Development of the Sm14/GLA-SE Schistosomiasis Vaccine Candidate: An Open, Non-Placebo-Controlled, Standardized-Dose Immunization Phase Ib Clinical Trial Targeting Healthy Young Women
Abstract
:1. Introduction
2. Materials and Methods
2.1. Vaccine Antigen and Adjuvant
2.2. Preclinical Experiments on Safety and Immunogenicity in Pregnant Rabbits and Respective Offspring following Sm14 Vaccination of the Mothers
2.3. Phase Ib Clinical Trial in Healthy Women
3. Results
3.1. Sm14 Vaccine Candidate Does Not Induce Any Toxicological Effects in Pregnant Rabbits
3.2. Sm14 Vaccine Candidate Does Not Induce Any Major Adverse Effects (AEs) in Healthy Women
3.3. Sm14 Does Induce Adaptive Immune Responses in Healthy Women
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Experimental Groups | Number of Fetuses | Size of Fetuses (cm) | Weight of Fetuses (g) | Number of Corpora Lutea | Number of Placentae (Deployments) | Number of Live Fetuses | Percentage of Live Male Fetuses/Litter |
---|---|---|---|---|---|---|---|
Sm14+GLA-SE | 6.60 ± 2.78 | 6.85 ± 2.40 | 23.43 ± 11.32 | 6.33 ± 3.14 | 7.58 ± 3.02 | 83 | 56.25 ± 30.24 |
PBS Control | 7.00 ± 3.24 | 7.10 ± 0.83 | 21.58 ± 7.32 | 7.25 ± 2.89 | 8.42 ± 2.99 | 84 | 55.60 ± 34.91 |
Proportion (95% Confidence Interval) | |||
---|---|---|---|
Type of Adverse Event | First Dose (Day 1) | Second Dose (Day 31) | Third Dose (Day 61) |
Number of participants | 10 | 10 * | 10 |
Serious adverse events | 0.000 (0.000, 0.308) | 0.000 (0.000, 0.308) | 0.000 (0.000, 0.308) |
Reactions at the site of injection Reaction to touch | 0.000 (0.000, 0.308) | 0.000 (0.000, 0.308) | 0.000 (0.000, 0.308) |
Erythema | 0.000 (0.000, 0.308) | 0.000 (0.000, 0.308) | 0.000 (0.000, 0.308) |
Induration | 0.000 (0.000, 0.308) | 0.000 (0.000, 0.308) | 0.000 (0.000, 0.308) |
Edema | 0.000 (0.000, 0.308) | 0.000 (0.000, 0.308) | 0.000 (0.000, 0.308) |
Local pain | 0.900 (0.555, 0.997) | 0.556 (0.212, 0.863) | 0.400 (0.122, 0.738) |
Involuntary muscle contractions, mild | 0.100 (0.003, 0.445) | 0.000 (0.000, 0.308) | 0.000 (0.000, 0.308) |
Day of Exam | New Symptoms since Previous Exam (Duration) | Relationship to the Sm14 Vaccine |
---|---|---|
D0 * | #10: Vomit, mild (1 day). #13: Sleepiness, mild (3 days). | Not related to the vaccine. |
D7 | #7: Fever (2 days). #8: Fever (1 day). | Fever in patients #7 and #8 probably related to vaccine |
D30 | #12: Gallstones, mild. | Not related to the vaccine. |
D37 | #10: Local hyperemia, mild (3 days). #13: Light hepatic steatosis; mild headache (1 day each on separate occasions) | Patient #10 probably related to vaccine; #13 possibly related to vaccine. |
D60 | #3: Cold (6 days). #10: Flu, mild (3 days). #14: Urinary tract infection, mild (3 days). | Not related to the vaccine. |
D67 | #1: Cervicalgia, mild (unknown duration). #5: Pain in right heel, mild (10 days). | Not related to the vaccine |
D90 | #7: Vaginal discharge, mild (3 days). #13: Flu, mild (5 days). | Not related to the vaccine |
D120 | #2: Slight elevation of GGT (1 day). #3: Moderate eosinophilia (1 day). #10: Mild headache (1 day). | Not related to the vaccine |
Type of Test | Tests Outside the Reference Values (RVs) by Participant Number (#) and Day of Occurrence | Toxicity Evaluation |
---|---|---|
Hematologic tests | ||
MCV (fl)-RV= (80–100) | #3 at D120 (MCV = 79.7) | No toxicity observed. |
Total Leukocytes (TL) (/µL) RV = (3600–11,000) ICTDR G1: 13,000–15,000 /mm3 | #2 at baseline (TL = 11,170) #10 at baseline (TL = 10,270) #13 at D90 (TL = 11,310) and D120 (TL = 10,940) | No toxicity observed. |
Eosinophil (E) (%) RV= (0–5) | #2: at D37 (E = 8), D67 (E = 6), and D120 (E = 6) #3 at baseline (E = 12), D7 (E = 10), D67 (E = 14), D90 (E = 21), and D120 (E = 19) #7 at baseline (E = 8), D7 (E = 12), and D90 (E = 7) #12 at baseline (E = 7), D37 (E = 7), D67 (E = 6), and D90 (E = 6) | ICTDR has no recommendations for toxicity. Elevated values at all follow-ups were probably not related to vaccine. |
Neutrophil (%)–RV = (0–5) | No values outside the RV. | No toxicity observed. |
Segmented neutrophil (SN) (%) RV = (40–78) | #2 at D90 (SN = 80, NCS) #3 at baseline (SN = 31) | ICTDR has no recommendations for toxicity. Elevated value at D90 was probably not related to vaccine. |
Lymphocytes (L) (%) RV = (20–50) | #2 at baseline (L = 16, NCS) and D90 (L = 13, NCS) #7 at D37 (L = 19, NCS) #10 at baseline (L = 17, NCS) and D90 (L = 16, NCS) | ICTDR has no recommendations for toxicity. No toxicity observed. |
Atypical lymphocyte | None observed | No toxicity observed. |
Monocytes (M) (%) RV = (2–10) | #1 at D120 (M = 13, NCS) #12 at D37 (M = 12, NCS) | ICTDR has no recommendations for toxicity. |
Hemoglobin (H) (g/dL) RV = (12.0–16.0) | #2 at baseline (H = 11.6, NCS) #3 at D7 (H = 11.6, NCS), D67 (H = 11.8, NCS), and D90 (H = 11.8, NCS) #5 at baseline (H = 11.6, NCS), D7 (H = 11.4, NCS), D37 (H = 11.7, NCS), D67 (H = 11.6, NCS), D90 (H = 11.4, NCS), and D120 (H = 11.9, NCS) #8 at D7 (H = 11.8, NCS), D37 (H = 11.8, NCS), and D120 (H = 11.7, NCS) #10 at D7 (H = 11.9, NCS) #13 at baseline (H = 11.6, NCS), D7 (H = 11.4, NCS), D37 (H = 11.0, NCS), D67 (H = 11.3, NCS), D90 (H = 11.6, NCS), and D120 (H = 11.3, NCS) | No toxicity observed. |
Platelets (/µL) RV = (140,000–400,000) | #14 at D37 (Platelets = 438,000, NCS) | No toxicity observed. |
Red blood cells (RBC) (M/µL) RV = (3.9–5.3) | #5 at baseline (RBC = 3.84), D7 (RBC = 3.79), and D90 (RBC = 3.85) #10 at D7 (RBC = 3.87) | No toxicity observed. |
Hematocrit (HM) (%) RV= (36–48) | #3 at baseline (HM = 35.4), D7 (HM = 35.9), and D67 (HM = 35.5) #5 at baseline (HM = 34.6), D7 (HM = 34.1), D37 (HM = 34.6), D67 (HM = 35.4), and D90 (HM = 34.3) #8 at D7 (HM = 35.9), D67 (HM = 35.9), and D120 (HM = 34.0) #10 at D7 (35.3) #13 at baseline (HM = 35.2), D7 (HM = 33.5), D37 (HM = 32.4), D67 (HM = 34.0), D90 (HM = 35.8), and D120 (HM = 32.9) | No toxicity observed. |
Basophil (%)–RV = (0–2), Myelocyte (%)–RV = 0, Metamyelocyte (%)–RV = 0 | None found in any participant during the entire study. | |
Activated partial thromboplastin time PTT (sec)-RV = (25.1–36.5) | #10 at D67 (PTT = 23.9) #14 at baseline (PTT = 24.3), D37 (PTT = 24.3), D90 (PTT = 23.8), and D120 (PTT = 24.0) | No toxicity observed. |
Prothrombin time (sec) RV = (9.4–12.5) | No values outside the RV. | No toxicity observed. |
Prothrombin ratio (PR) (%) RV = (70–100) | #2 at baseline (PR = 101, NCS), D7 (PR = 117, NCS), D37 (PR = 112, NCS), and D67 (PR = 113, NCS) #7 at D7 (PR = 103, NCS), and D90 (103, NCS) #10 at baseline (PR = 104, NCS), and D67 (PR = 101, NCS) #12 at baseline (PR = 104, NCS) #13 at baseline (PR = 112, NCS) #14 at baseline (PR = 115, NCS), and D7 (PR = 114, NCS), D37 (PR = 106, NCS), D90 (PR = 108, NCS), and D120 (PR = 115, NCS). | No toxicity observed. |
International Normalized Ratio (INR)–RV = (1.0–1.2) | No values were above the LR RV. | ICTDR has no recommendations for toxicity. No toxicity observed. |
Blood Chemistry | ||
Sodium (mmol/L) RV = (136–145) | No values were above the RV. | No toxicity observed. |
Potassium (K) (mmol/L) RV = (3.5–5.1) ICTDR G1: 5.6 to 6.0 mEq/L ICTDR G2: 6.0 to 6.5 mmol/L. | #1 at D37 (K = 5.4, NCS) and D67 (K = 5.7, G1). #10 at D37 (K = 5.2, NCS). | #1 did not show other symptoms or other abnormal laboratory findings and was considered to have no toxicity, according to medical chart. |
Liver function | ||
Total bilirubin (mg/dL) RV ≤ 1.2 | No values were above the RV. | No toxicity observed. |
Direct bilirubin (DB) (mg/dL) RV ≤ 0.3 | #1 at baseline (DB = 0.34) | No toxicity observed. |
Indirect bilirubin (mg/dL)–RV ≤ 0.7 | No values were above the LR RV. | No toxicity observed |
Alkaline Phosphatase (AP) (U/L) RV = (35–104) ICTDR G1 Lower Limit = 130 | #12 at D90 (AP = 105) #13 at baseline (AP = 119), D7 (AP = 118), D37 (AP = 106), D67 (AP = 106), D90 (AP = 123), and D120 (AP = 104) | No toxicity observed according to medical charts. High values for #13 are probably not due to vaccine (was high at baseline). |
AST (U/L)–RV ≤ 32 | #12 at D90 (AST = 37, NCS) | No toxicity observed. |
ALT (U/L) RV ≤ 33 ICTDR G1: (40–80) | #12 at D90 (ALT = 66, G1, NCS) #13 at D37 (ALT = 35), D67 (ALT = 35), and D90 (ALT = 33) | #12 above ICTDR threshold for grade 1 toxicity, but not clinically significant according to medical chart. No other toxicity observed. |
GGT (U/L) RV ≤ 40 ICTDR G1: (50–100) ICTDR G2: (101–200) ICTDR G3: (201–400) ICTDR G4: > 400 | #2 at baseline (GGT = 52, G1), D7 (GGT = 50), D37 (GGT = 58, G1), D67 (GGT = 57, G1), D90 (GGT = 68, G1), and D120 (GGT = 69, G1) #12 at baseline (GGT = 99, G1), D7(GGT = 106, G2), D37(GGT = 113, G2), D67(GGT = 95, G1), D90 (GGT = 240, G3), and D120 (GGT = 107, G2) #13 at baseline (GGT = 122, G2), D7(GGT = 123, G2), D37 (GGT = 112, G2), D67(GGT = 106, G2), D90 (GGT = 130, G2), and D120 (GGT = 102, G2) | Three participants had elevated GGT at baseline and all follow-ups, which were most likely not due to the vaccine. |
Kidney function | ||
Creatinine (C) (mg/dL) RV= (0.5–0.9) ICTDR G1: 0.99–1.35 | #13 at D67 (C = 0.95) and D120 (C = 0.94) | No toxicity observed. |
Urea (mg/dL) RV < 50 (for age ≤ 65) | No values were above the RV. | No toxicity observed. |
Other blood tests | ||
Calcitonin (pg/mL) RV ≤ 11.5 | No values were above the RV | No toxicity observed. |
Abdomen physical exam | ||
Abnormalities | None observed. | No toxicity observed. |
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Santini-Oliveira, M.; Machado Pinto, P.; Santos, T.d.; Vilar, M.M.; Grinsztejn, B.; Veloso, V.; Paes-de-Almeida, E.C.; Amaral, M.A.Z.; Ramos, C.R.; Marroquin-Quelopana, M.; et al. Development of the Sm14/GLA-SE Schistosomiasis Vaccine Candidate: An Open, Non-Placebo-Controlled, Standardized-Dose Immunization Phase Ib Clinical Trial Targeting Healthy Young Women. Vaccines 2022, 10, 1724. https://doi.org/10.3390/vaccines10101724
Santini-Oliveira M, Machado Pinto P, Santos Td, Vilar MM, Grinsztejn B, Veloso V, Paes-de-Almeida EC, Amaral MAZ, Ramos CR, Marroquin-Quelopana M, et al. Development of the Sm14/GLA-SE Schistosomiasis Vaccine Candidate: An Open, Non-Placebo-Controlled, Standardized-Dose Immunization Phase Ib Clinical Trial Targeting Healthy Young Women. Vaccines. 2022; 10(10):1724. https://doi.org/10.3390/vaccines10101724
Chicago/Turabian StyleSantini-Oliveira, Marília, Patrícia Machado Pinto, Tatiane dos Santos, Mônica Magno Vilar, Beatriz Grinsztejn, Valdilea Veloso, Elan C. Paes-de-Almeida, Maria A. Z. Amaral, Celso R. Ramos, Miryam Marroquin-Quelopana, and et al. 2022. "Development of the Sm14/GLA-SE Schistosomiasis Vaccine Candidate: An Open, Non-Placebo-Controlled, Standardized-Dose Immunization Phase Ib Clinical Trial Targeting Healthy Young Women" Vaccines 10, no. 10: 1724. https://doi.org/10.3390/vaccines10101724
APA StyleSantini-Oliveira, M., Machado Pinto, P., Santos, T. d., Vilar, M. M., Grinsztejn, B., Veloso, V., Paes-de-Almeida, E. C., Amaral, M. A. Z., Ramos, C. R., Marroquin-Quelopana, M., Coler, R., Reed, S., Ciol, M. A., Savino, W., Parra, J. d. C., Almeida, M. S. d. S., & Tendler, M. (2022). Development of the Sm14/GLA-SE Schistosomiasis Vaccine Candidate: An Open, Non-Placebo-Controlled, Standardized-Dose Immunization Phase Ib Clinical Trial Targeting Healthy Young Women. Vaccines, 10(10), 1724. https://doi.org/10.3390/vaccines10101724