Hepatitis E vaccine development

Figures & data

Figure 1. Process (A), (pre-)clinical (B) and regulatory (C) milestones during Hecolin® development from 1998 to 2012. * Final developmental process defined. **Final manufacturing process defined and implemented.

Table 2. Different scoring of efficacy of Hecolin^® vaccine against hepatitis E based on four different criteria for the disease or its protection against overall HEV infection in participants who received all three doses

Endpoint	Definition	No. episodes / No. subjects		Efficacy (%) (95%CI)
		Hecolin^® group	Control group
Hepatitis E (Criterion A)	(1) hepatitis-like symptoms lasting for at least 3 d; (2) ALT ≥ 2.5 × ULN*; (3) Positive for two or more acute HEV infection markers: HEV RNA, IgM anti-HEV by GL assay^& or E2 assay, ≥ 4-fold increase of IgG anti-HEV level (4) Confirmed by Date and Safety Monitoring Board	0 / 48,693	15 / 48,663	100 (72.1 - 100)
Hepatitis E (Criterion B)	(1) hepatitis-like symptoms lasting for at least 3 d; (2) ALT ≥ 2.5 × ULN; (3) Positive for two or more of acute HEV infection markers: HEV RNA, IgM anti-HEV by GL assay, ≥ 4-fold increase of IgG anti-HEV level	0 / 48,693	17 / 48,663	100 (77.3 - 100)
Hepatitis E (Criterion C)	(1) hepatitis-like symptoms lasting for at least 3 d; (2) ALT ≥ 10.0 × ULN; (3) Positive for two or more of acute HEV infection markers: HEV RNA, IgM anti-HEV by GL assay, ≥ 4-fold increase of IgG anti-HEV level	0 / 48,693	8 / 48,663	100 (41.5 - 100)
Hepatitis E (Criterion D)	(1) hepatitis-like symptoms lasting for at least 3 d; (2) ALT ≥ 1.0 × ULN; (3) Positive for two or more of acute HEV infection markers: HEV RNA, IgM anti-HEV by GL assay, ≥ 4-fold increase of IgG anti-HEV level	9 / 48,693	26 / 48,663	65.4 (26.2 - 83.8)
Overall HEV infection	(1) positive seroconversion or ≥ 4-times rising of antibody level in paired serum samples collected with 12-mo interval in two successive years after vaccination	22 / 3,567	101 / 3,548	78.3 (65.6 – 86.3)

Notes: *ULN, the upper limit of normal range. ^&GL assay produced by MP Diagnostics is based on peptides that do not overlap with the vaccine antigen, while E2 assay is based on proteins with similar conformational epitopes as the vaccine antigen.

Table 1. Clinical trials of the recombinant HE vaccine during late-stage development of Hecolin®

Trial	Study Purpose	No. of patients	Key conclusion	Ref.
Phase Ia (2005.1–2005.3)	Safety	44	✓ Well tolerated*
Phase IIa (2005.4–2005.11)	Safety, Dose schedule	457	✓ Well tolerated* ✓ 3 doses with a regimen of 0–1-6 min was selected
Phase IIb (2005.4–2005.11)	Safety, Dosage escalation	155	✓ Well tolerated* ✓ Seroconversion rate was 100% in all the subjects ✓ 30-μg dose was selected for a Phase III clinical trial
Phase III (2007.8–2009.5)	Safety, Efficacy, Immunogenicity	112 604	✓ Well tolerated in the general population* and showed preliminary evidence for safety in pregnant women. *^& ✓ Efficacy after three doses was 100% (95% CI 72·1–100). ✓ 98.7% of subjects had anti-HEV IgG response after receiving HE vaccine

Notes: * No vaccine-related SAEs were reported. ^&68 pregnant women were inadvertently vaccinated with 1 or more doses of HE vaccine or placebo vaccine during Phase III clinical trial; the AEs occurred in this population were analyzed.