Safety and immunogenicity of recombinant hepatitis E vaccine in healthy pregnant women between 14 and 34 weeks of gestation and non-pregnant women of reproductive age: Protocol for a Phase II, randomized, observer-blinded, placebo-controlled trial

Introduction

Hepatitis E virus (HEV) in pregnancy is associated with high maternal and perinatal morbidity and mortality. The safety and efficacy of the recombinant protein HEV vaccine (HEV239, Hecolin ^® ) have been established in non-pregnant adult populations but there is limited information among pregnant women. This trial has two co-primary objectives: 1) to assess pregnancy-related and/or serious safety events among pregnant women between 14 and 34 weeks of gestation receiving two Hecolin ^® doses four weeks apart compared to placebo recipients, and 2) to determine immune non-inferiority of pregnant recipients of two Hecolin ^® doses four weeks apart compared to non-pregnant women.

Methods and Analysis

This is a multi-site, randomized, observer-blinded, placebo-controlled vaccine safety and immunogenicity trial in pregnant women and non-pregnant women of reproductive age in Karachi, Pakistan. A total of 2,358 healthy women will be enrolled, including 2,208 pregnant women between 14 and 34 weeks of gestation, who will be randomized in a 1:1 ratio (stratified by gestational age, 14–27 and 28–34 weeks) to receive either Hecolin ^® or a normal saline placebo in two doses administered 1 month apart during pregnancy and a third dose administered postpartum, approximately 5 months after the second dose. A third arm of 150 non-pregnant women aged 16–45 years will receive Hecolin ^® on 0, 1, and 6 months. The co-primary outcomes will be (i) the proportion of pregnancy-related AESIs and SAEs in pregnant participants from the first dose until the end of study follow-up, compared with placebo, and (ii) the geometric mean concentration (GMC) of anti-HEV IgG at four weeks after the second dose, comparing pregnant vaccine recipients with non-pregnant vaccine recipients (non-inferiority margin of 0.67 for the GMC ratio). Immunogenicity will be evaluated in a pre-specified subset of 300 participants receiving Hecolin ^® , including 150 pregnant participants and 150 non-pregnant participants. Secondary outcomes will include maternal, neonatal, and infant safety outcomes, as well as immunogenicity according to the number of Hecolin ^® doses received and the trimester of vaccination.

Ethics and Dissemination

The trial was approved by the National Bioethics Committee (NBC) of Pakistan (Reference number: 4-87/NBC-910), the institutional Ethics Review Committee (ERC) of the Aga Khan University (Reference number: 8298), and the Institutional Review Board (IRB) of the International Vaccine Institute (IVI) (Reference number: 2022-007). All participants will provide written informed consent in accordance with Good Clinical Practice. The results will be submitted to World Health Organization (WHO) Strategic Advisory Group of Experts in Immunization (SAGE), and disseminated through conference presentations, and peer-reviewed publications.

Article Summary

• This study will directly enroll pregnant women, the population at highest risk of HEV-related maternal and perinatal morbidity and mortality, and will employ a randomized, observer-blinded, placebo-controlled clinical trial design to minimize bias in outcome assessment.

• The study will be conducted in peri-urban Karachi, Pakistan, an area endemic for hepatitis E virus (HEV) genotype 1 with documented outbreaks and ongoing endemic transmission, making the findings directly relevant to similarly HEV-endemic settings. While the findings are likely generalizable to other HEV-endemic settings, the high background burden of pregnancy-related adverse outcomes in Pakistan, including preterm birth, low birth weight, and maternal, fetal, and infant mortality, may result in higher observed adverse event rates in this study population.

• Participants in the first trimester of pregnancy were excluded; therefore, the safety of vaccine exposure during early gestation will not be assessed.

• Follow-up will be limited to six months postpartum, precluding assessment of the long-term durability of the immune response.

• A minimum interval of at least two weeks will be required between administration of the investigational product and other vaccines routinely given in pregnancy (e.g., tetanus toxoid), to avoid potential immune interference with immunogenicity assessment. Therefore, the safety and immunogenicity of concomitant administration with routine maternal vaccines will not be evaluated in this trial.