Single-dose BNT162b2 vaccine protects against asymptomatic SARS-CoV-2 infection

The BNT162b2 mRNA COVID-19 vaccine (Pfizer-BioNTech) is being utilised internationally for mass COVID-19 vaccination. Evidence of single-dose protection against symptomatic disease has encouraged some countries to opt for delayed booster doses of BNT162b2, but the effect of this strategy on rates of asymptomatic SARS-CoV-2 infection remains unknown. We previously demonstrated frequent pauci- and asymptomatic SARS-CoV-2 infection amongst healthcare workers (HCWs) during the UK’s first wave of the COVID-19 pandemic, using a comprehensive PCR-based HCW screening programme (Rivett et al., 2020; Jones et al., 2020). Here, we evaluate the effect of first-dose BNT162b2 vaccination on test positivity rates and find a fourfold reduction in asymptomatic infection amongst HCWs ≥12 days post-vaccination. These data provide real-world evidence of short-term protection against asymptomatic SARS-CoV-2 infection following a single dose of BNT162b2 vaccine, suggesting that mass first-dose vaccination will reduce SARS-CoV-2 transmission, as well as the burden of COVID-19 disease.


Introduction
The UK has initiated mass COVID-19 immunisation, with healthcare workers (HCWs) given early priority because of the potential for workplace exposure and risk of onward transmission to patients. The UK's Joint Committee on Vaccination and Immunisation has recommended maximising the number of people vaccinated with first doses at the expense of early booster vaccinations, based on single-dose efficacy against symptomatic COVID-19 disease (Department of Health and Social Care, 2021;Polack et al., 2020;Voysey et al., 2021).
At the time of writing, three COVID-19 vaccines have been granted emergency use authorisation in the UK, including the BNT162b2 mRNA COVID-19 vaccine (Pfizer-BioNTech). A vital outstanding question is whether this vaccine prevents asymptomatic as well as symptomatic SARS-CoV-2 infection or merely converts infections from symptomatic to asymptomatic. Sub-clinical infection following vaccination could continue to drive transmission. This is especially important because many UK HCWs have received this vaccine, and nosocomial COVID-19 infection has been a persistent problem.
Through the implementation of a 24 hour turnaround PCR-based comprehensive HCW screening programme at Cambridge University Hospitals NHS Foundation Trust (CUHNFT), we previously demonstrated the frequent presence of pauci-and asymptomatic infection amongst HCWs during the UK's first wave of the COVID-19 pandemic . Here, we evaluate the effect of first-dose BNT162b2 vaccination on test positivity rates and cycle threshold (Ct) values in the asymptomatic arm of our programme, which now offers weekly screening to all staff.

Results and discussion
Vaccination of HCWs at CUHNFT began on 8 December 2020, with mass vaccination from 8 January 2021. Here, we analyse data from 2 weeks spanning 18-31 January 2021, during which (1) the prevalence of COVID-19 amongst HCWs remained approximately constant and (2) we screened comparable numbers of vaccinated and unvaccinated HCWs. During this period, 4408 (week 1) and 4411 (week 2) PCR tests were performed on individuals reporting well to work, from a weekly on-site HCW population of~9000. We stratified HCWs <12 days or !12 days post-vaccination because this was the point at which protection against symptomatic infection began to appear in the phase III clinical trial (Polack et al., 2020). In the post-vaccination groups, the median number of days between vaccination and testing were 7 (interquartile range [IQR] 4-9; <12 day group) and 16 (14-18; !12 day group).
A marked reduction in infections was also seen when analyses were repeated with (1)  HCWs working in COVID-19 clinical areas were prioritised for vaccination, and a small number of clinically vulnerable HCWs were also given priority. Otherwise, vaccine allocation was arbitrary. Since asymptomatic infection was examined, the date of infection could have been earlier than the test date. These factors would all tend to lead to an underestimate of the vaccine's effect (bias towards the null). Because of the rapid decline in the incidence of SARS-CoV-2 infection in the Cambridge community, this study could only examine the short-term impact of single-dose BNT162b2 vaccination. The frequency of prior SARS-CoV-2 infection  was similar in all groups (seroprevalence 7.1%, unvaccinated; 5.6%, <12 days post-vaccination; 5.7%, !12 days post-vaccination), suggesting that this did not confound our observations. Taken together, our findings provide real-world evidence of short-term protection against asymptomatic SARS-CoV-2 infection after a single dose of BNT162b2 vaccine, at a time when the UK COVID-19 variant of concern 202012/01 (lineage B.1.1.7) accounted for the great majority of infections (24/29 sequenced isolates from asymptomatic HCWs). A fourfold reduction from 0.8% to 0.2% in asymptomatic infection is likely to be crucial in controlling nosocomial SARS-CoV-2 transmission. Nonetheless, protection is incomplete, suggesting that continuing asymptomatic HCW screening, social distancing, mask-wearing, and strict hand hygiene remain vital.  We previously described protocols for staff screening, sample collection, and results reporting in detail Jones et al., 2020). In general, these methods remained unchanged throughout this study period. Two parallel streams of entry into the testing programme included (1) HCW symptomatic and HCW symptomatic household contact screening arms and (2) an HCW asymptomatic screening arm. Since our prior description of the screening programme, weekly asymptomatic testing is now offered to all CUHNFT staff. Testing was performed (1) at temporary on-site 'Pods' and (2) via self-swabbing kits collected by HCWs. Individuals performed a self-swab of the oropharynx and anterior nasal cavity. Samples were subjected to RNA extraction and amplification using real-time RT-PCR, with all sample processing and analysis undertaken at the Cambridge COVID-19 Testing Centre (Lighthouse Laboratory).

Vaccination
HCW vaccination began at CUHNFT on 8 December 2020, with appointments made by invitation only for all high-risk HCWs working on-site. This was followed by self-booked appointments for HCWs working in designated COVID-19 clinical areas, from 8 January 2021 onwards. From 18 January 2021, vaccination was offered to all HCWs, with appointments made via a booking website and latterly using the hospital's electronic patient record system 'MyChart'. All vials of Pfizer-BioNTech COVID-19 Vaccine (BNT162b2) were stored at À74˚C, before being transferred to storage at 2-8˚C. From the moment the vials were removed from the freezer, they were given a 120 hr expiration date, of which 3 hr were dedicated to thawing the vaccines. All vaccine doses were administered intramuscularly by trained vaccinators, in accordance with the manufacturer's instructions. Vaccination was undertaken exclusively at an on-site vaccination centre, with mandatory mask-wearing and social distancing in place. HCWs remained at the on-site vaccination centre for a minimum observation period of 15 min after vaccination.

Data extraction and analysis
Swab result, vaccination details, and serology data for HCWs were extracted directly from the hospital-laboratory interface software, Epic (Verona, WI). Data were collated using Microsoft Excel and the figure produced with GraphPad Prism (GraphPad Software, La Jolla, CA). Fisher's exact test was used for the comparison of positive rates between groups, defined in the main text. Additionally, 95% confidence intervals were calculated using Wilson's method.