a significant exposure before the period of expected robust immunity, high risk exposures may be managed as for unvaccinated persons.

4) All vaccinated persons should continue to use recommended PPE when in close contact with unvaccinated persons. 5) Population and public health data being collected on positive COVID-19 tests occurring after vaccination should be combined with laboratory data on Ct values, identification of variant strain infections, and epidemiologic contact tracing data to prospectively monitor for evidence of forward transmission of infection from vaccinated persons.

Two months since the publication of the previous version of this report, 16 additional relevant studies have been published. Two of these are large household surveillance studies from the UK suggesting single or full dose of AZ and PfBnT vaccines may prevent household transmission of COVID-19 after 14 days of vaccination. More studies have found the vaccines to significantly reduce the risk of asymptomatic infection and seven of eight studies found significantly increased cycle threshold, suggestive of lower viral load, in AZ or PfBnT vaccinated individuals compared with unvaccinated. Some studies, such as the AZ vaccine RCTs, included data on cross sectional prevalence of positive SARS-CoV-2 RT-PCR from routine swabbing, which suggested efficacy against asymptomatic infection, although this was not routinely assessed in a comparable way across studies. Evidence regarding the Ct values for AZ vaccine and the PfBnT vaccine suggest their potential to reduce viral load and possibly transmission. Further research is needed to evaluate post-vaccination infectivity and transmission of both the wild type COVID-19 virus and the variants of concern from other jurisdictions.

. CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted July 2, 2021. . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted July 2, 2021. ; https://doi.org/10.1101/2021.06.29.21255526 doi: medRxiv preprint

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Appendix 1: Search Strategy Ovid Multifile Database: EBM Reviews -Cochrane Central Register of Controlled Trials <March 2021>

exp COVID-19 Vaccines

COVID-19 or COVID19) adj5 (immun* or inoculat* or vaccin*)).tw,kf

* or corona virus*) adj5 (immun* or inoculat* or vaccin*)).tw,kf

-nCoV or nCoV or n-CoV or SARS-CoV-2 or SARS-CoV2 or SARSCoV-2 or SARSCoV2 or SARS2) adj5 (immun* or inoculat* or vaccin*)).tw,kf

BNT162 or BNT162-01 or BNT162a1 or BNT162b1 or BNT162b2 or BNT162c2) and vaccin*) or N38TVC63NU).tw,kf

AZD1222 or ChAdOx1) and vaccin*) or Covishield$2 or B5S3K2V0G8).tw,kf. (290) 7 ((mRNA-1273 and vaccin*) or EPK39PL4R4).tw,kf

) and (COVID-19 or COVID19 or coronavirus* or corona virus* or 2019-nCoV or nCoV or n-CoV or SARS-CoV-2 or SARS-CoV2 or SARSCoV-2 or SARSCoV2 or SARS2)).tw,kf

RNA adj3 vaccin*) and (COVID-19 or COVID19 or coronavirus* or corona virus* or 2019-nCoV or nCoV or n-CoV or SARS-CoV-2 or SARS-CoV2 or SARSCoV-2 or SARSCoV2 or SARS2)).tw,kf

Ad5-nCoV and vaccin*) or hAdOx1 nCoV-19).tw,kf

Viral Vaccines/ and (Coronavirus/ or Betacoronavirus/ or Coronavirus Infections/)

* or decreas* or halt* or prevent* or reduc* or stop*) adj5 (COVID-19 or COVID19)).tw,kf

* or decreas* or halt* or prevent* or reduc* or stop*) adj5 (coronavirus* or corona virus*)).tw,kf

* or decreas* or halt* or prevent* or reduc* or stop*) adj5 (2019-nCoV or nCoV or n-CoV or SARS-CoV-2 or SARS-CoV2 or SARSCoV-2 or SARSCoV2 or SARS2)).tw,kf

* or decreas* or halt* or prevent* or reduc* or stop*) adj5 spread*).tw,kf

Coronavirus Infections/ep

Coronavirus Infections/tm [Transmission

Coronavirus Infections/vi

Infectious/ (350027) 29 (transmit* or transmissi* or infectiousness* or infectivit*).tw,kf. (1218179) 30 ((COVID-19 or COVID19) adj5 (caus* or pass or passed or passes or passing or spread*)).tw,kf

* or corona virus*) adj5 (caus* or pass or passed or passes or passing or spread*)).tw,kf

* or infection*) adj5 (caus* or pass or passed or passes or passing or spread*)).tw,kf

-nCoV or nCoV or n-CoV or SARS-CoV-2 or SARS-CoV2 or SARSCoV-2 or SARSCoV2 or SARS2) adj5 spread*).tw,kf

34 (unvaccinat* or nonvaccinat* or non-vaccinat* or "not vaccinat*").tw,kf. (41533)

Controlled Clinical Trials as Topic"/ (372323) 40 (randomi#ed or randomi#ation? or randomly or RCT or placebo*).tw,kf

* or doubl* or trebl* or tripl*) adj (mask* or blind* or dumm*)).tw,kf. (722847) 42 trial.ti

Controlled Trials as Topic

* or non-random* or quasi-random* or quasi-experiment*).tw,kf. (154248) 50 (nRCT or non-RCT).tw,kf

Controlled Before-After Studies/ (208005) 52 (control* adj3

54 time series.tw,kf. (75281) 55 (pre-adj3 post-).tw,kf. (286836) adj2 group?).tw,kf

exp Cohort Studies/ (2983557) 65 cohort?.tw,kf

Retrospective Studies/ (1693557) 67 (longitudinal or prospective or retrospective).tw,kf. (3742018) 68 ((followup or follow-up) adj (study or studies)).tw,kf. (129595) 69 Observational study.pt. (98909) 70 (observation$2 adj (study or studies)).tw,kf

population or population-based) adj (study or studies or analys#s)).tw,kf. (46388) 72 ((multidimensional or multi-dimensional) adj (study or studies)).tw,kf

comparative or comparison) adj (study or studies)).tw,kf

* or case-based or case-comparison) adj (study or studies)).tw,kf

Cross-Sectional Studies/ (649801) 78 (crosssection* or cross-section*).tw,kf

COVID-19 or COVID19) adj5 (immun* or inoculat* or vaccin*)).tw,kw

-nCoV or nCoV or n-CoV or SARS-CoV-2 or SARS-CoV2 or SARSCoV-2 or SARSCoV2 or SARS2) adj5 (immun* or inoculat* or vaccin*)).tw,kw. (8872) 87 (((BNT162 or BNT162-01 or BNT162a1 or BNT162b1 or BNT162b2 or BNT162c2) and vaccin*) or N38TVC63NU)

AZD1222 or ChAdOx1) and vaccin*) or Covishield$2 or B5S3K2V0G8).tw,kw

mRNA-1273 and vaccin*) or EPK39PL4R4).tw,kw

) and (COVID-19 or COVID19 or coronavirus* or corona virus* or 2019-nCoV or nCoV or n-CoV or SARS-CoV-2 or SARS-CoV2 or SARSCoV-2 or SARSCoV2 or SARS2)).tw,kw

RNA adj3 vaccin*) and (COVID-19 or COVID19 or coronavirus* or corona virus* or 2019-nCoV or nCoV or n-CoV or SARS-CoV-2 or SARS-CoV2 or SARSCoV-2 or SARSCoV2 or SARS2)).tw,kw

Ad5-nCoV and vaccin*) or hAdOx1 nCoV-19).tw,kw

95 (severe acute respiratory syndrome vaccine/ or virus vaccine/) and (coronavirinae/ or betacoronavirus/ or exp SARS-related coronavirus/ or coronavirus infection/) (1072)

* or decreas* or halt* or prevent* or reduc* or stop*) adj5 (COVID-19 or COVID19)).tw,kw

* or decreas* or halt* or prevent* or reduc* or stop*) adj5 (coronavirus* or corona virus*)).tw,kw

* or decreas* or halt* or prevent* or reduc* or stop*) adj5 (2019-nCoV or nCoV or n-CoV or SARS-CoV-2 or SARS-CoV2 or SARSCoV-2 or SARSCoV2 or SARS2)).tw,kw

* or decreas* or halt* or prevent* or reduc* or stop*) adj5 spread*).tw,kw

COVID-19 or COVID19) adj5 (caus* or pass or passed or passes or passing or spread*)).tw,kw

* or corona virus*) adj5 (caus* or pass or passed or passes or passing or spread*)).tw,kw

* or infection*) adj5 (caus* or pass or passed or passes or passing or spread*)).tw,kw

-nCoV or nCoV or n-CoV or SARS-CoV-2 or SARS-CoV2 or SARSCoV-2 or SARSCoV2 or SARS2) adj5 spread*).tw,kw

112 (unvaccinat* or nonvaccinat* or non-vaccinat* or "not vaccinat*").tw,kw. (41536)

118 (randomi#ed or randomi#ation? or randomly or RCT or placebo*).tw,kw. (3717620) 119 ((singl* or doubl* or trebl* or tripl*) adj (mask* or blind* or dumm*)).tw,kw. (751624) kw. (1026519) 126 (nonrandom* or non-random* or quasi-random* or quasi-experiment*)

146 (longitudinal or prospective or retrospective).tw,kw. (3762504) 147 follow up

followup or follow-up) adj (study or studies)).tw,kw

population or population-based) adj (study or studies or analys#s)).tw,kw. (54489) 153 ((multidimensional or multi-dimensional) adj (study or studies)).tw,kw

comparative or comparison) adj (study or studies)).tw,kw

COVID-19 or COVID19) adj5 (immun* or inoculat* or vaccin*)).ti,ab,kw. (14212) 167 ((coronavirus* or corona virus*) adj5 (immun* or inoculat* or vaccin*)).ti,ab,kw

CoV or SARS-CoV-2 or SARS-CoV2 or SARSCoV-2 or SARSCoV2 or SARS2) adj5 (immun* or inoculat* or vaccin*)).ti,ab,kw. (8872) 169 (((BNT162 or BNT162-01 or BNT162a1 or BNT162b1 or BNT162b2 or BNT162c2) and vaccin*) or N38TVC63NU)

AZD1222 or ChAdOx1) and vaccin*) or Covishield$2 or B5S3K2V0G8).ti,ab,kw

mRNA-1273 and vaccin*) or EPK39PL4R4).ti,ab,kw

) and (COVID-19 or COVID19 or coronavirus* or corona virus* or 2019-nCoV or nCoV or n-CoV or SARS-CoV-2 or SARS-CoV2 or SARSCoV-2 or SARSCoV2 or SARS2)).ti,ab,kw

COVID-19 or COVID19 or coronavirus* or corona virus* or 2019-nCoV or nCoV or n-CoV or SARS-CoV-2 or SARS-CoV2 or SARSCoV-2 or SARSCoV2 or SARS2)).ti,ab,kw. (51) 174 (LV-SMENP-DC and vaccin*).ti,ab,kw. (1) 175 ((Ad5-nCoV and vaccin*) or hAdOx1 nCoV-19).ti,ab,kw

Viral Vaccines/ and (Coronavirus/ or Betacoronavirus/ or Coronavirus Infections/)

Coronavirus Infections/pc

* or decreas* or halt* or prevent* or reduc* or stop*) adj5 (COVID-19 or COVID19)).ti,ab,kw

* or decreas* or halt* or prevent* or reduc* or stop*) adj5 (coronavirus* or corona virus*)).ti,ab,kw

* or decreas* or halt* or prevent* or reduc* or stop*) adj5 (2019-nCoV or nCoV or n-CoV or SARS-CoV-2 or SARS-CoV2 or SARSCoV-2 or SARSCoV2 or SARS2)).ti,ab,kw

* or decreas* or halt* or prevent* or reduc* or stop*) adj5 spread*).ti,ab,kw

Coronavirus Infections/ep

Coronavirus Infections/tm [Transmission

Coronavirus Infections/vi

193 (transmit* or transmissi* or infectiousness* or infectivit*).ti,ab,kw. (1223805) 194 ((COVID-19 or COVID19) adj5 (caus* or pass or passed or passes or passing or spread*)).ti,ab,kw

* or corona virus*) adj5 (caus* or pass or passed or passes or passing or spread*)).ti,ab,kw

* or infection*) adj5 (caus* or pass or passed or passes or passing or spread*)).ti,ab,kw

-nCoV or nCoV or n-CoV or SARS-CoV-2 or SARS-CoV2 or SARSCoV-2 or SARSCoV2 or SARS2) adj5 spread*).ti,ab,kw

198 (unvaccinat* or nonvaccinat* or non-vaccinat* or "not vaccinat*").ti,ab,kw. (41536)