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Workshop report: Schistosomiasis vaccine clinical development and product characteristics
Vaccine 34 (2016) 995–1001
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Conference report Workshop report: Schistosomiasis vaccine clinical development and product characteristics
a r t i c l e
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Keywords: Schistosomiasis Vaccine Clinical development plan (CDP) Preferred product characteristics (PPC) Target product profile (TPP)
a b s t r a c t A schistosomiasis vaccine meeting was organized to evaluate the utility of a vaccine in public health programs, to discuss clinical development paths, and to define basic product characteristics for desirable vaccines to be used in the context of schistosomiasis control and elimination programs. It was concluded that clinical evaluation of a schistosomiasis vaccine is feasible with appropriate trial design and tools. Some basic Preferred Product Characteristics (PPC) for a human schistosomiasis vaccine and for a veterinary vaccine for bovine use were also proposed.
1. Introduction As a follow-up from March 2013 meeting, which was cosponsored by the National Institute of Allergy and Infectious Diseases (NIAID) and the Bill & Melinda Gates Foundation (BMGF) [1], a schistosomiasis vaccine meeting was conducted in November 2013. The goal of the meeting was to continue discussing how a schistosomiasis vaccine should be used in public health programs, what the desirable Target Product Profile (TPP) for this vaccine should look like, and how a vaccine could be tested in clinical trials should there be one available in the near future. A group of 25 extramural schistosomiasis investigators, concerned intramural investigators, and Program Staff from the NIAID attended the meeting. It was concluded that clinical evaluation of a schistosomiasis vaccine in the field is likely feasible but would be challenging, and mathematical and computational modeling could be a valuable tool for informing the design of a TPP. Some basic product characteristics for a schistosomiasis vaccine for humans and a veterinary vaccine for bovines were proposed to guide early-stage product development. Below is a summary of the workshop discussions and of the further follow-on post-meeting group/subgroup communications and recommendations. 2. Timely opportunities for the schistosomiasis vaccine community Neglected Tropical Diseases (NTD), including schistosomiasis, continue to be a part of the NIAID’s Global Health agenda. Schistosomiasis is an acute and chronic disease caused by three major Schistosoma species, Schistosoma (S.) mansoni (S.m.), S. japonicum (S.j.), and S. haematobium (S.h.). The parasites establish their infection of human host by penetrating human skin in larval form and develop into adult worm in human body. Female worm would release eggs, which are either trapped in the body tissues causing immunopathology in intestinal (for S.m. or S.j.) or urogenital (for S.h.) organs or passed out in the urine or faeces to continue their life cycle and transmission. Vaccine against schistosomiasis is considered beneficial to the current control programs and a critical tool in 0264-410X/$ – see front matter http://dx.doi.org/10.1016/j.vaccine.2015.12.032
achieving the ultimate goal of global elimination of the diseases [1]. The Institute has already established several available preclinical service contract resources and the Vaccine Treatment and Evaluation Unit (VTEU) program to accelerate translational projects into new intervention tools, and it has supported discovery research and early development activities for NTD vaccine candidates, including several schistosomiasis vaccine candidates. In addition, the BMGF strongly supports current schistosomiasis control and elimination strategies and will continue to monitor and landscape advances toward new tool developments, including vaccines. Throughout the meeting presentations, it was apparent that financial support for most of the schistosomiasis vaccine early development mainly stemmed from the Governments and in some cases, some nonprofit organizations (Table 1). In the absence of prominent pharmaceutical involvement and limited support from other prominent organizations, it was highly encouraged that the schistosomiasis research community should actively strive to attract support from other non-conventional R&D investment sources. For example, the hookworm vaccine development effort, which is carried out by the Sabine Vaccine Institute, has attracted support from entities in the helminth endemic country Brazil. While the resource for schistosomiasis vaccine development has been constrained for decades, it was agreed that the community should work together to show unity of purpose, combine strengths, establish collaborations and integration of projects and strategies to maximize resources, and continue to show progress both conceptually and in real-time development effort. As the product development stage moves further downstream and more promising data are available, the development risk can be expected to decrease. More developers are anticipated to join in the mission to ultimately bring products to licensure. One of the major concerns for the community is the lack of understanding of the potential impact of a schistosomiasis vaccine on the global health. Since mathematical and computational modeling has been utilized to address the impact of new interventions and strengthening of business cases, several investigators presented their modeling tools to assess the vaccine impact on the schistosomiasis control and elimination program. One method [2]
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Table 1 Vaccine candidates in development and funders. Schistosoma
Vaccine
Development stage
Developer
R&D sponsors
S. haematobium
Monovalent recombinant protein Sh28GST (glutathione S-transferase) with adjuvant (Bilhvax)
Phase III
Inserm & Eurogentec
Inserm, EPLSa
S. mansoni
Monovalent recombinant protein Sm14 (fatty acid binding protein) in GLA-SE
Phase I trial completed
Fiocruz
Ministerio da Saude, Fiocruz, WHO
S. mansoni
Monovalent recombinant protein Sm-TSP-2 (tetraspanin surface antigen) with adjuvant
IND-filing, Phase I study on-going
Sabin Vaccine Institute
Blavatnik Charitable Foundation Mort Hyman NIAID
S. japonicum S. mansoni S. haematobium
DNA prime, recombinant protein boost Sj23 (Tetraspanin) and SjTPI (Glycolytic enzyme)
Field studies in water buffalo and cattle
Univ. of Georgia
Wellcome Trust NIAID NHMRCb
S. mansoni
Monovalent recombinant protein Sm-p80 (Calpain) with adjuvant
Preclinical process development
Texas Tech Univ. Health Sciences Center
NIAID Thrasher Research Fund Bill & Melinda Gates Foundation
S. japonicum
Monovalent recombinant protein Sj97 (paramyosin) with adjuvant ISA206
Proof-of-concept in animals
Brown University
NIAID
S. japonicum
Bivalent [SjIR (insulin receptor) or with SjTPI] recombinant proteins with adjuvant
Proof-of-concept in animals
Queensland Institute of Medical Research
NHMRC
a b
EPLS: Centre de Recherche Biomedicale, Espoir Pour La Sante. NHMRC: Australia National Health and Medical Research Council.
was to develop a clinical and economic outcome model to profile the costs, followed by developing an economic/operational model for each potential intervention, and subsequently link these models to a schistosomiasis transmission model to assess the impact of each intervention (in this case, vaccine) on transmission. The other method was to evaluate the impact of an intervention (e.g., vaccine) on transmission by studying the basic reproductive number R0 , defined as the average number of female offspring produced (that develop into adult worms) by one fertile female worm throughout her lifetime in the absence of density-dependent constraints, or by using mating probability in a stratified worm burden model, a compartment model that distributes human infectious burden among different infection intensity strata based on the observed field data [3]. Moreover, the group agreed that an important utility for the modeling is to guide the development of TPPs based on the desirable economic value or public health endpoint of a particular vaccine. Examples were presented to illustrate this application, such as the economic modeling for Visceral Leishmaniasis [4] or Chagas’ disease [5]. The modeling of schistosomiasis vaccine is still at its infant stage and many more researches are needed. Given the complexity of the schistosome biology and multiple existing interventions for the control and elimination program, some basic critical parameters worth incorporating were proposed: parasite species (S.m./S.h.); targeted parasite lifestages; level and duration of efficacy; costs of production and distribution; targeted population; and the types of vaccines (e.g., anti-fecundity or anti-infection). Similarly, several other possible vaccine or vaccination-related features were suggested for consideration. For example, immunity may not be complete and vaccine effects may be short-lived; prior infection/treatment can boost vaccine effects; and vaccines could affect worm fecundity and male to female balance or disrupt the balance between immunoregulation and immunopathology. 3. Vaccine candidates for schistosomiasis Recent progress in schistosomiasis vaccine development was discussed (Table 1). Several forms of vaccines are on the horizon. Bilhvax3, a vaccine candidate based on S.h. parasite protein glutathione S-transferase Sh28GST, which prevents both clinical
and parasitological recurrences of S.h. infection in children, is currently under Phase III of human clinical evaluation [6]. The panel also noted other vaccine candidates that reduce worm burden and egg outputs of S.m. infection in small animals and in some cases non-human primates (NHP) (e.g., S.m. proteins fatty acid binding protein Sm14, Tetraspanin Surface Protein antigen TSP-2, and calpain protein Sm-p80) [7–11], or kill established worms (Sm-p80) [12]. These candidates would most likely be developed as human prophylactic vaccines for susceptible populations in endemic areas. Currently, the Sm-p80 or the S.j. Insulin Receptor protein SjIRbased vaccine has also been shown to preferentially reduce female worm burden and reduce egg shedding in animals. The strong anti-fecundity impact of this type of vaccine provides additional transmission blocking benefits. Other vaccines like S.j. parasite proteins Tetraspanin Sj23/Glycolytic enzyme SjTPI, paramyosin Sj97, and SjIR-based vaccines, all of which have been tested in small animals and showed protection against S.j. infection [1,13–16], are being further tested in water buffalo prior to any human clinical trial. These vaccines would most likely first be developed as veterinary vaccines for bovines, which indirectly reduce parasite transmission to humans and thus potentially serve as transmissionblocking vaccines for human populations. The types of vaccines needed for global control and elimination programs were further discussed. Since schistosomes have a complex life cycle involving different developmental stages (e.g., cercariae, schistosomulae, adult worm) migrating through and residing in a variety of anatomical sites in the human host coupled with the prolonged time for disease induction and manifestation, the traditional term of infection cannot be clearly and easily elucidated for “schistosome infection”, as, for example, is clearly defined for an acute viral infection for which the timing or the anatomical site for infection or disease presentation are well known. As a result, there was apparent confusion in the schistosomiasis vaccine field about the terminology of a therapeutic vaccine vs. a prophylactic/preventive vaccine. Some investigators tended to define the therapeutic vaccine based on the infection status of the host (i.e., a vaccine intended for infected individuals) while others preferred to define a therapeutic vaccine based on the targeted biological stage of the parasite (i.e., a vaccine which exhibits efficacy against established adult worms in a chronic infection). Traditionally, a
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prophylactic vaccine is used to provide lasting protection against a new infection, whereas a therapeutic vaccine combats existing diseases instead of offering long-lasting protection against new infections or symptoms. Because the development strategy for a therapeutic vaccine is in general substantially different and less cumbersome than a prophylactic vaccine, the meeting participants emphasized that understanding the ultimate purpose of the vaccines would be essential for developing clear clinical or product development plans. Since a schistosomiasis vaccine will most likely be used in endemic settings in the context of other control programs, regardless of the infection status of the target individuals, the traditional definition seems more clear and accurate. Most of the vaccine candidates mentioned above could be developed as the traditionally defined prophylactic vaccines for human usage (i.e., to prevent new infection, hitherto to reduce disease recurrences or block further transmissions). Some candidates could have the advantage of being developed first as veterinary vaccines for bovine (to prevent new infection and reduce disease recurrences in bovines) and transmission-blocking vaccines for humans (to reduce further transmission from bovines to humans) before being developed as preventive vaccines for human use.
4. Clinical development plan (cdp) considerations Clinical evaluation of a schistosomiasis vaccine, especially an advanced efficacy trial, has been a great challenge to the community. A Phase I trial that evaluates safety, reactogenicity, and sometimes immunogenicity is less controversial and rather straightforward. Most likely, all the above-mentioned human vaccines will be targeted toward a broad population, especially children in endemic areas. These vaccines should be tested in naïve unexposed adults first (non-endemic area) before being tested in infected adults, and then age de-escalated into uninfected and infected children in endemic areas. There were discussions about the possibility of conducting the first Phase I safety study in endemic areas without any safety testing in naïve individuals in non-endemic areas if permission from the Regulatory agencies of the respective endemic countries could be obtained. However, this would risk being unable to conclusively dissect the causes of any potential safety issues (host vs. product), as seen in the case of the first Phase I hookworm vaccine trial in Brazil [17,18]. Most of the Phase I studies also include vaccine-specific antibodies, antibody isotyping, and cell-mediated immune responses as secondary endpoints to guide future Phase II immune studies. In some cases, multiple Phase I trials are designed to address doses, adjuvant, or route of administration issues. In general, a Phase II trial program is to continue evaluating the safety and immunogenicity of vaccines in endemic areas with similar trial design to the Phase I study, and involve a larger number of subjects. Investigators typically try to optimize doses, adjuvant, schedule of immunizations, and route of administration in Phase II studies. Additional considerations include designing phase II studies to collect preliminary efficacy data early in development to guide future Phase III trials in defining realistic clinical efficacy endpoints. Depending on the level of the disease prevalence, it may be challenging for the community to obtain any statistically meaningful information with a relatively small number of subjects. A Phase III efficacy trial was the focus of discussion. The community agreed that cohorts that are suitable for efficacy trials in endemic areas do exist. The level of disease prevalence varies from time to time, depending on the local drug treatment program, and there can be considerable variation in annual infection rates due to climatic conditions and changes in the environment. Nevertheless, with high reinfection rate in some areas such as in Leyte, Philippines
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where reinfection rate could be 50% at 6 months post treatment, a small Phase III efficacy trial with as few as 200 subjects per group to detect at least 50% reduction in incidence could be feasible. The group recommended some baseline epidemiology studies to characterize cohort populations should be carried out prior to efficacy trials to ensure trial feasibility. In addition, it has been a great challenge to the community to define clinical efficacy (the clinical endpoint for schistosomiasis vaccines) and the method to quantify the endpoints. Although multiple efficacy readouts can be performed for animal studies (such as worm burden, adult worm sex balance), the method to quantify human clinical efficacy endpoints (infection or pathology) could currently be limited to measurement of egg output. It was highly recommended that methods with great sensitivity, which are able to detect egg output early before clinical manifestation occurs, should be developed. A recently available CAA diagnostic assay that detects worm antigen for all three major human schistosome species in serum or urine with high sensitivity [19] could be an extremely valuable tool and should be further explored for detecting vaccine efficacy signals early in a Phase III trial, thus allowing a proxy for worm burden and also shortening the lengthy trial process. A method to assess male vs. female worm burden will still need to be developed to assess the potential efficacy of anti-fecundity vaccines on female–male worm imbalance. In fact, the pathological consequences of remaining male worm in the vaccinated individuals, if any, although not expected to present a problem, still remain unknown. Other caveats that could affect efficacy outcomes were also pointed out, such as the parasite infection history of the volunteers (or any other co-infections), pretreatment with praziquantel (PZQ) for de-worming and the fact that PZQ treatment does not always cure the individual, and the timing of treatment related to vaccination which could potentially alter the vaccinee’s immunological status. Thus far, the Bilhvax3 is the only example to illustrate a clinical development path for a schistosomiasis vaccine, although it might not be easily generalized to other types of schistosomiasis vaccines (Fig. 1). The vaccine is designed as a conjunct therapy with PZQ treatment for infected school-aged children. However, the ultimate efficacy in a Phase III design is represented by the prevention of emergence of clinical and parasitological recurrences of S.h. infection (ClinicalTrials.gov: NCT00870649). In the trial, the delay of the first recurrence of the pathology due to S.h. infection was measured during a 4-year follow-up period. The recurrence of pathology was indicated by positive micro-hematuria and appearance of parasite eggs in urine. In light of this, it might be more accurate to describe the Bilhvax 3 as a preventive vaccine since the vaccine is to provide a long-lasting protection against re-infection and recurrences of the pathology (Fig. 1). The clinical development of the vaccine started with a small size (N = 24) Phase Ia trial in healthy adult subjects in a non-endemic country, followed by a Phase Ib trial in healthy children in endemic area [6]. Once safety data and evidence of immunity were collected from the healthy population who received the vaccine alone, the vaccine, together with PZQ administration, was then subject to a Phase IIa/b study in infected adults followed by a Phase IId studies in infected children in endemic regions (Giles Riveau, unpublished data). The final Phase III controlled, randomized, double-blind efficacy trial was built on sufficient safety data from a total of 112 subjects of the prior Phase I and II studies, and to evaluate the vaccination together with PZQ treatment on prevention of clinical and pathological recurrences (https://clinicaltrials. gov/ct2/show/NCT00870649?term=NCT00870649&rank=1). The Phase II and III results are still pending and the future CDP beyond Phase III was not clear at this point. Nevertheless, participants acknowledged that the existing clinical development path of the Bilhvax represents a unique example demonstrating the feasibility of a clinical efficacy study for a schistosomiasis vaccine. Admittedly, it was recognized that an efficacy trial for a schistosomiasis
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Fig. 1. Clinical development path for the bilhvax vaccine candidate against urinary schistosomiasis recurrences. The adjuvanted recombinant Shj28GST protein Bilhvax vaccine was tested in a Phase III clinical trial carried out by the Biomedical Research Center EPLS, Saint-Louis, Senegal.
vaccine with a broader application, for example, a vaccine to prevent infections of all three human parasite species, would be more challenging, yet not insurmountable. The community should work together to carefully define clinical endpoints associated with different parasite infections and, if needed, design a set of integrated clinical endpoint measurements for vaccines targeting different forms of schistosomiasis. The topic of establishing a human challenge model to ease the burden and shorten the timeframe for clinical efficacy evaluation of schistosomiasis vaccines was raised. The meeting participants unanimously agreed that the community is still not ready to take on the endeavor, even with a highly sensitive diagnostic tool available that allows early detection and treatment of challenged individuals such as the CAA diagnostic assay. The fact that only one drug PZQ is available for treatment, the incomplete treatment effectiveness of the PZQ, and the possibility for larva trapped in tissues or lungs that cause pathology prior to symptom appearance, were acknowledged to present serious impediments to the development of a human Schistosoma challenge model. 5. Preferred product characteristics (ppc) Short of sufficient development interest from industry, the community must actively define a TPP to guide the thinking and development strategy. During the meeting, the TPP was not discussed extensively due to time constraints. The group realized the challenge at this stage of defining a universal TPP for vaccines against pathogens with unique geographical distributions, prevalence, biology, and disease presentations. It is agreed that some basic characteristics for a desirable vaccine could be tackled post-meeting by the group. Follow-up conversations among groups and subgroups have led to a tentative description of some basic Preferred Product Characteristics (PPC) for a human prophylactic vaccine against schistosomiasis (Table 2) and a veterinary vaccine against S.j. (Table 3). Depending on the types of schistosomiasis vaccines, the overall product development strategies need to be tailored to complement the existing control programs. The indication for a prophylactic vaccine should be to prevent infection caused by at least one
parasite species (acceptable) or all three species (optimistic) (Table 2). Ideally, the same vaccine may also have therapeutic effects to treat the existing disease (ideal). Preclinical evidence indicates that the proposed indications to prevent all forms of human schistosomiasis are not far from reality. Some vaccine candidates have been shown to reduce worm burdens caused by S.m., S.j., and/or S.h. infection, and kill the adult worms to reduce pathology caused by S.m. even though the level of protection or treatment efficacies may not be optimal. Since the vaccine will be used in the context of Mass Drug Administration (MDA) programs, the target population should be the susceptible individuals in endemic countries, most likely 18–59 years of age adults in highrisk occupations or areas and high-risk school age children (3–12 years of age) whose contact with infected water is frequent. The target level of protective efficacy is subject to debate. Some investigators considered that the proposed >75% reduction in overall egg shedding is too high for a vaccine to be used together with MDA and is likely unattainable. Other preclinical data did suggest that >75% reduction in egg output is possible, for example, the Sm-p80 vaccine (SchistoShield) had shown to provide close to 100% reduction in female worm burden; these observations are currently being confirmed using a larger sample size of baboons (n = 40) (Siddiqui, unpublished). Modeling data are surely needed and hopefully will be available soon to improve understanding and guide future development efforts. Given existing annual MDA programs, the duration of protection efficacy for the vaccine should be around 2–3 years, which would be superior to current PZQ drug performance. No annual boosting should be needed. Other product characteristics such as dosage, storage, and stability requirement were defined in the Table 2. Additionally, considering the pre-existing IgEassociated generalized urticarial event observed in a Phase I trial of a helminth vaccine, [16], one quality profile relevant to the safety of the schistosomiasis vaccine antigen was pointed out: the vaccine antigen should not react to IgE sera from endemic countries to prevent any potential allergic reaction, since the vaccine is intended for all susceptible individuals regardless of their prior infection history. This still remains controversial since the current best correlate of resistance to reinfection in the natural setting appears to be IgE levels [20–22]. Another important feature to consider is the scale
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Table 2 A prophylactic vaccine to prevent Schistosoma infection. Product characteristics items
Acceptable (minimum)
Target (optimistic)
Ideal (maximum)
Indication
Prevention of infection by one of the three human Schistosoma parasites (i.e., S. mansoni, S. haematobium, or S. japonicum)
Prevention of infection by all S. mansoni, S. haematobium, and S. japonicum parasites
Prevention of infection and treatment of Schistosomiasis caused by all S. mansoni, S. haematobium, and S. japonicum parasites
Target populations
Population in endemic countries or regions, especially adults (18–59 years of age) in high-risk occupations or areas and a high-risk school age children (3–12 years of age).
Population in endemic countries or regions, especially adults (18–59 years of age) in high-risk occupations or areas and a high-risk school age children (3–12 years of age).
Population in endemic countries or regions, especially adults (18–59 years of age) in high-risk occupations or areas and a high-risk school age children (3–12 years of age)
Efficacy
Reduce at least 75% infection by one of the S. parasite species
Reduce at least 75% infection by all human S. parasite species
Reduce at least 95% infection caused by all human S. parasite species
• Efficacy readout: egg output and/or
• Efficacy readout: egg output
worm burdena
and/or worm burdena
• Efficacy readout: egg output and/or worm burdena
Duration of protection Dosage Route of administration
2–3 years after last dosing Parenteral administration (e.g., I.M.)
2–3 years after the last dosing Parenteral administration
5–10 years after last dose I.M.
2 doses administration, no need for further doses after booster dose No more than 6 months period
2 doses needed, no need for further doses after booster dose About 3 month period
One dose injection for primary series, no need for booster One time administration
Quality profile of the product that defines safety and characteristics
The vaccine antigen should not react to IgE from target population; moderate local injection site reactions; incidence of SAEs no more than licensed vaccine product. The rest of the safety and reactogenicity will be developed and refined during the development process.
The vaccine antigen should not react to IgE from target population; moderate local injection site reactions; incidence of SAEs no more than licensed vaccine product. The rest of the safety and reactogenicity will be developed and refined during the development process.
No safety and reactogenicity concern.
Concomitant use
Can be co-administered with local MDA other interventions. No interference or adverse interactions with:
Same
Same
Frequency of dosing Duration of dosing Product criteria
• Prior or subsequent local antihelminth drug treatment (e.g., PZQ)
• Co-administered with any EPI vaccines
• Prior or subsequent routine child and adult vaccines within a two week window Manufacturing
a
Scale-up proposed
Initially suitable for Phase I study; further defined manufacturing process and product suitability will be followed after the Phase I investigation
Storage
−20 ◦ C–4 ◦ C
Store at −20 ◦ C–4 ◦ C
Store at 2–8 ◦ C or room temperature
Stability
Expected to be >3 years; investigational product can be >1 year
>3 years
>10 years
When method of detection available.
up for manufacturing. Given a substantial investment requirement for a scale-up manufacturing process, it may be wise to focus on a process suitable for a Phase I study first, and further optimize the manufacturing process and define the product suitability later after the Phase I investigation. Suggestions were also made that process reproducibility and low cost for manufacturing are essential early steps for a schistosomiasis vaccine seriously being considered for phase II studies and beyond. Strategies to maximize the utilization of limited investment resources and balance all the development risks will need to be considered carefully by the community.
For those vaccine candidates that could also be veterinary vaccines for bovines to prevent S.j. infection, their PPC for veterinary vaccines is rather straight forward (Table 3). The vaccine would be for local usage in water buffalos or cattle in some transmission hot spots in China and Southeast Asia; therefore, local animal health regulatory agencies should be consulted for product development strategies. It was pointed out that the safety profile of this vaccine seems less stringent than those for human application. Even a Grade II reactogenicity or vaccination-associated Adverse Event (AE) could be considered acceptable. The biggest debate was again
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Table 3 A veterinary vaccine for bovines (water buffalo/cattle) to reduce/eliminate human infection by Schistosoma japonicum. Product characteristics items
Acceptable (minimum)
Target (optimistic)
Ideal (maximum)
Indication
To prevent S. japonicum infection in water buffalo/cattle and reduce transmission of S. japonicum from water buffalo/cattle to humans
To prevent S. japonicum infection in water buffalo/cattle and reduce transmission of S. japonicum from water buffalo/cattle to humans
To prevent S. japonicum infection in water buffalo/cattle and reduce transmission of S. japonicum from water buffalo/cattle to humans
Target populations
Water buffalo/cattle in endemic countries or regions (Southeast Asia)
Water buffalo/cattle in endemic countries or regions (Southeast Asia)
Water buffalo/cattle in endemic countries or regions (Southeast Asia)
Efficacy
Prevention of infection in water buffalo/cattle by >60%, reduce transmission from bovines to humans by at least 60%
Prevention of infection in water buffalo/cattle by >80%, reduce transmission from bovines to humans by >80%
Prevention of infection in water buffalo/cattle by >90%, completely eliminate transmission from bovines to humans
• Reduce worm burdena or egg excre-
• Reduce worm burdena or egg
• Reduce worm burdena or egg
tion in water buffalo/cattle by >60% Reduce egg excretion by humans by >60%b
excretion in water buffalo/cattle by >80% Reduce egg excretion by humans by >60%b
excretion in water buffalo/cattle by >90% Reduce egg excretion by human by >90%b
•
Duration of protection Dosage Route of Administration
Product Criteria
Manufacturing
a b
At least 1 year after last vaccination Parenteral (IM/SC)
•
•
IM/SC
More than 1 year IM/SC
Frequency of dosing
3 vaccine doses; annual booster needed
2 vaccine doses; no need or no more frequent than annual booster
One vaccine dose; no need for booster
Duration of dosing
No more than 6 months
About 3 months
One time administration
Quality profile of the product that defines safety and characteristics
Grade II reactogenicity or vaccination associated AEs
Grade I reactogenicity or vaccination associated AEs
No safety and reactogenicity concern.
Concomitant use
Not applicable
same
same
Scale-up proposed Storage Stability
Sufficient for local usage −20 ◦ C–4 ◦ C Expected to be >3 years; investigational product can be >1 year
Sufficient for local usage −20 ◦ C–4 ◦ C >3 years
Sufficient for local usage Store at 4 ◦ C or room temperature. >10 years
When method of detection available without sacrificing the animals. Not essential for a veterinary vaccine, but will be if the vaccine is also intended for human benefit.
Table 4 Summary for schistosomiasis vaccine development. • Development of a vaccine and human clinical testing thought to be feasible; • Modeling is valuable in defining TPP and guiding funders to the relevance of the problem; • Early outlines of Preferred Product Characteristics are reported here; • Human challenge model for testing is deemed not feasible at the time; • Integrated clinical endpoint measurement would be needed for vaccines targeting different forms of diseases; • Sensitive assays for efficacy trials need to be established; • Collaborative research as well as synergized efforts are encouraged.
the level of protection. Based on previous modeling [23], a vaccine with 55–60% protection efficacy to reduce egg shedding in buffalos might be considered acceptable. This level of reduction could potentially translate into reduction in transmission to humans. One of the vaccine candidates (Sj23 and SjTPI) is now in field trials in several villages in Southeast China [24]. This will soon shed light on the feasibility of a veterinary vaccine on preventing infection in bovine and transmission from bovine to human, and will provide valuable information for potential downstream development of a human preventive vaccine. 6. Conclusions Salient conclusions as a result of the meeting discussion are highlighted in Table 4. With more vaccine candidates entering
into clinical development and field evaluation, it is an appropriate time for the community to strengthen collaborative research and identify opportunities and synergies so they can harmonize to drive agreed-upon candidates to the finish line. The existing tools and other new tools on the horizon have made clinical efficacy evaluation in the field possible. The PPC defines some basic features for a schistosomiasis vaccine product that reflects the existing control programs. It is a working document and necessitates frequent revision based on disease landscape changes and technology advancement. A detailed TPP for a vaccine applicable for global schistosomiasis control and elimination could be further defined in the future. Disclaimer This report is the summary of the collective views from the meeting participants and post-meeting communications and does not necessarily reflect the views of NIH and should not be construed as an official NIH position, policy or decision unless so designated by other documentation. No official endorsement should be made. Acknowledgments The authors would like to sincerely thank all the attendees of the workshop and to those individuals who also actively provided follow-on inputs and suggestions to formulate all the tables, and to Ms. Tammy Andros for her excellent administrative help in
Conference report / Vaccine 34 (2016) 995–1001
organizing the workshop and editorial review of the report. Meeting participants and post-meeting group members are Dr. Ayola Akim Adegnika, Leiden University Medical Center; Ms. Tammy Andros, University of Georgia; Dr. Robert Bergquist, Geospatial Health; Dr. Jeff Bethony, George Washington University; Dr. Paula Bryant, NIAID; Dr. Dan Colley, University of Georgia; Dr. Rodrigo Correa-Oliveira, Fiocruz; Dr. Stephen Davies, USUHS; Dr. Arminder Deol, Imperial College London; Dr. David Diemert, George Washington University; Dr. Susan Garges, NIAID; Dr. Richard Garratt, University of São Paulo; Dr. Lee Hall, NIAID; Dr. Don Harn, University of Georgia; Dr. Ron Hokke, Leiden University Medical Center; Dr. Peter Hotez, Baylor College of Medicine; Dr. Malcolm Jones, University of Queensland; Dr. Charles King, Case Western Reserve University; Dr. Jake Kurtis, Brown University; Dr. Bruce Lee, Johns Hopkins University; Dr. Lisette van Leishout, Leiden University Medical Center; Dr. Alex Loukas, James Cook University; Dr. Phil LoVerde, University of Texas; Dr. Don McManus, QIMR; Dr. Annie Mo, NIAID; Dr. John Pesce, NIAID; Dr. Steve Reed, Infectious Diseases Research Institute; Dr. Jutta Reinhard-Rupp, Merck Serono; Dr. Giles Riveau, Institut Pasteur Lille & Biomedical Research Center EPLS, Saint Louis, Senegal; Dr. Alan Sher, NIAID; Dr. Afzal Siddiqui, Texas Tech School of Medicine; Dr. Miriam Tendler, Oswaldo Cruz Foundation; Dr. Tom Wynn, NIAID; Dr. Hong You, Queensland Institute of Medical Research. References [1] Mo AX, Agosti JM, Walson JL, Hall BF, Gordon L. Schistosomiasis elimination strategies and potential role of a vaccine in achieving global health goals. Am J Trop Med Hyg 2014;90(1 (Jan)):54–60. [2] Evans DB, Guyatt HL. Human behaviour, cost-effectiveness analysis and research and development priorities: the case of a schistosomiasis vaccine. Trop Med Int Health 1997;2(11 (Nov)):A47–54. [3] Gurarie D, King CH, Wang X. A new approach to modelling schistosomiasis transmission based on stratified worm burden. Parasitology 2010;137(13 (Nov)):1951–65. [4] Lee BY, Bacon KM, Shah M, Kitchen SB, Connor DL, Slayton RB. The economic value of a visceral leishmaniasis vaccine in Bihar state, India. Am J Trop Med Hyg 2012;86(3 (Mar)):417–25. [5] Lee BY, Bacon KM, Wateska AR, Bottazzi ME, Dumonteil E, Hotez PJ. Modeling the economic value of a Chagas’ disease therapeutic vaccine. Hum Vaccin Immunother 2012;8(9 (Sep)):1293–301. [6] Riveau G, Deplanque D, Remoue F, et al. Safety and immunogenicity of rSh28GST antigen in humans: phase 1 randomized clinical study of a vaccine candidate against urinary schistosomiasis. PLoS Negl Trop Dis 2012;6(7 (Jul)):e1704. [7] Ahmad G, Zhang W, Torben W, et al. Preclinical prophylactic efficacy testing of Sm-p80-based vaccine in a nonhuman primate model of Schistosoma mansoni infection and immunoglobulin G and E responses to Sm-p80 in human serum samples from an area where schistosomiasis is endemic. J Infect Dis 2011;204(9 (Nov)):1437–49. [8] Pearson MS, Pickering DA, McSorley HJ, et al. Enhanced protective efficacy of a chimeric form of the schistosomiasis vaccine antigen Sm-TSP-2. PLoS Negl Trop Dis 2012;6(3):e1564. [9] Santini-Oliveira M, Coler RN, Parra J, Veloso V, Jayashankar L, Pinto PM, et al. Schistosomiasis vaccine candidate Sm14/GLA-SE: phase 1 safety and immunogenicity clinical trial in healthy, male adults. Vaccine 2015, http://dx.doi.org/10.1016/j.vaccine.2015.10.027 [Nov 10, pii: S0264410X(15)01442-5.]. [10] van DA, Smit CH, van EL, et al. Differential anti-glycan antibody responses in Schistosoma mansoni-infected children and adults studied by shotgun glycan microarray. PLoS Negl Trop Dis 2012;6(11):e1922.
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[11] Karmakar S, Zhang W, Ahmad G, et al. Cross-species protection: Schistosoma mansoni Sm-p80 vaccine confers protection against Schistosoma haematobium in hamsters and baboons. Vaccine 2014;32(11 (Mar 5)):1296–303. [12] Karmakar S, Zhang W, Ahmad G, et al. Use of an Sm-p80-based therapeutic vaccine to kill established adult schistosome parasites in chronically infected baboons. J Infect Dis 2014;209(12 (Feb 23)):1929–40. [13] Dai Y, Wang X, Tang J, et al. Enhancement of protective efficacy through adenoviral vectored vaccine priming and protein boosting strategy encoding triosephosphate isomerase (SjTPI) against Schistosoma japonicum in mice. PLoS One 2015;10(3):e0120792. [14] Zhu Y, Si J, Harn DA, et al. Schistosoma japonicum triose-phosphate isomerase plasmid DNA vaccine protects pigs against challenge infection. Parasitology 2006;132(Pt 1 (Jan)):67–71. [15] Jiz MA, Wu H, Olveda R, Jarilla B, Kurtis JD. Development of paramyosin as a vaccine candidate for schistosomiasis. Front Immunol 2015;6:347. [16] You H, Gobert GN, Cai P, Mou R, Nawaratna S, Fang G, et al. Suppression of the insulin receptors in adult Schistosoma japonicum impacts on parasite growth and development: further evidence of vaccine potential. PLoS Negl Trop Dis 2015;9(5 (May 11)):e0003730, http://dx.doi.org/10.1371/ journal.pntd.0003730. [17] Diemert DJ, Pinto AG, Freire J, et al. Generalized urticaria induced by the NaASP-2 hookworm vaccine: implications for the development of vaccines against helminths. J Allergy Clin Immunol 2012;130(1 (Jul)):169–76. [18] Hotez PJ, Diemert D, Bacon KM, et al. The human hookworm vaccine. Vaccine 2013;31(Suppl 2 (Apr 18)):B227–32. [19] Knopp S, Corstjens PL, Koukounari A, et al. Sensitivity and specificity of a urine circulating anodic antigen test for the diagnosis of Schistosoma haematobium in low endemic settings. PLoS Negl Trop Dis 2015;9(5 (May)):e0003752. [20] Silas S, Fitzsimmons CM, Jones FM, et al. Human IgE responses to different splice variants of Schistosoma mansoni tropomyosin: associations with immunity. Int J Parasitol 2014;44(6 (May)):381–90. [21] Hagan P, Blumenthal UJ, Dunn D, Simpson AJ, Wilkins HA. Human IgE, IgG4 and resistance to reinfection with Schistosoma haematobium. Nature 1991;349(6306 (Jan 17)):243–5. [22] Griffith Q, Liang Y, Whitworth P, et al. Immuno-evasive tactics by schistosomes identify an effective allergy preventative. Exp Parasitol 2015;153:139–50 [Jun]. [23] Woolhouse ME. Human schistosomiasis: potential consequences of vaccination. Vaccine 1995;13(12 (Aug)):1045–50. [24] Gray DJ, Li YS, Williams GM, et al. A multi-component integrated approach for the elimination of schistosomiasis in the People’s Republic of China: design and baseline results of a 4-year cluster-randomised intervention trial. Int J Parasitol 2014;44(9 (Aug)):659–68.
Annie X. Mo a,∗ Daniel G. Colley b a Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institute of Health, Bethesda, MD, USA b Center for Tropical and Emerging Global Diseases and the Department of Microbiology, University of Georgia, Athens, GA, USA ∗ Corresponding
author. Tel.: +01 240 627 3320; fax: +01 240 627 3467. E-mail address: [email protected] (A.X. Mo) 5 October 2015 10 December 2015 11 December 2015 Available online 22 December 2015
Contents lists available at ScienceDirect
Vaccine journal homepage: www.elsevier.com/locate/vaccine
Conference report Workshop report: Schistosomiasis vaccine clinical development and product characteristics
a r t i c l e
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Keywords: Schistosomiasis Vaccine Clinical development plan (CDP) Preferred product characteristics (PPC) Target product profile (TPP)
a b s t r a c t A schistosomiasis vaccine meeting was organized to evaluate the utility of a vaccine in public health programs, to discuss clinical development paths, and to define basic product characteristics for desirable vaccines to be used in the context of schistosomiasis control and elimination programs. It was concluded that clinical evaluation of a schistosomiasis vaccine is feasible with appropriate trial design and tools. Some basic Preferred Product Characteristics (PPC) for a human schistosomiasis vaccine and for a veterinary vaccine for bovine use were also proposed.
1. Introduction As a follow-up from March 2013 meeting, which was cosponsored by the National Institute of Allergy and Infectious Diseases (NIAID) and the Bill & Melinda Gates Foundation (BMGF) [1], a schistosomiasis vaccine meeting was conducted in November 2013. The goal of the meeting was to continue discussing how a schistosomiasis vaccine should be used in public health programs, what the desirable Target Product Profile (TPP) for this vaccine should look like, and how a vaccine could be tested in clinical trials should there be one available in the near future. A group of 25 extramural schistosomiasis investigators, concerned intramural investigators, and Program Staff from the NIAID attended the meeting. It was concluded that clinical evaluation of a schistosomiasis vaccine in the field is likely feasible but would be challenging, and mathematical and computational modeling could be a valuable tool for informing the design of a TPP. Some basic product characteristics for a schistosomiasis vaccine for humans and a veterinary vaccine for bovines were proposed to guide early-stage product development. Below is a summary of the workshop discussions and of the further follow-on post-meeting group/subgroup communications and recommendations. 2. Timely opportunities for the schistosomiasis vaccine community Neglected Tropical Diseases (NTD), including schistosomiasis, continue to be a part of the NIAID’s Global Health agenda. Schistosomiasis is an acute and chronic disease caused by three major Schistosoma species, Schistosoma (S.) mansoni (S.m.), S. japonicum (S.j.), and S. haematobium (S.h.). The parasites establish their infection of human host by penetrating human skin in larval form and develop into adult worm in human body. Female worm would release eggs, which are either trapped in the body tissues causing immunopathology in intestinal (for S.m. or S.j.) or urogenital (for S.h.) organs or passed out in the urine or faeces to continue their life cycle and transmission. Vaccine against schistosomiasis is considered beneficial to the current control programs and a critical tool in 0264-410X/$ – see front matter http://dx.doi.org/10.1016/j.vaccine.2015.12.032
achieving the ultimate goal of global elimination of the diseases [1]. The Institute has already established several available preclinical service contract resources and the Vaccine Treatment and Evaluation Unit (VTEU) program to accelerate translational projects into new intervention tools, and it has supported discovery research and early development activities for NTD vaccine candidates, including several schistosomiasis vaccine candidates. In addition, the BMGF strongly supports current schistosomiasis control and elimination strategies and will continue to monitor and landscape advances toward new tool developments, including vaccines. Throughout the meeting presentations, it was apparent that financial support for most of the schistosomiasis vaccine early development mainly stemmed from the Governments and in some cases, some nonprofit organizations (Table 1). In the absence of prominent pharmaceutical involvement and limited support from other prominent organizations, it was highly encouraged that the schistosomiasis research community should actively strive to attract support from other non-conventional R&D investment sources. For example, the hookworm vaccine development effort, which is carried out by the Sabine Vaccine Institute, has attracted support from entities in the helminth endemic country Brazil. While the resource for schistosomiasis vaccine development has been constrained for decades, it was agreed that the community should work together to show unity of purpose, combine strengths, establish collaborations and integration of projects and strategies to maximize resources, and continue to show progress both conceptually and in real-time development effort. As the product development stage moves further downstream and more promising data are available, the development risk can be expected to decrease. More developers are anticipated to join in the mission to ultimately bring products to licensure. One of the major concerns for the community is the lack of understanding of the potential impact of a schistosomiasis vaccine on the global health. Since mathematical and computational modeling has been utilized to address the impact of new interventions and strengthening of business cases, several investigators presented their modeling tools to assess the vaccine impact on the schistosomiasis control and elimination program. One method [2]
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Table 1 Vaccine candidates in development and funders. Schistosoma
Vaccine
Development stage
Developer
R&D sponsors
S. haematobium
Monovalent recombinant protein Sh28GST (glutathione S-transferase) with adjuvant (Bilhvax)
Phase III
Inserm & Eurogentec
Inserm, EPLSa
S. mansoni
Monovalent recombinant protein Sm14 (fatty acid binding protein) in GLA-SE
Phase I trial completed
Fiocruz
Ministerio da Saude, Fiocruz, WHO
S. mansoni
Monovalent recombinant protein Sm-TSP-2 (tetraspanin surface antigen) with adjuvant
IND-filing, Phase I study on-going
Sabin Vaccine Institute
Blavatnik Charitable Foundation Mort Hyman NIAID
S. japonicum S. mansoni S. haematobium
DNA prime, recombinant protein boost Sj23 (Tetraspanin) and SjTPI (Glycolytic enzyme)
Field studies in water buffalo and cattle
Univ. of Georgia
Wellcome Trust NIAID NHMRCb
S. mansoni
Monovalent recombinant protein Sm-p80 (Calpain) with adjuvant
Preclinical process development
Texas Tech Univ. Health Sciences Center
NIAID Thrasher Research Fund Bill & Melinda Gates Foundation
S. japonicum
Monovalent recombinant protein Sj97 (paramyosin) with adjuvant ISA206
Proof-of-concept in animals
Brown University
NIAID
S. japonicum
Bivalent [SjIR (insulin receptor) or with SjTPI] recombinant proteins with adjuvant
Proof-of-concept in animals
Queensland Institute of Medical Research
NHMRC
a b
EPLS: Centre de Recherche Biomedicale, Espoir Pour La Sante. NHMRC: Australia National Health and Medical Research Council.
was to develop a clinical and economic outcome model to profile the costs, followed by developing an economic/operational model for each potential intervention, and subsequently link these models to a schistosomiasis transmission model to assess the impact of each intervention (in this case, vaccine) on transmission. The other method was to evaluate the impact of an intervention (e.g., vaccine) on transmission by studying the basic reproductive number R0 , defined as the average number of female offspring produced (that develop into adult worms) by one fertile female worm throughout her lifetime in the absence of density-dependent constraints, or by using mating probability in a stratified worm burden model, a compartment model that distributes human infectious burden among different infection intensity strata based on the observed field data [3]. Moreover, the group agreed that an important utility for the modeling is to guide the development of TPPs based on the desirable economic value or public health endpoint of a particular vaccine. Examples were presented to illustrate this application, such as the economic modeling for Visceral Leishmaniasis [4] or Chagas’ disease [5]. The modeling of schistosomiasis vaccine is still at its infant stage and many more researches are needed. Given the complexity of the schistosome biology and multiple existing interventions for the control and elimination program, some basic critical parameters worth incorporating were proposed: parasite species (S.m./S.h.); targeted parasite lifestages; level and duration of efficacy; costs of production and distribution; targeted population; and the types of vaccines (e.g., anti-fecundity or anti-infection). Similarly, several other possible vaccine or vaccination-related features were suggested for consideration. For example, immunity may not be complete and vaccine effects may be short-lived; prior infection/treatment can boost vaccine effects; and vaccines could affect worm fecundity and male to female balance or disrupt the balance between immunoregulation and immunopathology. 3. Vaccine candidates for schistosomiasis Recent progress in schistosomiasis vaccine development was discussed (Table 1). Several forms of vaccines are on the horizon. Bilhvax3, a vaccine candidate based on S.h. parasite protein glutathione S-transferase Sh28GST, which prevents both clinical
and parasitological recurrences of S.h. infection in children, is currently under Phase III of human clinical evaluation [6]. The panel also noted other vaccine candidates that reduce worm burden and egg outputs of S.m. infection in small animals and in some cases non-human primates (NHP) (e.g., S.m. proteins fatty acid binding protein Sm14, Tetraspanin Surface Protein antigen TSP-2, and calpain protein Sm-p80) [7–11], or kill established worms (Sm-p80) [12]. These candidates would most likely be developed as human prophylactic vaccines for susceptible populations in endemic areas. Currently, the Sm-p80 or the S.j. Insulin Receptor protein SjIRbased vaccine has also been shown to preferentially reduce female worm burden and reduce egg shedding in animals. The strong anti-fecundity impact of this type of vaccine provides additional transmission blocking benefits. Other vaccines like S.j. parasite proteins Tetraspanin Sj23/Glycolytic enzyme SjTPI, paramyosin Sj97, and SjIR-based vaccines, all of which have been tested in small animals and showed protection against S.j. infection [1,13–16], are being further tested in water buffalo prior to any human clinical trial. These vaccines would most likely first be developed as veterinary vaccines for bovines, which indirectly reduce parasite transmission to humans and thus potentially serve as transmissionblocking vaccines for human populations. The types of vaccines needed for global control and elimination programs were further discussed. Since schistosomes have a complex life cycle involving different developmental stages (e.g., cercariae, schistosomulae, adult worm) migrating through and residing in a variety of anatomical sites in the human host coupled with the prolonged time for disease induction and manifestation, the traditional term of infection cannot be clearly and easily elucidated for “schistosome infection”, as, for example, is clearly defined for an acute viral infection for which the timing or the anatomical site for infection or disease presentation are well known. As a result, there was apparent confusion in the schistosomiasis vaccine field about the terminology of a therapeutic vaccine vs. a prophylactic/preventive vaccine. Some investigators tended to define the therapeutic vaccine based on the infection status of the host (i.e., a vaccine intended for infected individuals) while others preferred to define a therapeutic vaccine based on the targeted biological stage of the parasite (i.e., a vaccine which exhibits efficacy against established adult worms in a chronic infection). Traditionally, a
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prophylactic vaccine is used to provide lasting protection against a new infection, whereas a therapeutic vaccine combats existing diseases instead of offering long-lasting protection against new infections or symptoms. Because the development strategy for a therapeutic vaccine is in general substantially different and less cumbersome than a prophylactic vaccine, the meeting participants emphasized that understanding the ultimate purpose of the vaccines would be essential for developing clear clinical or product development plans. Since a schistosomiasis vaccine will most likely be used in endemic settings in the context of other control programs, regardless of the infection status of the target individuals, the traditional definition seems more clear and accurate. Most of the vaccine candidates mentioned above could be developed as the traditionally defined prophylactic vaccines for human usage (i.e., to prevent new infection, hitherto to reduce disease recurrences or block further transmissions). Some candidates could have the advantage of being developed first as veterinary vaccines for bovine (to prevent new infection and reduce disease recurrences in bovines) and transmission-blocking vaccines for humans (to reduce further transmission from bovines to humans) before being developed as preventive vaccines for human use.
4. Clinical development plan (cdp) considerations Clinical evaluation of a schistosomiasis vaccine, especially an advanced efficacy trial, has been a great challenge to the community. A Phase I trial that evaluates safety, reactogenicity, and sometimes immunogenicity is less controversial and rather straightforward. Most likely, all the above-mentioned human vaccines will be targeted toward a broad population, especially children in endemic areas. These vaccines should be tested in naïve unexposed adults first (non-endemic area) before being tested in infected adults, and then age de-escalated into uninfected and infected children in endemic areas. There were discussions about the possibility of conducting the first Phase I safety study in endemic areas without any safety testing in naïve individuals in non-endemic areas if permission from the Regulatory agencies of the respective endemic countries could be obtained. However, this would risk being unable to conclusively dissect the causes of any potential safety issues (host vs. product), as seen in the case of the first Phase I hookworm vaccine trial in Brazil [17,18]. Most of the Phase I studies also include vaccine-specific antibodies, antibody isotyping, and cell-mediated immune responses as secondary endpoints to guide future Phase II immune studies. In some cases, multiple Phase I trials are designed to address doses, adjuvant, or route of administration issues. In general, a Phase II trial program is to continue evaluating the safety and immunogenicity of vaccines in endemic areas with similar trial design to the Phase I study, and involve a larger number of subjects. Investigators typically try to optimize doses, adjuvant, schedule of immunizations, and route of administration in Phase II studies. Additional considerations include designing phase II studies to collect preliminary efficacy data early in development to guide future Phase III trials in defining realistic clinical efficacy endpoints. Depending on the level of the disease prevalence, it may be challenging for the community to obtain any statistically meaningful information with a relatively small number of subjects. A Phase III efficacy trial was the focus of discussion. The community agreed that cohorts that are suitable for efficacy trials in endemic areas do exist. The level of disease prevalence varies from time to time, depending on the local drug treatment program, and there can be considerable variation in annual infection rates due to climatic conditions and changes in the environment. Nevertheless, with high reinfection rate in some areas such as in Leyte, Philippines
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where reinfection rate could be 50% at 6 months post treatment, a small Phase III efficacy trial with as few as 200 subjects per group to detect at least 50% reduction in incidence could be feasible. The group recommended some baseline epidemiology studies to characterize cohort populations should be carried out prior to efficacy trials to ensure trial feasibility. In addition, it has been a great challenge to the community to define clinical efficacy (the clinical endpoint for schistosomiasis vaccines) and the method to quantify the endpoints. Although multiple efficacy readouts can be performed for animal studies (such as worm burden, adult worm sex balance), the method to quantify human clinical efficacy endpoints (infection or pathology) could currently be limited to measurement of egg output. It was highly recommended that methods with great sensitivity, which are able to detect egg output early before clinical manifestation occurs, should be developed. A recently available CAA diagnostic assay that detects worm antigen for all three major human schistosome species in serum or urine with high sensitivity [19] could be an extremely valuable tool and should be further explored for detecting vaccine efficacy signals early in a Phase III trial, thus allowing a proxy for worm burden and also shortening the lengthy trial process. A method to assess male vs. female worm burden will still need to be developed to assess the potential efficacy of anti-fecundity vaccines on female–male worm imbalance. In fact, the pathological consequences of remaining male worm in the vaccinated individuals, if any, although not expected to present a problem, still remain unknown. Other caveats that could affect efficacy outcomes were also pointed out, such as the parasite infection history of the volunteers (or any other co-infections), pretreatment with praziquantel (PZQ) for de-worming and the fact that PZQ treatment does not always cure the individual, and the timing of treatment related to vaccination which could potentially alter the vaccinee’s immunological status. Thus far, the Bilhvax3 is the only example to illustrate a clinical development path for a schistosomiasis vaccine, although it might not be easily generalized to other types of schistosomiasis vaccines (Fig. 1). The vaccine is designed as a conjunct therapy with PZQ treatment for infected school-aged children. However, the ultimate efficacy in a Phase III design is represented by the prevention of emergence of clinical and parasitological recurrences of S.h. infection (ClinicalTrials.gov: NCT00870649). In the trial, the delay of the first recurrence of the pathology due to S.h. infection was measured during a 4-year follow-up period. The recurrence of pathology was indicated by positive micro-hematuria and appearance of parasite eggs in urine. In light of this, it might be more accurate to describe the Bilhvax 3 as a preventive vaccine since the vaccine is to provide a long-lasting protection against re-infection and recurrences of the pathology (Fig. 1). The clinical development of the vaccine started with a small size (N = 24) Phase Ia trial in healthy adult subjects in a non-endemic country, followed by a Phase Ib trial in healthy children in endemic area [6]. Once safety data and evidence of immunity were collected from the healthy population who received the vaccine alone, the vaccine, together with PZQ administration, was then subject to a Phase IIa/b study in infected adults followed by a Phase IId studies in infected children in endemic regions (Giles Riveau, unpublished data). The final Phase III controlled, randomized, double-blind efficacy trial was built on sufficient safety data from a total of 112 subjects of the prior Phase I and II studies, and to evaluate the vaccination together with PZQ treatment on prevention of clinical and pathological recurrences (https://clinicaltrials. gov/ct2/show/NCT00870649?term=NCT00870649&rank=1). The Phase II and III results are still pending and the future CDP beyond Phase III was not clear at this point. Nevertheless, participants acknowledged that the existing clinical development path of the Bilhvax represents a unique example demonstrating the feasibility of a clinical efficacy study for a schistosomiasis vaccine. Admittedly, it was recognized that an efficacy trial for a schistosomiasis
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Fig. 1. Clinical development path for the bilhvax vaccine candidate against urinary schistosomiasis recurrences. The adjuvanted recombinant Shj28GST protein Bilhvax vaccine was tested in a Phase III clinical trial carried out by the Biomedical Research Center EPLS, Saint-Louis, Senegal.
vaccine with a broader application, for example, a vaccine to prevent infections of all three human parasite species, would be more challenging, yet not insurmountable. The community should work together to carefully define clinical endpoints associated with different parasite infections and, if needed, design a set of integrated clinical endpoint measurements for vaccines targeting different forms of schistosomiasis. The topic of establishing a human challenge model to ease the burden and shorten the timeframe for clinical efficacy evaluation of schistosomiasis vaccines was raised. The meeting participants unanimously agreed that the community is still not ready to take on the endeavor, even with a highly sensitive diagnostic tool available that allows early detection and treatment of challenged individuals such as the CAA diagnostic assay. The fact that only one drug PZQ is available for treatment, the incomplete treatment effectiveness of the PZQ, and the possibility for larva trapped in tissues or lungs that cause pathology prior to symptom appearance, were acknowledged to present serious impediments to the development of a human Schistosoma challenge model. 5. Preferred product characteristics (ppc) Short of sufficient development interest from industry, the community must actively define a TPP to guide the thinking and development strategy. During the meeting, the TPP was not discussed extensively due to time constraints. The group realized the challenge at this stage of defining a universal TPP for vaccines against pathogens with unique geographical distributions, prevalence, biology, and disease presentations. It is agreed that some basic characteristics for a desirable vaccine could be tackled post-meeting by the group. Follow-up conversations among groups and subgroups have led to a tentative description of some basic Preferred Product Characteristics (PPC) for a human prophylactic vaccine against schistosomiasis (Table 2) and a veterinary vaccine against S.j. (Table 3). Depending on the types of schistosomiasis vaccines, the overall product development strategies need to be tailored to complement the existing control programs. The indication for a prophylactic vaccine should be to prevent infection caused by at least one
parasite species (acceptable) or all three species (optimistic) (Table 2). Ideally, the same vaccine may also have therapeutic effects to treat the existing disease (ideal). Preclinical evidence indicates that the proposed indications to prevent all forms of human schistosomiasis are not far from reality. Some vaccine candidates have been shown to reduce worm burdens caused by S.m., S.j., and/or S.h. infection, and kill the adult worms to reduce pathology caused by S.m. even though the level of protection or treatment efficacies may not be optimal. Since the vaccine will be used in the context of Mass Drug Administration (MDA) programs, the target population should be the susceptible individuals in endemic countries, most likely 18–59 years of age adults in highrisk occupations or areas and high-risk school age children (3–12 years of age) whose contact with infected water is frequent. The target level of protective efficacy is subject to debate. Some investigators considered that the proposed >75% reduction in overall egg shedding is too high for a vaccine to be used together with MDA and is likely unattainable. Other preclinical data did suggest that >75% reduction in egg output is possible, for example, the Sm-p80 vaccine (SchistoShield) had shown to provide close to 100% reduction in female worm burden; these observations are currently being confirmed using a larger sample size of baboons (n = 40) (Siddiqui, unpublished). Modeling data are surely needed and hopefully will be available soon to improve understanding and guide future development efforts. Given existing annual MDA programs, the duration of protection efficacy for the vaccine should be around 2–3 years, which would be superior to current PZQ drug performance. No annual boosting should be needed. Other product characteristics such as dosage, storage, and stability requirement were defined in the Table 2. Additionally, considering the pre-existing IgEassociated generalized urticarial event observed in a Phase I trial of a helminth vaccine, [16], one quality profile relevant to the safety of the schistosomiasis vaccine antigen was pointed out: the vaccine antigen should not react to IgE sera from endemic countries to prevent any potential allergic reaction, since the vaccine is intended for all susceptible individuals regardless of their prior infection history. This still remains controversial since the current best correlate of resistance to reinfection in the natural setting appears to be IgE levels [20–22]. Another important feature to consider is the scale
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Table 2 A prophylactic vaccine to prevent Schistosoma infection. Product characteristics items
Acceptable (minimum)
Target (optimistic)
Ideal (maximum)
Indication
Prevention of infection by one of the three human Schistosoma parasites (i.e., S. mansoni, S. haematobium, or S. japonicum)
Prevention of infection by all S. mansoni, S. haematobium, and S. japonicum parasites
Prevention of infection and treatment of Schistosomiasis caused by all S. mansoni, S. haematobium, and S. japonicum parasites
Target populations
Population in endemic countries or regions, especially adults (18–59 years of age) in high-risk occupations or areas and a high-risk school age children (3–12 years of age).
Population in endemic countries or regions, especially adults (18–59 years of age) in high-risk occupations or areas and a high-risk school age children (3–12 years of age).
Population in endemic countries or regions, especially adults (18–59 years of age) in high-risk occupations or areas and a high-risk school age children (3–12 years of age)
Efficacy
Reduce at least 75% infection by one of the S. parasite species
Reduce at least 75% infection by all human S. parasite species
Reduce at least 95% infection caused by all human S. parasite species
• Efficacy readout: egg output and/or
• Efficacy readout: egg output
worm burdena
and/or worm burdena
• Efficacy readout: egg output and/or worm burdena
Duration of protection Dosage Route of administration
2–3 years after last dosing Parenteral administration (e.g., I.M.)
2–3 years after the last dosing Parenteral administration
5–10 years after last dose I.M.
2 doses administration, no need for further doses after booster dose No more than 6 months period
2 doses needed, no need for further doses after booster dose About 3 month period
One dose injection for primary series, no need for booster One time administration
Quality profile of the product that defines safety and characteristics
The vaccine antigen should not react to IgE from target population; moderate local injection site reactions; incidence of SAEs no more than licensed vaccine product. The rest of the safety and reactogenicity will be developed and refined during the development process.
The vaccine antigen should not react to IgE from target population; moderate local injection site reactions; incidence of SAEs no more than licensed vaccine product. The rest of the safety and reactogenicity will be developed and refined during the development process.
No safety and reactogenicity concern.
Concomitant use
Can be co-administered with local MDA other interventions. No interference or adverse interactions with:
Same
Same
Frequency of dosing Duration of dosing Product criteria
• Prior or subsequent local antihelminth drug treatment (e.g., PZQ)
• Co-administered with any EPI vaccines
• Prior or subsequent routine child and adult vaccines within a two week window Manufacturing
a
Scale-up proposed
Initially suitable for Phase I study; further defined manufacturing process and product suitability will be followed after the Phase I investigation
Storage
−20 ◦ C–4 ◦ C
Store at −20 ◦ C–4 ◦ C
Store at 2–8 ◦ C or room temperature
Stability
Expected to be >3 years; investigational product can be >1 year
>3 years
>10 years
When method of detection available.
up for manufacturing. Given a substantial investment requirement for a scale-up manufacturing process, it may be wise to focus on a process suitable for a Phase I study first, and further optimize the manufacturing process and define the product suitability later after the Phase I investigation. Suggestions were also made that process reproducibility and low cost for manufacturing are essential early steps for a schistosomiasis vaccine seriously being considered for phase II studies and beyond. Strategies to maximize the utilization of limited investment resources and balance all the development risks will need to be considered carefully by the community.
For those vaccine candidates that could also be veterinary vaccines for bovines to prevent S.j. infection, their PPC for veterinary vaccines is rather straight forward (Table 3). The vaccine would be for local usage in water buffalos or cattle in some transmission hot spots in China and Southeast Asia; therefore, local animal health regulatory agencies should be consulted for product development strategies. It was pointed out that the safety profile of this vaccine seems less stringent than those for human application. Even a Grade II reactogenicity or vaccination-associated Adverse Event (AE) could be considered acceptable. The biggest debate was again
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Conference report / Vaccine 34 (2016) 995–1001
Table 3 A veterinary vaccine for bovines (water buffalo/cattle) to reduce/eliminate human infection by Schistosoma japonicum. Product characteristics items
Acceptable (minimum)
Target (optimistic)
Ideal (maximum)
Indication
To prevent S. japonicum infection in water buffalo/cattle and reduce transmission of S. japonicum from water buffalo/cattle to humans
To prevent S. japonicum infection in water buffalo/cattle and reduce transmission of S. japonicum from water buffalo/cattle to humans
To prevent S. japonicum infection in water buffalo/cattle and reduce transmission of S. japonicum from water buffalo/cattle to humans
Target populations
Water buffalo/cattle in endemic countries or regions (Southeast Asia)
Water buffalo/cattle in endemic countries or regions (Southeast Asia)
Water buffalo/cattle in endemic countries or regions (Southeast Asia)
Efficacy
Prevention of infection in water buffalo/cattle by >60%, reduce transmission from bovines to humans by at least 60%
Prevention of infection in water buffalo/cattle by >80%, reduce transmission from bovines to humans by >80%
Prevention of infection in water buffalo/cattle by >90%, completely eliminate transmission from bovines to humans
• Reduce worm burdena or egg excre-
• Reduce worm burdena or egg
• Reduce worm burdena or egg
tion in water buffalo/cattle by >60% Reduce egg excretion by humans by >60%b
excretion in water buffalo/cattle by >80% Reduce egg excretion by humans by >60%b
excretion in water buffalo/cattle by >90% Reduce egg excretion by human by >90%b
•
Duration of protection Dosage Route of Administration
Product Criteria
Manufacturing
a b
At least 1 year after last vaccination Parenteral (IM/SC)
•
•
IM/SC
More than 1 year IM/SC
Frequency of dosing
3 vaccine doses; annual booster needed
2 vaccine doses; no need or no more frequent than annual booster
One vaccine dose; no need for booster
Duration of dosing
No more than 6 months
About 3 months
One time administration
Quality profile of the product that defines safety and characteristics
Grade II reactogenicity or vaccination associated AEs
Grade I reactogenicity or vaccination associated AEs
No safety and reactogenicity concern.
Concomitant use
Not applicable
same
same
Scale-up proposed Storage Stability
Sufficient for local usage −20 ◦ C–4 ◦ C Expected to be >3 years; investigational product can be >1 year
Sufficient for local usage −20 ◦ C–4 ◦ C >3 years
Sufficient for local usage Store at 4 ◦ C or room temperature. >10 years
When method of detection available without sacrificing the animals. Not essential for a veterinary vaccine, but will be if the vaccine is also intended for human benefit.
Table 4 Summary for schistosomiasis vaccine development. • Development of a vaccine and human clinical testing thought to be feasible; • Modeling is valuable in defining TPP and guiding funders to the relevance of the problem; • Early outlines of Preferred Product Characteristics are reported here; • Human challenge model for testing is deemed not feasible at the time; • Integrated clinical endpoint measurement would be needed for vaccines targeting different forms of diseases; • Sensitive assays for efficacy trials need to be established; • Collaborative research as well as synergized efforts are encouraged.
the level of protection. Based on previous modeling [23], a vaccine with 55–60% protection efficacy to reduce egg shedding in buffalos might be considered acceptable. This level of reduction could potentially translate into reduction in transmission to humans. One of the vaccine candidates (Sj23 and SjTPI) is now in field trials in several villages in Southeast China [24]. This will soon shed light on the feasibility of a veterinary vaccine on preventing infection in bovine and transmission from bovine to human, and will provide valuable information for potential downstream development of a human preventive vaccine. 6. Conclusions Salient conclusions as a result of the meeting discussion are highlighted in Table 4. With more vaccine candidates entering
into clinical development and field evaluation, it is an appropriate time for the community to strengthen collaborative research and identify opportunities and synergies so they can harmonize to drive agreed-upon candidates to the finish line. The existing tools and other new tools on the horizon have made clinical efficacy evaluation in the field possible. The PPC defines some basic features for a schistosomiasis vaccine product that reflects the existing control programs. It is a working document and necessitates frequent revision based on disease landscape changes and technology advancement. A detailed TPP for a vaccine applicable for global schistosomiasis control and elimination could be further defined in the future. Disclaimer This report is the summary of the collective views from the meeting participants and post-meeting communications and does not necessarily reflect the views of NIH and should not be construed as an official NIH position, policy or decision unless so designated by other documentation. No official endorsement should be made. Acknowledgments The authors would like to sincerely thank all the attendees of the workshop and to those individuals who also actively provided follow-on inputs and suggestions to formulate all the tables, and to Ms. Tammy Andros for her excellent administrative help in
Conference report / Vaccine 34 (2016) 995–1001
organizing the workshop and editorial review of the report. Meeting participants and post-meeting group members are Dr. Ayola Akim Adegnika, Leiden University Medical Center; Ms. Tammy Andros, University of Georgia; Dr. Robert Bergquist, Geospatial Health; Dr. Jeff Bethony, George Washington University; Dr. Paula Bryant, NIAID; Dr. Dan Colley, University of Georgia; Dr. Rodrigo Correa-Oliveira, Fiocruz; Dr. Stephen Davies, USUHS; Dr. Arminder Deol, Imperial College London; Dr. David Diemert, George Washington University; Dr. Susan Garges, NIAID; Dr. Richard Garratt, University of São Paulo; Dr. Lee Hall, NIAID; Dr. Don Harn, University of Georgia; Dr. Ron Hokke, Leiden University Medical Center; Dr. Peter Hotez, Baylor College of Medicine; Dr. Malcolm Jones, University of Queensland; Dr. Charles King, Case Western Reserve University; Dr. Jake Kurtis, Brown University; Dr. Bruce Lee, Johns Hopkins University; Dr. Lisette van Leishout, Leiden University Medical Center; Dr. Alex Loukas, James Cook University; Dr. Phil LoVerde, University of Texas; Dr. Don McManus, QIMR; Dr. Annie Mo, NIAID; Dr. John Pesce, NIAID; Dr. Steve Reed, Infectious Diseases Research Institute; Dr. Jutta Reinhard-Rupp, Merck Serono; Dr. Giles Riveau, Institut Pasteur Lille & Biomedical Research Center EPLS, Saint Louis, Senegal; Dr. Alan Sher, NIAID; Dr. Afzal Siddiqui, Texas Tech School of Medicine; Dr. Miriam Tendler, Oswaldo Cruz Foundation; Dr. Tom Wynn, NIAID; Dr. Hong You, Queensland Institute of Medical Research. References [1] Mo AX, Agosti JM, Walson JL, Hall BF, Gordon L. Schistosomiasis elimination strategies and potential role of a vaccine in achieving global health goals. Am J Trop Med Hyg 2014;90(1 (Jan)):54–60. [2] Evans DB, Guyatt HL. Human behaviour, cost-effectiveness analysis and research and development priorities: the case of a schistosomiasis vaccine. Trop Med Int Health 1997;2(11 (Nov)):A47–54. [3] Gurarie D, King CH, Wang X. A new approach to modelling schistosomiasis transmission based on stratified worm burden. Parasitology 2010;137(13 (Nov)):1951–65. [4] Lee BY, Bacon KM, Shah M, Kitchen SB, Connor DL, Slayton RB. The economic value of a visceral leishmaniasis vaccine in Bihar state, India. Am J Trop Med Hyg 2012;86(3 (Mar)):417–25. [5] Lee BY, Bacon KM, Wateska AR, Bottazzi ME, Dumonteil E, Hotez PJ. Modeling the economic value of a Chagas’ disease therapeutic vaccine. Hum Vaccin Immunother 2012;8(9 (Sep)):1293–301. [6] Riveau G, Deplanque D, Remoue F, et al. Safety and immunogenicity of rSh28GST antigen in humans: phase 1 randomized clinical study of a vaccine candidate against urinary schistosomiasis. PLoS Negl Trop Dis 2012;6(7 (Jul)):e1704. [7] Ahmad G, Zhang W, Torben W, et al. Preclinical prophylactic efficacy testing of Sm-p80-based vaccine in a nonhuman primate model of Schistosoma mansoni infection and immunoglobulin G and E responses to Sm-p80 in human serum samples from an area where schistosomiasis is endemic. J Infect Dis 2011;204(9 (Nov)):1437–49. [8] Pearson MS, Pickering DA, McSorley HJ, et al. Enhanced protective efficacy of a chimeric form of the schistosomiasis vaccine antigen Sm-TSP-2. PLoS Negl Trop Dis 2012;6(3):e1564. [9] Santini-Oliveira M, Coler RN, Parra J, Veloso V, Jayashankar L, Pinto PM, et al. Schistosomiasis vaccine candidate Sm14/GLA-SE: phase 1 safety and immunogenicity clinical trial in healthy, male adults. Vaccine 2015, http://dx.doi.org/10.1016/j.vaccine.2015.10.027 [Nov 10, pii: S0264410X(15)01442-5.]. [10] van DA, Smit CH, van EL, et al. Differential anti-glycan antibody responses in Schistosoma mansoni-infected children and adults studied by shotgun glycan microarray. PLoS Negl Trop Dis 2012;6(11):e1922.
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Annie X. Mo a,∗ Daniel G. Colley b a Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institute of Health, Bethesda, MD, USA b Center for Tropical and Emerging Global Diseases and the Department of Microbiology, University of Georgia, Athens, GA, USA ∗ Corresponding
author. Tel.: +01 240 627 3320; fax: +01 240 627 3467. E-mail address: [email protected] (A.X. Mo) 5 October 2015 10 December 2015 11 December 2015 Available online 22 December 2015