Protection against SARS-CoV-2 Omicron BA.4/5 variant following booster vaccination or breakthrough infection in the UK.

Following primary SARS-CoV-2 vaccination, whether boosters or breakthrough infections provide greater protection against SARS-CoV-2 infection is incompletely understood. Here we investigated SARS-CoV-2 antibody correlates of protection against new Omicron BA.4/5 (re-)infections and anti-spike IgG antibody trajectories after a third/booster vaccination or breakthrough infection following second vaccination in 154,149 adults ≥18 y from the United Kingdom general population. Higher antibody levels were associated with increased protection against Omicron BA.4/5 infection and breakthrough infections were associated with higher levels of protection at any given antibody level than boosters. Breakthrough infections generated similar antibody levels to boosters, and the subsequent antibody declines were slightly slower than after boosters. Together our findings show breakthrough infection provides longer-lasting protection against further infections than booster vaccinations. Our findings, considered alongside the risks of severe infection and long-term consequences of infection, have important implications for vaccine policy.

Long-term benefits of nonpharmaceutical interventions for endemic infections are shaped by respiratory pathogen dynamics.

COVID-19 nonpharmaceutical interventions (NPIs), including mask wearing, have proved highly effective at reducing the transmission of endemic infections. A key public health question is whether NPIs could continue to be implemented long term to reduce the ongoing burden from endemic pathogens. Here, we use epidemiological models to explore the impact of long-term NPIs on the dynamics of endemic infections. We find that the introduction of NPIs leads to a strong initial reduction in incidence, but this effect is transient: As susceptibility increases, epidemics return while NPIs are in place. For low R0 infections, these return epidemics are of reduced equilibrium incidence and epidemic peak size. For high R0 infections, return epidemics are of similar magnitude to pre-NPI outbreaks. Our results underline that managing ongoing susceptible buildup, e.g., with vaccination, remains an important long-term goal.

SARS-CoV-2 antibody trajectories after a single COVID-19 vaccination with and without prior infection.

Given high SARS-CoV-2 incidence, coupled with slow and inequitable vaccine roll-out in many settings, there is a need for evidence to underpin optimum vaccine deployment, aiming to maximise global population immunity. We evaluate whether a single vaccination in individuals who have already been infected with SARS-CoV-2 generates similar initial and subsequent antibody responses to two vaccinations in those without prior infection. We compared anti-spike IgG antibody responses after a single vaccination with ChAdOx1, BNT162b2, or mRNA-1273 SARS-CoV-2 vaccines in the COVID-19 Infection Survey in the UK general population. In 100,849 adults median (50 (IQR: 37-63) years) receiving at least one vaccination, 13,404 (13.3%) had serological/PCR evidence of prior infection. Prior infection significantly boosted antibody responses, producing higher peak levels and/or longer half-lives after one dose of all three vaccines than those without prior infection receiving one or two vaccinations. In those with prior infection, the median time above the positivity threshold was >1 year after the first vaccination. Single-dose vaccination targeted to those previously infected may provide at least as good protection to two-dose vaccination among those without previous infection.

Antibody responses and correlates of protection in the general population after two doses of the ChAdOx1 or BNT162b2 vaccines.

Antibody responses are an important part of immunity after Coronavirus Disease 2019 (COVID-19) vaccination. However, antibody trajectories and the associated duration of protection after a second vaccine dose remain unclear. In this study, we investigated anti-spike IgG antibody responses and correlates of protection after second doses of ChAdOx1 or BNT162b2 vaccines for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the United Kingdom general population. In 222,493 individuals, we found significant boosting of anti-spike IgG by the second doses of both vaccines in all ages and using different dosing intervals, including the 3-week interval for BNT162b2. After second vaccination, BNT162b2 generated higher peak levels than ChAdOX1. Older individuals and males had lower peak levels with BNT162b2 but not ChAdOx1, whereas declines were similar across ages and sexes with ChAdOX1 or BNT162b2. Prior infection significantly increased antibody peak level and half-life with both vaccines. Anti-spike IgG levels were associated with protection from infection after vaccination and, to an even greater degree, after prior infection. At least 67% protection against infection was estimated to last for 2-3 months after two ChAdOx1 doses, for 5-8 months after two BNT162b2 doses in those without prior infection and for 1-2 years for those unvaccinated after natural infection. A third booster dose might be needed, prioritized to ChAdOx1 recipients and those more clinically vulnerable.

Monitoring populations at increased risk for SARS-CoV-2 infection in the community using population-level demographic and behavioural surveillance.

BACKGROUND: The COVID-19 pandemic is rapidly evolving, with emerging variants and fluctuating control policies. Real-time population screening and identification of groups in whom positivity is highest could help monitor spread and inform public health messaging and strategy. METHODS: To develop a real-time screening process, we included results from nose and throat swabs and questionnaires taken 19 July 2020-17 July 2021 in the UK's national COVID-19 Infection Survey. Fortnightly, associations between SARS-CoV-2 positivity and 60 demographic and behavioural characteristics were estimated using logistic regression models adjusted for potential confounders, considering multiple testing, collinearity, and reverse causality. FINDINGS: Of 4,091,537 RT-PCR results from 482,677 individuals, 29,903 (0·73%) were positive. As positivity rose September-November 2020, rates were independently higher in younger ages, and those living in Northern England, major urban conurbations, more deprived areas, and larger households. Rates were also higher in those returning from abroad, and working in healthcare or outside of home. When positivity peaked December 2020-January 2021 (Alpha), high positivity shifted to southern geographical regions. With national vaccine roll-out from December 2020, positivity reduced in vaccinated individuals. Associations attenuated as rates decreased between February-May 2021. Rising positivity rates in June-July 2021 (Delta) were independently higher in younger, male, and unvaccinated groups. Few factors were consistently associated with positivity. 25/45 (56%) confirmed associations would have been detected later using 28-day rather than 14-day periods. INTERPRETATION: Population-level demographic and behavioural surveillance can be a valuable tool in identifying the varying characteristics driving current SARS-CoV-2 positivity, allowing monitoring to inform public health policy. FUNDING: Department of Health and Social Care (UK), Welsh Government, Department of Health (on behalf of the Northern Ireland Government), Scottish Government, National Institute for Health Research.

A Global lmmunological Observatory to meet a time of pandemics.

SARS-CoV-2 presents an unprecedented international challenge, but it will not be the last such threat. Here, we argue that the world needs to be much better prepared to rapidly detect, define and defeat future pandemics. We propose that a Global Immunological Observatory and associated developments in systems immunology, therapeutics and vaccine design should be at the heart of this enterprise.

Anti-spike antibody response to natural SARS-CoV-2 infection in the general population.

Understanding the trajectory, duration, and determinants of antibody responses after SARS-CoV-2 infection can inform subsequent protection and risk of reinfection, however large-scale representative studies are limited. Here we estimated antibody response after SARS-CoV-2 infection in the general population using representative data from 7,256 United Kingdom COVID-19 infection survey participants who had positive swab SARS-CoV-2 PCR tests from 26-April-2020 to 14-June-2021. A latent class model classified 24% of participants as 'non-responders' not developing anti-spike antibodies, who were older, had higher SARS-CoV-2 cycle threshold values during infection (i.e. lower viral burden), and less frequently reported any symptoms. Among those who seroconverted, using Bayesian linear mixed models, the estimated anti-spike IgG peak level was 7.3-fold higher than the level previously associated with 50% protection against reinfection, with higher peak levels in older participants and those of non-white ethnicity. The estimated anti-spike IgG half-life was 184 days, being longer in females and those of white ethnicity. We estimated antibody levels associated with protection against reinfection likely last 1.5-2 years on average, with levels associated with protection from severe infection present for several years. These estimates could inform planning for vaccination booster strategies.

Effect of Delta variant on viral burden and vaccine effectiveness against new SARS-CoV-2 infections in the UK.

The effectiveness of the BNT162b2 and ChAdOx1 vaccines against new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections requires continuous re-evaluation, given the increasingly dominant B.1.617.2 (Delta) variant. In this study, we investigated the effectiveness of these vaccines in a large, community-based survey of randomly selected households across the United Kingdom. We found that the effectiveness of BNT162b2 and ChAdOx1 against infections (new polymerase chain reaction (PCR)-positive cases) with symptoms or high viral burden is reduced with the B.1.617.2 variant (absolute difference of 10-13% for BNT162b2 and 16% for ChAdOx1) compared to the B.1.1.7 (Alpha) variant. The effectiveness of two doses remains at least as great as protection afforded by prior natural infection. The dynamics of immunity after second doses differed significantly between BNT162b2 and ChAdOx1, with greater initial effectiveness against new PCR-positive cases but faster declines in protection against high viral burden and symptomatic infection with BNT162b2. There was no evidence that effectiveness varied by dosing interval, but protection was higher in vaccinated individuals after a prior infection and in younger adults. With B.1.617.2, infections occurring after two vaccinations had similar peak viral burden as those in unvaccinated individuals. SARS-CoV-2 vaccination still reduces new infections, but effectiveness and attenuation of peak viral burden are reduced with B.1.617.2.

The origins of SARS-CoV-2: A critical review.

Since the first reports of a novel severe acute respiratory syndrome (SARS)-like coronavirus in December 2019 in Wuhan, China, there has been intense interest in understanding how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in the human population. Recent debate has coalesced around two competing ideas: a "laboratory escape" scenario and zoonotic emergence. Here, we critically review the current scientific evidence that may help clarify the origin of SARS-CoV-2.

Vaccine nationalism and the dynamics and control of SARS-CoV-2.

Vaccines provide powerful tools to mitigate the enormous public health and economic costs that the ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic continues to exert globally, yet vaccine distribution remains unequal among countries. To examine the potential epidemiological and evolutionary impacts of "vaccine nationalism," we extend previous models to include simple scenarios of stockpiling between two regions. In general, when vaccines are widely available and the immunity they confer is robust, sharing doses minimizes total cases across regions. A number of subtleties arise when the populations and transmission rates in each region differ, depending on evolutionary assumptions and vaccine availability. When the waning of natural immunity contributes most to evolutionary potential, sustained transmission in low-access regions results in an increased potential for antigenic evolution, which may result in the emergence of novel variants that affect epidemiological characteristics globally. Overall, our results stress the importance of rapid, equitable vaccine distribution for global control of the pandemic.

Antibody responses to SARS-CoV-2 vaccines in 45,965 adults from the general population of the United Kingdom.

We report that in a cohort of 45,965 adults, who were receiving either the ChAdOx1 or the BNT162b2 SARS-CoV-2 vaccines, in those who had no prior infection with SARS-CoV-2, seroconversion rates and quantitative antibody levels after a single dose were lower in older individuals, especially in those aged >60 years. Two vaccine doses achieved high responses across all ages. Antibody levels increased more slowly and to lower levels with a single dose of ChAdOx1 compared with a single dose of BNT162b2, but waned following a single dose of BNT162b2 in older individuals. In descriptive latent class models, we identified four responder subgroups, including a 'low responder' group that more commonly consisted of people aged >75 years, males and individuals with long-term health conditions. Given our findings, we propose that available vaccines should be prioritized for those not previously infected and that second doses should be prioritized for individuals aged >60 years. Further data are needed to better understand the extent to which quantitative antibody responses are associated with vaccine-mediated protection.

Ct threshold values, a proxy for viral load in community SARS-CoV-2 cases, demonstrate wide variation across populations and over time.

Background: Information on SARS-CoV-2 in representative community surveillance is limited, particularly cycle threshold (Ct) values (a proxy for viral load). Methods: We included all positive nose and throat swabs 26 April 2020 to 13 March 2021 from the UK's national COVID-19 Infection Survey, tested by RT-PCR for the N, S, and ORF1ab genes. We investigated predictors of median Ct value using quantile regression. Results: Of 3,312,159 nose and throat swabs, 27,902 (0.83%) were RT-PCR-positive, 10,317 (37%), 11,012 (40%), and 6550 (23%) for 3, 2, or 1 of the N, S, and ORF1ab genes, respectively, with median Ct = 29.2 (~215 copies/ml; IQR Ct = 21.9-32.8, 14-56,400 copies/ml). Independent predictors of lower Cts (i.e. higher viral load) included self-reported symptoms and more genes detected, with at most small effects of sex, ethnicity, and age. Single-gene positives almost invariably had Ct > 30, but Cts varied widely in triple-gene positives, including without symptoms. Population-level Cts changed over time, with declining Ct preceding increasing SARS-CoV-2 positivity. Of 6189 participants with IgG S-antibody tests post-first RT-PCR-positive, 4808 (78%) were ever antibody-positive; Cts were significantly higher in those remaining antibody negative. Conclusions: Marked variation in community SARS-CoV-2 Ct values suggests that they could be a useful epidemiological early-warning indicator. Funding: Department of Health and Social Care, National Institutes of Health Research, Huo Family Foundation, Medical Research Council UK; Wellcome Trust.

Impact of vaccination on new SARS-CoV-2 infections in the United Kingdom.

The effectiveness of COVID-19 vaccination in preventing new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in the general community is still unclear. Here, we used the Office for National Statistics COVID-19 Infection Survey-a large community-based survey of individuals living in randomly selected private households across the United Kingdom-to assess the effectiveness of the BNT162b2 (Pfizer-BioNTech) and ChAdOx1 nCoV-19 (Oxford-AstraZeneca; ChAdOx1) vaccines against any new SARS-CoV-2 PCR-positive tests, split according to self-reported symptoms, cycle threshold value (<30 versus ≥30; as a surrogate for viral load) and gene positivity pattern (compatible with B.1.1.7 or not). Using 1,945,071 real-time PCR results from nose and throat swabs taken from 383,812 participants between 1 December 2020 and 8 May 2021, we found that vaccination with the ChAdOx1 or BNT162b2 vaccines already reduced SARS-CoV-2 infections ≥21 d after the first dose (61% (95% confidence interval (CI) = 54-68%) versus 66% (95% CI = 60-71%), respectively), with greater reductions observed after a second dose (79% (95% CI = 65-88%) versus 80% (95% CI = 73-85%), respectively). The largest reductions were observed for symptomatic infections and/or infections with a higher viral burden. Overall, COVID-19 vaccination reduced the number of new SARS-CoV-2 infections, with the largest benefit received after two vaccinations and against symptomatic and high viral burden infections, and with no evidence of a difference between the BNT162b2 and ChAdOx1 vaccines.

Epidemiological dynamics of enterovirus D68 in the United States and implications for acute flaccid myelitis.

Acute flaccid myelitis (AFM) recently emerged in the United States as a rare but serious neurological condition since 2012. Enterovirus D68 (EV-D68) is thought to be a main causative agent, but limited surveillance of EV-D68 in the United States has hampered the ability to assess their causal relationship. Using surveillance data from the BioFire Syndromic Trends epidemiology network in the United States from January 2014 to September 2019, we characterized the epidemiological dynamics of EV-D68 and found latitudinal gradient in the mean timing of EV-D68 cases, which are likely climate driven. We also demonstrated a strong spatiotemporal association of EV-D68 with AFM. Mathematical modeling suggested that the recent dominant biennial cycles of EV-D68 dynamics may not be stable. Nonetheless, we predicted that a major EV-D68 outbreak, and hence an AFM outbreak, would have still been possible in 2020 under normal epidemiological conditions. Nonpharmaceutical intervention efforts due to the ongoing COVID-19 pandemic are likely to have reduced the sizes of EV-D68 and AFM outbreaks in 2020, illustrating the broader epidemiological impact of the pandemic.

Epidemiological and evolutionary considerations of SARS-CoV-2 vaccine dosing regimes.

Given vaccine dose shortages and logistical challenges, various deployment strategies are being proposed to increase population immunity levels to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Two critical issues arise: How timing of delivery of the second dose will affect infection dynamics and how it will affect prospects for the evolution of viral immune escape via a buildup of partially immune individuals. Both hinge on the robustness of the immune response elicited by a single dose as compared with natural and two-dose immunity. Building on an existing immuno-epidemiological model, we find that in the short term, focusing on one dose generally decreases infections, but that longer-term outcomes depend on this relative immune robustness. We then explore three scenarios of selection and find that a one-dose policy may increase the potential for antigenic evolution under certain conditions of partial population immunity. We highlight the critical need to test viral loads and quantify immune responses after one vaccine dose and to ramp up vaccination efforts globally.