Immunogenicity and safety of a tri-antigenic versus a mono-antigenic hepatitis B vaccine in adults (PROTECT): a randomised, double-blind, phase 3 trial

Summary

Background

The seroprotection rate (SPR) of hepatitis B vaccination in adults is suboptimal. The aim of this study was to compare the SPR of a tri-antigenic hepatitis B vaccine (TAV), with a mono-antigenic vaccine (MAV) in adults of all ages.

Methods

This was a multicentre, double-blind, phase 3, randomised controlled trial (PROTECT) comparing the immunogenicity and safety of TAV with MAV in 28 community and hospital sites in the USA, Finland, Canada, and Belgium. Adults (aged ≥18 years) seronegative for hepatitis B virus (HBV), including those with well-controlled common chronic conditions, were randomly assigned (1:1) and stratified by study centre and age according to a web-based permuted blocked randomisation. Participants received either TAV or MAV which were administered as an intramuscular dose (1 mL) of TAV (10 μg; Sci-B-Vac, VBI Vaccines [SciVac, Rehovot, Israel]) or MAV (20 μg; Engerix-B [GlaxoSmithKline Biologicals, Rixensart, Belgium]) on days 0, 28, and 168 with six study visits and 24 weeks of follow-up after the third vaccination. Participants, investigators, and those assessing outcomes were masked to group assignment. The co-primary outcomes were to show non-inferiority of the SPRs 4 weeks after the third vaccination with TAV versus MAV in adults aged 18 years and older, as well as superiority in adults aged 45 years and older. SPR was defined as the percentage of participants attaining anti-HBs titres of 10 mIU/mL or higher. Non-inferiority of TAV to MAV was concluded if the lower limit of the 95% CI for the between-group difference was greater than −5%. Non-inferiority was assessed in the per-protocol set of participants (aged ≥18 years) and superiority was assessed in all participants (aged ≥45 years) who received at least one vaccination and had at least one evaluable immunogenicity sample after baseline (full analysis set). Safety analyses were a secondary outcome and included all participants who received at least one injection. This trial is registered at Clinicaltrials.gov (NCT03393754) and EudraCT (2017–001819–36) and is closed to new participants.

Findings

Between Dec 13, 2017, and April 8, 2019, 1607 participants (796 allocated to TAV and 811 allocated to MAV) were randomly assigned and distributed across age cohorts of 18–44 years (299 of 1607; 18·6%), 45–64 years (716 of 1607; 44·6%), and 65 years and older (592 of 1607; 36·8%). In participants aged 18 years and older, SPR was 91·4% (656 of 718) in the TAV group versus 76·5% (553 of 723) in the MAV group (difference 14·9%, 95% CI 11·2–18·6), showing non-inferiority in the per-protocol set. In participants aged 45 years and older, SPR was 89·4% (559 of 625) in the TAV group versus 73·1% (458 of 627) in the MAV group (difference 16·4%, 95% CI 12·2–20·7), showing superiority in the full analysis set. TAV was associated with higher rates of mild or moderate injection site pain (63·2% [503 of 796] in TAV vs 36·3% [294 of 811] in MAV), tenderness (60·8% [484 of 796] in TAV vs 34·8% [282 of 811] in MAV), and myalgia (34·7% [276 of 796] vs 24·3% [197 of 811] in MAV). Otherwise, the safety profile of TAV was similar to that of MAV.

Interpretation

The safety and efficacy of TAV shows its usefulness for the prevention of HBV infection in adults, including those with stable and controlled chronic conditions.

Funding

VBI Vaccines.

Introduction

Hepatitis B virus (HBV) infection can cause liver inflammation, fibrosis, and liver injury, resulting in potentially life-threatening conditions through acute illness and chronic disease, including liver failure, cirrhosis, and cancer. Globally, up to 350 million people are chronically affected with HBV,¹ resulting in about 800 000 deaths annually from sequelae of infection.² Although the risk of acquiring chronic HBV infection is approximately 5% in adulthood, acute HBV progresses to chronic HBV in 20–40% of individuals with an impaired immune response.³ Millions living with HBV are unaware of their infection, since it is often asymptomatic. It is estimated that as few as 10·5% globally, and 34% of chronically infected patients in the USA are aware of their infection status, increasing the likelihood of spreading HBV.⁴ Moreover, increasing rates of injection drug users have contributed to the rise in HBV infection in North America and Europe. In the EU or European Economic Area, an estimated 4·7 million people are chronically infected, which combined with the persistently low adult vaccination rates, poses a serious threat of hepatitis B in Europe.⁵ The acute HBV infection rate in the USA increased by 20·7% in 2015, rising for the first time since 2006, with the sharpest increases occurring largely in states that have been affected most by the ongoing opioid epidemic.⁶

Research in context

Evidence before this study

Viral hepatitis continues to pose a serious threat to the health of millions of people worldwide. Despite the highly infectious nature of the hepatitis B virus (HBV), millions of people living with HBV do not know they are infected since the initial infection is often asymptomatic—it is estimated that as few as 10·5% of people globally, and 33% with chronic HBV in the USA are aware of their infection, increasing their likelihood of transmitting the virus. We searched PubMed, Medline, and EMBASE for articles published in English from Jan 1, 1990, to June 1, 2020, to identify any published phase 3 clinical trials assessing the efficacy of hepatitis B vaccines, containing small (HBsAg), medium (pre-S2), and large surface antigens (pre-S1) of the HBV envelope. We used the search terms “hepatitis B virus”, “pre-S1”, pre-S2”, “HepB vaccines”, “prophylaxis”, “vaccine”, and “clinical trials”. Hepatitis B vaccines, based on immunostimulatory adjuvants including aluminium hydroxide and synthetic cytosine phosphoguanine oligonucleotide, have been studied in phase 3 trials. The mono-antigenic hepatitis B vaccine, Engerix-B (MAV), containing the small HBsAg is associated with lower seroprotection rates (SPR) in men than in women, which progressively decreases with age. Furthermore, up to 40% of vaccinees miss the third injection, resulting in inadequate clinical protection against HBV infection.

Before the phase 3 clinical development programme of Sci-B-Vac (TAV) in Europe and North America, a total of 23 clinical trials has been completed in neonates, children, and adults since 1989 using the current or previous formulations of TAV. Of the completed studies, 11 were done in adults, of which ten were in generally healthy seronegative adults and one in adult non-responders to other hepatitis B vaccines. Data on these studies indicate that immunisations with TAV lead to high rates of seroprotection and development of high levels of anti-HBs titres. The tolerability and safety profile of TAV are favourable and comparable to other currently approved hepatitis B vaccines and the benefit–risk ratio continues to be positive and favourable for TAV vaccinations. A second phase 3 pivotal study CONSTANT (n=2838) was done to show TAV lot-to-lot manufacturing consistency and to compare safety and immunogenicity of TAV and MAV in 18–45 year olds. To our knowledge, PROTECT is the only phase 3 trial of TAV in the USA, Canada, and Europe that has reported results.

Added value of this study

Our trial is the first to investigate the non-inferiority and superiority of TAV compared with a standard dose of MAV in a primarily older adult population. A more potent hepatitis B vaccine that is more immunogenic, induces seroprotection faster, eliminates the need for re-vaccinations, and has a favourable safety profile has important public health implications. The significance of this study is the recognition that TAV is immunogenic in an older population that is not adequately protected following vaccination with current yeast-derived alum-adjuvanted MAVs.

The study met both its co-primary endpoints. TAV was non-inferior to MAV and induced higher SPR in adults aged 18 years or older, when compared with MAV after three doses, with statistical and clinical superiority in adults aged 45 years or older. The SPR of TAV compared with MAV in adults (aged ≥18 years) was higher and almost double at each timepoint in the first 6 months after the first injection.

Implications of all the available evidence

PROTECT showed that rapid and high SPRs are achievable with TAV, which highlights its potential use in at-risk populations in an accelerated manner, and is particularly desirable for unvaccinated health-care workers, public service sector workers, and the military. Higher SPRs that were consistent across key subgroups included in our analyses support the use of TAV in adults, including older adults with controlled chronic conditions. TAV is a vaccine with a 20-year history of safe and effective use in the prevention of HBV in Israel, and the results of the PROTECT study, along with the results of our second pivotal phase 3 study, CONSTANT, support public health efforts to eliminate new HBV infections.

The best way to prevent adult transmission of HBV is through successful vaccination. The adult hepatitis B vaccination rates, however, remain low in the USA and Europe, with vaccination rates of only about 25% among all adults (aged ≥19 years) in the USA,⁷ and ranges from 8% to 46% in Europe.⁵ By contrast with adults, neonatal and childhood hepatitis B vaccination programmes have been successful in most countries, meeting global targets to eliminate HBV infection.⁸ Improved hepatitis B vaccines are needed to ensure safe and effective seroprotection against HBV for all adults. Vaccination of adults with current standard mono-antigenic yeast-derived alum-adjuvanted hepatitis B vaccines (MAVs) have important limitations, including reduced immunogenicity in older adults, obese individuals, smokers, patients with diabetes, chronic kidney or liver failure,⁹ and low response rates after two doses, which prolongs the time to protection against HBV infection.¹⁰ Studies have shown that standard yeast-derived alum-adjuvanted hepatitis B vaccines are able to elicit seroprotection rates (SPRs) of 98·6% in healthy participants aged 16–40 years,¹¹ but only 59% in those aged 40 years and older,¹² underscoring that age is a major factor in vaccine response.9, 10, 11, 12

The tri-antigenic hepatitis B vaccine (TAV) is an alum-adjuvanted vaccine produced in mammalian cells that contains pre-S1, pre-S2, and S HBV surface antigens that resemble the naturally occurring HBV particles in terms of protein composition, glycosylation patterns, and harbours all antigenic epitopes and domains of the HBV envelope. Unlike currently available yeast-derived MAVs that only contain the small non-glycosylated S antigen (HBsAg), TAV expresses highly immunogenic T and B cell epitopes present in the pre-S1 and pre-S2 antigens, which might enhance immunogenicity13, 14, 15, 16 in populations with reduced immune responses to MAVs.

Previous studies of TAV have consistently shown that a three-dose regimen (administered at 0, 1, and 6 months) elicits very high SPRs (>98%) and high anti-HBs titres. Comparative studies in children and adults have shown that antibody responses with TAV after each dose are higher than MAVs, with high SPRs noted after the first, second, or third dose.16, 17, 18 In addition, TAV induced cellular immunity as well as protective anti-HBs titres in previously vaccinated individuals that were non-responders and low-responders.¹⁹ TAV had comparable SPR to MAV in young adults;20, 21 studies in older adults vaccinated with TAV were not available. The purpose of this phase 3 study (PROTECT) was to compare SPRs induced by TAV and MAV in adults (aged ≥18 years), including older adults with stable chronic comorbidities.