Deliverable D1.1
Development of a universal influenza vaccine based on tandem core technology
Grant agreement no. 602437
HEALTH.2013.2.3.0-1 – Innovation in vaccines
- Collaborative project -
D1.1
Biosafety report
WP 1 - Design of universal influenza VLPs based on
tandem core technology
Due date of deliverable:
month 3
Actual submission date:
dd / month / year
Start date of project:
September 1st 2013
Duration: 43 months
Lead beneficiary for this deliverable: IQUR LIMITED
Last editor: Dr. Mike Whelan, IQUR LIMITED
Contributors: Dr Mike Whelan, iQur Ltd
Project co-funded by the European Commission within the Seventh Framework Programme (2007-2013)
Dissemination Level
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Public
PP
Restricted to other programme participants (including the Commission Services)
RE
Restricted to a group specified by the consortium (including the Commission Services)
CO
Confidential, only for members of the consortium (including the Commission Services)
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History table
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Development of a universal influenza vaccine based on tandem core technology
Table of contents
History table ..................................................................................................................... 2
Table of contents .............................................................................................................. 3
Key word list ..................................................................................................................... 4
Definitions and acronyms ................................................................................................. 4
Acknowledgements .......................................................................................................... 5
Disclaimer ......................................................................................................................... 5
Executive summary........................................................................................................... 6
1.
Introduction .......................................................................................................... 7
1.1
1.2
1.3
General context ..................................................................................................... 7
Deliverable objectives ........................................................................................... 7
Background ........................................................................................................... 7
2.
Description of activities and research findings..................................................... 8
2.1
Rationale behind the safety assessment .............................................................. 8
2.2
Experimental evidence of tandem core safety ..................................................... 8
2.3
Literature evidence of core vaccine safety ........................................................... 9
2.4
EPAR evidence of safety ....................................................................................... 9
2.4.1 Safety of VLP based vaccines .............................................................................. 10
2.4.1.1 Gardasil: .................................................................................................. 10
2.4.1.2 Cervarix: .................................................................................................. 11
2.4.2 Safety of HBV vaccines........................................................................................ 12
2.4.2.1 HBVax Pro: .............................................................................................. 12
2.4.3 Safety of influenza vaccines ................................................................................ 12
2.4.3.1 Pandemic Influenza Vaccine: .................................................................. 12
2.4.3.2 Prepandemic influenza vaccine: ............................................................. 13
2.5
Overall assessment of safety .............................................................................. 14
3.
Conclusions and future steps ............................................................................. 15
4.
Publications resulting from the work described................................................. 15
5.
References .......................................................................................................... 15
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Key word list
VLP
Safety
Core protein
Vaccine
Definitions and acronyms
Acronyms
VLP
Definitions
Virus like particle
EPAR
European Public Assessment Report
EMA
European Medicines Agency
HBV
Hepatitis B virus
DNA
Deoxyribonucleic acid
HBc
HBV core protein
sAg
HBV surface antigen
TLR
Toll like receptor
MIR
Major Insertion Region
LPS
Lipopolysaccharide
CS
Circumsporozoite
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Acknowledgements
The research leading to this report has received funding from the European Union 7th
Framework Programme FP7-HEALTH-2013-INNOVATION-1 under grant agreement
number 602437.
Disclaimer
The content of this deliverable does not reflect the official opinion of the European
Union. Responsibility for the information and views expressed in the deliverable
therein lies entirely with the author(s).
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Executive summary
This report summarises the available safety data for tandem core VLP vaccine
platform, with the specific application of a universal influenza vaccine. The ultimate
aim of the Flutcore project is the carry out a Phase I safety (first in man) clinical trial.
Therefore, it is clearly impossible to provide an unequivocal safety assurance since the
required clinical work has not yet been completed. However, a synthesis of existing
preclinical and comparator clinical products leads to the conclusion that this product
will be safe for human administration and is unlikely to have any serious side-effects.
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1.
Introduction
1.1 General context
Data presented in this report will provide the scientific rationale behind our
assessment of the biological safety of tandem core™ based vaccines. It is our general
belief that vaccines based on this technology have a very good safety profile and
represent negligible risks to both animals and human subjects. This report fulfills
Deliverable 1.1 as outlined in the FLUTCORE project plan.
1.2 Deliverable objectives
The Flutcore project is based on the concept of using a VLP vaccine constructed from
HBV core protein. The variant of HBV core protein is called tandem core™. By
definition, VLPs are composed of protein and are thus deemed non-infectious.
However, it is not true to say that the VLP are completely devoid of all nucleic acids,
although this material is non-replicative. We will outline in this report why we think
that the safety profile for this vaccine platform is extremely good and is thus safe for
both animal and human vaccination trials.
1.3 Background
The Hepadnavirus hepatitis B virus contains partially double
stranded DNA. This is encased in a protein covering composed
of the core protein (HBc). Over this, is a protein/lipid layer
containing the surface antigen (sAg). Both the surface and
core proteins contain the remarkable property of being able
to form virus like particles. When expressed in the absence of
the rest of the viral genome, these proteins spontaneously
assemble into structures which closely resemble an intact
virus, but without the potentially infectious nucleic acid.
The formation of the HBc
nucleocapsid is particularly
relevant to this safety assessment and is driven by the
unique structure of the HBc protein itself. HBc contains
two anti-parallel a-helices, which form a unique “spike”
structure. A nucleic acid binding region is located at the
C-terminus, presumably involved with core protein’s
role in encapsulating the viral DNA. In the case of HBc,
90-120 dimers coalesce to form the VLP.
Core protein has profound immunological stimulating properties which can be
attributed to both TLR sequences and to the repetitive nature of the spike sequences.
As a result, core has often been used as a carrier molecule for other non-immunogenic
sequences, thereby conferring immunogenicity to them. The most favorable insertion
site is located at the tip of these spikes (MIR), although several groups have also
inserted antigens on to both the N and C termini. Both TLR 2 and 7 sequences are
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found within the core molecule. The ligands of these receptors are viral nucleic acids,
again, this is consistent with the role of core protein protecting the viral genome.
However, it has been shown that insertion of large or hydrophobic antigens into the
MIR can have a detrimental effect on core protein dimer formation. If a dimer fails to
form, then VLPs are not produced. The production of VLPs is required if core protein is
to be used as an antigen carrier due to both the inherent immunogenicity and high
antigen dose of the particles.
In order to overcome this limitation, iQur has
developed tandem core™ technology in which the
core protein is expressed as a dimer by using a
construct of two core proteins linked by a flexible
sequence of GGS repeats. These dimeric core
proteins still assemble into VLP in a manner similar to
monomeric core protein but have enhanced stability
(see
electron
micrographs
below). Furthermore, each dimeric core protein
contains two MIR sequences and therefore can,
theoretically, carry two different antigenic targets
simultaneously.
The biosafety of tandem core VLPs is discussed in
this report.
2.
Description of activities and research findings
2.1 Rationale behind the safety assessment
The assessment is broken up into three sections, based on the source of evidence.
Whilst the tandem core construct has not been used in the clinical setting at this time,
we believe that the clinical data behind the use of monomeric core vaccines may be
used interchangeably and has been used to back up many of the statements made in
this report. We do not believe that this assertion is unreasonable since tandem core is
comprised of both a full length and truncated core molecule. These are then linked
with a series of seven Gly-Gly-Ser repeats. Other than the linker sequence, the core
proteins are the same as those found in the wild-type protein. The linker itself is simply
a repetitive flexible sequence and is very unlikely to have any unexpected side effects.
2.2
Experimental evidence of tandem core safety
Tandem core proteins may be safely handled in the laboratory providing standard
precautions such as use of gloves are adhered to. Any risks associated with the product
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are more likely to be due to contaminants found after isolation from the expression
system. The VLPs themselves are non-infectious and, once purified, should be entirely
safe.
As mentioned above, tandem core proteins have not been used in the human clinical
setting at this time. However, iQur has carried out extensive preclinical testing using
these constructs loaded with a variety of antigens. Most testing has been carried out in
mice (both Balb/c and C57/bl6). VLPs have been delivered both in biocompatible
buffers and conjugated to the adjuvant alum (Imject, Pierce Scientific). In either case,
no adverse events were detected in any animal tested.
It was common to see the development of a small granulomatous mass at the injection
site. This was particularly prevalent in material delivered on alum. This was found to
resolve in 2-3 weeks. Histological analysis showed that these swellings were filled with
polymorphic immunologically active cells such as macrophages and neutrophils. These
data were interpreted as evidence of vaccine efficacy and no associated discomfort
was recorded in any of the animals.
The majority of in vivo experiments were carried out using material produced in
bacteria, although immunisations have also been carried out using VLP expressed in
Baculovirus, yeast and plants. In the case of E-coli produced material, it was possible
that granuloma formation was related to the amount of contaminating LPS found in
the samples. However, this has been comprehensively ruled out by expressing VLP in
the Clean-coli system (Lucent Technologies) which lacks the extracellular portion of the
LPS molecule.
2.3
Literature evidence of core vaccine safety
Monomeric core protein, conjugated to the CS antigen from malaria, has been used in
a Phase I clinical trial. These chimeric proteins were administered as a VLP vaccine.
Consequently, this trial is directly analogous to that proposed by the Flutcore
consortium. The vaccine was delivered both adjuvanted with alum (Nardin et al 2004)
and Montanide (Oliveira et al 2005).
In both trials, no serious adverse events were recorded. Minor inflammation was
detected at the injection site, but this is not uncommon for an active biological
vaccine.
2.4
EPAR evidence of safety
The European Medicines Agency publishes an EPAR for every medicine granted a
central marketing authorisation by the European Commission. EPARs are full scientific
assessment reports of medicines authorised at a European Union level. These reports
are particularly useful in assessing the safety of the tandem core based universal
influenza vaccine proposed by the Flutcore consortium. These reports have been
divided into three sections which cover all aspects of the project.
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2.4.1
Safety of VLP based vaccines
2.4.1.1 Gardasil: The HPV vaccine, Gardasil, has an excellent safety profile which has
been validated in several clinical trials, as well as from post-authorisation marketing
data. Gardasil is an adjuvanted non-infectious recombinant quadrivalent vaccine
prepared from the highly purified virus-like particles (VLPs) of the major capsid L1
protein of HPV types 6, 11, 16 and 18. The VLPs contain no viral DNA, they cannot
infect cells, reproduce or cause disease. HPV only infects humans, but animal studies
with analogous papillomaviruses suggest that the efficacy of LI VLP vaccines is
mediated by the development of a humoral immune response.
The most relevant data are as follows;
The vaccine showed safety in preclinical testing.
Single-dose and repeated-dose toxicity and local tolerance studies revealed no special
hazards to humans. Gardasil induced specific antibody responses against HPV types 6,
11, 16, and 18 in pregnant rats, following one or multiple intramuscular injections.
Antibodies against all four HPV types were transferred to the offspring during
gestation and possibly during lactation. There were no treatment-related effects on
developmental signs, behaviour, reproductive performance, or fertility of the
offspring. GARDASIL administered to male rats at the full human dose (120 mcg total
protein) had no effects on reproductive performance including fertility, sperm count,
and sperm motility, and there were no vaccine-related gross or histomorphologic
changes on the testes and no effects on testes weights.
The vaccine had an excellent safety profile.
In 7 clinical trials (6 placebo-controlled), individuals were administered Gardasil or
placebo on the day of enrollment and approximately 2 and 6 months thereafter. Few
individuals (0.2%) discontinued due to adverse reactions. Safety was evaluated in
either the entire study population (6 studies) or in a predefined subset (one study) of
the study population using vaccination report card (VRC)-aided surveillance for 14 days
after each injection of Gardasil or placebo. The individuals who were monitored using
VRC-aided surveillance included 10,088 individuals (6,995 females 9 to 45 years of age
and 3,093 males 9 to 26 years of age at enrollment) who received Gardasil and 7,995
individuals (5,692 females and 2,303 males) who received placebo.
The most common adverse reactions observed were injection-site adverse reactions
(77.1% of vaccinees within 5 days following any vaccination visit) and headache (16.6%
of the vaccinees). These adverse reactions usually were mild or moderate in intensity.
The most common side effect was erythema, pain or swelling at the injection site.
The vaccine can be used with several other vaccines.
Administration of Gardasil at the same time (but, for injected vaccines, at a different
injection site) as hepatitis B (recombinant) vaccine did not interfere with the immune
response to the HPV types. The seroprotection rates (proportion of individuals
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reaching seroprotective level anti-HBs >10 mIU/ml) were unaffected (96.5% for
concomitant vaccination and 97.5% for hepatitis B vaccine only). Anti-HBs geometric
mean antibody titres were lower on co-administration, but the clinical significance of
this observation is not known. Gardasil may be administered concomitantly with a
combined booster vaccine containing diphtheria (d) and tetanus (T) with either
pertussis [acellular, component] (ap) and/or poliomyelitis [inactivated] (IPV) (dTap, dTIPV, dTap-IPV vaccines) with no significant interference with antibody response to any
of the components of either vaccine. However, a trend of lower anti-HPV GMTs was
observed in the concomitant group. The clinical significance of this observation is not
known. This is based on the results from a clinical trial in which a combined dTap-IPV
vaccine was administered concomitantly with the first dose of Gardasil.
2.4.1.2 Cervarix: Cervarix is an adjuvanted non-infectious recombinant vaccine
prepared from the highly purified VLPs of the major capsid L1 protein of oncogenic
HPV types 16 and 18. Since the VLPs contain no viral DNA, they cannot infect cells,
reproduce or cause disease.
The most relevant data are as follows;
The vaccine showed safety in preclinical testing.
Non-clinical data reveal no special hazard for humans based on conventional studies of
safety pharmacology, acute and repeated dose toxicity, local tolerance, fertility,
embryo-foetal and postnatal toxicity (up to the end of the lactation period). Serological
data suggest a transfer of anti-HPV-16 and anti-HPV-18 antibodies via the milk during
the lactation period in rats. However, it is unknown whether vaccine-induced
antibodies are excreted in human breast milk.
The vaccine had an excellent safety profile.
The most common adverse reaction observed after vaccine administration was
injection site pain which occurred after 78% of all doses. The majority of these
reactions were of mild to moderate severity and were not long lasting. The most
common adverse reaction observed after vaccine administration was injection site
pain which occurred after 78% of all doses. The majority of these reactions were of
mild to moderate severity and were not long lasting
The vaccine can be used with several other vaccines.
Cervarix may be administered concomitantly with a combined booster vaccine
containing diphtheria (d), tetanus (T) and pertussis [acellular] (pa) with or without
inactivated poliomyelitis (IPV), (dTpa, dTpa-IPV vaccines), with no clinically relevant
interference with antibody response to any of the components of either vaccine. The
sequential administration of combined dTpa-IPV followed by Cervarix one month later
tended to elicit lower anti-HPV-16 and anti-HPV-18 GMTs as compared to Cervarix
alone. The clinical relevance of this observation is not known.
Cervarix may be administered concomitantly with a combined hepatitis A (inactivated)
and hepatitis B (rDNA) vaccine (Twinrix) or with hepatitis B (rDNA) vaccine (Engerix B).
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Administration of Cervarix at the same time as Twinrix has shown no clinically relevant
interference in the antibody response to the HPV and hepatitis A antigens. Anti-HBs
geometric mean antibody concentrations were significantly lower on coadministration, but the clinical relevance of this observation is not known since the
seroprotection rates remain unaffected. The proportion of subjects reaching anti-HBs ≥
10mIU/ml was 98.3% for concomitant vaccination and 100% for Twinrix given alone.
Similar results were observed when Cervarix was given concomitantly with Engerix B
with 97.9% of subjects reaching antigiven alone.
2.4.2 Safety of HBV vaccines
2.4.2.1 HBVax Pro: This vaccine for HBV is based on VLPs built from sAg. One dose (0.5
ml) contains 5µg HBV surface antigen, recombinant (HBsAg) adsorbed on amorphous
aluminium hydroxyphosphate sulfate (0.25 milligram Al+). The vaccine is produced in
Saccharomyces cerevisiae (strain 2150-2-3) yeast by recombinant DNA technology.
The most relevant data are as follows;
The vaccine had an excellent safety profile.
The most common side effects are found at the administration site. Local reactions
(injection site): Transient soreness, Erythema, Induration are common (≥1/100 to,
<1/10).
Fatigue, Fever, Malaise, Influenza-like symptoms, blood and the lymphatic system
disorders, immune system disorders, nervous system disorders, eye Disorders, vascular
disorders, respiratory, thoracic and mediastinal disorders, gastrointestinal disorders,
skin and subcutaneous tissue disorders, musculoskeletal, connective tissue and bone
disorders, elevation of liver enzymes are all classed as very rare (<1/10,000).
The vaccine can be used with several other vaccines.
Including hepatitis B immunoglobulin, booster doses of a previously received other
hepatitis B vaccine and concomitantly with other vaccines, using separate sites and
syringes.
2.4.3 Safety of influenza vaccines
2.4.3.1 Pandemic Influenza Vaccine: This is a whole virion influenza vaccine containing
inactivated containing antigen of pandemic strain (A/Vietnam/1203/2004 (H5N1) 7.5
µg per 0.5 ml dose). The virus was propagated in Vero cells (continuous cell line of
mammalian origin).
The most relevant data are as follows;
The vaccine showed safety in preclinical testing.
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Non-clinical studies demonstrated minor alterations in liver enzymes and calcium
levels in a repeat dose toxicity study in rats. Clinically significant alterations in liver
enzymes and calcium levels have not been seen to date in human clinical studies.
Animal reproductive and developmental toxicity studies do not indicate direct or
indirect harmful effects with respect to female fertility, pregnancy, embryonal/ foetal
development parturition or post natal development. Male fertility was not investigated
in the reproductive and developmental toxicity studies, however there were no
findings in the repeat-dose toxicity studies to indicate any vaccine-related changes to
the tissues of the male reproductive tract.
The vaccine had a good safety profile but anaphylaxis caused by the excipients used in
manufacture is problematical.
The vaccine cannot be given to individuals with a history of an anaphylactic (i.e. lifethreatening) reaction to the active substance, to any of the excipients (e.g.
formaldehyde, benzonase, sucrose) of this vaccine. However, in a pandemic situation,
it may be appropriate to give the vaccine, provided that facilities for resuscitation are
immediately available in case of need. Hypersensitivity reactions, including
anaphylaxis, have been reported following use of a similar whole virion, Vero cell
derived H1N1 influenza vaccine administered during a pandemic period. Such
reactions occurred both in patients with a history of multiple allergies and in patients
with no known allergy. Caution is needed when administering this vaccine to persons
with a known hypersensitivity (other than anaphylactic reaction) to the active
substance, to any of the excipients and to trace residues e.g. formaldehyde,
benzonase, or sucrose.
There is no data relating the administration of this vaccine with several other vaccines.
Therefore, healthcare providers need to assess the benefits and potential risks of
administering the vaccine in individuals with thrombocytopenia or any bleeding
disorder that would contraindicate intramuscular injection unless the potential benefit
outweighs the risk of bleedings. A protective response may not be induced in all
vaccinees (see section 5.1).
2.4.3.2 Prepandemic influenza vaccine: This vaccine is composed of Influenza virus
surface antigens (haemagglutinin and neuraminidase) of strain A/Vietnam/1194/2004
(H5N1)-like strain (NIBRG-14) 7.5 µg per 0.5 ml dose. The vaccine is propagated in
eggs.
The most relevant data are as follows;
The vaccine showed safety in preclinical testing.
Non-clinical data obtained with Prepandemic Influenza vaccine (H5N1) (surface
antigen, inactivated, adjuvanted) Novartis Vaccines and Diagnostics and with seasonal
influenza vaccine containing MF59C.1 adjuvant reveal no special hazard for humans
based on conventional studies of repeated dose toxicity, local tolerance, female
fertility, and reproductive and developmental toxicity (through the end of the lactation
period).
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The vaccine has a good safety profile but egg-based anaphylaxis reactions are
problematic.
The vaccine cannot be given to anyone with a history of an anaphylactic (i.e. lifethreatening) reaction to any of the constituents or trace residues (egg and chicken
proteins, ovalbumin, kanamycin and neomycin sulphate, formaldehyde and
cetyltrimethylammonium bromide (CTAB)) of this vaccine. However, in a pandemic
situation caused by the strain included in this vaccine, it may be appropriate to give
this vaccine to individuals with a history of anaphylaxis as defined above, provided that
facilities for resuscitation are immediately available in case of need. Very common
side effects include injection site swelling, injection site pain, injection site induration,
injection site redness, fatigue. Common effects are injection site ecchymosis, fever,
malaise, shivering. It is uncommon to detect influenza like illness and anaphylaxis is
rare.
The vaccine can be used with several other vaccines.
Data obtained in adults showed that co-administration of adjuvanted H5N1 vaccine
and seasonal (inactivated surface, non-adjuvanted) antigens did not lead to any
interference neither for seasonal strains nor for H5N1 strains. SRH antibody response
against an homologous H5N1 Vietnam strain at day 43 reached all CHMP criteria for all
3 strains. Co-administration was not associated with higher rates of local or systemic
reactions compared to administration of Prepandemic Influenza vaccine (H5N1)
(surface antigen, inactivated, adjuvanted) Novartis Vaccines and Diagnostics alone.
Therefore the data indicate that Prepandemic Influenza vaccine (H5N1) (surface
antigen, inactivated, adjuvanted) Novartis Vaccines and Diagnostics may be coadministered with non-adjuvanted seasonal influenza vaccines (with injections made
into opposite limbs).
2.5 Overall assessment of safety
In the absence of specific clinical data, we have examined the safety of a universal
influenza vaccine based on tandem core technology using relevant comparators.
A substantial body of preclinical experimental data exists within iQur which strongly
suggests that no major side-effects are associated with tandem core vaccines after
murine vaccination. These data include VLPs made from chimeric tandem cores which
carry a wide variety of antigens.
Clinical data does exist for HBc chimeric VLPs made from monomeric core proteins.
These are very similar to tandem core and only differ in the presence of a short protein
linker chain. Again, no serious adverse events were recorded.
Finally, a review has been carried out of EU EPAR data using vaccines which cover all
aspects of the project. We show data demonstrating the safety of (i) VLP based
vaccines (ii) vaccines based on HBV and (iii) influenza vaccines. In all cases a good
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safety profile was detected. The only possible exception being influenza vaccines made
in Vero cells or eggs, neither of which will be used in the Flutcore project.
3.
Conclusions and future steps
We believe that the body of both experimental and literature evidence is strongly in
favour of proposing that tandem core VLPs will have a good safety profile. We have
seen no evidence of unexpected side effects for either monomeric or tandem core
proteins. Furthermore, clinical data from several comparator products provides more
supportive evidence. Thus, we feel that the Flutcore project may be confident that no
adverse events are likely to occur once the project progresses through preclinical and
into the clinical phase.
4.
Publications resulting from the work described
N/A
5.
References
Nardin, Elizabeth H., Giane A. Oliveira, J. Mauricio Calvo-Calle, Kristiane Wetzel, Carolin
Maier, Ashley J. Birkett, Pramod Sarpotdar, Michael L. Corado, George B. Thornton,
and Annette Schmidt. "Phase I testing of a malaria vaccine composed of hepatitis B
virus core particles expressing Plasmodium falciparum circumsporozoite epitopes."
Infection and immunity 72, no. 11 (2004): 6519-6527.
Oliveira, Giane A., Kristiane Wetzel, J. Mauricio Calvo-Calle, Ruth Nussenzweig, Annette
Schmidt, Ashley Birkett, Filip Dubovsky et al. "Safety and enhanced immunogenicity of
a hepatitis B core particle Plasmodium falciparum malaria vaccine formulated in
adjuvant Montanide ISA 720 in a phase I trial." Infection and immunity 73, no. 6
(2005): 3587-3597.
Relevant EPARS
Gardasil: WC500021142
Cervarix: WC500024632
HBVax Pro: WC500046816
Pandemic Influenza vaccine H5N1: WC500049616
Prepandemic influenza vaccine: WC500101212
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