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The emergence of successive Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) during 2020 to 2022, each exhibiting increased epidemic growth relative to earlier circulating variants, has created a need to understand the drivers of such growth. However, both pathogen biology and changing host characteristics—such as varying levels of immunity—can combine to influence replication and transmission of SARS-CoV-2 within and between hosts. Disentangling the role of variant and host in individual-level viral shedding of VOCs is essential to inform Coronavirus Disease 2019 (COVID-19) planning and response and interpret past epidemic trends. Using data from a prospective observational cohort study of healthy adult volunteers undergoing weekly occupational health PCR screening, we developed a Bayesian hierarchical model to reconstruct individual-level viral kinetics and estimate how different factors shaped viral dynamics, measured by PCR cycle threshold (Ct) values over time. Jointly accounting for both interindividual variation in Ct values and complex host characteristics—such as vaccination status, exposure history, and age—we found that age and number of prior exposures had a strong influence on peak viral replication. Older individuals and those who had at least 5 prior antigen exposures to vaccination and/or infection typically had much lower levels of shedding. Moreover, we found evidence of a correlation between the speed of early shedding and duration of incubation period when comparing different VOCs and age groups. Our findings illustrate the value of linking information on participant characteristics, symptom profile and infecting variant with prospective PCR sampling, and the importance of accounting for increasingly complex population exposure landscapes when analysing the viral kinetics of VOCs. Trial Registration: The Legacy study is a prospective observational cohort study of healthy adult volunteers undergoing weekly occupational health PCR screening for SARS-CoV-2 at University College London Hospitals or at the Francis Crick Institute ( NCT04750356 ) (22,23). The Legacy study was approved by London Camden and Kings Cross Health Research Authority Research and Ethics committee (IRAS number 286469). The Legacy study was approved by London Camden and Kings Cross Health Research Authority Research and Ethics committee (IRAS number 286469) and is sponsored by University College London Hospitals. Written consent was given by all participants.

Background Routine asymptomatic testing using RT-PCR of people who interact with vulnerable populations, such as medical staff in hospitals or care workers in care homes, has been employed to help prevent outbreaks among vulnerable populations. Although the peak sensitivity of RT-PCR can be high, the probability of detecting an infection will vary throughout the course of an infection. The effectiveness of routine asymptomatic testing will therefore depend on testing frequency and how PCR detection varies over time. Methods We fitted a Bayesian statistical model to a dataset of twice weekly PCR tests of UK healthcare workers performed by self-administered nasopharyngeal swab, regardless of symptoms. We jointly estimated times of infection and the probability of a positive PCR test over time following infection; we then compared asymptomatic testing strategies by calculating the probability that a symptomatic infection is detected before symptom onset and the probability that an asymptomatic infection is detected within 7 days of infection. Results We estimated that the probability that the PCR test detected infection peaked at 77% (54–88%) 4 days after infection, decreasing to 50% (38–65%) by 10 days after infection. Our results suggest a substantially higher probability of detecting infections 1–3 days after infection than previously published estimates. We estimated that testing every other day would detect 57% (33–76%) of symptomatic cases prior to onset and 94% (75–99%) of asymptomatic cases within 7 days if test results were returned within a day. Conclusions Our results suggest that routine asymptomatic testing can enable detection of a high proportion of infected individuals early in their infection, provided that the testing is frequent and the time from testing to notification of results is sufficiently fast.

SARS-CoV-2 variant Omicron rapidly evolved over 2022, causing three waves of infection due to sub-variants BA.1, BA.2 and BA.4/5. We sought to characterise symptoms and viral loads over the course of COVID-19 infection with these sub-variants in otherwise-healthy, vaccinated, non-hospitalised adults, and compared data to infections with the preceding Delta variant of concern (VOC). In a prospective, observational cohort study, healthy vaccinated UK adults who reported a positive polymerase chain reaction (PCR) or lateral flow test, self-swabbed on alternate weekdays until day 10. We compared participant-reported symptoms and viral load trajectories between infections caused by VOCs Delta and Omicron (sub-variants BA.1, BA.2 or BA.4/5), and tested for relationships between vaccine dose, symptoms and PCR cycle threshold (Ct) as a proxy for viral load using Chi-squared (X2) and Wilcoxon tests. 563 infection episodes were reported among 491 participants. Across infection episodes, there was little variation in symptom burden (4 [IQR 3-5] symptoms) and duration (8 [IQR 6-11] days). Whilst symptom profiles differed among infections caused by Delta compared to Omicron sub-variants, symptom profiles were similar between Omicron sub-variants. Anosmia was reported more frequently in Delta infections after 2 doses compared with Omicron sub-variant infections after 3 doses, for example: 42% (25/60) of participants with Delta infection compared to 9% (6/67) with Omicron BA.4/5 (X.sup.2 P < 0.001; OR 7.3 [95% CI 2.7-19.4]). Fever was less common with Delta (20/60 participants; 33%) than Omicron BA.4/5 (39/67; 58%; X.sup.2 P = 0.008; OR 0.4 [CI 0.2-0.7]). Amongst infections with an Omicron sub-variants, symptoms of coryza, fatigue, cough and myalgia predominated. Viral load trajectories and peaks did not differ between Delta, and Omicron, irrespective of symptom severity (including asymptomatic participants), VOC or vaccination status. PCR Ct values were negatively associated with time since vaccination in participants infected with BA.1 ([beta] = -0.05 (CI -0.10-0.01); P = 0.031); however, this trend was not observed in BA.2 or BA.4/5 infections. Our study emphasises both the changing symptom profile of COVID-19 infections in the Omicron era, and ongoing transmission risk of Omicron sub-variants in vaccinated adults.

Background Little data exist on the COVID-19 vaccine response in African countries who despite having high disease burden, have low COVID-19 mortality rates. We investigated the longitudinal immune response in a West-African urban population upon COVID-19 vaccination, two years after the start of the pandemic. Methods The HERITAGE study is a prospective cohort study of 301 residents of Accra, Ghana. Participants received two doses of a COVID-19 vaccine (AZD1222 or BNT162b2) from December 2021 and were followed-up for 12 months. COVID-19 status was determined by RT-PCR at seven time points. Serological responses, including anti-Nucleocapsid IgG, anti-Spike IgG and live-virus neutralisation were determined at four time points during the 12 months follow-up. Results COVID-19 positivity was 19.3% at baseline and reduced rapidly upon vaccination. Serological analyses indicated previous exposure to SARS-CoV-2 in 80.5% of the HERITAGE participants. After vaccination, neutralising antibody titres (NAbTs) against six different SARS-CoV-2 variants significantly ( p  < 0.001) increased, with fold changes (FC) ranging from 1.87 to 4.59. Highest NAbTs were recorded in the previously exposed group. Participants without prior exposure showed a continues increase in NAbTs between months 3 and 12 for circulating variants (Omicron B.A2 (FC 2.44, p  < 0.001) and XBB.1.5 (FC 1.91, p  = 0.05)). By comparison a matched cohort from the UK-based LEGACY study showed generally lower NAbTs at baseline (HERITAGE vs LEGACY for Wild-type: 250.3 vs 141.3, p  < 0.0001, for A.27 84.6 vs 43.2, p  = 0.0129, for Eta 159.7 vs 118.1, p  = 0.3428, for Delta 158.6 vs 10.0, p  < 0.0001, for Omicron B.A2 153.7 vs 10.0, p  < 0.0001) and after receiving the vaccine (HERITAGE vs LEGACY for Wild-type: 882.6 vs 337.7, p  < 0.0001, for A.27 552.0 vs 227.7, p  = 0.0001, for Eta 682.2 vs 295.3, p  < 0.0001, for Delta 557.6 vs 165.1, p  < 0.0001, for Omicron B.A2 283.3 vs 124.2, p  < 0.0001). NAbTs kinetics between the two cohorts were more similar when analysis was restricted to previously unexposed participants when adjusted for circulating variants during the sampling period. Conclusions Two doses of AZD1222 or BNT162b2 significantly increased existing NAbTs against SARS-CoV-2 in a highly exposed population, showing durable boosting of pre-existing infection-induced immunity. This indicates the importance of considering local population exposure in vaccination design and deployment.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Third-dose coronavirus disease 2019 vaccines are being deployed widely but their efficacy has not been assessed adequately in vulnerable older people who exhibit suboptimal responses after primary vaccination series. This observational study, which was carried out by the VIVALDI study based in England, looked at spike-specific immune responses in 341 staff and residents in long-term care facilities who received an mRNA vaccine following dual primary series vaccination with BNT162b2 or ChAdOx1. Third-dose vaccination strongly increased antibody responses with preferential relative enhancement in older people and was required to elicit neutralization of Omicron. Cellular immune responses were also enhanced with strong cross-reactive recognition of Omicron. However, antibody titers fell 21–78% within 100 d after vaccine and 27% of participants developed a breakthrough Omicron infection. These findings reveal strong immunogenicity of a third vaccine in one of the most vulnerable population groups and endorse an approach for widespread delivery across this population. Ongoing assessment will be required to determine the stability of immune protection.

Heterogeneity in SARS-CoV-2 vaccine responses is not understood. Here, we identify four patterns of live-virus neutralizing antibody responses: individuals with hybrid immunity (with confirmed prior infection); rare individuals with low responses (paucity of S1-binding antibodies); and surprisingly, two further groups with distinct serological repertoires. One group – broad responders – neutralize a range of SARS-CoV-2 variants, whereas the other – narrow responders – neutralize fewer, less divergent variants. This heterogeneity does not correlate with Ancestral S1-binding antibody, rather the quality of the serological response. Furthermore, IgDlowCD27-CD137+ B cells and CCR6+ CD4+ T cells are enriched in broad responders before dose 3. Notably, broad responders have significantly longer infection-free time after their third dose. Understanding the control and persistence of these serological profiles could allow personalized approaches to enhance serological breadth after vaccination.