Risks of releasing imperfect Wolbachia strains for arbovirus control

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Arboviruses remain some of the most persistent public health threats globally, with over 100 million infections annually from pathogens such as dengue, chikungunya, and Zika viruses.1Stanaway JD Shepard DS Undurraga EA et al.The global burden of dengue: an analysis from the Global Burden of Disease Study 2013.Lancet Infect Dis. 2016; 16: 712-723Summary Full Text Full Text PDF PubMed Scopus (740) Google Scholar,2Puntasecca CJ King CH LaBeaud AD Measuring the global burden of chikungunya and Zika viruses: a systematic review.PLoS Negl Trop Dis. 2021; 15e0009055Crossref PubMed Scopus (79) Google Scholar After decades with few effective tools to combat the spread of arboviruses, Wolbachia has emerged as a transformative technology to combat multiple arboviral threats concurrently.3Utarini A Indriani C Ahmad RA et al.Efficacy of Wolbachia-infected mosquito deployments for the control of dengue.N Engl J Med. 2021; 384: 2177-2186Crossref PubMed Scopus (233) Google Scholar Wolbachia is a bacterium found in approximately half of the insect species but not in Aedes aegypti in the wild.4Ross PA Callahan AG Yang Q et al.An elusive endosymbiont: does Wolbachia occur naturally in Aedes aegypti?.Ecol Evol. 2020; 10: 1581-1591Crossref PubMed Scopus (55) Google Scholar,5Weinert LA Araujo-Jnr-Jnr EV Ahmed MZ Welch JJ The incidence of bacterial endosymbionts in terrestrial arthropods.Proc Biol Sci. 2015; 28220150249PubMed Google Scholar However, when Ae aegypti mosquitoes are infected with Wolbachia in the laboratory, their ability to transmit arboviruses is impaired. For example, in mosquitoes infected with the wMel strain of Wolbachia, at least 90% reduction in vector competence for dengue viruses was observed.6Walker T Johnson PH Moreira LA et al.The wMel Wolbachia strain blocks dengue and invades caged Aedes aegypti populations.Nature. 2011; 476: 450-453Crossref PubMed Scopus (934) Google Scholar Further, when Wolbachia-infected Ae aegypti males mate with wild-type mosquitoes, the offspring do not survive. Wolbachia-infected females will transmit the bacterium to the next generation (reproductive advantage), resulting in the spread of Wolbachia through the population. These findings have led to large field trials and planned deployments worldwide. A randomised controlled trial in Indonesia showed that the release of Wolbachia-infected mosquitoes led to a 77% drop in dengue cases in the release zones.3Utarini A Indriani C Ahmad RA et al.Efficacy of Wolbachia-infected mosquito deployments for the control of dengue.N Engl J Med. 2021; 384: 2177-2186Crossref PubMed Scopus (233) Google Scholar Almost all the releases to date have been done using local mosquito strains infected with the Wolbachia strain wMel; however, not all these releases have been successful. The wMel strain was unable to penetrate local mosquitoes in Tri Nguyen, Viet Nam, and resulted only with intermediate levels of introgression in Rio de Janeiro, Brazil, despite the release of over 70 million insects.7Nguyen TH Nguyen HL Nguyen TY et al.Field evaluation of the establishment potential of wMelPop Wolbachia in Australia and Vietnam for dengue control.Parasit Vectors. 2015; 8: 563Crossref PubMed Google Scholar,8Ribeiro dos Santos G Durovni B Saraceni V et al.Estimating the effect of the wMel release programme on the incidence of dengue and chikungunya in Rio de Janeiro, Brazil: a spatiotemporal modelling study.Lancet Infect Dis. 2022; 22: 1587-1595Summary Full Text Full Text PDF PubMed Scopus (20) Google Scholar The reason why introgression succeeds in some regions and not others remains unclear, but temperature is probably a crucial factor that affects introgression.9Hien NT Anh DD Le NH et al.Environmental factors influence the local establishment of Wolbachia in Aedes aegypti mosquitoes in two small communities in central Vietnam.Gates Open Res. 2021; 5: 147Crossref PubMed Google Scholar High temperatures lower the density of Wolbachia in mosquito cells, which can reduce both the vertical transmission of Wolbachia to offspring and the reproductive incompatibility maintaining Wolbachia in populations.10Ulrich JN Beier JC Devine GJ Hugo LE Heat sensitivity of wMel Wolbachia during Aedes aegypti development.PLoS Negl Trop Dis. 2016; 10e0004873Crossref PubMed Scopus (64) Google Scholar,11Ross PA Axford JK Yang Q et al.Heatwaves cause fluctuations in wMel Wolbachia densities and frequencies in Aedes aegypti.PLoS Negl Trop Dis. 2020; 14e0007958Crossref Scopus (57) Google Scholar These observations have led to the consideration of the use of other Wolbachia strains for future release programmes; for example, wAlbB has been successfully trialled in Malaysia.12Nazni WA Hoffmann AA NoorAfizah A et al.Establishment of Wolbachia strain wAlbB in Malaysian populations of Aedes aegypti for dengue control.Curr Biol. 2019; 29: 4241-4248.e5Summary Full Text Full Text PDF PubMed Scopus (200) Google Scholar Although new Wolbachia strains might lead to increased chances of successful introgression from release programmes, we argue that the choice of Wolbachia strain used in the releases should be considered carefully. Successfully introgressed Wolbachia appear excellent at persisting. Nearly all mosquitoes in Cairns, Australia, still carry Wolbachia, more than 9 years after the completion of the first release programme.13Ross PA Robinson KL Yang Q et al.A decade of stability for wMel Wolbachia in natural Aedes aegypti populations.PLoS Pathog. 2022; 18e1010256Crossref Scopus (33) Google Scholar This finding is promising if the Wolbachia strain in the mosquito population is continually successful at blocking arbovirus transmission. However, there is wide variability in the infection-blocking ability across Wolbachia strains.14Flores HA Taneja de Bruyne J O'Donnell TB et al.Multiple Wolbachia strains provide comparative levels of protection against dengue virus infection in Aedes aegypti.PLoS Pathog. 2020; 16e1008433Crossref Scopus (21) Google Scholar Further, the specific mosquito background might contribute to the infection-blocking ability of the Wolbachia strains15Liang X Tan CH Sun Q et al.Wolbachia wAlbB remains stable in Aedes aegypti over 15 years but exhibits genetic background-dependent variation in virus blocking.PNAS Nexus. 2022; 1pgac203Crossref Scopus (7) Google Scholar (appendix).See Online for appendix See Online for appendix Imperfect infection blocking might not only result in the failure to control arbovirus transmission, but the successful introgression of an imperfect Wolbachia strain could also be more problematic in the long term than a failed introgression. The inability of some Wolbachia strains to affect some viral genotypes might lead to the emergence of viruses that can evade Wolbachia's blocking mechanisms through selective pressure. Before the initiation of a release programme, the infection-blocking capacity of the candidate Wolbachia strain should be carefully considered against various arboviral strains. In addition, consideration should be given to whether the background mosquito population used for releases affects the strength of infection blocking by the strain of choice. Currently, researchers typically do not consider more than one, often heavily passaged, reference dengue virus per serotype. The diversity of blocking abilities across strains for other arboviruses, such as for chikungunya and Zika viruses, also remains largely unexplored. There are hundreds of known Wolbachia strains, each with varying degrees of temperature stability and infection-blocking capacity. Importantly, Wolbachia strain names refer to a group of related bacteria isolated from the same insect species, which might harbour substantial variability in infection blocking. For example, different isolates of wMel probably differ greatly in their ability to block viruses. The available potential options if Wolbachia strains with poor infection-blocking capacity become established in a population are unclear. Theoretically, displacing an established Wolbachia strain by introducing a new strain is feasible if the strains are bidirectionally incompatible, that is the males can only successfully reproduce with females infected with the same Wolbachia strain. However, this strategy will substantially increase the invasion threshold of the new strain and will probably preclude any spatial spread, which might be especially problematic if the established strain is more temperature tolerant than the new strain. Another solution to overcome the poor infection-blocking capacity of strains might be to use mosquitoes superinfected with both the original and new Wolbachia strains; however, the high fitness cost to the mosquito for carrying two Wolbachia strains might oppose the introgression.16Joubert DA Walker T Carrington LB et al.Establishment of a Wolbachia superinfection in Aedes aegypti mosquitoes as a potential approach for future resistance management.PLoS Pathog. 2016; 12e1005434Crossref PubMed Scopus (148) Google Scholar The feasibility of the above-mentioned approaches remains unexplored. Nevertheless, the potential risks should not prevent the use of the new technology that provides a transformative advancement in the ability to tackle a great threat to public health worldwide. There might be many Wolbachia strains that will achieve the right balance between facilitating complete introgression, even in high temperature settings, and resulting in high levels of blocking across viral strains. With careful planning, the benefits of these approaches can be maximised without compromising future control efforts. We declare no competing interests. Download .pdf (.12 MB) Help with pdf files Supplementary appendix