Downloaded by guest on October 2, 2021 rtcie hsdfeeta muersos a ae increase later as can response well initially immune While as differential serotypes. this serotype other protective, the infecting against the immunity temporary induces against infection and immunity serotypes, major long-lived four a has proven (12–19), DENV has gap dengue (20). to this challenge response devel- address immune and to complex the Research expanded but 11). have 7, vaccines (6, of containment opment control for vector sufficient that not preven- acknowledged is dengue generally the has transmission, community DENV tion in but trends (10), global management to dengue due of component necessary a control yellow and Zika, (6–9). chikungunya, fever other including and dengue diseases, of Aedes-borne transmission increased for have world mobility the human geographic primed increased and strategies, expanding 96 control vector The in tive resulting (1–5). of people cases range million symptomatic 390 of million infections annual mated D dengue over interventions. effectiveness to single-approach longer-lasting amplified, com- due produce this still impracticable of bination implementations is ambitious less elimination limitations, resource If continuous despite reintroductions. decade elimina- a for dengue short-term avoided cases enable all nearly could with tion, control alongside one-time, vector vaccination a routine new upheld, aggressive by is followed vaccines campaign in-development large-scale the of either performance preliminary by the well If impacts. effectiveness independent their amplifying beyond TIRS, with conven- synergistically The however, performs vaccines, benefits. in-development for separate hypothesized their model tional is from interfere: performance estimated alone, TIRS than either and lower outperforms CYD-TDV combination that the vac- found while large-scale We one-time, campaign. a cination and introductions; coverage evalu- staggered varying We levels; including vaccines. options, implementation in-development several CYD-TDV; for ated (WHO) vaccine, results dengue Organization preliminary licensed Health only and the World exper- for and guidance (TIRS) testing spraying outcomes residual trial indoor iments; targeted by informed are model agent-based an Yucat using for vaccination combine and that control setting these vector endemic evaluated novel of an We in control options approaches. management Effective integrated dengue unabated requires programs. seem likely control pathogens and vector ranges current 2019) expanding 27, by February have review for chikungunya, (received 2019 and 24, December by approved transmitted and FL, Viruses Gainesville, Florida, of University Singer, H. Burton by Edited 98195 WA Seattle, Washington, of University Biostatistics, ucisnCne eerhCne,Sate A98109; WA Seattle, Center, Research Cancer Hutchinson Australia; 4814, QLD M Townsville Kingdom; University, United Cook 7600; 7HT, James 32611; Africa WC1E Medicine, FL South London Gainesville, Stellenbosch, Medicine, Florida, University, Tropical of Stellenbosch & University Analysis, Hygiene and of Modelling School Epidemiological London for Diseases, Infectious of Modelling Mathematical a Vazquez-Prokopec M. Gonzalo c Hladish J. Thomas interventions with combined dengue of control effective Designing www.pnas.org/cgi/doi/10.1073/pnas.1903496117 eateto netosDsaeEieilg,Lno colo yin rpclMdcn,Lno CE7T ntdKingdom; United 7HT, WC1E London Medicine, Tropical & Hygiene of School London Epidemiology, Disease Infectious of Department eateto ilg,Uiest fFoia ansil,F 32611; FL Gainesville, Florida, of University Biology, of Department rd,Mxc 9700; Mexico erida, ´ h ol elhOgnzto WO osdr mosquito considers (WHO) Organization Health World The httraesnal aftegoa ouain ihesti- with population, global the half nearly threatens that an is (DENV) virus engue | etrcontrol vector n eio tt 7yo aa u nevninmodels intervention Our data. of y 37 to fit Mexico, an, Aedes ´ p. ai raiain ako utie effec- sustained of lack urbanization, rapid spp., j eateto niomna cecs mr nvriy tat,G 30322; GA Atlanta, University, Emory Sciences, Environmental of Department a,b,1,2 | egevaccines dengue Aedes alA .Pearson B. A. Carl , oqios uha ege Zika, dengue, as such mosquitoes, Aedes j .EiaehHalloran Elizabeth M. , g | eateto isaitc,Uiest fFoia ansil,F 32611; FL Gainesville, Florida, of University Biostatistics, of Department ahmtclmodeling mathematical oqiobrepathogen mosquito-borne c,d,e,1 l etrfrIfrneadDnmc fIfciu iess etl,W 80;and 98109; WA Seattle, Diseases, Infectious of Dynamics and Inference for Center o e Toh Ben Kok , i olbrtv ntfrEtmlgclBosas nvria Aut Universidad Bioassays, Entomological for Unit Collaborative b mrigPtoesIsiue nvriyo lrd,Gievle L32611; FL Gainesville, Florida, of University Institute, Pathogens Emerging k,l,m n r .LniiJr Longini M. Ira and , il xeiet n ahmtclmdln aesonthat for shown have considered modeling being mathematical and now experiments Field are malaria performance proven like against with methods approaches, insecticide-based (11), experimental drives more individuals, to of that 17) trials efficacy. about (16, III results 100% phase additional in to produce soon currently 60 will are and vaccines 19) by Both (18, developed respectively. 100% vaccines to 90 dengue in responses tetravalent other indicate Takeda two and immunogenic- NIH/Butantan/Merck for and challenge experiments human vaccinating (24, ity of on infection only results dengue depending Preliminary recommends prior 25). laboratory-confirmed efficacy now a past 90% WHO with with people to The Recipients (23). 68 22). dis- serotype showed (14, of infections infections risk natural increased natural first by infections: simi- for followed dengue had ease (12, natural immunity it serotypes to broad that outcomes all temporary concluded immune against promis- long-term however, effective lar studies, initially was Follow-up it were 13). that Dengvaxia), indicating as ing, known (commercially while effica- immunity durable be response. broad, To cross-reactive evoke negative (21). to this disease avoiding needs severe vaccine and a symptomatic cious, of risk the doi:10.1073/pnas.1903496117/-/DCSupplemental. at online information supporting contains article This 2 1 BY-NC-ND) (CC 4.0 NoDerivatives License distributed under is article access open This Submission.y Direct PNAS a is article This interest.y competing no declare authors The is ulse aur 3 2020. 23, January published First K.B.T. and paper. C.A.B.P., imple- I.M.L. the T.J.H. and wrote T.J.H., M.E.H., G.M.V.-P., data; P.M.-S., D.P.R., K.B.T., analyzed C.A.B.P., T.J.H., research; C.A.B.P. and and simulations; performed T.J.H. mented tools; K.B.T. reagents/analytic new and contributed C.A.B.P., T.J.H., designed research; I.M.L. and M.E.H., G.M.V.-P., P.M.-S., D.P.R., C.A.B.P., T.J.H., contributions: Author owo orsodnemyb drse.Eal [email protected] Email: addressed. be may correspondence whom To work.y this to equally contributed C.A.B.P. and T.J.H. D,wihw on oudrefr hncmie with combined when control. underperform vector increasing to found CYD- we using which if TDV, particularly program, control an dengue considering regions integrated effort. in control planning inform vector should results expanded These with combined dynamic when interfering control or effects amplifying plausible have can Yucat and programs of cination dengue state the of in programs simulation realistic Using Significance f oe etrcnrl r lobigdvlpd naddition In developed. being also are controls vector Novel CYD-TDV vaccine, candidate a for results trial III Phase in arcaRojas Patricia Diana , y PNAS k acn n netosDsaeDvso,Fred Division, Disease Infectious and Vaccine f | colo aua eore n Environment, and Resources Natural of School eray1,2020 11, February b,g,l g,h al Manrique-Saide Pablo , . y h raieCmosAttribution-NonCommercial- Commons Creative iiino ulcHat n Tropical and Health Public of Division n eio eso htvac- that show we Mexico, an, ´ y | https://www.pnas.org/lookup/suppl/ o.117 vol. 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SYSTEMS BIOLOGY household-based targeted indoor residual spraying [TIRS; apply- ing residual insecticides only to Ae. aegypti resting sites; e.g., exposed low walls (26, 27)] could be effective at preventing dengue cases in endemic areas (28, 29). TIRS has also been shown to be less expensive than classic indoor residual spraying (IRS) while maintaining a high level of efficacy (30). Unfortunately, both vaccination and vector control ap- proaches have operational downsides. Without large-scale, one- time campaigns in broad age groups (also known as “catch-up” campaigns), forecast models suggest that routine vaccination of narrow age groups with a conventional vaccine against dengue would take decades to achieve high effectiveness (31). Expanded vector control, on the other hand, initially shows remarkable effectiveness but dynamically fades over time as nat- urally acquired immunity in the population declines (29, 32). The timing of these trends is complementary, and simple ordi- nary differential equation models suggest that combining the interventions might address their separate weaknesses (33). While it is important to understand general trends, sim- ple models may not provide sufficiently accurate quantitative forecasts for real-world decision making. Based on prelimi- nary estimates of intervention performance, we used our fitted model of dengue transmission in the Mexican state of Yucat´an to quantitatively assess different deployment strategies. While Fig. 1. Agent-based model structure. (Upper) Our model’s state transition future intervention decisions will need to be guided by empiri- diagram for individual humans (E, Exposed; I, infectious [A, asymptomatic; cal data not yet available, our results will be useful for narrowing S, symptomatic; and W, withdrawn from daily activity]; R, recovered; and the potential programs for detailed consideration. This work S, susceptible) and mosquitoes (E, exposed; I, infectious; and S, susceptible). also demonstrates an intervention assessment framework, which Solid arrows denote possible transitions; dashed arrows denote the influ- ence of infectious mosquitoes and humans on DENV transmission rates. can be rapidly adjusted to account for updated intervention For humans, this series of transitions can occur for each serotype; each performance. mosquito may only be infected by a single serotype. (Lower) Overall model We evaluated distinct mechanisms representing CYD-TDV spatial structure, zooming to Izamal (Insets) to illustrate detailed struc- and an extrapolation of the ongoing phase III trials for the ture. Households, workplaces, and schools (Right Inset) are placed based NIH/Butantan/Merck and Takeda vaccines considering realis- on government data and are consistent with satellite imagery (Left Inset); tic deployment options: 80% attempted coverage via routine SI Appendix, Fig. S1 shows enlarged versions of Insets. Pixel size in density vaccination in children as well as adding a one-time catch-up map is 430 × 460 m. campaign at the same coverage. Quantitative findings vary sub- stantially depending on the vaccine mechanism assumed. When simulating the combination of CYD-TDV [given only to test- improvements and to provide a consistent benchmark for com- seropositive 9-y-old children, consistent with current WHO rec- parison (Fig. 2). These updated results are broadly consistent ommendations (25)] and TIRS, the two interventions interfere with those previously published. Here, we consider two vaccine across a range of transmission settings; while their combination intervention models: 1) a conventional vaccine model with generally outperforms either alone, the result is lower than what tetravalent, durable efficacy against infection of 70% (hereafter might be na¨ıvely expected given their individual benefits. How- D70E, with hypothetical efficacy based on the results in refs. ever, if either of the NIH/Butantan/Merck or Takeda vaccine 16–19; see Fig. S13 for alternative efficacy values) and 2) a trials achieves the target efficacy outcomes—namely, demon- natural infection-like model of CYD-TDV, which is initially per- strating a tetravalent, durable, highly efficacious vaccine—then fectly efficacious but linearly wanes to zero efficacy over 2 y and we predict that new vaccine will have an amplifying interac- contributes to infection history, administered only to individuals tion with TIRS, suggesting a promising integration of control who test seropositive, with 20% false seronegative and 5% false methods currently in development. seropositive rates (SI Appendix, Figs. S8–S11 show effects of alternative test performance assumptions). For both vaccine Results models, we assume that the efficacy is the probability that each Using an agent-based model of DENV transmission in the state exposure is resisted, also known as a “leaky” vaccine mechanism. of Yucat´an, Mexico (Fig. 1), we forecast the impact of vacci- Materials and Methods has full vaccine model details. nation and vector control interventions independently and in At the population level, these distinct vaccine models initially combination. These interventions were introduced in a popu- perform indistinguishably, but CYD-TDV performance drops lation with stable dengue dynamics, and we simulated 40 y of off after 2 y, coincident with waning protection at the individual intervention to capture long-term trends. level. As expected for both vaccine models, a catch-up campaign To assess intervention performance, we focus on annual effec- (i.e., a large-scale, one-time program covering individuals older tiveness, which is the fraction of cases (i.e., symptomatic infec- than routine recipients) increases the population-level effect, but tions) prevented across the entire population, aggregated at that effect wanes, either quickly with vaccine efficacy (CYD- yearly intervals from the start of the intervention. The reduction TDV model) or more slowly with demographic turnover (D70E is measured against a baseline scenario without interventions. model), and performance eventually converges with conducting We report cumulative effectiveness (i.e., the fraction of all routine-only vaccination. TIRS has high early effectiveness but cases prevented since the start of the intervention) as well as rapidly fades as naturally acquired population-level immunity interquartile prediction intervals in SI Appendix. wanes (29).

Single-Intervention Scenarios. We updated our previous Combination Interventions. We forecast performance of both vac- single-intervention simulations (29, 31, 34) to reflect model cine mechanisms in combination with TIRS. One way to estimate

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rvns5%o ae n intervention and cases of 50% prevents Annual Effectiveness 0.00 0.25 0.50 0.75 1.00 0.00 0.25 0.50 0.75 1.00 re) eut r grgtdanal,wt oepit enlarged points some with annually, aggregated are Results green). ; iuae efrac o igeitretos vrl annual Overall interventions. single for performance Simulated 102030400 h otabtosscenario—75% ambitious most the Lower, − 0.5)(1 le n acn-nyinterventions vaccine-only and blue) ; Year CYD-TDV, Routine-Only CYD-TDV, Routinew/Catchup D70E, Routine-Only D70E, Routinew/Catchup − 5 0 75% 50% 25% Lower Vaccine Model 0. )=0 = 6) Coverage % oprsti bench- this compares TIRS B ormi.How- remain. to .2] rvns6% we 60%, prevents Upper shows ¨ ıve Vaccine Only TIRS Only omneo obnditretosmyece apicto)o alshort na fall or (interference) (amplification) of exceed may interventions combined of (Lower formance simulation Actual independently. act (Upper interventions performance combination of 3. Fig. but now, possible is intervention one time (e.g., interven- feasible same the be of the might introduction tions staggered at a but interventions unrealistic, be ambitious might two beginning Interventions. tings, Combination D70E for work. Starts this Staggered in that explore repeat not by did mediated we eligibility be but could (35), declining testing effect therefore, This and benefits. (34), future reduces infections benefit experience more to still likely or ultimately would two are thus, model they if and CYD-TDV recipients TIRS seronegative This past to new eligibility. due each reduced seroprevalence however, benefits reduced vaccination, strictly has routine group cohort For for large TIRS. eligible this future and vaccination, from seropositive be after to vaccine; likely the more are they older, are thus, candidates and vaccination Catch-up campaign. catch-up a potential the have strongly. they more up, interact scaled to are interventions matches as This intuition: magnitude. interaction short-term campaign the catch-up increase a also with programs increasing Vaccination with coverage. inter- increases TIRS magnitude had interaction CYD-TDV The ones. while has fering D70E TIRS, general, with In interactions components. amplifying individual their of formance

Annual Effectiveness after y 15 to 10 the during amplification shows only CYD-TDV 0.00 0.25 0.50 0.75 1.00 0.00 0.25 0.50 0.75 1.00 siae s iuae obndefciees Na effectiveness. combined simulated vs. Estimated 102030400 v estimates. ¨ ıve PNAS | eray1,2020 11, February acltdb suigta single that assuming by calculated ) Year | Amplification Simulated Combination Simulated Combination Interference o.117 vol. Naive Estimate Naive Estimate 75% TIRS & CYD-TDV & 75% TIRS D70E & 75% TIRS CYD-TDV & 75% TIRS D70E & 75% TIRS Single Intervention Single Intervention hw htper- that shows ) | nsm set- some In o 6 no. v estimates ¨ ıve 75% TIRS CYD-TDV D70E | 3321

SYSTEMS BIOLOGY TIRS Coverage 25% 50% 75% 1.00

D70E Routine w/ Catchup 0.75 Routine-Only

0.50 Interaction Amplification Interference

Annual Effectiveness 0.25 CYD-TDV Routine w/ Catchup Routine-Only 0.00 0 10 20 30 40 0 10 20 30 40 0 10 20 30 40 Year

Fig. 4. Combined intervention effectiveness. D70E combined with TIRS ([Left] 25%, [Center] 50%, and [Right] 75% coverage) quickly results in dengue control that equals or exceeds na¨ıve estimates. Because CYD-TDV eligibility depends on past natural infection, reducing DENV transmission with TIRS leads to interference in our model.

the other is not ready to deploy, or both are available, but are too of this vaccine mechanism for different transmission levels by costly to start concurrently). Because both aggressive TIRS and varying mosquito population density (Fig. 6). CYD-TDV effec- routine D70E vaccination with a one-time catch-up campaign tiveness still follows mosquito density and thus, transmission are individually highly effective in the first few years, concur- when serostatus testing is required. The interaction between rent starts might have little advantage. We evaluated combined CYD-TDV and TIRS remains interfering at all densities that interventions that do not begin at the same time (Fig. 5), instead we considered. At the lowest transmission level, however, this delaying the second intervention by 2, 5, or 8 y. We also consid- effect is greatly diminished, likely because 75% TIRS in a ered a less aggressive catch-up campaign for D70E: instead of low-transmission setting causes individuals in the model to typ- all individuals older than age 2, we targeted only up to age 50 ically experience zero or one lifetime infection and thus, have and spread the campaign over 2 y rather than completing it in no need for CYD-TDV. Shifting from the as fitted to the 1 y. In all instances, we found that reducing the aggressiveness high-transmission setting, the long-term effectiveness of TIRS of the catch-up campaign had minimal consequences, and within decreases by roughly half, implying reduced effect on sero- 2 y of adding the second intervention, annual effectiveness was prevalence in routine vaccination candidates and shrinking the indistinguishable from starting interventions concurrently with interference deficit. the more intense catch-up campaign. The impact on cumulative effectiveness increased with the second intervention delay but Discussion was above 80% after 20 y in all scenarios. Forecasts indicate that even ambitious vector control programs or historically high levels of durable, efficacious vaccine cover- CYD-TDV Sensitivity to Mosquito Population Density. As shown pre- age would fail to reduce DENV transmission below the endemic viously (34), CYD-TDV vaccine effectiveness is sensitive to threshold year round (29, 31, 34). Based on data for the state transmission intensity in the target population. To extend these of Yucat´an, DENV transmissibility is high enough that, given results to combined interventions, we evaluated effectiveness regular reintroductions, the long-term burden is only reduced

Annual Effectiveness Cumulative Effectiveness 1.00

0.75 Intervention Scenario TIRS First Simultaneous 0.50 Reference

Vaccine Only 1.00 75% TIRS Only Effectiveness Combination 0.75 D70E First 0.50 0 5 10 15 20 0 5 10 15 20 Year

Fig. 5. Staggered starts for D70E combinations. Staggered starts (by 2, 5, and 8 y) for both TIRS followed by D70E (Upper) and D70E followed by TIRS (Lower) compared with concurrent start (dashed gray lines). Delaying either D70E or TIRS has limited impact: after the second intervention is introduced, annual effectiveness rapidly approaches that of simultaneous starts. All staggered scenarios have 75% TIRS coverage and routine vaccination with a smaller, slower, one-time catch-up campaign.

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Fig. Annual Effectiveness vnwtotpirtzn lmnto,udrtnigteben- the understanding elimination, prioritizing without Even con- other, each complement interventions these However, 0.00 0.25 0.50 0.75 1.00 v siae obntoscnitnl upromete nevninaoe lhuhol agnlyotefrigTR ntelws transmission lowest the in TIRS outperforming marginally only although alone, intervention either outperform consistently Combinations estimate. ¨ ıve 02 04 02 04 02 040 30 20 10 0 40 30 20 10 0 40 30 20 10 0 Y-D estvt omsut ouaindniy stasiso nrae,ln-empromneo otn Y-D obntosapproaches combinations CYD-TDV routine of performance long-term increases, transmission As density. population mosquito to sensitivity CYD-TDV 6 fetvns o h rtdcd and decade first the for effectiveness >96% 0 0%(itdRfrne 150% (FittedReference) 100% 50% bredsae.Lmtdsup- Limited diseases. 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Intervention Scenario Intervention Scenario TIRS &CYD-TDV Naive Estimate Only 75% TIRS Routine CYD-TDVOnly | o 6 no. | 3323

SYSTEMS BIOLOGY that option. Vector control might cease unintentionally due to tus of the recipient. When breakthrough infections occur, we assume that other circumstances (for example, civil unrest), but a deliber- the vaccine prevents 80.3% of severe cases, which instead manifest as nonse- ate decision to cease vector control seems unlikely: vaccination vere symptomatic cases (12). This vaccine model is plausible for some of the might be sufficient for dengue, but Aedes control reduces trans- vaccines that are in phase II and phase III trials (17, 38) and serves a work- mission of multiple diseases. Furthermore, past results indicate ing estimate until successful licensure of one or more of those products. We also provide results for 50 and 90% efficacy vaccines for this mechanism in SI that ceasing vector control, whether intentional or incidental, can Appendix, which can provide guidance on how intermediate efficacy values lead to extreme outbreaks (29). that we did not simulate would perform. We also did not consider alternative timings for CYD-TDV The CYD-TDV model is based on the mechanism identified by ref. 22 combinations as we found that effectiveness was consistently as providing the best explanation of the CYD-TDV trial data and is the below 40% after 15 y, regardless of whether it was coupled same model used by the UF modeling group in ref. 34. CYD-TDV is mod- with TIRS. The accepted model of CYD-TDV is essentially one eled as a three-dose vaccine delivered at 6-mo intervals only administered of protection against disease and only for vaccinees with some to individuals who test seropositive. The vaccine mechanism includes three level of prior dengue immunity (22, 24). Although interventions effects: 1) immunity against infection (supported by ref. 39) that wanes involving CYD-TDV generally reduced the dengue disease bur- linearly following each dose, from perfect to nothing over 2 y, resulting in a complete loss of immunity against infection after 3 y from the ini- den in our model, CYD-TDV is likely not compatible with a tial dose; 2) initial immunity against severe disease of 80.3% in the case strategy to eliminate or even substantially reduce dengue trans- of breakthrough infections, which also wanes linearly to nothing over 2 mission for more than a few years. As transmission decreased, y from the most recent dose; and 3) the vaccine increments infection his- the vaccine became less useful, whether due to TIRS (in combi- tory like a natural infection, meaning that individuals who falsely test nation strategies) or CYD-TDV itself (in catch-up campaigns). seropositive are at enhanced disease risk on their first natural infection. This outcome should be carefully considered in locations con- Seropositive recipients thus unambiguously benefit from the vaccine, if templating using the CYD-TDV vaccine in combination with only temporarily, while seronegative recipients eventually have an increased new vector control efforts. risk of disease from their next natural infection. Consistent with current Building a combined intervention program by deploying its WHO guidance (25), the vaccine is only administered to seropositive indi- viduals, which we determine using a serological test. In the results, we components in different years is just one way to address logis- assume a test with 5% false seropositive rate and 20% false seronegative tical constraints. More generally, deciding how best to allocate rate; SI Appendix has additional details and consequences of alternate test finite resources among multiple interventions remains an open characteristics. question to be regularly revisited as new data become avail- Vaccination with either mechanism probabilistically prevents infections able and additional products enter the market. While single when an exposure occurs based on the vaccines efficacy at that time. Over interventions might, in principle, be able to achieve the pre- each simulated day, infectious mosquitoes may bite individuals who are dicted level of effectiveness of combined interventions, they at the same locations (i.e., house, workplace, or school). Those individuals would require very high individual efficacy and coverage. Those who do not have naturally acquired immunity (i.e., no previous infection high-performance requirements are likely to be more difficult with the exposure serotype and no infection with any serotype within the last 2 y) are considered exposed due to such bites. If exposed indi- to achieve than introducing a combined intervention built with viduals have received a vaccine, they can resist infection with probability components that have good, but not astonishing, performance. equal to the vaccine efficacy. For durable vaccines, efficacy is constant; for Combining interventions may also have impacts beyond what waning vaccines, efficacy depends on the time since the individual was we have explored here; for example, reduction of Aedes popu- vaccinated. For both models, every exposure is an independent chance lations will have benefits with respect to other diseases spread by to break through the vaccine protection (i.e., the vaccine efficacy model the vector. is leaky). As our understanding of the mode of action, performance, The two vaccine models have different target age eligibility. For CYD- and costs of available interventions improves, the question of TDV, we consider routine-only vaccination of 9-y-old children and one-time which combinations are most effective will need to be revisited. catch-up campaigns for 10- to 50-y-old individuals. Because CYD-TDV is only recommended for use in seropositive candidates, the size of the eli- We show here, however, that interventions can be strongly syn- gible population is affected by recent dengue epidemics. In our fitted ergistic, offering public health officials a more powerful control model population, seroprevalence of 9-y-old children has a median of 56% strategy than might be na¨ıvely anticipated. (interquartile range: [51, 63%]) across replicates at steady state (SI Appendix has additional characterization of the synthetic population). After inter- Materials and Methods ventions are introduced, dengue incidence generally decreases, and thus, Using an agent-based model of dengue transmission in Yucatan,´ Mexico, so does seroprevalence among 9-y-old children, decreasing the eligible we simulated the impact of a range of single and combined interventions; population for CYD-TDV. SI Appendix has full details. The transmission model was fit to dengue case, For D70E, for all but the staggered start date combinations shown in serotype, and seroprevalence data using AbcSmc (37) and then, run until Fig. 5, we consider routine-only vaccination of 2-y-old children and one- dengue dynamics were stable. Each intervention scenario was simulated time catch-up campaigns for 3 y and older. For the results in Fig. 5, we limit 10,000 times (1,000 parameter combinations from the fitted posterior each the D70E catch-up campaign to 3- to 50-y-old individuals spread over 2 y. repeated with 10 different random seeds). For both vaccine models and both routine administration and the one-time catch-up campaign, we consider 80% of the target group for vaccine cover- TIRS Vector Control Model. TIRS campaigns occur annually. During a 90-d age. Since CYD-TDV is only administered to test-seropositive individuals, the rollout period starting in late May (specifically Julian day 147, the opti- realized coverage may be lower. mal date identified in ref. 29), 75% of houses, randomly drawn each year, are treated with an insecticide that remains active for 90 d. Treatment Effectiveness and Interaction Calculations. We calculate effectiveness date for individual houses is chosen randomly within the rollout period. In (annually or cumulatively) for a single or combination intervention actively protected households, the insecticide causes 13% excess daily vector strategy as mortality, which results in an 80% reduction in the hypothetical mosquito population size at that location as well as shorter lifespans for infectious cases with intervention X mosquitoes. effX = 1 − . cases without intervention

Vaccine Models. We consider two vaccine efficacy models, which we refer to The effectiveness difference between simulated and estimated com- as D70E (representing a performance estimate for the vaccines currently in bined interventions of a vaccination strategy V and a mosquito control trials) and CYD-TDV (intended to explicitly model that vaccine). strategy M is The simple efficacy vaccine, D70E, is similar to but simpler than the vaccine used in ref. 31: durable and 70% efficacious against all serotypes

conferred in a single dose. Vaccine performance is not affected by serosta- Φ = effV+M − (effV + effM − effV effM).

3324 | www.pnas.org/cgi/doi/10.1073/pnas.1903496117 Hladish et al. Downloaded by guest on October 2, 2021 Downloaded by guest on October 2, 2021 0 .C Katzelnick C. L. 20. Kirkpatrick D. B. 19. 8 .D Kirkpatrick D. B. 18. Roiz D. 10. 7 .S X. 17. Achee L. N. 11. 5 .M cwrz .E alrn .P ubn .M ogn r h egevaccine dengue The Jr, Longini M. I. Osorio Durbin, E. P. J. A. 16. Halloran, E. M. Schwartz, M. L. 15. Capeding R. M. 13. Villar L. 12. 4 .Sridhar S. 14. lds tal. et Hladish is results simulation the reproduce https://github.com/tjhladish/dengue . Appendix to GitHub, from necessary available code All Availability interquartile Data text; the in medians in are report intervals prediction and combination parameter by .A .T art,Tereegneo elwfever. yellow of reemergence The Barrett, T. D. A. 9. Jr Reiner C. R. 8. effective- in deficient control vector dengue Is McCall, J. P. Donegan, S. Bowman, R. L. spraying 7. space peridomestic of Effectiveness Horstick, O. Smith, L. Lenhart, A. Esu, E. 6. 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