Transmission Modelling for Human Non-Zoonotic Schistosomiasis Incorporating Vaccination: Guiding Decision-and Policymaking

: Schistosomiasis, acquired by skin-penetrating cercariae of dioecious digenean schistosomes during freshwater contact, afflicts nearly 260 and 440 million people with active infections and residual morbidity, respectively. About 10 million women at reproductive age contract schistosomiasis during gestation every year. Acute schistosomiasis is characterized by pre-patent pro-inflammatory CD4+ T-helper 1 or CD4+ Th1/T-helper 17 reactivity against immature schistosomulae. Chronic schistosomiasis is dominated by post-patent anti-inflammatory CD4+ T-helper 2 reactivity against ova epitopes. Flukes co-exist in immunocompetent definitive hosts as they are capable of evading their defense mechanisms. Preventive measures should be complemented by vaccination, inducing long-term protection against transmission, infection, and disease recurrence, given the latest advancements in schistosomal vaccines. Vaccines become pivotal when considering constraints of chemotherapy, i.e., lack of protection against re-infection, and evolving resistance or reduced sensitivity. Transmission models for human non-zoonotic schistosomiasis incorporating vaccination available in PubMed, Embase and Web of Science up to 31 December 2023 are presented. Besides conceptual model differences, predictions meant to guide decision-and policymaking reveal continued worm harboring that facilitates transmission besides residual infections. In addition, increased susceptibility to re-infection and rebound morbidity, both shifted to later life stages following the intervention, are forecasted. Consequently, a vaccination schedule is pivotal that considers the optimal age for initial immunization, i.e., pre-schoolchildren or schoolchildren in a cohort-based or population-based manner, while incorporating potential non-adherers promoting ongoing transmission. Longevity over magnitude of vaccine protection to antigenic schistosomal moieties is crucial. Accounting for pre-acquired immunity from natural exposure, in utero priming in addition to herd immunity, and induced by chemotherapy is crucial. Combining, as a multi-component approach, long-term effects of vaccination with short-term effects of chemotherapy as regular repeated vaccine-linked therapy seems most promising to achieve WHO’s endpoints of transmission elimination and morbidity control.

Infections of vertebrate hosts occur during freshwater contact infested with skinpenetrating cercariae that are disseminated by species-specific molluscs [26].Cercariae transform into schistosomulae, and migrate via pulmonary, cardiac, and portal blood vessels to the hepatic vasculature [42].They reach matured to schistosomes their oviposition sites within the mesenteric venules of the bowel/rectum or the venous plexus of the urinary bladder for pairing and sexual reproduction [42].Schistosomes, capable of persisting in immunocompetent definitive hosts for decades [43], spend much of their lives in copula [44].Despite the fact that they are monogamous, i.e., a single female fitted per male gynecophoric canal, competitive polygamic mating is possible [29,45].This facilitates homoand hetero-specific inter-and intra-species crossing in the hepatic portal system [46,47].Ova deposited within venules of the portal and perivesical vasculature are transported towards the intestine or urinary bladder/ureters to be expelled purposefully via fecal or urinary routes.Once shed, the vertebrate-to-mollusc transmission for asexual reproduction continues upon miracidia hatching into freshwater [5,36,[48][49][50][51].
The standard dose is efficacious against all species, though apparently better against S. japonicum over S. mansoni and S. haematobium, and mixed infections [115,127,128].WHO's recommended treatment regimen is administered in a mass drug administration (MDA) [129] or selective at-risk manner [24,130,131].The mode of treatment depends on prevalence, i.e., low or <10%, moderate or 10-50%, and high or ≥50%, and age, i.e., schoolchildren and adults.Diagnostic accuracy matters [24,71], as seen for nucleic acid tools detecting trace levels [132] that are reported subsequent to chemotherapy [132,133] and among apparently healthy individuals [42,134].Pre-schoolchildren, at present, are unlikely to receive PZQ [128], due to paucity of efficacy and safety data [130,132,135].Schoolchildren in low-risk settings receive PZQ twice during school time or once every three years, in addition to suspected cases [136].Schoolchildren and at-risk adults, including women of childbearing age, are treated once every two years and annually in moderate-risk and high-risk settings, respectively [14, 130,136,137].
An optimal vaccine induces non-sterilizing immunity and long-term ova reductions, preferably through killing of reproductive female worms while maintaining concomitant immunity against less-pathogenic single male worms [17,150,180,199,200]. Aimed for are reductions in worms and egg expulsion by ≥75% [9,10,77], as schistosomes are nonreplicating in hosts [6,16,138].Compatibility with therapeutics and vaccines of national immunization programs is desired [180,199].

Transmission Models
PubMed, Embase, and Web of Science databases were searched for transmission models tackling human non-zoonotic schistosomiasis through vaccination.See Table 1 for methodological details and models detected.
Woolhouse's [230,231] construct delineates a phase II trial applicable to S. haematobium and S. mansoni.A partial protective vaccine with waning efficacy is administered Supplementary or complementary to natural immunity built from age-dependent parasite exposure [221].
Limited impact on the cumulative worm burden and increased susceptibility to reinfestation are predicted within a 30-year simulation period [201].The latter results in rebound morbidity later in life [232], as opportunities to acquire natural immunity gradually and cumulatively [233] through trickle infections [29] are missed following the intervention.Consequently, what matters are the age of initial vaccination, with boosters throughout life, the parasitic targets of protective immunity, including magnitude of responsiveness to them [234], and vaccine effectiveness regarding duration, extent, and interaction with natural immunity [235].
Chan et al. [236] apply models, i.e., cohort model targeting pre-schoolchildren versus age-structured community-based model [223], to foresee the effects of an anti-establishment, anti-fecundity vaccine.Factors presumably impacting vaccine effectiveness relate to targeting naïve and previously or currently infested hosts as well as chemotherapy that induces additional antigen release.[236,237].Vaccinating once at an early age, inducing long-lived protection, or vaccinating repeatedly due to short-lived protection alters parasite transmission, which is impactable further when combined with MDA [238].

Though both models show reductions in infection intensities, residual infection and parasite transmission and harboring likely continue
Chan and colleagues [239] simulate vaccine impacts on S. mansoni infection intensity and longevity of protection, including indirect effects or herd immunity [17], among a random infant and child population.Efforts combining vaccination with targeted or mass chemotherapy are assessed too.The partial differential density-dependent model [240] encompasses age-dependent parasite exposure [233,241], natural acquired immunity [71,117,240] that develops gradually and cumulatively [242,243] with waning upon reduced exposure [233], and vaccine-induced immunity directed at infestation and ova shedding.Vaccine protection reaches 75% and lasts 10 years on average.Chemotherapy reduces the per capita worm burden by 95%.Vaccine and drug coverage total 80% each [239].
Simulations reveal pivotal far-reaching reduced infection intensities subsequent to vaccinating the 1-year cohort and indirect effects of diminished transmission among the unvaccinated, indicating herd immunity.Outcomes are augmentable by prior MDA.A major finding attributable to vaccination and chemotherapy is a drift in peak infestations towards older ages.Immunizing the 7-year cohort or the 1-year and 7-year cohorts results in additional substantially declined infection intensities that are further expendable by chemotherapy.Taken together, duration over magnitude of vaccine protection and drug impact [244] is pivotal to determine the optimal age for interventions [240].It needs to be considered that immunizing the youngest leaves them unprotected later in life, while immunizing schoolchildren protects them once they are at highest risk [239].Also, repeated administration of interventions is required if effects are short-lived [17,116].
Building on classical macro-parasite modeling [138], Stylianou et al. [113] utilize a simple deterministic concept for assessing partial efficacious vaccine effects on dynamics of S. mansoni cercariae and worms, and hosts upon immunization [245].Parasitic factors looked at are female fecundity and per capita mortality that impact mating and sexual reproduction.Hosts undergo annual infant immunization or mass immunization of random individuals from a homogeneous population.Including subjects afflicted by current or past parasite exposure raises concerns.Mating assuming monogamy [130,134,216,228], density-dependent ova expulsion [246], negative binomial distribution of schistosomes per host, and basic reproductive numbers (R 0 ) [17,247] are incorporated [113].R 0 takes values of 1.0-1.4,1.5-2.5, and >2.5, resembling low-, medium-, and high-transmission settings, respectively.Parasite-to-mollusc and parasite-to-vertebrate dynamics require weeks and several years, respectively [248].
Authors delineate that a 60% effective vaccine suffices to interrupt transmission in low and moderate settings.However, increased effectiveness or multiple annual boosters, equivalent to the approaches of Anderson et al. [249], are needed in high-transmission settings.The latter also applies if protection lasts less than 5-10 years.A vaccine addressing worm establishment and survival as well as female fecundity seems equally beneficial.In low-transmission settings, ≥18 years are required for breaking parasitic transfer.This is due to slow-building immunity and background mortality that both lower the proportion vaccinated and, thus, compromise herd immunity.MDA prior to immunization seems most beneficial.Combining human and animal MDA prior to vaccinating humans as well as bovines, as applied in endemic Asian settings [153,155], appears effective.This is because short-and long-term equilibrium prevalence, i.e., balanced prevalences or R 0 < 1, can be achieved, making schistosomal elimination more tangible [121,250].
Alsallaq et al. [248] employ an age-stratified, i.e., <4, 5-14, 15-24, and >24 years, deterministic compartmental model for S. haematobium based on a high-transmission Kenyan setting.They integrate exponential fecundity due to crowding or aggregation [25,249,251], and age-stratified worm burden, addressing chances of overdispersion [245].A partial efficacious vaccine is included that targets worm accumulation and mortality [251] as well as female fecundity, with 80% efficacy each, that lasts a decade or beyond two decades when combined with MDA.Vaccination is administered with/without MDA as a recurrent childhood campaign among naïve newborns, or mass vaccination while disregarding current or past parasitic exposure.PZQ kills worms with 75% efficacy within one month.
Predictions reveal that population-based mass vaccination and repeated mass or pulse vaccination over age-selective immunization is needed for short-and long-term impacts on schistosomal transmission, respectively [252].Longevity of protection matters, similar to findings of Chan et al. [238] and Anderson et al. [249].An optimal vaccine should preferably address the acquisition of cercariae that develop to schistosomes as well as the killing of established worms [164] to interrupt transmission.Combining mass chemotherapy with regular mass vaccination for optimized reduction in existing worms is most beneficial, which is demonstrated by dramatic declines in incidence rates [201], making schistosomiasis elimination appear more feasible.
Kura et al. [130,228] (Figure S1 Supplementary Materials) utilize an individual-based stochastic construct to forecast S. mansoni transmission [144,249].Subjects receive MDA alone, assuming 86.3% efficacy, immunization alone, presuming 100% efficacy, and immunization combined with MDA.The vaccine is given to children ≤5 and ≤15 years in a cohort-based and community-based approach, respectively, including a single or repeated catch-up campaign [228].Collyer et al.'s [253] individual-based stochastic model matches Kura's, except it contains 90% vaccine efficacy and 40% adult PZQ coverage.Graham et al.'s [254] flexible individual-based stochastic framework comprises chemotherapy for diverse transmission settings [148,155,222,237].It enables adding immunization and mollusciciding [148,155,222,237].Kura's endpoints are WHO's 5% morbidity control and 1% transmission elimination [164] in low-, moderate-, and high-risk sites, as per WHO's prevalence classification.Endpoints are assessed within 300 simulations over a 15-year period.Disregarding temporary and permanent non-adherers [43,255] due to random real-life-like allocation of interventions risks ongoing parasite transmission [134,136].Neglecting current and previous infestations may evoke adverse events [130,228].

Model Considerations
In addition to conceptual model differences, predictions derived build on vaccines of varying protection and effectiveness.Vaccines are administered as age-stratified cohortbased or mass population-based regimens with variable coverage levels.
Simulations meant to guide decision-and policymaking reveal continued worm harboring that facilitates transmission and residual infections, though dependent on the risk level of a setting.Susceptibility to re-infection and rebound morbidity increases as opportunities to acquire natural immunity gradually and cumulatively are shifted to later life stages following the intervention.
Consequently, time points of vaccination, including potential boosters throughout life, are pivotal.Targeting pre-schoolchildren likely leaves them unprotected later on, while targeting schoolchildren probably protects them when they are at highest risk.Longevity over magnitude of protection to antigenic schistosomal moieties is crucial.This is because long-lived protection aims for a single vaccine administration, while short-lived protection requires repeated administration.Notably, interactions with natural immunity [2] also derived from in utero priming and indirect effects or herd immunity must not be disregarded.Combining long-term effects of vaccination with short-term effects of chemotherapy [121] as regular repeated vaccine-linked therapy in contrast to a sole intervention seems most promising to achieve WHO's endpoints.
Sm-TSP-2 Alhydrogel-adjuvanted was given to healthy, non-exposed American male and non-pregnant female adults aged 18-50 years in a phase I safety, reactogenicity, and immunogenicity trial with 12-month follow-up.A total of 30 ug and 100 ug over 10 ug rSm-TSP-2 induced the highest IgG titers at 4.5 months post-immunization, with waning at 5.5 months among all arms [172,173].Sm-TSP-2/Alhydrogel was also administered to healthy, exposed Brazilian male and non-pregnant female adults aged 18-50 years in a phase Ib safety, reactogenicity, and immunogenicity trial with 12-month follow-up [171,174].IgG and IgG subclass immunoglobulins, with IgG1 being preponderant across arms, peaked two weeks after administering the third dose.Antibody levels declined across arms at the end of follow-up, except for the 100 ug arm.Findings from immunizing healthy, exposed Ugandan male and non-pregnant female adults aged 18-45 years with Sm-TSP-2/Alhydrogel in a phase I/IIb dose escalation, safety, immunogenicity, and efficacy trial with 23-month follow-up are pending publication (trial status: active, not recruiting) [170].
Sm14 GLA-SE-adjuvanted was administered intramuscularly followed by two boosters to healthy, non-exposed Brazilian male and non-pregnant female adults aged 18-49 years during the phase I safety and immunogenicity trial with 4-month follow-up.It led to augmenting total IgG titers in 88% of subjects, commencing from the first booster on day 30, as well as IgG1-4 subclasses, while lacking IgE expression [263,264].Findings from the Sm14/GLA-SE IIa dose escalation safety and immunogenicity trial with 3-month follow-up among healthy, exposed Senegalese male adults aged 18-45 years receiving a single pretreatment with PZQ [167] are pending publication (trial status: completed).Healthy and S. mansoniand/or S. haematobium-infected Senegalese children aged 8-11 years obtained Sm14/GLA-SE in a phase IIb safety and immunogenicity trial with 3-month follow-up subsequent to administering one pre-treatment with PZQ [169]; the findings are pending publication (trial status: completed).
Sh28GST Alhydrogel-adjuvanted was given subcutaneously to non-exposed Caucasian males aged 18-30 years in a phase I dose escalation, safety, tolerability, and immunity trial with 6-month follow-up.It elicited a preponderant IgG1 response over IgG2-4 subclasses following the first dose up to trial end, while IgA over IgE remained low throughout [265,266].S. haematobium-infested Senegalese male and female children aged 6-9 years received, in a phase III2 safety, efficacy, pathology, and immunogenicity trial with 38-month follow-up, Sh28GST/Alhydrogel sub-cutaneously subsequent to three doses of PZQ pre-treatment [181,182].The median follow-up without recurrence was 22.9 and 18.8 months among vaccinees and controls, respectively.At trial end, 86.4% of the vaccinated experienced ≥1 recurrence compared to 89.6% of controls.In the vaccine arm, total IgG titers were augmented up to month 65 and did not wane up to trial end.IgG1, IgG2, and IgG4 subclass immunoglobulins developed similar to total IgG, while IgG3, IgA, and IgE remained low throughout.
As raised by Anderson et al.
[134], acquired protective immunity, i.e., widening of antibody spectra with switching from ova-specific IgM and IgG1-2 to larval-and wormspecific IgE [270] in juvenile and adult hosts, respectively, needs to be considered when making predictions to guide decision-and policymaking.This is because intervening measures [117] and natural exposure [242,271] as well as in utero priming [11,48,76] may alter immunoresponses.Interferences among tegumental and cytosolic antigens [108] released subsequent to PZQ and vaccine antigens is speculated to cause non-specific unwanted immunoresponses [16].Also, Africans as opposed to Caucasians have more exhausted and activated natural killer cells, differentiated T-and B-cells, and pro-inflammatory monocytes [16].Mediated immunity alters immunoprofiles that possess phenotypical and functional heterogeneity due to concomitant infections and genetic diversity [16].
In addition to enhancing efforts of vaccination and chemotherapy as multi-component approaches [109], health education in line with socio-cultural and ethnic contexts is capable of impacting human hosts' behavioral attitudes sustainably [134].Pre-schoolchildren and schoolchildren from S. mansoni hyperendemic Marolambo, Madagascar, for instance, acquired better schistosomal understanding, i.e., 52-75% pre-education versus 83-98% posteducation, and knowledge about preventive measures, i.e., 32-63% pre-education to 79-96% post-education [272].Consequently, defecation into latrines over free-range and open water sources was practiced more often as well as minimizing water contacts [138,258], both associated to lower odds of schistosomal infestation [254].Experiences from a long-lasting health educational program directed at Chinese aged 6-60 years from the high-transmission area of Poyang Lake revealed augmented schistosomiasis knowledge, i.e., 85.4% (p < 0.001) in schoolchildren and 29.5% (p < 0.001) in women [118].Subsequently, water contacts by means of play and recreational activities and domestic chores declined, leading to reduced re-infections and prevalences by 83.7% and 63.4%, respectively.Effects were lower in males, likely due to occupational activities in agriculture and fishing.
Natural and, more importantly, anthropogenic environmental modifications raise concerns of breaking species isolation barriers [273] and derange dynamics and distributions of schistosomes [134,217,274].Species sympatry and interplay, host switching or spillover through heterogeneous mixing [34], and expansion to new favorable habitats facilitated by altered fluke vigor [26,273] are likely consequences [273,275].
Examples are the construction of water dams at Senegal and Bafing rivers, Senegal [276], or Yangtze River, China [156], and irrigation channels in the Awash Valley, Ethiopia [277], as well as forest clearance and agricultural development at Loum, Cameroon [278].Notably, Gurarie et al. [217,279] reported 1.1-and 4.7-fold increased risk of urinary and intestinal schistosomiasis, respectively, compared to non-irrigated settings.Destroying Madagascar's Dabara dam and adjunct irrigation channels reduced S. mansoni even without chemotherapy [217].King et al. [278] demonstrated S. haematobium as the dominant species in Cameroon within 25-30 years subsequent to deforestation and agricultural expansion in the 1960s.Also, regular, prolonged mollusciciding beyond the maximum worm life expectancy [248] by chemical and biological means, such as natural predators or competing organisms [109,134,258], impacts the schistosomal spread.Mollusciciding combined with chemotherapy decreases novel infections and re-infections [280-282], e.g., from 12.5-40% to <9% in S. mansoni endemic Makueni, Kenya [283], except for insufficient ecological overlap [284].
Movement of seasonal migrant laborers or seminomadic pastoralists seen in Richard-Toll, Senegal and Awash, Ethiopia [277,285], and large-scale population re-settlements around the Three Gorges Dam, China [156] increase concerns.Interestingly, human migration between Senegal and Corsica/France for occupational opportunities likely reintroduced schistosomiasis to Europe in 2013 despite paucity in understanding the presence of Bulinus spp.and Planorbarius spp.molluscs [286,287].

Conclusions
Model predictions aiming to support decision-and policymaking towards 1% transmission elimination and 5% morbidity control demonstrate that only a multi-component approach containing vaccination will likely be capable to address the WHO's goals.Combining long-term effects of vaccination with short-term effects of chemotherapy as regular repeated vaccine-linked therapy seems most promising.Notably, vaccine effects in simulations are derived solely from experimental animal models rather than human trials.The population targeted for intervening measures needs to be selected in the context of the risk level of a setting, and the measures' parasitic targets, i.e., infection, fecundity, establishment and morbidity, and coverage, i.e., 40-80% for PZA MDA and 60-100% for vaccine, as well as efficacy, i.e., 75-95% for PZQ MDA and 15-100% for vaccine, and longevity of protection, i.e., 1-3 yrs for PZQ MDA and 10-50 yrs for vaccine.Notably, longevity over magnitude of protection is pivotal.Addressing pre-schoolchildren likely leaves them unprotected later in life, while directing measures at schoolchildren probably protects them when they are at highest risk.Administering chemotherapy additionally to around 40% of adults may enhance population-based effects.Vaccination as well as antiparasitic therapy needs to be given repeatedly, as demonstrated by simulations, including catch-up campaigns, as immunity in addition to herd immunity builds slowly.Notably, non-adherence or noncompliance constituting sources of ongoing transmission, and current and/or previous infections, as well as existing acquired immunity, must be taken into account to avoid adverse events.

Table 1 .
Schistosomiasis dynamic transmission models containing vaccination as intervening measure.