This study provides an explicitly detailed description of the decline in malaria transmission in two districts of Zanzibar over a 12-year period. Reductions of more than 90% were observed in prevalence of infection, incidence of malaria and human biting rate. A major drop in child mortality was seen already following the introduction of ACTs in 2003, whereas the major drop in malaria transmission occurred after the introduction of vector control in 2005.
Coverage and sustainability of malaria control interventions
An overall good access to public health care, a continuous supply and adherence to RDTs and ACTs [
23‐
25] as well as sustained ACT efficacy [
26,
27] have supported a continued efficient management of clinical malaria episodes in all age groups.
Quite high and sustained coverage of effective vector control has been achieved, generally higher than in other sub-Saharan countries according to their national reports [
1]. Iterated household level distributions of LLINs with health information have resulted in consistently high degrees of reported use in children < 5 years and other age groups. Combined with high coverage of IRS, this appears to have had a significant (almost 100-fold) effect on the indoor vectorial capacity, as may be forecasted [
28,
29]. Both interventions are publically perceived as beneficial against malaria and biting insects in general [
30,
31]. However, the recent increase in pyrethroid resistance represents a major concern [
19]. The more costly carbamate or pirimiphos-methyl has therefore replaced pyrethroids in IRS whereas the pyrethroid impregnated LLINs may still provide relative protection [
32,
33]. Additionally, the change in biting behaviour of malaria vectors suggests outdoor malaria transmission poses another challenge to malaria elimination in Zanzibar. A similar shift in species proportions has been reported in other areas of Africa following wide-scale LLINs use and IRS programmes [
34‐
37]. Complementary antivectorial efforts targeting both pyrethroid resistant and outdoor resting mosquitoes are clearly required for successful malaria elimination in Zanzibar.
Malaria transmission impact
The initial rapid reduction in transmission from 2005 to 2007 in the two study districts [
8] (annual Rc about 0.5) was followed by a much slower decline with persistent low-level transmission from 2008 onwards. Although we focussed on two districts only, they appeared to be representative for all of Zanzibar. The malaria positivity rates in febrile patients reported from the health facilities in the other eight districts were quite similar to the rates in the two study districts during the study period [
14]. A new equilibrium of malaria pre-elimination stage transmission thus appears established despite continuing high community uptake of the conventional control interventions.
The reductions in malaria indices in Zanzibar are much more pronounced (around 5- to 10-fold higher) than those reported from other areas/countries of sub-Saharan Africa including Tanzania mainland [
1,
38‐
43]. In addition, these gains appear to be more sustained in Zanzibar than in many other areas where a tendency of resurgence may be occurring in the latest years [
1]. This highlights the uniqueness of the malaria elimination efforts in Zanzibar. There are probably multiple reasons for the effectiveness but we believe a major factor is higher population-level uptake of the interventions due in large part to the strong commitment of ZAMEP and the Zanzibar Government and strong involvement of the communities. An easy access to health care and accurate malaria treatment is probably also essential. We do not believe other general factors such as socioeconomic changes and sudden improvement in health care may have strongly influenced the impact on the rapid 10- to 100-fold reduction in malaria indices. A socio-economic development has probably occurred in Zanzibar as in many other areas of Africa during the study period, but would only account for a minor part of the malaria control impact.
The establishment of this new persistent level of low transmission contrasts with the malaria elimination feasibility report for Zanzibar based on mathematical modelling which predicted a possible annually continuous Rc of 0.5 and elimination achieved by 2020 if effective intervention coverage was kept at approximately 75% [
44]. There may be several reasons why this prediction became unrealistic. Firstly, malaria transmission is now more seasonal and geographically heterogeneous with clear foci of infection [
14], which may be driving current transmission [
45]. Secondly, sensitive molecular testing by PCR has highlighted the major reservoir of low-density asymptomatic parasitaemias across all age groups, which appears consistent with other low transmission areas [
46‐
48]. Importantly, these low-density parasitaemias may contribute significantly to the residual ongoing transmission [
49,
50] and interestingly this appears to be possible despite a major decline in HBRs (Table
4). An additional interesting finding was that the relative proportion of low-density
P. malariae infections increased after the initiation of interventions up to 2011. This may reflect greater longevity of untreated asymptomatic
P. malariae than
P. falciparum infections [
51] but relatively lower presently ongoing transmission.
Thirdly, imported malaria may represent a major hindrance for elimination. A relative risk factor for clinical malaria infection was indeed history of travel outside Zanzibar. Such travel, mainly to/from Tanzania mainland, was reported by 49% of clinical malaria patients (OR 70) in 2015. Neither recent nor previous travel were significant risk factors for asymptomatic infections. In 2010, travel outside Zanzibar was reported by only 9/121 (7%) malaria-confirmed patients (OR 9) [
23]. In 2013, travel outside of Zanzibar was reported by 30% of reported clinical malaria patients [
14]. A tentative interpretation of this may be that an increasingly important fraction of new clinical infections are acquired from outside Zanzibar although still somewhat less than reported estimates for Zanzibar based on modelling [
52]. Conversely our cross-sectional data, including the serology results, may suggest that many infections are locally acquired and possibly asymptomatic and thus remain as untreated residual infections for a significant period of time allowing for maintained residual local transmission [
53]. Hence, the official figures in Zanzibar of approximately 3000 malaria confirmed clinical infections significantly underestimate the actual incidence of newly acquired infections. Such figures may be better reflected by SCR estimates. Extrapolating the mean SCR for the two study districts (0.008 year
−1) to whole of Zanzibar would suggest over 10,000 new infections annually.
A fourth reason for the halt in malaria transmission reduction despite the significant reduction of HBRs is probably that the residual vector population mainly biting and resting outdoors is now less affected by indoor vector control. Hence, not having IRS recently performed was not identified as a major risk factor, while not sleeping under LLIN was only a risk factor for clinical malaria, again supporting that most transmission may occur outdoors. It also suggests that the preventive mass effects of LLIN use and IRS on indoor transmission are now more significant than the individually preventive effects. However, the spreading resistance to pyrethroids [
19] and more restricted coverage of IRS represent challenges for future sustained impact, although the exact epidemiological effects of resistance to the insecticide in the nets appear to vary [
32,
33], and indoor HBRs presently remain very low in our study area.
A fifth potential challenge is that malaria immunity is expected to decline as transmission reduces [
54]. An increased proportion of clinical malaria episodes was seen among patients > 5 years although such age shift was not yet seen among PCR detected low-density parasitaemias. These older age groups were previously likely to be clinically immuno-protected through previous repeated exposure. A reason for the relative age shift may however also be behavioural. Older age groups who remain outside in the evening are exposed to more outdoor biting mosquitoes and may be less prone to use LLINs against mosquitoes biting indoor. Finally, it may also result from more frequent travel to mainland Tanzania by older age groups.
It is commonly stated that it is easier to control/eliminate malaria on an island (ex Zanzibar) than in-country (e.g. Tanzania mainland). This is may be true for a small island with a small population [
55]. However, we do not believe this to be a major reason for the high impact on the two large islands of Zanzibar with populations over half a million each. There is obviously increased risk of imported malaria on the African continent between neighbouring countries through more crossing of borders as well as to some extent exchange of mosquitoes to nearby areas. But grossly besides the very border areas there should not be major differences between the malaria control efforts required in Zanzibar islands and mainland Tanzania. We therefore consider the findings and challenges in Zanzibar highly applicable to other African countries.
Public health impact
The study data provide evidence of a major improvement in child health. A highly significant reduction of all cause child mortality coincided with the introduction of ACT whereas the most significant reduction in malaria incidence occurred after the intensified vector control. Although there was a trend of reduction in under 5 child mortality already before 2003, the decline 2003–2005 was clearly more pronounced.
The reported child deaths to the Vital Registry probably represent an underestimated mortality but we believe the reporting rate remained rather similar during years of study, allowing for reasonably valid trend analysis. In addition, the specifically large mortality reduction during 2003–2006 cannot be explained by any other public health intervention at that time in Zanzibar. A major decrease in crude child mortality was also observed on Bioko Island after massive malaria control interventions [
42]. In parallel to our observed mortality reduction, there was also reduced hospitalisation for severe malaria [
56] and major reduction in severe anaemia requiring blood transfusions to < 5 children [
8], a common severe manifestation of malaria in sub-Saharan Africa. The overall reduction of clinical malaria episodes resulted in a decline in fever episodes especially in children, also noted by their caretakers and thus a good incentive for sustained LLIN use [
30,
31].
The strong impact on crude mortality may largely be explained directly by reduced malaria specific mortality from ACT preventing development of severe malaria manifestations and the vector control reducing malaria incidence. It may however also result indirectly from the general reduction of malaria infection and its associated anaemia, being a risk factor for severe manifestations of other concomitant bacterial infections [
57], e.g. septicaemia [
58] or pneumonia.
A new low malaria transmission epidemiology has emerged in Zanzibar with spatial, temporal and demographic foci of infection. These foci are likely to be influenced by outdoor transmission and increasing insecticidal resistance, a substantial asymptomatic parasite reservoir and an apparent increasing number of imported infections. All this necessitates the addition of new malaria control tools and strategies.
Screening (by RDT) and subsequent preventive treatment of asymptomatic but possible parasite carriers has now been introduced in households where clinical malaria episodes have been identified and potentially in the future within for example 300-m radius [
59]. Since 2012, IRS with carbamate and pirimiphos-methyl has been specifically targeting identified hotspots and larvicing interventions are being trialled in selected foci. Gametocytocidal single low-dose primaquine is being introduced along with ACT. General surveillance is also being reinforced by more comprehensive and regular epidemiological investigations of newly detected and reported cases, as well as more comprehensive monitoring of entomological insecticide resistance and parasitological drug resistance.
However, other possibly more aggressive approaches are also needed. This may include screen and treat strategies potentially including new highly sensitive diagnostics [
60‐
62] or targeted mass/focal drug administration [
59,
63] possibly including seasonal chemoprevention [
64,
65]. These actions may be targeted to hotspot areas [
66] and/or population groups at risk of residual parasite reservoir. Additional vector control targeting
An. arabiensis populations needs to be implemented, e.g. different outdoor mosquito “attract and kill” methods. Case detection and response also needs further development to ensure future rapid prevention of outbreaks especially from imported infections. Since imported malaria represents a significant barrier to malaria control and elimination efforts in Zanzibar, several additional preventive strategies may be considered, especially during high transmission season. Such interventions may include chemoprophylaxis to Zanzibar is travelling to mainland, and mass screening or presumptive treatment of anyone arriving from mainland. However, formal and informal exit and/or entry points from/to Zanzibar are numerous and the efficiency of for example screening and treatment may not be very significant with standard diagnostic tools [
61]. This will be explored in Zanzibar in the near future.
With old reinforced and new introduced interventions, the Rc presently around 1 may possibly be reduced to 0.5 again. The presently annually reported 3000 clinical malaria cases and our estimated 10,000 infections would then be reduced below 10 and a state of elimination potentially achieved by approximately 2026.