Oral MucoRice-CTB vaccine for safety and microbiota-dependent immunogenicity in humans: a phase 1 randomised trial
Summary: Background: There are an estimated 1·3–4·0 million cases of cholera and 20 000–140 000 cholera-related deaths worldwide each year. The rice-based cholera toxin B subunit (CTB) vaccine, MucoRice-CTB, is an oral candidate vaccine that does not require a cold chain, has shown efficacy in anim...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2021-09-01
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| Series: | The Lancet Microbe |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2666524720301968 |
| _version_ | 1818642075081506816 |
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| author | Yoshikazu Yuki, PhD Masanori Nojima, MD Osamu Hosono, MD Hirotoshi Tanaka, ProfMD Yasumasa Kimura, PhD Takeshi Satoh, PhD Seiya Imoto, ProfPhD Satoshi Uematsu, ProfMD Shiho Kurokawa, PhD Koji Kashima, PhD Mio Mejima, PhD Rika Nakahashi-Ouchida, PhD Yohei Uchida, MS Takanori Marui, MS Noritada Yoshikawa, MD Fumitaka Nagamura, ProfMD Kohtaro Fujihashi, ProfDDS Hiroshi Kiyono, ProfDDS |
| author_facet | Yoshikazu Yuki, PhD Masanori Nojima, MD Osamu Hosono, MD Hirotoshi Tanaka, ProfMD Yasumasa Kimura, PhD Takeshi Satoh, PhD Seiya Imoto, ProfPhD Satoshi Uematsu, ProfMD Shiho Kurokawa, PhD Koji Kashima, PhD Mio Mejima, PhD Rika Nakahashi-Ouchida, PhD Yohei Uchida, MS Takanori Marui, MS Noritada Yoshikawa, MD Fumitaka Nagamura, ProfMD Kohtaro Fujihashi, ProfDDS Hiroshi Kiyono, ProfDDS |
| author_sort | Yoshikazu Yuki, PhD |
| collection | DOAJ |
| description | Summary: Background: There are an estimated 1·3–4·0 million cases of cholera and 20 000–140 000 cholera-related deaths worldwide each year. The rice-based cholera toxin B subunit (CTB) vaccine, MucoRice-CTB, is an oral candidate vaccine that does not require a cold chain, has shown efficacy in animal models, and could be of benefit in places where there is a paucity of medical infrastructure. We aim to assess the safety, tolerability, and immunogenicity of MucoRice-CTB in humans. Methods: We did a double-blind, randomised, placebo-controlled, dose-escalation, phase 1 study at one centre in Tokyo, Japan. Eligible participants were healthy adult men with measurable serum and faecal antibodies against CTB at screening. Participants were excluded if they had allergy to rice; history of cholera or travellers' diarrhoea; poorly controlled constipation; abnormal results on hepatic, renal, or haematological screening tests; use of any over-the-counter drugs within 7 days before first administration; inability to use a medically acceptable means of contraception; or other reasons by medical judgment of the investigator. Three dose cohorts of participants were randomly assigned by block to receive oral MucoRice-CTB (1 g, 3 g, or 6 g) or placebo (1 g, 3 g, or 6 g), once every 2 weeks for 8 weeks (for a total of 4 doses). The dose groups were performed sequentially, and each dose cohort was completed before the higher dose cohort began. All medical staff, participants, and most trial staff were masked to treatment allocation. The primary outcomes were safety and tolerability, measured by 12-lead electrocardiogram; vital signs; haematology, biochemistry, and urinalysis; rice protein-specific serum IgE antibody concentration; and monitoring of adverse events. Participants were assessed at baseline and at 1, 2, 4, 6, 8, and 16 weeks after the first administration of vaccine or placebo. The safety analysis set included all participants enrolled in the trial who received at least one dose of the study drug or placebo and were compliant with good clinical practice. The full analysis population included all participants enrolled in the trial who received at least one dose of the study drug and for whom any data were obtained after the start of study drug administration. Meta-genomic analysis of study participants was performed using bacterial DNA from faecal samples before vaccination. This trial is registered with UMIN.ac.jp, UMIN000018001. Findings: Between June 23, 2015, and May 31, 2016, 226 participants were recruited and assessed for eligibility. 166 participants were excluded based on health condition or schedule. We then randomly selected 60 male volunteers aged 20–40 years who were enrolled and assigned to MucoRice-CTB (10 participants assigned to 1 g, 10 participants assigned to 3 g, and 10 participants assigned to 6 g), or placebo (10 participants assigned to 1 g, 10 participants assigned to 3 g, and 10 participants assigned to 6 g). All participants received at least one dose of study drug or placebo and were included in the safety analyses. Two participants given MucoRice-CTB 3 g and one participant given MucoRice-CTB 6 g were lost to follow-up and excluded from the efficacy analysis. Serum CTB-specific IgG and IgA antibody concentrations in participants who received 6 g MucoRice-CTB increased significantly in both a time-dependent and dose-dependent manner compared with those in the placebo groups (p for interaction=0·002 for IgG, p=0·004 for IgA). Genome analysis of subjects' faeces before vaccination revealed that compared to non-responders, responders had a gut microbiota of higher diversity with the presence of Escherichia coli and Shigella spp. 28 (93%) of 30 participants who received MucoRice-CTB at any dose had at least one adverse event during the study period, compared with 30 (100%) of 30 participants given placebo. Grade 3 or higher adverse events were reported in four participants in the MucoRice-CTB group (5 events) and four participants in the placebo group (10 events). The most common serious adverse event was haemoglobin decreased (2 events in 2 participants in the pooled MucoRice-CTB group, 2 events in 2 participants in the placebo group; all grade 3). Interpretation: Participants given MucoRice-CTB showed increased CTB-specific serum IgG and IgA antibody concentrations without inducing serious adverse events, indicating that MucoRice-CTB could be a safe and potent vaccine to prevent diarrhoeal disease. MucoRice-CTB induced neutralising antibodies against diarrhoeal toxins in a gut microbiota-dependent manner. A similar phase 1 trial will be done with participants of other ethnicities to substantiate our findings. Funding: Translational Research Acceleration Network Program of Japan Agency for Medical Research and Development; Ministry of Education, Culture, Sports, Science and Technology, Japan; Science and Technology Research Partnership for Sustainable Development; Grant-in-Aid for Scientific Research (S) (18H05280) (to H K) from the Japan Society for the Promotion of Science (JSPS); Grant-in-Aid for Young Scientists (B) (16K16144) (to Y K) from JSPS; Grant-in-Aid for Young Scientists (18K18148) (to Y K) from JSPS; Grant from International Joint Usage/Research Center (K3002), the Institute of Medical Science, University of Tokyo |
| first_indexed | 2024-12-16T23:37:17Z |
| format | Article |
| id | doaj.art-b7638b4df71d421f8e095b3d4a553c5c |
| institution | Directory Open Access Journal |
| issn | 2666-5247 |
| language | English |
| last_indexed | 2024-12-16T23:37:17Z |
| publishDate | 2021-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | The Lancet Microbe |
| spelling | doaj.art-b7638b4df71d421f8e095b3d4a553c5c2022-12-21T22:11:43ZengElsevierThe Lancet Microbe2666-52472021-09-0129e429e440Oral MucoRice-CTB vaccine for safety and microbiota-dependent immunogenicity in humans: a phase 1 randomised trialYoshikazu Yuki, PhD0Masanori Nojima, MD1Osamu Hosono, MD2Hirotoshi Tanaka, ProfMD3Yasumasa Kimura, PhD4Takeshi Satoh, PhD5Seiya Imoto, ProfPhD6Satoshi Uematsu, ProfMD7Shiho Kurokawa, PhD8Koji Kashima, PhD9Mio Mejima, PhD10Rika Nakahashi-Ouchida, PhD11Yohei Uchida, MS12Takanori Marui, MS13Noritada Yoshikawa, MD14Fumitaka Nagamura, ProfMD15Kohtaro Fujihashi, ProfDDS16Hiroshi Kiyono, ProfDDS17Division of Mucosal Immunology, International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Tokyo, JapanCenter for Translational Research, The Institute of Medical Science, The University of Tokyo, Tokyo, JapanDivision of Rheumatology, Center for Antibody and Vaccine Therapy, Department of Allergy and Rheumatology, The Institute of Medical Science, The University of Tokyo, Tokyo, JapanDivision of Rheumatology, Center for Antibody and Vaccine Therapy, Department of Allergy and Rheumatology, The Institute of Medical Science, The University of Tokyo, Tokyo, JapanDivision of Systems Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, JapanDivision of Systems Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, JapanHealth Intelligence Center, The Institute of Medical Science, The University of Tokyo, Tokyo, JapanDivision of Innate Immune Regulation, International Research and Development Center for Mucosal Vaccines and Division of Metagenome Medicine, Human Genetic Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Department of Immunology and Genomics, Osaka City University Graduate School of Medicine, Osaka, JapanDivision of Mucosal Immunology, International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Tokyo, JapanDivision of Mucosal Immunology, International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Asahi Kogyosha, Tokyo, JapanDivision of Mucosal Immunology, International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Tokyo, JapanDivision of Mucosal Immunology, International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Tokyo, JapanDivision of Mucosal Immunology, International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Tokyo, JapanDivision of Mucosal Immunology, International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Tokyo, JapanDivision of Rheumatology, Center for Antibody and Vaccine Therapy, Department of Allergy and Rheumatology, The Institute of Medical Science, The University of Tokyo, Tokyo, JapanDivision of Advanced Medicine Promotion, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo, JapanDivision of Clinical Vaccinology, International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Department of Pediatric Dentistry, The University of Alabama at Birmingham, Birmingham, AL, USADivision of Mucosal Immunology, International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Distinguished Professor Unit, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Department of Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan; Department of Medicine, School of Medicine and CU-UCSD Center for Mucosal Immunology, Allergy and Vaccine, University of California, San Diego, San Diego, CA, USA; Correspondence to: Dr Hiroshi Kiyono, IMSUT Distinguished Professor Unit, Division of Mucosal Immunology, International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, JapanSummary: Background: There are an estimated 1·3–4·0 million cases of cholera and 20 000–140 000 cholera-related deaths worldwide each year. The rice-based cholera toxin B subunit (CTB) vaccine, MucoRice-CTB, is an oral candidate vaccine that does not require a cold chain, has shown efficacy in animal models, and could be of benefit in places where there is a paucity of medical infrastructure. We aim to assess the safety, tolerability, and immunogenicity of MucoRice-CTB in humans. Methods: We did a double-blind, randomised, placebo-controlled, dose-escalation, phase 1 study at one centre in Tokyo, Japan. Eligible participants were healthy adult men with measurable serum and faecal antibodies against CTB at screening. Participants were excluded if they had allergy to rice; history of cholera or travellers' diarrhoea; poorly controlled constipation; abnormal results on hepatic, renal, or haematological screening tests; use of any over-the-counter drugs within 7 days before first administration; inability to use a medically acceptable means of contraception; or other reasons by medical judgment of the investigator. Three dose cohorts of participants were randomly assigned by block to receive oral MucoRice-CTB (1 g, 3 g, or 6 g) or placebo (1 g, 3 g, or 6 g), once every 2 weeks for 8 weeks (for a total of 4 doses). The dose groups were performed sequentially, and each dose cohort was completed before the higher dose cohort began. All medical staff, participants, and most trial staff were masked to treatment allocation. The primary outcomes were safety and tolerability, measured by 12-lead electrocardiogram; vital signs; haematology, biochemistry, and urinalysis; rice protein-specific serum IgE antibody concentration; and monitoring of adverse events. Participants were assessed at baseline and at 1, 2, 4, 6, 8, and 16 weeks after the first administration of vaccine or placebo. The safety analysis set included all participants enrolled in the trial who received at least one dose of the study drug or placebo and were compliant with good clinical practice. The full analysis population included all participants enrolled in the trial who received at least one dose of the study drug and for whom any data were obtained after the start of study drug administration. Meta-genomic analysis of study participants was performed using bacterial DNA from faecal samples before vaccination. This trial is registered with UMIN.ac.jp, UMIN000018001. Findings: Between June 23, 2015, and May 31, 2016, 226 participants were recruited and assessed for eligibility. 166 participants were excluded based on health condition or schedule. We then randomly selected 60 male volunteers aged 20–40 years who were enrolled and assigned to MucoRice-CTB (10 participants assigned to 1 g, 10 participants assigned to 3 g, and 10 participants assigned to 6 g), or placebo (10 participants assigned to 1 g, 10 participants assigned to 3 g, and 10 participants assigned to 6 g). All participants received at least one dose of study drug or placebo and were included in the safety analyses. Two participants given MucoRice-CTB 3 g and one participant given MucoRice-CTB 6 g were lost to follow-up and excluded from the efficacy analysis. Serum CTB-specific IgG and IgA antibody concentrations in participants who received 6 g MucoRice-CTB increased significantly in both a time-dependent and dose-dependent manner compared with those in the placebo groups (p for interaction=0·002 for IgG, p=0·004 for IgA). Genome analysis of subjects' faeces before vaccination revealed that compared to non-responders, responders had a gut microbiota of higher diversity with the presence of Escherichia coli and Shigella spp. 28 (93%) of 30 participants who received MucoRice-CTB at any dose had at least one adverse event during the study period, compared with 30 (100%) of 30 participants given placebo. Grade 3 or higher adverse events were reported in four participants in the MucoRice-CTB group (5 events) and four participants in the placebo group (10 events). The most common serious adverse event was haemoglobin decreased (2 events in 2 participants in the pooled MucoRice-CTB group, 2 events in 2 participants in the placebo group; all grade 3). Interpretation: Participants given MucoRice-CTB showed increased CTB-specific serum IgG and IgA antibody concentrations without inducing serious adverse events, indicating that MucoRice-CTB could be a safe and potent vaccine to prevent diarrhoeal disease. MucoRice-CTB induced neutralising antibodies against diarrhoeal toxins in a gut microbiota-dependent manner. A similar phase 1 trial will be done with participants of other ethnicities to substantiate our findings. Funding: Translational Research Acceleration Network Program of Japan Agency for Medical Research and Development; Ministry of Education, Culture, Sports, Science and Technology, Japan; Science and Technology Research Partnership for Sustainable Development; Grant-in-Aid for Scientific Research (S) (18H05280) (to H K) from the Japan Society for the Promotion of Science (JSPS); Grant-in-Aid for Young Scientists (B) (16K16144) (to Y K) from JSPS; Grant-in-Aid for Young Scientists (18K18148) (to Y K) from JSPS; Grant from International Joint Usage/Research Center (K3002), the Institute of Medical Science, University of Tokyohttp://www.sciencedirect.com/science/article/pii/S2666524720301968 |
| spellingShingle | Yoshikazu Yuki, PhD Masanori Nojima, MD Osamu Hosono, MD Hirotoshi Tanaka, ProfMD Yasumasa Kimura, PhD Takeshi Satoh, PhD Seiya Imoto, ProfPhD Satoshi Uematsu, ProfMD Shiho Kurokawa, PhD Koji Kashima, PhD Mio Mejima, PhD Rika Nakahashi-Ouchida, PhD Yohei Uchida, MS Takanori Marui, MS Noritada Yoshikawa, MD Fumitaka Nagamura, ProfMD Kohtaro Fujihashi, ProfDDS Hiroshi Kiyono, ProfDDS Oral MucoRice-CTB vaccine for safety and microbiota-dependent immunogenicity in humans: a phase 1 randomised trial The Lancet Microbe |
| title | Oral MucoRice-CTB vaccine for safety and microbiota-dependent immunogenicity in humans: a phase 1 randomised trial |
| title_full | Oral MucoRice-CTB vaccine for safety and microbiota-dependent immunogenicity in humans: a phase 1 randomised trial |
| title_fullStr | Oral MucoRice-CTB vaccine for safety and microbiota-dependent immunogenicity in humans: a phase 1 randomised trial |
| title_full_unstemmed | Oral MucoRice-CTB vaccine for safety and microbiota-dependent immunogenicity in humans: a phase 1 randomised trial |
| title_short | Oral MucoRice-CTB vaccine for safety and microbiota-dependent immunogenicity in humans: a phase 1 randomised trial |
| title_sort | oral mucorice ctb vaccine for safety and microbiota dependent immunogenicity in humans a phase 1 randomised trial |
| url | http://www.sciencedirect.com/science/article/pii/S2666524720301968 |
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