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.