Vaccination; Infection Clinical Trial
Official title:
Immunogenicity and Reactogenicity of Concomitantly Administered Hexavalent and Group B Meningococcal Vaccines in Infancy
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.
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).
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