1. Epidemiology and Global Health
  2. Microbiology and Infectious Disease
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Potential herd protection against Plasmodium falciparum infections conferred by mass antimalarial drug administrations

  1. Daniel M Parker  Is a corresponding author
  2. Sai Thein Than Tun
  3. Lisa J White
  4. Ladda Kajeechiwa
  5. May Myo Thwin
  6. Jordi Landier
  7. Victor Chaumeau
  8. Vincent Corbel
  9. Arjen M Dondorp
  10. Lorenz von Seidlein
  11. Nicholas J White
  12. Richard J Maude
  13. François Nosten
  1. University of California, United States
  2. Mahidol University, Thailand
  3. University of Oxford, United kingdom
  4. University of Montpellier, France
  5. Centre Hospitalier Universitaire de Montpellier, France
  6. Harvard University, United States
Research Article
Cite this article as: eLife 2019;8:e41023 doi: 10.7554/eLife.41023
9 figures, 8 tables and 1 additional file

Figures

Map indicating the locations of the study villages along the Myanmar-Thailand border; and the distribution of houses, mosquito catch sites and malaria posts within study sites.
https://doi.org/10.7554/eLife.41023.003
Clinical P.falciparum episodes (yellow square points) and uPCR-detected P. falciparum infections (blue dots) at house level over time (by survey month; month 0 (M0) through month 24 (M24)) for each of the four study villages.

Statistically significant clusters (detected using SaTScan) are indicated for both clinical episodes (underlying yellow circles) and uPCR-detected infections (underlying blue circles). Grey points indicate house locations for houses with no infections or episodes in a given time. In the maps clinical episodes are aggregated to align with surveys (i.e. M1, M2 and M3 aggregated into M3), though they were recorded and analyzed by individual month. The study was conducted from May 2013 through June 2015 (KNH began in June; TPN in May; HKT in July; and TOT in May of 2013).

https://doi.org/10.7554/eLife.41023.004
Spatiotemporal distribution of clinical P.falciparum episodes (yellow square points), uPCR-detected P. falciparum infections (blue dots), and a cluster of non-participation in MDA (grey circle/ochre border, detected using SatScan) in TOT village.

Season is indicated by colored squares in the top right corner of each map. A measure of the spread of clinical P. falciparum cases is given by the standard distance deviation (‘SDD’), indicated by the hollow circle with dark grey outline. One standard deviation is shown, indicating that roughly 68% of all cases lie inside of the circle. After MDA (M3), clinical episodes began occurring in the westernmost portion of the village. By month 15 (M15), clinical episodes were occurring throughout the village.

https://doi.org/10.7554/eLife.41023.005
Cumulative hazard of having a clinical P. falciparum episode by MDA adherence.

Cumulative hazard for clinical P. falciparum episodes in village TOT by (A) neighborhood MDA adherence (‘low non-adhere’ is a neighborhood with a low proportion of non-adherents; ‘high non-adhere’ is a neighborhood with a high proportion of non-adherents), (B) neighborhood adherence (same as in A) and individual adherence (‘individual non-participation’ indicates individuals who took no MDA while ‘individual participation’ indicates individuals who took at least 1 round of MDA). Figure 4B indicates that individuals who participated in MDA and lived in a neighborhood with low adherence had the highest risk of having a clinical episode post-MDA. Individuals who took no rounds of MDA but lived in a neighborhood with a high proportion of adherents had the lowest risk of acquiring a clinical episode post-MDA.

https://doi.org/10.7554/eLife.41023.006
Appendix 1—figure 1
Clinical P.vivax episodes (yellow square points) and uPCR-detected P. vivax infections (blue dots) at house level over time for each of the four study villages.

Statistically significant clusters (detected using SaTScan) are indicated for both clinical episodes (underlying yellow circles) and PCR-detected infections (underlying blue circles). MDA completion is indicated by the dark brown box bordering the survey time period (months 0 through 24, indicated as M0 – M24 along the x-axis). Blood stage P. vivax parasites were largely cleared following MDA. Since no accurate field diagnostic for glucose-6-phosphate dehydrogenase (G6PD) deficiency existed at the time, it was deemed unsafe to provide 7 or 14 days of the hypnozoitocidal drug primaquine. Many of the subsequent infections and clinical episodes are likely a result of re-emergence of hypnozoite-stage parasites rather than new P. vivax infections.

https://doi.org/10.7554/eLife.41023.014
Appendix 1— figure 2
Spatial clusters (detecting using SatScan) of non-participation in MDA.
https://doi.org/10.7554/eLife.41023.015
Appendix 1— figure 3
Human biting rate (HBR) for primary vectors by study month.
https://doi.org/10.7554/eLife.41023.016
Appendix 1— figure 4
Unspeciated uPCR-detected infection for each village and survey.
https://doi.org/10.7554/eLife.41023.017
Author response image 1

Tables

Table 1
Multivariable mixed effects logistic regression for odds of having a clinical P. falciparum episode (village TOT only).

The model includes a random intercept for individual participants, with repeat observations occurring within individuals over the study period.

https://doi.org/10.7554/eLife.41023.008
CovariateAORp-Value
Age 0 to 4Comparison
Age 5 to 143.41 (1.33–8.77)0.0104
Age 15 plus2.17 (0.86–5.46)0.1053
FemaleComparison
Male1.19 (0.66–2.11)0.5612
Participated in no rounds of MDAComparison
Participated in MDA (at least one round)1.43 (0.73–2.78)0.2994
No house member with clinical episodecomparison
House member with clinical episode3.43 (1.52–7.72)0.0004
Low neighborhood non-adherence to MDAcomparison
Mid neighborhood non-adherence to MDA2.00 (0.87–4.60)0.0879
High neighborhood non-adherence to MDA2.85 (1.28–6.37)0.0098
Mean village HBR1.09 (1.05–1.13)<0.0001
Study month1.19 (1.10–1.27)<0.0001
Table 2
Table of predictor variables (covariates) used in regressions.
https://doi.org/10.7554/eLife.41023.007
CovariateLevelDescription
Age groupIndividualOrdinal; age groups: 0 to 4; 5 to 14; and 15 and above
GenderIndividualBinary; male or female
Individual adherence to MDAIndividualBinary; whether an individual participated in MDA or not (at least one full round)
Household member with clinical episodeHouseholdBinary; one if another house member had a clinical episode and 0 if not
Household member with uPCR-detected infectionHouseholdBinary; one if another house member had a uPCR-detected infection and 0 if not
Neighborhood MDA non-adherenceHousehold/neighborhoodOrdinal (split into tertiles); proportion of people within 100 m radius who did not complete all three rounds of MDA
Human biting rate (HBR)VillageContinuous; average number of bites per person per night
Study monthVillageContinuous; 1–26 (from May 2013 through June 2015); included as a control
Appendix 1—table 1
Terciles (lower, middle and upper 1/3) of MDA non-adherence (% taking no rounds of MDA) in TOT
https://doi.org/10.7554/eLife.41023.011
High non-adherence>0.294
Mid non-adherence>0.20 and <0.294
Low non-adherence<0.20
Appendix 1—table 2
Multivariable mixed effects logistic regression for odds of having a clinical P. falciparum episode.

The model includes a random intercept for individual participants, with repeat observations occurring within individuals over the study period. Unlike the model in the main text (Table 1) neighborhood non-adherence to MDA and individual adherence to MDA are continuous covariates. Study month was included as a control (a linear specification was used, but polynomial specifications were also tested). The covariates for human biting rate (HBR) and having a house member with a clinical episode in the same month were specified as time-varying covariates.

https://doi.org/10.7554/eLife.41023.012
CovariateAORp-value
Age 0 to 4comparison
Age 5 to 143.5 (1.3–9.0)0.0112
Age 15 plus2.2 (0.9–5.6)0.1014
femalecomparison
Male1.2 (0.7–2.2)0.5147
no house member with clinical episodecomparison
house member with clinical episode3.8 (1.8–7.7)0.0003
proportion of MDA doses complete1.0 (1.0–1.1)0.4488
proportion of non-adherers in neighborhood1.4 (1.0–1.8)0.0380
mean village HBR1.1 (1.1–1.1)<0.0001
study month1.2 (1.1–1.3)<0.0001
Appendix 1—table 3
Logistic regression for the odds of having a uPCR-detected P. falciparum infection after MDA.

Individuals in the data were coded as having an infection if they were ever determined by uPCR to have an infection through blood screenings in full village blood surveys after MDA. Almost all P. falciparum episodes occurred in a single village (TOT) and the analysis for P. falciparum was only conducted on data from that village. HBR is not included in this regression as it varies across time.

https://doi.org/10.7554/eLife.41023.013
CovariateAORp-value
0 to 4comparison
five to 146.1 (1.1–113.9)0.0877
15 plus5.5 (1.1–99.3)0.1017
femalecomparison
male1.3 (0.6–2.7)0.5217
participated in no rounds of MDAcomparison
participated in MDA (at least one round)0.4 (0.2–1.1)0.0955
no house member with uPCR infectioncomparison
house member with uPCR infection1.1 (0.4–2.7)0.8039
no house member with clinical episodecomparison
house member with clinical episode1.7 (0.7–3.8)0.2029
low neighborhood non-adherence to MDAcomparison
mid neighborhood non-adherence to MDA1.1 (0.4–3.2)0.8743
high neighborhood non-adherence to MDA2.6 (1.0–7.1)0.0488
number of surveys attended1.3 (1.1–1.6)0.0075
Appendix 1—table 4
Multivariable mixed effects logistic regression for odds of having a clinical P. vivax episode.

The model includes a random intercept for individual participants, with repeat observations occurring within individuals over the study period. Study month was included as a control (a linear specification was used, but polynomial specifications were also tested). The covariates for human biting rate (HBR) and having a house member with a clinical episode in the same month were specified as time-varying covariates.

https://doi.org/10.7554/eLife.41023.018
CovariateAORp-value
Age 0 to 4comparison
Age 5 to 141.0 (0.4–2.4)0.9945
Age 15 plus0.4 (0.2–0.9)0.0358
femalecomparison
male0.8 (0.4–1.5)0.4687
participated in no rounds of MDAcomparison
participated in MDA (at least one round)1.7 (0.7–4.3)0.2678
no house member with clinical episodecomparison
house member with clinical episode5.8 (3.4–9.9)<0.0001
low neighborhood non-adherence to MDAcomparison
mid neighborhood non-adherence to MDA1.6 (0.3–7.6)0.5546
high neighborhood non-adherence to MDA1.8 (0.3–9.8)0.5205
mean village HBR1.0 (1.0–1.1)0.1447
village KNHcomparison
village TPN0.6 (0.2–1.8)0.3666
village HKT0.3 (0.1–1.5)0.1329
village TOT0.6 (0.1–3.4)0.6074
study month1.0 (1.0–1.1)0.0126
Appendix 1—table 5
Multivariable logistic regression for the odds of having a uPCR detected P. vivax infection after MDA.

Individuals in the data were coded as having an infection of either species if they were ever determined by uPCR to have an infection through blood screenings in full village blood surveys after MDA.

https://doi.org/10.7554/eLife.41023.019
CovariateAORp-value
0 to 4comparison
five to 142.6 (1.7–3.9)<0.0001
15 plus2.1 (1.4–3.2)0.0002
femalecomparison
male1.8 (1.4–2.2)<0.0001
participated in no rounds of MDAcomparison
participated in MDA (at least one round)0.6 (0.4–0.8)0.0027
no house member with uPCR infectioncomparison
house member with uPCR infection1.5 (1.2–1.9)0.0022
no house member with clinical episodecomparison
house member with clinical episode1.3 (1.0–1.7)0.0284
low neighborhood non-adherence to MDAcomparison
mid neighborhood non-adherence to MDA0.6 (0.4–1.1)0.0994
high neighborhood non-adherence to MDA0.6 (0.4–1.1)0.0945
KNHcomparison
TPN1.0 (0.7–1.5)0.8617
HKT1.4 (0.8–2.5)0.2614
TOT5.4 (2.9–9.8)<0.0001
number of surveys attended1.4 (1.3–1.5)<0.0001
Appendix 1—table 6
Household and population counts for study villages

Data used in this analysis are available following the Mahidol-Oxford Tropical Medicine Research Unit data access policy. Both the policy and application form are available at: http://www.tropmedres.ac/data-sharing.

https://doi.org/10.7554/eLife.41023.020
VillageHouseholdsPopulation
KNH86504
TPN75468
HKT1761338
TOT149919
total4863229

Data availability

The data used in these analyses are human subjects data from a sensitive population and organizational policy restricts data sharing for ethical and security considerations. Data can be accessed through the Data Access Committee at Mahidol Oxford Tropical Medicine Research Unit (MORU). The data sharing policy (including information on how to access the data) can be found here: http://www.tropmedres.ac/data-sharing.

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