Potential herd protection against Plasmodium falciparum infections conferred by mass antimalarial drug administrations
Mass drug administration ( MDA ) is the provision of medications to entire target populations and the approach has been used for many infectious diseases , including lymphatic filariasis , soil-transmitted helminths , onchocerciasis , schistosomiasis , and trachoma ( Keenan et al . , 2013 ) . MDA has historically been used for P . falciparum malaria ( Poirot et al . , 2013 ) and has recently been trialed in several locations in Africa ( Gitaka et al . , 2017; Mwesigwa et al . , 2018; Shekalaghe et al . , 2011 ) and Asia ( Manning et al . , 2018; Tripura et al . , 2018; Nguyen et al . , 2018; Pongvongsa et al . , 2018; Landier et al . , 2017a ) . It is being considered by several nations as a tool ( to be used in unison with other interventions ) for elimination ( World Health Organization , 2017; Zuber and Takala-Harrison , 2018 ) , and has already been implemented as an operational strategy in at least one modern setting ( Parker et al . , 2017; Landier et al . , 2018a ) . Given that drug pressure ( through provision of antimalarial drugs ) provides a survival advantage for resistant parasites , there has been some hesitance in using MDA for malaria . One historical malaria eradication campaign relied on the inclusion of sub-therapeutic levels of antimalarials distributed in table salt across large populations ( Pinotti et al . , 1955 ) . This program likely led to the emergence of parasite resistance in the same regions ( Wootton et al . , 2002 ) and this has in part led to hesitance among some institutions ( i . e . the World Health Organization and ministries of health ) to implement MDA for malaria ( World Health Organization , 2015a ) . MDA should ideally be used in settings with strong public health infrastructure , including easy access to diagnosis and treatment; an up-to-date and responsive surveillance system; and effective community engagement . Used appropriately , MDA can quickly reduce or eliminate parasite reservoirs and can act as a catalyst for subregional elimination of P . falciparum malaria ( Landier et al . , 2018a ) . While antimalarials are usually administered following diagnosis ( confirmed or presumed ) or used as a prophylactic , MDA is used because of an intended population- or community-level effect . The rationale is that the transmission potential or reproductive rate of malaria is so high that a sufficient amount of the parasite reservoir needs to be removed in order to disrupt transmission . This group-level effect is also referred to as a ‘herd effect’ ( John and Samuel , 2000; Pollard et al . , 2015 ) and the concept applies to most communicable diseases . If a sufficient amount of the population participates in MDA , transmission chains cannot be sustained and transmission will cease , ultimately leading to a reduction in malaria morbidity and mortality ( World Health Organization , 2017 ) . There is likely to be a context-specific critical threshold for MDA coverage , below which the reduction of the parasite reservoir is not sufficient to halt ongoing transmission . Some literature has suggested that at least 80% coverage and adherence of MDA in the targeted population is necessary in order for the MDA to be successful ( World Health Organization , 2015b ) . If the aim for antimalarial MDA is to interrupt transmission , the notion of a herd effect providing additional levels of population protection is plausible but has not been examined empirically ( Cotter et al . , 2013 ) . Drawing from detailed micro-epidemiological and spatial data from an MDA trial in Kayin State , Myanmar ( Figure 1 ) , we describe geographic and epidemiological patterns of clinical and subclinical P . falciparum malaria in villages undergoing MDA . We investigate associations between individual- and group-level participation in MDA ( potential direct and indirect effects , respectively ) ; subclinical infections; and clinical episodes of P . falciparum post-MDA . Such empirical research is important for providing an evidence base for further research , intervention , and policy work .
uPCR-detected P . falciparum infections were widespread in all villages at baseline ( Figure 2 ) . These infections were significantly reduced following MDA in all villages . The prevalence of uPCR-detected P . falciparum infections had reduced in two control villages ( villages TPN and HKT ) prior to MDA . There were statistically significant clusters of uPCR-detected P . falciparum infections in each village at baseline but subsequently no significant clusters were detected ( Figure 2 ) . Clusters of clinical P . falciparum episodes occurred in two villages ( KNH and TOT ) . The cluster in KNH occurred from M5 through M7 but included only four episodes . There were two separate clusters in village TOT . A cluster in the western portion of the village began in M12 and lasted until M18 ( with a total of 35 episodes ) . A single-house cluster occurred in the eastern portion of the village ( M15 through M18 ) with five episodes among four house members ( 2 in a 10 yo male , 1 in a 48 yo male , 1 in a 16 yo male , and 1 in a 48-year-old female ) . There were significant clusters of non-participation in the MDAs in three of the study villages ( TPN , HKT and TOT ( Appendix 1—figure 2 ) ) . The non-participation cluster in TOT made up a large portion of the western part of the village and included 115 individuals not participating in the MDA ( out of 919 total individuals in TOT ) . The non-participation clusters in HKT and TPN included 206 and 15 individuals respectively . Sporadic clinical P . falciparum episodes occurred in village TOT following MDA ( MDA was completed by M3 ) , followed by a small outbreak beginning in M12 ( Figures 2 and 3 ) . The first clinical P . falciparum episodes during this outbreak occurred among villagers who lived in the cluster of non-MDA participation ( Figure 3 ) . By M15 the clinical episodes were occurring through much of the village ( Figure 3 ) . Cumulative hazards plots of clinical P . falciparum episodes in village TOT illustrate the temporal patterns in infections according to neighborhood MDA non-adherence ( aggregated into terciles ) and individual participation in MDA ( Figure 4 ) . The proportion of individuals who had acquired a clinical P . falciparum episode began consistently increasing in M12 for those living in either mid or high MDA non-adherence neighborhoods . P . falciparum episodes among low MDA non-adherence neighborhoods began increasing approximately 1 month after the increase in high non-adherence neighborhoods but never reached the level experienced in either mid or high MDA non-adherence neighborhoods . 4 . 4% of all individuals in low MDA non-adherence neighborhoods had at least one clinical P . falciparum episode by the end of the study period , in comparison to 7 . 6% in mid and 9 . 6% in high MDA non-adherence neighborhoods ( log-rank test p-value=0 . 0485; Figure 4A ) . The increase in clinical P . falciparum episodes in M12 also coincided with an increase in HBR in village TOT ( Appendix 1—figure 3 ) . After MDA , clinical P . falciparum episodes in village TOT were most likely to occur among 5 to 14 year olds ( AOR: 3 . 41; CI: 1 . 33–8 . 77 , compared to 0 to 4 year olds ) and participants who lived in a house with someone else who had a clinical P . falciparum episode during the same month ( AOR: 3 . 43; CI: 1 . 52–7 . 72 ) , after adjusting for other covariates ( Table 1 ) . Individuals who lived in a neighborhood with a high proportion of people who did not adhere to MDA had 2 . 8 times the odds of having a clinical episode ( AOR: 2 . 85; CI: 1 . 28–6 . 37 ) compared to people who lived in neighborhoods where most people adhered to MDA ( Table 1 ) . The human biting rate was also associated with increased odds of having a clinical P . falciparum episode , with a 10% increase in odds for every one unit increase in HBR ( AOR: 1 . 09; CI: 1 . 05–1 . 13 ) .
The primary objective of this research was to look for a potential herd effect and at the impact of non-adherence with regard to MDA for P . falciparum malaria . There was an apparent group level effect from MDA adherence , suggesting herd protection and evident from three lines of evidence . First , clinical episodes decreased among all groups for a longer period than the prophylactic effect ( approximately 1 month ) of the administered antimalarials . This group level protective effect from MDA was also evident in the rainy season following MDA ( Figure 3 ) which corresponded to a surge in vector activity ( Appendix 1—figure 3 ) . Once the P . falciparum outbreak began ( M12 ) , there was a lag of approximately 1 month between the onset of clinical episodes in neighborhoods with mid and low MDA adherence and then occurred in neighborhoods with high MDA adherence ( Figure 4A ) . Second , neighborhoods with high MDA adherence never experienced the same levels of infection as those with mid or low MDA adherence ( Figure 4A ) . Individuals who participated in MDA but lived in a neighborhood with low adherence had the highest risk of having a clinical episode whereas those who did not participate in MDA but lived in a neighborhood with high adherence had the lowest risk of having a clinical P . falciparum episode ( Figure 4B ) . As has been described in other settings , this individual-level finding may be related to relative perceptions of risk; with potential complacency among individuals living in areas with lower levels of malaria ( Koenker et al . , 2013 ) . Third , the results from the multivariable logistic regression also suggest that living in a neighborhood with a high proportion of people who did not adhere to MDA was a significant risk factor for acquiring a clinical P . falciparum episode , after adjusting for individual MDA adherence and other important predictors of having a clinical episode ( Table 1 ) . To our knowledge , this is the first documentation of a herd effect conferred by MDA for P . falciparum malaria . The increase in clinical P . falciparum episodes post-MDA also corresponded to an increase in village HBR . HBR also peaked in one other village ( HKT ) at the same time as in village TOT ( Appendix 1—figure 3 ) , but occurred in the absence of a detectable parasite reservoir and the HBR did not persist at high levels . Evidence also suggests that the MP in TOT was not functioning well in the first year of the study ( reported in Landier et al . , 2017a ) . The combination of a persisting parasite reservoir and persistently high HBR ( from M13 – M18 ) in TOT likely explains the drastically different results between the study villages with regard to P . falciparum malaria elimination ( Figure 2 ) . A better functioning MP in TOT would likely have reduced the size of the outbreak . Clustering of uPCR-detected P . falciparum infections across houses occurred for limited periods of time only prior to MDA ( Figure 2 ) . This clustering suggests that interventions such as reactive case detection would have resulted in the detection of extra cases ( of both clinical and uPCR-detected P . falciparum ) when searching within houses and occasionally in neighboring houses , but these would have only been a small proportion of all infections within the villages ( Parker et al . , 2016 ) and would not have halted transmission . Conversely , community based early diagnosis and treatment and MDA with high participation , targeted at the village scale or larger , appear effective at reducing prevalence , incidence , and transmission of P . falciparum ( Landier et al . , 2018b ) . There are several limitations to this work . Individuals who did not participate in MDA also did not participate in blood screenings immediately after MDA ( i . e . M3 in village TOT ) . uPCR-detected infections are therefore likely to be underdiagnosed for these individuals , and it is likely that such infections clustered and overlapped with the clusters of non-adherence to MDA . While no genetic analyses were done with samples from the village , it is likely that these underdiagnosed infections , combined with the high HBR , led to a resurgence of clinical episodes . There is also evidence of a poorly functioning MP in this village , which could have led to undiagnosed clinical episodes , especially during the beginning of the study . Some infections are likely to be acquired outside of the village , leading to complex spatial patterns in infections that are mapped at the house level . Within-household clustering can be the result of within-household transmission , or shared exposure outside of the household or village among household members . Finally , these data come from a limited number of villages ( total of 4 ) , with analysis of P . falciparum episodes coming from the sole village that continued to have P . falciparum after MDA . Given that clinical P . falciparum episodes post-MDA were only possible to analyze in a single village , and that neighborhoods were not discrete and overlapped ( 100 m buffer around each house ) , a neighborhood-level effect was not included in this analysis . It is possible that the confidence intervals around the neighborhood MDA adherence variable are therefore too small and would not have been statistically significant had a neighborhood effect been included . This work would benefit from analyses with larger datasets . This work has relevance with regard to further research and practice concerning MDA . While participation is obviously crucial to success , there is unlikely to be a single adherence proportion that can be applied in all situations . In this study , the elimination efforts were successful in three out of four villages even though one of those villages ( HKT ) had a similar overall adherence to the village with P . falciparum remaining after MDA ( TOT ) . Likewise , this work points toward the need for considering spatial scale in MDA and in MDA adherence . Most current MDA trials and programs in the GMS and elsewhere consider a single village or community as the target unit . In some cases , especially when high prevalence villages are spatially clustered across a landscape , it may be necessary to target units above the village level ( i . e . groups of villages ) .
The study site consisted of four villages ( KNH , TPN , HKT , and TOT ) along the Myanmar-Thailand border , in Kayin ( Karen ) State , Myanmar ( Landier et al . , 2017b ) . The villages were selected based on P . falciparum malaria prevalence surveys using ultrasensitive quantitative PCR ( uPCR ) ( Imwong et al . , 2015 ) and were part of a MDA pilot study ( Landier et al . , 2017b ) . The northernmost village is approximately 105 km from the southernmost and the two closest villages , KNH and TPN are within 10 km of each other ( Figure 1 ) . The study was conducted from May 2013 through June 2015 . A full population census was completed in each of the four study villages at baseline May – June 2013 . Everyone enumerated in the census was given a unique identification code . Geographic coordinates were collected for all houses in the four study villages and a unique identification code was assigned to each house . All individuals were then linked to their respective houses . Blood surveys were conducted at baseline in each village , aiming to screen all individuals above an age of 9 months . Venous blood ( 3 mL ) was drawn from each participant , transported to a central laboratory and analyzed using a highly sensitive quantitative PCR ( uPCR ) assay with a limit of detection of 22 parasites per mL . ( Imwong et al . , 2014 ) . Infections detected through these blood screenings are hereafter referred to as uPCR-detected infections . Most ( 86% ) uPCR-detected infections were subclinical ( Landier et al . , 2017a ) and clinical infections were provided the standard treatment ( see below ) . A community-based malaria clinic ( referred to as a malaria post or MP ) was established in each village at the beginning of the project , as part of the malaria intervention . Village health workers were trained to diagnose malaria using rapid diagnostic tests ( RDTs ) and to treat RDT positive infections with dose based on weight and age . The ID code of each participant who self-presented at the MP was recorded , along with RDT results , and these cases are hereafter referred to as clinical malaria episodes of either P . falciparum or P . vivax . Malaria episodes were treated with dihydroartemisinin-piperaquine ( DHA + P ) for P . falciparum and chloroquine for P . vivax . Radical cure for P . vivax was not provided because the absence of G6PD ( Glucose-6-phosphate dehydrogenase ) tests required to prevent hemolysis in G6PD individuals ( Bancone et al . , 2014; Chu et al . , 2017 ) . MDAs were conducted in two villages at the beginning of the study ( month 0 , M0 ) and extended to the two control villages beginning in month 9 ( M9 ) . Restricted randomization was used to decide which villages received early or deferred MDA . MDA consisted of 3 days of DHA + P , with a single low dose of primaquine on the third day , repeated over three months ( M0 , M1 , M2 for the first group and M9 , M10 , M11 for the control group ) . Follow-up blood surveys were conducted in each village every third month after M0 until M18 . A final full blood survey was completed in each village at M24 . Mosquitoes were collected monthly using human landing catches to estimate the human biting rate ( HBR ) . Mosquito catching teams were based at five sites ( both indoors and outdoors ) within each of the four study villages ( total of 20 catch sites ) for five consecutive nights during the study period M0 through M20 . Mosquitoes were caught using glass tubes and later identified morphologically ( Ya-Umphan et al . , 2017 ) . The locations of study villages , MPs , catch sites , and village houses are indicated in Figure 1 .
The global malaria burden has decreased over the last decade and many nations are attempting elimination . Asymptomatic malaria infections are not normally diagnosed or treated , posing a major hurdle for elimination efforts . One solution to this problem is mass drug administration ( MDA ) , with success depending on adequate population participation . Here , we present a detailed spatial and temporal analysis of malaria episodes and asymptomatic infections in four villages undergoing MDA in Myanmar . In this study , individuals from neighborhoods with low MDA adherence had 2 . 85 times the odds of having a malaria episode post-MDA in comparison to those from high adherence neighborhoods , regardless of individual participation , suggesting a herd effect . High mosquito biting rates , living in a house with someone else with malaria , or having an asymptomatic malaria infection were also predictors of clinical episodes . Spatial clustering of non-adherence to MDA , even in villages with high overall participation , may frustrate elimination efforts .
The global burden of malaria has decreased over the last decade . Many countries now aim to banish malaria . One obstacle to elimination is people who carry malaria parasites without showing symptoms . These asymptomatic people are unlikely to be diagnosed and treated and may contribute to further spread of malaria . One way to clear all malaria infections would be to ask everyone in a community to take antimalarial drugs at the same time , even if they do not feel ill . This tactic is most likely to work in communities that are already reducing malaria infections by other means . For example , by treating symptomatic people and using bed nets to prevent bites from malaria-infected mosquitos . Several studies have shown that mass drug administration is a promising approach to reduce malaria infections . But its success depends on enough people participating . If enough community members take antimalarial drugs , then even those who cannot participate , such as young children or pregnant women , should be less likely to get malaria . This is called the herd effect . Now , Parker et al . demonstrate that mass antimalarial drug administration reduces infections with malaria caused by the parasite Plasmodium falciparum . The analysis looked at malaria infections among residents of four villages in the Kayin State of Myanmar that used mass antimalarial drug administration . People who lived in neighborhoods with high participation in mass drug administration were almost three times less likely to get malaria than people who lived in communities with low participation . Even people who did not take part benefited . The analysis suggests that mass antimalaria drug administration benefits individuals and their communities if enough people take part . To be successful , malaria elimination programs that wish to use mass drug administration should approach communities in a way that encourages high levels of participation .