key: cord-0971092-64ozs157
authors: Marcelin, Jasmine R; Pettifor, Audrey; Janes, Holly; Brown, Elizabeth R; Kublin, James G; Stephenson, Kathryn E
title: COVID-19 Vaccines and SARS-CoV-2 Transmission in the Era of New Variants: A Review and Perspective
date: 2022-03-10
journal: Open Forum Infect Dis
DOI: 10.1093/ofid/ofac124
sha: ba04844357bd24e2341b6d059e505dee8ea2c3dc
doc_id: 971092
cord_uid: 64ozs157

COVID-19 vaccines have yielded definitive prevention and major reductions in morbidity and mortality from SARS-CoV-2 infection, even in the context of emerging and persistent variants-of-concern. Newer variants have revealed less vaccine protection against infection and attenuation of vaccine effects on transmission. COVID-19 vaccines still likely reduce transmission compared to not being vaccinated at all, even with variants of concern, however determining the magnitude of transmission reduction is constrained by challenges of performing these studies, requiring accurate linkage of infections to vaccine status and timing thereof, particularly within households. In this review we synthesize the currently available data on the impact of COVID-19 vaccines on infection, serious illness, and transmission; we also identify the challenges and opportunities associated with policy development based on this data.

In just over 1 year, over 10 billion doses of COVID-19 vaccines have been administered globally [1] , with 10 vaccines granted emergency use listing by the World Health Organization so far, including mRNA, adenovirus-vectored, soluble protein, and inactivated virus vaccines [2] . These vaccines have demonstrated efficacy in preventing symptomatic COVID-19 in randomized controlled trials, in the context of both the original SARS-CoV-2 strains (D614 and D614G) and real world effectiveness against variants-of-concern [3] .

Economists at Indiana University and the RAND Corporation, estimated that COVID-19 vaccination prevented at least 140,000 deaths in the United States alone by May, 2021 [4] .

While COVID-19 vaccines have yielded definitive prevention and major reductions in morbidity and mortality from SARS-CoV-2 infection, the impact of these vaccines against asymptomatic infection, viral shedding, and secondary SARS-CoV-2 transmission with emerging variants is more nuanced [5] . Real world effectiveness studies in the context of the Alpha variant suggest that multiple vaccines do reduce infection and onward transmission [6] [7] [8] , but the coordinated, robust surveillance systems needed to track this in real time for emerging variants of concern are lacking. This dearth of real-time data stymies policy makers, who are navigating public policy decisions around primary and booster vaccination, the roll-out of monoclonal antibodies and small-molecule antivirals, and guidance on non-pharmaceutical interventions like masking. Many misinterpreting reports of increased breakthrough infections as evidence of whole-sale loss of vaccine protection against transmission have resulted in public confusion on the topic, and these questions are even more pronounced given emergence of the most recent variant-of-concern as of November 2021, Omicron (B.1.1.529) [9] .

A c c e p t e d M a n u s c r i p t

In this review, we outline the literature on the impact of COVID-19 vaccines on SARS-CoV-2 infection, peak and duration of viral shedding, and transmission of SARS-CoV-2 following vaccination, with an emphasis on COVID-19 vaccine effects against variants-of-concern.

COVID-19 vaccines remain a critical tool to in the path to ending the pandemic, even in the context of newer variants and waning immunity. We argue that surveillance of transmission among both vaccinated and unvaccinated populations is woefully inadequate, leaving policy makers uninformed and vulnerable to poor decision-making in the face of potentially more transmissible variants on the horizon. Prospective studies evaluating vaccine efficacy in the context of evolving variants are necessary for providing definitive answers about the magnitude of reduction in infection and transmission of SARS-CoV-2 variants.

Our understanding of transmission of SARS-CoV-2 and the impact that vaccines have on reducing risk have significant policy implications. As of January 2022 the CDC continues to recommend that individuals in areas of substantial or high transmission should wear masks indoors in public regardless of vaccination status, due to the increased transmissibility of SARS-CoV-2 [10, 11] , although by February 2022 many states have begun to reverse mask mandates [12] . Given the general overwhelmed state of hospital systems and overworked state of healthcare workers, ultra-conservative isolation and return-to-work policies for infected workers may result in both absenteeism (further overwhelming the system with possible delays in care due to understaffing) or presenteeism (placing patients at risk for being infected when workers come to work sick) [13] [14] [15] . In December 2021, CDC recommended a 5 day isolation after a positive SARS-CoV-2 test for vaccinated, A c c e p t e d M a n u s c r i p t asymptomatic individuals while keeping the 10-day isolation for unvaccinated individuals [16] . Understanding SARS-COV-2 transmission and when individuals can safely return to work, school, and public venues also has economic implications including more businesses remaining open, fewer days off from work for vaccinated sick workers, and less negative employment change overall, which may lead to improved psychological distress and more equitable racial distribution of negative impacts [17] .

The first step in preventing transmission is preventing infection. If an individual is not infected, they cannot transmit virus to someone else. Therefore, when considering how well a vaccine protects against transmission, we must first determine how well it protects against infections, including asymptomatic infections. If a vaccine can prevent an overwhelming majority of infections, it will have a major impact on curtailing the epidemic, protecting the vaccinated as well as their close contacts ( Figure 1 ). Total vaccine protection against infection is sometimes referred to as sterilizing immunity, and while it can be achieved in individual cases it is exceedingly rare for any vaccine to achieve this across a population of vaccinated individuals [18] . The mechanism of sterilizing immunity is typically attributed to the presence of neutralizing antibodies that can bind to surface structures on an infectious particle, such as the Spike (S) protein on the surface of SARS-CoV-2, and inhibit entry into cells to block replication before it begins [18] . Neutralizing antibody to mRNA-1273 vaccine has also been shown to be a direct correlate of protection against symptomatic SARS-CoV-2 infection among mRNA-1273 recipients, though whether vaccine-induced neutralizing antibodies are a correlate of protection against all infections and for other vaccine platforms A c c e p t e d M a n u s c r i p t remains unknown [19] . Vaccinated individuals can experience breakthrough infections, which can be either symptomatic or asymptomatic, people who are immunocompromised may have less robust responses to vaccination and thereby less protection against disease [20] [21] [22] , and evolution of SARS-CoV-2 variants may interfere with development of neutralizing antibodies thereby leading to these breakthrough infections or rendering monoclonal antibodies obsolete [23] .

In the setting of breakthrough infections however, vaccines can also reduce the likelihood of onward transmission [24] , by decreasing the magnitude and duration of viral shedding, reducing the degree of symptoms, and possibly rendering breakthrough viruses less infectious ( Figure 1 ). Perhaps most significant among these effects is a vaccine-induced reduction in viral shedding. Among those infected with SARS-CoV-2, nasopharyngeal viral load may be a strong direct correlate for human-to-human transmission [25] . Evidence for this is nuanced and based on models [26, 27] or non-human primate studies that have shown that COVID-19 vaccines reduce viral load in the lower and upper respiratory tracts [28, 29] . One study found no link between viral load cycle threshold and transmission in a college student cohort [30] , and while a large prospective cohort showed no significant difference between cycle threshold peaks of symptomatic vs asymptomatic individuals, vaccinated individuals had faster viral load clearance and therefore lower overall duration of infection [31, 32] . Unfortunately, we have not yet identified the best laboratory method for reliable prediction of infectiousness [33] , therefore these inferences of the vaccine effect on infectiousness remain indirect and imperfect. From a mechanistic standpoint, vaccines eliciting neutralizing antibodies block the SARS-CoV-2 spike protein from interaction with A c c e p t e d M a n u s c r i p t the ACE2 receptor at the mucosal surface and obstruct viral entry into cells, but not all cells may be protected [34] . While some cells may not escape infection resulting in brief bursts of viral replication, the total magnitude of viral replication will be reduced. Moreover, vaccineinduced T cell immunity and other non-neutralizing immune responses can further limit spread of small pockets of mucosal infection, reducing the duration of infection. In addition to reducing viral shedding, vaccine-induced immune responses may also limit symptoms during breakthrough infections by preventing progression of disease from the mucosal compartment to the lower respiratory track and the rest of the body. Furthermore, a vaccine may have a 'sieve effect' whereby vaccination preferentially blocks infection with viruses that are more transmissible [35, 36] .

Despite the fact that over 60% of world's population has received at least one dose of a COVID-19 vaccine [1] , nearly all countries have experienced a surge of infections from April to December 2021. The drivers of the continued population transmission of SARS-CoV-2 are multi-factorial ( Figure 2 ). The emergence of new, highly transmissible viral variants in January/February of 2021 [37] , complete saturation by the Delta variant by July 2021 and subsequent dominance of the Omicron variant in towards the end of 2021/early 2022 with concern for even greater vaccine escape [38] , is an important factor. Potential waning of vaccine-induced immunity, immune evasion by new variants and increased pathogenicity of variants are others; evasion of the immune response, whether from natural infection or vaccine resistance, has been observed with other infectious diseases [39] [40] [41] . A root cause of much of ongoing transmission is the inequitable distribution of COVID-19 vaccines globally, leaving low-income countries particularly vulnerable to unabated infections and attendant A c c e p t e d M a n u s c r i p t onward transmission and the risk for development of new variants of concern [42] .

Importantly, in addition to the virus and vaccine effects, several other factors may influence transmission, including individual immune system function and comorbidities, community behaviors (e.g., masking, isolation, travel, and large gatherings), seasonal effects (e.g., cold weather forcing people indoors), and the impact of natural or hybrid immune response to infection ( Figure 1 ).

In late 2020, the United Kingdom reported a new SARS-CoV-2 variant, designated Alpha (B.1.1.7) [43] . This variant was found to be 50-75% more transmissible than previously circulating strains and had a higher secondary attack rate [44, 45] . The Alpha variant contained several mutations in the Spike protein, which did not confer significant immune evasion of vaccine-induced neutralizing antibody responses as tested in vitro [46, 47] . Data from both observational cohort studies and randomized, controlled clinical trials during the period of time in which Alpha was the predominant circulating strain in study location (Alpha period) confirmed that COVID-19 vaccines maintained activity against the Alpha variant, including partial protection against infection regardless of symptoms (Table 1) [3, [48] [49] [50] [51] [52] [53] [54] [55] [56] [57] [58] [59] . A meta-analysis of 12 studies found that the effectiveness of the adenovirus vectored-vaccines against infection was 73% (95% CI 69-77%) and for mRNA vaccines it was 85% (95% CI 82-88%) in participants ≥18 years [3] . Some of these data provides evidence of effectiveness against Beta and Gamma variant strains as well [48, 55] . Furthermore, evidence suggested that individuals with vaccine breakthrough SARS-CoV-2 infection during the Alpha period were less likely to transmit to household contacts than unvaccinated individuals with SARS-CoV-2 infection. For example, Prunas et al. analyzed a database of M a n u s c r i p t over 2 million individuals in Israel who had received 2 doses of BNT162b2 between June 2020 and March 2021, in which positive SARS-CoV-2 tests were linked by addresses allowing the tracking of index cases and household contacts [8] . Modeling estimated that vaccination reduced susceptibility to infection by ~80% and reduced infectiousness by 41%, resulting in an overall inferred reduction in transmission risk of 88.5% [60, 61] .

Data from the United Kingdom also suggested that vaccination led to a 40-50% reduction in transmission of breakthrough infections following only a single dose of either ChAdOx1 or BNT162b2, in a large centralized database study of households with positive SARS-CoV-2 tests in England during January to February 2021 [62] . Following full vaccination, investigators in the Netherlands calculated that vaccination led to a 70% reduction in transmission of breakthrough infections between February to May 2021 in a study utilizing detailed contact tracing strategies [63] . Interestingly when evaluating transmission pairs, the estimated attack rate was 10% if either member of the pair was vaccinated, vs. 30% for unvaccinated-unvaccinated pairs [60, 61] supporting benefit of vaccination of some household members even when others remain unvaccinated. Investigators also demonstrated reductions in the development of COVID-19 among household members of vaccinated healthcare workers in Scotland [64] , and among non-immune household members of individuals who demonstrated either vaccine-induced or natural infectioninduced immunity to COVID-19 in Sweden [65] .

The likely mechanisms behind this reduced transmission of breakthrough infections were decreases in viral shedding and symptoms. In the United States, Thompson et 

A c c e p t e d M a n u s c r i p t prospective cohort of US health care workers between December 2020 and April 2021 who received weekly nasal SARS-CoV-2 PCR [61] . Investigators found that vaccination led to a reduction of mean peak viral load from 3.8 log 10 copies/μl to 2.3 log 10 copies/μl, and a reduction of duration of RNA detection from 9 days to 3 days. Moreover, infected vaccinated participants had shorter duration of symptoms and only 25% had fever compared to 63% of unvaccinated participants. Pouwels et al. also showed that vaccination with multiple different platforms significantly reduced viral load in breakthrough infections compared to non-breakthrough infections in the Alpha period [60] .

The Delta variant (B.1.617.2 lineage) was first identified in India in December 2020 and became the prevalent variant worldwide by July 2021. The Delta variant is highly transmissible compared to both Alpha and ancestral strains, potentially due to the L452R mutation in the Spike protein leading to better binding avidity with the ACE2 receptor [60, [66] [67] [68] . Unlike the Alpha variant, the Delta variant also appears to partially evade immuneresponses in vitro [69] , though very high D164 S-specific neutralizing antibody titers can overcome this evasion in laboratory studies [70, 71] . A vast majority of reports regarding protection against Delta infection focuses on symptomatic infection.

Real-world data during the period of time in which Delta was the predominant circulating strain in the study location (Delta period) suggests that vaccine effectiveness against symptomatic SARS-CoV-2 infection is attenuated compared to the pre-Delta period, but that A c c e p t e d M a n u s c r i p t protection against moderate to severe disease remains very strong [72] . Observational studies of mRNA-1273 have shown a reduction in protection against symptomatic illness from >93% for Alpha to as low as 84% for Delta, but mRNA-1273 remained >90% effective against moderate to severe disease [51, [73] [74] [75] [76] . For ChAdOx1, vaccine effectiveness also decreased after two doses from 75% for Alpha to 67% for Delta infections, but protection against moderate-to-severe disease remained much higher at 82% [77, 78] . Preliminary data from South Africa shows that Ad26.COV2.S maintains strong protection against moderate to severe COVID-19 [79] , as do inactivated COVID-19 vaccines studied in Guangdong, China [80] .

BNT162b2 also decreased in effectiveness against symptomatic illness from 94% for Alpha to 88% for Delta infections but maintained effectiveness of 93% against hospitalizations for infections with the Delta variant [77, 81] . It is unclear if these reductions in effectiveness against disease are due to Delta immune evasion or waning immunity, as evidenced by studies that show that attenuation is focused on older age groups or people more remotely vaccinated [75, 82] .

While COVID-19 vaccines (particularly mRNA) have maintained robust protection against symptomatic illness and moderate to severe disease from recent variants, there appears to be a more marked attenuation in protection against infection (Table 2) [56, 60, 74, 78, 81, [83] [84] [85] . For example, estimates of mRNA-1273 effectiveness against infections among nursing home residents decreased from 74.7% against Alpha to 50.6% against Delta [83] , with other studies also estimating mRNA and Ad-vectored vaccine effectiveness in the 50-60% range against Delta infection, particularly for BNT162b2 [74, 78, 81, 84, 85] . Estimates of Ad26.COV2.S against Delta -predominant COVID-19 disease suggest vaccine effectiveness of 60-65% for preventing emergency department/urgent care encounters or hospitalizations A c c e p t e d M a n u s c r i p t for COVID-19 [75] . However, not all studies have estimated such sharp reductions in effectiveness against Delta, with other data suggesting rates closer to 70-80% range for mRNA vaccines [60, 84, 85] .

Because the Delta surge occurred simultaneously with waning immunity for most vaccinated individuals globally, it is difficult to disentangle the precise mechanism for the attenuation of vaccine effectiveness observed during the Delta period. Nevertheless, the evidence suggests a reduced impact of vaccines against transmission by virtue of the increased rate of breakthrough infections (Step 1 of vaccine effects on transmission, Figure 1 ). There also appears to be a reduction in the vaccine effect on the infectiousness of breakthrough infections (Step 2 of vaccine effects on transmission, Figure 1 ), as suggested by data from Singanayagam et al., who performed a prospective, longitudinal study of ambulatory close contacts of confirmed COVID-19 cases [86] . In this study, the secondary attack rate among household contacts exposed to fully vaccinated index cases was no different than those exposed to unvaccinated index cases (25% vs. 23%, respectively). In contrast, Harris et al. While peak viral load may be the same between breakthrough and non-breakthrough infections, the total duration of viral shedding may not be the same. Investigators in Singapore found that the viral kinetics of breakthrough infections were significantly different than in unvaccinated infections, with a steeper decline in viral load and accelerated clearance [88] . Singanayagam also found that vaccinated individuals had a faster mean rate of viral load decline than did unvaccinated individuals, as did Kissler et al. [32, 86] . Moreover, Shamier et al. found that breakthrough infections were much less likely to be culture positive (i.e.., live virus) compared to non-breakthrough infections, even when samples had the same viral load on PCR) [89] . In contrast, in a study of a subset of 70 symptomatic persons who provided swabs for serial testing in a Texas prison, no significant difference was found in the median interval between reported symptom onset and last positive RT-PCR result in vaccinated versus unvaccinated persons (9 vs. 11 days) [90] . Virus was cultured from 42% of unvaccinated samples compared to 38% of fully vaccinated samples (with the limitation that this data may not reflect the viral kinetics of asymptomatic infections).

A c c e p t e d M a n u s c r i p t These data suggest that there may be vaccine effects on the total duration of shedding of infectious virus which may not necessarily translate to meaningful reductions in household transmission, perhaps because most transmission may occur during early, peak shedding periods and during so-called 'superspreader events' [91, 92] . A retrospective study in the UK found a more pronounced effect of reduction of onward transmission with vaccination against the Alpha variant compared with Delta; however although vaccination was associated with higher cycle threshold (Ct) values (aka lower viral loads), differences in Ct values alone did not fully explain the effect of vaccination [93] . Furthermore, breakthrough Delta infections could still be less transmittable at the population level. Phylogenetic evaluation of the Massachusetts outbreak in a highly vaccinated population suggested an overdispersion phenomenon in which a few individuals propagated most transmission events, suggesting that not all cases with high viral load detected by PCR ended up as the source of secondary transmission [92, 94] .

There is comparatively little data on COVID-19 vaccine effects on transmission of other variants-of-concern such as Beta and Gamma. Hitchings et al. evaluated CoronaVac (an inactivated vaccine) during the Gamma variant wave in Manaus, Brazil and found that after two doses, the vaccine was 37.9% effective against all SARS-CoV-2 infection [53] . Sadoff et al.

found that Ad26.COV2.S was 66% effective against asymptomatic infections that included a large proportion of Beta, given 15% of the study population was from South Africa during their Beta surge [55] . There is no additional published data on viral dynamics and secondary transmission of breakthrough infections for these variants.

A c c e p t e d M a n u s c r i p t

In November 2021, a new variant was reported in South Africa that was noted to overtake Delta sequences in surveillance data and was subsequently designated the variant-ofconcern Omicron (B.1.1.529); as of February 2022 it has been identified in almost every country worldwide, and is the predominant circulating strain in the US since January 2022 [9] . The BA.1 Omicron variant has over 30 mutations in the Spike protein, including changes that associated with increased transmissibility and immune evasion [38, 95] .

Available data demonstrates reduced mRNA vaccine effectiveness against Omicron, compared with Delta (Table 2 ) [96, 97] . The full impact of COVID-19 vaccines on transmission of Omicron is still being evaluated, however data suggests increased transmission with higher secondary attack rates in households compared with rates during Delta predominant period [98] . Evolving data regarding the clinical impact of Omicron suggests that despite increased infections and hospitalization rates, there is a reduced risk of severe disease and death compared with Delta [99] [100] [101] [102] . However, the rates of infection and hospitalization in children and adolescents increased rapidly during the Omicron wave, a feature of Delta but not other variants [103] .

The waning effects of vaccines against the Omicron variant are concerning [96] . Preliminary reports suggest that prior infection-and vaccine-induced antibody neutralization response against Omicron is significantly reduced[38, 104-106] -possibly explaining increased infection rates, while vaccine-induced cellular immune responses may remain robust in response to Omicron, possibly explaining protection against severe disease [107] . There is evidence that 3 doses may be needed to maintain a similar level of effectiveness against Omicron than was achieved with 2 doses against prior variants [97, 105, 108, 109] , and A c c e p t e d M a n u s c r i p t vaccine effectiveness may be significantly reduced in immunocompromised people even with 3 doses [97] . Vaccinated individuals (and even those boosted) are still at risk of acquisition of SARS-CoV-2, however unvaccinated people had rates of infection and hospitalization with Omicron that were 3.8 and 23.0 times higher compared with vaccinated people who had received boosters [110] . As such, the CDC still recommends booster doses for people older than 12yrs [111] , and a 4 th dose for people with immunocompromising conditions [112] .

The BA.2 sublineage of Omicron has emerged with additional mutations distinguishing it from the predominant BA.1 lineage [113] . Preliminary data suggests BA.2 may be more transmissible than BA.1, even in individuals who have been fully vaccinated, however the largest secondary attack rates occurred among unvaccinated household individuals [98] . [114] . Evolution of mutations leading to future variants of concern continues to be a possibility and should embolden worldwide vaccination efforts to reduce the proportion of individuals susceptible to future infections.

This review highlights several limitations to understanding SARS-CoV-2 transmission patterns effectively. First, retrospective observational studies have a delay in providing information, leading to a situation in which the literature applies to a variant that is already A c c e p t e d M a n u s c r i p t out of circulation. However, given the progression of this pandemic with rapidly evolving variants, even prospective studies may find themselves engaging in a race against time to the "next variant", or collecting data prospectively that spans the course of more than one variant wave.

Second, many studies rely predominantly on proxy markers of asymptomatic infection (such as seroconversion) or are based on relatively infrequent PCR testing (e.g., less than twice weekly). Both incorporate 'length bias', with individuals with short-duration infections or who never seroconvert misclassified as uninfected. If missed infections occur more often among vaccinated individuals, due to shortened duration of shedding or reduced seroconversion, this will inflate estimates of vaccine effects against SARS-CoV-2 infection.

Furthermore, it will inflate estimates of vaccine effects on secondary transmission to the extent that testing of contacts/household members is triggered by diagnosis of the index case.

A related issue occurs when infection is exclusively or predominantly triggered by an event such as onset of COVID-19 symptoms or potential SARS-CoV-2 exposure. If the frequency of the trigger is not balanced across vaccinated and unvaccinated groups, as in the case of symptom-prompted testing, infections will be differentially misclassified leading to bias.

A c c e p t e d M a n u s c r i p t transmission. Symptom-prompted testing will also miss characterizing the effect of vaccination on shedding of asymptomatic infections.

Evaluating vaccine effects on secondary transmission requires distinguishing primary and secondary infection events within transmission clusters, e.g., households. However, even prospective household transmission studies may have challenges. First, it may be difficult to accurately account for possible shared (e.g., siblings at daycare or adults with similar friend circles) or other community-acquired exposures and challenging to determine directionality of transmission in a household when community spread is high. Additionally, while frequent testing would provide the most complete viral load trajectory, perfect adherence to daily procedures is difficult, even with incentives, because sometimes participants forget, or perhaps lack motivation to test. Furthermore, it is possible that individuals with more personal concern about COVID-19 may have greater incentive to adhere to testing procedures, which could potentially result in systematic bias when evaluating viral load trajectories. However, even with frequent, systematic SARS-CoV-2 testing of all members of transmission units, inferring transmission chains is challenging, given that individuals are likely infectious only for a few days early in the course of infection and just on or before the onset of any symptoms that develop [31, 115] . When testing is infrequent or triggered by symptoms or potential SARS-CoV-2 exposure, it is considerably more challenging, and misclassification of transmission events is very likely. This misclassification will bias estimates of vaccine effects on secondary transmission.

A c c e p t e d M a n u s c r i p t Finally, uncontrolled studies are subject to confounding, possibly due to differential likelihood of exposure to SARS-CoV-2 status or different behavior influencing transmission conditional on vaccination status. The driving forces of these differences may not be captured in the collected data or adequately controlled for in the design. Confounding is a major concern especially in settings such as the US where there has been politicization of vaccines and other prevention measures, and in settings where vaccine access is limited by prioritization guidance. Retrospective observational studies are especially subject to uncontrolled confounding given limited capability to retrospectively capture exposure/transmission variables.

Despite the challenges outlined above in accurately measuring vaccine effects on transmission, it is nevertheless critical to push forward and invest in such research. In particular, we recommend increased support for prospective studies that (1) follow individuals with routine, frequent PCR testing for viral quantification, infectiousness testing, and sequencing, (2) simultaneously collect risk behavior information on these individuals, as well as vaccination history, comorbidities, demographic data and symptomatology, (3) prospectively follow secondary contacts of these individuals (e.g., their households) to accurately infer transmission events and calculate secondary attack rates, as well as capture full viral load trajectories on both asymptomatic and symptomatic individuals and (4) provide rapid, transparent sharing of data to inform real-time evidence-based public health decision-making. While no study is perfect, this type of prospective 'household transmission study' would provide invaluable data on vaccine effects on SARS-CoV-2 transmission that is more robust than most retrospective studies can provide. M a n u s c r i p t A c c e p t e d M a n u s c r i p t M a n u s c r i p t M a n u s c r i p t M a n u s c r i p t VOC, variant of concern; VE, vaccine effectiveness/efficacy; RCT; randomized controlled trial; PCR, polymerase chain reaction M a n u s c r i p t

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Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine

Effectiveness of the mRNA-1273 Vaccine during a SARS-CoV-2 Delta Outbreak in a Prison

Interim Estimates of COVID-19 Vaccine Effectiveness Against COVID-19-Associated Emergency Department or Urgent Care Clinic Encounters and Hospitalizations Among Adults During SARS-CoV-2 B.1.617.2 (Delta) Variant Predominance -Nine States

Sustained Effectiveness of Pfizer-BioNTech and Moderna Vaccines Against COVID-19 Associated Hospitalizations Among Adults -United States

Effectiveness of Covid-19 Vaccines against the B.1.617.2 (Delta) Variant

Effectiveness of ChAdOx1 nCoV-19 vaccine against SARS-CoV-2 infection during the delta (B.1.617.2) variant surge in India: a test-negative, case-control study and a mechanistic study of post-vaccination immune responses

J&J shot effective against Delta variant in large South Africa study

Effectiveness of Inactivated COVID-19 Vaccines Against Illness Caused by the B.1.617.2 (Delta) Variant During an Outbreak in Guangdong, China : A Cohort Study

Effectiveness of mRNA BNT162b2 COVID-19 vaccine up to 6 months in a large integrated health system in the USA: a retrospective cohort study

Phase 3 Trial of mRNA-1273 during the Delta-Variant Surge

Effectiveness of Pfizer-BioNTech and Moderna Vaccines in Preventing SARS-CoV-2 Infection Among Nursing Home Residents Before and During Widespread Circulation of the SARS-CoV-2 B.1.617.2 (Delta) Variant -National Healthcare Safety Network

SARS-CoV-2 Delta VOC in Scotland: demographics, risk of hospital admission, and vaccine effectiveness

BNT162b2 and mRNA-1273 COVID-19 vaccine effectiveness against the SARS-CoV-2 Delta variant in Qatar

Community transmission and viral load kinetics of the SARS-CoV-2 delta (B.1.617.2) variant in vaccinated and unvaccinated individuals in the UK: a prospective, longitudinal, cohort study

Outbreak of SARS-CoV-2 Infections, Including COVID-19 Vaccine Breakthrough Infections, Associated with Large Public Gatherings -Barnsy

Virological and serological kinetics of SARS-CoV-2 Delta variant vaccine breakthrough infections: a multicentre cohort study

Virological characteristics of SARS-CoV-2 vaccine breakthrough infections in health care workers

Outbreak of SARS-CoV-2 B.1.617.2 (Delta) Variant Infections Among Incarcerated Persons in a Federal Prison -Texas

Superspreading events in the transmission dynamics of SARS-CoV-2: Opportunities for interventions and control

Estimating the overdispersion in COVID-19 transmission using outbreak sizes outside China

Effect of Covid-19 Vaccination on Transmission of Alpha and Delta Variants

Transmission from vaccinated individuals in a large SARS-CoV-2 Delta variant outbreak

FREQUENTLY ASKED QUESTIONS FOR THE B.1.1.529 MUTATED SARS-COV-2 LINEAGE IN SOUTH AFRICA

Vaccine effectiveness against SARS-CoV-2 infection with the Omicron or Delta variants following a two-dose or booster BNT162b2 or mRNA-1273 vaccination series: A Danish cohort study

Effectiveness of mRNA-1273 against SARS-CoV-2 Omicron and Delta variants

SARS-CoV-2 Omicron VOC Transmission in Danish Households

Trends in Disease Severity and Health Care Utilization During the Early Omicron Variant Period Compared with Previous SARS-CoV-2 High Transmission Periods -United States

Clinical Characteristics and Outcomes Among Adults Hospitalized with Laboratory-Confirmed SARS-CoV-2 Infection During Periods of B.1.617.2 (Delta) and B.1.1.529 (Omicron) Variant Predominance -One Hospital

Estimates of SARS-CoV-2 Omicron Variant Severity in Ontario, Canada

Early assessment of the clinical severity of the SARS-CoV-2 omicron variant in South Africa: a data linkage study

Hospitalizations of Children and Adolescents with Laboratory-Confirmed COVID-19 -COVID-NET, 14 States

Booster of mRNA-1273 Vaccine Reduces SARS-CoV-2 Omicron Escape from Neutralizing Antibodies

Striking antibody evasion manifested by the Omicron variant of SARS-CoV-2

Neutralization of Severe Acute Respiratory Syndrome Coronavirus 2 Omicron Variant by Sera From BNT162b2 or CoronaVac Vaccine Recipients

Vaccines Elicit Highly Conserved Cellular Immunity to SARS-CoV-2 Omicron

Association Between 3 Doses of mRNA COVID-19 Vaccine and Symptomatic Infection Caused by the SARS-CoV-2 Omicron and Delta Variants

Clinical Severity and mRNA Vaccine Effectiveness for Omicron, Delta, and Alpha SARS-CoV-2 Variants in the United States: A Prospective Observational Study

SARS-CoV-2 Infection and Hospitalization Among Adults Aged ≥18 Years, by Vaccination Status, Before and During SARS-CoV-2 B.1.1.529 (Omicron) Variant Predominance

COVID-19 Vaccine Booster Shots

COVID-19 Vaccines for Moderately or Severely Immunocompromised People

World Health Organization. Tracking SARS-CoV-2 variants

Comparable Neutralization of the SARS-CoV-2 Omicron BA.1 and BA.2 Variants

SARS-CoV-2, SARS-CoV, and MERS-CoV viral load dynamics, duration of viral shedding, and infectiousness: a systematic review and meta-analysis

A c c e p t e d M a n u s c r i p t