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Safety in Lactation: Vaccines and antisera

21 September 2020Although vaccines and toxoids (diphtheria and tetanus) are considered to be compatible with breastfeeding, their use should be limited to those situations where there is…
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Refrigerated Storage

Engerix BGSK

GSK
Engerix B
20 micrograms/mL suspension for injection

In the event of an inadvertent temperature excursion the following data may be used:
A maximum cumulative time of 168 hours is permitted for the vaccine to be at temperatures above 8°C through to 25°C or 72 hours at temperatures above 8°C through to 37°C is permitted.

Please also refer to the manufacturer’s product literature for recommended storage information at https://www.medicines.org.uk.
Contact GSK in cases where the product has been exposed to temperature deviation other than described above. Refer to the current BNF for company contact details.

No, when exposed to conditions described above
Yes, when exposed to conditions described above

If any amount of time is spent above 25°C through to 37°C the maximum cumulative time of 72 hours applies, as these two temperature excursions (up to 25°C or 37°C) must not be combined.

18 December 2019
London MI Service

FendrixGSK

GSK
Fendrix
Suspension for injection

In the event of an inadvertent temperature excursion the following data may be used:
A maximum cumulative time of 72 hours is permitted for the vaccine to be at temperatures above 8°C through to 37°C.
Please also refer to the manufacturer’s product literature for recommended storage information at https://www.medicines.org.uk.
Contact GSK in cases where the product has been exposed to temperature deviation other than described above. Refer to the current BNF for company contact details.

No, if exposed to conditions described above
Yes, if exposed to conditions described above
18 December 2019
London MI Service

HBvaxPROMerck Sharp & Dohme Limited

Merck Sharp & Dohme Limited
HBvaxPRO
Suspension for injection in pre-filled syringe

In the event of an inadvertent temperature excursion the following data may be used:

HBvaxPRO can be administered provided total (cumulative multiple excursion) time out of refrigeration (at temperatures between 8°C and 25°C) does not exceed 72 hours.

Cumulative multiple excursions between 0°C and 2°C are also permitted as long as the total time between 0°C and 2°C does not exceed 72 hours. These are not, however, recommendations for storage.

Please also refer to the manufacturer’s product literature for recommended storage information at https://www.medicines.org.uk

15 May 2020
London MI Service

Lactation Safety Information

Yes
Inactivated vaccine (monovalent or in combination with hepatitis A)
11 September 2020

New Medicines

Hepatitis B infection

Information

Vaccine
VBI Vaccines
VBI Vaccines

Development and Regulatory status

None
Pre-registration (Filed)
Pre-registration (Filed)
Dec 20VBI have submitted a BLA to the U.S. FDA seeking approval of the Company’s 3-antigen prophylactic hepatitis B vaccine [7].
Nov 20VBI have announced the submission of a MAA to the European Medicines Agency for their 3-antigen prophylactic hepatitis B vaccine candidate to be used in adults [6].
Dec 17PIII testing started, aiming for filing in 2019 [3]
Jul 17VBI Vaccines has announced plans for a global PIII clinical program for Sci-B-Vac, its third-generation recombinant hepatitis B vaccine, following positive discussions with the US FDA, the EMA, and Health Canada. The vaccine is already approved in 15 countries worldwide. Sci-B-Vac is the only commercial hep B vaccine to include the S antigen and the pre-s1 and pre-s2 surface antigens. The company hopes to demonstrate superiority vs GSK´s Engerix B [1].

Category

Third-generation recombinant hep B vaccine. It contains all the antigenic epitopes and domains of the HBV envelope, including S1, pre-S1 and pre-S2 antigens, and is produced from Chinese hamster ovary cells [2].
In the UK around 1 person in 350 is thought to have chronic (persistent) hepatitis B infection
Hepatitis B infection
Intramuscular

Trial or other data

Nov 19Topline data from PIII CONSTANT study is expected Jan 20 [6]. 19/12/2019 15:56:30
Jun 19VBI vaccines announce PIII PROTECT study met both co-primary endpoints of non-inferiority in all adults age ≥18 years, and superiority in adults age ≥ 45 years [5].
Nov 18VBI Vaccines announced that they have completed vaccination and enrollment in the PROTECT and CONSTANT studies. Top-line data is expected for PROTECT mid-year 2019 and for CONSTANT around 2019 year end [2].
Jul 17The PIII program in the US, Europe and Canada will consist of two separate 15-month studies to compare Sci-B-Vac to Engerix B. PROTECT will be a double-blind RCT in adults (n=1600)who will receive either a three-dose course of Sci-B-Vac 10mcg or a three-dose course of Engerix B 20mcg. The co-primary objectives of the study will be to demonstrate non-inferiority of Sci-B-Vac vs. Engerix-B four weeks after the third vaccination, and to demonstrate superiority of Sci-B-Vac vs. Engerix B four weeks after the third vaccination in adults >45 years. The study will also include multiple secondary objectives to evaluate the speed to seroprotection and the overall safety and tolerability of Sci-B-Vac vs. Engerix-B. CONSTANT will be a double-blind, four-arm RCT. Adults (n=3200) aged 18-45 years will be randomised in a 1:1:1:1 ratio to receive one of four three-dose courses: Lot A, Lot B, Lot C of Sci-B-Vac, or Engerix-B. The primary objective of this study will be to demonstrate lot-to-lot consistency for immune response across three independent, consecutive lots of Sci-B-Vac. The secondary objective will be to evaluate safety and efficacy of Sci-B-Vac vs. Engerix-B [1].

Heplisav-BHepatitis B infection; immunisation against hep B in healthy subjects and patients with renal disease

Information

Heplisav-B
Vaccine
Dynavax
Dynavax

Development and Regulatory status

Phase III Clinical Trials
Approved (Licensed)
Launched
Feb 21Dynavax has not announced whether it plans to seek a licence in the UK, and there is nothing on the MHRA website to indicate whether an application has or will be filed [32,33].
Feb 21Approved in the EU [31].
Dec 20Recommended for EU approval by CHMP - the full indication is "for the active immunisation against hepatitis B virus infection (HBV) caused by all known subtypes of hepatitis B virus in adults 18 years of age and older." Its use should be in accordance with official recommendations [30].
Apr 19EMA accepts MAA for review [29].
Jan 19Company is in the process of finding a suitable distribution partner for UK, before filing in the UK or EU [28].
Nov 18HEPLISAV-B was launched in the US in Q1 2018 [27].
Nov 17The FDA has approved Heplisav-B. While the company is open to partnering, it intends to market the vaccine early in 2018 whether a partner is found or not. Marketing points will be greater seroconversion rates vs. Engerix-B on a one-month, two-dose schedule [26].
Sep 17Assuming final approval by Nov 2017, Dynavax hope to launch Heplisav-B in the US early 2018 [25].
Aug 17The review date for approval in the US has been extended by three months (previously set as 10th Aug 2017) to finalise details of the postmarketing study requested the FDA to ensure accurate, timely collection of real-world safety data from Heplisav-B use [24].
Jul 17After two earlier attempts came up short, an FDA Advisory Committee has favoured Dynavax’s hepatitis B candidate Heplisav-B by a vote of 12 to 1, with three abstentions, although concerns were again expressed over safety and sufficiency of the proposed design of the postmarketing surveillance program. However the committee recognised the stronger protection offered by Heplisav vs. Engerix B (95% vs. 81% seroprotection), and that the two-dose regimen over one month compared to three doses over 6 months offered the potential to improve compliance. The company have announced they are willing to work with the FDA for an appropriate postmarketing pharmacovigilance program, and US launch is expected in 2018 [23].
Mar 17Dynavax announces that the FDA has accepted for review the company responses to the Nov 16 Complete Response Letter, and has therefore established a Prescription Drug User Fee Act action date of 10th Aug 2017 [22].
Nov 16FDA issues a third complete response letter, prompting Dynavax to start looking for a partner. Dynavax attributed the complete response letter, in part, to the FDA´s inability to assess additional details it provided in October before the end of the review period. The details were submitted to allay FDA concerns about specific adverse events of special interest and an imbalance in the number of cardiac events seen in one trial of Heplisav-B. The FDA cited these concerns, as well as others relating to safety analyses and postmarketing commitments, in its CRL. The FDA requested no additional clinical trials, nor did it flag worries about autoimmune adverse events [21].
Apr 16FDA extends the Prescription Drug User Fee Act (PDUFA) action date for Heplisav-B by three months to December 15, 2016. On the request of the FDA, Dynavax has submitted individual trial data sets that, which the FDA considers to be a major amendment to the BLA, so needing a full review [20].
Mar 16Filed in the US for immunisation against hepatitis B infection in adults 18 years of age and older. The FDA has established September 15, 2016 as the Prescription Drug User Fee Act (PDUFA) action date [18].
Feb 14EU filing withdrawn. The EMA Day 180 List of Outstanding Issues indicate that the current HEPLISAV safety database is considered to be too small to rule out a risk of less common serious adverse events. Dynavax expects to begin shortly an additional HEPLISAV trial, HBV-23, that is intended to provide a safety database sufficient to support licensure [15].
Oct 13The Company is currently preparing its response to the EMA’s 120-day list of questions to be submitted in Q4 2013. It is likely that some issues will require clarification at the 180-day list [14].
Jun 13The FDA had provided some fresh insights into the safety data it wants to see before it can approve Heplisav which will delay approval. The company are unlikely to file for restricted approval in patients with CKD [13].
Feb 13US marketing application is rejected in a complete response letter from the FDA. The agency wants further evaluation of safety in the broad age group of 18 to 70 and expressed concerns over the possibility of rare autoimmune events associated with novel adjuvants. It also raised questions about process validation and manufacturing controls and facilities. It is possible that the FDA may approve the vaccine in a restricted group (CKD or >40 years of age) [11].
Nov 12The FDA advisory panel voted 13-1 that data adequately demonstrated immunogenicity but voted 8-5 with one abstention that there was insufficient data to adequately support the safety of HEPLISAV [10].
Aug 12EMA has accepted the filing for Heplisav, intended for immunisation of adults aged 18 to 70 years of age AND those with CKD [8].
Aug 12The FDA Vaccines and Related Biological Products Advisory Committee will discuss HEPLISAV at its meeting on November 14-15, 2012 [9].
Jul 12Filed in the EU for immunisation against infection caused by all known subtypes of hepatitis B virus in adults with chronic kidney disease [7].
Jun 12FDA has accepted for review, HEPLISAV for immunization against infection caused by all known subtypes of hepatitis B virus in adults 18 through 70 years of age. The company plan to file in the EU in the third quarter of 2012 [6].
Apr 12Filed in the US for immunization against infection caused by all known subtypes of hepatitis B virus in adults 18 to70 years of age [5].
Mar 12Dynavax plans to file in the US by mid-May for an indication in healthy adults 18-70 years of age for a 2-dose vaccination regimen at 0 and 1 month. A supplemental filing with an indication and 3-dose primary vaccination regimen for patients with CKD will be filed when the first indication is approved [4].
Oct 11Company plan to file in US and EU early 2012 [2].

Category

Adult vaccine combining hepatitis B surface antigen with a proprietary Toll-like Receptor 9 agonist known as ISS to enhance the immune response
In the UK around 1 person in 350 is thought to have chronic (persistent) hepatitis B infection [12].
Hepatitis B infection; immunisation against hep B in healthy subjects and patients with renal disease
Intramuscular

Trial or other data

Aug 17In response to safety concerns highlighted by the FDA, Dynavax plan to conduct a PIV study in collaboration with Kaiser Permanente Northern California to monitor medical records for 20,000 Heplisav-B recipients against 20,000 others who receive Engerix-B during a 12-month follow-up. It´s likely that cardiac incidents, for which an imbalance was seen in a PIII study, will be the main focus [24].
Apr 16Dynavax announce RCT (number of patients not stated) found significantly higher seroprotection rate of 95 vs. 81% for Heplisav-B and Engerix-B, respectively. Rates of local/systemic reactions, adverse events, serious adverse events, and deaths were similar between the groups [19].
Mar 16The US filing is based on positive immunogenicity results from clinical trials that have generated safety data in more than 10,000 participants. Results of these trials showed that two doses of HEPLISAV-B given one month apart provides significantly higher rates of protection with an equivalent safety profile compared to three doses of Engerix-B, a currently marketed hepatitis B vaccine that is administered over six months. In Phase 3 studies across all participants, HEPLISAV-B achieved peak seroprotection rates of 95.7% vs. 79.5% for Engerix-B. Additionally, in more than 1,100 participants with diabetes, HEPLISAV-B provided seroprotection rates of 90% vs. 65.1% for Engerix-B [18].
Nov 14HEPLISAV PIII safety trial, HBV-23 (an observer-blinded, randomised, and active-controlled, study) has completed its first pre-specified safety review and an independent panel has recommended that it continue unchanged. Adult pts received 2:1, a 2-dose series of HEPLISAV-B or a 3-dose series of control vaccine, Engerix-B®. Over 50% reached 12 wks follow-up and two additional reviews and safety observation is scheduled to continue for 12 months. All study visits are expected to be completed by October, 2015 [17].
Apr 14The new PIII safety and immunogenicity study of HEPLISAV-B (HBV-23) has started. Dynavax expects that all study subjects will be enrolled by the end of 2014 and all follow-up will be completed by Q4 2015. HBV-23 is an observer-blinded trial which will enrol ~8,250 adults (18-70) who will be randomized 2:1 to receive a 2-dose series of HEPLISAV-B or a 3-dose series of a control vaccine, Engerix-B®, stratified by site, age group and type 2 diabetes status. Safety follow-up will continue to week 56. The co-primary objectives are to evaluate the overall safety and demonstrate the noninferiority of the seroprotection rate induced by HEPLISAV-B vs Engerix-B at Week 28 in subjects with T2DM [16].
Oct 13Dynavax announced the design of a new PIII study, HBV-23, which is intended to provide a sufficiently-sized safety database for the FDA to complete its review. It will be an 8,000 subject, observer-blinded, randomized, active-controlled, multicenter trial of HEPLISAV vs Engerix-B in adults 18 to 70 years of age. The primary objectives will be overall safety and the noninferiority of the peak seroprotection rate induced by HEPLISAV in subjects with type 2 diabetes mellitus. The study will start Q1 2014 [14].
Mar 12Final data from a pivotal PIII trial in patients with chronic kidney disease (CKD) reported. The trial included 516 patients aged 18-75 with CKD (stage 3b or higher) in the US Canada and Germany who received 3 doses of HEPLISAV at 0, 1 and 6 months or 4 double doses of Engerix-B at 0, 1, 2 and 6 months (8 doses total). 90% vs 82% of patients, respectively, had seroprotection (P=0.01) at 7 months (primary endpoint) and 48% vs 20% had seroprotection at 2 months. In a separate trial, in 119 CKD patients on hemodialysis who had failed to develop seroprotection after two or more previous vaccination series with licensed vaccines, immune responses were compared 4 weeks after a single booster dose of HEPLISAV or Fendrix or two booster doses of Engerix-B. 44% vs 31% and 21% of patients, resepctively, developed seroprotection [4].
Mar 12Results of an early PIII trial (HBV-04) conducted in Asia published online in the journal VACCINE. The trial compared the safety and immunogenicity of HEPLISAV with Engerix-B® in 412 adults 40-70 years of age. The seroprotection rate at one month after the second dose was 97% vs 24%, respectively (p < 0.0001) and at one month after the third dose, rates were 100% and 73% (p < 0.0001). Seroprotection rates at one year after the first dose were 100% and 69% for (p < 0.0001) [3].
Feb 12Published online in Journal Vaccine: "Comparison of Safety and Immunogenicity of Two Doses of Investigational Hepatitis B Virus Surface Antigen Co-administered with an Immunostimulatory Phosphorothioate Oligodeoxyribonucleotide and Three Doses of a Licensed Hepatitis B Vaccine in Healthy Adults 18-55 Years of Age" describes the results from one of the two pivotal Phase 3 trials of HEPLISAV.
Sep 11Data from P3 HBV-16 trial determining if the immunogenicity of 2 doses of Heplisav was non-inferior/superior to 3 doses of Engerix B. Modified ITT population included all pts that had received at least one dose of any of the 4 Heplisav doses or Engerix B and had at least one post-vaccination immunogenicity result: Heplisav (n=1947) with Engerix-B (n=476). Heplisav generated a faster, higher and longer-lasting response vs Engerix B. At the primary endpoint (week 12 for Heplisav and week 32 for Engerix), earlier seroprotection seen with Heplisav: 89% vs. 69% with Engerix. Peak seroprotection was 95% at week 24 for Heplisav vs. 71% at week 28 for Engerix B. At week 52 the seroprotection was 92% with Heplisav vs. 59% with Engerix B [1].