Long-term neutralizing antibody dynamics against SARS-CoV-2 in symptomatic and asymptomatic infections: a systematic review and meta-analysis

BackgroundThe kinetics of the neutralizing antibody response against SARS-CoV-2 is crucial for responding to the pandemic as well as developing vaccination strategies. We aimed to fit the antibody curves in symptomatic and asymptomatic individuals. MethodsWe systematically searched PubMed, Embase, Web of Science, and Europe PMC for articles published in English between Jan 1, 2020, and Oct 2, 2022. Studies evaluating neutralizing antibody from people who had a natural SARS-CoV-2 infection history were included. Study quality was assessed using a modified standardized scoring system. We fitted dynamic patterns of neutralizing antibody using a generalized additive model and a generalized additive mixed model. We also used linear regression model to conduct both univariate and multivariable analyses to explore the potential affecting factors on antibody levels. This study is registered with PROSPERO, CRD42022348636. Results7,343 studies were identified in the initial search, 50 were assessed for eligibility after removal of duplicates as well as inappropriate titles, abstracts and full-text review, and 48 studies (2,726 individuals, 5,670 samples) were included in the meta-analysis after quality assessment. The neutralization titer of people who infected with SARS-CoV-2 prototype strain peaked around 27 days (217.4, 95%CI: 187.0-252.9) but remained below the Omicron BA.5 protection threshold all the time after illness onset or confirmation. Furthermore, neither symptomatic infections nor asymptomatic infections could provide over 50% protection against Omicron BA.5 sub-lineage. It also showed that the clinical severity and the type of laboratory assays may significantly correlated with the level of neutralizing antibody. ConclusionsThis study provides a comprehensive mapping of the dynamic of neutralizing antibody against SARS-CoV-2 prototype strain induced by natural infection and compared the dynamic patterns between prototype and variant strains. It suggests that the protection probability provided by natural infection is limited. Therefore, timely vaccination is necessary for both previously infected symptomatic and asymptomatic individuals.

SARS-CoV-2 containment was achievable during the early stage of the pandemic: a retrospective modelling study of the Xinfadi outbreak in Beijing

Prior to the emergence of the Omicron variant, many cities in China had been able to maintain a "Zero-COVID" policy. They were able to achieve this without blanket city-wide lockdown and through widespread testing and an extensive set of nonpharmaceutical interventions (NPIs), such as mask wearing, contact tracing, and social distancing. We wanted to examine the effectiveness of such a policy in containing SARS-CoV-2 in the early stage of the pandemic. Therefore, we developed a fully stochastic, spatially structured, agent-based model of SARS-CoV-2 ancestral strain and reconstructed the Beijing Xinfadi outbreak through computational simulations. We found that screening for symptoms and among high-risk populations served as methods to discover cryptic community transmission in the early stage of the outbreak. Effective contact tracing could greatly reduce transmission. Targeted community lockdown and temporal mobility restriction could slow down the spatial spread of the virus, with much less of the population being affected. Population-wide mass testing could further improve the speed at which the outbreak is contained. Our analysis suggests that the containment of SARS-CoV-2 ancestral strains was certainly possible. Outbreak suppression and containment at the beginning of the pandemic, before the virus had the opportunity to undergo extensive adaptive evolution with increasing fitness in the human population, could be much more cost-effective in averting the overall pandemic disease burden and socioeconomic cost.

Estimation of disease burden and clinical severity of COVID-19 caused by Omicron BA.2 in Shanghai, February-June 2022

BackgroundAn outbreak of COVID-19 caused by the SARS-CoV-2 Omicron BA.2 sublineage occurred in Shanghai, China from February to June 2022. The government organized multiple rounds of molecular test screenings for the entire population, providing a unique opportunity to capture the majority of subclinical infections and better characterize disease burden and the full spectrum of Omicron BA.2 clinical severity. MethodsUsing daily reports from the websites of the Shanghai Municipal Health Commission, we estimated the incidence of infections, severe/critical infections, and deaths to assess the disease burden. By adjusting for right censoring and Reverse Transcription-Polymerase Chain Reaction (RT{square}PCR) sensitivity, we provide estimates of clinical severity, including the infection fatality risk, symptomatic case fatality risk, and risk of developing severe/critical disease upon infection. FindingsFrom February 26 to June 30, 2022, the overall infection rate, severe/critical infection rate, and mortality rate were 2.74 (95% CI: 2.73-2.74) per 100 individuals, 6.34 (95% CI: 6.02-6.66) per 100,000 individuals and 2.42 (95% CI: 2.23-2.62) per 100,000 individuals, respectively. The severe/critical infection rate and mortality rate increased with age with the highest rates of 125.29 (95% CI: 117.05-133.44) per 100,000 and 57.17 (95% CI: 51.63-62.71) per 100,000 individuals, respectively, noted in individuals aged 80 years or older. The overall fatality risk and risk of developing severe/critical disease upon infection were 0.09% (95% CI: 0.08-0.10%) and 0.23% (95% CI: 0.20-0.25%), respectively. Having received at least one vaccine dose led to a 10-fold reduction in the risk of death for infected individuals aged 80 years or older. InterpretationUnder the repeated population-based screenings and strict intervention policies implemented in Shanghai, our results found a lower disease burden and mortality of the outbreak compared to other settings and countries, showing the impact of the successful outbreak containment in Shanghai. The estimated low clinical severity of this Omicron BA.2 epidemic in Shanghai highlight the key contribution of vaccination and availability of hospital beds to reduce the risk of death. FundingKey Program of the National Natural Science Foundation of China (82130093). Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed and Europe PMC for manuscripts published or posted on preprint servers after January 1, 2022 using the following query: ("SARS-CoV-2 Omicron") AND ("burden" OR "severity"). No studies that characterized the whole profile of disease burden and clinical severity during the Shanghai Omicron outbreak were found. One study estimated confirmed case fatality risk between different COVID-19 waves in Hong Kong; other outcomes, such as fatality risk and risk of developing severe/critical illness upon infection, were not estimated. One study based on 21 hospitals across the United States focused on Omicron-specific in-hospital mortality based on a limited sample of inpatients (565). In southern California, United States, a study recruited more than 200 thousand Omicron-infected individuals and estimated the 30-day risk of hospital admission, intensive care unit admission, mechanical ventilation, and death. None of these studies estimated infection and mortality rates or other indictors associated with disease burden. Overall, the disease burden and clinical severity of the Omicron BA.2 variant have not been fully characterized, especially in populations predominantly immunized with inactivated vaccines. Added value of this studyThe large-scale and multiround molecular test screenings conducted on the entire population during the Omicron BA.2 outbreak in Shanghai, leading to a high infection ascertainment ratio, provide a unique opportunity to capture the majority of subclinical infections. As such, our study provides a comprehensive assessment of both the disease burden and clinical severity of the SARS-CoV-2 Omicron BA.2 sublineage, which are especially lacking for populations predominantly immunized with inactivated vaccines. Implications of all the available evidenceWe estimated the disease burden and clinical severity of the Omicron BA.2 outbreak in Shanghai in February-June 2022. These estimates are key to properly interpreting field evidence and assessing the actual spread of Omicron in other settings. Our results also provide support for the importance of strategies to prevent overwhelming the health care system and increasing vaccine coverage to reduce mortality.

Epidemiological characteristics and transmission dynamics of the outbreak caused by the SARS-CoV-2 Omicron variant in Shanghai, China: a descriptive study

BackgroundIn early March 2022, a major outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant spread rapidly throughout Shanghai, China. Here we aimed to provide a description of the epidemiological characteristics and spatiotemporal transmission dynamics of the Omicron outbreak under the population-based screening and lockdown policies implemented in Shanghai. MethodsWe extracted individual information on SARS-CoV-2 infections reported between January 1 and May 31, 2022, and on the timeline of the adopted non-pharmacological interventions. The epidemic was divided into three phases: i) sporadic infections (January 1-February 28), ii) local transmission (March 1-March 31), and iii) city-wide lockdown (April 1 to May 31). We described the epidemic spread during these three phases and the subdistrict-level spatiotemporal distribution of the infections. To evaluate the impact on the transmission of SARS-CoV-2 of the adopted targeted interventions in Phase 2 and city-wide lockdown in Phase 3, we estimated the dynamics of the net reproduction number (Rt). FindingsA surge in imported infections in Phase 1 triggered cryptic local transmission of the Omicron variant in early March, resulting in the largest coronavirus disease 2019 (COVID-19) outbreak in mainland China since the original wave. A total of 626,000 SARS-CoV-2 infections were reported in 99.5% (215/216) of the subdistricts of Shanghai. The spatial distribution of the infections was highly heterogeneous, with 40% of the subdistricts accounting for 80% of all infections. A clear trend from the city center towards adjacent suburban and rural areas was observed, with a progressive slowdown of the epidemic spread (from 544 to 325 meters/day) prior to the citywide lockdown. During Phase 2, Rt remained well above 1 despite the implementation of multiple targeted interventions. The citywide lockdown imposed on April 1 led to a marked decrease in transmission, bringing Rt below the epidemic threshold in the entire city on April 14 and ultimately leading to containment of the outbreak. InterpretationOur results highlight the risk of widespread outbreaks in mainland China, particularly under the heightened pressure of imported infections. The targeted interventions adopted in March 2022 were not capable of halting transmission, and the implementation of a strict, prolonged city-wide lockdown was needed to successfully contain the outbreak, highlighting the challenges for successfully containing Omicron outbreaks. FundingKey Program of the National Natural Science Foundation of China (82130093). Research in contextO_ST_ABSEvidence before this studyC_ST_ABSOn May 24, 2022, we searched PubMed and Europe PMC for papers published or posted on preprint servers after January 1, 2022, using the following query: ("SARS-CoV-2" OR "Omicron" OR "BA.2") AND ("epidemiology" OR "epidemiological" OR "transmission dynamics") AND ("Shanghai"). A total of 26 studies were identified; among them, two aimed to describe or project the spread of the 2022 Omicron outbreak in Shanghai. One preprint described the epidemiological and clinical characteristics of 376 pediatric SARS-CoV-2 infections in March 2022, and the other preprint projected the epidemic progress in Shanghai, without providing an analysis of field data. In sum, none of these studies provided a comprehensive description of the epidemiological characteristics and spatiotemporal transmission dynamics of the outbreak. Added value of this studyWe collected individual information on SARS-CoV-2 infection and the timeline of the public health response. Population-based screenings were repeatedly implemented during the outbreak, which allowed us to investigate the spatiotemporal spread of the Omicron BA.2 variant as well as the impact of the implemented interventions, all without enduring significant amounts of underreporting from surveillance systems, as experienced in other areas. This study provides the first comprehensive assessment of the Omicron outbreak in Shanghai, China. Implications of all the available evidenceThis descriptive study provides a comprehensive understanding of the epidemiological features and transmission dynamics of the Omicron outbreak in Shanghai, China. The empirical evidence from Shanghai, which was ultimately able to curtail the outbreak, provides invaluable information to policymakers on the impact of the containment strategies adopted by the Shanghai public health officials to prepare for potential outbreaks caused by Omicron or novel variants.

Assessing the feasibility of sustaining a 'Zero-COVID' policy in China in the era of highly transmissible variants

We developed a spatially structured, fully stochastic, individual-based SARS-CoV-2 transmission model to evaluate the feasibility of sustaining SARS-CoV-2 local containment in mainland China considering currently dominant Omicron variants, Chinas current immunization level, and non-pharmaceutical interventions (NPIs). We also built a statistical model to estimate the overall disease burden under various hypothetical mitigation scenarios. We found that due to high transmissibility, neither Omicron BA.1 or BA.2 could be contained by Chinas pre-Omicron NPI strategies which were successful prior to the emergence of the Omicron variants. However, increased intervention intensity, such as enhanced population mobility restrictions and multi-round mass testing, could lead to containment success. We estimated that an acute Omicron epidemic wave in mainland China would result in significant number of deaths if China were to reopen under current vaccine coverage with no antiviral uptake, while increasing vaccination coverage and antiviral uptake could substantially reduce the disease burden. As Chinas current vaccination has yet to reach high coverage in older populations, NPIs remain essential tools to maintain low levels of infection while building up protective population immunity, ensuring a smooth transition out of the pandemic phase while minimizing the overall disease burden.

Global diversity of policy, coverage, and demand of COVID-19 vaccines: a descriptive study

BackgroundHundreds of millions of doses of COVID-19 vaccines have been administered globally, but progress in vaccination varies considerably between countries. We aim to provide an overall picture of COVID-19 vaccination campaigns, including policy, coverage, and demand of COVID-19 vaccines. MethodsWe conducted a descriptive study of vaccination policy and doses administered data obtained from multiple public sources as of 23 October 2021. We used these data to develop coverage indicators and explore associations of vaccine coverage with socioeconomic and healthcare-related factors. We estimated vaccine demand as numbers of doses required to complete vaccination of countries target populations according to their national immunization program policies. FindingsUse of both mRNA and adenovirus vectored vaccines was the most commonly used COVID-19 vaccines formulary in high-income countries, while adenovirus vectored vaccines were the most widely used vaccines worldwide (176 countries). Almost all countries (98.3%, 173/176) have authorized vaccines for the general public, with 53.4% (94/176) targeting individuals over 12 years and 33.0% (58/176) targeting those [≥]18 years. Forty-one and sixty-seven countries have started additional-dose and booster-dose vaccination programs, respectively. Globally, there have been 116.5 doses administered per 100 target population, although with marked inter-region and inter-country heterogeneity. Completed vaccination series coverage ranged from 0% to more than 95.0% of country target populations, and numbers of doses administered ranged from 0 to 239.6 per 100 target population. Doses administered per 100 total population correlated with healthcare access and quality index (R2 = 0.58), socio-demographic index (R2 = 0.56), and GDP per capita (R2 = 0.65). At least 5.54 billion doses will be required to complete interim vaccination programs - 4.65 billion for primary immunization and 0.89 billion for additional/booster programs. Globally, 0.84 and 0.96 dose per individual in the target population are needed for primary immunization and additional/booster programs, respectively. InterpretationThere is wide country-level disparity and inequity in COVID-19 vaccines rollout, suggesting large gaps in immunity, especially in low-income countries. FundingKey Program of the National Natural Science Foundation of China, the US National Institutes of Health. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed for articles in any language published up to October 21, 2021, using the following search terms: ("COVID-19" OR "SARS-CoV-2") AND ("vaccination" OR "vaccine") AND ("inequalit*" OR "inequity" OR "disparit*" OR "heterogeneity"). We also searched for dashboards associated with vaccine rollout from public websites. We identified several studies on tracking global inequalities of vaccine access, one of which constructed a COVID-19 vaccine dashboard (Our World in Data), and another that explored disparities in COVID-19 vaccination among different-income countries. However, we found no studies that depict global COVID-19 vaccination policies country-by-country and estimate demand for vaccine necessary to completely vaccinate countries designated target populations. Added value of this studyTo our knowledge, our study provides the most recent picture of COVID-19 vaccination campaigns, focusing on global vaccination policy and target-population demand. We found a diverse portfolio of vaccines in five technical platforms being administered globally, with 173 countries having authorized administration of vaccines to the general public in various age groups. We observed inter-region and inter-country heterogeneity in one-or-more-dose and full-dose coverage; countries with higher socio-demographic or health resource-related levels had higher coverage. We estimated dose-level demand for completing primary immunization programs and additional/booster dose programs separately. Implications of all the available evidenceWorldwide disparity and inequity of vaccine rollout implies that susceptibility among unvaccinated populations in some countries may impede or reverse pandemic control, especially in face of the emergence of variants and the dilemma of waning antibodies. Our findings suggest that global-level responses to the pandemic - financially, politically, and technically - are needed to overcome complex challenges that lie ahead.

Prediction of long-term kinetics of vaccine-elicited neutralizing antibody and time-varying vaccine-specific efficacy against the SARS-CoV-2 Delta variant by clinical endpoint

Evidence on vaccine-specific protection over time and boosting impact against the Delta variant across different clinical endpoints and age groups is urgently needed. To address this, we used a previously published model, combined with neutralization data for four vaccines - mRNA-1273, BNT162b2, NVX-CoV2373, and CoronaVac - to evaluate long-term dynamics of neutralizing antibody and to predict time-varying efficacy against the Delta variant by specific vaccine, age group, and clinical severity. We found that booster vaccination produces higher neutralization titers compared with titers observed following primary-series vaccination for all vaccines studied. We estimate the efficacies of mRNA-1273 and BNT162b2 against Delta variant infection to be 63.5% (95%CI: 51.4-67.3%) and 78.4% (95%CI: 72.2-83.5%), respectively, 14-30 days after the second dose, and that efficacies decreased to 36.0% (95%CI: 24.1-58.0%) and 38.5% (95%CI: 28.7-49.1%) 6-8 months later. After administration of booster doses, efficacies against the Delta variant would be 97.0% (95%CI: 96.4-98.5%) and 97.2% (95.7-98.1%). All four vaccines are predicted to provide good protection against severe illness from the Delta variant after both primary and booster vaccination. Long-term monitoring and surveillance of antibody dynamics and vaccine protection, as well as further validation of neutralizing antibody or other markers that can serve as correlates of protection against SARS-CoV-2 and its variants are needed to inform COVID-19 pandemic preparedness.

Landscape of SARS-CoV-2 genomic surveillance, public availability extent of genomic data, and epidemic shaped by variants: a global descriptive study

BackgroundGenomic surveillance has shaped our understanding of SARS-CoV-2 variants, which have proliferated globally in 2021. Characterizing global genomic surveillance, sequencing coverage, the extent of publicly available genomic data coupled with traditional epidemiologic data can provide evidence to inform SARS-CoV-2 surveillance and control strategies. MethodsWe collected country-specific data on SARS-CoV-2 genomic surveillance, sequencing capabilities, public genomic data, and aggregated publicly available variant data. We divided countries into three levels of genomic surveillance and sequencing availability based on predefined criteria. We downloaded the merged and deduplicated SARS-CoV-2 sequences from multiple public repositories, and used different proxies to estimate the sequencing coverage and public availability extent of genomic data, in addition to describing the global dissemination of variants. FindingsSince the start of 2021, the COVID-19 global epidemic clearly featured increasing circulation of Alpha, which was rapidly replaced by the Delta variant starting around May 2021 and reaching a global prevalence of 96.6% at the end of July 2021. SARS-CoV-2 genomic surveillance and sequencing availability varied markedly across countries, with 63 countries performing routine genomic surveillance and 79 countries with high availability of SARS-CoV-2 sequencing. Less than 3.5% of confirmed SARS-CoV-2 infections were sequenced globally since September 2020, with the lowest sequencing coverage in the WHO regions of Eastern Mediterranean, South East Asia, and Africa. Across different variants, 28-52% of countries with explicit reporting on variants shared less than half of their variant sequences in public repositories. More than 60% of demographic and 95% of clinical data were absent in GISAID metadata accompanying sequences. InterpretationOur findings indicated an urgent need to expand sequencing capacity of virus isolates, enhance the sharing of sequences, the standardization of metadata files, and supportive networks for countries with no sequencing capability. Research in context Evidence before this studyOn September 3, 2021, we searched PubMed for articles in any language published after January 1, 2020, using the following search terms: ("COVID-19" OR "SARS-CoV-2") AND ("Global" OR "Region") AND ("genomic surveillance" OR "sequencing" OR "spread"). Among 43 papers identified, few papers discussed the global diversity in genomic surveillance, sequencing, public availability of genomic data, as well as the global spread of SARS-CoV-2 variants. A paper from Furuse employed the publicly GISAID data to evaluate the SARS-CoV-2 sequencing effort by country from the perspectives of "fraction", "timeliness", and "openness". Another viewpoint paper by Case Western Reserve Universitys team discussed the impediments of genomic surveillance in several countries during the COVID-19 pandemic. The paper as reported by Campbell and colleagues used the GISAID data to present the global spread and estimated transmissibility of recently emerged SARS-CoV-2 variants. We also found several studies that reported the country-level genomic surveillance and spread of variants. To our knowledge, no research has quantitatively depicted the global SARS-CoV-2 genomic surveillance, sequencing ability, and public availability extent of genomic data. Added value of this studyThis study collected country-specific data on SARS-CoV-2 genomic surveillance, sequencing capabilities, public genomic data, and aggregated publicly available variant data as of 20 August 2021. We found that genomic surveillance strategies and sequencing availability is globally diverse. Less than 3.5% of confirmed SARS-CoV-2 infections were sequenced globally since September 2020. Our analysis of publicly deposited SARS-CoV-2 sequences and officially reported number of variants implied that the public availability extent of genomic data is low in some countries, and more than 60% of demographic and 95% of clinical data were absent in GISAID metadata accompanying sequences. We also described the pandemic dynamics shaped by VOCs. Implications of all the available evidenceOur study provides a landscape for global sequencing coverage and public availability extent of sequences, as well as the evidence for rapid spread of SRAS-CoV-2 variants. The pervasive spread of Alpha and Delta variants further highlights the threat of SARS-CoV-2 mutations despite the availability of vaccines in many countries. It raised an urgent need to do more work on defining the ideal sampling schemes for different purposes (e.g., identifying new variants) with an additional call to share these data in public repositories to allow for further rapid scientific discovery.

Prediction of vaccine efficacy of the Delta variant

The emergence of SARS-CoV-2 variants have raised concerns over the protective efficacy of the current generation of vaccines, and it remains unclear to what extent, if any, different variants impact the efficacy and effectiveness of various SARS-CoV-2 vaccines. We systematically searched for studies of SARS-CoV-2 vaccine efficacy and effectiveness, as well as neutralization data for variants, and used a previously published statistical model to predict vaccine efficacy against variants. Overall, we estimate the efficacy of mRNA-1273 and ChAdOx1 nCoV-19 against infection caused by the Delta variant to be 25-50% lower than that of prototype strains. The predicted efficacy against symptomatic illness of the mRNA vaccines BNT162b2 and mRNA-1273 are 95.1% (UI: 88.4-98.1%) and 80.8% (60.7-92.3%), respectively, which are higher than that of adenovirus-vector vaccines Ad26.COV2.S (44.8%, UI: 29.8-60.1%) and ChAdOx1 nCoV-19 (41.1%, 19.8-62.8%). Taken together, these results suggest that the development of more effective vaccine strategies against the Delta variant may be needed. Finally, the use of neutralizing antibody titers to predict efficacy against variants provides an additional tool for public health decision making, as new variants continue to emerge.

A booster dose is immunogenic and will be needed for older adults who have completed two doses vaccination with CoronaVac: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial

ImportanceWhether herd immunity through mass vaccination is sufficient to curb SARS-CoV-2 transmission requires an understanding of the duration of vaccine-induced immunity, and the necessity and timing of booster doses. Objective: To evaluate immune persistence of two priming doses of CoronaVac, and immunogenicity and safety of a third dose in healthy adults [≥]60 years. Design, setting, and participants: We conducted a vaccine booster study built on a single-center, randomized, double-blind phase 1/2 trial of the two-dose schedule of CoronaVac among healthy adults[≥]60 years in Hebei, China. We examined neutralizing antibody titres six months or more after the second dose in all participants. We provided a third dose to 303 participants recruited in phase 2 trial to assess their immune responses. InterventionsTwo formulations (3 g, and 6 g) were used in phase 1 trial, and an additional formulation of 1.5 g was used in phase 2 trial. All participants were given two doses 28 days apart and followed up 6 months after the second dose. Participants in phase 2 received a third dose 8 months after the second dose. Main outcomes and measuresGeometric mean titres (GMT) of neutralizing antibodies to live SARS-CoV-2 and adverse events were assessed at multiple time points following vaccination. ResultsNeutralizing antibody titres dropped below the seropositive cutoff of 8 at 6 months after the primary vaccination in all vaccine groups in the phase 1/2 trial. A third dose given 8 months or more after the second dose significantly increased neutralizing antibody levels. In the 3 g group (the licensed formulation), GMT increased to 305 [95%CI 215.3-432.0] on day 7 following the third dose, an approximately 7-fold increase compared with the GMT 28 days after the second dose. All solicited adverse reactions reported within 28 days after a booster dose were of grade 1 or 2 severity. Conclusion and relevanceNeutralizing antibody titres declined substantially six months after two doses of CoronaVac among older adults. A booster dose rapidly induces robust immune responses. This evidence could help policymakers determine the necessity and the timing of a booster dose for older adults. Trial registrationClinicalTrials.gov (NCT04383574).

Herd immunity induced by COVID-19 vaccination programs to suppress epidemics caused by SARS-CoV-2 wild type and variants in China

BackgroundTo allow a return to a pre-COVID-19 lifestyle, virtually every country has initiated a vaccination program to mitigate severe disease burden and control transmission. However, it remains to be seen whether herd immunity will be within reach of these programs. MethodsWe developed a data-driven model of SARS-CoV-2 transmission for China, a population with low prior immunity from natural infection. The model is calibrated considering COVID-19 natural history and the estimated transmissibility of the Delta variant. Three vaccination programs are tested, including the one currently enacted in China and model-based estimates of the herd immunity level are provided. ResultsWe found that it is unlike to reach herd immunity for the Delta variant given the relatively low efficacy of the vaccines used in China throughout 2021, the exclusion of underage individuals from the targeted population, and the lack of prior natural immunity. We estimate that, assuming a vaccine efficacy of 90% against the infection, vaccine-induced herd immunity would require a coverage of 93% or higher of the Chinese population. However, even when vaccine-induced herd immunity is not reached, we estimated that vaccination programs can reduce SARS-CoV-2 infections by 53-58% in case of an epidemic starts to unfold in the fall of 2021. ConclusionsEfforts should be taken to increase populations confidence and willingness to be vaccinated and to guarantee highly efficacious vaccines for a wider age range.

Comprehensive mapping of neutralizing antibodies against SARS-CoV-2 variants induced by natural infection or vaccination

BackgroundImmunity after SARS-CoV-2 infection or vaccination has been threatened by recently emerged SARS-CoV-2 variants. A systematic summary of the landscape of neutralizing antibodies against emerging variants is needed. MethodsWe systematically searched PubMed, Embase, Web of Science, and 3 pre-print servers for studies that evaluated neutralizing antibodies titers induced by previous infection or vaccination against SARS-CoV-2 variants and comprehensively collected individual data. We calculated lineage-specific GMTs across different study participants and types of neutralization assays. FindingsWe identified 56 studies, including 2,483 individuals and 8,590 neutralization tests, meeting the eligibility criteria. Compared with lineage B, we estimate a 1.5-fold (95% CI: 1.0-2.2) reduction in neutralization against the B.1.1.7, 8.7-fold (95% CI: 6.5-11.7) reduction against B.1.351 and 5.0-fold (95% CI: 4.0-6.2) reduction against P.1. The estimated neutralization reductions for B.1.351 compared to lineage B were 240.2-fold (95% CI: 124.0-465.6) reduction for non-replicating vector platform, 4.6-fold (95% CI: 4.0-5.2) reduction for RNA platform, and 1.6-fold (95% CI: 1.2-2.1) reduction for protein subunit platform. The neutralizing antibodies induced by administration of inactivated vaccines and mRNA vaccines against lineage P.1 were also remarkably reduced by an average of 5.9-fold (95% CI: 3.7-9.3) and 1.5-fold (95% CI: 1.2-1.9). InterpretationOur findings indicate that the antibody response established by natural infection or vaccination might be able to effectively neutralize B.1.1.7, but neutralizing titers against B.1.351 and P.1 suffered large reductions. Standardized protocols for neutralization assays, as well as updating immune-based prevention and treatment, are needed. FundingChinese National Science Fund for Distinguished Young Scholars Research in contextO_ST_ABSEvidence before this studyC_ST_ABSSeveral newly emerged SARS-CoV-2 variants have raised significant concerns globally, and there is concern that SARS-CoV-2 variants can evade immune responses that are based on the prototype strain. It is not known to what extent do emerging SARS-CoV-2 variants escape the immune response induced by previous infection or vaccination. However, existing studies of neutralizing potency against SARS-CoV-2 variants are based on limited numbers of samples and lack comparability between different laboratory methods. Furthermore, there are no studies providing whole picture of neutralizing antibodies induced by prior infections or vaccination against emerging variants. Therefore, we systematically reviewed and quantitively synthesized evidence on the degree to which antibodies from previous SARS-CoV-2 infection or vaccination effectively neutralize variants. Added value of this studyIn this study, 56 studies, including 2,483 individuals and 8,590 neutralization tests, were identified. Antibodies from natural infection or vaccination are likely to effectively neutralize B.1.1.7, but neutralizing titers against B.1.351 and P.1 suffered large reductions. Lineage B.1.351 escaped natural-infection-mediated neutralization the most, with GMT of 79.2 (95% CI: 68.5-91.6), while neutralizing antibody titers against the B.1.1.7 variant were largely preserved (254.6, 95% CI: 214.1-302.8). Compared with lineage B, we estimate a 1.5-fold (95% CI: 1.0-2.2) reduction in neutralization against the B.1.1.7, 8.7-fold (95% CI: 6.5-11.7) reduction against B.1.351 and 5.0-fold (95% CI: 4.0-6.2) reduction against P.1. The neutralizing antibody response after vaccinating with non-replicating vector vaccines against lineage B.1.351 was worse than responses elicited by vaccines on other platforms, with levels lower than that of individuals who were previously infected. The neutralizing antibodies induced by administration of inactivated vaccines and mRNA vaccines against lineage P.1 were also remarkably reduced by an average of 5.9-fold (95% CI: 3.7-9.3) and 1.5-fold (95% CI: 1.2-1.9). Implications of all the available evidenceOur findings indicate that antibodies from natural infection of the parent lineage of SARS-CoV-2 or vaccination may be less able to neutralize some emerging variants, and antibody-based therapies may need to be updated. Furthermore, standardized protocols for neutralizing antibody testing against SARS-CoV-2 are needed to reduce lab-to-lab variations, thus facilitating comparability and interpretability across studies.

Model-based evaluation of alternative reactive class closure strategies against COVID-19

There are contrasting results concerning the effect of reactive school closure on SARS-CoV-2 transmission. To shed light on this controversy, here we develop a data-driven computational model of SARS-CoV-2 transmission to investigate mechanistically the effect on COVID-19 outbreaks of school closure strategies based on syndromic surveillance and antigen screening of students. We found that by reactively closing classes based on syndromic surveillance, SARS-CoV-2 infections are reduced by no more than 13.1% (95%CI: 8.6%-20.2 %), due to the low probability of timely symptomatic case identification among the young population. We thus investigated an alternative triggering mechanism based on repeated screening of students using antigen tests. Should population-level social distancing measures unrelated to schools enable maintaining the reproduction number (R) at 1.3 or lower, an antigen-based screening strategy is estimated to fully prevent COVID-19 outbreaks in the general population. Depending on the contribution of schools to transmission, this strategy can either prevent COVID-19 outbreaks for R up to 1.9 or to at least greatly reduce outbreak size in very conservative scenarios about school contribution to transmission. Moving forward, the adoption of antigen-based screenings in schools could be instrumental to limit COVID-19 burden while vaccines continue to roll out through 2021, especially in light of possible continued emergence of SARS-CoV-2 variants.

Can a COVID-19 vaccination program guarantee the return to a pre-pandemic lifestyle?

AbstractCOVID-19 vaccination is being conducted in over 190 countries/regions to control SARS-CoV-2 transmission and return to a pre-pandemic lifestyle. However, understanding when non-pharmaceutical interventions (NPIs) can be lifted as immunity builds up remain a key question for policy makers. To address it, we built a data-driven model of SARS-CoV-2 transmission for China. We estimated that to prevent the escalation of local outbreaks to widespread epidemics, stringent NPIs need to remain in place at least one year after the start of vaccination. Should NPIs alone be capable to keep the reproduction number (Rt) around 1.3, the synergetic effect of NPIs and vaccination could reduce up to 99% of COVID-19 burden and bring Rt below the epidemic threshold in about 9 months. Maintaining strict NPIs throughout 2021 is of paramount importance to reduce COVID-19 burden while vaccines are distributed to the population, especially in large populations with little natural immunity.

Global, regional, and national estimates of target population sizes for COVID-19 vaccination

BackgroundCOVID-19 vaccine prioritization and allocation strategies that maximize health benefit through efficient use of limited resources are urgently needed. We aimed to provide global, regional, and national estimates of target population sizes for COVID-19 vaccination to inform country-specific immunization strategies on a global scale. MethodsBased on a previous study of international allocation for pandemic COVID-19 vaccines, we classified the entire world population into eleven priority groups. Information on priority groups was derived from a multi-pronged search of official websites, media sources and academic journal articles. The sizes of different priority groups were projected for 194 countries globally. ResultsOverall, the size of COVID-19 vaccine recipient population varied markedly by goals of the vaccination program and geography. The general population aged <60 years without any underlying condition accounts for the majority of the total population (5.2 billion people, 68%), followed by 2.3 billion individuals at risk of severe disease, and 246.9 million essential workers which are critical to maintaining a functional society. Differences in the demographic structure, presence of underlying conditions, and number of essential workers led to highly variable estimates of target populations both at the WHO region and country level. In particular, Europe has the highest share of essential workers (6.8%) and the highest share of individuals with underlying conditions (37.8%), two priority categories to maintain societal functions and reduce severe burden. In contrast, Africa has the highest share of healthy adults, school-age individuals, and infants (77.6%), which are the key groups to target to reduce community transmission. InterpretationThe sizeable distribution of target groups on a country and regional bases underlines the importance of equitable and efficient vaccine prioritization and allocation globally. The direct and indirect benefits of COVID-19 vaccination should be balanced by considering local differences in demography and health.

Serological evidence of human infection with SARS-CoV-2: a systematic review and meta-analysis

BackgroundA rapidly increasing number of serological surveys for anti-SARS-CoV-2 antibodies have been reported worldwide. A synthesis of this large corpus of data is needed. PurposeTo evaluate the quality of serological studies and provide a global picture of seroprevalence across demographic and occupational groups, and to provide guidance for conducting better serosurveys. Data sourcesWe searched PubMed, Embase, Web of Science, and 4 pre-print servers for English-language papers published from December 1, 2019 to September 25, 2020. Study selectionSerological studies evaluating SARS-CoV-2 seroprevalence in humans. Data extractionTwo investigators independently extracted data from studies. Data SynthesisMost of 230 serological studies, representing tests in >1,400,000 individuals, identified were of low quality based on a standardized study quality scale. In the 51 studies of higher quality, high-risk healthcare workers had higher seroprevalence of 17.1% (95% CI: 9.9-24.4%), compared to low-risk healthcare workers and general population of 5.4% (0.7-10.1%) and 5.3% (4.2-6.4%). Seroprevalence varied hugely across WHO regions, with lowest seroprevalence of general population in Western Pacific region (1.7%, 0.0-5.0%). Generally, the young (<20 years) and the old ([≥]65 years) were less likely to be seropositive compared to middle-aged (20-64 years) populations. Seroprevalence correlated with clinical COVID-19 reports, with pooled average of 7.7 (range: 2.0 to 23.1) serologically-detected-infections per confirmed COVID-19 case. LimitationsSome heterogeneity cannot be well explained quantitatively. ConclusionsThe overall quality of seroprevalence studies examined was low. The relatively low seroprevalence among general populations suggest that in most settings, antibody-mediated herd immunity is far from being reached. Given the relatively narrow range of estimates of the ratio of serologically-detected infections to confirmed cases across different locales, reported case counts may help provide insights into the true proportion of the population infected. Primary Funding sourceNational Science Fund for Distinguished Young Scholars (PROSPERO: CRD42020198253).

Disease burden and clinical severity of the first pandemic wave of COVID-19 in Wuhan, China

The pandemic of novel coronavirus disease 2019 (COVID-19) began in Wuhan, China, where a first wave of intense community transmission was cut short by interventions. Using multiple data source, we estimated the disease burden and clinical severity of COVID-19 by age in Wuhan from December 1, 2019 to March 31, 2020. We adjusted estimates for sensitivity of laboratory assays and accounted for prospective community screenings and healthcare seeking behaviors. Rates of symptomatic cases, medical consultations, hospitalizations and deaths were estimated at 796 (95%CI: 703-977), 489 (472-509), 370 (358-384), and 36.2 (35.0-37.3) per 100,000 persons, respectively. The COVID-19 outbreak in Wuhan had higher burden than the 2009 influenza pandemic or seasonal influenza, and that clinical severity was similar to that of the 1918 influenza pandemic. Our comparison puts the COVID-19 pandemic into context and could be helpful to guide intervention strategies and preparedness for the potential resurgence of COVID-19.

Transmission heterogeneities, kinetics, and controllability of SARS-CoV-2

A long-standing question in infectious disease dynamics is the role of transmission heterogeneities, particularly those driven by demography, behavior and interventions. Here we characterize transmission risk between 1,178 SARS-CoV-2 infected individuals and their 15,648 close contacts based on detailed contact tracing data from Hunan, China. We find that 80% of secondary transmissions can be traced back to 14% of SARS-CoV-2 infections, indicating substantial transmission heterogeneities. Regression analysis suggests a marked gradient of transmission risk scales positively with the duration of exposure and the closeness of social interactions, after adjusted for demographic and clinical factors. Population-level physical distancing measures confine transmission to families and households; while case isolation and contact quarantine reduce transmission in all settings. Adjusted for interventions, the reconstructed infectiousness profile of a typical SARS-CoV-2 infection peaks just before symptom presentation, with ~50% of transmission occurring in the pre-symptomatic phase. Modelling results indicate that achieving SARS-CoV-2 control would require the synergistic efforts of case isolation, contact quarantine, and population-level physical distancing measures, owing to the particular transmission kinetics of this virus.

The impact of relaxing interventions on human contact patterns and SARS-CoV-2 transmission in China

Non-pharmaceutical interventions to control COVID-19 spread have been implemented in several countries with different intensity, timing, and impact on transmission. As a result, post-lockdown COVID-19 dynamics are heterogenous and difficult to interpret. Here we describe a set of contact surveys performed in four Chinese cities (Wuhan, Shanghai, Shenzhen, and Changsha) during the pre-pandemic, lockdown, and post-lockdown period to quantify the transmission impact of relaxing interventions via changes in age-specific contact patterns. We estimate that the mean number of contacts increased 5%-17% since the end of the lockdown but are still 3-7 times lower than their pre-pandemic levels. We find that post-lockdown contact patterns in China are still sufficiently low to keep SARS-CoV-2 transmission under control. We also find that the impact of school interventions depends non-linearly on the share of other activities being resumed. When most community activities are halted, school closure leads to a 77% decrease in the reproductive number; in contrast, when social mixing outside of schools is at pre-pandemic level, school closure leads to a 5% reduction in transmission. Moving forward, to control COVID-19 spread without resorting to a lockdown, it will be key to dose relaxation in social mixing in the community and strengthen targeted interventions. One Sentence SummarySocial contacts estimated in the post-lockdown period in four large Chinese cities are not sufficient to sustain local SARS-CoV-2 transmission.

Infectivity, susceptibility, and risk factors associated with SARS-CoV-2 transmission under intensive contact tracing in Hunan, China

BackgroundSeveral parameters driving the transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain unclear, including age-specific differences in infectivity and susceptibility, and the contribution of inapparent infections to transmission. Robust estimates of key time-to-event distributions remain scarce as well. MethodsWe collected individual records for 1,178 SARS-CoV-2 infected individuals and their 15,648 contacts identified by contact tracing and monitoring over the period from January 13 to April 02, 2020 in Hunan Province, China. We provide descriptive statistics of the characteristics of cases and their close contacts; we fitted distributions to time-to-key-events distributions and infectiousness profile over time; and we used generalized linear mixed model to estimate risk factors for susceptibility and transmissibility of SARS-CoV-2. ResultsWe estimated the mean serial interval at 5.5 days (95%CI -5.0, 19.9) and the mean generation time at 5.5 days (95%CI 1.7, 11.6). The infectiousness was estimated to peak 1.8 days before symptom onset, with 95% of transmission events occurring between 7.6 days before and 7.3 days after the date of symptom onset. The proportion of pre-symptomatic transmission was estimated to be 62.5%. We estimated that at least 3.5% of cases were generated asymptomatic individuals. SARS-CoV-2 transmissibility was not significantly different between working-age adults (15-59 years old) and other age groups (0-14 years old: p-value=0.16; 60 years and over: p-value=0.33), whilst susceptibility to SARS-CoV-2 infection was estimated to increase with age (p-value=0.03). In addition, transmission risk was higher for household contacts (p-value<0.001), decreased for higher generations within a cluster (second generation: odds ratio=0.13, p-value<0.001; generations 3-4: odds ratio=0.05, p-value<0.001, relative to generation 1), and decreased for infectors with a larger number of contacts (p-value=0.04). InterpretationOur findings warn of the possible relevant contribution of children to SARS-CoV-2 transmission. When lockdown interventions are in place, we found that odds of transmission are highest in the household setting but, with the relaxation of interventions, other settings (including schools) could bear a higher risk of transmission. Moreover, the estimated relevant fraction of pre-symptomatic and asymptomatic transmission highlight the importance of large-scale testing, contact tracing activities, and the use of personnel protective equipment during the COVID-19 pandemic.