Age-shifting in malaria incidence as a result of induced immunological deficit: a simulation study

Pemberton‑Ross et al. Malar J (2015) 14:287 DOI 10.1186/s12936-015-0805-1 Open Access RESEARCH Age‑shifting in malaria incidence as a result of induced immunological deficit: a simulation study Peter Pemberton‑Ross1,2*, Thomas A Smith1,2, Eva Maria Hodel3, Katherine Kay3 and Melissa A Penny1,2 Abstract Effective population-level interventions against Plasmodium falciparum malaria lead to age-shifts, delayed morbid‑ ity or rebounds in morbidity and mortality whenever they are deployed in ways that do not permanently interrupt transmission. When long-term intervention programmes target specific age-groups of human hosts, the age-specific morbidity rates ultimately adjust to new steady-states, but it is very difficult to study these rates and the temporal dynamics leading up to them empirically because the changes occur over very long time periods. This study investi‑ gates the age and magnitude of age- and time- shifting of incidence induced by either pre-erythrocytic vaccination (PEV) programmes or seasonal malaria chemo-prevention (SMC), using an ensemble of individual-based stochastic simulation models of P. falciparum dynamics. The models made various assumptions about immunity decay, trans‑ mission heterogeneity and were parameterized with data on both age-specific infection and disease incidence at different levels of exposure, on the durations of different stages of the parasite life-cycle and on human demography. Effects of transmission intensity, and of levels of access to malaria treatment were considered. While both PEV and SMC programmes are predicted to have overall strongly positive health effects, a shift of morbidity into older children is predicted to be induced by either programme if transmission levels remain static and not reduced by other inter‑ ventions. Predicted shifting of burden continue into the second decade of the programme. Even if long-term surveil‑ lance is maintained it will be difficult to avoid mis-attribution of such long-term changes in age-specific morbidity patterns to other factors. Conversely, short-lived transient changes in incidence measured soon after introduction of a new intervention may give over-positive views of future impacts. Complementary intervention strategies could be designed to specifically protect those age-groups at risk from burden shift. Keywords: Malaria, Epidemiology, Vaccines, Chemoprevention, Age shift Background Countries and organizations aiming to reduce the publichealth burden of malaria have at their disposal an increasing number of options for intervention. These cover a wide range of modes of action, potential strategies of deployment and cost, making comprehensive analysis of effectiveness and cost-effectiveness challenging. It is not possible to cover all intervention combinations of interest by field trials, thus modeling and simulation can be useful to interpolate, optimize intervention packages and explore hypotheses [1]. *Correspondence: peter.pemberton‑ 1 Swiss Tropical and Public Health Institute, 4002 Basel, Switzerland Full list of author information is available at the end of the article This is particularly the case for analyses of the long-term effects of infection blocking interventions such as long-lasting insecticide-treated nets (LLINs) [2–4] or pre-erythrocytic vaccines (PEV) [5–7], but also to chemotherapy and prophylaxis strategies including test and treat [2], mass drug administration (MDA) [8] or seasonal malaria chemo-prevention (SMC; formerly referred to as Intermittent Preventive Treatment in children or IPTc) [9]. These interventions drive complex interplay of exposure and delay of natural immunity that may have counter-intuitive effects on subsequent transmission and burden [10, 11]. The advantages of infection blocking interventions are clear; the immediate burden associated with the infection is averted, and at the same time onward transmission of the parasite can be © 2015 Pemberton-Ross et al. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons. org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Pemberton‑Ross et al. Malar J (2015) 14:287 prevented with high enough coverage of the whole population, and thus not just those receiving the intervention may be protected [12]. Such interventions directly reduce immune challenge to individuals using the interventions. MDA strategies typically stipulate age-stratified cohorts for treatment, which even in the ideal scenario of a programme with perfect coverage and compliance will only cover a given individual for the length of time they remain in the designated age band [13]. Current strategies for interventions often target children under five years of age, leaving them without protection at older ages. Excess disease incidence resulting from the immunological opportunity cost will, therefore, be expected in age groups older than those treated if everything else remains static. In addition, reductions in transmission either to intervened and non-intervened individuals also reduce immune challenge and hence acquisition of natural immunity and also potentially allows decay of pre-existing immunity. This does not argue against interventions that delay immunity acquisition, but highlights the additional need to continue or increase coverage interventions for these individuals. Averting infection and disease in one age group is thus likely to be accompanied by an excess of episodes in older age groups of the same individuals: referred to as an age-shift. Such age-shifts of clinical disease are a result of changes in exposure and delay of blood-stage malaria infection immunity acquisition, and are a general characteristic of infectious disease epidemiology [14], especially where (as with malaria) there is typically endemic stability [15] rather than epidemics. There have consequently been recurrent suggestions that interventions blocking malaria infection may lead to increases in clinical and severe disease burden in older individuals or at later time points [16–20]. While age-shifts, delays or rebounds are clearly predicted by many theoretical models of malaria dynamics [15, 21], direct measurement of these effects is generally impractical because of the short duration of most field trials, such as those used to establish the efficacy of ITNs [22–24] or of the RTS,S PEV [25, 26]. Where randomization is maintained for long enough, as in recent Phase II RTS,S trials [27, 28], a conventionally limited empirical analysis (i.e., one without accompanying serologica (...truncated)