Abstract
We present a method to measure the relative transmissibility (“transmission fitness”) of one strain of a pathogen compared to another. The model is applied to data from “competitive mixtures” experiments in which animals are co-infected with a mixture of two strains. We observe the mixture in each animal over time and over multiple generations of transmission. We use data from influenza experiments in ferrets to demonstrate the approach. Assessment of the relative transmissibility between two strains of influenza is important in at least three contexts: 1) Within the human population antigenically novel strains of influenza arise and compete for susceptible hosts. 2) During a pandemic event, a novel sub-type of influenza competes with the existing seasonal strain(s). The unfolding epidemiological dynamics are dependent upon both the population's susceptibility profile and the inherent transmissibility of the novel strain compared to the existing strain(s). 3) Neuraminidase inhibitors (NAIs), while providing significant potential to reduce transmission of influenza, exert selective pressure on the virus and so promote the emergence of drug-resistant strains. Any adverse outcome due to selection and subsequent spread of an NAI-resistant strain is exquisitely dependent upon the transmission fitness of that strain. Measurement of the transmission fitness of two competing strains of influenza is thus of critical importance in determining the likely time-course and epidemiology of an influenza outbreak, or the potential impact of an intervention measure such as NAI distribution. The mathematical framework introduced here also provides an estimate for the size of the transmitted inoculum. We demonstrate the framework's behaviour using data from ferret transmission studies, and through simulation suggest how to optimise experimental design for assessment of transmissibility. The method introduced here for assessment of mixed transmission events has applicability beyond influenza, to other viral and bacterial pathogens.
Highlights
Under the selective pressure from the host immune system on the influenza haemagglutinin (HA) and the ecological environment, antigenically novel HA ‘drift variants’ of influenza A (IAV) generated by random mutation during replication emerge and circulate in the human population
We re-iterate that our use of data from the contact transmission study [8] is to demonstrate proof-of-principle, and that our results cannot be seen as definitive for the particular influenza virus pair used in that experiment, due to the small number of observed transmission events and some of the limitations as discussed earlier in Section Effects due to data ascertainment limitations
We predict that an average 3.8 virions were responsible for each transmission event, with a variance for our estimate of 5.9, but we caution that this estimate is based on an assumption of data recorded without error
Summary
Under the selective pressure from the host immune system on the influenza haemagglutinin (HA) and the ecological environment, antigenically novel HA ‘drift variants’ of influenza A (IAV) generated by random mutation during replication emerge and circulate in the human population. Intermittent cross-species transmission and/or re-assortment events have the potential to generate antigenically novel (at least for the HA and NA genes) mutant strains of IAV. If transmissible such strains have pandemic potential [1]. As seen in 1918/19, 1957 and 1968, following a brief period of co-circulation with the existing seasonal strain, the pandemic strain typically drives to extinction the previously circulating seasonal variant, to which there is greater prior immunity. In 2010, indications are that the 2009 pandemic H1N1 has replaced the seasonal H1N1 but not the seasonal H3N2 [1,2]
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