Comparing the age and sex trajectories of SARS-CoV-2 morbidity and mortality with other respiratory pathogens.

Comparing age and sex differences in SARS-CoV-2 hospitalization and mortality with MERS-CoV, seasonal coronaviruses, influenza and other health outcomes opens the way to generating hypotheses as to underlying mechanisms driving disease risk. Using 60-year-olds as a reference age group, we find that relative rates of hospitalization and mortality associated with the emergent coronaviruses are lower during childhood and start to increase earlier (around puberty) as compared with influenza and seasonal coronaviruses. The changing distribution of disease risk by age for emerging pathogens appears to broadly track the gradual deterioration of the immune system (immunosenescence), which starts around puberty. By contrast, differences in severe disease risk by age from endemic pathogens are more decoupled from the immune ageing process. Intriguingly, age-specific sex differences in hospitalizations are largely similar across endemic and emerging infections. We discuss potential mechanisms that may be associated with these patterns.

SARS-CoV-2 Outbreak Dynamics in an Isolated US Military Recruit Training Center With Rigorous Prevention Measures.

BACKGROUND: Marine recruits training at Parris Island experienced an unexpectedly high rate of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, despite preventive measures including a supervised, 2-week, pre-entry quarantine. We characterize SARS-CoV-2 transmission in this cohort. METHODS: Between May and November 2020, we monitored 2,469 unvaccinated, mostly male, Marine recruits prospectively during basic training. If participants tested negative for SARS-CoV-2 by quantitative polymerase chain reaction (qPCR) at the end of quarantine, they were transferred to the training site in segregated companies and underwent biweekly testing for 6 weeks. We assessed the effects of coronavirus disease 2019 (COVID-19) prevention measures on other respiratory infections with passive surveillance data, performed phylogenetic analysis, and modeled transmission dynamics and testing regimens. RESULTS: Preventive measures were associated with drastically lower rates of other respiratory illnesses. However, among the trainees, 1,107 (44.8%) tested SARS-CoV-2-positive, with either mild or no symptoms. Phylogenetic analysis of viral genomes from 580 participants revealed that all cases but one were linked to five independent introductions, each characterized by accumulation of mutations across and within companies, and similar viral isolates in individuals from the same company. Variation in company transmission rates (mean reproduction number R 0 ; 5.5 [95% confidence interval [CI], 5.0, 6.1]) could be accounted for by multiple initial cases within a company and superspreader events. Simulations indicate that frequent rapid-report testing with case isolation may minimize outbreaks. CONCLUSIONS: Transmission of wild-type SARS-CoV-2 among Marine recruits was approximately twice that seen in the community. Insights from SARS-CoV-2 outbreak dynamics and mutations spread in a remote, congregate setting may inform effective mitigation strategies.

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

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

Immuno-epidemiology and the predictability of viral evolution.

Understanding viral evolution depends on a synthesis of evolutionary biology and immuno-epidemiology.

The importance of the generation interval in investigating dynamics and control of new SARS-CoV-2 variants.

Inferring the relative strength (i.e. the ratio of reproduction numbers) and relative speed (i.e. the difference between growth rates) of new SARS-CoV-2 variants is critical to predicting and controlling the course of the current pandemic. Analyses of new variants have primarily focused on characterizing changes in the proportion of new variants, implicitly or explicitly assuming that the relative speed remains fixed over the course of an invasion. We use a generation-interval-based framework to challenge this assumption and illustrate how relative strength and speed change over time under two idealized interventions: a constant-strength intervention like idealized vaccination or social distancing, which reduces transmission rates by a constant proportion, and a constant-speed intervention like idealized contact tracing, which isolates infected individuals at a constant rate. In general, constant-strength interventions change the relative speed of a new variant, while constant-speed interventions change its relative strength. Differences in the generation-interval distributions between variants can exaggerate these changes and modify the effectiveness of interventions. Finally, neglecting differences in generation-interval distributions can bias estimates of relative strength.

Why do some coronaviruses become pandemic threats when others do not?

Despite multiple spillover events and short chains of transmission on at least 4 continents, Middle East Respiratory Syndrome Coronavirus (MERS-CoV) has never triggered a pandemic. By contrast, its relative, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has, despite apparently little, if any, previous circulation in humans. Resolving the unsolved mystery of the failure of MERS-CoV to trigger a pandemic could help inform how we understand the pandemic potential of pathogens, and probing it underscores a need for a more holistic understanding of the ways in which viral genetic changes scale up to population-level transmission.

The required size of cluster randomized trials of nonpharmaceutical interventions in epidemic settings.

To control the SARS-CoV-2 pandemic and future pathogen outbreaks requires an understanding of which nonpharmaceutical interventions are effective at reducing transmission. Observational studies, however, are subject to biases that could erroneously suggest an impact on transmission, even when there is no true effect. Cluster randomized trials permit valid hypothesis tests of the effect of interventions on community transmission. While such trials could be completed in a relatively short period of time, they might require large sample sizes to achieve adequate power. However, the sample sizes required for such tests in outbreak settings are largely undeveloped, leaving unanswered the question of whether these designs are practical. We develop approximate sample size formulae and simulation-based sample size methods for cluster randomized trials in infectious disease outbreaks. We highlight key relationships between characteristics of transmission and the enrolled communities and the required sample sizes, describe settings where trials powered to detect a meaningful true effect size may be feasible, and provide recommendations for investigators in planning such trials. The approximate formulae and simulation banks may be used by investigators to quickly assess the feasibility of a trial, followed by more detailed methods to more precisely size the trial. For example, we show that community-scale trials requiring 220 clusters with 100 tested individuals per cluster are powered to identify interventions that reduce transmission by 40% in one generation interval, using parameters identified for SARS-CoV-2 transmission. For more modest treatment effects, or when transmission is extremely overdispersed, however, much larger sample sizes are required.

Assessing the risk of vaccine-driven virulence evolution in SARS-CoV-2.

The evolution of SARS-CoV-2 virulence, or lethality, threatens to exacerbate the burden of COVID-19 on society. How might COVID-19 vaccines alter selection for increased SARS-CoV-2 virulence? Framing current evidence surrounding SARS-CoV-2 biology and COVID-19 vaccines in the context of evolutionary theory indicates that prospects for virulence evolution remain uncertain. However, differential effects of vaccinal immunity on transmission and disease severity between respiratory compartments could select for increased virulence. To bound expectations for this outcome, we analyse an evo-epidemiological model. Synthesizing model predictions with vaccine efficacy data, we conclude that while vaccine-driven virulence remains a theoretical possibility, the risk is low if vaccines provide sustained robust protection against infection. Furthermore, we found that any increases in transmission concomitant with increases in virulence would be unlikely to threaten prospects for herd immunity in a highly immunized population. Given that virulence evolution would nevertheless impact unvaccinated individuals and populations with low vaccination rates, it is important to achieve high vaccination rates worldwide and ensure that vaccinal immunity provides robust protection against both infection and disease, potentially through the use of booster doses.

The evolution of powerful yet perilous immune systems.

The mammalian immune system packs serious punch against infection but can also cause harm: for example, coronavirus disease 2019 (COVID-19) made headline news of the simultaneous power and peril of human immune responses. In principle, natural selection leads to exquisite adaptation and therefore cytokine responsiveness that optimally balances the benefits of defense against its costs (e.g., immunopathology suffered and resources expended). Here, we illustrate how evolutionary biology can predict such optima and also help to explain when/why individuals exhibit apparently maladaptive immunopathological responses. Ultimately, we argue that the evolutionary legacies of multicellularity and life-history strategy, in addition to our coevolution with symbionts and our demographic history, together explain human susceptibility to overzealous, pathology-inducing cytokine responses. Evolutionary insight thereby complements molecular/cellular mechanistic insights into immunopathology.

Existing human mobility data sources poorly predicted the spatial spread of SARS-CoV-2 in Madagascar.

For emerging epidemics such as the COVID-19 pandemic, quantifying travel is a key component of developing accurate predictive models of disease spread to inform public health planning. However, in many LMICs, traditional data sets on travel such as commuting surveys as well as non-traditional sources such as mobile phone data are lacking, or, where available, have only rarely been leveraged by the public health community. Evaluating the accuracy of available data to measure transmission-relevant travel may be further hampered by limited reporting of suspected and laboratory confirmed infections. Here, we leverage case data collected as part of a COVID-19 dashboard collated via daily reports from the Malagasy authorities on reported cases of SARS-CoV-2 across the 22 regions of Madagascar. We compare the order of the timing of when cases were reported with predictions from a SARS-CoV-2 metapopulation model of Madagascar informed using various measures of connectivity including a gravity model based on different measures of distance, Internal Migration Flow data, and mobile phone data. Overall, the models based on mobile phone connectivity and the gravity-based on Euclidean distance best predicted the observed spread. The ranks of the regions most remote from the capital were more difficult to predict but interestingly, regions where the mobile phone connectivity model was more accurate differed from those where the gravity model was most accurate. This suggests that there may be additional features of mobility or connectivity that were consistently underestimated using all approaches but are epidemiologically relevant. This work highlights the importance of data availability and strengthening collaboration among different institutions with access to critical data - models are only as good as the data that they use, so building towards effective data-sharing pipelines is essential.

A Global lmmunological Observatory to meet a time of pandemics.

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

Infectious disease in an era of global change.

The twenty-first century has witnessed a wave of severe infectious disease outbreaks, not least the COVID-19 pandemic, which has had a devastating impact on lives and livelihoods around the globe. The 2003 severe acute respiratory syndrome coronavirus outbreak, the 2009 swine flu pandemic, the 2012 Middle East respiratory syndrome coronavirus outbreak, the 2013-2016 Ebola virus disease epidemic in West Africa and the 2015 Zika virus disease epidemic all resulted in substantial morbidity and mortality while spreading across borders to infect people in multiple countries. At the same time, the past few decades have ushered in an unprecedented era of technological, demographic and climatic change: airline flights have doubled since 2000, since 2007 more people live in urban areas than rural areas, population numbers continue to climb and climate change presents an escalating threat to society. In this Review, we consider the extent to which these recent global changes have increased the risk of infectious disease outbreaks, even as improved sanitation and access to health care have resulted in considerable progress worldwide.

Characterizing human mobility patterns in rural settings of sub-Saharan Africa.

Human mobility is a core component of human behavior and its quantification is critical for understanding its impact on infectious disease transmission, traffic forecasting, access to resources and care, intervention strategies, and migratory flows. When mobility data are limited, spatial interaction models have been widely used to estimate human travel, but have not been extensively validated in low- and middle-income settings. Geographic, sociodemographic, and infrastructure differences may impact the ability for models to capture these patterns, particularly in rural settings. Here, we analyzed mobility patterns inferred from mobile phone data in four Sub-Saharan African countries to investigate the ability for variants on gravity and radiation models to estimate travel. Adjusting the gravity model such that parameters were fit to different trip types, including travel between more or less populated areas and/or different regions, improved model fit in all four countries. This suggests that alternative models may be more useful in these settings and better able to capture the range of mobility patterns observed.

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

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

A general model for the demographic signatures of the transition from pandemic emergence to endemicity.

Anticipating the medium- and long-term trajectory of pathogen emergence has acquired new urgency given the ongoing COVID-19 pandemic. For many human pathogens, the burden of disease depends on age and previous exposure. Understanding the intersection between human population demography and transmission dynamics is therefore critical. Here, we develop a realistic age-structured mathematical model that integrates demography, social mixing, and immunity to establish a plausible range for future age incidence and mortality. With respect to COVID-19, we identify a plausible transition in the age structure of risks once the disease reaches seasonal endemism across a range of immunity durations and relative severity of primary versus subsequent reinfections. We train the model using diverse real-world demographies and age-structured mixing to bound expectations for changing age incidence and disease burden. The mathematical framework is flexible and can help tailor mitigation strategies in countries worldwide with varying demographies and social mixing patterns.

Variation in SARS-CoV-2 outbreaks across sub-Saharan Africa.

A surprising feature of the SARS-CoV-2 pandemic to date is the low burdens reported in sub-Saharan Africa (SSA) countries relative to other global regions. Potential explanations (for example, warmer environments1, younger populations2-4) have yet to be framed within a comprehensive analysis. We synthesized factors hypothesized to drive the pace and burden of this pandemic in SSA during the period from 25 February to 20 December 2020, encompassing demographic, comorbidity, climatic, healthcare capacity, intervention efforts and human mobility dimensions. Large diversity in the probable drivers indicates a need for caution in interpreting analyses that aggregate data across low- and middle-income settings. Our simulation shows that climatic variation between SSA population centers has little effect on early outbreak trajectories; however, heterogeneity in connectivity, although rarely considered, is likely an important contributor to variance in the pace of viral spread across SSA. Our synthesis points to the potential benefits of context-specific adaptation of surveillance systems during the ongoing pandemic. In particular, characterizing patterns of severity over age will be a priority in settings with high comorbidity burdens and poor access to care. Understanding the spatial extent of outbreaks warrants emphasis in settings where low connectivity could drive prolonged, asynchronous outbreaks resulting in extended stress to health systems.

Lives saved with vaccination for 10 pathogens across 112 countries in a pre-COVID-19 world.

Background: Vaccination is one of the most effective public health interventions. We investigate the impact of vaccination activities for Haemophilus influenzae type b, hepatitis B, human papillomavirus, Japanese encephalitis, measles, Neisseria meningitidis serogroup A, rotavirus, rubella, Streptococcus pneumoniae, and yellow fever over the years 2000-2030 across 112 countries. Methods: Twenty-one mathematical models estimated disease burden using standardised demographic and immunisation data. Impact was attributed to the year of vaccination through vaccine-activity-stratified impact ratios. Results: We estimate 97 (95%CrI[80, 120]) million deaths would be averted due to vaccination activities over 2000-2030, with 50 (95%CrI[41, 62]) million deaths averted by activities between 2000 and 2019. For children under-5 born between 2000 and 2030, we estimate 52 (95%CrI[41, 69]) million more deaths would occur over their lifetimes without vaccination against these diseases. Conclusions: This study represents the largest assessment of vaccine impact before COVID-19-related disruptions and provides motivation for sustaining and improving global vaccination coverage in the future. Funding: VIMC is jointly funded by Gavi, the Vaccine Alliance, and the Bill and Melinda Gates Foundation (BMGF) (BMGF grant number: OPP1157270 / INV-009125). Funding from Gavi is channelled via VIMC to the Consortium's modelling groups (VIMC-funded institutions represented in this paper: Imperial College London, London School of Hygiene and Tropical Medicine, Oxford University Clinical Research Unit, Public Health England, Johns Hopkins University, The Pennsylvania State University, Center for Disease Analysis Foundation, Kaiser Permanente Washington, University of Cambridge, University of Notre Dame, Harvard University, Conservatoire National des Arts et Métiers, Emory University, National University of Singapore). Funding from BMGF was used for salaries of the Consortium secretariat (authors represented here: TBH, MJ, XL, SE-L, JT, KW, NMF, KAMG); and channelled via VIMC for travel and subsistence costs of all Consortium members (all authors). We also acknowledge funding from the UK Medical Research Council and Department for International Development, which supported aspects of VIMC's work (MRC grant number: MR/R015600/1).JHH acknowledges funding from National Science Foundation Graduate Research Fellowship; Richard and Peggy Notebaert Premier Fellowship from the University of Notre Dame. BAL acknowledges funding from NIH/NIGMS (grant number R01 GM124280) and NIH/NIAID (grant number R01 AI112970). The Lives Saved Tool (LiST) receives funding support from the Bill and Melinda Gates Foundation.This paper was compiled by all coauthors, including two coauthors from Gavi. Other funders had no role in study design, data collection, data analysis, data interpretation, or writing of the report. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.