Review 1: "Dramatic Resurgence of Malaria after 7 Years of Intensive Vector Control Interventions in Eastern Uganda"

RR:C19 Evidence Scale rating by reviewer:

• Strong. The main study claims are very well-justified by the data and analytic methods used. There is little room for doubt that the study produced has very similar results and conclusions as compared with the hypothetical ideal study. The study’s main claims should be considered conclusive and actionable without reservation.

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Review: This paper from a leading malaria research group in Uganda describes, in a long term, longitudinal, population and health cost based surveillance study, how a change in the chemical insecticide used for indoor residual spraying led to an increase in malaria. This work is important for malaria policy and will find widespread, generalizable interest and impact. I do have some suggestions for the authors to improve the manuscript to enable further higher impact, both on the field (for further research by others) and on policy makers who must decide on economically/financially feasible ways to enact useful malaria control strategies.

The data support the conclusions drawn in the study. The conclusions are particularly robust because the association of insecticide with malaria incidents used in indoor residual spraying in the area of Tororo, the focus of the present study, was compared to a comparable control area, further, the changing back and forth of the insecticide, Actellic to Fludora Fusion/SumiShield to Actellic was associated with less malaria with the Actellic, which is another internal control that adds confidence to the conclusions drawn from the data presented.

I am confused whether the authors are measuring malaria cases (case definition is not precisely specified) vs. parasite prevalence as determined by qPCR/lab testing. This is another reason “burden” is not an ideal descriptor to use, except to describe actual disease burden.

However, I might suggest that the reader would take a more circumspect lesson than some of the ways that the authors describe their conclusions:

• I would not use “dramatic” unless there was a large increase in severe malaria. This is not described, and the use of “dramatic” is overwrought.

• “Burden” of malaria is not precisely used in the manuscript and either ought to be clarified or replaced by number of cases.

The authors would be encouraged to reorganize their description of severe malaria (rare); it is not mentioned in abstract and seems to be buried in lines 329ff: Despite the high burden [???] of malaria in this study, only 4 of 2,266 episodes (0.2%) met WHO criteria for severe malaria: 2 cases of severe anemia (Hb < 5.0 gm/dL) occurred in children with confirmed sickle cell disease, one of whom died; 1 case of severe anemia occurred in a 1 year old child who recovered; and 1 case of jaundice occurred in a 3 year old child who recovered.

I would suggest that “burden” be replaced by “rate” as a more neutral, and accurate, descriptor.

The use of a highly sensitive qPCR to estimate Pf prevalence prospectively is important; this should described as a rate of infection, not as a “burden” of infection.

From the outset of the manuscript, the work is presented/written as a descriptive study, yet there are comparisons nominally with a control group. It would improve the quality of the manuscript if the authors could directly state the hypothesis they are going to test, the rationale for how they will test the hypothesis (longitudinal study, study and control groups with clear descriptions of the similarities and differences in the Tororo vs. Busia malaria situations and ongoing malaria control strategies).

In the abstract, Busia is the comparator is noted but it would be helpful in the abstract to note that this district is adjacent to Tororo (presumably comparable in term of sociodemographics, malaria indices, geography etc?) and has never had in indoor residual spraying carried out as a public health measure. This is noted in the main text but it would be more helpful to include it for clarification in the abstract. In the methods, the malaria characteristics of Busia are detailed finally; a suggestion might be to reorganize this description in the manuscript because it is an essential control.

Entomological surveillance for infected mosquitoes was done by using CDC light traps to capture mosquitoes; this may be a limited way to catch anophelines. Human landing catches were not done, which is more accurate.

Entomological surveillance for insecticide resistance in field-caught (indoor resting only), blood-fed (blood source unknown) was done by aspirating. This is limited and a major gap in this papere and in the field is whether IRS leads to mosquito adaptation to resting outdoors after blood meal.