Prospective malaria control using entomopathogenic fungi: comparative evaluation of impact on transmission and selection for resistance

Background Chemical insecticides against adult mosquitoes are a key element in most malaria management programmes, but their efficacy is threatened by the evolution of insecticide-resistant mosquitoes. By killing only older mosquitoes, entomopathogenic fungi can in principle significantly impact parasite transmission while imposing much less selection for resistance. Here an assessment is made as to which of the wide range of possible virulence characteristics for fungal biopesticides best realise this potential. Methods With mathematical models that capture relevant timings and survival probabilities within successive feeding cycles, transmission and resistance-management metrics are used to compare susceptible and resistant mosquitoes exposed to no intervention, to conventional instant-kill interventions, and to delayed-action biopesticides with a wide range of virulence characteristics. Results Fungal biopesticides that generate high rates of mortality at around the time mosquitoes first become able to transmit the malaria parasite offer potential for large reductions in transmission while imposing low fitness costs. The best combinations of control and resistance management are generally accessed at high levels of coverage. Strains which have high virulence in malaria-infected mosquitoes but lower virulence in malaria-free mosquitoes offer the ultimate benefit in terms of minimizing selection pressure whilst maximizing impact on transmission. Exploiting this phenotype should be a target for product development. For indoor residual spray programmes, biopesticides may offer substantial advantages over the widely used pyrethroid-based insecticides. Not only do fungal biopesticides provide substantial resistance management gains in the long term, they may also provide greater reductions in transmission before resistance has evolved. This is because fungal spores do not have contact irritancy, reducing the chances that a blood-fed mosquito can survive an encounter and thus live long enough to transmit malaria. Conclusions Delayed-action products, such as fungal biopesticides, have the potential to achieve reductions in transmission comparable with those achieved with existing instant-kill insecticides, and to sustain this control for substantially longer once resistant alleles arise. Given the current insecticide resistance crisis, efforts should continue to fully explore the operational feasibility of this alternative approach.

The probability of surviving to the start of cycle i with an existing malaria infection, and no biopesticide infection, , ,0 i m v , is the probability of surviving, with a malaria infection but no biopesticide infection, to the start of the previous cycle, and then surviving biting a non-human host or biting a human host without becoming infected by a biopesticide, and then surviving through laying.
      , ,0 1, 1,0 1, 1,0,1 1, 1,0,2 1, 1,0,3 1 1, 1 1 1 The probability of surviving to the start of cycle i with no malaria infection, and a newly acquired biopesticide infection, ,0,1 i v , is the probability of surviving, with no malaria or biopesticide infection, to the start of the previous cycle, and then surviving biting a human host, not acquiring a malaria infection and becoming infected by a biopesticide, and then surviving through laying, without being killed by any rapid biopesticide mortality.      ,0,1 1,0,0 1,0,0,2 1,0,0,3 1 1,0 1 1 The probability of surviving to the start of cycle i with an existing malaria infection, and a newly acquired biopesticide infection, , , i m l v , is the probability of surviving, with a malaria infection but no biopesticide infection, to the start of the previous cycle, surviving biting a human host and becoming infected by a biopesticide, and then surviving through laying, without being killed by any rapid biopesticide mortality.

  
, ,1 1, 1,0 1, 1,0,2 1, 1,0,3 1 1, 1 The probability of surviving to the start of cycle i with no malaria infection, and an existing biopesticide infection, ,0, i l v , is the probability of surviving, with no malaria infection and an existing biopesticide infection, to the start of the previous cycle, and then surviving biting a non-human host or biting a human host without acquiring a malaria infection, then surviving through laying, with survival probabilities reflecting additional mortality from the biopesticide infection.

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    , , 1, 1, 1 1, 1, 1,1 1, 1, 1,2 1, 1, 1,3 1 1, 1, 1 The probabilities of surviving through cycle i are calculated as follows. The average probability, , , i m l s , that mosquitoes starting cycle i with any malaria status and an existing biopesticide infection, will survive to the start of cycle i + 1 is calculated as the probability of surviving biting a non-human host, plus the probability of biting a human host without being killed by conventional instant-kill insecticides, and then surviving to lay.

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The average probability, , ,0 i m s , that mosquitoes starting cycle i with any malaria status and no biopesticide infection, will survive to the start of cycle i + 1 is calculated as the probability of surviving biting a non-human host, plus the probability of biting a human host without being killed by conventional instant-kill insecticides, and then either not acquiring a biopesticide infection, or acquiring a biopesticide infection but not being killed by the biopesticide before the end of the cycle, and then surviving to lay.
The probabilities of surviving host seeking and biting in cycle i, , , ,