Virological characteristics of the SARS-CoV-2 Omicron BA.2 spike.

Soon after the emergence and global spread of the SARS-CoV-2 Omicron lineage BA.1, another Omicron lineage, BA.2, began outcompeting BA.1. The results of statistical analysis showed that the effective reproduction number of BA.2 is 1.4-fold higher than that of BA.1. Neutralization experiments revealed that immunity induced by COVID vaccines widely administered to human populations is not effective against BA.2, similar to BA.1, and that the antigenicity of BA.2 is notably different from that of BA.1. Cell culture experiments showed that the BA.2 spike confers higher replication efficacy in human nasal epithelial cells and is more efficient in mediating syncytia formation than the BA.1 spike. Furthermore, infection experiments using hamsters indicated that the BA.2 spike-bearing virus is more pathogenic than the BA.1 spike-bearing virus. Altogether, the results of our multiscale investigations suggest that the risk of BA.2 to global health is potentially higher than that of BA.1.

Virological characteristics of the SARS-CoV-2 Omicron BA.2 subvariants, including BA.4 and BA.5.

After the global spread of the SARS-CoV-2 Omicron BA.2, some BA.2 subvariants, including BA.2.9.1, BA.2.11, BA.2.12.1, BA.4, and BA.5, emerged in multiple countries. Our statistical analysis showed that the effective reproduction numbers of these BA.2 subvariants are greater than that of the original BA.2. Neutralization experiments revealed that the immunity induced by BA.1/2 infections is less effective against BA.4/5. Cell culture experiments showed that BA.2.12.1 and BA.4/5 replicate more efficiently in human alveolar epithelial cells than BA.2, and particularly, BA.4/5 is more fusogenic than BA.2. We further provided the structure of the BA.4/5 spike receptor-binding domain that binds to human ACE2 and considered how the substitutions in the BA.4/5 spike play roles in ACE2 binding and immune evasion. Moreover, experiments using hamsters suggested that BA.4/5 is more pathogenic than BA.2. Our multiscale investigations suggest that the risk of BA.2 subvariants, particularly BA.4/5, to global health is greater than that of original BA.2.

Population impact of SARS-CoV-2 variants with enhanced transmissibility and/or partial immune escape.

SARS-CoV-2 variants of concern exhibit varying degrees of transmissibility and, in some cases, escape from acquired immunity. Much effort has been devoted to measuring these phenotypes, but understanding their impact on the course of the pandemic-especially that of immune escape-has remained a challenge. Here, we use a mathematical model to simulate the dynamics of wild-type and variant strains of SARS-CoV-2 in the context of vaccine rollout and nonpharmaceutical interventions. We show that variants with enhanced transmissibility frequently increase epidemic severity, whereas those with partial immune escape either fail to spread widely or primarily cause reinfections and breakthrough infections. However, when these phenotypes are combined, a variant can continue spreading even as immunity builds up in the population, limiting the impact of vaccination and exacerbating the epidemic. These findings help explain the trajectories of past and present SARS-CoV-2 variants and may inform variant assessment and response in the future.

A speed limit on serial strain replacement from original antigenic sin.

Many pathogens evolve to escape immunity, yet it remains difficult to predict whether immune pressure will lead to diversification, serial replacement of one variant by another, or more complex patterns. Pathogen strain dynamics are mediated by cross-protective immunity, whereby exposure to one strain partially protects against infection by antigenically diverged strains. There is growing evidence that this protection is influenced by early exposures, a phenomenon referred to as original antigenic sin (OAS) or imprinting. In this paper, we derive constraints on the emergence of the pattern of successive strain replacements demonstrated by influenza, SARS-CoV-2, seasonal coronaviruses, and other pathogens. We find that OAS implies that the limited diversity found with successive strain replacement can only be maintained if [Formula: see text] is less than a threshold set by the characteristic antigenic distances for cross-protection and for the creation of new immune memory. This bound implies a "speed limit" on the evolution of new strains and a minimum variance of the distribution of infecting strains in antigenic space at any time. To carry out this analysis, we develop a theoretical model of pathogen evolution in antigenic space that implements OAS by decoupling the antigenic distances required for protection from infection and strain-specific memory creation. Our results demonstrate that OAS can play an integral role in the emergence of strain structure from host immune dynamics, preventing highly transmissible pathogens from maintaining serial strain replacement without diversification.

Reconstructing household transmission dynamics to estimate the infectiousness of asymptomatic influenza virus infections.

There has long been controversy over the potential for asymptomatic cases of the influenza virus to have the capacity for onward transmission, but recognition of asymptomatic transmission of COVID-19 stimulates further research into this topic. Here, we develop a Bayesian methodology to analyze detailed data from a large cohort of 727 households and 2515 individuals in the 2009 pandemic influenza A(H1N1) outbreak in Hong Kong to characterize household transmission dynamics and to estimate the relative infectiousness of asymptomatic versus symptomatic influenza cases. The posterior probability that asymptomatic cases [36% of cases; 95% credible interval (CrI): 32%, 40%] are less infectious than symptomatic cases is 0.82, with estimated relative infectiousness 0.57 (95% CrI: 0.11, 1.54). More data are required to strengthen our understanding of the contribution of asymptomatic cases to the spread of influenza.

A Noncoding A-to-U Kozak Site Change Related to the High Transmissibility of Alpha, Delta, and Omicron VOCs.

Three prevalent SARS-CoV-2 variants of concern (VOCs) emerged and caused epidemic waves. It is essential to uncover advantageous mutations that cause the high transmissibility of VOCs. However, viral mutations are tightly linked, so traditional population genetic methods, including machine learning-based methods, cannot reliably detect mutations conferring a fitness advantage. In this study, we developed an approach based on the sequential occurrence order of mutations and the accelerated furcation rate in the pandemic-scale phylogenomic tree. We analyzed 3,777,753 high-quality SARS-CoV-2 genomic sequences and the epidemiology metadata using the Coronavirus GenBrowser. We found that two noncoding mutations at the same position (g.a28271-/u) may be crucial to the high transmissibility of Alpha, Delta, and Omicron VOCs although the noncoding mutations alone cannot increase viral transmissibility. Both mutations cause an A-to-U change at the core position -3 of the Kozak sequence of the N gene and significantly reduce the protein expression ratio of ORF9b to N. Using a convergent evolutionary analysis, we found that g.a28271-/u, S:p.P681H/R, and N:p.R203K/M occur independently on three VOC lineages, suggesting that coordinated changes of S, N, and ORF9b proteins are crucial to high viral transmissibility. Our results provide new insights into high viral transmissibility co-modulated by advantageous noncoding and nonsynonymous changes.

Multiscale selection in spatially structured populations.

The spatial structure of populations is key to many (eco-)evolutionary processes. In such cases, the strength and sign of selection on a trait may depend on the spatial scale considered. An example is the evolution of altruism: selection in local environments often favours cheaters over altruists, but this can be outweighed by selection at larger scales, favouring clusters of altruists over clusters of cheaters. For populations subdivided into distinct groups, this effect is described formally by multilevel selection theory. However, many populations do not consist of non-overlapping groups but rather (self-)organize into other ecological patterns. We therefore present a mathematical framework for multiscale selection. This framework decomposes natural selection into two parts: local selection, acting within environments of a certain size, and interlocal selection, acting among them. Varying the size of the local environments subsequently allows one to measure the contribution to selection of each spatial scale. To illustrate the use of this framework, we apply it to models of the evolution of altruism and pathogen transmissibility. The analysis identifies how and to what extent ecological processes at different spatial scales contribute to selection and compete, thus providing a rigorous underpinning to eco-evolutionary intuitions.

Characterization of an Emergent Chicken H3N8 Influenza Virus in Southern China: a Potential Threat to Public Health.

Although influenza A viruses of several subtypes have occasionally infected humans, to date only those of the H1, H2, and H3 subtypes have led to pandemics and become established in humans. The detection of two human infections by avian H3N8 viruses in April and May of 2022 raised pandemic concerns. Recent studies have shown the H3N8 viruses were introduced into humans from poultry, although their genesis, prevalence, and transmissibility in mammals have not been fully elucidated. Findings generated from our systematic influenza surveillance showed that this H3N8 influenza virus was first detected in chickens in July 2021 and then disseminated and became established in chickens over wider regions of China. Phylogenetic analyses revealed that the H3 HA and N8 NA were derived from avian viruses prevalent in domestic ducks in the Guangxi-Guangdong region, while all internal genes were from enzootic poultry H9N2 viruses. The novel H3N8 viruses form independent lineages in the glycoprotein gene trees, but their internal genes are mixed with those of H9N2 viruses, indicating continuous gene exchange among these viruses. Experimental infection of ferrets with three chicken H3N8 viruses showed transmission through direct contact and inefficient transmission by airborne exposure. Examination of contemporary human sera detected only very limited antibody cross-reaction to these viruses. The continuing evolution of these viruses in poultry could pose an ongoing pandemic threat. IMPORTANCE A novel H3N8 virus with demonstrated zoonotic potential has emerged and disseminated in chickens in China. It was generated by reassortment between avian H3 and N8 virus(es) and long-term enzootic H9N2 viruses present in southern China. This H3N8 virus has maintained independent H3 and N8 gene lineages but continues to exchange internal genes with other H9N2 viruses to form novel variants. Our experimental studies showed that these H3N8 viruses were transmissible in ferrets, and serological data suggest that the human population lacks effective immunological protection against it. With its wide geographical distribution and continuing evolution in chickens, other spillovers to humans can be expected and might lead to more efficient transmission in humans.

SARS-CoV-2 transmissibility compared between variants of concern and vaccination status.

Since the start of the SARS-CoV-2 pandemic in late 2019, several variants of concern (VOC) have been reported to have increased transmissibility. In addition, despite the progress of vaccination against SARS-CoV-2 worldwide, all vaccines currently in used are known to protect only partially from infection and onward transmission. We combined phylogenetic analysis with Bayesian inference under an epidemiological model to infer the reproduction number (Rt) and also trace person-to-person transmission. We examined the impact of phylogenetic uncertainty and sampling bias on the estimation. Our result indicated that lineage B had a significantly higher transmissibility than lineage A and contributed to the global pandemic to a large extent. In addition, although the transmissibility of VOCs is higher than other exponentially growing lineages, this difference is not very high. The probability of detecting onward transmission from patients infected with SARS-CoV-2 VOCs who had received at least one dose of vaccine was approximate 1.06% (3/284), which was slightly lower but not statistically significantly different from a probability of 1.21% (10/828) for unvaccinated individuals. In addition to VOCs, exponentially growing lineages in each country should also be account for when tailoring prevention and control strategies. One dose of vaccination could not efficiently prevent the onward transmission of SARS-CoV-2 VOCs. Consequently, nonpharmaceutical interventions (such as wearing masks and social distancing) should still be implemented in each country during the vaccination period.

Study of the Prediction of Vibrations in Soft Soil Foundations Based on Field Tests.

To explore the prediction of vibrations in soft soil foundations, in light of the construction of laboratories with microvibration requirements on soft soil foundations which are subject to the limitations of urban land planning, field testing was conducted, and the soil surface vibration responses were recorded at different distances from a road under various highway traffic loads. By analyzing the data which summarize the characteristics of soft soil foundations, it is clarified that the vibration response of soft soil foundations mainly occurs at low frequencies, and the vibration response under road traffic loads is prone to resonance at the natural frequency of soft soil foundations. Subsequently, a new vibration prediction method based on the vibration transmission ratio is proposed, and its effectiveness and accuracy based on transmissibility are verified. This research study provides a reference for laboratories constructed on soft soil and for surrounding traffic planning.

Influence of Nasopharyngeal Viral Load on the Spread of the Omicron BA.2 Variant.

We used variant typing polymerase chain reaction to describe the evolution of severe acute respiratory syndrome coronavirus 2 Omicron sublineages between December 2021 and mid-March 2022. The selective advantage of the BA.2 variant over BA.1 is not due to greater nasopharyngeal viral loads.

Continued adaptation of A/H2N2 viruses during pandemic circulation in humans.

Influenza A viruses of the H2N2 subtype sparked a pandemic in 1957 and circulated in humans until 1968. Because A/H2N2 viruses still circulate in wild birds worldwide and human population immunity is low, the transmissibility of six avian A/H2N2 viruses was investigated in the ferret model. None of the avian A/H2N2 viruses was transmitted between ferrets, suggesting that their pandemic risk may be low. The transmissibility, receptor binding preference and haemagglutinin (HA) stability of human A/H2N2 viruses were also investigated. Human A/H2N2 viruses from 1957 and 1958 bound to human-type α2,6-linked sialic acid receptors, but the 1958 virus had a more stable HA, indicating adaptation to replication and spread in the new host. This increased stability was caused by a previously unknown stability substitution G205S in the 1958 H2N2 HA, which became fixed in A/H2N2 viruses after 1958. Although individual substitutions were identified that affected the HA receptor binding and stability properties, they were not found to have a substantial effect on transmissibility of A/H2N2 viruses via the air in the ferret model. Our data demonstrate that A/H2N2 viruses continued to adapt during the first year of pandemic circulation in humans, similar to what was previously shown for the A/H1N1pdm09 virus.

Swine H1N1 Influenza Virus Variants with Enhanced Polymerase Activity and HA Stability Promote Airborne Transmission in Ferrets.

Understanding how animal influenza A viruses (IAVs) acquire airborne transmissibility in humans and ferrets is needed to prepare for and respond to pandemics. Here, we investigated in ferrets the replication and transmission of swine H1N1 isolates P4 and G15, whose majority population had decreased polymerase activity and poor hemagglutinin (HA) stability, respectively. For both isolates, a minor variant was selected and transmitted in ferrets. Polymerase-enhancing variant PA-S321 airborne-transmitted and propagated in one ferret. HA-stabilizing variant HA1-S210 was selected in all G15-inoculated ferrets and was transmitted by contact and airborne routes. With an efficient polymerase and a stable HA, the purified minor variant G15-HA1-S210 had earlier and higher peak titers in inoculated ferrets and was recovered at a higher frequency after airborne transmission than P4 and G15. Overall, HA stabilization played a more prominent role than polymerase enhancement in the replication and transmission of these viruses in ferrets. The results suggest pandemic risk-assessment studies may benefit from deep sequencing to identify minor variants with human-adapted traits. IMPORTANCE Diverse IAVs circulate in animals, yet few acquire the viral traits needed to start a human pandemic. A stabilized HA and mammalian-adapted polymerase have been shown to promote the adaptation of IAVs to humans and ferrets (the gold-standard model for IAV replication, pathogenicity, and transmissibility). Here, we used swine IAV isolates of the gamma lineage as a model to investigate the importance of HA stability and polymerase activity in promoting replication and transmission in ferrets. These are emerging viruses that bind to both α-2,6- and α-2,3-linked receptors. Using isolates containing mixed populations, a stabilized HA was selected within days in inoculated ferrets. An enhanced polymerase was also selected and propagated after airborne transmission to a ferret. Thus, HA stabilization was a stricter requirement, yet both traits promoted transmissibility. Knowing the viral traits needed for pandemic potential, and the relative importance of each, will help identify emerging viruses of greatest concern.

Anticipating the transmissibility of the 2022 mpox outbreak.

An ongoing outbreak of monkeypox virus (MPXV) was first reported in the United Kingdom on 6 May 2022. As of 17 November, there had been a total of 80 221 confirmed MPXV cases in over 110 countries. Based on data reported between 6 May and 30 June 2022 in the United Kingdom, Spain, and Germany, we applied a deep learning approach using convolutional neural networks to evaluate the parameters of the 2022 MPXV outbreak. The basic reproduction number (R0 ) of MPXV was estimated to be 2.32 in the United Kingdom, which indicates the active diffusion of MPXV since the beginning of the outbreak. The data from Spain and Germany produced higher median R0 values of 2.42 and 2.88, respectively. Importantly, the estimated R0 of MPXV in the three countries tends to the previously calculated R0 of smallpox (3.50 to 6.00). Furthermore, the incubation (1/ε) and infectious (1/γ) period was predicted between 9 and 10 days and 4-5 days, respectively. The R0 value derived from MPXV is consistent with the significantly increasing number of cases, indicating the risk of a rapid spread of MPXV worldwide, which would provide important insights for the prevention and control of MPXV epidemic.

Isolation and characterization of mammalian orthoreovirus from bats in the United States.

Mammalian orthoreovirus (MRV) infects many mammalian species including humans, bats, and domestic animals. To determine the prevalence of MRV in bats in the United States, we screened more than 900 bats of different species collected during 2015-2019 by a real-time reverse-transcription polymerase chain reaction assay; 4.4% bats tested MRV-positive and 13 MRVs were isolated. Sequence and phylogenetic analysis revealed that these isolates belonged to four different strains/genotypes of viruses in Serotypes 1 or 2, which contain genes similar to those of MRVs detected in humans, bats, bovine, and deer. Further characterization showed that these four MRV strains replicated efficiently on human, canine, monkey, ferret, and swine cell lines. The 40/Bat/USA/2018 strain belonging to the Serotype 1 demonstrated the ability to infect and transmit in pigs without prior adaptation. Taken together, this is evidence for different genotypes and serotypes of MRVs circulating in US bats, which can be a mixing vessel of MRVs that may spread to other species, including humans, resulting in cross-species infections.

A comparison of transmissibility of SARS-CoV-2 variants of concern.

BACKGROUND: The World Health Organization (WHO) has currently detected five Variants of Concern of SARS-CoV-2 having the WHO labels of 'Alpha', 'Beta', 'Gamma', 'Delta' and 'Omicron'. We aimed to assess and compare the transmissibility of the five VOCs in terms of basic reproduction number, time-varying reproduction number and growth rate. METHODS: Publicly available data on the number of analyzed sequences over two-week windows for each country were extracted from covariants.org and GISAID initiative database. The ten countries which reported the highest number of analyzed sequences for each of the five variants were included in the final dataset and was analyzed using R language. The epidemic curves for each variant were estimated utilizing the two-weekly discretized incidence data using local regression (LOESS) models. The basic reproduction number was estimated with the exponential growth rate method. The time-varying reproduction number was calculated for the estimated epidemic curves by the ratio of the number of new infections generated at time step t to the total infectiousness of infected individuals at time t, using the EpiEstim package. RESULTS: The highest R0 for the variants Alpha (1.22), Beta (1.19), Gamma (1.21), Delta (1.38) and Omicron (1.90) were reported from Japan, Belgium, the United States, France and South Africa, respectively. Nine out of ten epidemic curves with the highest estimated growth rates and reproduction numbers were due to the Omicron variant indicating the highest transmissibility. CONCLUSIONS: The transmissibility was highest in the Omicron variant followed by Delta, Alpha, Gamma and Beta respectively.

Epidemic dynamics with time-varying transmission risk reveal the role of disease stage-dependent infectiousness.

A key characteristic of acute communicable diseases is the infectiousness that varies over time as the infection dynamics evolve within a host, which influences the risk of transmission in different stages of the disease. Despite the evidence of time-varying transmission risk, most dynamic models of epidemics assume a constant transmission rate during the infectious period. Recent work has shown the difference in epidemic dynamics when this assumption is relaxed and different transmission rates are used by discretizing the infectious period into multiple sub-periods. Here, we develop an age-structured model to integrate a continuous time-varying transmission risk, based on an established correlation between the viral dynamics and infectiousness profile. Taking into account the natural history and parameter estimates of COVID-19 caused by the original strain of SARS-CoV-2, we demonstrate the difference in temporal epidemic dynamics when a continuous time-varying transmission probability is used as compared to multiple constant transmission probabilities. Our results show a significant difference between the incidence curves in terms of the magnitude and peak time, even when the reproduction number and total number of infections are the same for continuous and discrete transmission probabilities. Finally, we demonstrate the spurious outcome of preventing an epidemic through the isolation of infectious individuals when constant transmission probabilities are used, highlighting the importance of integrating a continuous time-dependent transmission parameter in dynamic models. These findings suggest a more cautious interpretation of model outcomes, especially those that are intended to evaluate the effectiveness of interventions and inform policy decisions for disease mitigation strategies.

Cooperative and structural relationships of the trimeric Spike with infectivity and antibody escape of the strains Delta (B.1.617.2) and Omicron (BA.2, BA.5, and BQ.1).

Herein, we conducted simulations of trimeric Spike from several SARS-CoV-2 variants of concern (Delta and Omicron sub-variants BA.2, BA.5, and BQ.1) and investigated the mechanisms by which specific mutations confer resistance to neutralizing antibodies. We observed that the mutations primarily affect the cooperation between protein domains within and between protomers. The substitutions K417N and L452R expand hydrogen bonding interactions, reducing their interaction with neutralizing antibodies. By interacting with nearby residues, the K444T and N460K mutations in the SpikeBQ.1 variant potentially reduces solvent exposure, thereby promoting resistance to antibodies. We also examined the impact of D614G, P681R, and P681H substitutions on Spike protein structure that may be related to infectivity. The D614G substitution influences communication between a glycine residue and neighboring domains, affecting the transition between up- and -down RBD states. The P681R mutation, found in the Delta variant, enhances correlations between protein subunits, while the P681H mutation in Omicron sub-variants weakens long-range interactions that may be associated with reduced fusogenicity. Using a multiple linear regression model, we established a connection between inter-protomer communication and loss of sensitivity to neutralizing antibodies. Our findings underscore the importance of structural communication between protein domains and provide insights into potential mechanisms of immune evasion by SARS-CoV-2. Overall, this study deepens our understanding of how specific mutations impact SARS-CoV-2 infectivity and shed light on how the virus evades the immune system.

Association between ozone and influenza transmissibility in China.

BACKGROUND: Common air pollutants such as ozone (O3), sulfur dioxide (SO2), nitrogen dioxide (NO2), and particulate matter play significant roles as influential factors in influenza-like illness (ILI). However, evidence regarding the impact of O3 on influenza transmissibility in multi-subtropical regions is limited, and our understanding of the effects of O3 on influenza transmissibility in temperate regions remain unknown. METHODS: We studied the transmissibility of influenza in eight provinces across both temperate and subtropical regions in China based on 2013 to 2018 provincial-level surveillance data on influenza-like illness (ILI) incidence and viral activity. We estimated influenza transmissibility by using the instantaneous reproduction number ([Formula: see text]) and examined the relationships between transmissibility and daily O3 concentrations, air temperature, humidity, and school holidays. We developed a multivariable regression model for [Formula: see text] to quantify the contribution of O3 to variations in transmissibility. RESULTS: Our findings revealed a significant association between O3 and influenza transmissibility. In Beijing, Tianjin, Shanghai and Jiangsu, the association exhibited a U-shaped trend. In Liaoning, Gansu, Hunan, and Guangdong, the association was L-shaped. When aggregating data across all eight provinces, a U-shaped association was emerged. O3 was able to accounted for up to 13% of the variance in [Formula: see text]. O3 plus other environmental drivers including mean daily temperature, relative humidity, absolute humidity, and school holidays explained up to 20% of the variance in [Formula: see text]. CONCLUSIONS: O3 was a significant driver of influenza transmissibility, and the association between O3 and influenza transmissibility tended to display a U-shaped pattern.

Possibility of mpox viral transmission and control from high-risk to the general population: a modeling study.

BACKGROUND: Mpox is an emerging infectious disease that is now a global hazard. The strategies for preventing and controlling mpox should be further investigated in terms of transmission characteristics, infection risk among different populations, and ideal therapeutic approaches. METHODS: A multi-group dynamic model was used to quantify the transmissibility of mpox. We further analyzed the transmission risk from men who have sex with men (MSM) to non-MSM and evaluated the effects of three intervention measures, including community-based prevention, early detection, and vaccination. RESULTS: The median value of effective reproduction number (Reff) and probability of contact via a single contact (q) among MSM worldwide is 3.11 (interquartile range [IQR]: 2.82-5.57) and 2.15% (IQR: 1.95-3.84%). We found that the cumulative incidence rate of non-MSM is much lower than that of MSM (< 1/2048) when the possibility of infection (including the percentage of high-risk behaviors of contact degree [C] and q) was lowered to less than 1 in 100,000. When comparing the three intervention measures, if we want to control the cumulative incidence rate to 5.96 × 10-8 we need to increase the vaccine coverage to 81% or reduce the transmission rate factor (Cq) to 70% or shorten the transmission period to 74%. CONCLUSIONS: Mpox has high transmissibility in MSM, which required minimize the risk of infection and exposure to high-risk populations. Community prevention and control is the top priority of interventions to contain the spread of mpox.