Can ship travel contain COVID-19 outbreak after re-opening: a Bayesian meta-analysis.

Large gatherings of people on cruise ships and warships are often at high risk of COVID-19 infections. To assess the transmissibility of SARS-CoV-2 on warships and cruise ships and to quantify the effectiveness of the containment measures, the transmission coefficient (ß), basic reproductive number (R0), and time to deploy containment measures were estimated by the Bayesian Susceptible-Exposed-Infected-Recovered model. A meta-analysis was conducted to predict vaccine protection with or without non-pharmaceutical interventions (NPIs). The analysis showed that implementing NPIs during voyages could reduce the transmission coefficients of SARS-CoV-2 by 50%. Two weeks into the voyage of a cruise that begins with 1 infected passenger out of a total of 3,711 passengers, we estimate there would be 45 (95% CI:25-71), 33 (95% CI:20-52), 18 (95% CI:11-26), 9 (95% CI:6-12), 4 (95% CI:3-5), and 2 (95% CI:2-2) final cases under 0%, 10%, 30%, 50%, 70%, and 90% vaccine protection, respectively, without NPIs. The timeliness of strict NPIs along with implementing strict quarantine and isolation measures is imperative to contain COVID-19 cases in cruise ships. The spread of COVID-19 on ships was predicted to be limited in scenarios corresponding to at least 70% protection from prior vaccination, across all passengers and crew.

Potential impact of individual exposure histories to endemic human coronaviruses on age-dependent severity of COVID-19.

BACKGROUND: Cross-reactivity to SARS-CoV-2 from exposure to endemic human coronaviruses (eHCoV) is gaining increasing attention as a possible driver of both protection against infection and COVID-19 severity. Here we explore the potential role of cross-reactivity induced by eHCoVs on age-specific COVID-19 severity in a mathematical model of eHCoV and SARS-CoV-2 transmission. METHODS: We use an individual-based model, calibrated to prior knowledge of eHCoV dynamics, to fully track individual histories of exposure to eHCoVs. We also model the emergent dynamics of SARS-CoV-2 and the risk of hospitalisation upon infection. RESULTS: We hypothesise that primary exposure with any eHCoV confers temporary cross-protection against severe SARS-CoV-2 infection, while life-long re-exposure to the same eHCoV diminishes cross-protection, and increases the potential for disease severity. We show numerically that our proposed mechanism can explain age patterns of COVID-19 hospitalisation in EU/EEA countries and the UK. We further show that some of the observed variation in health care capacity and testing efforts is compatible with country-specific differences in hospitalisation rates under this model. CONCLUSIONS: This study provides a "proof of possibility" for certain biological and epidemiological mechanisms that could potentially drive COVID-19-related variation across age groups. Our findings call for further research on the role of cross-reactivity to eHCoVs and highlight data interpretation challenges arising from health care capacity and SARS-CoV-2 testing.

Estimating the false-negative test probability of SARS-CoV-2 by RT-PCR.

BackgroundReverse-transcription PCR (RT-PCR) assays are used to test for infection with the SARS-CoV-2 virus. RT-PCR tests are highly specific and the probability of false positives is low, but false negatives are possible depending on swab type and time since symptom onset.AimTo determine how the probability of obtaining a false-negative test in infected patients is affected by time since symptom onset and swab type.MethodsWe used generalised additive mixed models to analyse publicly available data from patients who received multiple RT-PCR tests and were identified as SARS-CoV-2 positive at least once.ResultsThe probability of a positive test decreased with time since symptom onset, with oropharyngeal (OP) samples less likely to yield a positive result than nasopharyngeal (NP) samples. The probability of incorrectly identifying an uninfected individual due to a false-negative test was considerably reduced if negative tests were repeated 24 hours later. For a small false-positive test probability (<0.5%), the true number of infected individuals was larger than the number of positive tests. For a higher false-positive test probability, the true number of infected individuals was smaller than the number of positive tests.ConclusionNP samples are more sensitive than OP samples. The later an infected individual is tested after symptom onset, the less likely they are to test positive. This has implications for identifying infected patients, contact tracing and discharging convalescing patients who are potentially still infectious.

Contact between bird species of different lifespans can promote the emergence of highly pathogenic avian influenza strains.

Outbreaks of highly pathogenic strains of avian influenza viruses (AIVs) cause considerable economic losses to the poultry industry and also pose a threat to human life. The possibility that one of these strains will evolve to become transmissible between humans, sparking a major influenza pandemic, is a matter of great concern. Most studies so far have focused on assessing these odds from the perspective of the intrinsic mutability of AIV rather than the ecological constraints to invasion faced by the virus population. Here we present an alternative multihost model for the evolution of AIV in which the mode and tempo of mutation play a limited role, with the emergence of strains being determined instead principally by the prevailing profile of population-level immunity. We show that (i) many of the observed differences in influenza virus dynamics among species can be captured by our model by simply varying host lifespan and (ii) increased contact between species of different lifespans can promote the emergence of potentially more virulent strains that were hitherto suppressed in one of the species.

Antibody responses to avian influenza viruses in wild birds broaden with age.

For viruses such as avian influenza, immunity within a host population can drive the emergence of new strains by selecting for viruses with novel antigens that avoid immune recognition. The accumulation of acquired immunity with age is hypothesized to affect how influenza viruses emerge and spread in species of different lifespans. Despite its importance for understanding the behaviour of avian influenza viruses, little is known about age-related accumulation of immunity in the virus's primary reservoir, wild birds. To address this, we studied the age structure of immune responses to avian influenza virus in a wild swan population (Cygnus olor), before and after the population experienced an outbreak of highly pathogenic H5N1 avian influenza in 2008. We performed haemagglutination inhibition assays on sampled sera for five avian influenza strains and show that breadth of response accumulates with age. The observed age-related distribution of antibody responses to avian influenza strains may explain the age-dependent mortality observed during the highly pathogenic H5N1 outbreak. Age structures and species lifespan are probably important determinants of viral epidemiology and virulence in birds.

MANTIS: an R package that simulates multilocus models of pathogen evolution.

BACKGROUND: In host-pathogen systems the development of immunity by the host places pressure on pathogens, by setting up competition between genetic variants due to the establishment of cross-protective responses. These pressures can lead to pathogen-specific, ubiquitous dynamic behaviours. Understanding the evolutionary forces that shape these patterns is one of the key goals of computationally simulated epidemiological models. Despite the contribution of such research methods in recent years to our current understanding of pathogen evolution, the availability of free software tools for the general public remains scarce. RESULTS: We developed the Multilocus ANTIgenic Simulator (MANTIS) software package for the R statistical environment. MANTIS can simulate and analyse epidemiological time-series generated under the biological assumptions of the strain theory of host-pathogen systems by Gupta et al. CONCLUSIONS: MANTIS wraps a C/C++ ordinary-differential equations system and Runge-Kutta solver into a set of user-friendly R functions. These include routines to numerically simulate the system and others to analyse, visualize and export results. For this, the package offers its own set of time-series plotting and exportation functions. MANTIS's main goal is to serve as a free, ready-to-use academic software tool. Its open source nature further provides an opportunity for users with advanced programming skills to expand its capabilities. Here, we describe the background theory, implementation, basic functionality and usage of this package. MANTIS is freely available from http://www.eeid.ox.ac.uk/mantis under the GPL license.

Influenza outbreaks.

Influenza is a virus that causes considerable morbidity and mortality in human populations every year. This fact, coupled with its perceived pandemic potential, means that influenza features prominently in both scientific literature and the media. In this review we focus on the biological assumptions behind theoretical attempts to understand the seasonal and evolutionary dynamics of influenza through mathematical modelling and suggest that the largely unchallenged dogma upon which most efforts are currently based is sorely lacking.

Reverse immunodynamics: a new method for identifying targets of protective immunity.

Despite a dramatic increase in our ability to catalogue variation among pathogen genomes, we have made far fewer advances in using this information to identify targets of protective immunity. Epidemiological models predict that strong immune selection can cause antigenic variants to structure into genetically discordant sets of antigenic types (e.g. serotypes). A corollary of this theory is that targets of immunity may be identified by searching for non-overlapping associations of amino acids among co-circulating antigenic variants. We propose a novel population genetics methodology that combines such predictions with phylogenetic analyses to identify genetic loci (epitopes) under strong immune selection. We apply this concept to the AMA-1 protein of the malaria parasite Plasmodium falciparum and find evidence of epitopes among certain regions of low variability which could render them ideal vaccine candidates. The proposed method can be applied to a myriad of multi-strain pathogens for which vast amounts of genetic data has been collected in recent years.

Impact of Comorbidity on Fatality Rate of Patients with Middle East Respiratory Syndrome.

To date, 1841 cases of Middle East respiratory syndrome coronavirus (MERS-CoV) infection have been reported worldwide, with 652 deaths. We used a publically available case line list to explore the effect of relevant factors, notably underlying comorbidities, on fatal outcome of Middle East respiratory syndrome (MERS) cases up to the end of October 2016. A Bayesian Weibull proportional hazards regression model was used to assess the effect of comorbidity, age, epidemic period and sex on the fatality rate of MERS cases and its variation across countries. The crude fatality rate of MERS cases was 32.1% (95% credibility interval (CI): 29.9%, 34.3%). Notably, the incremental change of daily death rate was most prominent during the first week since disease onset with an average increase of 13%, but then stabilized in the remaining two weeks when it only increased 3% on average. Neither sex, nor country of infection were found to have a significant impact on fatality rates after taking into account the age and comorbidity status of patients. After adjusting for age, epidemic period, MERS patients with comorbidity had around 4 times the risk for fatal infection than those without (adjusted hazard ratio of 3.74 (95% CI: 2.57, 5.67)).

Relationship between haemagglutination inhibition titre and immunity to influenza in ferrets.

Our understanding of the antigenic evolution of the human influenza virus is chiefly derived from experiments in which serum from influenza infected ferrets is tested against panels of virus isolates in the haemagglutination inhibition (HI) assay. The interpretation of these results has been much aided by the development of antigenic mapping techniques, which suppose that the antigenic distance between two different influenza viruses is directly proportional to their fold-difference in titre in this assay. Yet, antigenic distance is not necessarily the same as cross-protection, and high levels of protection have been observed in humans against strains to which they have low HI titres. However, no study has previously addressed the relationship between HI titre and cross-protection in ferrets: the standard animal model. This study fills this gap by analysing published data where pre-challenge HI titres are available for individual ferrets, and post-challenge outcomes have been recorded. Ultimately, this work confirms that it is the absolute, rather than relative, HI titre that determines the extent of immunity and that there is a threshold HI titre beyond which ferrets are completely protected from infection. Nevertheless, this titre is much higher in ferrets than has been suggested for humans. Further, we are consequently able to show that using distance between strains within an antigenic map to predict cross-protection between influenza viruses can be misleading.

Five challenges in modelling interacting strain dynamics.

Population epidemiological models where hosts can be infected sequentially by different strains have the potential to help us understand many important diseases. Researchers have in recent years started to develop and use such models, but the extra layer of complexity from multiple strains brings with it many technical challenges. It is therefore hard to build models which have realistic assumptions yet are tractable. Here we outline some of the main challenges in this area. First we begin with the fundamental question of how to translate from complex small-scale dynamics within a host to useful population models. Next we consider the nature of so-called "strain space". We describe two key types of host heterogeneities, and explain how models could help generate a better understanding of their effects. Finally, for diseases with many strains, we consider the challenge of modelling how immunity accumulates over multiple exposures.

Effects of neutralizing antibodies on escape from CD8+ T-cell responses in HIV-1 infection.

Despite substantial advances in our knowledge of immune responses against HIV-1 and of its evolution within the host, it remains unclear why control of the virus eventually breaks down. Here, we present a new theoretical framework for the infection dynamics of HIV-1 that combines antibody and CD8(+) T-cell responses, notably taking into account their different lifespans. Several apparent paradoxes in HIV pathogenesis and genetics of host susceptibility can be reconciled within this framework by assigning a crucial role to antibody responses in the control of viraemia. We argue that, although escape from or progressive loss of quality of CD8(+) T-cell responses can accelerate disease progression, the underlying cause of the breakdown of virus control is the loss of antibody induction due to depletion of CD4(+) T cells. Furthermore, strong antibody responses can prevent CD8(+) T-cell escape from occurring for an extended period, even in the presence of highly efficacious CD8(+) T-cell responses.

The antigenic evolution of influenza: drift or thrift?

It is commonly assumed that antibody responses against the influenza virus are polarized in the following manner: strong antibody responses are directed at highly variable antigenic epitopes, which consequently undergo 'antigenic drift', while weak antibody responses develop against conserved epitopes. As the highly variable epitopes are in a constant state of flux, current antibody-based vaccine strategies are focused on the conserved epitopes in the expectation that they will provide some level of clinical protection after appropriate boosting. Here, we use a theoretical model to suggest the existence of epitopes of low variability, which elicit a high degree of both clinical and transmission-blocking immunity. We show that several epidemiological features of influenza and its serological and molecular profiles are consistent with this model of 'antigenic thrift', and that identifying the protective epitopes of low variability predicted by this model could offer a more viable alternative to regularly update the influenza vaccine than exploiting responses to weakly immunogenic conserved regions.

The effects of tertiary and quaternary infections on the epidemiology of dengue.

The epidemiology of dengue is characterised by irregular epidemic outbreaks and desynchronised dynamics of its four co-circulating virus serotypes. Whilst infection by one serotype appears to convey life-long protection to homologous infection, it is believed to be a risk factor for severe disease manifestations upon secondary, heterologous infection due to the phenomenon of Antibody-Dependent Enhancement (ADE). Subsequent clinical infections are rarely reported and, since the majority of dengue infections are generally asymptomatic, it is not clear if and to what degree tertiary or quaternary infections contribute to dengue epidemiology. Here we investigate the effect of third and subsequent infections on the transmission dynamics of dengue and show that although the qualitative patterns are largely equivalent, the system more readily exhibits the desynchronised serotype oscillations and multi-annual epidemic outbreaks upon their inclusion. More importantly, permitting third and fourth infections significantly increases the force of infection without resorting to high basic reproductive numbers. Realistic age-prevalent patterns and seroconversion rates are therefore easier reconciled with a low value of dengue's transmission potential if allowing for more than two infections; this should have important consequences for dengue control and intervention measures.