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HK1156325A - Varicella zoster virus vaccine - Google Patents

Varicella zoster virus vaccineDownload PDF

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Publication number
HK1156325A
HK1156325AHK11110169.1AHK11110169AHK1156325AHK 1156325 AHK1156325 AHK 1156325AHK 11110169 AHK11110169 AHK 11110169AHK 1156325 AHK1156325 AHK 1156325A
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Hong Kong
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vzv
day
gevar
antigen
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HK11110169.1A
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Chinese (zh)
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Emmanuel Jules Hanon
Jean Stephenne
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Glaxosmithkline Biologicals Sa
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Description

This invention relates to compositions capable of inducing an immune response against Varicella-Zoster Virus.
Varicella- Zoster Virus (VZV) is a human herpes virus which is the etiological agent of chicken pox (varicella) and shingles (zoster). Varicella results from an initial, or primary infection, usually contracted during childhood which is relatively benign. However, for adults who were not exposed to varicella during childhood, and occasionally to individuals who are immunocomprised, VZV can be life-threatening. Similarly, a VZV infection can be life-threatening to neonates, for the virus is capable of crossing the placenta. With direct contact, varicella is known to be a highly transmissible infectious disease.
Like most Herpes-Viruses, VZV has a tendency to infect some cells in which its development is arrested. After a variable latent period, the Varicella-Zoster (VZ) virus can be released to initiate infection in other cells. This reactivation of the VZ virus causes an estimated 5 million cases of zoster annually (Plotkin et al., Postgrad Med J 61: 155-63 (1985)). Zoster is characterized by inflammation of the cerebral ganglia and peripheral nerves, and it is associated with acute pain.
It has been shown that humans vaccinated with attenuated strains of VZV have received protective immunity from VZV infections (Arbeter et al., J. Pediatr 100 886-93 (1982) andBrunell et al., Lancet ii: 1069- 72 (1982)). In particular the OKA strain of VZV has been used in trials for the prevention of herpes zoster and post herpetic neuralgia. The OKA strain has also been used in the preparation of vaccines for chickenpox for many years and is well characterised - for example seeEP651789 and references therein.
A large clinical trial using the OKA strain for the zoster indication has been published inThe New England Journal of Medicine 2005, number 22, Volume 352:2271-2284 (M.N. Oxman et al).
There is still a need for improved vaccines against herpes zoster and related disorders such as post herpetic neuralgia (PHN).
Statement of InventionFirst aspect
The present invention provides in a first aspect an immunogenic composition comprising a VZV antigen or immunogenic derivative therof in combination with a live attenuated VZV or whole inactivated VZV.
The invention further relates to a vaccine composition comprising a VZV antigen or immunogenic derivative therof in combination with a live attenuated VZV or whole inactivated VZV.
The invention further relates to a method of preventing and/or decreasing the severity of herpes zoster and/or post herpetic neuralgia (PHN) comprising delivering to an individual an immunogenic composition comprising a VZV antigen or immunogenic derivative therof in combination with a live attenuated VZV or whole inactivated VZV.
In a further embodiment the invention relates to a method of preventing and/or decreasing the severity of herpes zoster and/or post herpetic neuralgia, the method comprising sequential or concomitant delivery to an individual of a VZV antigen or immunogenic derivative therof and a live attenuated VZV or whole inactivated VZV.
In a still further embodiment the invention relates to a kit comprising a live attenuated VZV or whole inactivated VZV and, separately, a VZV antigen or immunogenic derivative therof, the components suitable for concomitant or sequential delivery, or for mixing as a single composition prior to delivery.
The invention also relates to a method for the manufacture of an immunogenic composition, the method comprising combining a live attenuated VZV or whole inactivated VZV with a VZV antigen or immunogenic derivative therof.
The invention further relates to use of a live attenuated VZV strain or whole inactivated VZV and a VZV antigen or immunogenic derivative thereof in the preparation of an immunogenic composition for preventing and/or decreasing the severity of herpes zoster and/or post herpetic neuralgia.
Second aspect
In a second aspect the invention relates to an immunogenic composition and/or vaccine comprising gE or an immunogenic derivative or immunogenic fragment thereof in combination with a TH1- adjuvant.
The invention also relates to use of a composition comprising gE or an immunogenic derivative or immunogenic fragment thereof in combination with a TH1- adjuvant, in the preparation of a medicament for the prevention or amelioration of herpes zoster reactivation and/or post herpetic neuralgia.
The invention also relates to a method for the prevention or amelioration of herpes zoster reactivation and/or post herpetic neuralgia, the method comprising delivering to an individual in need thereof an immunogenic composition or vaccine comprising gE or an immunogenic derivative or immunogenic fragment thereof in combination with a TH1- adjuvant.
Figures
  • Figure 1 discloses the sequence of a truncated VZV gE.
  • Figures 2 - 4 disclose humoral responses obtained in human clinical trials using compositions of the invention.
  • Figures 5 and 6 disclose cell mediated immunity obtained in human clinical trials using compositions of the invention.
Detailed description
In its broadest aspect the present invention relates to compositions and regimes as described herein for provoking an immune response to VZV. In one aspect the immune response generated by exposure to such compositions is suitably reproducibly higher and statistically significant when compared to that obtained in individuals who have received no exposure to the compositions of the invention. The immune response may be assessed by analysis of any one or more aspects of CMI response and/or antibody responses using any of the techniques outlined below.
In another aspect the invention relates to approaches for preventing and/or decreasing the severity of herpes zoster and/or post herpetic neuralgia (PHN). For the avoidance of doubt, the invention relates in one aspect to use in the prevention of the incidence of zoster. Where zoster does occur then the severity of the reactivation of zoster is suitably reduced compared with an unvaccinated control (amelioration of zoster). In a further aspect, where zoster does occur, the invention relates to use in the prevention of the incidence of PHN. In a further aspect where PHN does occur then the severity of the PHN is suitably reduced compared with an unvaccinated control (amelioration of PHN). Reduction in severity can suitably be assessed by a reduction in the pain caused by zoster or PHN, for example, using known measures of burden of pain (e.g.Coplan et al J Pain 2004; 5 (6) 344 - 56). Reduction in severity can also be assessed by other criteria such as duration of zoster or PHN, proportion of body area affected by zoster or PHN; or the site of zoster/PHN.
The above statements relate to all aspects of the invention.
Where a live attenuated strain is used in the first aspect of the invention, then in one aspect the live attenuated VZV strain is the OKA strain, a strain well known in the art, for example as disclosed inArbeter et al. (Journal of Pediatrics, vol 100, No 6, p886 ff),WO9402596, and references therein, such asUS 3985615, all incorporated herein by reference. Any other suitable live attenuated strain may also be used in the invention. For example, the Varilrix™ and Varivax™ strains are both appropriate and commercially available and could be employed in the invention.
Whole inactivated VZV strains, such as inactivated VZV OKA are also suitable for use in the present invention.
The VZV antigen for use in the invention may be any suitable VZV antigen or immunogenic derivative thereof, suitably being a purified VZV antigen.
In one aspect the antigen or derivative is one that is able to elicit, when delivered in combination, concomitantly or sequentially with a live attenuated VZV strain or whole inactivated VZV, an immune response which is improved over that elicited by the live attenuated strain/whole inactivated strain alone or by the VZV antigen alone. Such a response may be, for example, improved in terms of one or more of the magnitude of immune response, duration of immune response, the number or % or responders, or the breadth of response (e.g. the range of antibody or T cell responses detected), or may provide an improvement at the clinical level in terms of incidence, reduction of pain or symptoms. Improvements in the immune response can be assessed by, for example, antibody levels or cell mediated immunity (CMI) activity using standard techniques in the art; improvements at the clinical level can be also assessed using known clinical criteria.
In particular, in one aspect the immune response elicited by the composition or vaccine of present invention shows one or more of:
  • a statistically significant increase in the CMI and/or antibody response, in comparison with pre-vaccination levels, when compared to VZV antigen or live attenuated strain/whole inactivated strain alone;
  • An improved multivalent CMI response, in comparison with pre-vaccination levels, when compared to VZV antigen or live attenuated strain/whole inactivated strain alone. A multivalent CMI response considers a range of markers for CMI such as (but not limited to) IFN gamma, IL2, TNF alpha and CD40L and an improved multivalent response induces a CMI response across a wider range of such markers or a higher response in one or more of the markers when compared to a VZV antigen or live attenuated strain/whole inactivated strain alone;
  • Better persistent CMI or antibody response, in comparison with pre-vaccination levels, when compared to VZV antigen or live attenuated strain/whole inactivated strain alone. In one aspect persistence is measured over after 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 12 months, 24 months, 36 months or 48 months.
In one aspect improvements in the immune response are assessed in the elderly population, suitably the populations over 50 years of age, for whom the risk of zoster or PHN is increased with respect to the population under 50 years of age. Improved immune responses can also be examined in immuno-compromised populations. In one aspect such populations are target populations for any embodiment of the present invention.
In one aspect the population is over 50 years, suitably over 60 years, over 70 years, or even over 80 years and above. In one aspect the population is 50-70 years old.
Thus in one aspect the invention relates to use of the compositions and approaches of the invention in preventing and/or decreasing the severity of zoster or PHN in humans over 50 years of age.
In one aspect the invention relates to use of the compositions and approaches of the invention in preventing and/or decreasing the severity of zoster or PHN in immunocompromised individuals, such as transplant patients or those who are HIV positive.
The term 'immunogenic derivative' encompasses any molecule which retains the ability to induce an immune response to VZV following administration to man. Immunogenic compounds herein are suitably capable of reacting detectably within an immunoassay (such as an ELISA or T-cell stimulation assay) with antisera and/or T-cells from a patient with VZV. Screening for immunogenic activity can be performed using techniques well known to the skilled artisan. For example, such screens can be performed using methods such as those described in Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, 1988.
Suitable methods for the generation of derivatives are well known in the art and include standard molecular biology techniques as disclosed, for example, inSambrook et al [Molecular Cloning: A Laboratory Manual, third edition, 2000, Cold Spring Harbor Laboratory Press], such as techniques for the addition, deletion, substitution or rearrangement of amino acids or chemical modifications thereof. In one aspect derivatives include, for example, truncations or other fragments.
In one aspect derivatives in the context of this invention are amino acid sequences comprising epitopes, i.e., antigenic determinants substantially responsible for the immunogenic properties of a polypeptide and being capable of eliciting an immune response, in one aspect being T cell epitopes.
In one aspect, the level of immunogenic activity of the immunogenic derivative is at least about 50%, in one aspect at least about 70% and in one aspect at least or greater than about 90% of the immunogenicity for the polypeptide from which it is derived, suitably as assessed by immunoassay techniques described above. In some aspects of the invention immunogenic portions may be identified that have a level of immunogenic activity greater than that of the corresponding full-length polypeptide, e.g., having greater than about 100% or 150% or more immunogenic activity.
In one aspect the VZV antigen is a glycoprotein, in one aspect the gE antigen (also known as gpl), or immunogenic derivative thereof.
The gE antigen, anchorless derivatives thereof (which are also immunogenic derivatives) and production thereof is described inEP0405867 and references therein [see alsoVafai A. Antibody binding sites on truncated forms of varicalla-zoster virus gpI(gE) glycoprotein Vaccine 1994 12:1265-9].EP192902 also discloses gE and production thereof.
The disclosure of all cited documents is herein fully incorporated by reference.
In one aspect gE is a truncated gE having the sequence offigure 1 herein, and as disclosed inVirus research, vol 40, 1996 p199 ff, herein incorporated fully by reference. Reference to gE hereinafter includes reference to truncated gE, unless otherwise apparent from the context.
Other suitable antigens include, by way of example, gB, gH, gC, gI, IE63 (eg see ,Huang et al. J. Virol. 1992, 66: 2664,Sharp et al. J. Inf. Dis. 1992, 165:852,Debrus, J Virol. 1995 May;69(5):3240-5 and references therein), IE62 (eg see Arvin et al. J. Immunol. 1991 146:257, Sabella J Virol. 1993 Dec;67(12):7673-6 and references therein) ORF4 or ORF 10 (Arvin et al. Viral Immunol. 2002 15: 507.)
The present invention herein also contemplates that antigen combinations may be used with the live attenuated or killed VZV, and in one aspect gE may be included in any such combination. In one aspect the invention relates to combinations of gE with IE63 and gE with IE62, for example.
VZV antigens and derivatives of VZV antigens can be tested for suitable immunogenic activity by use in the model systems as described in the Examples of the present application, or by clinical trials in humans. One or more of the following indicators of activity are suitable for consideration in assessment of immunogenic activity:
  • Increased CD4 or CD8 T cell responses to VZV or antigen derivatives.
  • Elevation in VZV or antigens derivative specific antibodies.
  • Enhanced production of cytokines such as interferon γ or IL-2 or TNF α
  • Enhanced expression of CD40L on CD4 and CD8 T cells.
  • Reduction in the incidence of zoster below the incidence found in the general population of similarly at risk individuals, and likewise reduced disease severity and /or associated pain below the incidence found in the general population of similarly at risk individuals.
Increases or reductions, as described above, are suitably statistically significant with respect to appropriate controls, such as an age-matched non-vaccinated group. In one aspect the live attenuated VZV or killed VZV and the VZV antigen or antigen derivatives do not significantly interfere with one another, such that when used in combination the 2 components are still able to provide an immunogenic response to VZV. In one aspect the response is a protective immunogenic response, whether the 2 components are used as a composition or used in sequential administration or coadministration. It will be appreciated that some interference is tolerated, however, provided that the overall protective immune response is improved in some way (increased in magnitude, increased % responders or broadened antigenic responses, for example) over that of either of the original components used individually.
In one aspect the invention relates to the combination of the gE antigen and the OKA strain, used for concomitant or sequential administration, in either order. Where delivery is concomitant then the 2 components are delivered into different injection sites but during the same day, for example. In one aspect different delivery routes are used for the 2 components, in particular subcutaneous delivery for the virus strain such as OKA and intramuscular delivery for the antigen such as gE
The present invention also extends to cover, in all embodiments described, the use of combinations of VZV antigens or derivatives with a live attenuated VZV strain or killed VZV. Suitable combinations of antigens include in one aspect gE or immunogenic derivative thereof.
The combined composition, or either or both of the individual components may additionally comprise an adjuvant or immunostimulant such as but not limited to detoxified lipid A from any source and non-toxic derivatives of lipid A, saponins and other reagents, suitably capable of stimulating a TH1 type response.
In one aspect the composition comprises an adjuvant capable of stimulating a TH1 type response.
High levels of Th1-type cytokines tend to favour the induction of cell mediated immune responses to a given antigen, whilst high levels of Th2-type cytokines tend to favour the induction of humoral immune responses to the antigen.
The distinction of Th1 and Th2-type immune response is not absolute. In reality an individual will support an immune response which is described as being predominantly Th1 or predominantly Th2. However, it is often convenient to consider the families of cytokines in terms of that described in murine CD4 +ve T cell clones by Mosmann and Coffman (Mosmann, T.R. and Coffman, R.L. (1989) TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annual Review of Immunology, 7, p145-173). Traditionally, Th1-type responses are associated with the production of the INF-γ and IL-2 cytokines by T-lymphocytes. Other cytokines often directly associated with the induction of Th1-type immune responses are not produced by T-cells, such as IL-12. In contrast, Th2-type responses are associated with the secretion of IL-4, IL-5, IL-6, IL-10.
Suitable adjuvant systems which promote a predominantly Th1 response include, Monophosphoryl lipid A or a derivative thereof, particularly 3-de-O-acylated monophosphoryl lipid A. It has long been known that enterobacterial lipopolysaccharide (LPS) is a potent stimulator of the immune system, although its use in adjuvants has been curtailed by its toxic effects. A non-toxic derivative of LPS, monophosphoryl lipid A (MPL), produced by removal of the core carbohydrate group and the phosphate from the reducing-end glucosamine, has been described byRibi et al (1986, Immunology and Immunopharmacology of bacterial endotoxins, Plenum Publ. Corp., NY, p407-419) and has the following structure:
A further detoxified version of MPL results from the removal of the acyl chain from the 3-position of the disaccharide backbone, and is called 3-O-Deacylated monophosphoryl lipid A (3D-MPL). It can be purified and prepared by the methods taught inGB 2122204B, which reference also discloses the preparation of diphosphoryl lipid A, and 3-O-deacylated variants thereof.
In one aspect 3D-MPL is in the form of an emulsion having a small particle size less than 0.2µm in diameter, and its method of manufacture is disclosed inWO 94/21292. Aqueous formulations comprising monophosphoryl lipid A and a surfactant have been described inWO9843670A2.
The bacterial lipopolysaccharide derived adjuvants to be formulated in the compositions of the present invention may be purified and processed from bacterial sources, or alternatively they may be synthetic. For example, purified monophosphoryl lipid A is described in Ribi et al 1986 (supra), and 3-O-Deacylated monophosphoryl or diphosphoryl lipid A derived fromSalmonella sp. is described inGB 2220211 andUS 4912094. Other purified and synthetic lipopolysaccharides have been described (Hilgers et al., 1986, Int.Arch.Allergy.Immunol., 79(4):392-6;Hilgers et al., 1987, Immunology, 60(1): 141-6; andEP 0 549 074 B1). In one aspect the bacterial lipopolysaccharide adjuvant is 3D-MPL.
Accordingly, the LPS derivatives that may be used in the present invention are those immunostimulants that are similar in structure to that of LPS or MPL or 3D-MPL. In another embodiment of the present invention the LPS derivatives may be an acylated monosaccharide, which is a sub-portion to the above structure of MPL.
Saponins are taught in:Lacaille-Dubois, M and Wagner H. (1996. A review of the biological and pharmacological activities of saponins. Phytomedicine vol 2 pp 363-386). Saponins are steroid or triterpene glycosides widely distributed in the plant and marine animal kingdoms. Saponins are noted for forming colloidal solutions in water which foam on shaking, and for precipitating cholesterol. When saponins are near cell membranes they create pore-like structures in the membrane which cause the membrane to burst. Haemolysis of erythrocytes is an example of this phenomenon, which is a property of certain, but not all, saponins.
Saponins are known as adjuvants in vaccines for systemic administration. The adjuvant and haemolytic activity of individual saponins has been extensively studied in the art (Lacaille-Dubois and Wagner,supra). For example, Quil A (derived from the bark of the South American tree Quillaja Saponaria Molina), and fractions thereof, are described inUS 5,057,540 and "Saponins as vaccine adjuvants", Kensil, C. R., Crit Rev Ther Drug Carrier Syst, 1996, 12 (1-2):1-55; andEP 0 362 279 B1. Particulate structures, termed Immune Stimulating Complexes (ISCOMS), comprising fractions of Quil A are haemolytic and have been used in the manufacture of vaccines (Morein, B.,EP 0 109 942 B1;WO 96/11711;WO 96/33739). The haemolytic saponins QS21 and QS17 (HPLC purified fractions of Quil A) have been described as potent systemic adjuvants, and the method of their production is disclosed inUS Patent No.5,057,540 andEP 0 362 279 B1. Other saponins which have been used in systemic vaccination studies include those derived from other plant species such as Gypsophila and Saponaria (Bomford et al., Vaccine, 10(9):572-577, 1992).
An enhanced system involves the combination of a non-toxic lipid A derivative and a saponin derivative particularly the combination of QS21 and 3D-MPL as disclosed inWO 94/00153, or a less reactogenic composition where the QS21 is quenched with cholesterol as disclosed inWO 96/33739. In one aspect the combination of QS21 with 3D MPL is used in the present invention.
In one aspect the adjuvant for use in the invention comprises QS21 and a liposomal formulation comprising cholesterol and 3D MPL.
A particularly potent adjuvant formulation involving QS21 and 3D-MPL in an oil in water emulsion is described inWO 95/17210 and is also suitable for use in the present invention.
Accordingly in one embodiment of the present invention there is provided a composition comprising a VZV antigen or derivative of the present invention adjuvanted with detoxified lipid A or a non-toxic derivative of lipid A. In one aspect the composition is adjuvanted with a monophosphoryl lipid A or derivative thereof.
In one aspect the composition additionally comprises a saponin, which in one aspect is QS21, and in another aspect is QS21 quenched with cholesterol as disclosed inWO 96/33739.
The immunogenic composition of the invention optionally comprises an oil in water emulsion, which may be used in combination with other adjuvants such as QS21 and/or 3D MPL as disclosed above. Adjuvant formulations comprising an oil in water emulsion are disclosed inWO991124 andWO9912565, incorporated herein by reference.
An alternative adjuvant choice is an unmethylated CpG dinucleotides ("CpG"). CpG is an abbreviation for cytosine-guanosine dinucleotide motifs present in nucleic acid. CpG oligonucleotides are disclosed inWO 96/02555 andEP 468520.
In one aspect a combination of any of the adjuvants of the invention described herein (QS21 or QS21 quenched with cholesterol + 3DMPL, optionally with an oil in water emulsion) is used with gE, or immunogenic derivative thereof, used in concomitant or sequential administration with a live attenuated VZV or inactivated whole VZV.
The present invention also provides a method for producing a kit suitable for inducing an immune response against zoster, the method comprising mixing a VZV antigen preparation of the present invention together with an adjuvant or adjuvant combination, and combining in a kit with a live attenuated VZV.
The amount of VZV antigen is selected as an amount which induces an immunoprotective response without significant, adverse side effects in typical vaccines. Such amount will vary depending upon which specific immunogen is employed and how it is presented. Generally, it is expected that each dose will comprise 1-1000 µg of protein, such as 2-100 µg, or 5-60 µg. Where gE is used then in one aspect 25 - 100 µg of gE may be used in humans, such as 40-100µg of gE for human use, in one aspect about 25µg, about 50µg or about 100µg of gE, suitably 25µg, 50µg or 100µg gE. For the OKA strain, for example, a suitable dose is 500 - 50000 pfu/0.5 ml, such as 2000 - 6000 pfu/0.5 ml, with a suitable dose of the GSK Varilrix Oka strain for example being 6000-25,000 per dose, for example 10,000 pfu/dose. Higher doses such as 30,000 pfu, 40000 pfu, 50,000 pfu 60,000 pfu, 70000 pfu, 80000 pfu, 90000 pfu or even 100000 pfu may be employed.
An optimal amount for a particular vaccine can be ascertained by standard studies involving observation of appropriate immune responses in subjects. Following an initial vaccination, subjects may receive one or several booster immunisation adequately spaced.
The composition(s) of the present invention may be formulated for any appropriate manner of administration, including for example, topical, oral, nasal, mucosal, intravenous, intradermal, intraperitoneal, subcutaneous and intramuscular administration. Delivery of the OKA strain is, in one aspect, by subcutaneous delivery.
The immunogenic composition of the present invention may be used in a vaccine composition, optionally in combination with an adjuvant and/or (other) suitable carrier.
The VZV antigen and attenuated VZV of the present invention may be used together in a composition to provoke an immune response to VZV, or separately - either concomitantly or sequentially in a prime boost regime. For concomitant or sequential delivery the components of the vaccine may be used in either order. In one embodiment, delivery of a live attenuated VZV or whole inactivated VZV is followed by a VZV antigen or immunogenic derivative thereof. In another embodiment delivery of a VZV antigen or immunogenic derivative therof is followed by delivery of live attenuated VZV or whole inactivated VZV.
The invention further relates to a method of preventing and/or decreasing the severity of herpes zoster and/or post herpetic neuralgia comprising delivering to an individual at risk of zoster an immunogenic composition comprising a live attenuated VZV and a VZV antigen.
In a further embodiment the invention relates to a method of preventing and/or decreasing the severity of herpes zoster and/or post herpetic neuralgia comprising sequential or concomitant delivery to an individual at risk of zoster of a live attenuated VZV and a VZV antigen.
In one aspect the invention relates to a prime boost regime wherein a VZV antigen, in one aspect an adjuvanted antigen, is delivered first, after which the immune system is boosted with delivery of an attenuated VZV.
A prime boost regime in humans comprises, in one aspect, priming with 25 - 100 µg gE, in one aspect 40 - 100 µg gE , such as 50 or about 50 µg gE, or an immunogenic derivative thereof, adjuvanted with QS21 (for example QS21 quenched with cholesterol as described above) and 3D-MPL, and boosting with the OKA strain of VZV.
Where prime boost regimes are used, or where multiple vaccination regimes are used, then 2, 3, 4 or more immunisations may be employed. Suitable regimes for prime boost include 1, 2, 3, 4, 5 or 6 months between individual immunisations.
A prime boost schedule comprises, in one aspect, delivery of a VZV antigen or immunogenic derivative thereof, suitably an adjuvanted VZV antigen or derivative, at 0 months and boosting with a live attenuated VZV at 2M.
In an alternative delivery schedule there is concomitant delivery of both of the two individual components (VZV antigen or derivative and live attenuated VZV) at both 0 and 2 months.
In a still further embodiment the invention relates to a kit comprising a live attenuated VZV or inactivated whole VZV and a VZV antigen.
The invention also relates to a method for the manufacture of an immunogenic composition, the method comprising combining a live attenuated VZV/whole inactivated and a VZV antigen.
The invention further relates to use of a live attenuated VZV strain in the preparation of a combination vaccine with a VZV antigen for the prevention of herpes zoster, and to use of a VZV antigen in the preparation of a combination vaccine with a live attenuated VZV strain for the prevention of herpes zoster.
In a second, aspect of the invention a gE antigen, or immunogenic derivative or immunogenic fragment thereof, may be used with an adjuvant to provide an immunogenic composition or vaccine. That is, the gE antigen or immunogenic derivative or immunogenic fragment thereof may be used in a vaccination schedule in the absence of a live attenuated strain or whole inactivated strain.
Thus the second aspect of the invention relates to an immunogenic composition or vaccine comprising gE or immunogenic derivative or immunogenic fragment thereof in combination with a TH1- adjuvant.
The invention also particularly relates to use of a composition comprising gE or an immunogenic derivative or immunogenic fragment thereof in combination with a TH-1 adjuvant, in the preparation of a medicament for the prevention or amelioration of herpes zoster reactivation and/or post herpetic neuralgia.
The term "immunogenic derivative" in respect of gE is as described above, along with methods to obtain such derivatives such as fragments of gE. Immunogenic fragments as described herein are immunogenic derivatives which retain the ability to induce an immune response to VZV following administration to man.
In one aspect of the invention a gE truncate is used in which gE has a C terminal truncation.
In one aspect the truncation removes from 4 to 20 percent of the total amino acid residues at the carboxy terminal end.
In one aspect the gE is lacking the carboxy terminal anchor region (suitably approximately amino acids 547- 623 of the wild type sequence).
In one aspect gE is a truncated gE having the sequence offigure 1 herein, and as disclosed inVirus research, (Haumont et al Vol 40, 1996 p199 - 204), herein incorporated fully by reference.
Reference to gE hereinafter includes reference to truncated gE, or other fragments or derivative of gE, unless otherwise apparent from the context.
In another aspect of the invention the composition comprises full length gE.
In another aspect the gE or derivative or fragment thereof is lyophilised. In another aspect the gE or derivative or fragment thereof is reconstituted in a solution containing an adjuvant (such as an adjuvant containing QS21, cholesterol and 3D MPL) before delivery.
In one embodiment the composition or vaccine comprises gE and a TH-1 adjuvant and does not comprise an IE63 antigen or portion thereof. In one embodiment the composition or vaccine comprises gE and a TH-1 adjuvant and does not comprise any other VZV antigen. In one embodiment the composition or vaccine comprises gE and a TH-1 adjuvant and does not comprise any other viral antigen.
In one aspect the gE or immunogenic fragment thereof is not in the form of a fusion protein.
In one aspect the composition or vaccine consists essentially of QS21, a truncated VZV gE antigen and liposomes comprising cholesterol and 3D-MPL.
In one aspect the composition or vaccine consists of 3D-MPL, QS21, a truncated VZV gE antigen, liposomes comprising cholesterol and a pharmaceutically acceptable carrier.
The composition may be used in the preparation of a medicament for the prevention or amelioration of herpes zoster reactivation and/or post herpetic neuralgia.
The composition or vaccine is suitably used in the population of people 50 or older than 50. Suitably the population is the population of those older than 55, 60, 65, 70, 75, 80, or older than 80. Suitably the population is 50-70 years.
In one aspect the population of individuals are those who have had varicella or who have had a live varicella vaccine.
Thus the invention relates to use of a composition as described above in the preparation of a medicament for the prevention or amelioration of herpes zoster reactivation and/or post herpetic neuralgia in a population of people 50 or above.
The invention thus also relates to a method for the prevention or amelioration of herpes zoster reactivation and/or post herpetic neuralgia, the method comprising delivering to an individual in need thereof a composition of the invention.
In one aspect the composition of the first and second aspects of the invention are used in those individuals in whom the varicella zoster virus has not reactivated.
The composition may be used at doses and delivery routes as outlined above for the first aspect of the invention. Specifically the amount of gE antigen is selected as an amount which induces an immunoprotective response without significant, adverse side effects in typical vaccines. Such amount will vary depending upon which specific immunogen is employed and how it is presented. Generally, it is expected that each dose will comprise 1-1000 µg of protein, such as 2-100 µg, or 5-60 µg. Where gE is used then suitably 25 - 100µg gE is used, in one aspect 40- 100µg of gE, such as about 25µg, 50µg or about 100µg of gE, suitably 25µg, 50µg or 100µg gE. An optimal amount for a particular vaccine can be ascertained by standard studies involving observation of appropriate immune responses in subjects. Following an initial vaccination, subjects may receive one or several booster immunisation adequately spaced.
In one aspect the gE and adjuvant composition or vaccine is used in a one dose delivery regime. In one aspect the gE and adjuvant composition or vaccine is used in a two dose delivery regime.
In one aspect the composition or vaccine of the invention is used in a 2 dose regime with a 2 month spacing between doses.
In one aspect the TH-1 adjuvant is any adjuvant identified above for the first aspect of the invention. In particular, a combination of 3D MPL and QS21 may be used, for example as disclosed inWO94/00153, or a less reactogenic composition where the QS21 is quenched with cholesterol as disclosed inWO 96/33739 andUS6846489. An alternative adjuvant comprises QS21 and 3D-MPL in an oil in water emulsion as described inWO 95/17210.
In one aspect a formulation comprises a C terminal truncation of the VZV gE antigen, for example that given inFigure 1, in combination with 3D MPL and QS21.
In another aspect the invention relates to a kit comprising, as separate components, a TH-1 adjuvant and a gE antigen or immunogenic fragment thereof, as described above, suitable for extemporaneous preparation of a vaccine composition. In one aspect both components are liquids. In one aspect one component is lyophilised and is suitable for reconstitution with the other component. In one aspect the kit comprises a gE antigen having the sequence offigure 1 and an adjuvant comprising QS21 and liposomes comprising cholesterol and 3D MPL.
Vaccine preparation is generally described inNew Trends and Developments in Vaccines, Voller et al. (eds), University Park Press, Baltimore, Maryland, 1978.
Aspects of the present invention include:
  1. A An immunogenic composition comprising a VZV antigen or immunogenic derivative therof in combination with a live attenuated VZV or whole inactivated VZV.
  2. B A method of preventing and/or decreasing the severity of herpes zoster and/or post herpetic neuralgia (PHN) comprising delivering to an individual an immunogenic composition comprising a VZV antigen or immunogenic derivative therof in combination with a live attenuated VZV or whole inactivated VZV.
  3. C A method of preventing and/or decreasing the severity of herpes zoster and/or post herpetic neuralgia, the method comprising sequential or concomitant delivery to an individual of a VZV antigen or immunogenic derivative therof and a live attenuated VZV or whole inactivated VZV.
  4. D A method according to paragraph C wherein a VZV antigen is delivered before live attenuated VZV.
  5. E A method according to paragraph C wherein a VZV antigen is delivered after live attenuated VZV.
  6. F A method according to paragraph C wherein a VZV antigen is delivered concomitantly with live attenuated VZV, preferably with each component in a different arm of a patient.
  7. G A kit comprising a live attenuated VZV or whole inactivated VZV and, separately, a VZV antigen or immunogenic derivative therof, the components suitable for concomitant or sequential delivery, or for mixing as a single composition prior to delivery.
  8. H A method for the manufacture of an immunogenic composition, the method comprising combining a live attenuated VZV or whole inactivated VZV with a VZV antigen or immunogenic derivative therof.
  9. I Use of a live attenuated VZV strain in the preparation of an immunogenic composition for preventing and/or decreasing the severity of herpes zoster and/or post herpetic neuralgia, wherein the live attenuated VZV strain is used in combination with a VZV antigen or immunogenic derivative therof
  10. J Use of a whole inactivated VZV strain in the preparation of an immunogenic composition for preventing and/or decreasing the severity of herpes zoster and/or post herpetic neuralgia, wherein the whole inactivated VZV strain is used in combination with a VZV antigen or immunogenic derivative therof
  11. K Use of a VZV antigen or immunogenic derivative therof in the preparation of an immunogenic composition for preventing and/or decreasing the severity of herpes zoster and/or post herpetic neuralgia, wherein the VZV antigen is used in combination with a live attenuated VZV strain or whole inactivated VZV strain
  12. L Use according to any of paragraphs I-K wherein the antigen or derivative thereof is delivered in a prime boost approach before the VZV strain.
  13. M Use according to any of paragraphs I-K wherein the antigen or derivative thereof is delivered in a prime boost approach after the VZV strain.
  14. N Use according to any of paragraphs I-K wherein the antigen or derivative thereof is delivered concomitantly with the VZV strain.
  15. O Use according to any of paragraphs I-K wherein the antigen or derivative thereof is delivered in admixture with the VZV strain.
  16. P A use, method, kit, or composition according to any preceding paragraph wherein the live attenuated VZV strain is the OKA strain
  17. Q A use method, kit, composition according to any preceding paragraph wherein the VZV antigen the gE antigen or immunogenic derivative thereof.
  18. R A use, method, kit, composition or vaccine according to any preceding claim wherein the VZV antigen is delivered with an adjuvant capable of stimulating a The type response.
The present invention is illustrated by the following, non limiting Examples.
Example 1
Three experimental groups may be set up to study both aspects of the invention:
10, 2 months
2OKA strain (Varilrix™) ∼10,000 pfu/dose0,2 months
3Concomitant administration of 50 µg gE + AS1 group
(as in 1) with Varilrix™ (as in 2)0, 2 months
Human volunteers (for example, 50 per group - healthy, aged 50- 70 years) can be selected to be vaccinated according to the above protocol, and results may be assessed by measuring both cell mediated immunity and antibody responses, for example by intracellular staining (ICS, Roederer et al. 2004 Clin. Immunol. 110: 199) or ELISA techniques respectively, these being well known in the art.
Specific cell-mediated immunity may be evaluated by, for example, in vitro incubation of patient PBMC with varicella-zoster virus extracts as well as specific VZV antigens or peptides gE , IE63 and IE62. Analysis may be made at the level of, for example:
  1. a Lymphoproliferation (data expressed as Stimulation Index [SI]): GM, GM fold increase and % of responders
  2. b Analysis of IFNγ or IL2 or TNFα, or CD 40L expression by CD4 and CD8 cells by ICS (intracellular cytokine staining) : GM, GM fold increase and % of responders
Efficacy can be assessed by looking for a significant increase in the CMI and /or antibody response in comparison with pre-vaccination levels.
Efficacy of other antigens or approaches can be assessed using these or similar techniques, and comparing pre-vaccination levels with post vaccination levels.
Example 2
The experiment of Example 1 was carried out in human volunteers of different ages, as follows:
Group A
gE AS1 in adults 18 - 30 years
Group B
gE delivered concomitantly with the Varilrix OKA strain 18 - 30 years
Group C
Varilrix OKA strain alone in adults 50-70 years
Group D
gE AS1 in adults 50-70 years
Group E
gE delivered concomitantly with the Varilrix OKA strain 50-70 years
The vaccination schedule was as follows:
A18-3010gE-AS1gE-AS1
B18-3010gE-AS1 + Varilrix™gE AS1+Varilrix™
C50-7045Varilrix™Varilrix™
D50-7045gE-AS1gE-AS1
E50-7045gE-AS1 + Varilrix™gE-AS1+Varilrix™
The adjuvant AS1 comprises 3D MPL and QS21 in a quenched form with cholesterol, and was made as described inWO9633739, incorporated herein by reference. In particular the AS1 adjuvant was prepared essentially as Example 1.1 ofW09633739. The adjuvant comprises: liposomes, which in turn comprise dioleoyl phosphatidylcholine (DOPC), cholesterol and 3D MPL [in an amount of 1000µg DOPC, 250 µg cholesterol and 50 µg 3D MPL , each value given approx per vaccine dose], QS21 [50µg/dose], PBS and water to a volume of 0.5ml.
In the process of production of liposomes containing MPL the DOPC (Dioleyl phosphatidylcholine), cholesterol and MPL are dissolved in ethanol. A lipid film is formed by solvent evaporation under vacuum. Phosphate Buffer Saline or PBS (9 mM Na2HPO4, 41 mM KH2PO4, 100 mM NaCl) at pH 6.1 is added and the mixture is submitted to prehomogenization followed by microfluidization at 15,000 psi (20 cycles). This leads to the production of liposomes which are sterile filtered through a 0.22 µm membrane in an aseptic (class 100) area. The sterile product is then distributed in sterile glass containers and stored in a cold room (+2 to +8°C). In this way the liposomes produced contain MPL in the membrane (the "MPL in" embodiment ofW09633739).
The truncated gE ofFigure 1 was expressed in CHO K1 cells using standard techniques and purified using, in order, anion exchange chromatography, hydrophobic interaction chromatography, ion exchange chromatography, diafiltration, and nanofiltration followed by sterilisation through a 0.22 µm filter.
In particular, the following steps were used in the purification of gE
First stage :anion exchange chromatography
The culture supernatant containing the gE (approx. 30 mg/l) is purified, either directly after clarification of the cell suspension or after defrosting at 4°C. After transfer into a 20-litre carboy, the pH of the supernatant is adjusted to 6.
The capture stage takes place at ambient temperature on a chromatography column containing a Q Sepharose XL resin.
After sanitisation with sodium hydroxide, the column is conditioned in the capture buffer (piperazine 20 mM pH 6). The supernatant is then loaded on the column and the column is washed with equilibration buffer and a solution of piperazine 20 mM + NaCl 150 mM pH 6.
The fraction containing the gE is then eluted with a solution of piperazine 20 mM + NaCl 250 mM at pH 6.
Second stage :hydrophobic interaction chromatography
This chromatography stage takes place at ambient temperature on a Toyopearl butyl-650 M resin (Tosoh Biosep).
The fraction eluted with 20 mM piperazine + 250 mM NaCl in the Q Sepharose XL stage is made up to 1M in ammonium sulphate and adjusted to pH 7.5.
After sanitisation with sodium hydroxide and before loading of this fraction, the column is conditioned in the capture buffer (50 mM KH2PO4 + 1M ammonium sulphate pH 7.5). After loading, the column is washed with buffer 50 mM KH2PO4 + 100 mM (NH4)2SO4 pH 7.5. The gE is eluted with buffer 50 mM KH2PO4 + 25 mM (NH4)2SO4 pH 7.5.
Third stage :affinity chromatography on immobilised metal ion
This chromatography stage takes place at ambient temperature on a Chelating Sepharose Fast Flow resin. This resin is saturated in metal ion (Ni) by application of a nickel sulphate solution (1%) and excess unbound ions (Ni), removed by washing. The gE fraction eluted at 50 mM KH2PO4 + 25 mM (NH4)2SO4 pH 7.5 in the hydrophobic phase is made up to 0.5 M NaCl and adjusted to pH 7.5.
After sanitisation, the column is equilibrated in the capture buffer (50 mM KH2PO4 + 0.5 M NaCl pH 7.5). The gE solution is loaded on the column, which is then washed with a solution of 50 mM KH2PO4 + 0.5 M NaCl pH 5.6. The gE is then eluted with a buffer of 50 mM sodium acetate + 0.5 M NaCl pH 5, and neutralised with a Tris 1M solution pH 9.5.
Fourth stage :diafiltration
The buffer exchange and the elimination of salts from the gE fraction eluted at pH 5 in the previous stage are carried out by tangential ultrafiltration. This stage is carried out entirely at +4°C.
The ultrafiltration is run by the Millipore Proflux M12 system, fitted with a 10 kDa Pellicon2 Mini membrane of regenerated cellulose (cat: P2C010C01) of limit nominal molecular weight and a surface area of 0.1 m2 placed in a Pellicon2 mini-cassette housing (cat.XX42PMINI).
After rinsing with water and sanitisation with sodium hydroxide, the whole system with membrane is rinsed with 2 litres of modified PBS buffer (= 8.1 mM Na2HPO42H2O, 1.47 mM KH2PO4, 137 mM NaCl, 2.68 mM KCL pH 7.2) and then equilibrated with 2 litres of the same buffer until a pH value of 7.2 is reached in the permeate.
The measurement of the permeability of the membrane is verified. The integrity test on the membrane is carried out by putting the system under pressure up to 1 bar before and at the end of the diafiltration stage. If this membrane is used twice with an interval of one week, the integrity will be tested 3 times (once before each ultrafiltration and once after the second filtration). The membrane is considered to be intact if the loss of pressure recorded over 5 minutes is less than 0.1 bar.
The concentration of the gE fraction eluted at pH 5 in the affinity stage is evaluated by measuring the optical density at 280 nm. The correlation between the absorbance at 280 nm and the protein concentration of the gE by microBCA is fixed at 1 OD280 = 1.75 mg/ml.
The solution containing the gE is dia-filtered against 10 volumes of modified PBS buffer (= 8.1 mM Na2HPO42H2O, 1.47 mM KH2PO4, 137 mM NaCl, 2.68 mM KCL pH 7.2). The pressure conditions are set such that the diafiltration period is about 1½-2 hours (permeate flow approx. 60 ml/min). The diafiltration residue is then recovered and on the basis of the baseline OD280 the membrane is rinsed with modified PBS to give an approximate final concentration of 0.4 mg/ml.
Fifth stage :nanofiltration
This next stage makes it possible to eliminate viruses with a diameter of more than 15 nm by retention. The stage is carried out entirely at +4°C.
The nanofiltration is carried out on a PLANOVA 15N filter (mean pore size 15 nm; filtration surface area 0.12 m2 (ASAHI cat: 15NZ-120)). Under a constant pressure of 0.45 bar, the gE solution is filtered on the membrane and recovered on the other side with viruses removed.
The pipes and housing (column XK50) are sanitised for 2 hours with a solution of NaOH 0.5M. The whole is then rinsed and neutralised with the modified PBS buffer (same buffer as for the diafiltration) until a pH value of 7.2 is achieved.
After fixing the nanofilter PLANOVA 15N (feed side) under the casing, the filter is rinsed and equilibrated with a modified PBS solution.
The diafiltration residue containing the gE solution is first pre-filtered through 0.22 µm (mini kleenpak OU Acropak20, depending on the volume to be filtered) before being nano-filtered at a constant pressure of 0.45 bar on the PLANOVA 15N.
At the end of nanofiltration, the filter is rinsed with a sufficient volume of modified PBS to give a final concentration of the bulk of approx. 0.3 mg/ml.
To end, the membrane is washed with 50 ml modified PBS. The solution is recovered through the residue outlet.
The integrity tests on the PLANOVA 15N membrane are then carried out as follows :
  • the first test consists of putting the membrane under pressure (1.0 kg/cm2) and observing for formation of air bubbles. This test detects any large splits.
  • the second test: elimination of particles of gold (PARTICORPLANOVA-QCVAL4) verifies the structure of the membrane (good distribution of large pores and capillaries).
Vaccine composition
The gE component of the vaccine comprises 50 µg gE and the excipients sodium chloride, potassium chloride, monopotassium phosphate, disodium phosphate and water for injection as well as the AS1 adjuvant. The function of the inorganic salts is to ensure isotonicity and physiological pH.
In a sterile glass container, water for injection, concentrated phosphate buffered saline and gE antigen were mixed in order to reach the ingredient concentration as below:
gE50 µg
Sodium chloride (NaCl)1603 µg
288 µg
40 µg
Potassium chloride (KCl)40 µg
Water for injectionq.s. ad 0.2 mL
The solution is mixed for 30 to 40 minutes. The pH is checked and adjusted at 7.2 ± 0.1 with HCI or NaCl or appropriate and stir for an additional 10 minutes.
The final bulk was stored in polypropylene bottles at -20°C and transferred to GSK Bio for filling. The vaccine is filled into 3 ml, sterile, siliconised glass vials (0.25 ml/vial) which are closed with grey chlorobutyl rubber stoppers and sealed with central tear-off aluminium cap. The inspected, approved vials are then stored at - 20°C.
Vaccine delivery
The gE-AS1 vaccine for administration was obtained by mixing the liquid antigen preparation with the liquid AS 1 adjuvant immediately prior to injection (a maximum of one hour before injection). The OKA (Varilrix™) was a commercially available lot prepared according to the manufacturer's instructions.
Vaccine formulations were as follows:
VaccinegE
Formulation50 µg VZV (gE) antigen in 0.2 ml volume
AS 1 in 0.5 ml volume
PresentationGlass vial containing liquid gE
Total Dose Volume*0.7ml (after reconstitution)
VaccineVarilrix with diluent
Formulation
0/5ml volume
PresentationGlass vial containing lyophilized
vaccine for reconstitution
Total Dose Volume*0.5 ml
The gE AS 1 component was administered by intramuscular injection.The Varilrix component was administered by subcutaneous injection.
Analysis of results
The clinical trial protocol, filed in preparation for the clinical trial, outlined the types of studies that were to be carried out in the trial, as follows:
  1. a Lymphoproliferation (data expressed as Stimulation Index [SI]): GM, fold increase in GM and % of responders after stimulation by VZV lysate.
  2. b IFN gamma and/or IL2, TNF alpha, CD40L, CD4 and CD8 response by ICS (intracellular staining) : GM, - fold increase in GM and % of responders after stimulation by VZV lysate and gE, IE62 and IE63 peptides.
Lymphoproliferation
Peripheral blood antigen-specific lymphocytes can be restimulated in vitro to proliferate if incubated with their corresponding antigen. Consequently, the amount of antigen specific lymphocytes can be estimated by counting tritiated thymidine incorporation assay. In the present study, VZV antigen or peptide derived from VZV proteins will be used as antigen to restimulate VZV-specific lymphocytes. Results will be expressed as a stimulation index (SI) which corresponds to the ratio between antigen-specific and background lymphoproliferation.
Cytokine Flow Cytometry (CFC)
Peripheral blood antigen-specific CD4 and CD8 T cells can be restimulated in vitro to express CD40L, IL-2, TNF alpha and IFN gamma if incubated with their corresponding antigen. Consequently, antigen-specific CD4 and CD8 T cells can be enumerated by flow cytometry following conventional immunofluorescence labelling of cellular phenotype as well as intracellular cytokines production. In the present study, VZV antigen or peptide derived from VZV proteins will be used as antigen to restimulate VZV-specific T cells. Results will be expressed as a frequency of cytokine(s)-positive CD4 or CD8 T cell within the CD4 or CD8 T cell sub-population.
Specific antibody (anti-VZV and anti-gE)
Antibody levels against VZV and gE will be measured using classical ELISA assays.
Results of the experiment are shown in tabular form.Figures 2-6 present results in a graphical form for antibody (Figures 2-4, see tables 1.1 a - c) and CMI responses (Figures 5 and6 - see table C1 / "CD4 all doubles" test with gE antigen or Varilirix, median values).
HUMORAL IMMUNE RESPONSE
Table I.1a Seropositivity rates and GMTs for VZV IGG antibodies (ATP cohort for immunogenicity)...........................................................Table I.1b Seropositivity rates and GMTs for VZV.GE antibodies (ATP cohort for immunogenicity)...........................................................Table I.1c Seropositivity rates and GMTs for IFA antibodies (ATP cohort for immunogenicity)....................................................................Table I.2b Seroconversion rates for gE antibody titer at each post-vaccination time point (ATP cohort for immunogenicity)........................Table I.3a Vaccine response for VZV antibody titer at each post-vaccination time point (ATP cohort for immunogenicity)........................Table I.3b Vaccine response for gE antibody titer at each post-vaccination time point (ATP cohort for immunogenicity)........................Table I.3c Vaccine response for IFA antibody titer at each post-vaccination time point (ATP cohort for immunogenicity)........................
VZV IGGgE/YPRE101010069.21001875.91077.23266.8455.04634.0
PI(M1)101010069.210014843.08457.726049.06051.065242.0
PI(M2)101010069.210010697.66768.216908.43167.029622.0
PII(M3)101010069.210014330.610492.919571.97173.030894.0
gEVAR/YPRE101010069.21001047.4519.32112.6300.05754.0
PI(M1)101010069.210012859.47063.023412.83346.049163.0
PI(M2)101010069.210010072.25631.418014.73678.036289.0
PII(M3)101010069.210015245.79930.923404.86381.036534.0
VAR/EPRE454510092.1100856.9647.51134.1100.05377.0
PI(M1)454510092.11002538.82072.33110.3288.08034.0
PI(M2)454510092.11002292.21880.62793.9374.07549.0
PII(M3)454510092.11002338.31933.62827.7523.016994.0
gE/EPRE454510092.1100940.1744.21187.6208.04221.0
PI(M1)454510092.11005897.44594.77569.5659.027042.0
PI(M2)454510092.11004523.03570.65729.4598.019268.0
PII(M3)454510092.11009083.97437.611094.52493.042073.0
gEVAR/EPRE444410092.01001165.1954.61422.1209.05558.0
PI(M1)444410092.01008371.76637.210559.52509.056066.0
PI(M2)444410092.01006849.15422.68650.81753.055958.0
PII(M3)444410092.01009849.18201.711827.33528.038664.0
gE/Y = gE-AS1/18-30 years; gEVAR/Y = gE-AS1+Varilrix/18-30 years; VAR/E = Varilrix/50-70 years; gE/E = gE-AS1/50-70 years; gEVAR/E = gE-AS1 +Varilrix/50-70 years; GMC = geometric mean antibody concentration calculated on all subjects; N = number of subjects with available results; n/% = number/percentage of subjects with concentration within the specified range; 95% CI = 95% confidence interval; LL = Lower Limit, UL = Upper Limit; MIN/MAX = Minimum/Maximum; PRE = Pre-vaccination dose 1; PI(M1) = Post-vacciantion dose 1 (Month 1) PI(M2) = Post-vaccination dose 1 (Month 2); PII(M3) = Post-vaccination dose 2 (Month 3)
VZV.GEgE/YPRE10880.044.497.5302.6120.5759.9<109.02169.0
PI(M1)101010069.210018365.09610.635094.15697.0106829.0
PI(M2)101010069.210011076.67037.417433.93528.030190.0
PII(M3)101010069.210015842.611543.421743.17502.030487.0
gEVAR/YPRE10770.034.893.3190.396.4375.6<109.0661.0
PI(M1)101010069.210016225.78657.330410.63613.058950.0
PI(M2)101010069.210011554.76312.521150.43656.047423.0
PII(M3)101010069.210018101.211384.728780.07649.044539.0
VAR/EPRE443579.564.790.2266.9189.6375.8<109.05866.0
PI(M1)454510092.11001011.3770.01328.2177.06386.0
PI(M2)454510092.1100948.1701.61281.2127.06759.0
PII(M3)454510092.11001146.9841.51563.0164.016249.0
gE/EPRE453782.267.992.0231.1178.8298.7<109.0899.0
PI(M1)454510092.11006099.14401.98450.8367.040101.0
PI(M2)454510092.11004844.23406.56888.8288.042488.0
PII(M3)454510092.110014816.812122.218110.23047.058792.0
gEVAR/EPRE444295.584.599.4336.1268.0421.5<109.01531.0
PI(M1)444410092.01008272.66071.111272.4363.054878.0
PI(M2)444410092.01007870.45937.010433.41512.084465.0
PII(M3)444410092.010016616.013972.319760.04774.061558.0
gE/Y = gE-AS1/18-30 years; gEVAR/Y = gE-AS1+Varilrix/18-30 years; VAR/E = Varilrix/50-70 years; gE/E = gE-AS1/50-70 years; gEVAR/E = gE-AS1+Varilrix/50-70 years; GMC = geometric mean antibody concentration calculated on all subjects; N = number of subjects with available results; n/% = number/percentage of subjects with concentration within the specified range; 95% CI = 95% confidence interval; LL = Lower Limit, UL = Upper Limit; MIN/MAX = Minimum/Maximum; PRE = Pre-vaccination dose 1; PI(M1) = Post-vacciantion dose 1 (Month 1) PI(M2) = Post-vaccination dose 1 (Month 2); PII(M3) = Post-vaccination dose 2 (Month 3)
IFAgE/YPRE101010069.21001351.2691.92638.8256.04096.0
PI(M1)101010069.210010809.46040.019345.14096.065536.0
PI(M2)101010069.210012416.86631.623248.72048.032768.0
PII(M3)101010069.210014263.110423.619516.88192.032768.0
gEVAR/YPRE101010069.2100776.0321.61872.5256.016384.0
PI(M1)101010069.21009410.15638.815703.74096.032768.0
PI(M2)101010069.210014263.18546.923802.48192.065536.0
PII(M3)101010069.210012416.88173.618862.68192.032768.0
VAR/EPRE454510092.1100686.1508.5925.6128.08192.0
PI(M1)454510092.11002702.42115.63451.9512.032768.0
PI(M2)454510092.11001838.71454.02325.2256.016384.0
PII(M3)454510092.11002144.91707.42694.4256.08192.0
gE/EPRE454510092.1100597.3452.8787.8128.08192.0
PI(M1)454510092.11006402.64799.28541.8512.032768.0
PI(M2)454510092.11004356.33247.05844.7256.032768.0
PII(M3)454510092.110010163.58426.412258.71024.032768.0
gEVAR/EPRE444410092.0100783.4620.8988.7128.04096.0
PI(M1)444410092.01009004.16946.411671.32048.065536.0
PI(M2)444410092.01006169.44908.27754.62048.032768.0
PII(M3)444410092.010011225.99284.513573.34096.032768.0
gE/Y = gE-AS1/18-30 years; gEVAR/Y = gE-AS1+Varilrix/18-30 years; VAR/E = Varilrix/50-70 years; gE/E = gE-AS1/50-70 years; gEVAR/E = gE-AS1+Varilrix/50-70 years; GMT = geometric mean antibody titre calculated on all subjects; N = number of subjects with available results; n/% = number/percentage of subjects with titre within the specified range; 95% CI = 95% confidence interval; LL = Lower Limit, UL = Upper Limit;MIN/MAX = Minimum/Maximum; PRE = Pre-vaccination dose 1; PI(M1) = Post-vacciantion dose 1 (Month 1): PI(M2) = Post-vaccination dose 1 (Month 2); PII(M3) = Post-vaccination dose 2 (Month 3)
gE/YMonth 122100.015.8100.0
Month 222100.015.8100.0
Month 322100.015.8100.0
gEVAR/YMonth 133100.029.2100.0
Month 233100.029.2100.0
Month 333100.029.2100.0
VAR/EMonth 199100.066.4100.0
Month 299100.066.4100.0
Month 399100.066.4100.0
gE/EMonth 188100.063.1100.0
Month 288100.063.1100.0
Month 388100.063.1100.0
gEVAR/EMonth 122100.015.8100.0
Month 222100.015.8100.0
Month 322100.015.8100.0
gE/Y = gE-AS1/18-30 years; gEVAR/Y = gE-AS1+Varilrix/18-30 years; VAR/E = Varilrix/50-70 years; gE/E = gE-AS1/50-70 years; gEVAR/E = gE-AS1+Varilrix/50-70 years; N = number of seronegative subjects at day 0 n/% = number/percentage of initially seronegative subjects who became seropositive at the specified post-vaccination time point; 95% CI = 95% confidence interval; LL = Lower Limit, UL = Upper Limit
gE/YMonth 110770.034.893.3
Month 210660.026.287.8
Month 310990.055.599.7
gEVAR/YMonth 11010100.069.2100.0
Month 21010100.069.2100.0
Month 31010100.069.2100.0
VAR/EMonth 1451124.412.939.5
Month 2451022.211.237.1
Month 3451124.412.939.5
gE/EMonth 1452964.448.878.1
Month 2452453.337.968.3
Month 3453986.773.294.9
gEVAR/EMonth 1443375.059.786.8
Month 2442761.445.575.6
Month 3443886.472.694.8
gE/Y = gE-AS1/18-30 years; gEVAR/Y = gE-AS1+Varilrix/18-30 years; VAR/E = Varilrix/50-70 years; gE/E = gE-AS1/50-70 years; gEVAR/E = gE-AS1+Varilrix/50-70 years; N = number of seropositive subjects at day 0 n/% = number/percentage of initially seropositive subjects with a four-fold increase at the specified post-vaccination time point; 95% CI = 95% confidence interval; LL = Lower Limit, UL = Upper Limit
gE/YMonth 18787.547.399.7
Month 28787.547.399.7
Month 388100.063.1100.0
gEVAR/YMonth 177100.059.0100.0
Month 277100.059.0100.0
Month 377100.059.0100.0
VAR/EMonth 1351028.614.646.3
Month 2351028.614.646.3
Month 3351234.319.152.2
gE/EMonth 1373594.681.899.3
Month 2373389.274.697.0
Month 33737100.090.5100.0
gEVAR/EMonth 1424197.687.499.9
Month 2424197.687.499.9
Month 34242100.091.6100.0
gE/Y = gE-AS1/18-30 years; gEVAR/Y = gE-AS1+Varilrix/18-30 years; VAR/E = Varilrix/50-70 years; gE/E = gE-AS1/50-70 years; gEVAR/E = gE-AS1+Varilrix/50-70 years; N = number of seropositive subjects at day 0; n/% = number/percentage of initially seropositive subjects with a four-fold increase at the specified post-vaccination time point;95% CI = 95% confidence interval; LL = Lower Limit, UL = Upper Limit
gE/YMonth 110880.044.497.5
gE/YMonth 210880.044.497.5
gE/YMonth 31010100.069.2100.0
gEVAR/YMonth 110990.055.599.7
gEVAR/YMonth 210990.055.599.7
gEVAR/YMonth 310990.055.599.7
VAR/EMonth 1452760.044.374.3
VAR/EMonth 2451942.227.757.8
VAR/EMonth 3452862.246.576.2
gE/EMonth 1454191.178.897.5
gE/EMonth 2453782.267.992.0
gE/EMonth 34545100.092.1100.0
gEVAR/EMonth 1444193.281.398.6
gEVAR/EMonth 2444193.281.398.6
gEVAR/EMonth 3444397.788.099.9
gE/Y = gE-AS1/18-30 years; gEVAR/Y = gE-AS1+Varilrix/18-30 years; VAR/E = Varilrix/50-70 years; gE/E = gE-AS1/50-70 years; gEVAR/E = gE-AS1+Varilrix/50-70 years; N = number of seropositive subjects at day 0 n/% = number/percentage of initially seropositive subjects with a four-fold increase at the specified post-vaccination time point; 95% CI = 95% confidence interval; LL = Lower Limit, UL = Upper Limit
LIST OF TABLES - ANALYSIS CELL MEDIATED IMUNE RESPONSES
  • Table C.1 Intracellular Cytokine Staining (ICS): Descriptive Statistics on CD4 T cells at each time point (Total vaccinated Cohort)...................................................
  • Supplementary Table C.1 Intracellular Cytokine Staining (ICS): Descriptive Statistics on CD8 T cells at each time point (Total vaccinated Cohort) .......................................
  • Table C.2 Intracellular Cytokine Staining (ICS): Inferential statistics: P-values from Kruskal-Wallis Tests for CD4 T cells at each time point (Total Vaccinated Cohort) ....
  • Supplementary Table C.2 Intracellular Cytokine Staining (ICS): Inferential statistics: P-values from Kruskal-Wallis Tests for CD8 T cells at each time point (Total Vaccinated Cohort) ........................................................................................
  • Table C.3 Intracellular Cytokine Staining (ICS): Descriptive Statistics on CD4 T cells at POST-PRE (Total vaccinated Cohort).........................................................
  • Supplementary Table C.3 Intracellular Cytokine Staining (ICS): Descriptive Statistics on CD8 T cells at POST-PRE (Total vaccinated Cohort) .............................................
  • Table C.4 Intracellular Cytokine Staining (ICS): Inferential statistics: P-values from Kruskal-Wallis Tests for CD4 T cells at POST-PRE (Total Vaccinated Cohort) .....
  • Supplementary Table C.4 Intracellular Cytokine Staining (ICS): Inferential statistics: P-values from Kruskal-Wallis Tests for CD8 T cells at POST-PRE (Total Vaccinated Cohort) ..................................................................................................
CD4-ALL DOUBLESPool gEgE/YDay 091213.44202.591.001.00139.00385.00490.00
Month 1911383.781629.94256.00342.00807.001333.005207.00
Month 2911787.561818.51497.00677.00919.001775.005539.00
Month 3912739.891856.98581.001770.002234.002909.006963.00
gEVAR/YDay 0100253.20246.761.001.00246.00391.00783.00
Month 11001179.70991.681.00567.00979.001364.003535.00
Month 2911546.44886.57116.00846.001996.002092.002538.00
Month 31003298.501477.171699.001970.002944.004924.005840.00
VAR/EDay 0441299.98922.481.001.00126.00238.006152.00
Month 1432458.281256.041.0089.00194.00294.008000.00
Month 2441246.09243.711.0087.50177.00339.001252.00
Month 3450476.401149.121.001.00151.00365.006264.00
gE/EDay 0441166.27180.381.001.00104.50291.50657.00
Month 1423849.101090.911.00226.00540.00949.004487.00
Month 2432522.12577.931.00115.00402.00627.002372.00
Month 34323221.912534.701.001184.002323.004767.0011480.00
gEVAR/EDay 0450206.02265.711.0036.00158.00249.001552.00
Month 1441826.70614.401.00322.50770.001158.502927.00
Month 2450509.16411.891.00166.00447.00737.001553.00
Month 34502918.042522.398.001081.001902.004251.0010468.00
VarilrixgE/YDay 0911045.78770.48369.00544.00761.001067.002590.00
Month 1911302.671378.051.00314.00597.001877.004109.00
Month 2911656.001224.33561.00890.001238.002019.004494.00
Month 3911816.33994.51590.001241.001368.002540.003755.00
gEVAR/YDay 01001188.40580.19412.00783.001058.501535.002332.00
Month 11001090.001168.311.00610.00770.001123.004267.00
Month 2912659.781316.29873.001868.002282.004171.004246.00
Month 31003369.702127.991147.001738.002854.504494.007745.00
VAR/EDay 0441581.02635.921.00129.50415.00753.503327.00
Month 1432992.351093.911.00268.00661.001447.005359.00
Month 2441815.75928.071.00222.50517.001065.004575.00
Month 3450984.67832.161.00364.00774.001278.003287.00
gE/EDay 0441758.18982.521.0081.50395.00929.504479.00
Month 14231216.601674.071.00307.00591.001410.007779.00
Month 2432869.351017.901.00217.00543.001072.004556.00
Month 34322192.421977.1456.00840.001862.002557.009167.00
gEVAR/EDay 0450510.73512.131.00219.00376.00675.002218.00
Month 14411179.501005.411.00434.50982.001529.004478.00
Month 2450961.78915.991.00292.00704.001078.003975.00
Month 34502484.471713.46109.001270.002008.003429.006585.00
CD4 - CD40LPool gEgE/YDay 091204.67193.661.001.00139.00356.00490.00
Month 1911347.331570.63244.00400.00768.001273.005021.00
Month 2911724.441737.50466.00660.00869.001859.005252.00
Month 3912567.891723.12514.001744.001905.002813.006414.00
gEVAR/YDay 0100253.80240.231.0041.00265.50361.00752.00
Month 11001122.30999.381.00480.00948.001266.003534.00
Month 2911520.33898.50116.00732.002045.002068.002633.00
Month 31003169.301452.281555.001857.002910.504539.005840.00
VAR/EDay 0441292.50872.611.001.00119.50238.505812.00
Month 1432444.931175.201.0070.00214.00316.007453.00
Month 2441242.66242.661.0095.00178.00333.001252.00
Month 3450465.671124.331.0018.00154.00365.006072.00
gE/EDay 0441158.55173.141.005.5098.50290.50564.00
Month 1423840.791061.431.00237.00530.00910.004428.00
Month 2432529.58558.231.00147.00365.00645.002251.00
Month 34323133.652453.671.001172.002294.004703.0010561.00
gEVAR/EDay 0450206.16257.801.0035.00167.00278.001525.00
Month 1441814.57606.931.00314.00773.001153.002762.00
Month 2450515.11400.691.00204.00459.00737.001523.00
Month 34502898.402512.5097.001073.001915.004200.0010418.00
VarilrixgE/YDay 0911027.78746.06373.00544.00761.001033.002507.00
Month 1911264.111345.951.00277.00554.001854.003992.00
Month 2911609.671112.38561.00978.001238.001992.004094.00
Month 3911750.67987.16573.001039.001329.002556.003598.00
gEVAR/YDay 01001174.60581.33379.00747.001061.501535.002327.00
Month 11001051.701159.051.00610.00706.501019.004211.00
Month 2912623.561344.14873.001726.002281.004168.004273.00
Month 31003229.202099.641089.001624.002797.004400.007592.00
VAR/EDay 0441574.57617.511.00129.50410.00785.503268.00
Month 1432976.981068.411.00282.00661.001386.005305.00
Month 2441801.14922.731.00230.50519.501044.004601.00
Month 3450965.73817.641.00409.00733.001255.003264.00
gE/EDay 0441742.41978.831.0085.00367.50906.004506.00
Month 14231184.311577.031.00307.00608.001410.007748.00
Month 2432868.701000.522.00195.00521.001020.004435.00
Month 34322143.841963.9264.00840.001849.002508.009008.00
gEVAR/EDay 0450506.91508.061.00177.00367.00586.002191.00
Month 14411172.111005.5219.00452.00949.501507.504478.00
Month 2450963.98907.437.00325.00680.001091.003975.00
Month 34502438.441675.6973.001239.002008.003372.006538.00
CD4 - IFNγPool gEgE/YDay 091111.00101.801.001.00104.00154.00295.00
Month 191966.891288.871.00212.00499.00824.003972.00
Month 2911263.671422.73193.00498.00665.001298.004705.00
Month 3911952.441798.75358.001189.001302.002103.006292.00
gEVAR/YDay 0100177.30118.5824.00112.00138.00242.00437.00
Month 1100823.50948.601.00272.00591.00851.003334.00
Month 2911087.22751.6039.00503.001290.001626.002226.00
Month 31002285.601272.751146.001243.001967.002691.005437.00
VAR/EDay 0441174.95478.341.0029.5054.50154.003179.00
Month 1432290.14764.081.0047.0092.00220.004988.00
Month 2441172.70201.531.0040.50117.00216.001105.00
Month 3450279.49586.441.001.00100.00193.003226.00
gE/EDay 0441128.91150.941.0010.5075.50197.00586.00
Month 1423513.38768.051.0055.00250.00520.003471.00
Month 2432293.86414.901.0048.00144.00333.001894.00
Month 34321672.331602.241.00596.001307.002104.006309.00
gEVAR/EDay 0450123.78173.171.0036.0076.00159.001078.00
Month 1441474.86405.901.00161.00326.00746.501536.00
Month 2450295.87316.871.0068.00190.00425.001132.00
Month 34501516.181303.2167.00620.001024.002188.005829.00
VarilrixgE/YDay 091855.44722.82310.00391.00577.00839.002466.00
Month 1911051.891228.061.00247.00384.001462.003637.00
Month 2911283.671065.12410.00475.00966.001482.003808.00
Month 3911362.44910.53448.00833.001045.001873.003297.00
gEVAR/YDay 0100946.70536.60438.00548.00822.501097.002162.00
Month 1100921.301143.991.00365.00586.001047.004042.00
Month 2912176.561249.74838.001181.001711.003439.003885.00
Month 31002715.601892.41716.001327.002380.503836.006992.00
VAR/EDay 0441481.73550.511.0095.50367.50600.002960.00
Month 1432827.30941.731.00253.00529.001287.004765.00
Month 2441641.86757.753.00160.00444.50797.503922.00
Month 3450772.67690.721.00244.00580.001003.002797.00
gE/EDay 0441629.98847.281.0072.50228.00819.003920.00
Month 1423972.521380.481.00186.00419.001154.006695.00
Month 2432673.05857.441.00137.00371.00730.004126.00
Month 34321581.981625.9958.00618.001381.001735.007796.00
gEVAR/EDay 0450386.82395.991.0092.00263.00483.001579.00
Month 1441937.20879.651.00338.50656.501132.503637.00
Month 2450786.73775.901.00343.00566.00901.003205.00
Month 34501769.781236.321.00884.001439.002289.004992.00
CD4-IL2Pool gEgE/YDay 091166.44178.371.001.0066.00337.00420.00
Month 1911259.441464.99240.00371.00768.001119.004701.00
Month 2911662.111698.78402.00593.00892.001721.005076.00
Month 3912317.671497.67410.001423.002011.002595.005534.00
gEVAR/YDay 0100237.20233.771.0050.00231.00349.00751.00
Month 1100987.90796.311.00509.00751.501361.002799.00
Month 2911404.67723.26270.00802.001905.001975.002029.00
Month 31002747.801210.111436.001563.002367.504296.004451.00
VAR/EDay 0441269.98833.311.0033.00119.00212.005582.00
Month 1432388.26995.891.0058.00164.00293.006248.00
Month 2441211.18231.641.0053.50158.00286.501182.00
Month 3450397.51916.411.002.00146.00329.004728.00
gE/EDay 0441149.86153.061.001.0095.50252.00550.00
Month 1423761.98992.385.00157.00451.50800.004039.00
Month 2432467.58523.511.00103.00329.00541.002094.00
Month 34322809.072307.311.001037.002177.004347.0010316.00
gEVAR/EDay 0450165.16246.511.0035.00116.00203.001551.00
Month 1441712.59540.931.00228.00728.501048.002381.00
Month 2450465.58354.741.00184.00385.00667.001239.00
Month 34502550.272304.361.00945.001713.003910.009561.00
VarilrixgE/YDay 091941.44645.88446.00492.00617.00967.002217.00
Month 1911092.221164.691.00249.00469.001576.003480.00
Month 2911482.001067.28393.00906.001148.001715.003938.00
Month 3911551.22851.75484.00869.001275.002083.003112.00
gEVAR/YDay 01001074.70505.73414.00748.00988.001265.002094.00
Month 1100903.00887.481.00486.00650.50880.003256.00
Month 2912403.331122.05989.001679.002086.003309.004127.00
Month 31002791.901716.411043.001472.002186.503978.006004.00
VAR/EDay 0441536.80592.241.00135.50403.50710.003190.00
Month 1432866.63984.531.00220.00608.001154.004813.00
Month 2441711.09830.591.00204.50452.50907.504261.00
Month 3450828.56733.601.00331.00632.001076.002948.00
gE/EDay 0441701.02866.811.0097.50280.00885.503493.00
Month 14231076.551440.991.00233.00548.001316.006726.00
Month 2432785.88884.511.00167.00515.00971.003707.00
Month 34321866.371721.011.00670.001569.002295.007835.00
gEVAR/EDay 0450465.67489.701.00142.00334.00557.002107.00
Month 14411056.59942.7618.00441.50802.001408.504071.00
Month 2450885.89853.161.00328.00628.001013.003815.00
Month 34502114.201524.7472.00993.001660.003199.005671.00
CD4-TNFαPool gEgE/YDay 09199.3394.451.0032.0068.00189.00245.00
Month 191659.56926.82114.00155.00201.00757.002960.00
Month 291891.111360.2071.00261.00347.00868.004435.00
Month 3911423.331570.82238.00494.00914.001350.005269.00
gEVAR/YDay 0100117.00157.251.001.0028.00265.00380.00
Month 1100649.30523.3734.00352.00551.00805.001952.00
Month 291804.67520.9639.00504.00717.001191.001578.00
Month 31001770.00890.04470.001223.001865.002258.003054.00
VAR/EDay 0441211.11697.051.001.0073.00158.004652.00
Month 1432271.98755.071.0043.00109.00217.004812.00
Month 2441149.80172.341.0038.50109.00233.001007.00
Month 3450291.98713.571.001.00108.00198.004213.00
gE/EDay 0441125.23143.921.001.0054.00213.00531.00
Month 1423444.05585.761.0064.00283.50473.002574.00
Month 2432319.30371.771.00103.00225.00425.001808.00
Month 34321902.561602.671.00779.001414.002860.007655.00
gEVAR/EDay 0450153.76193.781.0033.00129.00190.001025.00
Month 1441432.39326.711.00135.50410.50694.501479.00
Month 2450318.69273.851.0096.00265.00438.001097.00
Month 34501662.401570.031.00671.001091.002194.006609.00
VarilrixgE/YDay 091754.44694.51260.00286.00315.00902.002217.00
Month 191812.11925.841.00131.00370.001275.002851.00
Month 2911204.56980.05420.00690.00738.001436.003581.00
Month 3911129.33872.35286.00592.00719.001539.002972.00
gEVAR/YDay 0100816.50449.18239.00597.00733.001024.001577.00
Month 1100660.20520.39217.00342.00482.50895.001965.00
Month 2911789.67952.77418.001084.001396.002627.003273.00
Month 31002016.501220.42437.001321.001774.003179.004156.00
VAR/EDay 0441467.02590.331.0086.50303.00607.503075.00
Month 1432751.72934.461.00223.00405.001079.004794.00
Month 2441638.30813.041.00215.50340.00812.003974.00
Month 3450711.04662.111.00268.00535.00865.002893.00
gE/EDay 0441623.09800.321.0096.50257.50833.503426.00
Month 1423862.481203.331.00197.00389.001091.005641.00
Month 2432664.63820.9922.00142.00334.00845.003582.00
Month 34321508.671419.811.00537.001353.001836.006451.00
gEVAR/EDay 0450405.42379.351.00168.00260.00558.001616.00
Month 1441814.70780.821.00274.50574.50989.003311.00
Month 2450699.20628.491.00232.00549.00898.002501.00
Month 34501634.801160.3073.00854.001450.002097.004405.00
gE/Y = gE-AS1/18-30 years; gEVAR/Y = gE-AS1+Varilrix/18-30 years; VAR/E = Varilrix/50-70 years; gE/E = gE-AS1/50-70 years; gEVAR/E = gE-AS1+Varilrix/50-70 years; N = number of subjects with available results; N miss.= number of subjects with missing results; SD = Standard Deviation; Min, Max = Minimum, Maximum; Q1,Q3 = First , Third quartile
CD8-ALL DOUBLESPool gEgE/YDay 09137.7848.761.001.001.0068.00137.00
Month 19161.78111.151.001.001.0068.00345.00
Month 291587.671585.681.001.001.00137.004811.00
Month 39138.6750.041.001.001.0067.00141.00
gEVAR/YDay 0100151.00246.451.001.0035.00206.00742.00
Month 110034.3065.701.001.001.0064.00205.00
Month 29139.00114.001.001.001.001.00343.00
Month 3100177.80313.491.001.0036.00272.001013.00
VAR/EDay 044140.3279.951.001.001.0068.00348.00
Month 143233.1659.811.001.001.0072.00216.00
Month 243241.1475.201.001.001.0070.00284.00
Month 345029.2062.991.001.001.001.00286.00
gE/EDay 044123.6450.661.001.001.001.00221.00
Month 142335.1782.741.001.001.0028.00422.00
Month 243245.0272.291.001.001.0073.00368.00
Month 343234.7486.801.001.001.001.00461.00
gEVAR/EDay 043215.5839.751.001.001.001.00220.00
Month 144140.2563.631.001.001.0070.50296.00
Month 245030.3855.591.001.001.0068.00267.00
Month 345077.04205.131.001.001.0071.001135.00
VarilrixgE/YDay 091506.111386.231.001.002.0069.004198.00
Month 191594.891659.251.001.001.00120.005015.00
Month 291990.222761.191.001.0068.00136.008351.00
Month 391419.331152.891.001.001.0071.003491.00
gEVAR/YDay 010042.3068.031.001.001.0067.00214.00
Month 110021.5045.551.001.001.001.00134.00
Month 29177.33105.581.001.001.00142.00274.00
Month 310098.40149.121.001.0037.00141.00481.00
VAR/EDay 0441228.18753.261.001.001.00138.004822.00
Month 1432205.77502.361.001.0070.00149.003021.00
Month 2441191.41509.661.001.0034.00136.003158.00
Month 3450356.691417.741.001.0070.00170.009496.00
gE/EDay 0441244.86491.441.001.0071.50224.502300.00
Month 1423279.14611.611.001.0068.00225.002909.00
Month 2432236.79551.541.001.0066.00225.002663.00
Month 3432245.67489.681.001.0071.00201.002491.00
gEVAR/EDay 0432159.93381.141.001.001.00130.002072.00
Month 1441188.82311.581.001.0069.50217.001398.00
Month 2450223.47517.021.001.001.00212.002491.00
Month 3450304.16520.031.001.00143.00290.002487.00
CD8- CD40LPool gEgE/YDay 09130.1134.571.001.001.0068.0068.00
Month 19154.22112.891.001.001.0067.00345.00
Month 291565.111593.601.001.001.0068.004811.00
Month 39116.2230.211.001.001.001.0070.00
gEVAR/YDay 0100130.10235.431.001.001.00206.00674.00
Month 110034.3065.701.001.001.0064.00205.00
Month 29131.3391.001.001.001.001.00274.00
Month 3100164.20315.171.001.002.00204.001013.00
VAR/EDay 044113.6631.151.001.001.001.00142.00
Month 14329.6529.291.001.001.001.00153.00
Month 24325.1919.421.001.001.001.00105.00
Month 345012.6231.581.001.001.001.00142.00
gE/EDay 044112.3226.281.001.001.001.0076.00
Month 142314.3127.821.001.001.001.0078.00
Month 243217.2633.861.001.001.001.00146.00
Month 343214.1632.291.001.001.001.00150.00
gEVAR/EDay 04327.1619.481.001.001.001.0071.00
Month 144118.9546.551.001.001.001.00221.00
Month 245022.7143.701.001.001.001.00200.00
Month 345045.80146.311.001.001.001.00780.00
VarilrixgE/YDay 091260.56651.121.001.0068.0069.001992.00
Month 191235.78609.461.001.001.00120.001854.00
Month 291291.22741.431.001.0068.0071.002264.00
Month 391240.78644.211.001.001.0070.001954.00
gEVAR/YDay 010021.0032.211.001.001.0067.0069.00
Month 11001.000.001.001.001.001.001.00
Month 29124.0049.341.001.001.001.00142.00
Month 310062.60153.101.001.001.001.00481.00
VAR/EDay 044115.8933.391.001.001.001.00152.00
Month 143231.9558.901.001.001.0068.00261.00
Month 244117.9345.211.001.001.001.00156.00
Month 345017.8439.121.001.001.001.00152.00
gE/EDay 044123.4553.701.001.001.001.50227.00
Month 142325.0265.401.001.001.001.00363.00
Month 243211.1630.541.001.001.001.00154.00
Month 343220.4944.841.001.001.001.00218.00
gEVAR/EDay 043225.5848.471.001.001.001.00147.00
Month 144127.9355.291.001.001.0068.00304.00
Month 245012.1838.151.001.001.001.00225.00
Month 345019.8043.491.001.001.001.00209.00
CD8-IFNγPool gEgE/YDay 09115.2228.261.001.001.001.0068.00
Month 19138.4435.551.001.0067.0068.0072.00
Month 291215.78472.211.001.0068.00135.001464.00
Month 39131.1150.031.001.001.0066.00141.00
gEVAR/YDay 010089.40110.491.001.0068.00143.00336.00
Month 110013.9027.201.001.001.001.0067.00
Month 29131.1168.871.001.001.001.00205.00
Month 310062.4066.911.001.0068.0076.00202.00
VAR/EDay 044130.7774.581.001.001.001.00348.00
Month 143221.3050.451.001.001.001.00216.00
Month 243238.8169.551.001.001.0070.00284.00
Month 345015.1338.771.001.001.001.00146.00
gE/EDay 044112.9128.231.001.001.001.00110.00
Month 142330.4071.671.001.001.001.00351.00
Month 243236.7773.761.001.001.0066.00368.00
Month 343231.3385.071.001.001.001.00461.00
gEVAR/EDay 043212.6338.391.001.001.001.00220.00
Month 144125.3649.381.001.001.0035.00230.00
Month 245011.6725.171.001.001.001.0075.00
Month 345058.51147.371.001.001.0070.00851.00
VarilrixgE/YDay 091475.111319.181.001.001.001.003984.00
Month 191561.781644.431.001.001.001.004946.00
Month 291935.222701.841.001.001.0070.008139.00
Month 391403.891183.381.001.001.001.003559.00
gEVAR/YDay 010049.3087.981.001.001.0068.00283.00
Month 110028.6058.231.001.001.001.00144.00
Month 29161.4486.911.001.001.0068.00208.00
Month 310078.20100.951.001.0034.50147.00274.00
VAR/EDay 0441223.32719.341.001.001.00134.004534.00
Month 1432208.47507.581.001.0070.00213.003021.00
Month 2441185.43499.141.001.001.50145.503085.00
Month 3450342.331408.211.001.0031.00147.009423.00
gE/EDay 0441227.52482.151.001.001.00204.502216.00
Month 1423273.88613.111.001.0066.00225.002909.00
Month 2432228.79542.441.001.0070.00206.002591.00
Month 3432235.33490.731.001.0069.00189.002491.00
gEVAR/EDay 0432156.53390.281.001.001.0076.002000.00
Month 1441177.48309.131.001.0067.00217.001398.00
Month 2450220.84518.381.001.001.00147.002491.00
Month 3450291.38515.671.001.0092.00290.002418.00
CD8-IL2Pool gEgE/YDay 09122.6732.551.001.001.0062.0068.00
Month 19161.78111.151.001.001.0068.00345.00
Month 291557.671595.671.001.001.0068.004811.00
Month 39131.3350.211.001.001.0066.00141.00
gEVAR/YDay 0100136.90232.251.001.001.00206.00674.00
Month 110034.3065.701.001.001.0064.00205.00
Month 29139.00114.001.001.001.001.00343.00
Month 3100170.70315.261.001.0035.50272.001013.00
VAR/EDay 044120.3046.601.001.001.001.00223.00
Month 143213.1436.171.001.001.001.00153.00
Month 243216.2643.321.001.001.001.00212.00
Month 345017.4938.461.001.001.001.00152.00
gE/EDay 044116.5543.921.001.001.001.00212.00
Month 142319.2936.161.001.001.001.00140.00
Month 243228.5354.261.001.001.0066.00221.00
Month 343216.2844.661.001.001.001.00229.00
gEVAR/EDay 04327.2119.471.001.001.001.0071.00
Month 144125.8451.641.001.001.006.50221.00
Month 245024.1844.411.001.001.003.00149.00
Month 345045.76148.501.001.001.001.00851.00
VarilrixgE/YDay 091102.78207.481.001.001.0069.00640.00
Month 191151.78359.311.001.001.00120.001098.00
Month 291227.78503.561.001.0068.00136.001556.00
Month 39193.56181.121.001.001.0071.00559.00
gEVAR/YDay 010014.4028.251.001.001.001.0069.00
Month 11007.6020.871.001.001.001.0067.00
Month 29139.1160.891.001.001.0067.00142.00
Month 310062.60153.101.001.001.001.00481.00
VAR/EDay 044199.27241.071.001.001.0073.001223.00
Month 143278.49122.701.001.0066.00109.00575.00
Month 244197.00226.121.001.001.0075.501028.00
Month 3450144.38452.961.001.001.00137.002994.00
gE/EDay 0441140.34240.411.001.0033.50153.001271.00
Month 1423124.21246.931.001.001.00145.001017.00
Month 243299.79166.751.001.001.00144.00863.00
Month 3432148.19264.301.001.0014.00145.001173.00
gEVAR/EDay 043268.81116.271.001.001.0077.00573.00
Month 144187.89122.661.001.0068.00141.00521.00
Month 2450113.91231.461.001.001.00138.001127.00
Month 3450163.44232.531.001.0071.00215.00967.00
CD8-TNFαPool gEgE/YDay 09123.3333.501.001.001.0068.0068.00
Month 1911.000.001.001.001.001.001.00
Month 29115.8944.671.001.001.001.00135.00
Month 39123.8949.041.001.001.001.00141.00
gEVAR/YDay 010035.0065.201.001.001.0068.00201.00
Month 11001.000.001.001.001.001.001.00
Month 2918.5622.671.001.001.001.0069.00
Month 31008.0021.101.001.001.001.0068.00
VAR/EDay 044132.2075.141.001.001.001.50348.00
Month 143233.0563.481.001.001.0072.00288.00
Month 243231.4067.101.001.001.0012.00284.00
Month 345019.8048.191.001.001.001.00207.00
gE/EDay 044118.8044.111.001.001.001.00221.00
Month 142332.6077.371.001.001.0037.00422.00
Month 243230.0247.351.001.001.0066.00221.00
Month 343224.5367.551.001.001.001.00306.00
gEVAR/EDay 043215.7940.141.001.001.001.00220.00
Month 144128.9157.441.001.001.0033.50230.00
Month 245021.1341.061.001.001.001.00149.00
Month 345052.49124.921.001.001.0069.00709.00
VarilrixgE/YDay 091459.331297.021.001.001.002.003913.00
Month 191535.671526.031.001.001.0070.004603.00
Month 291928.112730.861.001.001.0067.008210.00
Month 391373.221090.661.001.001.001.003281.00
gEVAR/YDay 010035.6068.511.001.001.0067.00214.00
Month 110021.5045.551.001.001.001.00134.00
Month 29169.33102.761.001.001.0070.00274.00
Month 310044.2077.201.001.001.0073.00215.00
VAR/EDay 0441200.27729.981.001.001.0075.004678.00
Month 1432168.60469.561.001.0034.00141.002805.00
Month 2441159.45432.791.001.001.00129.502717.00
Month 3450309.731310.431.001.001.00133.008765.00
gE/EDay 0441201.23441.881.001.001.00150.502057.00
Month 1423230.05531.941.001.0047.50225.002545.00
Month 2432221.44535.051.001.0066.00225.002591.00
Month 3432189.44402.521.001.0061.00189.002125.00
gEVAR/EDay 0432133.88332.421.001.001.0072.001712.00
Month 1441172.50306.321.001.0067.00212.501398.00
Month 2450190.29470.521.001.001.00147.002340.00
Month 3450255.16490.591.001.0071.00215.002279.00
gE/Y = gE-AS1/18-30 years; gEVAR/Y = gE-AS1+Varilrix/18-30 years; VAR/E = Varilrix/50-70 years; gE/E = gE-AS1/50-70 years; gEVAR/E = gE-AS1+Varilrix/50-70 years; N = number of subjects with available results; N miss.= number of subjects with missing results; SD = Standard Deviation; Min, Max = Minimum, Maximum; Q1,Q3 = First , Third quartile
CD4VAR\ E and gEVAR\ EPool gEALL DOUBLES0.50250.00000.00150.0000
CD40L0.44480.00000.00040.0000
IFNγ0.59000.00010.09560.0000
IL20.64150.00000.00010.0000
TNFα0.26340.00000.00190.0000
VarilrixALL DOUBLES0.71180.14890.31480.0000
CD40L0.64880.16640.26090.0000
IFNγ0.36020.29050.22770.0000
IL20.48800.14420.24060.0000
TNFα0.86310.26240.24550.0000
VAR\ E and gE\ EPool gEALL DOUBLES0.97640.00040.01000.0000
CD40L0.97650.00030.00260.0000
IFNγ0.96650.02280.29610.0000
IL20.71830.00010.00350.0000
TNFα0.90260.00690.00530.0000
VarilrixALL DOUBLES0.90690.99650.85520.0002
CD40L0.89040.97900.91550.0002
IFNγ0.88060.57970.68680.0010
IL20.96010.98600.90540.0003
TNFα0.60730.97190.81540.0016
gE\ E and gEVAR\ EPool gEALL DOUBLES0.49510.17770.57020.4832
CD40L0.37310.22150.53120.5368
IFNγ0.77320.23310.59580.8576
IL20.94060.30590.41810.5069
TNFα0.39490.20390.56130.3287
VarilrixALL DOUBLES0.84690.18760.24090.2687
CD40L0.98030.19800.20600.2277
IFNγ0.75200.21030.12050.2182
IL20.72110.21350.23750.3045
TNFα0.81180.21340.18170.2778
VAR/E = Varilrix/50-70 yearsgE/E = gE-AS1/50-70 yearsgEVAR/E = gE-AS1+Varilrix/50-70 years
CD8VAR\ E and gEVAR\ EPool gEALL DOUBLES0.14770.44180.81410.2762
CD40L0.28970.25130.01260.3511
IFNγ0.16950.40690.04780.0478
IL20.27050.13160.20080.5872
TNFα0.29680.70170.64700.0947
VarilrixALL DOUBLES0.92670.76050.96510.1197
CD40L0.62600.91110.65120.8826
IFNγ0.98460.96110.92250.1009
IL20.70270.69630.46260.1181
TNFα0.90470.46550.99290.1639
VAR\ E and gE\ EPool gEALL DOUBLES0.41170.96080.45700.9320
CD40L0.78910.26360.03150.7302
IFNγ0.49220.56720.79600.3690
IL20.60920.21370.14160.6416
TNFα0.58910.88280.46330.9530
VarilrixALL DOUBLES0.23360.91680.47920.6436
CD40L0.59690.34430.69680.8133
IFNγ0.36060.93420.30190.5406
IL20.17430.65090.25770.4652
TNFα0.34050.76270.38690.5577
gE\ E and gEVAR\ EPool gEALL DOUBLES0.49420.33220.29750.3120
CD40L0.18310.98980.60470.5555
IFNγ0.45150.81290.09480.2325
IL20.61710.72240.84390.3147
TNFα0.60640.74720.25710.1078
VarilrixALL DOUBLES0.25240.84790.44100.2783
CD40L0.95940.33850.90950.9433
IFNγ0.34650.92770.36910.2849
IL20.23330.52630.71010.4173
TNFα0.46780.71670.31980.4684
VAR/E = Varilrix/50-70 yearsgE/E = gE-AS1/50-70 yearsgEVAR/E = gE-AS1+Varilrix/50-70 years
CD4 - ALL DOUBLESPool gEgE/YMonth 1911170.331640.79-80.00230.00434.001332.005096.00
Month 2911574.111884.90256.00496.00723.001285.005428.00
Month 3912526.441927.96442.001329.002233.002647.006852.00
gEVAR/YMonth 1100926.50846.70-348.00393.00865.501363.002752.00
Month 2911308.56846.35-233.00845.001681.001995.002178.00
Month 31003045.301361.871288.001969.002830.504533.005057.00
VAR/EMonth 1423147.90460.77-436.00-49.0025.50155.001898.00
Month 2432-84.23947.38-5979.00-60.0035.00179.00658.00
Month 3441173.161441.28-5191.00-128.000.00146.006263.00
gE/EMonth 1423691.741008.97-163.00135.00310.00826.004210.00
Month 2432352.00515.95-337.0039.00206.00485.001974.00
Month 34233118.482537.47-112.001324.002344.504620.0011479.00
gEVAR/EMonth 1441616.02505.69-184.00165.00597.50902.002377.00
Month 2450303.13389.20-549.0052.00266.00515.001234.00
Month 34502712.022508.85-542.00925.001601.004223.0010467.00
VarilrixgE/YMonth 191256.89842.23-811.00-214.00-87.00712.001612.00
Month 291610.22651.41-72.00129.00361.00831.001904.00
Month 391770.56891.01-787.00548.00718.001165.002343.00
gEVAR/YMonth 1100-98.401180.58-1610.00-647.00-31.5075.002732.00
Month 2911547.67993.79225.00797.001286.002179.003188.00
Month 31002181.301781.51151.00698.001867.002861.006210.00
VAR/EMonth 1423366.95798.30-663.000.00173.00536.004145.00
Month 2432169.07569.41-2100.00-39.00197.00325.001608.00
Month 3441362.93662.91-2100.0054.00267.50633.501906.00
gE/EMonth 1423524.74946.86-660.000.00229.00734.004178.00
Month 243295.30633.65-1405.00-205.0018.00254.001961.00
Month 34231533.691557.01-600.00528.001090.002181.007044.00
gEVAR/EMonth 1441664.14765.08-555.00184.50575.001109.003364.00
Month 2450451.04652.53-397.0034.00244.00639.002601.00
Month 34501973.731577.3070.00918.001480.002659.006575.00
CD4 - CD40LPool gEgE/YMonth 1911142.671567.96-77.00290.00434.001272.004889.00
Month 2911519.781786.74336.00465.00680.001369.005120.00
Month 3912363.221772.92375.001303.001870.002323.006282.00
gEVAR/YMonth 1100868.50852.69-348.00381.00813.001265.002782.00
Month 2911278.44841.17-233.00691.001620.002027.002048.00
Month 31002915.501350.461150.001816.002785.504273.005088.00
VAR/EMonth 1423141.24434.95-487.00-22.0044.00161.001837.00
Month 2432-80.09893.99-5627.00-74.0026.00195.00601.00
Month 3441169.661401.60-4969.00-100.006.50136.006071.00
gE/EMonth 1423691.05975.64-183.00154.00323.00814.004153.00
Month 2432367.37493.31-306.0064.00222.00546.001976.00
Month 34233036.882447.00-189.001342.002320.004568.0010509.00
gEVAR/EMonth 1441603.75496.38-112.00183.00583.50878.502268.00
Month 2450308.96364.06-493.00115.00266.00515.001185.00
Month 34502692.242497.48-397.00918.001652.004189.0010417.00
VarilrixgE/YMonth 191236.33828.70-790.00-212.00-62.00634.001594.00
Month 291581.89584.04-74.00217.00361.00781.001587.00
Month 391722.89892.40-737.00210.00747.001091.002284.00
gEVAR/YMonth 1100-122.901156.16-1604.00-613.00-114.5075.002676.00
Month 2911519.671018.54259.00684.001228.002137.003210.00
Month 31002054.601759.6736.00554.001840.502421.006057.00
VAR/EMonth 1423355.62780.99-623.0025.00150.50529.004128.00
Month 2432160.72567.36-2024.00-32.00158.00349.001631.00
Month 3441351.45663.33-2024.004.00199.00616.501972.00
gE/EMonth 1423509.52852.27-679.00-5.00213.50747.003242.00
Month 2432109.05630.36-1378.00-181.0027.00257.002004.00
Month 34231501.021546.41-881.00562.001036.502095.007128.00
gEVAR/EMonth 1441661.55758.32-487.00155.50593.501066.503519.00
Month 2450457.07652.72-411.0033.00290.00580.002646.00
Month 34501931.531542.7171.00916.001427.002686.006529.00
CD4 - IFNγPool gEgE/YMonth 191855.891270.64-83.0056.00498.00823.003836.00
Month 2911152.671414.76192.00402.00511.001087.004569.00
Month 3911841.441805.38254.00894.001227.001892.006156.00
gEVAR/YMonth 1100646.20866.49-241.00194.00402.00739.002897.00
Month 291898.89743.23-203.00367.001064.001602.001789.00
Month 31002108.301216.76920.001089.001854.502667.005000.00
VAR/EMonth 1423104.52323.14-231.00-17.0029.5084.001809.00
Month 2432-25.56505.62-3122.00-24.0033.00117.00561.00
Month 344199.75731.24-2787.00-32.0011.0088.503037.00
gE/EMonth 1423395.14676.51-72.0045.00174.50333.003116.00
Month 2432161.98330.61-305.005.0054.00219.001539.00
Month 34231583.481568.34-47.00491.001224.002077.006308.00
gEVAR/EMonth 1441350.95333.21-34.0091.00270.50554.001349.00
Month 2450172.09273.80-186.008.0082.00274.001062.00
Month 34501392.401301.10-29.00484.00875.001961.005786.00
VarilrixgE/YMonth 191196.44699.90-663.00-156.00-144.00431.001472.00
Month 291428.22503.10-132.0084.00332.00743.001342.00
Month 391507.00696.10-781.00196.00471.00831.001563.00
gEVAR/YMonth 1100-25.401073.83-1588.00-456.00-20.00106.002599.00
Month 2911246.56985.4988.00467.00945.001661.003056.00
Month 31001768.901593.80168.00634.001485.502136.005549.00
VAR/EMonth 1423309.07689.54-701.0016.00187.50396.003829.00
Month 2432116.07496.80-1934.00-74.00134.00283.001515.00
Month 3441254.25539.74-1750.0023.00161.50445.001861.00
gE/EMonth 1423405.48723.30-631.00-25.00204.00515.002775.00
Month 243233.23464.33-1258.00-102.0042.00204.001236.00
Month 34231042.861155.33-529.00402.00805.001590.006357.00
gEVAR/EMonth 1441548.59714.90-621.00111.00374.50757.503276.00
Month 2450399.91618.77-454.0047.00231.00474.002730.00
Month 34501382.961099.42-1.00652.001088.001679.004831.00
CD4-IL2Pool gEgE/YMonth 1911093.001486.37-40.00228.00465.001118.004669.00
Month 2911495.671762.08316.00524.00623.001301.005044.00
Month 3912151.221569.05344.001086.002010.002510.005502.00
gEVAR/YMonth 1100750.70647.88-348.00466.00613.001063.002048.00
Month 2911167.22708.40-79.00801.001192.001802.001974.00
Month 31002510.601142.731026.001562.002307.503545.004153.00
VAR/EMonth 1423106.40368.83-361.00-83.0054.00126.001897.00
Month 2432-85.70860.78-5429.00-81.000.00159.00634.00
Month 3441125.251203.10-4856.00-80.500.00137.004576.00
gE/EMonth 1423617.10907.63-49.00128.00312.50692.003736.00
Month 2432314.26460.49-271.0025.00189.00389.001723.00
Month 34232711.762304.960.001008.002082.004222.0010315.00
gEVAR/EMonth 1441543.70465.89-111.00104.00508.50826.001920.00
Month 2450300.42336.69-460.00103.00300.00429.001088.00
Month 34502385.112307.17-460.00819.001478.003888.009485.00
VarilrixgE/YMonth 191150.78735.34-812.00-271.00-77.00664.001263.00
Month 291540.56597.57-125.00211.00316.00712.001721.00
Month 391609.78735.25-565.00377.00576.00895.001986.00
gEVAR/YMonth 1100-171.70949.81-1498.00-545.00-111.00135.001991.00
Month 2911396.11925.12443.00678.001111.001980.003192.00
Month 31001717.201413.72133.00532.001356.502606.004739.00
VAR/EMonth 1423290.62714.95-689.005.00161.00401.003784.00
Month 2432121.05534.68-2122.00-83.00134.00369.001492.00
Month 3441257.48599.43-1964.00-17.00196.00504.501857.00
gE/EMonth 1423438.14817.33-695.00-21.00173.00644.003233.00
Month 243271.42575.91-1320.00-274.0069.00255.001678.00
Month 34231254.761389.73-548.00382.00827.501798.006315.00
gEVAR/EMonth 1441586.45695.20-363.00169.50437.50858.003292.00
Month 2450420.22582.63-416.0078.00185.00545.002287.00
Month 34501648.531355.4271.00742.001148.002418.005462.00
CD4-TNFαPool gEgE/YMonth 191560.22934.1412.0065.00123.00756.002903.00
Month 291791.781375.333.00149.00315.00623.004378.00
Month 3911324.001590.20206.00415.00831.001105.005212.00
gEVAR/YMonth 1100532.30452.83-11.00253.00503.50651.001572.00
Month 291715.00462.6538.00503.00712.001039.001314.00
Month 31001653.00811.66465.001195.001850.501931.002902.00
VAR/EMonth 142351.69229.81-470.00-57.0041.00115.001215.00
Month 2432-86.14688.49-4412.00-46.002.00126.00254.00
Month 344177.75960.07-3944.00-80.001.0094.004212.00
gE/EMonth 1423325.40519.68-165.000.00161.50419.002302.00
Month 2432191.19319.19-246.000.00119.00225.001367.00
Month 34231815.831594.15-152.00690.001389.502762.007491.00
gEVAR/EMonth 1441275.16261.28-156.0057.50233.50480.001045.00
Month 2450164.93267.03-494.0026.00126.00316.00675.00
Month 34501508.641548.74-433.00508.00875.002193.006403.00
VarilrixgE/YMonth 19157.67443.72-683.00-219.0047.00528.00634.00
Month 291450.11411.03-101.00184.00411.00513.001364.00
Month 391374.89664.84-945.00113.00404.00637.001536.00
gEVAR/YMonth 1100-156.30634.57-1203.00-365.00-107.50217.00941.00
Month 2911047.56757.92179.00535.00765.001585.002566.00
Month 31001200.00918.82-123.00626.001214.501693.003132.00
VAR/EMonth 1423250.64695.21-805.00-33.00138.50287.003707.00
Month 2432110.26519.34-1984.00-121.00103.00294.001491.00
Month 3441210.23548.98-1984.00-10.00167.50423.501806.00
gE/EMonth 1423298.93637.78-566.00-45.00146.50405.002494.00
Month 243229.81538.43-1359.00-171.0013.00150.001845.00
Month 3423967.051085.98-609.00239.00707.501502.004441.00
gEVAR/EMonth 1441405.30604.26-432.0090.00304.50554.502871.00
Month 2450293.78495.54-347.00-34.00167.00324.002242.00
Month 34501229.381061.80-73.00492.00913.001565.004380.00
gE/Y = gE-AS1/18-30 years; gEVAR/Y = gE-AS1+Varilrix/18-30 years; VAR/E = Varilrix/50-70 years; gE/E = gE-AS1/50-70 years; gEVAR/E = gE-AS1+Varilrix/50-70 years; N = number of subjects with available results; N miss.= number of subjects with missing results; SD = Standard Deviation; Min, Max = Minimum, Maximum; Q1,Q3 = First , Third quartile
CD8-ALL DOUBLESPool gEgE/YMonth 19124.00136.52-136.00-61.000.0067.00344.00
Month 291549.891599.52-67.00-2.000.0069.004810.00
Month 3910.8983.03-136.00-61.000.0065.00140.00
gEVAR/YMonth 1100-116.70198.88-537.00-139.00-34.000.0063.00
Month 291-128.67170.57-413.00-205.00-68.000.000.00
Month 310026.80117.89-142.00-68.000.0069.00271.00
VAR/EMonth 1423-13.3897.87-278.00-65.000.000.00210.00
Month 2423-3.5076.50-222.00-22.000.000.00209.00
Month 3441-10.48107.47-347.00-11.000.000.00285.00
gE/EMonth 142310.4595.31-211.000.000.001.00421.00
Month 243222.5195.28-220.000.000.0070.00367.00
Month 34237.2988.24-211.000.000.000.00460.00
gEVAR/EMonth 142326.1269.05-71.000.000.0068.00295.00
Month 243216.1662.56-147.000.000.0067.00201.00
Month 343265.00217.39-219.000.000.0070.001134.00
VarilrixgE/YMonth 19188.78274.69-67.00-1.000.000.00817.00
Month 291484.111376.23-1.000.001.0068.004153.00
Month 391-86.78246.23-707.00-68.000.000.00135.00
gEVAR/YMonth 1100-20.8071.94-141.00-66.000.000.00133.00
Month 29130.44143.10-213.00-66.000.00139.00273.00
Month 310056.10163.61-213.000.0035.00140.00414.00
VAR/EMonth 1423-31.67340.22-1801.00-71.000.0074.00491.00
Month 2432-52.51298.58-1664.00-68.000.0068.00362.00
Month 3441131.75725.55-611.00-26.000.00104.504674.00
gE/EMonth 142359.62265.24-296.00-72.000.0081.001015.00
Month 2432-10.51382.79-1736.00-42.000.0071.001242.00
Month 342328.60190.71-423.00-71.000.0072.00597.00
gEVAR/EMonth 14235.90351.50-1924.00-1.000.0073.00694.00
Month 243215.98365.42-1594.00-70.000.00143.001213.00
Month 3432129.19225.91-149.000.0016.00265.00916.00
CD8- CD40LPool gEgE/YMonth 19124.11127.75-67.00-61.000.000.00344.00
Month 291535.001604.13-67.000.000.000.004810.00
Month 391-13.8955.72-67.00-67.000.000.0069.00
gEVAR/YMonth 1100-95.80189.16-469.00-139.000.000.0063.00
Month 291-113.11179.39-413.00-205.000.000.000.00
Month 310034.10138.26-210.000.000.0069.00339.00
VAR/EMonth 1423-4.4043.17-141.000.000.000.00152.00
Month 2423-7.2937.64-141.000.000.000.00104.00
Month 3441-0.7737.03-73.000.000.000.00102.00
gE/EMonth 14231.4539.39-75.000.000.000.0076.00
Month 24326.3345.80-75.000.000.000.00145.00
Month 3423-1.9336.10-75.000.000.000.0072.00
gEVAR/EMonth 142310.8648.91-70.000.000.000.00220.00
Month 243216.5645.02-70.000.000.0065.00145.00
Month 343240.72152.63-70.000.000.000.00779.00
VarilrixgE/YMonth 191-24.7856.16-138.00-67.000.000.0051.00
Month 29130.67102.65-68.00-1.000.0069.00272.00
Month 391-19.7846.08-73.00-67.000.000.0068.00
gEVAR/YMonth 1100-20.0032.21-68.00-66.000.000.000.00
Month 2910.7868.53-68.00-66.000.000.00141.00
Month 310041.60134.83-68.000.000.000.00414.00
VAR/EMonth 142316.1763.26-72.000.000.000.00260.00
Month 24322.0948.77-73.000.000.000.00153.00
Month 34412.3443.59-73.000.000.000.00146.00
gE/EMonth 14232.1480.48-149.000.000.000.00362.00
Month 2432-11.2359.14-218.000.000.000.00152.00
Month 3423-1.9376.17-226.000.000.000.00217.00
gEVAR/EMonth 14233.0551.88-135.000.000.000.00157.00
Month 2432-12.8847.07-145.000.000.000.0078.00
Month 3432-4.9146.80-145.000.000.000.0073.00
CD8-IFNγPool gEgE/YMonth 19123.2245.52-61.000.004.0066.0067.00
Month 291200.56477.92-61.000.0067.00133.001463.00
Month 39115.8965.31-67.000.000.0065.00140.00
gEVAR/YMonth 1100-75.50120.41-335.00-142.00-34.000.0063.00
Month 291-68.1159.39-142.00-131.00-67.000.000.00
Month 3100-27.0056.93-134.00-68.000.000.0067.00
VAR/EMonth 1423-15.5275.76-278.000.000.000.00193.00
Month 24232.4362.84-139.000.000.000.00192.00
Month 3441-15.3279.50-347.000.000.000.0075.00
gE/EMonth 142316.9372.52-109.000.000.000.00282.00
Month 243223.5884.49-109.000.000.0065.00367.00
Month 342318.5770.71-66.000.000.000.00392.00
gEVAR/EMonth 142313.5562.27-146.000.000.000.00229.00
Month 2432-0.4740.58-147.000.000.000.0074.00
Month 343248.56146.44-144.000.000.0068.00781.00
VarilrixgE/YMonth 19186.67344.40-284.000.000.000.00962.00
Month 291460.111388.68-215.000.000.0066.004155.00
Month 391-71.22165.93-425.000.000.000.0068.00
gEVAR/YMonth 1100-20.7071.64-139.00-67.000.000.00133.00
Month 2916.78136.42-282.00-1.000.0067.00204.00
Month 310028.90155.44-282.000.000.50146.00273.00
VAR/EMonth 1423-23.81304.92-1513.000.000.0073.00561.00
Month 2432-53.65284.04-1449.000.000.0065.00289.00
Month 3441121.93758.36-610.00-0.500.0073.004889.00
gE/EMonth 142374.10267.93-296.00-2.000.0071.001088.00
Month 2432-4.00372.80-1652.00-66.000.0068.001170.00
Month 342337.74175.85-339.00-3.000.0074.00670.00
gEVAR/EMonth 1423-0.81360.67-1999.000.000.0073.00694.00
Month 243216.63341.39-1452.00-66.000.0072.001213.00
Month 3432119.21197.20-284.000.0016.00221.00659.00
CD8-IL2Pool gEgE/YMonth 19139.11127.97-67.00-61.000.0067.00344.00
Month 291535.001604.48-67.00-61.000.0067.004810.00
Month 3918.6771.13-67.00-61.000.0065.00140.00
gEVAR/YMonth 1100-102.60186.54-469.00-139.000.000.0063.00
Month 291-113.00162.73-413.00-205.000.000.000.00
Month 310033.80125.98-142.000.000.0069.00339.00
VAR/EMonth 1423-7.7957.52-148.000.000.000.00152.00
Month 2423-2.9068.64-222.000.000.000.00211.00
Month 3441-4.0264.96-222.000.000.000.00151.00
gE/EMonth 14232.0052.68-211.000.000.000.00139.00
Month 243213.2864.17-211.000.000.0065.00218.00
Month 3423-4.1959.14-211.000.000.000.00228.00
gEVAR/EMonth 142319.6759.09-70.000.000.0011.00220.00
Month 243218.0548.05-70.000.000.0065.00148.00
Month 343240.63153.41-66.000.000.000.00850.00
VarilrixgE/YMonth 19149.00156.22-67.000.000.000.00458.00
Month 291125.00298.57-1.000.000.0070.00916.00
Month 391-9.2273.85-81.00-68.000.000.00136.00
gEVAR/YMonth 1100-6.8037.82-68.000.000.000.0066.00
Month 29123.2276.53-68.000.000.0066.00141.00
Month 310048.20155.17-68.000.000.000.00480.00
VAR/EMonth 1423-23.52167.46-648.00-67.000.0069.00211.00
Month 2432-10.63110.07-289.00-72.000.001.00361.00
Month 344146.75299.86-687.000.000.0069.001771.00
gE/EMonth 1423-10.98155.68-266.00-110.000.000.00539.00
Month 2432-40.56207.85-1030.00-72.000.000.00367.00
Month 342313.12137.98-226.00-71.000.0060.00662.00
gEVAR/EMonth 142321.33123.99-425.00-2.000.0071.00488.00
Month 243229.33179.40-301.00-66.000.0068.00831.00
Month 343286.84165.87-136.000.000.00199.00709.00
CD8-TNFαPool gEgE/YMonth 191-22.3333.50-67.00-67.000.000.000.00
Month 291-7.4440.26-67.000.000.000.0067.00
Month 3910.5659.77-67.00-1.000.000.00140.00
gEVAR/YMonth 1100-34.0065.20-200.00-67.000.000.000.00
Month 291-30.2268.11-200.000.000.000.001.00
Month 3100-27.0071.95-200.00-67.000.000.0067.00
VAR/EMonth 1423-6.7190.36-278.000.000.000.00210.00
Month 2423-6.6778.03-219.00-1.000.000.00209.00
Month 3441-11.9889.66-347.000.000.000.00206.00
gE/EMonth 142312.9586.37-184.000.000.007.00421.00
Month 243210.8169.64-220.000.000.0065.00220.00
Month 34235.4565.44-140.000.000.000.00305.00
gEVAR/EMonth 142314.1072.50-219.000.000.000.00229.00
Month 24326.2857.99-219.000.000.000.00148.00
Month 343239.09129.10-219.000.000.0068.00639.00
VarilrixgE/YMonth 19176.33232.77-71.000.000.000.00690.00
Month 291468.781436.63-143.000.000.000.004297.00
Month 391-86.11218.67-632.00-1.000.000.0070.00
gEVAR/YMonth 1100-14.1070.26-141.00-66.000.000.00133.00
Month 29129.89146.91-213.00-66.000.0069.00273.00
Month 31008.60118.21-213.00-66.000.0072.00214.00
VAR/EMonth 1423-40.52354.84-1873.00-68.000.0069.00491.00
Month 2432-51.70327.59-1961.000.000.006.00361.00
Month 3441110.00653.00-991.000.000.0073.004087.00
gE/EMonth 142352.86220.80-455.00-4.000.0071.00869.00
Month 243217.14356.23-1493.00-19.000.0071.001312.00
Month 342315.07172.57-571.000.000.0070.00449.00
gEVAR/EMonth 142315.48312.96-1711.000.000.00134.00694.00
Month 243210.81297.77-1440.00-66.000.0067.00838.00
Month 3432109.00211.09-148.000.000.00205.00904.00
gE/Y = gE-AS1/18-30 years; gEVAR/Y = gE-AS1+Varilrix/18-30 years; VAR/E = Varilrix/50-70 years; gE/E = gE-AS1/50-70 years; gEVAR/E = gE-AS1+Varilrix/50-70 years; N = number of subjects with available results; N miss.= number of subjects with missing results; SD = Standard Deviation; Min, Max = Minimum, Maximum; Q1,Q3 = First , Third quartile
CD4VAR\ E and gEVAR\ EPool gEALL DOUBLES0.00000.00040.0000
CD40L0.00000.00020.0000
IFNγ0.00000.04290.0000
IL20.00000.00000.0000
TNFα0.00000.00090.0000
VarilrixALL DOUBLES0.00780.17360.0000
CD40L0.00900.07270.0000
IFNγ0.02610.04470.0000
IL20.00670.05750.0000
TNFα0.06200.19570.0000
VAR\ E and gE\E EPool gEALL DOUBLES0.00000.00040.0000
CD40L0.00000.00010.0000
IFNγ0.00010.08800.0000
IL20.00000.00030.0000
TNFα0.00090.00180.0000
VarilrixALL DOUBLES0.53700.11200.0000
CD40L0.51370.22170.0000
IFNγ0.72050.23670.0000
IL20.57910.35990.0000
TNFα0.84400.08800.0001
gE\ E and gEVAR\E EPool gEALL DOUBLES0.31000.66120.3060
CD40L0.39960.71340.3350
IFNγ0.23660.71340.6835
IL20.47070.36290.4148
TNFα0.39230.71340.2480
VarilrixALL DOUBLES0.10340.00490.1231
CD40L0.12620.00540.1305
IFNγ0.08320.00210.0910
IL20.09210.00400.0831
TNFα0.11790.00350.1372
VAR/E = Varilrix/50-70 yearsgE/E = gE-AS1/50-70 yearsgEVAR/E = gE-AS1+Varilrix/50-70 years
CD8VAR\ E and gEVAR\E EPool gEALL DOUBLES0.05750.20690.1364
CD40L0.16470.01130.1579
IFNγ0.14110.87590.0360
IL20.04560.10800.1442
TNFα0.29380.33560.0499
VarilrixALL DOUBLES0.63630.81160.1785
CD40L0.69440.41510.9266
IFNγ0.59530.81080.0486
IL20.66560.55670.1544
TNFα0.36770.87880.2679
VAR\ E and gE\ EPool gEALL DOUBLES0.29130.11590.9259
CD40L0.58850.25420.9217
IFNγ0.19000.31130.4158
IL20.16870.12880.8127
TNFα0.37000.20080.8454
VarilrixALL DOUBLES0.90670.94360.4197
CD40L0.13820.45740.7783
IFNγ0.74450.68410.8567
IL20.18930.39800.3536
TNFα0.67160.81320.6206
gE\ E and gEVAR\ EPool gEALL DOUBLES0.33080.61650.1380
CD40L0.48010.22310.1503
IFNγ0.92590.29110.1157
IL20.43061.00000.0678
TNFα0.97970.63430.0646
VarilrixALL DOUBLES0.54470.76700.0227
CD40L0.24900.99130.8265
IFNγ0.49400.53950.0801
IL20.07050.18270.0264
TNFα0.62000.77540.1098
VAR/E = Varilrix/50-70 yearsgE/E = gE-AS1/50-70 yearsgEVAR/E = gE-AS1+Varilrix/50-70 years
LIST OF TABLES- LYMPHOPROLIFERATIONPAGE
Table L.1
Descriptive statistics on the Stimulating Index for lymphoproliferation (ATP cohort for immunogenicity) .....
Table L.2
Lymphoproliferation: Geometric Mean (ATP cohort for immunogenicity) .....
Table L.3
Lymphoproliferation: Inferential statistics on Stimultaing Index (ATP cohort for immunogenicity) .....
Table L.4
Lymphoproliferation: Fold increase in Geometric Mean (GMR) (ATP cohort for immunogenicity) .....
0,1CPAU/mlVZVVAR/EDay044127.4035.811.069.9017.2233.96221.53
Month 144129.8225.700.949.3623.6645.6692.16
Month 243227.5017.975.6113.9024.0134.6295.32
Month 343229.3424.536.7213.6220.5536.93124.46
gE/EDay043221.8617.721.219.6617.7628.1591.05
Month 142328.3623.992.5512.1321.8531.99107.18
Month 242327.4722.901.6214.8520.7132.88138.04
Month 342328.5217.802.1615.2824.9240.8787.26
gE/YDay 010037.5016.319.3628.8533.8843.1167.30
Month 19142.8728.455.4224.8938.0444.23102.82
Month 210047.7829.7312.3524.7942.9163.27108.21
Month 310047.7725.648.8725.9844.7974.2782.49
gEVAR/EDay042219.3021.141.356.2717.7922.49136.88
Month 142228.6318.393.3115.0821.6944.1368.92
Month 242230.9224.151.9711.9723.0649.9296.33
Month 343137.5129.044.4519.9229.9843.02142.50
gEVAR/YDay010049.6422.4229.4539.2241.2857.67106.72
Month 110054.4329.4418.4227.5349.9677.50105.66
Month 29151.8324.7411.0734.8752.8574.3482.69
Month 310047.6921.3716.1934.2750.7966.2577.75
1 CPAU/mlVZVVAR/EDay 044135.7329.280.8115.4727.3249.16143.45
Month 144143.0828.021.5822.6734.4358.49122.15
Month 243250.1687.0012.2723.1634.6841.08586.25
Month 343236.0223.738.5617.3628.6346.93116.31
gE/EDay 043232.5426.564.5917.9127.8839.18139.71
Month 142335.0225.591.5419.9728.3237.30110.93
Month 242335.7322.521.4621.9131.2041.19107.68
Month 342337.3419.848.3720.3632.5552.9285.04
gE/YDay 010043.9723.269.3031.0543.4353.0287.99
Month 19151.1035.476.3137.6044.4257.47132.58
Month 210054.2420.5816.7344.2051.5371.0288.07
Month 310056.0437.1913.7235.8445.3168.27143.80
gEVAR/EDay 042229.1324.911.2012.5423.7039.25146.46
Month 142239.1023.603.0122.2833.1852.91108.05
Month 242241.1126.677.6721.9035.0055.75126.34
Month 343146.6733.813.9824.3435.1164.97151.51
gEVAR/YDay 010059.6032.7527.6639.9046.2675.47138.10
Month 110071.9045.9221.9524.5461.95117.28145.08
Month 29168.7136.1628.7734.8969.0194.82128.29
Month 310067.5034.9018.2936.6762.0392.64118.24
20 µg/mlgEVAR/EDay 04412.853.080.771.241.682.8114.30
Month 14413.533.870.571.342.034.3120.96
Month 24324.095.080.861.542.124.6430.33
Month 34323.663.010.601.532.485.7214.05
gE/EDay 04323.455.780.781.111.932.9937.21
Month 142312.6910.720.765.418.8817.6345.95
Month 242311.7611.430.934.358.4414.4651.08
Month 342330.3421.831.9715.6921.1640.12101.46
gE/YDay01002.621.241.011.752.183.714.88
Month 19119.0915.692.176.6713.1235.8143.15
Month 210025.5018.519.3710.3116.6732.6160.58
Month 310037.4621.694.7227.7831.1152.8476.56
gEVAR/EDay04223.847.700.591.171.493.6149.50
Month 14229.789.700.943.826.4412.7449.37
Month 24229.898.260.793.888.9013.3043.68
Month 343134.0325.883.0114.9230.6945.24117.38
gEVAR/YDay 01005.785.631.852.423.267.5320.39
Month 110019.8016.755.899.8013.7718.3851.54
Month 29124.3814.388.009.0322.4038.4944.11
Month 310033.1719.706.7211.1532.5052.4558.00
4 µg/mlgEVAR/EDay 04412.192.640.671.141.372.3014.80
Month 14413.473.550.261.311.874.7017.20
Month 24322.862.940.621.101.523.5515.40
Month 34323.302.690.471.362.364.2011.36
gE/EDay 04322.744.000.291.041.373.2425.55
Month 142310.0812.660.652.844.4914.4967.46
Month 24238.078.230.872.884.0210.1638.39
Month 342328.1321.361.7814.5820.8336.28104.34
gE/YDay01002.851.950.851.122.703.696.21
Month 19114.3915.260.835.179.0613.7349.06
Month 210019.8114.604.719.7513.6428.9951.20
Month 310032.5317.613.9326.8432.6043.7156.99
gEVAR/EDay 04223.306.690.661.111.562.6443.49
Month 14227.409.690.882.334.808.1058.76
Month 24226.946.770.912.255.379.2840.34
Month 343130.4525.084.029.6324.4243.85110.76
gEVAR/YDay01004.153.071.311.912.855.6510.99
Month 110015.9610.923.8610.9613.0015.9840.77
Month 29121.5714.613.088.9122.2026.8247.30
Month 310030.1119.583.588.6130.1351.6654.23
gE/Y = gE-AS1/18-30 years; gEVAR/Y = gE-AS1+Varilrix/18-30 years; VAR/E = Varilrix/50-70 years; gE/E = gE-AS1/50-70 years; gEVAR/E = gE-AS1+Varilrix/50-70 years; N = number of subjects with available results; N miss.= number of subjects with missing results; SD = Standard Deviation; Min, Max = Minimum, Maximum; Q1,Q3 = First , Third quartile
O,1CPAU/mlVZVVAR/EDay044115.691.06221.53
Month 144119.100.9492.16
Month 243222.625.6195.32
Month 343222.776.72124.46
gE/EDay043215.381.2191.05
Month 142320.482.55107.18
Month 242321.231.62138.04
Month 342322.602.1687.26
gE/YDay 010033.699.3667.30
Month 19133.795.42102.82
Month 210039.6612.35108.21
Month 310040.088.8782.49
gEVAR/EDay042212.941.35136.88
Month 142222.673.3168.92
Month 242222.031.9796.33
Month 343128.624.45142.50
gEVAR/YDay010046.2829.45106.72
Month 110046.6818.42105.66
Month 29144.8711.0782.69
Month 310042.4816.1977.75
1 CPAU/mlVZVVAR/EDay 044122.890.81143.45
Month 144133.481.58122.15
Month 243234.4412.27586.25
Month 343229.768.56116.31
gE/EDay 043224.614.59139.71
Month 142327.631.54110.93
Month 242329.721.46107.68
Month 342331.848.3785.04
gE/YDay 010037.539.3087.99
Month 19139.836.31132.58
Month 210049.8916.7388.07
Month 310046.6013.72143.80
gEVAR/EDay 042220.591.20146.46
Month 142232.043.01108.05
Month 242233.527.67126.34
Month 343135.943.98151.51
gEVAR/YDay 010053.4427.66138.10
Month 110057.7621.95145.08
Month 29160.2828.77128.29
Month 310058.4418.29118.24
20 µg/mlgEVAR/EDay 04412.050.7714.30
Month 14412.410.5720.96
Month 24322.750.8630.33
Month 34322.710.6014.05
gE/EDay04322.150.7837.21
Month 14238.480.7645.95
Month 24237.760.9351.08
Month 342323.311.97101.46
gE/YDay01002.361.014.88
Month 19112.712.1743.15
Month 210020.509.3760.58
Month 310030.144.7276.56
gEVAR/EDay 04222.080.5949.50
Month 14226.680.9449.37
Month 24227.090.7943.68
Month 343125.273.01117.38
gEVAR/YDay 01004.291.8520.39
Month 110015.215.8951.54
Month 29120.068.0044.11
Month 310026.116.7258.00
4 µg/mlgEVAR/EDay 04411.630.6714.80
Month 14412.370.2617.20
Month 24322.030.6215.40
Month 34322.480.4711.36
gE/EDay 04321.750.2925.55
Month 14235.740.6567.46
Month 24235.360.8738.39
Month 342320.951.78104.34
gE/YDay 01002.260.856.21
Month 1918.550.8349.06
Month 210015.554.7151.20
Month 310025.273.9356.99
gEVAR/EDay 04221.940.6643.49
Month 14224.640.8858.76
Month 24224.900.9140.34
Month 343121.474.02110.76
gEVAR/YDay01003.311.3110.99
Month 110013.143.8640.77
Month 29116.143.0847.30
Month 310022.093.5854.23
gE/Y = gE-AS1/18-30 years gEVAR/Y = gE-AS1+Varilrix/18-30 years VAR/E = Varilrix/50-70 yearsgE/E = gE-AS1/50-70 years gEVAR/E = gE-AS1+Varilrix/50-70 years N = number of subjects with available resultsN miss.= number of subjects with missing results GMT= Geometric Mean TiterLL,UL= Lower, Upper Limit of 95% confidence interval Min, Max = Minimum, Maximum
gE\ Y and GEVAR\ Y0,1CPAU/mlVZVDay 00.1509
Month 10.3272
Month 20.6242
Month 30.8206
1 CPAU/mlVZVDay 00.3643
Month 10.3691
Month 20.5676
Month 30.3643
20 µg/mlgEDay 00.0963
Month 10.7440
Month 20.8065
Month 30.7624
4 µg/mlgEDay 00.2899
Month 10.3691
Month 20.9349
Month 30.7624
VAR\ E and gE\ E0,1CPAU/mlVZVDay 00.9594
Month 10.9037
Month 20.7317
Month 30.6226
1 CPAU/mlVZVDay 00.6899
Month 10.1062
Month 20.5041
Month 30.4657
20 µg/mlgEDay 00.9526
Month 10.0000
Month 20.0000
Month 30.0000
4 µg/mlgEDay 00.7342
Month 10.0002
Month 20.0000
Month 30.0000
gE\ E and gEVAR\ E0,1CPAU/mlVzAgDay 00.3794
Month 10.5489
Month 20.6939
Month 30.1903
1 CPAU/mlVzAgDay 00.5097
Month 10.2412
Month 20.3855
Month 30.3653
20 µg/mlgEDay 00.6226
Month 10.1375
Month 20.6164
Month 30.5737
4 µg/mlgEDay 00.6226
Month 10.4524
Month 20.8161
Month 30.9160
VAR\ E and gEVAR\ E0,1CPAU/mlVzAgDay 00.5059
Month 10.5922
Month 20.8812
Month 30.0913
1 CPAU/mlVzAgDay 00.2688
Month 10.5803
Month 20.7450
Month 30.1253
20 µg/mlgEDay 00.7690
Month 10.0000
Month 20.0000
Month 30.0000
4 µg/mlgEDay 00.3553
Month 10.0016
Month 20.0000
Month 30.0000
gE/Y = gE-AS1/18-30 years gEVAR/Y = gE-AS1+Varilrix/18-30 years VAR/E = Varilrix/50-70 yearsgE/E = gE-AS1/50-70 years gEVAR/E = gE-AS1+Varilrix/50-70 years
0,1CPAU/mlVZVVAR/EMonth1/Month04321.541.012.340.0427.05
Month2/Month04231.651.052.580.0952.56
Month3/Month04232.041.392.990.2948.92
gE/EMonth1/Month04141.391.011.920.1518.32
Month2/Month04141.420.942.120.0220.08
Month3/Month04141.861.382.520.1314.83
gE/YMonth1/Month0910.680.281.610.051.53
Month2/Month01001.010.731.400.441.72
Month3/Month01001.160.881.530.612.17
gEVAR/EMonth1/Month04042.101.453.040.1331.67
Month2/Month04042.061.363.110.0658.19
Month3/Month04133.222.284.540.8682.33
gEVAR/YMonth1/Month01000.870.631.200.341.44
Month2/Month0910.870.521.430.181.37
Month3/Month01000.640.371.110.121.06
1 CPAU/mlVZVVAR/EMonth1/Month04321.731.172.560.0686.17
Month2/Month04231.631.062.510.08124.71
Month3/Month04231.791.242.590.4770.57
gE/EMonth1/Month04141.180.901.530.0513.44
Month2/Month04141.160.821.640.0118.94
Month3/Month04141.641.232.180.0919.91
gE/YMonth1/Month0910.750.321.730.051.38
Month2/Month01001.140.911.420.781.81
Month3/Month01001.211.011.460.831.69
gEVAR/EMonth1/Month04041.851.402.430.4615.65
Month2/Month04041.821.332.490.1348.63
Month3/Month04132.521.883.380.8880.53
gEVAR/YMonth1/Month01000.930.751.170.481.33
Month2/Month0910.980.791.220.601.26
Month3/Month01000.760.461.260.151.29
20 µg/mlgEVAR/EMonth1/Month04321.351.041.750.1611.02
Month2/Month04231.461.101.940.2720.90
Month3/Month04231.901.422.540.3926.66
gE/EMonth1/Month04144.262.986.070.2274.67
Month2/Month04143.622.415.460.0528.79
Month3/Month041413.909.1621.070.31205.73
gE/YMonth1/Month0913.841.1712.650.1112.75
Month2/Month01007.455.1510.773.9115.23
Month3/Month010012.507.4121.103.1437.77
gEVAR/EMonth1/Month04043.892.905.220.9528.69
Month2/Month04043.862.545.870.0338.27
Month3/Month041317.9212.6525.381.38172.56
gEVAR/YMonth1/Month01003.071.406.720.3815.77
Month2/Month0914.092.107.981.8515.42
Month3/Month01004.251.6011.300.2815.60
4 µg/mlgEVAR/EMonth1/Month04321.751.362.250.088.82
Month2/Month04231.401.031.890.1236.27
Month3/Month04232.171.602.950.5166.05
gE/EMonth1/Month04143.322.344.690.3136.29
Month2/Month04143.102.024.760.0425.22
Month3/Month041414.329.3921.820.26110.97
gE/YMonth1/Month0912.880.7511.060.0721.03
Month2/Month01005.913.3210.522.4931.74
Month3/Month010010.955.6221.373.0748.19
gEVAR/EMonth1/Month04042.902.263.710.5422.40
Month2/Month04042.962.084.210.1035.98
Month3/Month041316.4011.6223.151.51237.09
gEVAR/YMonth1/Month01003.431.617.320.4116.60
Month2/Month0913.981.769.010.9131.37
Month3/Month01004.651.7212.600.3019.48
gE/Y = gE-AS1/18-30 yearsgEVAR/Y = gE-AS1+Varilrix/18-30 yearsVAR/E = Varilrix/50-70 yearsgE/E = gE-AS1/50-70 yearsgEVAR/E = gE-AS1+Varilrix/50-70 yearsN = number of subjects with available resultsN miss.= number of subjects with missing resultsGMR= Geometric Mean ratioLL,UL= Lower, Upper Limit of 95% confidence interval for GMRMin, Max = Minimum, Maximum
Conclusions
The gE AS 1 vaccine and the concomitant delivery of gE AS 1 with the OKA strain both provoke a good immune response in comparison to the response obtained by the OKA strain alone.
Example 3
Immunogenicity was tested of different doses of gE (25, 50 and 100 µg) with or without AS1 adjuvant and of different schedules of administration (1 vaccination with 100 µg of gE versus 2 vaccinations with different doses of gE) in the elderly population (≥60 YOA). Five experimental groups were set up as follows:
gE251BgE 25 µg + AS10,2
gE501BgE 50 µg + AS10,2
gE1001BgE 100µg + AS10,2
gE100SgE 100 µg + Saline0,2
S gE1BSaline0
gE 100 µg + AS12
Human volunteers were selected to ensure a 1:4 ratio of the tested population across two aga strata, ie 60-69 YOA and ≥70 YOA.
The adjuvant AS1 formulation contained 1000 µg of dioleylphosphatidylcholine (DOPC), 250 µg of cholesterol, 50 µg of MPL and 50 µg of QS21 per 0.5 mL dose in phosphate buffer and can be obtained as described for example 2.
The Saline formulation contained 150 mM NaCl.
The truncated gE as described for example 2 was used and was provided in lyophilised form as monodos vials containing 62.5 µg of recombinant purified gE in saccharose and phosphate buffer.
The vaccines for administration were obtained by reconstituting the vaccine immediately prior to injection (maximum one hour before injection). Vaccine formulations were as follows:
  • gE251B - 25 µg dose: 1 vial of gE reconstituted with 2 vials of AS1 and injection of 0.5 mL of the reconstituted vaccine
  • 50 µg dose: 1 vial of gE reconstituted with 1 vial of AS1 and injection of 0.5 mL of the reconstituted vaccine
  • 100 µg dose: 2 vials of gE reconstituted with 1 vial of AS1 and injection of 0.5 mL of the reconstituted vaccine
In the control group, where gE was administered without the AS1 adjuvant, the lyophilised gE antigen was reconstituted with Saline immediately prior to injection (maximum one hour before injection) as follows:
  • 100 µg dose: 2 vials of gE reconstituted with 1 vial of Saline and injection of 0.5 mL of the reconstituted vaccine
Immunogenicity and/or efficacy of the vaccinations was evaluated on the basis of both humoral and cell mediated immune respons. Results of the experiment are shown hereunder.
Cell mediated immune respons
Specific CMI was evaluated as follows: IFN-γ and/or IL-2, TNF-α, CD40L, CD4/CD8 T cell response by ICS using Cytokine Flow Cytometry (CFC, see example 2) after stimulation by the gE protein.
- Frequency of gE-specific CD4 T cells producing at least two different cytokines following 2 vaccinations (Month 3)
Descriptive statistics of the frequency of gE-specific CD4 T cells producing at least 2 cytokines (all doubles) in response to gE, overall and by age cohort, are presented in Table C.5 and Table C.6, respectively. The frequency of gE-specific CD4 T cells is the difference between the frequency at induction by gE and the frequency at background. When null or negative, the value was reported as 1 gE-specific CD4 T cell per million CD4 T cells in order to allow using logarithm-transformation prior to analysis. Descriptive Statistics of Frequency of gE-specific CD4 T Cells Secreting at Least 2 Different Cytokines (ALL DOUBLES Cytokines) per Million Cells - ATP Cohort for Immunogenicity
PRE(D0)gE251B152194.47214.961.0055.07151.20260.531654.55
gE501B146225.47370.671.0062.30122.18290.223238.46
gE1001B142201.17230.961.0036.32159.55272.281719.38
SgE1B149203.70221.970.2159.50137.57256.881256.29
gE100S48145.95164.571.0036.81110.70199.59884.72
PI(M2)gE251B152459.01401.251.00217.97368.54554.612794.49
gE501B150482.84425.730.87236.79382.57615.513442.70
gE1001B142489.45423.521.00215.02376.97614.822537.94
S gE1B150173.91181.861.0045.55121.59255.71955.56
gE100S48230.28250.701.0056.66134.93346.051292.10
PII(M3)gE251B1512246.291976.4230.09946.281751.752882.5412280.75
gE501B1482372.071877.43194.231210.801755.392987.7112841.61
gE1001B1442569.292052.74218.661155.401792.203458.0914020.93
S gE1B148670.80606.931.00328.65524.87777.554516.89
gE100S47550.11448.151.00250.00468.30636.311873.65
 Descriptive Statistics of Frequency of gE-specific CD4 T Cells Secreting at Least 2 Different Cytokines (ALL DOUBLES Cytokines) per Million Cells - ATP Cohort for Immunogenicity
1. gE251B = 25 µg gE/AS1; gE501B = 50 µg gE/AS1; gE1001B = 100 µg gE/AS1 S gE1B = Saline + 100 µg gE/AS1; gE100S =100 µg gE/Saline2. N = number of subjects in the subsets with available results3. SD = Standard Deviation; Q1, Q3 = First and third quartiles; MIN/MAX = Minimum/Maximum4. PRE(D0) = Pre-vaccination at Day 0; PI(M2) = Post-vaccination 1 at Month 2; PII(M3) = Post-vaccination 2 at Month 3
 Descriptive Statistics of Frequency of gE-specific CD4 T Cells Secreting at Least 2 Different Cytokines (ALL DOUBLES Cytokines) per Million Cells by age Cohort - ATP Cohort for Immunogenicity
60-69yPRE(D0)gE251B31173.55175.601.0064.17165.59214.58890.30
gE501B23159.68127.971.0073.29134.28268.76451.97
gE1001B25206.84234.371.0022.55159.92213.551037.53
S gE1B29243.91212.089.5383.01216.42305.161074.26
gE100S11128.5082.341.0041.47124.86195.22263.04
PI(M2)gE251B30450.12311.601.00209.80353.71672.761238.41
gE501B28490.02338.8992.44236.17404.75661.211359.15
gE1001B25541.36454.921.00281.97466.02683.232237.14
S gE1B29161.54152.951.0035.44108.84255.71489.00
gE100S11222.19281.641.0098.66116.29338.351003.27
PII(M3)gE251B322158.752155.36159.591058.541748.302605.1011892.07
gE501B282072.59679.031117.251518.841909.782702.293264.07
gE1001B273086.652872.14218.661267.762549.454596.5314020.93
S gE1B30627.81282.47154.06398.05639.08813.321306.21
gE100S11673.01388.22143.11468.30601.09892.651603.47
70y+PRE(D0)gE251B121199.84224.271.0053.37150.26296.111654.55
gE501B123237.77399.221.0058.96118.34299.263238.46
gE1001B117199.96231.231.0038.88151.98272.281719.38
S gE1B120193.99224.070.2148.23127.69235.621256.29
gE100S37151.14182.631.0036.6496.48203.96884.72
PI(M2)gE251B122461.20421.461.00220.09372.72514.132794.49
gE501B122481.19444.460.87236.79382.57600.563442.70
gE1001B117478.36417.741.00215.02355.22599.022537.94
S gE1B121176.88188.581.0051.57123.16250.71955.56
gE100S37232.69244.941.0041.92160.89362.281292.10
PII(M3)gE251B1192269.841934.5530.09907.171801.232930.7112280.75
gE501B1202441.952055.11194.231172.961722.833229.7312841.61
gE1001B1172449.901808.00256.631154.881778.483407.917963.65
S gE1B118681.73665.171.00320.65491.03768.174516.89
gE100S36512.55463.351.00208.57388.49610.661873.65
 Descriptive Statistics of Frequency of gE-specific CD4 T Cells Secreting at Least 2 Different Cytokines (ALL DOUBLES Cytokines) per Million Cells by age Cohort - ATP Cohort for Immunogenicity
1. 60-69y = 60-69 YOA; 70y+ = ≥ 70 YOA2. gE251B = 25 µg gE/AS1; gE501B = 50 µg gE/AS1; gE1001B = 100 µg gE/AS1 S gE1B = Saline + 100 µg gE/AS1; gE100S =100 µg gE/Saline3. N = number of subjects in the subsets with available results4. SD = Standard Deviation; Q1, Q3 = First and third quartiles; MIN/MAX = Minimum/Maximum5. PRE(D0) = Pre-vaccination at Day 0; PI(M2) = Post-vaccination 1 at Month 2; PII(M3) = Post-vaccination 2 at Month 3
- Comparison of gE-specific frequency response to gE between vaccine formulations
Statistical analysis based on the rank-transformation of the frequency of gE-specific CD4 T cells identified as secreting at least 2 cytokines (all doubles) using a 1-way ANOVA (t-test) overall and by age cohort, are presented in Table C.7 and Table C.8, respectively. The median frequencies at Month 3 are presented together with the 1-sided p-values of the rank difference with the best treatment, adjusted according to Hsu's procedure for multiple comparisons against the best treatment. Median of Frequency of gE-specific CD4 T Cell Secreting ALL DOUBLES Cytokines at Month 3 and p-Values for Multiple Comparisons with Best Between Vaccine Groups According to Hsu's Procedure - ATP Cohort for Immunogenicity
gE251B946.281751.752882.540.0952
gE501B1210.801755.392987.710.6241
gE1001B1155.401792.203458.09.
SgE1B328.65524.87777.55< 0.0001
gE100S250.00468.30636.31< 0.0001
 Median of Frequency of gE-specific CD4 T Cell Secreting ALL DOUBLES Cytokines at Month 3 and p-Values for Multiple Comparisons with Best Between Vaccine Groups According to Hsu's Procedure - ATP Cohort for Immunogenicity
gE251B = 25 µg gE/AS1; gE501B = 50 µg gE/AS1; gE1001B = 100 µg gE/AS1S gE1B = Saline + 100 µg gE/AS1; gE100S =100 µg gE/SalineInferiority to the Best Treatment p-value = The smallest α-level at which the population mean of this group can be rejected as the best treatmentMedian estimates are provided as rank-transformation was used; Normalisation using rank transformation
 Median of Frequency of gE-specific CD4 T Cell Secreting ALL DOUBLES Cytokines at Month 3 and p-Values for Multiple Comparisons with Best Between Vaccine Groups According to Hsu's Procedure by age Cohort - ATP Cohort for Immunogenicity
60-69ygE251B1058.541748.302605.100.1214
gE501B1518.841909.782702.290.5635
gE1001B1267.762549.454596.53.
S gE1B398.05639.08813.32< 0.0001
gE100S468.30601.09892.65< 0.0001
70y+gE251B907.171801.232930.710.2997
gE501B1172.961722.833229.730.7449
gE1001B1154.881778.483407.91.
S gE1B320.65491.03768.17< 0.0001
gE100S208.57388.49610.66< 0.0001
 Median of Frequency of gE-specific CD4 T Cell Secreting ALL DOUBLES Cytokines at Month 3 and p-Values for Multiple Comparisons with Best Between Vaccine Groups According to Hsu's Procedure by age Cohort - ATP Cohort for Immunogenicity
60-69y = 60-69 YOA; 70y+ = ≥ 70 YOAgE251B = 25 µg gE/AS1; gE501B = 50 µg gE/AS1; gE1001B = 100 µg gE/AS1S gE1B = Saline + 100 µg gE/AS1; gE100S = 100 µg gE/SalineInferiority to the Best Treatment p-value = The smallest α-level at which the population mean of this group can be rejected as the best treatmentMedian estimates are provided as rank-transformation was used; Normalisation using rank transformation
- Frequency odds ratio over background for gE-specific CD4 T cells producing at least 2 cytokines following 2 vaccinations (Month 3)
For small frequencies of cytokine-secreting CD4 T cells, the frequency odds are numerically very close to the frequency itself. As a consequence, frequency odds ratio over background may be interpreted as the fold increase in gE antigen-specific CD4 T cell response, following induction, as compared to non-specific cytokine-secreting CD4 T cell level (background).
Descriptive statistics of the frequency odds ratio of gE-specific CD4 T cells identified as producing at least 2 cytokines (all doubles), overall and by age cohort, are presented in Table C.9 and Table C.10, respectively. Descriptive Statistics of Frequency Odds Ratio of gE-specific CD4 T Cells Secreting at Least 2 Different Cytokines (ALL DOUBLES) - ATP Cohort for Immunogenicity
PRE(D0)gE251B1521.981.140.471.261.662.459.40
gE501B1463.147.460.421.291.602.4871.71
gE1001B1422.202.300.341.181.682.3420.12
S gE1B1493.148.370.331.281.702.7492.02
gE100S481.851.160.601.151.621.977.32
PI(M2)gE251B1524.034.080.791.922.764.3728.44
gE501B1504.164.650.421.902.824.4833.69
gE1001B1424.314.830.752.043.124.5646.82
S gE1B1502.653.850.141.231.632.7433.76
gE100S482.784.380.851.261.922.7131.29
PII(M3)gE251B15112.9613.451.105.128.8915.6296.62
gE501B14814.2814.731.865.399.2416.5185.94
gE1001B14421.1665.171.865.7510.5821.81779.89
S gE1B1486.4010.110.332.364.006.7398.54
gE100S474.213.160.812.073.235.1614.71
 Descriptive Statistics of Frequency Odds Ratio of gE-specific CD4 T Cells Secreting at Least 2 Different Cytokines (ALL DOUBLES) - ATP Cohort for Immunogenicity
gE251B =25 µg gE/AS1; gE501b = 50 µg gE/AS1; gE1001B = 100 µg gE/AS1S gE1B = Saline + 100 µg gE/AS1; gE100S =100 µg gE/SalineN = number of subjects in the subsets with available resultsSD = Standard Deviation; Q1,Q3 = First and third quartiles; MIN/MAX = Minimum/MaximumPRE(D0) = Pre-vaccination at Day 0; PI(M2) = Post-vaccination 1 at Month 2; PII(M3) = Post-vaccination 2 at Month 3The odds-ratios are calculated using the the frequency of CD4 secreting cytokines, upon in vitro stimulation with the specific antigen, at the numerator and the frequency of the CD4 secreting cytokines with the medium only (background level) at the denominator. The odds-ratios represent the fold-increase in the specific response compared to the background level. The odds (f / 1-f) and the raw frequencies (f) are numerically equivalent and may be interpreted the same way due to the very low frequencies of CD4 secreting cytokines over the total CD4.
 Descriptive Statistics of Frequency Odds Ratio of gE-specific CD4 T Cells Secreting at Least 2 Different Cytokines: ALL DOUBLES Cytokines by age Cohort - ATP Cohort for Immunogenicity
60-69yPRE(D0)gE251B311.860.750.471.341.722.373.69
gE501B231.861.070.701.291.552.145.50
gE1001B251.930.990.531.091.752.654.81
S gE1B294.108.341.071.592.062.8345.64
gE100S112.301.890.891.151.592.337.32
PI(M2)gE251B304.535.060.952.282.924.2628.44
gE501B283.522.671.241.882.624.4111.93
gE1001B254.402.930.752.443.845.1013.91
S gE1B292.622.860.141.201.662.7413.86
gE100S112.311.460.941.171.443.755.06
PII(M3)gE251B3213.4214.801.674.329.0015.5571.13
gE501B2811.197.773.465.998.8214.4634.77
gE1001B2719.5215.911.867.4314.8629.1164.63
S gE1B308.2912.031.752.854.438.3165.43
gE100S114.743.101.772.644.155.1612.37
70y+PRE(D0)gE251B1212.011.230.621.241.652.479.40
gE501B1233.388.100.421.281.662.5971.71
gE1001B1172.262.490.341.191.652.1120.12
S gE1B1202.918.390.331.221.562.6792.02
gE100S371.720.820.601.161.651.964.40
PI(M2)gE251B1223.903.820.791.872.764.4725.63
gE501B1224.304.990.421.932.994.4833.69
gE1001B1174.295.160.952.022.944.4546.82
S gE1B1212.664.060.151.251.622.6633.76
gE100S372.924.940.851.281.932.4331.29
PII(M3)gE251B11912.8313.131.105.378.8315.7296.62
gE501B12015.0015.861.865.279.5718.6085.94
gE1001B11721.5371.962.415.6610.3421.03779.89
S gE1B1185.929.560.332.233.916.6698.54
gE100S364.053.200.811.892.935.3714.71
 Descriptive Statistics of Frequency Odds Ratio of gE-specific CD4 T Cells Secreting at Least 2 Different Cytokines: ALL DOUBLES Cytokines by age Cohort - ATP Cohort for Immunogenicity
60-69y = 60-69 YOA; 70y+ = ≥ 70 YOAgE251B = 25 µg gE/AS1; gE501B = 50 µg gE/AS1; gE1001B = 100 µg gE/AS1S gE1B = Saline + 100 µg gE/AS1; gE100S =100 µg gE/SalineN = number of subjects in the subsets with available resultsSD = Standard Deviation; Q1,Q3 = First and third quartiles; MIN/MAX = Minimum/MaximumPRE(D0) = Pre-vaccination at Day 0; PI(M2) = Post-vaccination 1 at Month 2; PII(M3) = Post-vaccination 2 at Month 3The odds-ratios are calculated using the the frequency of CD4 secreting cytokines, upon in vitro stimulation with the specific antigen, at the numerator and the frequency of the CD4 secreting cytokines with the medium only (background level) at the denominator. The odds-ratios represent the fold-increase in the specific response compared to the background level. The odds (f / 1-f) and the raw frequencies (f) are numerically equivalent and may be interpreted the same way due to the very low frequencies of CD4 secreting cytokines over the total CD4.
Humoral immunity
Humoral response was evaluated on the basis of the anti-gE and anti-VZV antibody concentrations measured using classical ELISA assays.
-Anti-gE antibodies
Seropositivity Rates and Geometric Mean Concentrations of Anti-gE Antibodies - ATP Cohort for Immunogenicity
gE251BPRE(D0)15714793.688.696.9351.6306.2403.8<109.03624.0
PI(M2)15715710097.71003667.63158.64258.7275.032783.0
PII(M3)15515510097.61009315.38283.210476.11016.038632.0
gE501BPRE(D0)15614190.484.694.5312.8268.1365.0<109.08659.0
PI(M2)15615498.795.499.84139.43443.84975.4<109.042265.0
PII(M3)15615610097.710012898.011681.214241.6716.052743.0
gE1001BPRE(D0)15114596.091.698.5416.1355.0487.7<109.074430.0
PI(M2)15115110097.61005485.64657.26461.3219.040878.0
PII(M3)15115110097.610015626.514030.317404.32149.0159531.0
S gE1BPRE(D0)15314494.189.197.3337.2285.8397.7<109.022206.0
PI(M2)15314494.189.197.3361.5304.6429.0<109.017261.0
PII(M3)15315310097.61006287.25372.07358.3668.0132861.0
gE100SPRE(D0)504692.080.897.8323.7245.2427.3<109.04659.0
PI(M2)504998.089.499.92148.91461.83158.9<109.016410.0
PII(M3)494910092.71004298.33220.05737.7229.020228.0
 Seropositivity Rates and Geometric Mean Concentrations of Anti-gE Antibodies - ATP Cohort for Immunogenicity
gE251B = 25 µg gE/AS1; gE501B = 50 µg gE/AS1; gE1001B = 100 µg gE/AS1; S gE1B = Saline + 100 µggE/AS1; gE100S = 100 µg gE/Saline; N = Number of subjects with available results; MIN/MAX = Minimum/Maximum; n/% = number/percentage of seropositive subjects (anti-gE Ab concentration ≥ 109 EU/mL);GMC = Geometric Mean Concentration; 95% CI = 95% confidence interval, LL = Lower Limit, UL = Upper Limit;PRE(D0) = Pre-vaccination at Day 0; PI(M2) = Post-vaccination 1 at Month 2; PII(M3) = Post-vaccination 2 at Month 3
 Seropositivity Rates and Geometric Mean Concentrations of Anti-gE Antibodies by age Cohort- ATP Cohort for Immunogenicity
60-69ygE251BPRE(D0)323210089.1100465.2350.4617.5142.03624.0
PI(M2)323210089.11005002.83651.86853.6743.032783.0
PII(M3)323210089.110012131.99522.115457.03630.038632.0
gE501BPRE(D0)292793.177.299.2335.2239.3469.6<109.02862.0
PI(M2)292910088.11006500.24954.88527.61272.019130.0
PII(M3)292910088.110013105.910736.015998.84396.052743.0
gE1001BPRE(D0)292896.682.299.9357.8255.6500.8<109.02297.0
PI(M2)292910088.11007283.45175.110250.8817.035296.0
PII(M3)292910088.110020900.016799.426001.48396.080812.0
S gE1BPRE(D0)312890.374.298.0294.0210.4410.9<109.02390.0
PI(M2)312787.170.296.4298.4205.1434.1<109.02268.0
PII(M3)313110088.81008863.96292.812485.51326.0132861.0
gE100SPRE(D0)111110071.5100457.0322.0648.7255.01406.0
PI(M2)111110071.51003956.62134.47334.4728.016410.0
PII(M3)111110071.51005627.93431.39230.71572.018291.0
70y+gE251BPRE(D0)12511592.085.896.1327.3279.6383.0<109.02901.0
PI(M2)12512510097.11003387.42861.54010.0275.032413.0
PII(M3)12312310097.01008696.67615.19931.81016.037829.0
gE501BPRE(D0)12711489.883.194.4307.9258.5366.8<109.08659.0
PI(M2)12712598.494.499.83734.13012.84627.9<109.042265.0
PII(M3)12712710097.110012851.011466.014403.3716.038250.0
gE1001BPRE(D0)12211795.990.798.7431.3359.8517.0<109.074430.0
PI(M2)12212210097.01005128.14258.76175.1219.040878.0
PII(M3)12212210097.010014582.912921.716457.62149.0159531.0
S gE1BPRE(D0)12211695.189.698.2349.1288.5422.5<109.022206.0
PI(M2)12211795.990.798.7379.6312.6460.8<109.017261.0
PII(M3)12212210097.01005761.84831.96870.7668.097614.0
gE100SPRE(D0)393589.775.897.1293.7208.6413.5<109.04659.0
PI(M2)393897.486.599.91809.01142.62864.2<109.012551.0
PII(M3)383810090.71003975.72800.15644.8229.020228.0
 Seropositivity Rates and Geometric Mean Concentrations of Anti-gE Antibodies by age Cohort- ATP Cohort for Immunogenicity
60-69y = 60-69 YOA ; 70y+ = ≥ 70 YOAgE251B = 25 µg gE/AS1; gE501B = 50 µg gE/AS1; gE1001B = 100 µg gE/AS1S gE1B = Saline + 100 µg gE/AS1; gE100S =100 µg gE/SalineN = Number of subjects with available results; MIN/MAX = Minimum/Maximumn/% = number/percentage of seropositive subjects (anti-gE Ab concentration ≥ 109 EU/mL)GMC = Geometric Mean Concentration; 95% CI = 95% confidence interval, LL = Lower Limit, UL = Upper Limit PRE(D0) = Pre-vaccination at Day 0; PI(M2) = Post-vaccination 1 at Month 2; PII(M3) = Post-vaccination 2 at Month 3
Vaccine response rates for anti-gE Abs, overall and by age cohort, are presented in Table I.6 and Table I.7, respectively. Vaccine response is defined as an anti-gE Ab concentration ≥ 109 EU/mL after vaccination for seronegative subjects at baseline and an increase in anti-gE Ab concentration after vaccination of ≥ 4-fold the pre-vaccination Ab concentration for seropositive subjects at baseline. Vaccine Response Rates for Anti-gE Antibodies at PI(M2) and PII(M3) - ATP Cohort for Immunogenicity
VZV-gE AbgE251BPI(M2)15713082.876.088.4
PII(M3)15514996.191.898.6
gE501BPI(M2)15613485.979.490.9
PII(M3)15615498.795.499.8
gE1001BPI(M2)15112985.478.890.6
PII(M3)15114898.094.399.6
S gE1BPI(M2)15342.60.76.6
PII(M3)15313990.885.194.9
gE100SPI(M2)503468.053.380.5
PII(M3)494489.877.896.6
 Vaccine Response Rates for Anti-gE Antibodies at PI(M2) and PII(M3) - ATP Cohort for Immunogenicity
gE251B = 25 µg gE/AS1; gE501B = 50 µg gE/AS1; gE1001B = 100 µg gE/AS1S gE1B = Saline + 100 µg gE/AS1; gE100S =100 µg gE/SalineVaccine response defined as:For initially seronegative subjects, anti-gE Ab concentration ≥ 109 EU/mL after vaccinationFor initially seropositive subjects, Ab concentration after vaccination ≥ 4-fold the pre-vaccination Ab concentrationN = Number of subjects with pre- and post-vaccination results availablen/% = Number/percentage of responders95% CI = 95% confidence interval, LL = Lower Limit, UL = Upper LimitPI(M2) = Post-vaccination 1 at Month 2; PII(M3) = Post-vaccination 2 at Month 3
 Vaccine Response Rates for Anti-gE Antibodies at PI(M2) and PII(M3) by age Cohort- ATP Cohort for Immunogenicity
VZV-gE Ab60-69ygE251BPI(M2)322784.467.294.7
PII(M3)323196.983.899.9
gE501BPI(M2)292896.682.299.9
PII(M3)292910088.1100
gE1001BPI(M2)292793.177.299.2
PII(M3)292910088.1100
S gE1BPI(M2)3113.20.116.7
PII(M3)313110088.8100
gE100SPI(M2)11981.848.297.7
PII(M3)111110071.5100
70y+gE251BPI(M2)12510382.474.688.6
PII(M3)12311895.990.898.7
gE501BPI(M2)12710683.575.889.5
PII(M3)12712598.494.499.8
gE1001BPI(M2)12210283.675.889.7
PII(M3)12211997.593.099.5
S gE1BPI(M2)12232.50.57.0
PII(M3)12210888.581.593.6
gE100SPI(M2)392564.147.278.8
PII(M3)383386.871.995.6
 Vaccine Response Rates for Anti-gE Antibodies at PI(M2) and PII(M3) by age Cohort- ATP Cohort for Immunogenicity
-Anti-VZV antibodies
Seropositivity Rates and Geometric Mean Concentrations of Anti-VZV Antibodies - ATP Cohort for Immunogenicity
gE251BPRE(D0)15715699.496.51001334.91181.91507.7<50.06844.0
PI(M2)15715699.496.51004408.13847.75050.1<50.038164.0
PII(M3)15515510097.61008821.67959.39777.41321.032598.0
gE501BPRE(D0)15615610097.71001212.01063.91380.764.012662.0
PI(M2)15615610097.71005131.94469.85892.0421.044613.0
PII(M3)15615610097.710011451.010507.912478.71524.049474.0
gE1001BPRE(D0)15115110097.61001510.71336.41707.7152.068382.0
PI(M2)15115110097.61006511.75723.17409.0508.033621.0
PII(M3)15115110097.610014143.512876.915534.72158.078040.0
S gE1BPRE(D0)15315310097.61001356.31184.91552.6117.036343.0
PI(M2)15315310097.61001341.61177.71528.3132.015272.0
PII(M3)15315310097.61006432.25591.87398.9808.074966.0
gE100SPRE(D0)505010092.91001422.51153.41754.5166.07368.0
PI(M2)505010092.91003481.22756.04397.3493.015656.0
PII(M3)494910092.71005357.64297.36679.4585.021567.0
 Seropositivity Rates and Geometric Mean Concentrations of Anti-VZV Antibodies - ATP Cohort for Immunogenicity
gE251B = 25 µg gE/AS1; gE501B = 50 µg gE/AS1; gE1001B = 100 µg gE/AS1S gE1B = Saline + 100 µg gE/AS1; gE100S =100 µg gE/SalineN = Number of subjects with available results; MIN/MAX = Minimum/Maximumn/% = number/percentage of seropositive subjects (anti-VZV Ab concentration ≥ 50 mIU/mL)GMC = Geometric Mean Concentration; 95% CI = 95% confidence interval, LL = Lower Limit, UL = Upper Limit PRE(D0) = Pre-vaccination at Day 0; PI(M2) = Post-vaccination 1 at Month 2; PII(M3) = Post-vaccination 2 at Month 3
 Seropositivity Rates and Geometric Mean Concentrations of Anti-VZV Antibodies by age Cohort - ATP Cohort for Immunogenicity
60-69ygE251BPRE(D0)323210089.11001630.31243.22137.8388.06844.0
PI(M2)323196.983.899.95202.23399.07961.9<50.034920.0
PII(M3)323210089.110011045.28954.313624.24235.032537.0
gE501BPRE(D0)292910088.11001566.91231.01994.4387.05856.0
PI(M2)292910088.11007683.05851.810087.12320.044613.0
PII(M3)292910088.110012090.110180.514358.06056.049474.0
gE1001BPRE(D0)292910088.11001250.8888.11761.6152.04981.0
PI(M2)292910088.11007698.05749.010307.91449.027693.0
PII(M3)292910088.110018330.915329.521920.07720.045039.0
S gE1BPRE(D0)313110088.81001285.71007.71640.5450.05590.0
PI(M2)313110088.81001320.31033.51686.6351.04632.0
PII(M3)313110088.81009053.56792.012067.91990.051504.0
gE100SPRE(D0)111110071.51001429.31034.31975.3708.03377.0
PI(M2)111110071.51004065.72768.95969.91223.012230.0
PII(M3)111110071.51005164.23630.17346.52783.012374.0
70y+gE251BPRE(D0)12512499.295.61001268.31106.31454.0<50.05221.0
PI(M2)12512510097.11004225.03692.74834.1503.038164.0
PII(M3)12312310097.01008320.57403.79350.81321.032598.0
gE501BPRE(D0)12712710097.11001143.0984.01327.664.012662.0
PI(M2)12712710097.11004680.14008.45464.4421.039159.0
PII(M3)12712710097.110011309.910245.012485.41524.040445.0
gE1001BPRE(D0)12212210097.01001580.11388.11798.6262.068382.0
PI(M2)12212210097.01006257.85413.27234.1508.033621.0
PII(M3)12212210097.010013298.011958.314787.72158.078040.0
S gE1BPRE(D0)12212210097.01001374.91172.51612.2117.036343.0
PI(M2)12212210097.01001347.11156.41569.3132.015272.0
PII(M3)12212210097.01005897.15036.06905.4808.074966.0
gE100SPRE(D0)393910091.01001420.61095.91841.6166.07368.0
PI(M2)393910091.01003332.12504.34433.6493.015656.0
PII(M3)383810090.71005414.94121.37114.5585.021567.0
 Seropositivity Rates and Geometric Mean Concentrations of Anti-VZV Antibodies by age Cohort - ATP Cohort for Immunogenicity
60-69y = 60-69 YOA ; 70y+ = ≥ 70 YOAgE251B = 25 µg gE/AS1; gE501B = 50 µg gE/AS1; gE1001B = 100 µg gE/AS1S gE1B = Saline + 100 µg gE/AS1; gE100S =100 µg gE/SalineN = Number of subjects with available results; MIN/MAX = Minimum/Maximumn/% = number/percentage of seropositive subjects (anti-VZV Ab concentration ≥ 50 mIU/mL)GMC = Geometric Mean Concentration; 95% CI = 95% confidence interval, LL = Lower Limit, UL = Upper Limit PRE(D0) = Pre-vaccination at Day 0; PI(M2) = Post-vaccination 1 at Month 2; PII(M3) = Post-vaccination 2 at Month 3
Vaccine response rates for anti-VZV Abs, overall and by age cohort, are presented in Table I.10 and Table I.11, respectively. Vaccine response is defined as an anti-VZV Ab concentration ≥ 50 mIU/mL after vaccination for seronegative subjects at baseline and as an increase in anti-VZV Ab concentration after vaccination of ≥ 4-fold the pre-vaccination Ab concentration for seropositive subjects at baseline. Vaccine Response Rates for Anti-VZV Antibodies at PI(M2) and PII(M3) - ATP Cohort for Immunogenicity
VZV IgGgE251BPI(M2)1575836.929.445.0
PII(M3)15510869.761.876.8
gE501BPI(M2)1568453.845.761.8
PII(M3)15612882.175.187.7
gE1001BPI(M2)1518153.645.461.8
PII(M3)15112280.873.686.7
S gE1BPI(M2)15300.00.02.4
PII(M3)1538152.944.761.1
gE100SPI(M2)501428.016.242.5
PII(M3)491938.825.253.8
 Vaccine Response Rates for Anti-VZV Antibodies at PI(M2) and PII(M3) - ATP Cohort for Immunogenicity
 Vaccine Response Rates for Anti-VZV Antibodies at PI(M2) and PII(M3) by age Cohort - ATP Cohort for Immunogenicity
VZV IgG60-69ygE251BPI(M2)321237.521.156.3
PII(M3)322371.953.386.3
gE501BPI(M2)291655.235.773.6
PII(M3)292275.956.589.7
gE1001BPI(M2)292069.049.284.7
PII(M3)292896.682.299.9
S gE1BPI(M2)3100.00.011.2
PII(M3)312271.052.085.8
gE100SPI(M2)11436.410.969.2
PII(M3)11436.410.969.2
70y+gE251BPI(M2)1254636.828.445.9
PII(M3)1238569.160.177.1
gE501BPI(M2)1276853.544.562.4
PII(M3)12710683.575.889.5
gE1001BPI(M2)1226150.040.859.2
PII(M3)1229477.068.684.2
S gE1BPI(M2)12200.00.03.0
PII(M3)1225948.439.257.6
gE100SPI(M2)391025.613.042.1
PII(M3)381539.524.056.6
 Vaccine Response Rates for Anti-VZV Antibodies at PI(M2) and PII(M3) by age Cohort - ATP Cohort for Immunogenicity
60-69y = 60-69 YOA ; 70y+ = ≥ 70 YOAgE251B = 25 µg gE/AS1; gE501B = 50 µg gE/AS1; gE1001B = 100 µg gE/AS1S gE1B = Saline + 100 µg gE/AS1; gE100S =100 µg gE/SalineVaccine response defined as:For initially seronegative subjects, anti-VZV Ab concentration ≥ 50 mIU/mL after vaccinationFor initially seropositive subjects, Ab concentration after vaccination ≥ 4-fold the pre-vaccination Ab concentrationN = Number of subjects with pre- and post-vaccination results availablen/% = Number/percentage of responders95% CI = 95% confidence interval, LL = Lower Limit, UL = Upper LimitPI(M2) = Post-vaccination 1 at Month 2; PII(M3) = Post-vaccination 2 at Month 3
Conclusions
The gE/AS 1 vaccine provokes a good immune response in the elderly populations of ≥ 60 and ≥ 70 YOA, and, in a varying gE dosage range.

Claims (15)

  1. Use of an immunogenic composition comprising VZV gE, or immunogenic fragment thereof, and a TH-1 adjuvant in the preparation of a medicament for the prevention or amelioration of shingles and/or post herpetic neuralgia in a population of individuals older than 50 or immunocompromised individuals.
  2. Use according to claim 1 wherein the population is of individuals older than 60.
  3. Use according to any of the preceding claims wherein the population is of individuals older than 70.
  4. Use according to claim 1 wherein the population is of immunocompromised individuals.
  5. Use according to any preceding claim wherein the individuals have had varicella or who have had a live varicella vaccine.
  6. Use according to any preceding claim wherein in the individuals the varicella zoster virus has not reactivated.
  7. Use according to any preceding claim wherein the adjuvant comprises QS21.
  8. Use according to any preceding claim wherein the adjuvant comprises liposomes comprising cholesterol.
  9. Use according to any preceding claim wherein the adjuvant comprises 3D MPL.
  10. Use according to claim 9 wherein the MPL is comprised within a liposome.
  11. Use according to any preceding claim wherein the gE is a C- terminal truncate.
  12. Use according to claim 11 wherein the gE has the amino acid sequence of Figure 1.
  13. Use according to any preceding claim wherein the composition comprises 25 to 100 µg gE.
  14. Use according to any preceding claim in a 2 dose delivery regime.
  15. A kit comprising as separate components, a TH-1 adjuvant and a VZV gE antigen or immunogenic fragment thereof, suitable for extemporaneous preparation of a vaccine composition for the prevention or amelioration of shingles and/or post herpetic neuralgia in a population of individuals older than 50 and immunocompromised individuals.
HK11110169.1A2005-03-032008-02-25Varicella zoster virus vaccineHK1156325A (en)

Applications Claiming Priority (1)

Application NumberPriority DateFiling DateTitle
GB0504436.72005-03-03

Related Parent Applications (1)

Application NumberTitlePriority DateFiling Date
HK08102085.4AAdditionHK1111427B (en)2005-03-032006-03-01Varicella zoster virus vaccine

Related Child Applications (1)

Application NumberTitlePriority DateFiling Date
HK08102085.4ADivisionHK1111427B (en)2005-03-032006-03-01Varicella zoster virus vaccine

Publications (1)

Publication NumberPublication Date
HK1156325Atrue HK1156325A (en)2012-06-08

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