Safety, Tolerability, and Immunogenicity of the Invaplex<sub>AR-Detox</sub> <i>Shigella</i> Vaccine Co-Administered with the dmLT Adjuvant in Dutch and Zambian Adults: Study Protocol for a Multi-Center, Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation Phase Ia/b Clinical Trial
Background: Shigella infections remain endemic in places with poor sanitation and are a leading cause of diarrheal mortality globally, as well as a major contributor to gut enteropathy and stunting. There are currently no licensed vaccines for shigellosis but it has been estimated that an effective...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-01-01
|
| Series: | Vaccines |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2076-393X/13/1/48 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832587367023640576 |
|---|---|
| author | Geert V. T. Roozen Nsofwa Sukwa Masuzyo Chirwa Jessica A. White Marcus Estrada Nicole Maier Kevin R. Turbyfill Renee M. Laird Akamol E. Suvarnapunya Aicha Sayeh Flavia D’Alessio Candice Marion Laura Pattacini Marie-Astrid Hoogerwerf Rajagopal Murugan Manuela Terrinoni Jan R. Holmgren Sodiomon B. Sirima Sophie Houard Michelo Simuyandi Meta Roestenberg |
| author_facet | Geert V. T. Roozen Nsofwa Sukwa Masuzyo Chirwa Jessica A. White Marcus Estrada Nicole Maier Kevin R. Turbyfill Renee M. Laird Akamol E. Suvarnapunya Aicha Sayeh Flavia D’Alessio Candice Marion Laura Pattacini Marie-Astrid Hoogerwerf Rajagopal Murugan Manuela Terrinoni Jan R. Holmgren Sodiomon B. Sirima Sophie Houard Michelo Simuyandi Meta Roestenberg |
| author_sort | Geert V. T. Roozen |
| collection | DOAJ |
| description | Background: Shigella infections remain endemic in places with poor sanitation and are a leading cause of diarrheal mortality globally, as well as a major contributor to gut enteropathy and stunting. There are currently no licensed vaccines for shigellosis but it has been estimated that an effective vaccine could avert 590,000 deaths over a 20-year period. A challenge to effective Shigella vaccine development has been the low immunogenicity and protective efficacy of candidate Shigella vaccines in infants and young children. Additionally, a new vaccine might be less immunogenic in a highly endemic setting compared to a low endemic setting (“vaccine hyporesponsiveness”). The use of a potent adjuvant enhancing both mucosal and systemic immunity might overcome these problems. Invaplex<sub>AR-Detox</sub> is an injectable Shigella vaccine that uses a novel combination of conserved invasion plasmid antigen proteins and a serotype-specific bacterial lipopolysaccharide attenuated for safe intramuscular administration. The adjuvant dmLT has been shown to enhance Shigella immune responses in mice, has safely been administered intramuscularly, and was shown to enhance immune responses in healthy volunteers when given in combination with other antigens in phase I trials. This article describes the protocol of a study that will be the first to assess the safety, tolerability, and immunogenicity of Invaplex<sub>AR-Detox</sub> co-administered with dmLT in healthy adults in low-endemic and high-endemic settings. Methods: In a multi-center, randomized, double-blind, and placebo-controlled dose-escalation phase Ia/b trial, the safety, tolerability, and immunogenicity of three intramuscular vaccinations administered 4 weeks apart with 2.5 µg or 10 µg of Invaplex<sub>AR-Detox</sub> vaccine, alone or in combination with 0.1 µg of the dmLT adjuvant, will first be assessed in a total of 50 healthy Dutch adults (phase Ia) and subsequently in 35 healthy Zambian adults (phase Ib) aged 18–50 years. The primary outcome is safety, and secondary outcomes are humoral and cellular immune responses to the adjuvanted or non-adjuvanted vaccine. Discussion: This trial is part of the ShigaPlexIM project that aims to advance the early clinical development of an injectable Shigella vaccine and to make the vaccine available for late-stage clinical development. This trial addresses the issue of hyporesponsiveness in an early stage of clinical development by testing the vaccine and adjuvant in an endemic setting (Zambia) after the first-in-human administration and the dose-escalation has proven safe and tolerable in a low-endemic setting (Netherlands). Besides strengthening the vaccine pipeline against a major diarrheal disease, another goal of the ShigaPlexIM project is to stimulate capacity building and strengthen global North-South relations in clinical research. Trial registration: EU CT number: 2023-506394-35-02, ClinicalTrials.gov identifier: NCT05961059. |
| format | Article |
| id | doaj-art-868081c91648401c80e0ce170ae1c524 |
| institution | Kabale University |
| issn | 2076-393X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Vaccines |
| spelling | doaj-art-868081c91648401c80e0ce170ae1c5242025-01-24T13:51:46ZengMDPI AGVaccines2076-393X2025-01-011314810.3390/vaccines13010048Safety, Tolerability, and Immunogenicity of the Invaplex<sub>AR-Detox</sub> <i>Shigella</i> Vaccine Co-Administered with the dmLT Adjuvant in Dutch and Zambian Adults: Study Protocol for a Multi-Center, Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation Phase Ia/b Clinical TrialGeert V. T. Roozen0Nsofwa Sukwa1Masuzyo Chirwa2Jessica A. White3Marcus Estrada4Nicole Maier5Kevin R. Turbyfill6Renee M. Laird7Akamol E. Suvarnapunya8Aicha Sayeh9Flavia D’Alessio10Candice Marion11Laura Pattacini12Marie-Astrid Hoogerwerf13Rajagopal Murugan14Manuela Terrinoni15Jan R. Holmgren16Sodiomon B. Sirima17Sophie Houard18Michelo Simuyandi19Meta Roestenberg20Leiden University Center for Infectious Diseases, Leiden University Medical Center, 2333 ZA Leiden, The NetherlandsCentre for Infectious Disease Research Zambia, Lusaka P.O. Box 34681, ZambiaCentre for Infectious Disease Research Zambia, Lusaka P.O. Box 34681, ZambiaPATH, Seattle, WA 98121, USAPATH, Seattle, WA 98121, USAPATH, Seattle, WA 98121, USAWalter Reed Army Institute of Research, Silver Spring, MD 20910, USAWalter Reed Army Institute of Research, Silver Spring, MD 20910, USAWalter Reed Army Institute of Research, Silver Spring, MD 20910, USAEuropean Vaccine Initiative, 69115 Heidelberg, GermanyEuropean Vaccine Initiative, 69115 Heidelberg, GermanyEuropean Vaccine Initiative, 69115 Heidelberg, GermanyLeiden University Center for Infectious Diseases, Leiden University Medical Center, 2333 ZA Leiden, The NetherlandsLeiden University Center for Infectious Diseases, Leiden University Medical Center, 2333 ZA Leiden, The NetherlandsLeiden University Center for Infectious Diseases, Leiden University Medical Center, 2333 ZA Leiden, The NetherlandsDepartment of Microbiology and Immunology, University of Gothenburg, 40530 Gothenburg, SwedenDepartment of Microbiology and Immunology, University of Gothenburg, 40530 Gothenburg, SwedenGroupe de Recherche Action en Santé, Ouagadougou 06 BP 10248, Burkina FasoEuropean Vaccine Initiative, 69115 Heidelberg, GermanyCentre for Infectious Disease Research Zambia, Lusaka P.O. Box 34681, ZambiaLeiden University Center for Infectious Diseases, Leiden University Medical Center, 2333 ZA Leiden, The NetherlandsBackground: Shigella infections remain endemic in places with poor sanitation and are a leading cause of diarrheal mortality globally, as well as a major contributor to gut enteropathy and stunting. There are currently no licensed vaccines for shigellosis but it has been estimated that an effective vaccine could avert 590,000 deaths over a 20-year period. A challenge to effective Shigella vaccine development has been the low immunogenicity and protective efficacy of candidate Shigella vaccines in infants and young children. Additionally, a new vaccine might be less immunogenic in a highly endemic setting compared to a low endemic setting (“vaccine hyporesponsiveness”). The use of a potent adjuvant enhancing both mucosal and systemic immunity might overcome these problems. Invaplex<sub>AR-Detox</sub> is an injectable Shigella vaccine that uses a novel combination of conserved invasion plasmid antigen proteins and a serotype-specific bacterial lipopolysaccharide attenuated for safe intramuscular administration. The adjuvant dmLT has been shown to enhance Shigella immune responses in mice, has safely been administered intramuscularly, and was shown to enhance immune responses in healthy volunteers when given in combination with other antigens in phase I trials. This article describes the protocol of a study that will be the first to assess the safety, tolerability, and immunogenicity of Invaplex<sub>AR-Detox</sub> co-administered with dmLT in healthy adults in low-endemic and high-endemic settings. Methods: In a multi-center, randomized, double-blind, and placebo-controlled dose-escalation phase Ia/b trial, the safety, tolerability, and immunogenicity of three intramuscular vaccinations administered 4 weeks apart with 2.5 µg or 10 µg of Invaplex<sub>AR-Detox</sub> vaccine, alone or in combination with 0.1 µg of the dmLT adjuvant, will first be assessed in a total of 50 healthy Dutch adults (phase Ia) and subsequently in 35 healthy Zambian adults (phase Ib) aged 18–50 years. The primary outcome is safety, and secondary outcomes are humoral and cellular immune responses to the adjuvanted or non-adjuvanted vaccine. Discussion: This trial is part of the ShigaPlexIM project that aims to advance the early clinical development of an injectable Shigella vaccine and to make the vaccine available for late-stage clinical development. This trial addresses the issue of hyporesponsiveness in an early stage of clinical development by testing the vaccine and adjuvant in an endemic setting (Zambia) after the first-in-human administration and the dose-escalation has proven safe and tolerable in a low-endemic setting (Netherlands). Besides strengthening the vaccine pipeline against a major diarrheal disease, another goal of the ShigaPlexIM project is to stimulate capacity building and strengthen global North-South relations in clinical research. Trial registration: EU CT number: 2023-506394-35-02, ClinicalTrials.gov identifier: NCT05961059.https://www.mdpi.com/2076-393X/13/1/48<i>Shigella</i>shigellosisdiarrheal diseasevaccineadjuvantInvaplex |
| spellingShingle | Geert V. T. Roozen Nsofwa Sukwa Masuzyo Chirwa Jessica A. White Marcus Estrada Nicole Maier Kevin R. Turbyfill Renee M. Laird Akamol E. Suvarnapunya Aicha Sayeh Flavia D’Alessio Candice Marion Laura Pattacini Marie-Astrid Hoogerwerf Rajagopal Murugan Manuela Terrinoni Jan R. Holmgren Sodiomon B. Sirima Sophie Houard Michelo Simuyandi Meta Roestenberg Safety, Tolerability, and Immunogenicity of the Invaplex<sub>AR-Detox</sub> <i>Shigella</i> Vaccine Co-Administered with the dmLT Adjuvant in Dutch and Zambian Adults: Study Protocol for a Multi-Center, Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation Phase Ia/b Clinical Trial Vaccines <i>Shigella</i> shigellosis diarrheal disease vaccine adjuvant Invaplex |
| title | Safety, Tolerability, and Immunogenicity of the Invaplex<sub>AR-Detox</sub> <i>Shigella</i> Vaccine Co-Administered with the dmLT Adjuvant in Dutch and Zambian Adults: Study Protocol for a Multi-Center, Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation Phase Ia/b Clinical Trial |
| title_full | Safety, Tolerability, and Immunogenicity of the Invaplex<sub>AR-Detox</sub> <i>Shigella</i> Vaccine Co-Administered with the dmLT Adjuvant in Dutch and Zambian Adults: Study Protocol for a Multi-Center, Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation Phase Ia/b Clinical Trial |
| title_fullStr | Safety, Tolerability, and Immunogenicity of the Invaplex<sub>AR-Detox</sub> <i>Shigella</i> Vaccine Co-Administered with the dmLT Adjuvant in Dutch and Zambian Adults: Study Protocol for a Multi-Center, Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation Phase Ia/b Clinical Trial |
| title_full_unstemmed | Safety, Tolerability, and Immunogenicity of the Invaplex<sub>AR-Detox</sub> <i>Shigella</i> Vaccine Co-Administered with the dmLT Adjuvant in Dutch and Zambian Adults: Study Protocol for a Multi-Center, Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation Phase Ia/b Clinical Trial |
| title_short | Safety, Tolerability, and Immunogenicity of the Invaplex<sub>AR-Detox</sub> <i>Shigella</i> Vaccine Co-Administered with the dmLT Adjuvant in Dutch and Zambian Adults: Study Protocol for a Multi-Center, Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation Phase Ia/b Clinical Trial |
| title_sort | safety tolerability and immunogenicity of the invaplex sub ar detox sub i shigella i vaccine co administered with the dmlt adjuvant in dutch and zambian adults study protocol for a multi center randomized double blind placebo controlled dose escalation phase ia b clinical trial |
| topic | <i>Shigella</i> shigellosis diarrheal disease vaccine adjuvant Invaplex |
| url | https://www.mdpi.com/2076-393X/13/1/48 |
| work_keys_str_mv | AT geertvtroozen safetytolerabilityandimmunogenicityoftheinvaplexsubardetoxsubishigellaivaccinecoadministeredwiththedmltadjuvantindutchandzambianadultsstudyprotocolforamulticenterrandomizeddoubleblindplacebocontrolleddoseescalationphaseiabclinicaltrial AT nsofwasukwa safetytolerabilityandimmunogenicityoftheinvaplexsubardetoxsubishigellaivaccinecoadministeredwiththedmltadjuvantindutchandzambianadultsstudyprotocolforamulticenterrandomizeddoubleblindplacebocontrolleddoseescalationphaseiabclinicaltrial AT masuzyochirwa safetytolerabilityandimmunogenicityoftheinvaplexsubardetoxsubishigellaivaccinecoadministeredwiththedmltadjuvantindutchandzambianadultsstudyprotocolforamulticenterrandomizeddoubleblindplacebocontrolleddoseescalationphaseiabclinicaltrial AT jessicaawhite safetytolerabilityandimmunogenicityoftheinvaplexsubardetoxsubishigellaivaccinecoadministeredwiththedmltadjuvantindutchandzambianadultsstudyprotocolforamulticenterrandomizeddoubleblindplacebocontrolleddoseescalationphaseiabclinicaltrial AT marcusestrada safetytolerabilityandimmunogenicityoftheinvaplexsubardetoxsubishigellaivaccinecoadministeredwiththedmltadjuvantindutchandzambianadultsstudyprotocolforamulticenterrandomizeddoubleblindplacebocontrolleddoseescalationphaseiabclinicaltrial AT nicolemaier safetytolerabilityandimmunogenicityoftheinvaplexsubardetoxsubishigellaivaccinecoadministeredwiththedmltadjuvantindutchandzambianadultsstudyprotocolforamulticenterrandomizeddoubleblindplacebocontrolleddoseescalationphaseiabclinicaltrial AT kevinrturbyfill safetytolerabilityandimmunogenicityoftheinvaplexsubardetoxsubishigellaivaccinecoadministeredwiththedmltadjuvantindutchandzambianadultsstudyprotocolforamulticenterrandomizeddoubleblindplacebocontrolleddoseescalationphaseiabclinicaltrial AT reneemlaird safetytolerabilityandimmunogenicityoftheinvaplexsubardetoxsubishigellaivaccinecoadministeredwiththedmltadjuvantindutchandzambianadultsstudyprotocolforamulticenterrandomizeddoubleblindplacebocontrolleddoseescalationphaseiabclinicaltrial AT akamolesuvarnapunya safetytolerabilityandimmunogenicityoftheinvaplexsubardetoxsubishigellaivaccinecoadministeredwiththedmltadjuvantindutchandzambianadultsstudyprotocolforamulticenterrandomizeddoubleblindplacebocontrolleddoseescalationphaseiabclinicaltrial AT aichasayeh safetytolerabilityandimmunogenicityoftheinvaplexsubardetoxsubishigellaivaccinecoadministeredwiththedmltadjuvantindutchandzambianadultsstudyprotocolforamulticenterrandomizeddoubleblindplacebocontrolleddoseescalationphaseiabclinicaltrial AT flaviadalessio safetytolerabilityandimmunogenicityoftheinvaplexsubardetoxsubishigellaivaccinecoadministeredwiththedmltadjuvantindutchandzambianadultsstudyprotocolforamulticenterrandomizeddoubleblindplacebocontrolleddoseescalationphaseiabclinicaltrial AT candicemarion safetytolerabilityandimmunogenicityoftheinvaplexsubardetoxsubishigellaivaccinecoadministeredwiththedmltadjuvantindutchandzambianadultsstudyprotocolforamulticenterrandomizeddoubleblindplacebocontrolleddoseescalationphaseiabclinicaltrial AT laurapattacini safetytolerabilityandimmunogenicityoftheinvaplexsubardetoxsubishigellaivaccinecoadministeredwiththedmltadjuvantindutchandzambianadultsstudyprotocolforamulticenterrandomizeddoubleblindplacebocontrolleddoseescalationphaseiabclinicaltrial AT marieastridhoogerwerf safetytolerabilityandimmunogenicityoftheinvaplexsubardetoxsubishigellaivaccinecoadministeredwiththedmltadjuvantindutchandzambianadultsstudyprotocolforamulticenterrandomizeddoubleblindplacebocontrolleddoseescalationphaseiabclinicaltrial AT rajagopalmurugan safetytolerabilityandimmunogenicityoftheinvaplexsubardetoxsubishigellaivaccinecoadministeredwiththedmltadjuvantindutchandzambianadultsstudyprotocolforamulticenterrandomizeddoubleblindplacebocontrolleddoseescalationphaseiabclinicaltrial AT manuelaterrinoni safetytolerabilityandimmunogenicityoftheinvaplexsubardetoxsubishigellaivaccinecoadministeredwiththedmltadjuvantindutchandzambianadultsstudyprotocolforamulticenterrandomizeddoubleblindplacebocontrolleddoseescalationphaseiabclinicaltrial AT janrholmgren safetytolerabilityandimmunogenicityoftheinvaplexsubardetoxsubishigellaivaccinecoadministeredwiththedmltadjuvantindutchandzambianadultsstudyprotocolforamulticenterrandomizeddoubleblindplacebocontrolleddoseescalationphaseiabclinicaltrial AT sodiomonbsirima safetytolerabilityandimmunogenicityoftheinvaplexsubardetoxsubishigellaivaccinecoadministeredwiththedmltadjuvantindutchandzambianadultsstudyprotocolforamulticenterrandomizeddoubleblindplacebocontrolleddoseescalationphaseiabclinicaltrial AT sophiehouard safetytolerabilityandimmunogenicityoftheinvaplexsubardetoxsubishigellaivaccinecoadministeredwiththedmltadjuvantindutchandzambianadultsstudyprotocolforamulticenterrandomizeddoubleblindplacebocontrolleddoseescalationphaseiabclinicaltrial AT michelosimuyandi safetytolerabilityandimmunogenicityoftheinvaplexsubardetoxsubishigellaivaccinecoadministeredwiththedmltadjuvantindutchandzambianadultsstudyprotocolforamulticenterrandomizeddoubleblindplacebocontrolleddoseescalationphaseiabclinicaltrial AT metaroestenberg safetytolerabilityandimmunogenicityoftheinvaplexsubardetoxsubishigellaivaccinecoadministeredwiththedmltadjuvantindutchandzambianadultsstudyprotocolforamulticenterrandomizeddoubleblindplacebocontrolleddoseescalationphaseiabclinicaltrial |