more effective new hepatitis b vaccine

​ A new and seemingly much better hepatitis B vaccine is in the pipeline (see https://www.cdc.gov/mmwr/volumes/67/wr/mm6715a5.htm), approved by the Advisory Committee on Immunization Practices on February 21, 2018.

Details:

--Current hepatitis B vaccines have a similar aluminum adjuvant. The new vaccine, Heplisav-B (HepB-CpG), has a purified HepB surface antigen (HBsAg) combined with small synthetic immunostimulatory cytidine-phosphate-guanosine oligodeoxynucleotide (CpG-ODN) motifs (1018 adjuvant). The 1018 adjuvant binds to Toll-like receptor 9 to stimulate a directed immune response to HBsAg. This vaccine contains no preservatives.

--Data from 4 randomized controlled trials assessed its efficacy (using the surrogate marker of HBsAb levels >10 mIU/mL), and 6 studies assessed adverse events

    --Seroprotective antibody levels were achieved in 90.0 to 100% of subjects after 2 doses, vs 70.5 to 90.2% of subjects receiving 3 doses of the older Engerix-B vaccine, deemed to be a GRADE evidence type 2 (downgraded because the studies used only the surrogate marker)

        --A 2006 study of 99 healthy, seronegative people aged 18-28 immunized with Heplisav-B vs Engerix-B: 79% of the former developed a protective antibody response 4 weeks after dose 1, vs 12% given Engerix-B (geometric mean concentration GMC 23.0 vs 1.87 mIU/mL); 1 week after dose 2, 100% vs 18% had protective levels (GMC 1603 vs 2.40 mIU/mL)

        --A 2012 study of 2415 healthy adults aged 18-55 found a seroprotective immune response in 95.1% with Heplisav-B vs 81.1% with Engerix-B, with dramatically higher GMC levels at each point after vaccine administration until week 28 (at which point they were the same).

        --A 2013 study of healthy subjects to age 40-70 comparing the immunogenicity of 2 doses of the new vaccine vs 3 doses of Engerix-B found a seroprotective antibody response in 90.0% vs 70.5% on Engerix-B

        --A 2018 study of 8374 participants aged 18-70 (including 961 with diabetes) similarly compared immunogenicity at week 28, 90.0% with Heplisav-B vs 65.1% with Engerix-B had a sero-protective antibody response:

            --by age, the sero-protective response in those on Heplisav-B decreased from 100% for 18-29 yo to 91.6% in 60-70 yo, vs 93.9% down to 72.6% for Engerix-B

            --diabetics had 90.0% vs 65.1% response rate

            --obese patients 94.7% vs 75.4%

            --smokers 95.9% vs 78.6%

        --another 2013 study assessed 521 patients aged 18-75 with chronic kidney disease (GFR <45, including patients with renal failure), finding seroprotection rates (by HBsAb titer >10) of 89.9% with Heplisav-B vs 81.8% with Engerix-B, and 73.6% vs 63.2% achieving a titre >100 mIU/mL. and those on hemodialysis developed protective antibody responses within 8-12 weeks aftger the first dose of Heplisav-B [in this case particularly, in those about to go on hemodialysis it is important to get a good response sooner than later]

    --Safety profiles from 9871 subjects receiving the new vaccine vs 4385 on Engerix-B were: 45.6% vs 45.7% for mild adverse effects; 5.4% vs 6.3% for serious adverse events, and 0.27% vs 0.14% for cardiovascular events. This body of evidence was deemed to be GRADE evidence type 1

        --Mild injection site tenderness was more common after Heplisav-B (74 to 77%) than Engerix -B (34 to 58%). overall, there were no significant differences between the older vaccines and this new one, including no changes in a few markers of autoimmunity (ANA, andi-ds-DNA), though one person developed Wegener's, but one developed systemic vasculitis in the Engerix-B group (2012 study); another study found small numbers of cases of hypothyroidism or vitiligo in the Heplisav-B group

Recommendations: 

--HepB-CpG is recommended for persons >18 yo, and is administered as 2 doses, one month apart, as an intra-muscular injection in the deltoid region of the upper arm.

--The data on pregnant women is insufficient to recommend this vaccine during pregnancy. no studies involved people younger than 18

--In patients having had vaccines from a different manufacturer, there are limited data. There is no problem beginning the full 2 dose series of the new vaccine after someone has had one or more doses of an older vaccine

--For patients who require postvaccination serologic testing (e.g. hemodialysis patients, HIV or other immunocompromised persons, healthcare personnel, sex partners of HBsAg-positive people), postvaccination serologic testing can be done 1 to 2 months after the 2nd dose.

--Those patients whose antibody responses are inadequate can receive either revaccination with 2 doses or revaccination with one dose followed by serologic testing 1 to 2 months later and a 2nd dose if there serologic response were inadequate. Receiving more than 2 vaccination series is not considered appropriate, other than those who are on hemodialysis.

--Heplisav-B may also be given to healthcare personnel or others initially vaccinated with an older vaccine many years before, but whose titer was insufficient at the time of hire or matriculation

Commentary:

--there seem to be real advantages to the new vaccine:

    --2 shots vs 3, and the shots are 1 month apart (so probably logistically easier for all to complete the series)

    --the immunologic response to only 1 dose is much higher with Heplisav-B, so probably better protection with incomplete series

--there are several concerns, however:

    --there are limited data on the full array of conditions (HIV, alcoholism, etc) which may affect antibody response, so inadequate data to support the vaccine

    ​--all of this is based on a surrogate marker ("protective" vaccine titers), which probably but not necessarily translates into disease protection.  a small leap of faith

    --i am always a bit concerned when medications/vaccines tweak the immune system, given the potential for affecting an unexpected array of consequences in the long-term (eg cancer, infections, autoimmune diseases, etc).  it is somewhat reassuring that the first studies are 12 years ago and no apparent issue.

so,

Heplisav-B seems pretty good. the rapid protection, the apparently high levels of protection even after only one shot, the apparent lack of significant adverse events compared to the older vaccines, and the efficacy in older patients and those with renal failure all speak to a significant benefit over prior Hep B vaccines.  As with the new zoster vaccine (see http://gmodestmedblogs.blogspot.com/2017/10/fda-approves-new-zoster-vaccine.html ), i suspect this one will supplant the older ones soon, at least for adults. i am still concerned about the long-term effects of an immunomodulatory vaccine, especially in infants and kids, but so far so good. and, of course, there is that little sticky issue of its cost....