Safety of Hepatitis E vaccines
The HepE vaccine safety Working Group and the Strategic Advisory Group of Experts on Immunization (SAGE) updated the review of the safety of the hepatitis E vaccine Hecolin® in pregnancy. Recommendations on the use of Hecolin® were discussed previously by SAGE in October 2014,1 and a WHO position paper on use of the vaccine was issued in 2015.2 At the GACVS meeting in November 2023, 2 new post-licensure studies on the safety of Hecolin® in pregnancy, from Bangladesh and South Sudan, were presented. GACVS recommended that an ad hoc working group be considered to review the studies and any additional information and report to GACVS at a future meeting. The Hepatitis E Vaccine Safety Working Group was formed in January 2024, and the outcomes of the review were presented at the SAGE meeting on 12 March 2024.3 A key observation was a potential relation between Hecolin® vaccine administered around the onset of pregnancy and spontaneous abortion. A large cluster randomized controlled trial of Hecolin® in women of child-bearing age in rural Bangladesh indicated a higher rate of spontaneous abortion among participants who received the Hecolin® vaccine either during early pregnancy or within 90 days of pregnancy than among those who received a control hepatitis B vaccine. No increased risk of spontaneous abortion was found among women who received Hecolin® >90 days before pregnancy, and there was no difference between the groups in the rates of stillbirth or induced abortion at any of the 3 periods of exposure. Most of the women who were vaccinated during pregnancy received the vaccine in the first 7 weeks of gestation.
A matched observational cohort study conducted during a reactive vaccination campaign in the Bentiu camp for internally displaced people in South Sudan found no increased risk of fetal loss associated with exposure to the Hecolin® vaccine. The Working Group also considered other data provided by the manufacturer of Hecolin® (Innovax) and studies of the safety outcomes with other protein subunit vaccines when administered shortly before or during pregnancy. The Working Group concluded at this stage that the safety signal of spontaneous abortion associated with exposure to the Hecolin® vaccine in the 90 days before pregnancy and during early pregnancy in the cluster randomized trial in Bangladesh cannot be disregarded. While there is no conclusive evidence of a safety problem with Hecolin® vaccination and spontaneous abortion, an increased risk cannot be excluded and the finding warrants further investigation. The Working Group recommended additional analysis of the data from the study in Bangladesh to better understand the reported risk but considered that this would likely not refute the finding. The group recommended that the analysis address the relation between spontaneous abortion and the timing of vaccine administration, particularly before pregnancy`, to determine whether the risk is related to the time very close to conception. The Working Group also recommended analysis of other vaccine-related adverse events and other maternal risk factors, such as age, parity and prior exposure to hepatitis E virus (HEV). It was noted that it might be difficult to conduct a large randomized controlled trial to assess the risk of spontaneous abortion; however, any study of vaccines in settings with a high risk of hepatitis E disease should include an analysis of spontaneous abortion, other pregnancy-related outcomes and other AEFIs, in addition to assessing vaccine effectiveness. Hepatitis E disease poses significant risks of morbidity, mortality and adverse pregnancy outcomes in pregnant women, including fetal loss. The Working Group therefore recommended that the benefits of vaccination be considered in relation to the potential risk of spontaneous abortion in the event of pregnancy occurring around the time of vaccination. Furthermore, the Group noted that consideration by the WHO SAGE of future use of the hepatitis E vaccine should include examination of the potential benefits of vaccination in each setting (e.g. an outbreak). In such situations, strategies could be used to avoid vaccination at the onset of or during early pregnancy, with a detailed analysis of safety outcomes. The Committee also received an update on SAGE recommendations on use of the vaccine after the March 2024 meeting. SAGE concluded that, in fragile, conflictaffected and vulnerable settings with documented HEV circulation where the risk of severe disease in pregnancy is high, the benefits of vaccinating women of childbearing age outweigh the potential harms. SAGE stressed the importance of accompanying vaccine use with a learning agenda in vaccine campaigns, when possible. SAGE encouraged additional research on hepatitis E vaccination during pregnancy, in people living with HIV and in people aged <16 years. In addition, SAGE asked to be informed about the outcomes of further analysis of the Bangladesh trial. SAGE approved use of a 2-dose schedule (0 and 1 month of age) instead of the 3-dose schedule during campaigns. GACVS concurred with the conclusions and recommendations of the Working Group and stressed the importance of additional safety assessments of Hecolin® when used in outbreak settings. The Committee encouraged additional analyses of the Bangladesh trial to clarify the potential relation between Hecolin® vaccination, onset of pregnancy and adverse pregnancy outcomes, in particular spontaneous abortion. The Committee also noted that the findings of the Bangladesh study might be due to a protective effect of hepatitis B vaccine against spontaneous abortion, although it was not aware of any evidence of such an effect of hepatitis B vaccines, and recommended further investigation of this hypothesis.
1 See No. 50, 2014, pp. 561–576.
2 Hepatitis E vaccine: WHO position paper, May 2015. Geneva: World Health Organization; 2015 (https://www.who.int/publications/i/item/WER9018-185-200, accessed May 2024).
3 See No. 22, 2024, pp. 285–306
Extract from report of GACVS meeting of 13-15 November 2023, published in the WHO Weekly Epidemiological Record on 1st March 2024
The objectives of the session were to provide updates on safety of Hepatitis E vaccine and solicit recommendations on the proposed plans of safety monitoring of Hepatitis E vaccine. Two new studies were brought to the Committee’s attention to evaluate the safety of Hepatitis E vaccine in pregnancy.
GACVS members thanked the presenters for the comprehensive and complex work presented, asked additional questions, and provided suggestions for additional data, context, and analyses. Given the amount of data produced in these studies, GACVS recommended that an ad hoc working group be considered to review the studies and any additional information provided in detail and report back to GACVS at a future meeting.
Safety profile of a recombinant hepatitis E vaccine
Extract from report of GACVS meeting of 11-12 June 2014, published in the WHO Weekly Epidemiological Record on 18 July 2014
The recombinant hepatitis E vaccine (Hecolin), also designated HEV 239, encompasses amino acids 368-606 of the HEV open reading frame 2 (ORF2) capsid protein from HEV genotype 1 and is expressed as a non-fusion protein in Escherichia coli. The purified HEV 239 assembles as homodimers resulting in virus-like particles. The vaccine contains 30 µg of the purified antigen and 0.8 mg aluminium hydroxide suspended in 0.5 ml buffered saline. It is manufactured by Xiamen Innovax Biotech, Xiamen China. It was approved by the Chinese Food and Drug Administration in 2011 and has been available since October 2012.
Pre-licensure safety and immunogenicity data were presented. The vaccine was evaluated in Phase 1 and 2 pre-licensure trials designed to evaluate the optimal dose and regimen of Hecolin. The efficacy and safety of the vaccine was evaluated in a randomized, double-blind, controlled Phase 3 clinical trial in >112 000 healthy subjects 16–65 years of age irrespective of anti-HEV antibody status. That study was conducted between August 2007 and June 2009 in the Jiangsu Province of China, a region where HEV genotype 4 is the predominant genotype, with genotype 1 also circulating. Study participants were randomized 1:1 to receive either Hecolin (n = 56 302) or a licensed hepatitis B vaccine (n = 56 302) administered through intramuscular injection in 3 doses (0, 1 and 6 months). Participants were followed for 19 months.
Data showed that the vaccine was immunogenic and efficacious. To assess local and systemic solicited and unsolicited adverse events a subset consisting of 1316 participants in the Hecolin group and 1329 participants in the control group (participants from one township) were observed for 30 minutes and then assessed by home visits at 6, 24, 48 and 72 hours, as well as 7, 14 and 28 days after each dose. Other study participants were asked to report any adverse events to nearby clinics within 1 month after each dose without active follow-up visits. In addition, the investigators used data obtained from the local medical insurance system covering the whole study area (11 townships) to identify hospitalizations and deaths among the trial participants during the 19-month follow-up period. After reviewing the hospital records related to these serious adverse events, the investigators categorized them according to the Medical Dictionary for Regulatory Activities (MedDRA). Overall, safety data derived from Phase 1, 2 and 3 clinical trials suggested that the vaccine was well tolerated. Short-term (72 hours) local and systemic solicited adverse event data obtained from the “reactogenicity subset” that participated in the Phase 3 clinical trial showed more frequent local adverse events in the Hecolin group compared to the active control group. The solicited systemic adverse events and unsolicited adverse events occurred at similar rates between study groups. There appeared to be no difference in serious adverse events or death identified in the Hecolin group compared to the active control group. Because there was no active follow-up the number of severe adverse events and deaths among trial participants could not be ascertained.
In the Phase 3 clinical trial there were 37 women in the Hecolin group and 31 women in the placebo group who were inadvertently administered vaccine during pregnancy. The vaccine appeared to be well tolerated in pregnant women with rates of adverse events similar to those observed in matched non-pregnant women. Nineteen of the pregnant women in the Hecolin group and 14 in the active placebo group underwent elective abortion. There were 18 and 17 live births in the Hecolin and active control groups, respectively. Weight, body lengths and gestational age of the babies were comparable in the 2 groups. However, the overall sample size was too small to allow a conclusive statement on the safety of Hecolin in pregnant women and their babies. The safety of Hecolin was also evaluated in HBsAg-positive persons and the data are reassuring; however the analysis subset did not include persons with ongoing liver disease as this was an exclusion criterion for the trial.
The Chinese CDC has established an online reporting system to collect post-marketing safety information and to date has not identified any safety concerns. A small Phase 4 trial in the elderly (>65 years of age) is ongoing, as well as an extended follow-up trial of the Phase 3 study cohort. In addition, Hecolin is being used as an active control arm in an ongoing Phase 3 study of a human papilloma virus (HPV) vaccine in approximately 7300 healthy women.
In summary, available safety data on Hecolin derived from Phase 1, 2 and 3 clinical trials in healthy subjects are reassuring. However, GACVS noted that there are no safety data in paediatric subjects (<16 years="" of="" age),="" the="" elderly="" (="">65 years of age), persons with underlying diseases or conditions such as those who are immunosuppressed persons or have liver disease and thus recommended that studies be conducted to assess the safety of Hecolin in these subpopulations. Any follow-up of those inadvertently vaccinated in pregnancy during the HPV trial should be useful to assess safety in this group. The committee also noted that there are as yet no studies to evaluate the safety and immunogenicity of Hecolin when given concomitantly with other vaccines. In addition, GACVS recommended that a Phase 4 post-marketing study be conducted once the vaccine is in more widespread use to further assess the safety profile of Hecolin, in particular with regard to serious and rare adverse events.
Full report of GACVS meeting of 11-12 June 2014, published in the WHO Weekly Epidemiological Record on 18 July 2014