Alison P. Galvani

Ecological and immunological determinants of influenza evolution

In pandemic and epidemic forms, influenza causes substantial, sometimes catastrophic, morbidity and mortality. Intense selection from the host immune system drives antigenic change in influenza A and B, resulting in continuous replacement of circulating strains with new variants able to re-infect hosts immune to earlier types. This ‘antigenic drift’ often requires a new vaccine to be formulated before each annual epidemic. However, given the high transmissibility and mutation rate of influenza, the constancy of genetic diversity within lineages over time is paradoxical. Another enigma is the replacement of existing strains during a global pandemic caused by ‘antigenic shift’—the introduction of a new avian influenza A subtype into the human population. Here we explore ecological and immunological factors underlying these patterns using a mathematical model capturing both realistic epidemiological dynamics and viral evolution at the sequence level. By matching model output to phylogenetic patterns seen in sequence data collected through global surveillance, we find that short-lived strain-transcending immunity is essential to restrict viral diversity in the host population and thus to explain key aspects of drift and shift dynamics.

Optimizing Influenza Vaccine Distribution

Rethinking Vaccine Distribution The distribution of vaccines is a complex issue lying at the intersection of public health, economics, and ethics and it cannot be decided in hindsight as an epidemic unfolds. Thus, mathematical modeling can be valuable for guiding policy, and Medlock and Galvani (p. 1705, published online 20 August) present an analysis of how to distribute influenza vaccine among different age groups in a way that will minimize transmission. Scenarios were developed for different outcomes that tell us what happens, in terms of numbers of infections, mortality, and cost, when various cohorts are targeted for vaccination under different epidemic conditions, and compare 1918- and 1957-like epidemics. The scenarios could apply equally well to antiviral drug distribution. The conclusion is that the current recommendations for vaccine distribution from the U.S. Centers for Disease Control and Prevention may need to be revised to include age-related patterns of transmission to minimize the impact of epidemic influenza. Age-related transmission patterns should be incorporated into vaccine distribution policy to minimize the impact of epidemics. The criteria to assess public health policies are fundamental to policy optimization. Using a model parametrized with survey-based contact data and mortality data from influenza pandemics, we determined optimal vaccine allocation for five outcome measures: deaths, infections, years of life lost, contingent valuation, and economic costs. We find that optimal vaccination is achieved by prioritization of schoolchildren and adults aged 30 to 39 years. Schoolchildren are most responsible for transmission, and their parents serve as bridges to the rest of the population. Our results indicate that consideration of age-specific transmission dynamics is paramount to the optimal allocation of influenza vaccines. We also found that previous and new recommendations from the U.S. Centers for Disease Control and Prevention both for the novel swine-origin influenza and, particularly, for seasonal influenza, are suboptimal for all outcome measures.

Evaluating plague and smallpox as historical selective pressures for the CCR5-Δ32 HIV-resistance allele

The high frequency, recent origin, and geographic distribution of the CCR5-Δ32 deletion allele together indicate that it has been intensely selected in Europe. Although the allele confers resistance against HIV-1, HIV has not existed in the human population long enough to account for this selective pressure. The prevailing hypothesis is that the selective rise of CCR5-Δ32 to its current frequency can be attributed to bubonic plague. By using a population genetic framework that takes into account the temporal pattern and age-dependent nature of specific diseases, we find that smallpox is more consistent with this historical role.

Epidemiology meets evolutionary ecology

The rapid expansion and increasing mobility of human populations make understanding the evolution of parasite virulence a public health priority. The potential for the swift evolution of virulence in response to changes in host ecology has motivated the integration of evolutionary ecology with epidemiological theory, as part of the emerging field of evolutionary epidemiology. Virulence is the product of complex interactions among evolutionary, ecological and epidemiological processes. Recent models that incorporate ideas from both evolutionary ecology and epidemiology generate predictions that could not be made by either discipline alone. These models predict that the ecological or evolutionary changes affecting population dynamics of disease, such as spatial structuring, within-host dynamics, polymorphism in host resistance, host longevity and population size, impose selection on virulence. As disease incidence increases, it becomes particularly important to take into account the implications of infection by multiple parasite strains. Evolutionary epidemic models also identify the potential importance of immune evasion and optimal virulence for the selection of sex in parasites. Thus, merging epidemiology with evolutionary ecology has widespread potential to help us answer evolutionary questions and to guide public health policy.

Group interest versus self-interest in smallpox vaccination policy

The recent threat of bioterrorism has fueled debate on smallpox vaccination policy for the United States. Certain policy proposals call for voluntary mass vaccination; however, if individuals decide whether to vaccinate according to self-interest, the level of herd immunity achieved may differ from what is best for the population as a whole. We present a synthesis of game theory and epidemic modeling that formalizes this conflict between self-interest and group interest and shows that voluntary vaccination is unlikely to reach the group-optimal level. This shortfall results in a substantial increase in expected mortality after an attack.

Long-standing influenza vaccination policy is in accord with individual self-interest but not with the utilitarian optimum

Influenza vaccination is vital for reducing infection-mediated morbidity and mortality. To maximize effectiveness, vaccination programs must anticipate the effects of public perceptions and attitudes on voluntary adherence. A vaccine allocation strategy that is optimal for the population is not necessarily optimal for an individual. For epidemic influenza, the elderly have the greatest risk of influenza mortality, yet children are responsible for most of the transmission. The long-standing recommendations of the Centers for Disease Control follow the dictates of individual self-interest and prioritize the elderly for vaccination. However, preferentially vaccinating children may dramatically reduce community-wide influenza transmission. A potential obstacle to this is that the personal utility of vaccination is lower for children than it is for the elderly. We parameterize an epidemiological game-theoretic model of influenza vaccination with questionnaire data on actual perceptions of influenza and its vaccine to compare Nash equilibria vaccination strategies driven by self-interest with utilitarian strategies for both epidemic and pandemic influenza. Our results reveal possible strategies to bring Nash and utilitarian vaccination levels into alignment.

Strategies for containing Ebola in West Africa.

The ongoing Ebola outbreak poses an alarming risk to the countries of West Africa and beyond. To assess the effectiveness of containment strategies, we developed a stochastic model of Ebola transmission between and within the general community, hospitals, and funerals, calibrated to incidence data from Liberia. We find that a combined approach of case isolation, contact-tracing with quarantine, and sanitary funeral practices must be implemented with utmost urgency in order to reverse the growth of the outbreak. As of 19 September, under status quo, our model predicts that the epidemic will continue to spread, generating a predicted 224 (134 to 358) daily cases by 1 December, 280 (184 to 441) by 15 December, and 348 (249 to 545) by 30 December. A combination of hygienic practices could feasibly check Ebola within 6 months. Recharging Ebola mitigation measures Effective drugs and vaccines for Ebola virus are not available, so what can be done? Pandey et al. used a mathematical model to analyze transmission in different scenarios: the community, hospitals, and at funerals. Achieving full compliance with any single control measure, such as case isolation, is impossible under prevailing conditions. However, with a minimum of 60% compliance, a combination of case isolation, hygienic burial, and contact tracing could reduce daily case numbers to single figures in 5 to 6 months. Success will also require persistence and sensitivity to local customs. Science, this issue p. 991

Epidemiology: Dimensions of superspreading

Analyses of contact-tracing data on the spread of infectious disease, combined with mathematical models, show that control measures require better knowledge of variability in individual infectiousness.Coughs and sneezes...From Typhoid Mary to SARS, it has long been known that some people spread disease more than others. But for diseases transmitted via casual contact, contagiousness arises from a plethora of social and physiological factors, so epidemiologists have tended to rely on population averages to assess a diseases potential to spread. A new analysis of outbreak data shows that individual differences in infectiousness exert powerful influences on the epidemiology of ten deadly diseases. SARS and measles (and perhaps avian influenza) show strong tendencies towards ‘superspreading events’ that can ignite explosive epidemics — but this same volatility makes outbreaks more likely to fizzle out. Smallpox and pneumonic plague, two potential bioterrorism agents, show steadier growth but still differ markedly from the traditional average-based view. These findings are relevant to how emerging diseases are detected and controlled.

Prevention of nosocomial transmission of extensively drug-resistant tuberculosis in rural South African district hospitals: an epidemiological modelling study

BACKGROUND Extensively drug-resistant (XDR) tuberculosis has spread among hospitalised patients in South Africa, but the epidemic-level effect of hospital-based infection control strategies remains unknown. We modelled the plausible effect of rapidly available infection control strategies on the overall course of the XDR tuberculosis epidemic in a rural area of South Africa. METHODS We investigated the effect of administrative, environmental, and personal infection control measures on the epidemic trajectory of XDR tuberculosis in the rural community of Tugela Ferry. Assessments were done with a mathematical model incorporating over 2 years of longitudinal inpatient and community-based data. The model simulated inpatient airborne tuberculosis transmission, community tuberculosis transmission, and the effect of HIV and antiretroviral therapy. FINDINGS If no new interventions are introduced, about 1300 cases of XDR tuberculosis are predicted to occur in the area of Tugela Ferry by the end of 2012, more than half of which are likely to be nosocomially transmitted. Mask use alone would avert fewer than 10% of cases in the overall epidemic, but could prevent a large proportion of cases of XDR tuberculosis in hospital staff. The combination of mask use with reduced hospitalisation time and a shift to outpatient therapy could prevent nearly a third of XDR tuberculosis cases. Supplementing this approach with improved ventilation, rapid drug resistance testing, HIV treatment, and tuberculosis isolation facilities could avert 48% of XDR tuberculosis cases (range 34-50%) by the end of 2012. However, involuntary detention could result in an unexpected rise in incidence due to restricted isolation capacity. INTERPRETATION A synergistic combination of available nosocomial infection control strategies could prevent nearly half of XDR tuberculosis cases, even in a resource-limited setting. XDR tuberculosis transmission will probably continue in the community, indicating the need to develop and implement parallel community-based programmes.

Dynamics and control of Ebola virus transmission in Montserrado, Liberia: a mathematical modelling analysis

BACKGROUND A substantial scale-up in public health response is needed to control the unprecedented Ebola virus disease (EVD) epidemic in west Africa. Current international commitments seek to expand intervention capacity in three areas: new EVD treatment centres, case ascertainment through contact tracing, and household protective kit allocation. We aimed to assess how these interventions could be applied individually and in combination to avert future EVD cases and deaths. METHODS We developed a transmission model of Ebola virus that we fitted to reported EVD cases and deaths in Montserrado County, Liberia. We used this model to assess the effectiveness of expanding EVD treatment centres, increasing case ascertainment, and allocating protective kits for controlling the outbreak in Montserrado. We varied the efficacy of protective kits from 10% to 50%. We compared intervention initiation on Oct 15, 2014, Oct 31, 2014, and Nov 15, 2014. The status quo intervention was defined in terms of case ascertainment and capacity of EVD treatment centres on Sept 23, 2014, and all behaviour and contact patterns relevant to transmission as they were occurring at that time. The primary outcome measure was the expected number of cases averted by Dec 15, 2014. FINDINGS We estimated the basic reproductive number for EVD in Montserrado to be 2·49 (95% CI 2·38-2·60). We expect that allocating 4800 additional beds at EVD treatment centres and increasing case ascertainment five-fold in November, 2014, can avert 77 312 (95% CI 68 400-85 870) cases of EVD relative to the status quo by Dec 15, 2014. Complementing these measures with protective kit allocation raises the expectation as high as 97 940 (90 096-105 606) EVD cases. If deployed by Oct 15, 2014, equivalent interventions would have been expected to avert 137 432 (129 736-145 874) cases of EVD. If delayed to Nov 15, 2014, we expect the interventions will at best avert 53 957 (46 963-60 490) EVD cases. INTERPRETATION The number of beds at EVD treatment centres needed to effectively control EVD in Montserrado substantially exceeds the 1700 pledged by the USA to west Africa. Accelerated case ascertainment is needed to maximise effectiveness of expanding the capacity of EVD treatment centres. Distributing protective kits can further augment prevention of EVD, but it is not an adequate stand-alone measure for controlling the outbreak. Our findings highlight the rapidly closing window of opportunity for controlling the outbreak and averting a catastrophic toll of EVD cases and deaths. FUNDING US National Institutes of Health.