The 6-in-1 Vaccine Study

Vaccination; Infection Clinical Trial

Official title:

Immunogenicity and Reactogenicity of Concomitantly Administered Hexavalent and Group B Meningococcal Vaccines in Infancy

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT03880669
• Other study ID #: OVG 2018/05
• Status: Not yet recruiting
• Phase: Phase 4
• Start date: March 31, 2019
• Est. completion date: April 30, 2022

Study information

• Verified date: March 2019
• Source: University of Oxford
• Contact: Parvinder Aley, PhD
• Phone: 01865 611400
• Email: parvinder.aley[@]paediatrics.ox.ac.uk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

In 2017 the hepatitis B vaccine was added to the United Kingdom (UK) routine immunisation programme.An infection with the hepatitis B virus can cause severe inflammation of the liver and can cause severe long term liver damage.So that the hepatitis B vaccine can be introduced to the UK's childhood immunisation schedule without increasing the number of vaccine injections, the previously used '5-in-1' vaccine was replaced by a '6-in-1' vaccine. The '6-in-1' vaccine protects against diphtheria, tetanus, poliovirus, whooping cough (pertussis), hepatitis B and Haemophilus influenzae b (Hib). There are two licensed '6-in-1'vaccines available and these are called Infanrix hexa (6in 1(IH)and Vaxelis (6 in 1(V)).

The Infanrix hexa vaccine is currently used routinely in the UK. We know from previous research studies that this vaccine works well with the other vaccines in the UK schedule, including the meningococcal B vaccine (MenB or Bexsero). At present we do not have this information for the Vaxelis vaccine, and it is important to check this as the components of Vaxelis are slightly different from Infanrix hexa. If we can show that immunisation with Vaxelis creates a similar response from the immune system to Infanrix hexa and is just as safe when given in the immunisation schedule along with the MenB vaccine, the National Health Service (NHS) in the UK will be able to use either vaccine for children in the UK. This will increase the flexibility and resilience of the UK's routine immunisation schedule.

Description:

BACKGROUND AND RATIONALE. Hepatitis B virus (HBV) is a viral illness that results in inflammation of the liver. It causes significant morbidity and mortality worldwide and is the most common chronic viral infection in the world. It is estimated that up to 30% of the world's population has serological evidence of a current or past HBV infection. HBV can manifest either as an acute illness causing nausea, malaise, abdominal pain and jaundice or as an often asymptomatic chronic infection. Chronic HBV infection can lead to liver cirrhosis and hepatocellular carcinoma. HBV is blood borne and transmitted via exposure to infected blood or bodily fluids contaminated by blood. One of the most common forms of transmission is vertical or perinatal transmission of HBV from infected mothers to neonates. Low and middle-income countries have disproportionally higher rates of HBV thus there is a high prevalence in immigrants to higher-income countries.Of those who develop an acute HBV infection, 95% of babies, 20-30% of children and less than 5% of adults will go on to have a chronic infection. There is no available treatment for an acute HBV infection whilst antivirals such as Tenofovir can improve chronic HBV infections by slowing cirrhosis and reducing the risk of liver cancer. Given the complications associated with HBV,prevention of transmission is the best method for controlling this infection. Prevention includes avoidance of transmission from infected people via counselling against high risk behaviours, screening of blood products and more stringent infection control in healthcare settings through universal precautions. By far the most effective way of controlling HBV is through vaccination.The first HBV vaccine was developed in 1982 and is in widespread use. Most vaccines for HBV were developed using recombinant DNA to express a protein (antigen) against hepatitis (HBsAg). HBV vaccines are available in monovalent (single), combination (with Hepatitis A) and multivalent forms(with multiple other vaccines). Routine immunisation of neonates is a common practice worldwide with the World Health Organisation (WHO) recommending a dose of HBV at birth followed by either a 2 or 3 dose schedule. Completion of either of these programmes induces protective antibody levels in up to 95% of infants, children and adolescents. The burden of HBV in the UK reflects that of other high-income countries. In 2016 there were 453 cases of acute HBV reported and an annual incidence of 0.82 per 100,000 people. During the same period 11,901 cases of HBV were recorded, the remainder being chronic infections.The UK added a vaccine for HBV to the routine child hood immunisation schedule in 2017 as part of a multivalent vaccine. Multivalent vaccines are cost effective on a population level as they reduce the number of needles that need to be administered thus reducing the risk of complications, the number of vaccine healthcare visits needed and cost and improve compliance and vaccine coverage.

Characteristics of the licensed vaccines:

6in1(IH)(Infanrix hexa). Developed by GlaxoSmithKline, 6in1(IH)is a multivalent vaccine that protects against diphtheria, tetanus, pertussis, poliomyelitis,Haemophilus influenza type B (Hib) and hepatitis B virus (HBV). It is licensed in Europe and has been widely used internationally with data to support its efficacy and safety. It is available in a powder and suspension for injection form. 6 in 1(IH) has been included in the UK's routine immunisation schedule at 2, 3 and 4 months of age since 2017. It is made up of diphtheria and tetanus toxoid, Bordetella pertussis antigens (pertussis toxoid, filamentous haemagglutinin and pertactin), inactivated poliovirus (type 1 -3), Hib polysaccharide conjugated to tetanus toxoid as the carrier protein and hepatitis B surface antigen.

6 in 1(V) (Vaxelis). One of the other multivalent vaccines that contains Hepatitis B currently licensed in Europe is 6 in 1(V). Developed jointly by Merck/Merck Sharp & Dohme (MSD) and Sanofi Pasteur, 6 in 1(V) is available as a fully liquid and ready to use injection and protects against the same organisms as 6 in 1(IH) however the structure of some components differs. 6 in 1(V) contains diphtheria and tetanus toxoid, Bordetella pertussis antigens (including pertussis toxoid, filamentous haemagglutinin, pertactin and fimbriae types 2 and 3), inactivated poliovirus (including type 1 -3),Hib polysaccharide conjugated to a meningococcal outer membrane complex (OMPC )and hepatitis B surface antigen. It is the structure of the Hib component that may be relevant to the use of 6 in 1(V) in the UK. 4CMenB is the meningococcal B vaccine currently in use in the UK's routine immunisation schedule at 2, 4 and 12 months of age. The structure of 4CMenBincludes meningococcal outer membrane vesicles which carries with it a theoretical risk of a carrier induced epitopic suppression of the Hib responses of 6 in 1(V) when given concurrently with 4CMenB.This interaction has the potential to lead to the creation of a birth cohort with sub-optimal responses to the Hib antigen of 6 in 1(V) and thus risk are-emergence of Hib as was seen in the UK in 1999 -2003.(6)There is also the possibility that the combination of the OMPC from 6 in 1(V) and 4CMenB could cause increased systemic and local vaccine adverse reactions when co-administered (as compared to adverse reactions that can occur using the existing schedule). In the absence of any evidence to show that these concerns are unfounded, it is possible that the use of 6 in 1(V) in the UK immunisation schedule would be seen as inappropriate. This could limit the flexibility of vaccine procurement for the UK government.

Aim of the Trial:

We plan to conduct a head-to-head unblinded randomised trial comparing the immunogenicity and reactogenicity at 5 and 13 months of both licensed diptheria-tetanus-pertussis (DTaP)-Hib-inactivated polio virus (IPV)-hepatitis B (HepB) vaccines when administered at 2, 3 and 4 months of age alongside the current UK vaccination schedule (including 4CMenB).

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 240
• Est. completion date: April 30, 2022
• Est. primary completion date: October 30, 2021
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 8 Weeks to 13 Weeks

Eligibility

Inclusion Criteria:

• Healthy infants aged 8 to 13+0 weeks who are yet to receive their routine 2 month immunisations

• Parents/legal guardians are over 16 years of age, and are willing and able to consent to enrol their child/children in the study

• Parents/legal guardians able comply with the requirements of the trial protocol and have internet access for the duration of the study

• Parents/legal guardians are willing to allow their General Practitioner, health visitor and consultant, if appropriate, to be notified of participation in the trial.

• Participants born at equal to or greater than 37 weeks gestation

• Participants are due to receive their primary immunisations, aged 8 to 13 weeks (i.e. the day the child turns 13 weeks of age)at enrolment

Exclusion Criteria:

• Parents/legal guardians of children are on the delegation log of this study

• Confirmed or suspected immunodeficiency

• Fulfill any of the contraindications to vaccination as specified in The Green Book

• Confirmed anaphylactic reaction/s to any constituent/s or excipient/s of the vaccine(s)

• Confirmed anaphylactic reaction to neomycin, streptomycin or polymyxin B (which may be present in trace amounts in the tetanus vaccine),kanamycin, histidine, sodium chloride or sucrose (which may be present in trace amounts in the Meningococcal B vaccine) or to gelatin (which may be present in trace amounts in the measles-mumps-rubella (MMR) vaccine)

• Latex hypersensitivity (the syringe cap of the Meningococcal B vaccine Bexsero may contain natural rubber latex)

• Any other significant disease or disorder which, in the opinion of the Investigator, may either put the participants at risk because of participation in the trial, or may influence the result of the trial, or the participant's ability to participate in the trial.

• Child is currently participating in another interventional clinical trial

Related Conditions & MeSH terms

• Vaccination; Infection

Intervention

Biological:
• Infanrix hexa or Vaxelis
6in1(Infanrix hexa) is a multivalent vaccine that protects against diphtheria, tetanus, pertussis, poliomyelitis,Haemophilus influenza type B (Hib) and hepatitis B virus (HBV). 6in1(Vaxelis) is a multivalent vaccine that protects against diphtheria, tetanus, pertussis, poliomyelitis,Haemophilus influenza type B (Hib) and hepatitis B virus (HBV).

Locations

Country	Name	City	State
United Kingdom	Centre for Clinical Vaccinology & Tropical Medicine (CCVTM)	Oxford	Oxfordshire

Sponsors (2)

Lead Sponsor	Collaborator
University of Oxford	MCM Vaccines B.V.

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Compare the immunogenicity of the Hib component of 6 in 1(Infanrix hexa) and 6 in 1(Vaxelis) when co-administered with 4CMenB in the UK routine immunisation schedule at 5 months of age.	Measurement of anti-polyribosylribitol phosphate (PRP) (Hib) immunoglobulin G (IgG) concentrations at 5 months of age as measured by ELISA.	At 5 months of age (at least 4 weeks after administration of the last dose of either 6 in 1(IH) and 6 in 1(V) primary immunisations).
Secondary	Compare the anti-PRP(Hib) IgG concentrations at 13 months of age (1 month after administration of Hib-meningococcal C (MenC) at 12 months of age) in participants primed with 6 in 1(Infanrix hexa) and6 in 1(Vaxelis).	Measurement the anti-PRP (Hib) IgG concentrations at 13 months of age as measured by ELISA.	At 13 months of age (at least 4 weeks after the Hib-MenC vaccination at 12 months of age).
Secondary	The immunogenicity of the other antigens in the routine immunisation schedule incorporating either 6 in 1(Infanrix hexa) or 6 in 1(Vaxelis).	Measurement the IgG concentrations at 5 and 13 months of: a) Diphtheria-toxoid, b)Tetanus toxoid, c) Hepatitis B virus, d) Vaccine-serotype pneumococcal capsule antigens, e) Pertussis antigens, f) Poliovirus neutralising antibodies.; Measure serum bactericidal titres at 5 and 13 months of age of: a) 3 reference serogroup B meningococcal strains, b) Serogroup C meningococcus.	At 5 and 13 months of age (approximately 4 weeks after completion of the primary routine immunisations and approximately 4 weeks after the booster doses in the routine immunisation schedule).
Secondary	The reactogenicity of 6 in 1(Infanrix hexa) and 6 in 1(Vaxelis) when administered in the routine UK immunisation schedule.	Record solicited local and systemic adverse events within 5 days of immunisations.	In the 5 days post immunisation as recorded in participant diaries.