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Система продуцированияHansenula polymorpha(Pichia angusta)
Адекватность - свойства продукта экспрессииЭффективность ndash простая воспроизводимая технологияЭкономичность ndash низкая себестоимость продуктаProved - отработанное масштабное производство без рекламаций
(технологических или реализуемого продукта)
Дизайн Клонирование и Экспрессия структурных антигеновHBV и HCV = VLP
Технология- lab-scale - pilot scaleQCPre-clinical trials
Внедрение технологии и регистрация продуктов
Разработка противо-вирусных вакцин гепатитов В и С
Model of E2 glycoprotein The linear sequence of E2 ectodomain of the JFH-1 strain (GenBank access number AB237837) is represented as a chain of beads (coloured circles) labelled with the corresponding amino acids and threaded onto a class II fold which is an adapted version of the model published by Krey et al [7] (doi101371journalppat1000762g006) Amino acids are numbered with respect to the polyprotein of HCV strain H77 consensus sequence (GenBank accession number AF009606) used as a general reference The three putative domains are presented in red (DI) yellow (DII) and blue (DIII) the variable regions (HVR1 HVR2 and IgVR) are indicated in brown and the stem region is in grey Circles in pale and bright colours represent residues in the background and foreground of the domains respectively Disulphide bonds are indicated by black bars and glycosylation sites are shown by green circles numbered sequentially Amino acids of the putative fusion peptide are contoured in red and residues that participate in CD81 binding are contoured in blue
Ever closer to a prophylactic vaccine for HCVExpert Opin Biol Ther 2013 August13(8)1109-1124FreyChoo (Novartis)
CHO-derived E1-T2 with MP59Elmowalid Insect cells derived HCV-LP
() очевидно применение вакцин 3-го и 4-го поколений для иммунизации подростков ранее привитых по стандартной схеме для новорожденных по причинам - снижения уровня anti-HBs часто до недетектируемого уровня через 10-12 лет - особой важности достоточности иммунитета в критическом для заражения возрасте 13-16 лет
Поколе
ния
Состав
антигенов
Особенности Назначение
I HBsAg
(S preS2)
Была разработана в конце 70-х годов XX века на основе HBsAg выделяемого и очищенного из плазмы крови пациентов хронических носителей вируса гепатита В
Более не применяется в качестве профилактической вакцины
II HBsAg
(S)
Рекомбинантная на основе экспрессии S- области в клетках дрожжей
В настоящее время применяется для массовой иммунизации населения
III HBsAg
(S preS1 preS2)
Рекомбинантная на основе экспрессии preS-S области в дрожжах или перевиваемых клетках млекопитающих
Разработана для массовой иммунизации не иммунизированных II поколением как более эффективная
IVa HBsAg (S)
HBcAg (core)
Рекомбинантная на основе экспрессии в дрожжах Hansenula HBsAg и HBcAg вируса геапатита В
Предлагается для лечения хронических вирусоносителей
IVb HBsAg
(S preS1 preS2)
HBcAg (core)
Рекомбинантная на основе экспрессии в дрожжах Hansenula всех структурных белков вируса геапатита В
Предлагается как наиболее эффективная для массовой иммунизации не вакцинированных II поколением и лечения вирусоносителей
NLB
Классификация вакцин на основе вирусспецифического антигенного состава
HBV-дикий вирус
Anti-HBs пресс в результате массовой вакцинации Исходно5-7 мутантовЧерез 20 лет22 мутантов
Мутантные формы прогрессивно накапливаются у привитыхУ невакцинированных это случайные мутации а у привитых ndash MHR HBsAg
Анти-вирусная терапияс помощью нуклеозидных аналоговМутации происходят направленно в Pol-последовательности но фактически меняют аа последовательность в MHR HBsAg что приводит к неузнаванию anti-HBs
Мутанты иммунно-происхождения
Мутанты Pol-происхождения
Не узнают anti-HBs
Узнают anti-preS1 anti-preS2 anti-HBc
Вакцина 3-го пок
Вакцина 4в - пок
Drug-resistant mutations rtM204I (sI195M) and rtM204V (sW196S) caused significant reduction in antigenicity for the immune-escaped HBsAg mutants sG145K and sG145R which may hamper HBV diagnosis and disease controlVirology Journal 2013 10292
Due to the overlap between the polymerase and envelope genes drug-resistant mutants are accompanied by amino acid changes in the envelope proteins as well
Ito K et al J Virol 20108412850-12861
The HBV polymerase gene overlaps completely with the genes of the 3 surface (S) antigen proteins The area boxed by dashed lines indicates the area of the HBsAg immunodominant area and the HBV reverse transcription area indicates the genome area most likely to produce mutants in both genesHBsAg mutations selected during antiviral therapy can lead to a virus escaping HBV vaccination
Horvat RT Lab Med 201142(8)488-496
Several conditions have been recognized in which HBV escape mutants arise in clinical practice bulltreatment with anti-HBs immunoglobulin eg after liver transplantation to avoid reinfection of the graft (2332) bullantiviral therapy by itself as the reading frames of the envelope and polymerase genes overlap
and several resistance mutations in the polymerase selected during antiviral therapy simultaneously alter the antigenicity of HBsAg (2021 31) bullde novo infection of vaccinated individuals with escape mutants (19)
Moreover Datta et al recently reported that HBV variants with the sG145R immune escape mutation are frequently ldquohiderdquo in the peripheral blood leukocyte compartment of infected individuals and may then serve as a source of reactivation or transmission (7)
J Virol 2010 vol 84 no 2 1026-1033
По современным оценкам частота мутаций HBsAg среди вакцинированных колеблется от 2 до 28
Из-за повсеместной вакцинации частота мутаций будет возрастать
Математическая модель предсказывает исчезновение ВГВ дикого типа в областях с HBsAg-эндемичностью и появление S генных мутаций в течение 100 лет как следствия универсальной ВГВ-вакцинации
Гилязова ДГ руководитель отдела Иммунохимия ООО Текан
httpwwwlabmedicinarufilesPREZENTACII20-2020122320Gilyazovapdf
HBV-дикий вирус
Anti-HBs пресс в результате массовой вакцинации Исходно5-7 мутантовЧерез 20 лет22 мутантов
Мутантные формы прогрессивно накапливаются у привитыхУ невакцинированных это случайные мутации а у привитых ndash MHR HBsAg
Анти-вирусная терапияс помощью нуклеозидных аналоговМутации происходят направленно в Pol-последовательности но фактически меняют аа последовательность в MHR HBsAg что приводит к неузнаванию anti-HBs
Мутанты иммунно-происхождения
Мутанты Pol-происхождения
Не узнают anti-HBs
Узнают anti-preS1 anti-preS2 anti-HBc
Вакцина 3-го пок
Вакцина 4в - пок
Drug-resistant mutations rtM204I (sI195M) and rtM204V (sW196S) caused significant reduction in antigenicity for the immune-escaped HBsAg mutants sG145K and sG145R which may hamper HBV diagnosis and disease controlVirology Journal 2013 10292
Type of Vaccine Vaccine Antigen Adjuvant Host Cell Target Current Status References
Peptide
(a) Palmitolylated TT830-843 HTL
epitope covalently linked to the HBcAg 18 ndash27 CTL epitope
NACytotoxic T Lymphocyt
e
Phase II clinical trial
Livingston et al 1999 [22]
(b) HBV core antigen 18-27
peptide + tetanus taxoid peptide 830
843+palmic acid molecules
NACytotoxic T Lymphocyt
e
Pre-clinical amp clinical
Vitiello et al 1995 [23]
ProteinHBsAganti-
HBsIgAlum
Cytotoxic T Lymphocyt
e
Phase II clinical trial
Wen et al 2003
Xu et al 2008 [28]
DNA
Small(S) and middle (preS2S) proteins of the HBV envelope
(HBsAg)
NACD8+ T
Lymphocyte
Phase I clinical trial
Mancini et al 2004
Vector-basedModified
prHBV13HBVcore protein
NA
CD4+ and CD8+ T
Lymphocyte
Pre-clinicalDeng et al
2009 [8]
Cell-based
DCs pulsed with HBs28-39 peptide or
recombinant preS2S particles
NACytotoxic T Lymphocyt
ePre-clinical
Akbar et al 2004 [36]
Therapeutic Vaccine for Hepatitis B virusJ Infect Dis Immunol Tech 2012 11
Release Summary February 12 2014httpwwwbusinesswirecomnewshome20140212005051enCreation-ABIVAX---Leader-Therapeutic-Vaccines-FrenchU3PoW_ldW8AAbivax creation of ABIVAX - a leader in therapeutic vaccines and the first French company to sign an exclusive partnering agreement with Cuba in healthcareABIVAX specializes in therapeutic vaccines and antivirals combining the technologies and the product portfolios of three French biotech companies financed by Truffle CapitaABIVAX already has two therapeutic vaccines in development one in a Phase IIb clinical trial in patients with chronic hepatitis B
The HBsAgndashHBcAg vaccine candidate was safe well tolerated and immunogenic in this phase I study in healthy adults To our knowledge this is the first demonstration of safety and immunogenicity for a nasal vaccine candidate comprising HBV antigensThe vaccine elicited anti-HBc seroconversion in 100 of subjects as early as day 30 of the immunization schedule while a seroprotective anti-HBs titer (ge10 IUl) was at a maximum at day 90 (75) International Journal of Infectious DiseasesVolume 11 Issue 5 September 2007
A novel therapeutic hepatitis B vaccine induces cellular and humoral immune responses and breaks tolerance in hepatitis B virus (HBV) transgenic miceBuchmann P1 Dembek C Kuklick L Jaumlger C Tedjokusumo R von Freyend MJ Drebber U Janowicz Z Melber K Protzer U
1Rhein Biotech GmbH Duesseldorf Germany pbuchmanneudynavaxcomVaccine 2013 631(8)A paradigm of therapeutic vaccination is the potent induction of T-cell responses against key viral antigens ndash besides activation of a humoral immune response We have evaluated the potential of a novel vaccine formulation comprising particulate hepatitis B surface (HBsAg) and core antigen (HBcAg) and the saponin-based ISCOMATRIXtrade adjuvant for its ability to stimulate T and B cell responses in C57BL6 mice and its ability to break tolerance in HBV transgenic (HBVtg) mice The vaccine induced multifunctional HBsAg- and HBcAg-specific CD8+ T cells detected by staining for IFNγ TNFα and IL-2 as well as high antibody titers against both antigens Vaccination of HBVtg animals induced potent HBsAg- and HBcAg-specific CD8+ T-cell responses in spleens and HBcAg-specific CD8+ T-cell responses in livers as well as anti-HBs seroconversion two weeks post injection Vaccination further reduced HBcAg expression in livers of HBVtg mice without causing liver damage In summary this study demonstrates therapeutic efficacy of a novel vaccine formulation in a mouse model of immunotolerant chronic HBV infection
HBsAg-HBcAg vaccine version - IV generation
PreS1 is the priority target antigen for the new HBV vaccines because PreS1 has a greater number of immunogenic T cell and B cell epitopes than the S protein (9 12 15) including a strong T cell epitope (aa 21 to 28) and an effective B cell epitope (aa 12 to 32 and 32 to 53) The PreS1 protein has binding sites for liver cells (aa 21 to 47) that play an important role in viral attachment and entry (13 15) Neurath et al have shown that direct immunization with a PreS1 polypeptide (aa 21 to 47) can protect against HBV infection in chimpanzees (21) Additionally the PreS1 antibody is produced earlier than the S antibody and the PreS1-specific cell-mediated immunity may help overcome immune unresponsiveness to the S protein in certain individuals (19 24) Therefore the PreS1 antigen may play an important role in the neutralization blockade and clearance of HBV infections
Clin Vaccine Immun 2011 18(11) 1789-1795
Inclusion of PreS2S antigen in vaccine formulation could also mitigate the chances of non-responsiveness of vaccines against escape variants (Yamada et al 2001) The PreS2S gene is comprises of S gene with an extra 165 nucleotides at 5rsquo end (Tai et al 1997) and antigen is involved in nucleocapsid interaction (Poisson et al 1997) and extra cellular secretion of HBV particles (Le Seyec et al 1998) playing an important role in full stimulation of humoral and cellular immune responses In addition the PreS2S protein is also important for immunological responses at T-cell level and has T-cell and B-cell recognition sites spanning amino acids 1-25 of the protein (Neurath et al 1986) making it most suitable candidate antigen for HBV vaccine development This study describes the heterologous expression of a characterized PreS2S gene from genotype D of HBV in P pastoris The antigen will help to increase the efficacy of HBV recombinant vaccines
Pak J Bot 2012 44 355-359
Use of Pre-S Protein-Containing Hepatitis B Virus Surface Antigens and a Powerful Adjuvant To Develop an Immune Therapy for Chronic Hepatitis B Virus InfectionJung Sun Yum Byung Cheol Ahn [] and Hong Mo Moon
Clin Vaccine Immun 19(2) 2012
Роль preS-областей
J Hep 2011 54 1286-1296
НИИ вакцин и сывороток им И И Мечникова РАМН Москва
Сочетанная терапия laquoвакцина + альфа-2 бета-интерферонraquo позволила получить подавление вирусной репликации в первые 1ndash2 месяца от начала лечения у 786 больных сероконверсию HВsAg на анти-HВs mdash у 964 Исчезновение HВеAg наблюдалось через 6 месяца у всех больных а анти-HВе через 2ndash3 месяца от начала лечения появились у всех больных Наблюдение за пациентами в течение трех лет и более показало что стойкий ответ на лечение отмечался у 24 (857) К концу лечения нормализовались все популяции лимфоцитов высоким оставался только уровень лимфоцитов экспрессирующих рецептор к ИЛ-2 (CD25+) оставались сниженными резервы фагоцитоза и кислородзависимого киллинга [5]Таким образом вакцинация против ГВ является актуальной и необходимой больным с ХЗП пациентам с ХГВ иили ХГС носителям ВГВ иили ВГС поскольку способствует подавлению вирусной репликации у хронических вирусоносителей может играть существенную роль в контроле над виремией значительно повышает эффективность лечения ХВГ
Афигенова ВП Костинов МП 2011
Study Calls Into Question Effectiveness of Hepatitis B Vaccine for NewbornsDecember 17 2013httparticlesmercolacomsitesarticlesarchive20131217newborn-hepatitis-b-vaccineaspxBy Dr JM Mercola
New Study Hepatitis B Vaccination at Birth May Not Prevent Hidden InfectionsA new study is raising another red flag that the practice of universally vaccinating all newborn babies for hepatitis B is seriously flawed The researchers followed 259 babies born to hepatitis-B-positive mothers for two years in order to determine whether vaccinating such babies prevents asymptomatic occult HBV (hepatitis B virus) infectionThe researchers found that while the vaccine may help prevent overt HBV transmission it was not effective in preventing occult HBV infection in babies which may occur in up to 40 percent of babies born to hepatitis B-positive mothersHepatitis B Shot May Be Ineffective by the Time Your Child Is a TeenagerAnother issue to consider if you are weighing the benefits and risks of giving your newborn infant or young child hepatitis B vaccine is that vaccine acquired immunity often does not persist until a child reaches his or her teenage years ndash the time when acquiring a hepatitis B infection may be more likely Research shows that by that time the protection from the childhood vaccine may have long since wanedOne study found that about 15 percent of teens who received the full series of hepatitis B shots as infants tested positive for hepatitis B surface antigen (HBsAg) which is an early indicator of infection or a sign that the person is a chronic carrier of the virus3This percentage was even higher among teens who had received the hepatitis B vaccine off schedule or whose mothers were high risk meaning they tested positive for hepatitis B e antigen (HBeAg) In other words it appears that in many children hepatitis B vaccine acquired immunity does NOT provide lasting protection A Healthy Immune System Can Resolve Hepatitis B InfectionEven if you have been vaccinated as a child itrsquos important to remember that you may not be protected from these risks and could still be infected via IV drug abuse sexual activity with an infected partner a blood transfusion with contaminated blood or even getting a manicure or pedicurehellipFortunately in most cases the hepatitis B infection will resolve on its own provided you have a well-functioning immune system Symptoms can be relieved bybullRestingbullAvoiding foods that weaken your immune function such as sugarsfructose grains and processed foods Healthful foods that help boost your immune system include fermented foods and organic vegetablesbullOptimizing your vitamin D levelsbullDrinking plenty of pure waterbullAvoiding alcohol and drugs
Причинно-следственныеbull Перееданиеbull Неадекватное питаниеbull Вредные привычкиbull Гиподинамия либо перегрузкиbull Неадекватное дыханиеbull Неадекватность мироощущения (стресс дефицит мотивации подавленность- депрессия)bull ИНТОКСИКАЦИЯbull ПОДАВЛЕННОСТЬ ИММУНИТЕТА
Предлагаемая схема клинического эксперимента на хронических носителях гепатитов В и С для изучения лечебных курсов
Курс оздоровления направленный на восстановление иммунной системы
Тераперапевтическая Вакцинация Курс анти-Вирусной ТерапииСовместное применение Вакцины и анти-Вирусного Курса
М О Н И Т О Р И Н Г по всем иммуно-параметрам ДНКРНК печеночные ферменты др
Ожидаемые результатыbull Влияние оздоровления-восстановления на течение хронического ГВbull Роль предварительного оздоровления-восстановления на каждый из методов леченияbull Сравнительная эффективность вакцины анти-вирусного курса и комбинации на фоне предварительного оздоровления-восстановления и без фона
() Курс относится к категории SPA
Model of E2 glycoprotein The linear sequence of E2 ectodomain of the JFH-1 strain (GenBank access number AB237837) is represented as a chain of beads (coloured circles) labelled with the corresponding amino acids and threaded onto a class II fold which is an adapted version of the model published by Krey et al [7] (doi101371journalppat1000762g006) Amino acids are numbered with respect to the polyprotein of HCV strain H77 consensus sequence (GenBank accession number AF009606) used as a general reference The three putative domains are presented in red (DI) yellow (DII) and blue (DIII) the variable regions (HVR1 HVR2 and IgVR) are indicated in brown and the stem region is in grey Circles in pale and bright colours represent residues in the background and foreground of the domains respectively Disulphide bonds are indicated by black bars and glycosylation sites are shown by green circles numbered sequentially Amino acids of the putative fusion peptide are contoured in red and residues that participate in CD81 binding are contoured in blue
Ever closer to a prophylactic vaccine for HCVExpert Opin Biol Ther 2013 August13(8)1109-1124FreyChoo (Novartis)
CHO-derived E1-T2 with MP59Elmowalid Insect cells derived HCV-LP
() очевидно применение вакцин 3-го и 4-го поколений для иммунизации подростков ранее привитых по стандартной схеме для новорожденных по причинам - снижения уровня anti-HBs часто до недетектируемого уровня через 10-12 лет - особой важности достоточности иммунитета в критическом для заражения возрасте 13-16 лет
Поколе
ния
Состав
антигенов
Особенности Назначение
I HBsAg
(S preS2)
Была разработана в конце 70-х годов XX века на основе HBsAg выделяемого и очищенного из плазмы крови пациентов хронических носителей вируса гепатита В
Более не применяется в качестве профилактической вакцины
II HBsAg
(S)
Рекомбинантная на основе экспрессии S- области в клетках дрожжей
В настоящее время применяется для массовой иммунизации населения
III HBsAg
(S preS1 preS2)
Рекомбинантная на основе экспрессии preS-S области в дрожжах или перевиваемых клетках млекопитающих
Разработана для массовой иммунизации не иммунизированных II поколением как более эффективная
IVa HBsAg (S)
HBcAg (core)
Рекомбинантная на основе экспрессии в дрожжах Hansenula HBsAg и HBcAg вируса геапатита В
Предлагается для лечения хронических вирусоносителей
IVb HBsAg
(S preS1 preS2)
HBcAg (core)
Рекомбинантная на основе экспрессии в дрожжах Hansenula всех структурных белков вируса геапатита В
Предлагается как наиболее эффективная для массовой иммунизации не вакцинированных II поколением и лечения вирусоносителей
NLB
Классификация вакцин на основе вирусспецифического антигенного состава
HBV-дикий вирус
Anti-HBs пресс в результате массовой вакцинации Исходно5-7 мутантовЧерез 20 лет22 мутантов
Мутантные формы прогрессивно накапливаются у привитыхУ невакцинированных это случайные мутации а у привитых ndash MHR HBsAg
Анти-вирусная терапияс помощью нуклеозидных аналоговМутации происходят направленно в Pol-последовательности но фактически меняют аа последовательность в MHR HBsAg что приводит к неузнаванию anti-HBs
Мутанты иммунно-происхождения
Мутанты Pol-происхождения
Не узнают anti-HBs
Узнают anti-preS1 anti-preS2 anti-HBc
Вакцина 3-го пок
Вакцина 4в - пок
Drug-resistant mutations rtM204I (sI195M) and rtM204V (sW196S) caused significant reduction in antigenicity for the immune-escaped HBsAg mutants sG145K and sG145R which may hamper HBV diagnosis and disease controlVirology Journal 2013 10292
Due to the overlap between the polymerase and envelope genes drug-resistant mutants are accompanied by amino acid changes in the envelope proteins as well
Ito K et al J Virol 20108412850-12861
The HBV polymerase gene overlaps completely with the genes of the 3 surface (S) antigen proteins The area boxed by dashed lines indicates the area of the HBsAg immunodominant area and the HBV reverse transcription area indicates the genome area most likely to produce mutants in both genesHBsAg mutations selected during antiviral therapy can lead to a virus escaping HBV vaccination
Horvat RT Lab Med 201142(8)488-496
Several conditions have been recognized in which HBV escape mutants arise in clinical practice bulltreatment with anti-HBs immunoglobulin eg after liver transplantation to avoid reinfection of the graft (2332) bullantiviral therapy by itself as the reading frames of the envelope and polymerase genes overlap
and several resistance mutations in the polymerase selected during antiviral therapy simultaneously alter the antigenicity of HBsAg (2021 31) bullde novo infection of vaccinated individuals with escape mutants (19)
Moreover Datta et al recently reported that HBV variants with the sG145R immune escape mutation are frequently ldquohiderdquo in the peripheral blood leukocyte compartment of infected individuals and may then serve as a source of reactivation or transmission (7)
J Virol 2010 vol 84 no 2 1026-1033
По современным оценкам частота мутаций HBsAg среди вакцинированных колеблется от 2 до 28
Из-за повсеместной вакцинации частота мутаций будет возрастать
Математическая модель предсказывает исчезновение ВГВ дикого типа в областях с HBsAg-эндемичностью и появление S генных мутаций в течение 100 лет как следствия универсальной ВГВ-вакцинации
Гилязова ДГ руководитель отдела Иммунохимия ООО Текан
httpwwwlabmedicinarufilesPREZENTACII20-2020122320Gilyazovapdf
HBV-дикий вирус
Anti-HBs пресс в результате массовой вакцинации Исходно5-7 мутантовЧерез 20 лет22 мутантов
Мутантные формы прогрессивно накапливаются у привитыхУ невакцинированных это случайные мутации а у привитых ndash MHR HBsAg
Анти-вирусная терапияс помощью нуклеозидных аналоговМутации происходят направленно в Pol-последовательности но фактически меняют аа последовательность в MHR HBsAg что приводит к неузнаванию anti-HBs
Мутанты иммунно-происхождения
Мутанты Pol-происхождения
Не узнают anti-HBs
Узнают anti-preS1 anti-preS2 anti-HBc
Вакцина 3-го пок
Вакцина 4в - пок
Drug-resistant mutations rtM204I (sI195M) and rtM204V (sW196S) caused significant reduction in antigenicity for the immune-escaped HBsAg mutants sG145K and sG145R which may hamper HBV diagnosis and disease controlVirology Journal 2013 10292
Type of Vaccine Vaccine Antigen Adjuvant Host Cell Target Current Status References
Peptide
(a) Palmitolylated TT830-843 HTL
epitope covalently linked to the HBcAg 18 ndash27 CTL epitope
NACytotoxic T Lymphocyt
e
Phase II clinical trial
Livingston et al 1999 [22]
(b) HBV core antigen 18-27
peptide + tetanus taxoid peptide 830
843+palmic acid molecules
NACytotoxic T Lymphocyt
e
Pre-clinical amp clinical
Vitiello et al 1995 [23]
ProteinHBsAganti-
HBsIgAlum
Cytotoxic T Lymphocyt
e
Phase II clinical trial
Wen et al 2003
Xu et al 2008 [28]
DNA
Small(S) and middle (preS2S) proteins of the HBV envelope
(HBsAg)
NACD8+ T
Lymphocyte
Phase I clinical trial
Mancini et al 2004
Vector-basedModified
prHBV13HBVcore protein
NA
CD4+ and CD8+ T
Lymphocyte
Pre-clinicalDeng et al
2009 [8]
Cell-based
DCs pulsed with HBs28-39 peptide or
recombinant preS2S particles
NACytotoxic T Lymphocyt
ePre-clinical
Akbar et al 2004 [36]
Therapeutic Vaccine for Hepatitis B virusJ Infect Dis Immunol Tech 2012 11
Release Summary February 12 2014httpwwwbusinesswirecomnewshome20140212005051enCreation-ABIVAX---Leader-Therapeutic-Vaccines-FrenchU3PoW_ldW8AAbivax creation of ABIVAX - a leader in therapeutic vaccines and the first French company to sign an exclusive partnering agreement with Cuba in healthcareABIVAX specializes in therapeutic vaccines and antivirals combining the technologies and the product portfolios of three French biotech companies financed by Truffle CapitaABIVAX already has two therapeutic vaccines in development one in a Phase IIb clinical trial in patients with chronic hepatitis B
The HBsAgndashHBcAg vaccine candidate was safe well tolerated and immunogenic in this phase I study in healthy adults To our knowledge this is the first demonstration of safety and immunogenicity for a nasal vaccine candidate comprising HBV antigensThe vaccine elicited anti-HBc seroconversion in 100 of subjects as early as day 30 of the immunization schedule while a seroprotective anti-HBs titer (ge10 IUl) was at a maximum at day 90 (75) International Journal of Infectious DiseasesVolume 11 Issue 5 September 2007
A novel therapeutic hepatitis B vaccine induces cellular and humoral immune responses and breaks tolerance in hepatitis B virus (HBV) transgenic miceBuchmann P1 Dembek C Kuklick L Jaumlger C Tedjokusumo R von Freyend MJ Drebber U Janowicz Z Melber K Protzer U
1Rhein Biotech GmbH Duesseldorf Germany pbuchmanneudynavaxcomVaccine 2013 631(8)A paradigm of therapeutic vaccination is the potent induction of T-cell responses against key viral antigens ndash besides activation of a humoral immune response We have evaluated the potential of a novel vaccine formulation comprising particulate hepatitis B surface (HBsAg) and core antigen (HBcAg) and the saponin-based ISCOMATRIXtrade adjuvant for its ability to stimulate T and B cell responses in C57BL6 mice and its ability to break tolerance in HBV transgenic (HBVtg) mice The vaccine induced multifunctional HBsAg- and HBcAg-specific CD8+ T cells detected by staining for IFNγ TNFα and IL-2 as well as high antibody titers against both antigens Vaccination of HBVtg animals induced potent HBsAg- and HBcAg-specific CD8+ T-cell responses in spleens and HBcAg-specific CD8+ T-cell responses in livers as well as anti-HBs seroconversion two weeks post injection Vaccination further reduced HBcAg expression in livers of HBVtg mice without causing liver damage In summary this study demonstrates therapeutic efficacy of a novel vaccine formulation in a mouse model of immunotolerant chronic HBV infection
HBsAg-HBcAg vaccine version - IV generation
PreS1 is the priority target antigen for the new HBV vaccines because PreS1 has a greater number of immunogenic T cell and B cell epitopes than the S protein (9 12 15) including a strong T cell epitope (aa 21 to 28) and an effective B cell epitope (aa 12 to 32 and 32 to 53) The PreS1 protein has binding sites for liver cells (aa 21 to 47) that play an important role in viral attachment and entry (13 15) Neurath et al have shown that direct immunization with a PreS1 polypeptide (aa 21 to 47) can protect against HBV infection in chimpanzees (21) Additionally the PreS1 antibody is produced earlier than the S antibody and the PreS1-specific cell-mediated immunity may help overcome immune unresponsiveness to the S protein in certain individuals (19 24) Therefore the PreS1 antigen may play an important role in the neutralization blockade and clearance of HBV infections
Clin Vaccine Immun 2011 18(11) 1789-1795
Inclusion of PreS2S antigen in vaccine formulation could also mitigate the chances of non-responsiveness of vaccines against escape variants (Yamada et al 2001) The PreS2S gene is comprises of S gene with an extra 165 nucleotides at 5rsquo end (Tai et al 1997) and antigen is involved in nucleocapsid interaction (Poisson et al 1997) and extra cellular secretion of HBV particles (Le Seyec et al 1998) playing an important role in full stimulation of humoral and cellular immune responses In addition the PreS2S protein is also important for immunological responses at T-cell level and has T-cell and B-cell recognition sites spanning amino acids 1-25 of the protein (Neurath et al 1986) making it most suitable candidate antigen for HBV vaccine development This study describes the heterologous expression of a characterized PreS2S gene from genotype D of HBV in P pastoris The antigen will help to increase the efficacy of HBV recombinant vaccines
Pak J Bot 2012 44 355-359
Use of Pre-S Protein-Containing Hepatitis B Virus Surface Antigens and a Powerful Adjuvant To Develop an Immune Therapy for Chronic Hepatitis B Virus InfectionJung Sun Yum Byung Cheol Ahn [] and Hong Mo Moon
Clin Vaccine Immun 19(2) 2012
Роль preS-областей
J Hep 2011 54 1286-1296
НИИ вакцин и сывороток им И И Мечникова РАМН Москва
Сочетанная терапия laquoвакцина + альфа-2 бета-интерферонraquo позволила получить подавление вирусной репликации в первые 1ndash2 месяца от начала лечения у 786 больных сероконверсию HВsAg на анти-HВs mdash у 964 Исчезновение HВеAg наблюдалось через 6 месяца у всех больных а анти-HВе через 2ndash3 месяца от начала лечения появились у всех больных Наблюдение за пациентами в течение трех лет и более показало что стойкий ответ на лечение отмечался у 24 (857) К концу лечения нормализовались все популяции лимфоцитов высоким оставался только уровень лимфоцитов экспрессирующих рецептор к ИЛ-2 (CD25+) оставались сниженными резервы фагоцитоза и кислородзависимого киллинга [5]Таким образом вакцинация против ГВ является актуальной и необходимой больным с ХЗП пациентам с ХГВ иили ХГС носителям ВГВ иили ВГС поскольку способствует подавлению вирусной репликации у хронических вирусоносителей может играть существенную роль в контроле над виремией значительно повышает эффективность лечения ХВГ
Афигенова ВП Костинов МП 2011
Study Calls Into Question Effectiveness of Hepatitis B Vaccine for NewbornsDecember 17 2013httparticlesmercolacomsitesarticlesarchive20131217newborn-hepatitis-b-vaccineaspxBy Dr JM Mercola
New Study Hepatitis B Vaccination at Birth May Not Prevent Hidden InfectionsA new study is raising another red flag that the practice of universally vaccinating all newborn babies for hepatitis B is seriously flawed The researchers followed 259 babies born to hepatitis-B-positive mothers for two years in order to determine whether vaccinating such babies prevents asymptomatic occult HBV (hepatitis B virus) infectionThe researchers found that while the vaccine may help prevent overt HBV transmission it was not effective in preventing occult HBV infection in babies which may occur in up to 40 percent of babies born to hepatitis B-positive mothersHepatitis B Shot May Be Ineffective by the Time Your Child Is a TeenagerAnother issue to consider if you are weighing the benefits and risks of giving your newborn infant or young child hepatitis B vaccine is that vaccine acquired immunity often does not persist until a child reaches his or her teenage years ndash the time when acquiring a hepatitis B infection may be more likely Research shows that by that time the protection from the childhood vaccine may have long since wanedOne study found that about 15 percent of teens who received the full series of hepatitis B shots as infants tested positive for hepatitis B surface antigen (HBsAg) which is an early indicator of infection or a sign that the person is a chronic carrier of the virus3This percentage was even higher among teens who had received the hepatitis B vaccine off schedule or whose mothers were high risk meaning they tested positive for hepatitis B e antigen (HBeAg) In other words it appears that in many children hepatitis B vaccine acquired immunity does NOT provide lasting protection A Healthy Immune System Can Resolve Hepatitis B InfectionEven if you have been vaccinated as a child itrsquos important to remember that you may not be protected from these risks and could still be infected via IV drug abuse sexual activity with an infected partner a blood transfusion with contaminated blood or even getting a manicure or pedicurehellipFortunately in most cases the hepatitis B infection will resolve on its own provided you have a well-functioning immune system Symptoms can be relieved bybullRestingbullAvoiding foods that weaken your immune function such as sugarsfructose grains and processed foods Healthful foods that help boost your immune system include fermented foods and organic vegetablesbullOptimizing your vitamin D levelsbullDrinking plenty of pure waterbullAvoiding alcohol and drugs
Причинно-следственныеbull Перееданиеbull Неадекватное питаниеbull Вредные привычкиbull Гиподинамия либо перегрузкиbull Неадекватное дыханиеbull Неадекватность мироощущения (стресс дефицит мотивации подавленность- депрессия)bull ИНТОКСИКАЦИЯbull ПОДАВЛЕННОСТЬ ИММУНИТЕТА
Предлагаемая схема клинического эксперимента на хронических носителях гепатитов В и С для изучения лечебных курсов
Курс оздоровления направленный на восстановление иммунной системы
Тераперапевтическая Вакцинация Курс анти-Вирусной ТерапииСовместное применение Вакцины и анти-Вирусного Курса
М О Н И Т О Р И Н Г по всем иммуно-параметрам ДНКРНК печеночные ферменты др
Ожидаемые результатыbull Влияние оздоровления-восстановления на течение хронического ГВbull Роль предварительного оздоровления-восстановления на каждый из методов леченияbull Сравнительная эффективность вакцины анти-вирусного курса и комбинации на фоне предварительного оздоровления-восстановления и без фона
() Курс относится к категории SPA
Ever closer to a prophylactic vaccine for HCVExpert Opin Biol Ther 2013 August13(8)1109-1124FreyChoo (Novartis)
CHO-derived E1-T2 with MP59Elmowalid Insect cells derived HCV-LP
() очевидно применение вакцин 3-го и 4-го поколений для иммунизации подростков ранее привитых по стандартной схеме для новорожденных по причинам - снижения уровня anti-HBs часто до недетектируемого уровня через 10-12 лет - особой важности достоточности иммунитета в критическом для заражения возрасте 13-16 лет
Поколе
ния
Состав
антигенов
Особенности Назначение
I HBsAg
(S preS2)
Была разработана в конце 70-х годов XX века на основе HBsAg выделяемого и очищенного из плазмы крови пациентов хронических носителей вируса гепатита В
Более не применяется в качестве профилактической вакцины
II HBsAg
(S)
Рекомбинантная на основе экспрессии S- области в клетках дрожжей
В настоящее время применяется для массовой иммунизации населения
III HBsAg
(S preS1 preS2)
Рекомбинантная на основе экспрессии preS-S области в дрожжах или перевиваемых клетках млекопитающих
Разработана для массовой иммунизации не иммунизированных II поколением как более эффективная
IVa HBsAg (S)
HBcAg (core)
Рекомбинантная на основе экспрессии в дрожжах Hansenula HBsAg и HBcAg вируса геапатита В
Предлагается для лечения хронических вирусоносителей
IVb HBsAg
(S preS1 preS2)
HBcAg (core)
Рекомбинантная на основе экспрессии в дрожжах Hansenula всех структурных белков вируса геапатита В
Предлагается как наиболее эффективная для массовой иммунизации не вакцинированных II поколением и лечения вирусоносителей
NLB
Классификация вакцин на основе вирусспецифического антигенного состава
HBV-дикий вирус
Anti-HBs пресс в результате массовой вакцинации Исходно5-7 мутантовЧерез 20 лет22 мутантов
Мутантные формы прогрессивно накапливаются у привитыхУ невакцинированных это случайные мутации а у привитых ndash MHR HBsAg
Анти-вирусная терапияс помощью нуклеозидных аналоговМутации происходят направленно в Pol-последовательности но фактически меняют аа последовательность в MHR HBsAg что приводит к неузнаванию anti-HBs
Мутанты иммунно-происхождения
Мутанты Pol-происхождения
Не узнают anti-HBs
Узнают anti-preS1 anti-preS2 anti-HBc
Вакцина 3-го пок
Вакцина 4в - пок
Drug-resistant mutations rtM204I (sI195M) and rtM204V (sW196S) caused significant reduction in antigenicity for the immune-escaped HBsAg mutants sG145K and sG145R which may hamper HBV diagnosis and disease controlVirology Journal 2013 10292
Due to the overlap between the polymerase and envelope genes drug-resistant mutants are accompanied by amino acid changes in the envelope proteins as well
Ito K et al J Virol 20108412850-12861
The HBV polymerase gene overlaps completely with the genes of the 3 surface (S) antigen proteins The area boxed by dashed lines indicates the area of the HBsAg immunodominant area and the HBV reverse transcription area indicates the genome area most likely to produce mutants in both genesHBsAg mutations selected during antiviral therapy can lead to a virus escaping HBV vaccination
Horvat RT Lab Med 201142(8)488-496
Several conditions have been recognized in which HBV escape mutants arise in clinical practice bulltreatment with anti-HBs immunoglobulin eg after liver transplantation to avoid reinfection of the graft (2332) bullantiviral therapy by itself as the reading frames of the envelope and polymerase genes overlap
and several resistance mutations in the polymerase selected during antiviral therapy simultaneously alter the antigenicity of HBsAg (2021 31) bullde novo infection of vaccinated individuals with escape mutants (19)
Moreover Datta et al recently reported that HBV variants with the sG145R immune escape mutation are frequently ldquohiderdquo in the peripheral blood leukocyte compartment of infected individuals and may then serve as a source of reactivation or transmission (7)
J Virol 2010 vol 84 no 2 1026-1033
По современным оценкам частота мутаций HBsAg среди вакцинированных колеблется от 2 до 28
Из-за повсеместной вакцинации частота мутаций будет возрастать
Математическая модель предсказывает исчезновение ВГВ дикого типа в областях с HBsAg-эндемичностью и появление S генных мутаций в течение 100 лет как следствия универсальной ВГВ-вакцинации
Гилязова ДГ руководитель отдела Иммунохимия ООО Текан
httpwwwlabmedicinarufilesPREZENTACII20-2020122320Gilyazovapdf
HBV-дикий вирус
Anti-HBs пресс в результате массовой вакцинации Исходно5-7 мутантовЧерез 20 лет22 мутантов
Мутантные формы прогрессивно накапливаются у привитыхУ невакцинированных это случайные мутации а у привитых ndash MHR HBsAg
Анти-вирусная терапияс помощью нуклеозидных аналоговМутации происходят направленно в Pol-последовательности но фактически меняют аа последовательность в MHR HBsAg что приводит к неузнаванию anti-HBs
Мутанты иммунно-происхождения
Мутанты Pol-происхождения
Не узнают anti-HBs
Узнают anti-preS1 anti-preS2 anti-HBc
Вакцина 3-го пок
Вакцина 4в - пок
Drug-resistant mutations rtM204I (sI195M) and rtM204V (sW196S) caused significant reduction in antigenicity for the immune-escaped HBsAg mutants sG145K and sG145R which may hamper HBV diagnosis and disease controlVirology Journal 2013 10292
Type of Vaccine Vaccine Antigen Adjuvant Host Cell Target Current Status References
Peptide
(a) Palmitolylated TT830-843 HTL
epitope covalently linked to the HBcAg 18 ndash27 CTL epitope
NACytotoxic T Lymphocyt
e
Phase II clinical trial
Livingston et al 1999 [22]
(b) HBV core antigen 18-27
peptide + tetanus taxoid peptide 830
843+palmic acid molecules
NACytotoxic T Lymphocyt
e
Pre-clinical amp clinical
Vitiello et al 1995 [23]
ProteinHBsAganti-
HBsIgAlum
Cytotoxic T Lymphocyt
e
Phase II clinical trial
Wen et al 2003
Xu et al 2008 [28]
DNA
Small(S) and middle (preS2S) proteins of the HBV envelope
(HBsAg)
NACD8+ T
Lymphocyte
Phase I clinical trial
Mancini et al 2004
Vector-basedModified
prHBV13HBVcore protein
NA
CD4+ and CD8+ T
Lymphocyte
Pre-clinicalDeng et al
2009 [8]
Cell-based
DCs pulsed with HBs28-39 peptide or
recombinant preS2S particles
NACytotoxic T Lymphocyt
ePre-clinical
Akbar et al 2004 [36]
Therapeutic Vaccine for Hepatitis B virusJ Infect Dis Immunol Tech 2012 11
Release Summary February 12 2014httpwwwbusinesswirecomnewshome20140212005051enCreation-ABIVAX---Leader-Therapeutic-Vaccines-FrenchU3PoW_ldW8AAbivax creation of ABIVAX - a leader in therapeutic vaccines and the first French company to sign an exclusive partnering agreement with Cuba in healthcareABIVAX specializes in therapeutic vaccines and antivirals combining the technologies and the product portfolios of three French biotech companies financed by Truffle CapitaABIVAX already has two therapeutic vaccines in development one in a Phase IIb clinical trial in patients with chronic hepatitis B
The HBsAgndashHBcAg vaccine candidate was safe well tolerated and immunogenic in this phase I study in healthy adults To our knowledge this is the first demonstration of safety and immunogenicity for a nasal vaccine candidate comprising HBV antigensThe vaccine elicited anti-HBc seroconversion in 100 of subjects as early as day 30 of the immunization schedule while a seroprotective anti-HBs titer (ge10 IUl) was at a maximum at day 90 (75) International Journal of Infectious DiseasesVolume 11 Issue 5 September 2007
A novel therapeutic hepatitis B vaccine induces cellular and humoral immune responses and breaks tolerance in hepatitis B virus (HBV) transgenic miceBuchmann P1 Dembek C Kuklick L Jaumlger C Tedjokusumo R von Freyend MJ Drebber U Janowicz Z Melber K Protzer U
1Rhein Biotech GmbH Duesseldorf Germany pbuchmanneudynavaxcomVaccine 2013 631(8)A paradigm of therapeutic vaccination is the potent induction of T-cell responses against key viral antigens ndash besides activation of a humoral immune response We have evaluated the potential of a novel vaccine formulation comprising particulate hepatitis B surface (HBsAg) and core antigen (HBcAg) and the saponin-based ISCOMATRIXtrade adjuvant for its ability to stimulate T and B cell responses in C57BL6 mice and its ability to break tolerance in HBV transgenic (HBVtg) mice The vaccine induced multifunctional HBsAg- and HBcAg-specific CD8+ T cells detected by staining for IFNγ TNFα and IL-2 as well as high antibody titers against both antigens Vaccination of HBVtg animals induced potent HBsAg- and HBcAg-specific CD8+ T-cell responses in spleens and HBcAg-specific CD8+ T-cell responses in livers as well as anti-HBs seroconversion two weeks post injection Vaccination further reduced HBcAg expression in livers of HBVtg mice without causing liver damage In summary this study demonstrates therapeutic efficacy of a novel vaccine formulation in a mouse model of immunotolerant chronic HBV infection
HBsAg-HBcAg vaccine version - IV generation
PreS1 is the priority target antigen for the new HBV vaccines because PreS1 has a greater number of immunogenic T cell and B cell epitopes than the S protein (9 12 15) including a strong T cell epitope (aa 21 to 28) and an effective B cell epitope (aa 12 to 32 and 32 to 53) The PreS1 protein has binding sites for liver cells (aa 21 to 47) that play an important role in viral attachment and entry (13 15) Neurath et al have shown that direct immunization with a PreS1 polypeptide (aa 21 to 47) can protect against HBV infection in chimpanzees (21) Additionally the PreS1 antibody is produced earlier than the S antibody and the PreS1-specific cell-mediated immunity may help overcome immune unresponsiveness to the S protein in certain individuals (19 24) Therefore the PreS1 antigen may play an important role in the neutralization blockade and clearance of HBV infections
Clin Vaccine Immun 2011 18(11) 1789-1795
Inclusion of PreS2S antigen in vaccine formulation could also mitigate the chances of non-responsiveness of vaccines against escape variants (Yamada et al 2001) The PreS2S gene is comprises of S gene with an extra 165 nucleotides at 5rsquo end (Tai et al 1997) and antigen is involved in nucleocapsid interaction (Poisson et al 1997) and extra cellular secretion of HBV particles (Le Seyec et al 1998) playing an important role in full stimulation of humoral and cellular immune responses In addition the PreS2S protein is also important for immunological responses at T-cell level and has T-cell and B-cell recognition sites spanning amino acids 1-25 of the protein (Neurath et al 1986) making it most suitable candidate antigen for HBV vaccine development This study describes the heterologous expression of a characterized PreS2S gene from genotype D of HBV in P pastoris The antigen will help to increase the efficacy of HBV recombinant vaccines
Pak J Bot 2012 44 355-359
Use of Pre-S Protein-Containing Hepatitis B Virus Surface Antigens and a Powerful Adjuvant To Develop an Immune Therapy for Chronic Hepatitis B Virus InfectionJung Sun Yum Byung Cheol Ahn [] and Hong Mo Moon
Clin Vaccine Immun 19(2) 2012
Роль preS-областей
J Hep 2011 54 1286-1296
НИИ вакцин и сывороток им И И Мечникова РАМН Москва
Сочетанная терапия laquoвакцина + альфа-2 бета-интерферонraquo позволила получить подавление вирусной репликации в первые 1ndash2 месяца от начала лечения у 786 больных сероконверсию HВsAg на анти-HВs mdash у 964 Исчезновение HВеAg наблюдалось через 6 месяца у всех больных а анти-HВе через 2ndash3 месяца от начала лечения появились у всех больных Наблюдение за пациентами в течение трех лет и более показало что стойкий ответ на лечение отмечался у 24 (857) К концу лечения нормализовались все популяции лимфоцитов высоким оставался только уровень лимфоцитов экспрессирующих рецептор к ИЛ-2 (CD25+) оставались сниженными резервы фагоцитоза и кислородзависимого киллинга [5]Таким образом вакцинация против ГВ является актуальной и необходимой больным с ХЗП пациентам с ХГВ иили ХГС носителям ВГВ иили ВГС поскольку способствует подавлению вирусной репликации у хронических вирусоносителей может играть существенную роль в контроле над виремией значительно повышает эффективность лечения ХВГ
Афигенова ВП Костинов МП 2011
Study Calls Into Question Effectiveness of Hepatitis B Vaccine for NewbornsDecember 17 2013httparticlesmercolacomsitesarticlesarchive20131217newborn-hepatitis-b-vaccineaspxBy Dr JM Mercola
New Study Hepatitis B Vaccination at Birth May Not Prevent Hidden InfectionsA new study is raising another red flag that the practice of universally vaccinating all newborn babies for hepatitis B is seriously flawed The researchers followed 259 babies born to hepatitis-B-positive mothers for two years in order to determine whether vaccinating such babies prevents asymptomatic occult HBV (hepatitis B virus) infectionThe researchers found that while the vaccine may help prevent overt HBV transmission it was not effective in preventing occult HBV infection in babies which may occur in up to 40 percent of babies born to hepatitis B-positive mothersHepatitis B Shot May Be Ineffective by the Time Your Child Is a TeenagerAnother issue to consider if you are weighing the benefits and risks of giving your newborn infant or young child hepatitis B vaccine is that vaccine acquired immunity often does not persist until a child reaches his or her teenage years ndash the time when acquiring a hepatitis B infection may be more likely Research shows that by that time the protection from the childhood vaccine may have long since wanedOne study found that about 15 percent of teens who received the full series of hepatitis B shots as infants tested positive for hepatitis B surface antigen (HBsAg) which is an early indicator of infection or a sign that the person is a chronic carrier of the virus3This percentage was even higher among teens who had received the hepatitis B vaccine off schedule or whose mothers were high risk meaning they tested positive for hepatitis B e antigen (HBeAg) In other words it appears that in many children hepatitis B vaccine acquired immunity does NOT provide lasting protection A Healthy Immune System Can Resolve Hepatitis B InfectionEven if you have been vaccinated as a child itrsquos important to remember that you may not be protected from these risks and could still be infected via IV drug abuse sexual activity with an infected partner a blood transfusion with contaminated blood or even getting a manicure or pedicurehellipFortunately in most cases the hepatitis B infection will resolve on its own provided you have a well-functioning immune system Symptoms can be relieved bybullRestingbullAvoiding foods that weaken your immune function such as sugarsfructose grains and processed foods Healthful foods that help boost your immune system include fermented foods and organic vegetablesbullOptimizing your vitamin D levelsbullDrinking plenty of pure waterbullAvoiding alcohol and drugs
Причинно-следственныеbull Перееданиеbull Неадекватное питаниеbull Вредные привычкиbull Гиподинамия либо перегрузкиbull Неадекватное дыханиеbull Неадекватность мироощущения (стресс дефицит мотивации подавленность- депрессия)bull ИНТОКСИКАЦИЯbull ПОДАВЛЕННОСТЬ ИММУНИТЕТА
Предлагаемая схема клинического эксперимента на хронических носителях гепатитов В и С для изучения лечебных курсов
Курс оздоровления направленный на восстановление иммунной системы
Тераперапевтическая Вакцинация Курс анти-Вирусной ТерапииСовместное применение Вакцины и анти-Вирусного Курса
М О Н И Т О Р И Н Г по всем иммуно-параметрам ДНКРНК печеночные ферменты др
Ожидаемые результатыbull Влияние оздоровления-восстановления на течение хронического ГВbull Роль предварительного оздоровления-восстановления на каждый из методов леченияbull Сравнительная эффективность вакцины анти-вирусного курса и комбинации на фоне предварительного оздоровления-восстановления и без фона
() Курс относится к категории SPA
() очевидно применение вакцин 3-го и 4-го поколений для иммунизации подростков ранее привитых по стандартной схеме для новорожденных по причинам - снижения уровня anti-HBs часто до недетектируемого уровня через 10-12 лет - особой важности достоточности иммунитета в критическом для заражения возрасте 13-16 лет
Поколе
ния
Состав
антигенов
Особенности Назначение
I HBsAg
(S preS2)
Была разработана в конце 70-х годов XX века на основе HBsAg выделяемого и очищенного из плазмы крови пациентов хронических носителей вируса гепатита В
Более не применяется в качестве профилактической вакцины
II HBsAg
(S)
Рекомбинантная на основе экспрессии S- области в клетках дрожжей
В настоящее время применяется для массовой иммунизации населения
III HBsAg
(S preS1 preS2)
Рекомбинантная на основе экспрессии preS-S области в дрожжах или перевиваемых клетках млекопитающих
Разработана для массовой иммунизации не иммунизированных II поколением как более эффективная
IVa HBsAg (S)
HBcAg (core)
Рекомбинантная на основе экспрессии в дрожжах Hansenula HBsAg и HBcAg вируса геапатита В
Предлагается для лечения хронических вирусоносителей
IVb HBsAg
(S preS1 preS2)
HBcAg (core)
Рекомбинантная на основе экспрессии в дрожжах Hansenula всех структурных белков вируса геапатита В
Предлагается как наиболее эффективная для массовой иммунизации не вакцинированных II поколением и лечения вирусоносителей
NLB
Классификация вакцин на основе вирусспецифического антигенного состава
HBV-дикий вирус
Anti-HBs пресс в результате массовой вакцинации Исходно5-7 мутантовЧерез 20 лет22 мутантов
Мутантные формы прогрессивно накапливаются у привитыхУ невакцинированных это случайные мутации а у привитых ndash MHR HBsAg
Анти-вирусная терапияс помощью нуклеозидных аналоговМутации происходят направленно в Pol-последовательности но фактически меняют аа последовательность в MHR HBsAg что приводит к неузнаванию anti-HBs
Мутанты иммунно-происхождения
Мутанты Pol-происхождения
Не узнают anti-HBs
Узнают anti-preS1 anti-preS2 anti-HBc
Вакцина 3-го пок
Вакцина 4в - пок
Drug-resistant mutations rtM204I (sI195M) and rtM204V (sW196S) caused significant reduction in antigenicity for the immune-escaped HBsAg mutants sG145K and sG145R which may hamper HBV diagnosis and disease controlVirology Journal 2013 10292
Due to the overlap between the polymerase and envelope genes drug-resistant mutants are accompanied by amino acid changes in the envelope proteins as well
Ito K et al J Virol 20108412850-12861
The HBV polymerase gene overlaps completely with the genes of the 3 surface (S) antigen proteins The area boxed by dashed lines indicates the area of the HBsAg immunodominant area and the HBV reverse transcription area indicates the genome area most likely to produce mutants in both genesHBsAg mutations selected during antiviral therapy can lead to a virus escaping HBV vaccination
Horvat RT Lab Med 201142(8)488-496
Several conditions have been recognized in which HBV escape mutants arise in clinical practice bulltreatment with anti-HBs immunoglobulin eg after liver transplantation to avoid reinfection of the graft (2332) bullantiviral therapy by itself as the reading frames of the envelope and polymerase genes overlap
and several resistance mutations in the polymerase selected during antiviral therapy simultaneously alter the antigenicity of HBsAg (2021 31) bullde novo infection of vaccinated individuals with escape mutants (19)
Moreover Datta et al recently reported that HBV variants with the sG145R immune escape mutation are frequently ldquohiderdquo in the peripheral blood leukocyte compartment of infected individuals and may then serve as a source of reactivation or transmission (7)
J Virol 2010 vol 84 no 2 1026-1033
По современным оценкам частота мутаций HBsAg среди вакцинированных колеблется от 2 до 28
Из-за повсеместной вакцинации частота мутаций будет возрастать
Математическая модель предсказывает исчезновение ВГВ дикого типа в областях с HBsAg-эндемичностью и появление S генных мутаций в течение 100 лет как следствия универсальной ВГВ-вакцинации
Гилязова ДГ руководитель отдела Иммунохимия ООО Текан
httpwwwlabmedicinarufilesPREZENTACII20-2020122320Gilyazovapdf
HBV-дикий вирус
Anti-HBs пресс в результате массовой вакцинации Исходно5-7 мутантовЧерез 20 лет22 мутантов
Мутантные формы прогрессивно накапливаются у привитыхУ невакцинированных это случайные мутации а у привитых ndash MHR HBsAg
Анти-вирусная терапияс помощью нуклеозидных аналоговМутации происходят направленно в Pol-последовательности но фактически меняют аа последовательность в MHR HBsAg что приводит к неузнаванию anti-HBs
Мутанты иммунно-происхождения
Мутанты Pol-происхождения
Не узнают anti-HBs
Узнают anti-preS1 anti-preS2 anti-HBc
Вакцина 3-го пок
Вакцина 4в - пок
Drug-resistant mutations rtM204I (sI195M) and rtM204V (sW196S) caused significant reduction in antigenicity for the immune-escaped HBsAg mutants sG145K and sG145R which may hamper HBV diagnosis and disease controlVirology Journal 2013 10292
Type of Vaccine Vaccine Antigen Adjuvant Host Cell Target Current Status References
Peptide
(a) Palmitolylated TT830-843 HTL
epitope covalently linked to the HBcAg 18 ndash27 CTL epitope
NACytotoxic T Lymphocyt
e
Phase II clinical trial
Livingston et al 1999 [22]
(b) HBV core antigen 18-27
peptide + tetanus taxoid peptide 830
843+palmic acid molecules
NACytotoxic T Lymphocyt
e
Pre-clinical amp clinical
Vitiello et al 1995 [23]
ProteinHBsAganti-
HBsIgAlum
Cytotoxic T Lymphocyt
e
Phase II clinical trial
Wen et al 2003
Xu et al 2008 [28]
DNA
Small(S) and middle (preS2S) proteins of the HBV envelope
(HBsAg)
NACD8+ T
Lymphocyte
Phase I clinical trial
Mancini et al 2004
Vector-basedModified
prHBV13HBVcore protein
NA
CD4+ and CD8+ T
Lymphocyte
Pre-clinicalDeng et al
2009 [8]
Cell-based
DCs pulsed with HBs28-39 peptide or
recombinant preS2S particles
NACytotoxic T Lymphocyt
ePre-clinical
Akbar et al 2004 [36]
Therapeutic Vaccine for Hepatitis B virusJ Infect Dis Immunol Tech 2012 11
Release Summary February 12 2014httpwwwbusinesswirecomnewshome20140212005051enCreation-ABIVAX---Leader-Therapeutic-Vaccines-FrenchU3PoW_ldW8AAbivax creation of ABIVAX - a leader in therapeutic vaccines and the first French company to sign an exclusive partnering agreement with Cuba in healthcareABIVAX specializes in therapeutic vaccines and antivirals combining the technologies and the product portfolios of three French biotech companies financed by Truffle CapitaABIVAX already has two therapeutic vaccines in development one in a Phase IIb clinical trial in patients with chronic hepatitis B
The HBsAgndashHBcAg vaccine candidate was safe well tolerated and immunogenic in this phase I study in healthy adults To our knowledge this is the first demonstration of safety and immunogenicity for a nasal vaccine candidate comprising HBV antigensThe vaccine elicited anti-HBc seroconversion in 100 of subjects as early as day 30 of the immunization schedule while a seroprotective anti-HBs titer (ge10 IUl) was at a maximum at day 90 (75) International Journal of Infectious DiseasesVolume 11 Issue 5 September 2007
A novel therapeutic hepatitis B vaccine induces cellular and humoral immune responses and breaks tolerance in hepatitis B virus (HBV) transgenic miceBuchmann P1 Dembek C Kuklick L Jaumlger C Tedjokusumo R von Freyend MJ Drebber U Janowicz Z Melber K Protzer U
1Rhein Biotech GmbH Duesseldorf Germany pbuchmanneudynavaxcomVaccine 2013 631(8)A paradigm of therapeutic vaccination is the potent induction of T-cell responses against key viral antigens ndash besides activation of a humoral immune response We have evaluated the potential of a novel vaccine formulation comprising particulate hepatitis B surface (HBsAg) and core antigen (HBcAg) and the saponin-based ISCOMATRIXtrade adjuvant for its ability to stimulate T and B cell responses in C57BL6 mice and its ability to break tolerance in HBV transgenic (HBVtg) mice The vaccine induced multifunctional HBsAg- and HBcAg-specific CD8+ T cells detected by staining for IFNγ TNFα and IL-2 as well as high antibody titers against both antigens Vaccination of HBVtg animals induced potent HBsAg- and HBcAg-specific CD8+ T-cell responses in spleens and HBcAg-specific CD8+ T-cell responses in livers as well as anti-HBs seroconversion two weeks post injection Vaccination further reduced HBcAg expression in livers of HBVtg mice without causing liver damage In summary this study demonstrates therapeutic efficacy of a novel vaccine formulation in a mouse model of immunotolerant chronic HBV infection
HBsAg-HBcAg vaccine version - IV generation
PreS1 is the priority target antigen for the new HBV vaccines because PreS1 has a greater number of immunogenic T cell and B cell epitopes than the S protein (9 12 15) including a strong T cell epitope (aa 21 to 28) and an effective B cell epitope (aa 12 to 32 and 32 to 53) The PreS1 protein has binding sites for liver cells (aa 21 to 47) that play an important role in viral attachment and entry (13 15) Neurath et al have shown that direct immunization with a PreS1 polypeptide (aa 21 to 47) can protect against HBV infection in chimpanzees (21) Additionally the PreS1 antibody is produced earlier than the S antibody and the PreS1-specific cell-mediated immunity may help overcome immune unresponsiveness to the S protein in certain individuals (19 24) Therefore the PreS1 antigen may play an important role in the neutralization blockade and clearance of HBV infections
Clin Vaccine Immun 2011 18(11) 1789-1795
Inclusion of PreS2S antigen in vaccine formulation could also mitigate the chances of non-responsiveness of vaccines against escape variants (Yamada et al 2001) The PreS2S gene is comprises of S gene with an extra 165 nucleotides at 5rsquo end (Tai et al 1997) and antigen is involved in nucleocapsid interaction (Poisson et al 1997) and extra cellular secretion of HBV particles (Le Seyec et al 1998) playing an important role in full stimulation of humoral and cellular immune responses In addition the PreS2S protein is also important for immunological responses at T-cell level and has T-cell and B-cell recognition sites spanning amino acids 1-25 of the protein (Neurath et al 1986) making it most suitable candidate antigen for HBV vaccine development This study describes the heterologous expression of a characterized PreS2S gene from genotype D of HBV in P pastoris The antigen will help to increase the efficacy of HBV recombinant vaccines
Pak J Bot 2012 44 355-359
Use of Pre-S Protein-Containing Hepatitis B Virus Surface Antigens and a Powerful Adjuvant To Develop an Immune Therapy for Chronic Hepatitis B Virus InfectionJung Sun Yum Byung Cheol Ahn [] and Hong Mo Moon
Clin Vaccine Immun 19(2) 2012
Роль preS-областей
J Hep 2011 54 1286-1296
НИИ вакцин и сывороток им И И Мечникова РАМН Москва
Сочетанная терапия laquoвакцина + альфа-2 бета-интерферонraquo позволила получить подавление вирусной репликации в первые 1ndash2 месяца от начала лечения у 786 больных сероконверсию HВsAg на анти-HВs mdash у 964 Исчезновение HВеAg наблюдалось через 6 месяца у всех больных а анти-HВе через 2ndash3 месяца от начала лечения появились у всех больных Наблюдение за пациентами в течение трех лет и более показало что стойкий ответ на лечение отмечался у 24 (857) К концу лечения нормализовались все популяции лимфоцитов высоким оставался только уровень лимфоцитов экспрессирующих рецептор к ИЛ-2 (CD25+) оставались сниженными резервы фагоцитоза и кислородзависимого киллинга [5]Таким образом вакцинация против ГВ является актуальной и необходимой больным с ХЗП пациентам с ХГВ иили ХГС носителям ВГВ иили ВГС поскольку способствует подавлению вирусной репликации у хронических вирусоносителей может играть существенную роль в контроле над виремией значительно повышает эффективность лечения ХВГ
Афигенова ВП Костинов МП 2011
Study Calls Into Question Effectiveness of Hepatitis B Vaccine for NewbornsDecember 17 2013httparticlesmercolacomsitesarticlesarchive20131217newborn-hepatitis-b-vaccineaspxBy Dr JM Mercola
New Study Hepatitis B Vaccination at Birth May Not Prevent Hidden InfectionsA new study is raising another red flag that the practice of universally vaccinating all newborn babies for hepatitis B is seriously flawed The researchers followed 259 babies born to hepatitis-B-positive mothers for two years in order to determine whether vaccinating such babies prevents asymptomatic occult HBV (hepatitis B virus) infectionThe researchers found that while the vaccine may help prevent overt HBV transmission it was not effective in preventing occult HBV infection in babies which may occur in up to 40 percent of babies born to hepatitis B-positive mothersHepatitis B Shot May Be Ineffective by the Time Your Child Is a TeenagerAnother issue to consider if you are weighing the benefits and risks of giving your newborn infant or young child hepatitis B vaccine is that vaccine acquired immunity often does not persist until a child reaches his or her teenage years ndash the time when acquiring a hepatitis B infection may be more likely Research shows that by that time the protection from the childhood vaccine may have long since wanedOne study found that about 15 percent of teens who received the full series of hepatitis B shots as infants tested positive for hepatitis B surface antigen (HBsAg) which is an early indicator of infection or a sign that the person is a chronic carrier of the virus3This percentage was even higher among teens who had received the hepatitis B vaccine off schedule or whose mothers were high risk meaning they tested positive for hepatitis B e antigen (HBeAg) In other words it appears that in many children hepatitis B vaccine acquired immunity does NOT provide lasting protection A Healthy Immune System Can Resolve Hepatitis B InfectionEven if you have been vaccinated as a child itrsquos important to remember that you may not be protected from these risks and could still be infected via IV drug abuse sexual activity with an infected partner a blood transfusion with contaminated blood or even getting a manicure or pedicurehellipFortunately in most cases the hepatitis B infection will resolve on its own provided you have a well-functioning immune system Symptoms can be relieved bybullRestingbullAvoiding foods that weaken your immune function such as sugarsfructose grains and processed foods Healthful foods that help boost your immune system include fermented foods and organic vegetablesbullOptimizing your vitamin D levelsbullDrinking plenty of pure waterbullAvoiding alcohol and drugs
Причинно-следственныеbull Перееданиеbull Неадекватное питаниеbull Вредные привычкиbull Гиподинамия либо перегрузкиbull Неадекватное дыханиеbull Неадекватность мироощущения (стресс дефицит мотивации подавленность- депрессия)bull ИНТОКСИКАЦИЯbull ПОДАВЛЕННОСТЬ ИММУНИТЕТА
Предлагаемая схема клинического эксперимента на хронических носителях гепатитов В и С для изучения лечебных курсов
Курс оздоровления направленный на восстановление иммунной системы
Тераперапевтическая Вакцинация Курс анти-Вирусной ТерапииСовместное применение Вакцины и анти-Вирусного Курса
М О Н И Т О Р И Н Г по всем иммуно-параметрам ДНКРНК печеночные ферменты др
Ожидаемые результатыbull Влияние оздоровления-восстановления на течение хронического ГВbull Роль предварительного оздоровления-восстановления на каждый из методов леченияbull Сравнительная эффективность вакцины анти-вирусного курса и комбинации на фоне предварительного оздоровления-восстановления и без фона
() Курс относится к категории SPA
HBV-дикий вирус
Anti-HBs пресс в результате массовой вакцинации Исходно5-7 мутантовЧерез 20 лет22 мутантов
Мутантные формы прогрессивно накапливаются у привитыхУ невакцинированных это случайные мутации а у привитых ndash MHR HBsAg
Анти-вирусная терапияс помощью нуклеозидных аналоговМутации происходят направленно в Pol-последовательности но фактически меняют аа последовательность в MHR HBsAg что приводит к неузнаванию anti-HBs
Мутанты иммунно-происхождения
Мутанты Pol-происхождения
Не узнают anti-HBs
Узнают anti-preS1 anti-preS2 anti-HBc
Вакцина 3-го пок
Вакцина 4в - пок
Drug-resistant mutations rtM204I (sI195M) and rtM204V (sW196S) caused significant reduction in antigenicity for the immune-escaped HBsAg mutants sG145K and sG145R which may hamper HBV diagnosis and disease controlVirology Journal 2013 10292
Due to the overlap between the polymerase and envelope genes drug-resistant mutants are accompanied by amino acid changes in the envelope proteins as well
Ito K et al J Virol 20108412850-12861
The HBV polymerase gene overlaps completely with the genes of the 3 surface (S) antigen proteins The area boxed by dashed lines indicates the area of the HBsAg immunodominant area and the HBV reverse transcription area indicates the genome area most likely to produce mutants in both genesHBsAg mutations selected during antiviral therapy can lead to a virus escaping HBV vaccination
Horvat RT Lab Med 201142(8)488-496
Several conditions have been recognized in which HBV escape mutants arise in clinical practice bulltreatment with anti-HBs immunoglobulin eg after liver transplantation to avoid reinfection of the graft (2332) bullantiviral therapy by itself as the reading frames of the envelope and polymerase genes overlap
and several resistance mutations in the polymerase selected during antiviral therapy simultaneously alter the antigenicity of HBsAg (2021 31) bullde novo infection of vaccinated individuals with escape mutants (19)
Moreover Datta et al recently reported that HBV variants with the sG145R immune escape mutation are frequently ldquohiderdquo in the peripheral blood leukocyte compartment of infected individuals and may then serve as a source of reactivation or transmission (7)
J Virol 2010 vol 84 no 2 1026-1033
По современным оценкам частота мутаций HBsAg среди вакцинированных колеблется от 2 до 28
Из-за повсеместной вакцинации частота мутаций будет возрастать
Математическая модель предсказывает исчезновение ВГВ дикого типа в областях с HBsAg-эндемичностью и появление S генных мутаций в течение 100 лет как следствия универсальной ВГВ-вакцинации
Гилязова ДГ руководитель отдела Иммунохимия ООО Текан
httpwwwlabmedicinarufilesPREZENTACII20-2020122320Gilyazovapdf
HBV-дикий вирус
Anti-HBs пресс в результате массовой вакцинации Исходно5-7 мутантовЧерез 20 лет22 мутантов
Мутантные формы прогрессивно накапливаются у привитыхУ невакцинированных это случайные мутации а у привитых ndash MHR HBsAg
Анти-вирусная терапияс помощью нуклеозидных аналоговМутации происходят направленно в Pol-последовательности но фактически меняют аа последовательность в MHR HBsAg что приводит к неузнаванию anti-HBs
Мутанты иммунно-происхождения
Мутанты Pol-происхождения
Не узнают anti-HBs
Узнают anti-preS1 anti-preS2 anti-HBc
Вакцина 3-го пок
Вакцина 4в - пок
Drug-resistant mutations rtM204I (sI195M) and rtM204V (sW196S) caused significant reduction in antigenicity for the immune-escaped HBsAg mutants sG145K and sG145R which may hamper HBV diagnosis and disease controlVirology Journal 2013 10292
Type of Vaccine Vaccine Antigen Adjuvant Host Cell Target Current Status References
Peptide
(a) Palmitolylated TT830-843 HTL
epitope covalently linked to the HBcAg 18 ndash27 CTL epitope
NACytotoxic T Lymphocyt
e
Phase II clinical trial
Livingston et al 1999 [22]
(b) HBV core antigen 18-27
peptide + tetanus taxoid peptide 830
843+palmic acid molecules
NACytotoxic T Lymphocyt
e
Pre-clinical amp clinical
Vitiello et al 1995 [23]
ProteinHBsAganti-
HBsIgAlum
Cytotoxic T Lymphocyt
e
Phase II clinical trial
Wen et al 2003
Xu et al 2008 [28]
DNA
Small(S) and middle (preS2S) proteins of the HBV envelope
(HBsAg)
NACD8+ T
Lymphocyte
Phase I clinical trial
Mancini et al 2004
Vector-basedModified
prHBV13HBVcore protein
NA
CD4+ and CD8+ T
Lymphocyte
Pre-clinicalDeng et al
2009 [8]
Cell-based
DCs pulsed with HBs28-39 peptide or
recombinant preS2S particles
NACytotoxic T Lymphocyt
ePre-clinical
Akbar et al 2004 [36]
Therapeutic Vaccine for Hepatitis B virusJ Infect Dis Immunol Tech 2012 11
Release Summary February 12 2014httpwwwbusinesswirecomnewshome20140212005051enCreation-ABIVAX---Leader-Therapeutic-Vaccines-FrenchU3PoW_ldW8AAbivax creation of ABIVAX - a leader in therapeutic vaccines and the first French company to sign an exclusive partnering agreement with Cuba in healthcareABIVAX specializes in therapeutic vaccines and antivirals combining the technologies and the product portfolios of three French biotech companies financed by Truffle CapitaABIVAX already has two therapeutic vaccines in development one in a Phase IIb clinical trial in patients with chronic hepatitis B
The HBsAgndashHBcAg vaccine candidate was safe well tolerated and immunogenic in this phase I study in healthy adults To our knowledge this is the first demonstration of safety and immunogenicity for a nasal vaccine candidate comprising HBV antigensThe vaccine elicited anti-HBc seroconversion in 100 of subjects as early as day 30 of the immunization schedule while a seroprotective anti-HBs titer (ge10 IUl) was at a maximum at day 90 (75) International Journal of Infectious DiseasesVolume 11 Issue 5 September 2007
A novel therapeutic hepatitis B vaccine induces cellular and humoral immune responses and breaks tolerance in hepatitis B virus (HBV) transgenic miceBuchmann P1 Dembek C Kuklick L Jaumlger C Tedjokusumo R von Freyend MJ Drebber U Janowicz Z Melber K Protzer U
1Rhein Biotech GmbH Duesseldorf Germany pbuchmanneudynavaxcomVaccine 2013 631(8)A paradigm of therapeutic vaccination is the potent induction of T-cell responses against key viral antigens ndash besides activation of a humoral immune response We have evaluated the potential of a novel vaccine formulation comprising particulate hepatitis B surface (HBsAg) and core antigen (HBcAg) and the saponin-based ISCOMATRIXtrade adjuvant for its ability to stimulate T and B cell responses in C57BL6 mice and its ability to break tolerance in HBV transgenic (HBVtg) mice The vaccine induced multifunctional HBsAg- and HBcAg-specific CD8+ T cells detected by staining for IFNγ TNFα and IL-2 as well as high antibody titers against both antigens Vaccination of HBVtg animals induced potent HBsAg- and HBcAg-specific CD8+ T-cell responses in spleens and HBcAg-specific CD8+ T-cell responses in livers as well as anti-HBs seroconversion two weeks post injection Vaccination further reduced HBcAg expression in livers of HBVtg mice without causing liver damage In summary this study demonstrates therapeutic efficacy of a novel vaccine formulation in a mouse model of immunotolerant chronic HBV infection
HBsAg-HBcAg vaccine version - IV generation
PreS1 is the priority target antigen for the new HBV vaccines because PreS1 has a greater number of immunogenic T cell and B cell epitopes than the S protein (9 12 15) including a strong T cell epitope (aa 21 to 28) and an effective B cell epitope (aa 12 to 32 and 32 to 53) The PreS1 protein has binding sites for liver cells (aa 21 to 47) that play an important role in viral attachment and entry (13 15) Neurath et al have shown that direct immunization with a PreS1 polypeptide (aa 21 to 47) can protect against HBV infection in chimpanzees (21) Additionally the PreS1 antibody is produced earlier than the S antibody and the PreS1-specific cell-mediated immunity may help overcome immune unresponsiveness to the S protein in certain individuals (19 24) Therefore the PreS1 antigen may play an important role in the neutralization blockade and clearance of HBV infections
Clin Vaccine Immun 2011 18(11) 1789-1795
Inclusion of PreS2S antigen in vaccine formulation could also mitigate the chances of non-responsiveness of vaccines against escape variants (Yamada et al 2001) The PreS2S gene is comprises of S gene with an extra 165 nucleotides at 5rsquo end (Tai et al 1997) and antigen is involved in nucleocapsid interaction (Poisson et al 1997) and extra cellular secretion of HBV particles (Le Seyec et al 1998) playing an important role in full stimulation of humoral and cellular immune responses In addition the PreS2S protein is also important for immunological responses at T-cell level and has T-cell and B-cell recognition sites spanning amino acids 1-25 of the protein (Neurath et al 1986) making it most suitable candidate antigen for HBV vaccine development This study describes the heterologous expression of a characterized PreS2S gene from genotype D of HBV in P pastoris The antigen will help to increase the efficacy of HBV recombinant vaccines
Pak J Bot 2012 44 355-359
Use of Pre-S Protein-Containing Hepatitis B Virus Surface Antigens and a Powerful Adjuvant To Develop an Immune Therapy for Chronic Hepatitis B Virus InfectionJung Sun Yum Byung Cheol Ahn [] and Hong Mo Moon
Clin Vaccine Immun 19(2) 2012
Роль preS-областей
J Hep 2011 54 1286-1296
НИИ вакцин и сывороток им И И Мечникова РАМН Москва
Сочетанная терапия laquoвакцина + альфа-2 бета-интерферонraquo позволила получить подавление вирусной репликации в первые 1ndash2 месяца от начала лечения у 786 больных сероконверсию HВsAg на анти-HВs mdash у 964 Исчезновение HВеAg наблюдалось через 6 месяца у всех больных а анти-HВе через 2ndash3 месяца от начала лечения появились у всех больных Наблюдение за пациентами в течение трех лет и более показало что стойкий ответ на лечение отмечался у 24 (857) К концу лечения нормализовались все популяции лимфоцитов высоким оставался только уровень лимфоцитов экспрессирующих рецептор к ИЛ-2 (CD25+) оставались сниженными резервы фагоцитоза и кислородзависимого киллинга [5]Таким образом вакцинация против ГВ является актуальной и необходимой больным с ХЗП пациентам с ХГВ иили ХГС носителям ВГВ иили ВГС поскольку способствует подавлению вирусной репликации у хронических вирусоносителей может играть существенную роль в контроле над виремией значительно повышает эффективность лечения ХВГ
Афигенова ВП Костинов МП 2011
Study Calls Into Question Effectiveness of Hepatitis B Vaccine for NewbornsDecember 17 2013httparticlesmercolacomsitesarticlesarchive20131217newborn-hepatitis-b-vaccineaspxBy Dr JM Mercola
New Study Hepatitis B Vaccination at Birth May Not Prevent Hidden InfectionsA new study is raising another red flag that the practice of universally vaccinating all newborn babies for hepatitis B is seriously flawed The researchers followed 259 babies born to hepatitis-B-positive mothers for two years in order to determine whether vaccinating such babies prevents asymptomatic occult HBV (hepatitis B virus) infectionThe researchers found that while the vaccine may help prevent overt HBV transmission it was not effective in preventing occult HBV infection in babies which may occur in up to 40 percent of babies born to hepatitis B-positive mothersHepatitis B Shot May Be Ineffective by the Time Your Child Is a TeenagerAnother issue to consider if you are weighing the benefits and risks of giving your newborn infant or young child hepatitis B vaccine is that vaccine acquired immunity often does not persist until a child reaches his or her teenage years ndash the time when acquiring a hepatitis B infection may be more likely Research shows that by that time the protection from the childhood vaccine may have long since wanedOne study found that about 15 percent of teens who received the full series of hepatitis B shots as infants tested positive for hepatitis B surface antigen (HBsAg) which is an early indicator of infection or a sign that the person is a chronic carrier of the virus3This percentage was even higher among teens who had received the hepatitis B vaccine off schedule or whose mothers were high risk meaning they tested positive for hepatitis B e antigen (HBeAg) In other words it appears that in many children hepatitis B vaccine acquired immunity does NOT provide lasting protection A Healthy Immune System Can Resolve Hepatitis B InfectionEven if you have been vaccinated as a child itrsquos important to remember that you may not be protected from these risks and could still be infected via IV drug abuse sexual activity with an infected partner a blood transfusion with contaminated blood or even getting a manicure or pedicurehellipFortunately in most cases the hepatitis B infection will resolve on its own provided you have a well-functioning immune system Symptoms can be relieved bybullRestingbullAvoiding foods that weaken your immune function such as sugarsfructose grains and processed foods Healthful foods that help boost your immune system include fermented foods and organic vegetablesbullOptimizing your vitamin D levelsbullDrinking plenty of pure waterbullAvoiding alcohol and drugs
Причинно-следственныеbull Перееданиеbull Неадекватное питаниеbull Вредные привычкиbull Гиподинамия либо перегрузкиbull Неадекватное дыханиеbull Неадекватность мироощущения (стресс дефицит мотивации подавленность- депрессия)bull ИНТОКСИКАЦИЯbull ПОДАВЛЕННОСТЬ ИММУНИТЕТА
Предлагаемая схема клинического эксперимента на хронических носителях гепатитов В и С для изучения лечебных курсов
Курс оздоровления направленный на восстановление иммунной системы
Тераперапевтическая Вакцинация Курс анти-Вирусной ТерапииСовместное применение Вакцины и анти-Вирусного Курса
М О Н И Т О Р И Н Г по всем иммуно-параметрам ДНКРНК печеночные ферменты др
Ожидаемые результатыbull Влияние оздоровления-восстановления на течение хронического ГВbull Роль предварительного оздоровления-восстановления на каждый из методов леченияbull Сравнительная эффективность вакцины анти-вирусного курса и комбинации на фоне предварительного оздоровления-восстановления и без фона
() Курс относится к категории SPA
Due to the overlap between the polymerase and envelope genes drug-resistant mutants are accompanied by amino acid changes in the envelope proteins as well
Ito K et al J Virol 20108412850-12861
The HBV polymerase gene overlaps completely with the genes of the 3 surface (S) antigen proteins The area boxed by dashed lines indicates the area of the HBsAg immunodominant area and the HBV reverse transcription area indicates the genome area most likely to produce mutants in both genesHBsAg mutations selected during antiviral therapy can lead to a virus escaping HBV vaccination
Horvat RT Lab Med 201142(8)488-496
Several conditions have been recognized in which HBV escape mutants arise in clinical practice bulltreatment with anti-HBs immunoglobulin eg after liver transplantation to avoid reinfection of the graft (2332) bullantiviral therapy by itself as the reading frames of the envelope and polymerase genes overlap
and several resistance mutations in the polymerase selected during antiviral therapy simultaneously alter the antigenicity of HBsAg (2021 31) bullde novo infection of vaccinated individuals with escape mutants (19)
Moreover Datta et al recently reported that HBV variants with the sG145R immune escape mutation are frequently ldquohiderdquo in the peripheral blood leukocyte compartment of infected individuals and may then serve as a source of reactivation or transmission (7)
J Virol 2010 vol 84 no 2 1026-1033
По современным оценкам частота мутаций HBsAg среди вакцинированных колеблется от 2 до 28
Из-за повсеместной вакцинации частота мутаций будет возрастать
Математическая модель предсказывает исчезновение ВГВ дикого типа в областях с HBsAg-эндемичностью и появление S генных мутаций в течение 100 лет как следствия универсальной ВГВ-вакцинации
Гилязова ДГ руководитель отдела Иммунохимия ООО Текан
httpwwwlabmedicinarufilesPREZENTACII20-2020122320Gilyazovapdf
HBV-дикий вирус
Anti-HBs пресс в результате массовой вакцинации Исходно5-7 мутантовЧерез 20 лет22 мутантов
Мутантные формы прогрессивно накапливаются у привитыхУ невакцинированных это случайные мутации а у привитых ndash MHR HBsAg
Анти-вирусная терапияс помощью нуклеозидных аналоговМутации происходят направленно в Pol-последовательности но фактически меняют аа последовательность в MHR HBsAg что приводит к неузнаванию anti-HBs
Мутанты иммунно-происхождения
Мутанты Pol-происхождения
Не узнают anti-HBs
Узнают anti-preS1 anti-preS2 anti-HBc
Вакцина 3-го пок
Вакцина 4в - пок
Drug-resistant mutations rtM204I (sI195M) and rtM204V (sW196S) caused significant reduction in antigenicity for the immune-escaped HBsAg mutants sG145K and sG145R which may hamper HBV diagnosis and disease controlVirology Journal 2013 10292
Type of Vaccine Vaccine Antigen Adjuvant Host Cell Target Current Status References
Peptide
(a) Palmitolylated TT830-843 HTL
epitope covalently linked to the HBcAg 18 ndash27 CTL epitope
NACytotoxic T Lymphocyt
e
Phase II clinical trial
Livingston et al 1999 [22]
(b) HBV core antigen 18-27
peptide + tetanus taxoid peptide 830
843+palmic acid molecules
NACytotoxic T Lymphocyt
e
Pre-clinical amp clinical
Vitiello et al 1995 [23]
ProteinHBsAganti-
HBsIgAlum
Cytotoxic T Lymphocyt
e
Phase II clinical trial
Wen et al 2003
Xu et al 2008 [28]
DNA
Small(S) and middle (preS2S) proteins of the HBV envelope
(HBsAg)
NACD8+ T
Lymphocyte
Phase I clinical trial
Mancini et al 2004
Vector-basedModified
prHBV13HBVcore protein
NA
CD4+ and CD8+ T
Lymphocyte
Pre-clinicalDeng et al
2009 [8]
Cell-based
DCs pulsed with HBs28-39 peptide or
recombinant preS2S particles
NACytotoxic T Lymphocyt
ePre-clinical
Akbar et al 2004 [36]
Therapeutic Vaccine for Hepatitis B virusJ Infect Dis Immunol Tech 2012 11
Release Summary February 12 2014httpwwwbusinesswirecomnewshome20140212005051enCreation-ABIVAX---Leader-Therapeutic-Vaccines-FrenchU3PoW_ldW8AAbivax creation of ABIVAX - a leader in therapeutic vaccines and the first French company to sign an exclusive partnering agreement with Cuba in healthcareABIVAX specializes in therapeutic vaccines and antivirals combining the technologies and the product portfolios of three French biotech companies financed by Truffle CapitaABIVAX already has two therapeutic vaccines in development one in a Phase IIb clinical trial in patients with chronic hepatitis B
The HBsAgndashHBcAg vaccine candidate was safe well tolerated and immunogenic in this phase I study in healthy adults To our knowledge this is the first demonstration of safety and immunogenicity for a nasal vaccine candidate comprising HBV antigensThe vaccine elicited anti-HBc seroconversion in 100 of subjects as early as day 30 of the immunization schedule while a seroprotective anti-HBs titer (ge10 IUl) was at a maximum at day 90 (75) International Journal of Infectious DiseasesVolume 11 Issue 5 September 2007
A novel therapeutic hepatitis B vaccine induces cellular and humoral immune responses and breaks tolerance in hepatitis B virus (HBV) transgenic miceBuchmann P1 Dembek C Kuklick L Jaumlger C Tedjokusumo R von Freyend MJ Drebber U Janowicz Z Melber K Protzer U
1Rhein Biotech GmbH Duesseldorf Germany pbuchmanneudynavaxcomVaccine 2013 631(8)A paradigm of therapeutic vaccination is the potent induction of T-cell responses against key viral antigens ndash besides activation of a humoral immune response We have evaluated the potential of a novel vaccine formulation comprising particulate hepatitis B surface (HBsAg) and core antigen (HBcAg) and the saponin-based ISCOMATRIXtrade adjuvant for its ability to stimulate T and B cell responses in C57BL6 mice and its ability to break tolerance in HBV transgenic (HBVtg) mice The vaccine induced multifunctional HBsAg- and HBcAg-specific CD8+ T cells detected by staining for IFNγ TNFα and IL-2 as well as high antibody titers against both antigens Vaccination of HBVtg animals induced potent HBsAg- and HBcAg-specific CD8+ T-cell responses in spleens and HBcAg-specific CD8+ T-cell responses in livers as well as anti-HBs seroconversion two weeks post injection Vaccination further reduced HBcAg expression in livers of HBVtg mice without causing liver damage In summary this study demonstrates therapeutic efficacy of a novel vaccine formulation in a mouse model of immunotolerant chronic HBV infection
HBsAg-HBcAg vaccine version - IV generation
PreS1 is the priority target antigen for the new HBV vaccines because PreS1 has a greater number of immunogenic T cell and B cell epitopes than the S protein (9 12 15) including a strong T cell epitope (aa 21 to 28) and an effective B cell epitope (aa 12 to 32 and 32 to 53) The PreS1 protein has binding sites for liver cells (aa 21 to 47) that play an important role in viral attachment and entry (13 15) Neurath et al have shown that direct immunization with a PreS1 polypeptide (aa 21 to 47) can protect against HBV infection in chimpanzees (21) Additionally the PreS1 antibody is produced earlier than the S antibody and the PreS1-specific cell-mediated immunity may help overcome immune unresponsiveness to the S protein in certain individuals (19 24) Therefore the PreS1 antigen may play an important role in the neutralization blockade and clearance of HBV infections
Clin Vaccine Immun 2011 18(11) 1789-1795
Inclusion of PreS2S antigen in vaccine formulation could also mitigate the chances of non-responsiveness of vaccines against escape variants (Yamada et al 2001) The PreS2S gene is comprises of S gene with an extra 165 nucleotides at 5rsquo end (Tai et al 1997) and antigen is involved in nucleocapsid interaction (Poisson et al 1997) and extra cellular secretion of HBV particles (Le Seyec et al 1998) playing an important role in full stimulation of humoral and cellular immune responses In addition the PreS2S protein is also important for immunological responses at T-cell level and has T-cell and B-cell recognition sites spanning amino acids 1-25 of the protein (Neurath et al 1986) making it most suitable candidate antigen for HBV vaccine development This study describes the heterologous expression of a characterized PreS2S gene from genotype D of HBV in P pastoris The antigen will help to increase the efficacy of HBV recombinant vaccines
Pak J Bot 2012 44 355-359
Use of Pre-S Protein-Containing Hepatitis B Virus Surface Antigens and a Powerful Adjuvant To Develop an Immune Therapy for Chronic Hepatitis B Virus InfectionJung Sun Yum Byung Cheol Ahn [] and Hong Mo Moon
Clin Vaccine Immun 19(2) 2012
Роль preS-областей
J Hep 2011 54 1286-1296
НИИ вакцин и сывороток им И И Мечникова РАМН Москва
Сочетанная терапия laquoвакцина + альфа-2 бета-интерферонraquo позволила получить подавление вирусной репликации в первые 1ndash2 месяца от начала лечения у 786 больных сероконверсию HВsAg на анти-HВs mdash у 964 Исчезновение HВеAg наблюдалось через 6 месяца у всех больных а анти-HВе через 2ndash3 месяца от начала лечения появились у всех больных Наблюдение за пациентами в течение трех лет и более показало что стойкий ответ на лечение отмечался у 24 (857) К концу лечения нормализовались все популяции лимфоцитов высоким оставался только уровень лимфоцитов экспрессирующих рецептор к ИЛ-2 (CD25+) оставались сниженными резервы фагоцитоза и кислородзависимого киллинга [5]Таким образом вакцинация против ГВ является актуальной и необходимой больным с ХЗП пациентам с ХГВ иили ХГС носителям ВГВ иили ВГС поскольку способствует подавлению вирусной репликации у хронических вирусоносителей может играть существенную роль в контроле над виремией значительно повышает эффективность лечения ХВГ
Афигенова ВП Костинов МП 2011
Study Calls Into Question Effectiveness of Hepatitis B Vaccine for NewbornsDecember 17 2013httparticlesmercolacomsitesarticlesarchive20131217newborn-hepatitis-b-vaccineaspxBy Dr JM Mercola
New Study Hepatitis B Vaccination at Birth May Not Prevent Hidden InfectionsA new study is raising another red flag that the practice of universally vaccinating all newborn babies for hepatitis B is seriously flawed The researchers followed 259 babies born to hepatitis-B-positive mothers for two years in order to determine whether vaccinating such babies prevents asymptomatic occult HBV (hepatitis B virus) infectionThe researchers found that while the vaccine may help prevent overt HBV transmission it was not effective in preventing occult HBV infection in babies which may occur in up to 40 percent of babies born to hepatitis B-positive mothersHepatitis B Shot May Be Ineffective by the Time Your Child Is a TeenagerAnother issue to consider if you are weighing the benefits and risks of giving your newborn infant or young child hepatitis B vaccine is that vaccine acquired immunity often does not persist until a child reaches his or her teenage years ndash the time when acquiring a hepatitis B infection may be more likely Research shows that by that time the protection from the childhood vaccine may have long since wanedOne study found that about 15 percent of teens who received the full series of hepatitis B shots as infants tested positive for hepatitis B surface antigen (HBsAg) which is an early indicator of infection or a sign that the person is a chronic carrier of the virus3This percentage was even higher among teens who had received the hepatitis B vaccine off schedule or whose mothers were high risk meaning they tested positive for hepatitis B e antigen (HBeAg) In other words it appears that in many children hepatitis B vaccine acquired immunity does NOT provide lasting protection A Healthy Immune System Can Resolve Hepatitis B InfectionEven if you have been vaccinated as a child itrsquos important to remember that you may not be protected from these risks and could still be infected via IV drug abuse sexual activity with an infected partner a blood transfusion with contaminated blood or even getting a manicure or pedicurehellipFortunately in most cases the hepatitis B infection will resolve on its own provided you have a well-functioning immune system Symptoms can be relieved bybullRestingbullAvoiding foods that weaken your immune function such as sugarsfructose grains and processed foods Healthful foods that help boost your immune system include fermented foods and organic vegetablesbullOptimizing your vitamin D levelsbullDrinking plenty of pure waterbullAvoiding alcohol and drugs
Причинно-следственныеbull Перееданиеbull Неадекватное питаниеbull Вредные привычкиbull Гиподинамия либо перегрузкиbull Неадекватное дыханиеbull Неадекватность мироощущения (стресс дефицит мотивации подавленность- депрессия)bull ИНТОКСИКАЦИЯbull ПОДАВЛЕННОСТЬ ИММУНИТЕТА
Предлагаемая схема клинического эксперимента на хронических носителях гепатитов В и С для изучения лечебных курсов
Курс оздоровления направленный на восстановление иммунной системы
Тераперапевтическая Вакцинация Курс анти-Вирусной ТерапииСовместное применение Вакцины и анти-Вирусного Курса
М О Н И Т О Р И Н Г по всем иммуно-параметрам ДНКРНК печеночные ферменты др
Ожидаемые результатыbull Влияние оздоровления-восстановления на течение хронического ГВbull Роль предварительного оздоровления-восстановления на каждый из методов леченияbull Сравнительная эффективность вакцины анти-вирусного курса и комбинации на фоне предварительного оздоровления-восстановления и без фона
() Курс относится к категории SPA
Several conditions have been recognized in which HBV escape mutants arise in clinical practice bulltreatment with anti-HBs immunoglobulin eg after liver transplantation to avoid reinfection of the graft (2332) bullantiviral therapy by itself as the reading frames of the envelope and polymerase genes overlap
and several resistance mutations in the polymerase selected during antiviral therapy simultaneously alter the antigenicity of HBsAg (2021 31) bullde novo infection of vaccinated individuals with escape mutants (19)
Moreover Datta et al recently reported that HBV variants with the sG145R immune escape mutation are frequently ldquohiderdquo in the peripheral blood leukocyte compartment of infected individuals and may then serve as a source of reactivation or transmission (7)
J Virol 2010 vol 84 no 2 1026-1033
По современным оценкам частота мутаций HBsAg среди вакцинированных колеблется от 2 до 28
Из-за повсеместной вакцинации частота мутаций будет возрастать
Математическая модель предсказывает исчезновение ВГВ дикого типа в областях с HBsAg-эндемичностью и появление S генных мутаций в течение 100 лет как следствия универсальной ВГВ-вакцинации
Гилязова ДГ руководитель отдела Иммунохимия ООО Текан
httpwwwlabmedicinarufilesPREZENTACII20-2020122320Gilyazovapdf
HBV-дикий вирус
Anti-HBs пресс в результате массовой вакцинации Исходно5-7 мутантовЧерез 20 лет22 мутантов
Мутантные формы прогрессивно накапливаются у привитыхУ невакцинированных это случайные мутации а у привитых ndash MHR HBsAg
Анти-вирусная терапияс помощью нуклеозидных аналоговМутации происходят направленно в Pol-последовательности но фактически меняют аа последовательность в MHR HBsAg что приводит к неузнаванию anti-HBs
Мутанты иммунно-происхождения
Мутанты Pol-происхождения
Не узнают anti-HBs
Узнают anti-preS1 anti-preS2 anti-HBc
Вакцина 3-го пок
Вакцина 4в - пок
Drug-resistant mutations rtM204I (sI195M) and rtM204V (sW196S) caused significant reduction in antigenicity for the immune-escaped HBsAg mutants sG145K and sG145R which may hamper HBV diagnosis and disease controlVirology Journal 2013 10292
Type of Vaccine Vaccine Antigen Adjuvant Host Cell Target Current Status References
Peptide
(a) Palmitolylated TT830-843 HTL
epitope covalently linked to the HBcAg 18 ndash27 CTL epitope
NACytotoxic T Lymphocyt
e
Phase II clinical trial
Livingston et al 1999 [22]
(b) HBV core antigen 18-27
peptide + tetanus taxoid peptide 830
843+palmic acid molecules
NACytotoxic T Lymphocyt
e
Pre-clinical amp clinical
Vitiello et al 1995 [23]
ProteinHBsAganti-
HBsIgAlum
Cytotoxic T Lymphocyt
e
Phase II clinical trial
Wen et al 2003
Xu et al 2008 [28]
DNA
Small(S) and middle (preS2S) proteins of the HBV envelope
(HBsAg)
NACD8+ T
Lymphocyte
Phase I clinical trial
Mancini et al 2004
Vector-basedModified
prHBV13HBVcore protein
NA
CD4+ and CD8+ T
Lymphocyte
Pre-clinicalDeng et al
2009 [8]
Cell-based
DCs pulsed with HBs28-39 peptide or
recombinant preS2S particles
NACytotoxic T Lymphocyt
ePre-clinical
Akbar et al 2004 [36]
Therapeutic Vaccine for Hepatitis B virusJ Infect Dis Immunol Tech 2012 11
Release Summary February 12 2014httpwwwbusinesswirecomnewshome20140212005051enCreation-ABIVAX---Leader-Therapeutic-Vaccines-FrenchU3PoW_ldW8AAbivax creation of ABIVAX - a leader in therapeutic vaccines and the first French company to sign an exclusive partnering agreement with Cuba in healthcareABIVAX specializes in therapeutic vaccines and antivirals combining the technologies and the product portfolios of three French biotech companies financed by Truffle CapitaABIVAX already has two therapeutic vaccines in development one in a Phase IIb clinical trial in patients with chronic hepatitis B
The HBsAgndashHBcAg vaccine candidate was safe well tolerated and immunogenic in this phase I study in healthy adults To our knowledge this is the first demonstration of safety and immunogenicity for a nasal vaccine candidate comprising HBV antigensThe vaccine elicited anti-HBc seroconversion in 100 of subjects as early as day 30 of the immunization schedule while a seroprotective anti-HBs titer (ge10 IUl) was at a maximum at day 90 (75) International Journal of Infectious DiseasesVolume 11 Issue 5 September 2007
A novel therapeutic hepatitis B vaccine induces cellular and humoral immune responses and breaks tolerance in hepatitis B virus (HBV) transgenic miceBuchmann P1 Dembek C Kuklick L Jaumlger C Tedjokusumo R von Freyend MJ Drebber U Janowicz Z Melber K Protzer U
1Rhein Biotech GmbH Duesseldorf Germany pbuchmanneudynavaxcomVaccine 2013 631(8)A paradigm of therapeutic vaccination is the potent induction of T-cell responses against key viral antigens ndash besides activation of a humoral immune response We have evaluated the potential of a novel vaccine formulation comprising particulate hepatitis B surface (HBsAg) and core antigen (HBcAg) and the saponin-based ISCOMATRIXtrade adjuvant for its ability to stimulate T and B cell responses in C57BL6 mice and its ability to break tolerance in HBV transgenic (HBVtg) mice The vaccine induced multifunctional HBsAg- and HBcAg-specific CD8+ T cells detected by staining for IFNγ TNFα and IL-2 as well as high antibody titers against both antigens Vaccination of HBVtg animals induced potent HBsAg- and HBcAg-specific CD8+ T-cell responses in spleens and HBcAg-specific CD8+ T-cell responses in livers as well as anti-HBs seroconversion two weeks post injection Vaccination further reduced HBcAg expression in livers of HBVtg mice without causing liver damage In summary this study demonstrates therapeutic efficacy of a novel vaccine formulation in a mouse model of immunotolerant chronic HBV infection
HBsAg-HBcAg vaccine version - IV generation
PreS1 is the priority target antigen for the new HBV vaccines because PreS1 has a greater number of immunogenic T cell and B cell epitopes than the S protein (9 12 15) including a strong T cell epitope (aa 21 to 28) and an effective B cell epitope (aa 12 to 32 and 32 to 53) The PreS1 protein has binding sites for liver cells (aa 21 to 47) that play an important role in viral attachment and entry (13 15) Neurath et al have shown that direct immunization with a PreS1 polypeptide (aa 21 to 47) can protect against HBV infection in chimpanzees (21) Additionally the PreS1 antibody is produced earlier than the S antibody and the PreS1-specific cell-mediated immunity may help overcome immune unresponsiveness to the S protein in certain individuals (19 24) Therefore the PreS1 antigen may play an important role in the neutralization blockade and clearance of HBV infections
Clin Vaccine Immun 2011 18(11) 1789-1795
Inclusion of PreS2S antigen in vaccine formulation could also mitigate the chances of non-responsiveness of vaccines against escape variants (Yamada et al 2001) The PreS2S gene is comprises of S gene with an extra 165 nucleotides at 5rsquo end (Tai et al 1997) and antigen is involved in nucleocapsid interaction (Poisson et al 1997) and extra cellular secretion of HBV particles (Le Seyec et al 1998) playing an important role in full stimulation of humoral and cellular immune responses In addition the PreS2S protein is also important for immunological responses at T-cell level and has T-cell and B-cell recognition sites spanning amino acids 1-25 of the protein (Neurath et al 1986) making it most suitable candidate antigen for HBV vaccine development This study describes the heterologous expression of a characterized PreS2S gene from genotype D of HBV in P pastoris The antigen will help to increase the efficacy of HBV recombinant vaccines
Pak J Bot 2012 44 355-359
Use of Pre-S Protein-Containing Hepatitis B Virus Surface Antigens and a Powerful Adjuvant To Develop an Immune Therapy for Chronic Hepatitis B Virus InfectionJung Sun Yum Byung Cheol Ahn [] and Hong Mo Moon
Clin Vaccine Immun 19(2) 2012
Роль preS-областей
J Hep 2011 54 1286-1296
НИИ вакцин и сывороток им И И Мечникова РАМН Москва
Сочетанная терапия laquoвакцина + альфа-2 бета-интерферонraquo позволила получить подавление вирусной репликации в первые 1ndash2 месяца от начала лечения у 786 больных сероконверсию HВsAg на анти-HВs mdash у 964 Исчезновение HВеAg наблюдалось через 6 месяца у всех больных а анти-HВе через 2ndash3 месяца от начала лечения появились у всех больных Наблюдение за пациентами в течение трех лет и более показало что стойкий ответ на лечение отмечался у 24 (857) К концу лечения нормализовались все популяции лимфоцитов высоким оставался только уровень лимфоцитов экспрессирующих рецептор к ИЛ-2 (CD25+) оставались сниженными резервы фагоцитоза и кислородзависимого киллинга [5]Таким образом вакцинация против ГВ является актуальной и необходимой больным с ХЗП пациентам с ХГВ иили ХГС носителям ВГВ иили ВГС поскольку способствует подавлению вирусной репликации у хронических вирусоносителей может играть существенную роль в контроле над виремией значительно повышает эффективность лечения ХВГ
Афигенова ВП Костинов МП 2011
Study Calls Into Question Effectiveness of Hepatitis B Vaccine for NewbornsDecember 17 2013httparticlesmercolacomsitesarticlesarchive20131217newborn-hepatitis-b-vaccineaspxBy Dr JM Mercola
New Study Hepatitis B Vaccination at Birth May Not Prevent Hidden InfectionsA new study is raising another red flag that the practice of universally vaccinating all newborn babies for hepatitis B is seriously flawed The researchers followed 259 babies born to hepatitis-B-positive mothers for two years in order to determine whether vaccinating such babies prevents asymptomatic occult HBV (hepatitis B virus) infectionThe researchers found that while the vaccine may help prevent overt HBV transmission it was not effective in preventing occult HBV infection in babies which may occur in up to 40 percent of babies born to hepatitis B-positive mothersHepatitis B Shot May Be Ineffective by the Time Your Child Is a TeenagerAnother issue to consider if you are weighing the benefits and risks of giving your newborn infant or young child hepatitis B vaccine is that vaccine acquired immunity often does not persist until a child reaches his or her teenage years ndash the time when acquiring a hepatitis B infection may be more likely Research shows that by that time the protection from the childhood vaccine may have long since wanedOne study found that about 15 percent of teens who received the full series of hepatitis B shots as infants tested positive for hepatitis B surface antigen (HBsAg) which is an early indicator of infection or a sign that the person is a chronic carrier of the virus3This percentage was even higher among teens who had received the hepatitis B vaccine off schedule or whose mothers were high risk meaning they tested positive for hepatitis B e antigen (HBeAg) In other words it appears that in many children hepatitis B vaccine acquired immunity does NOT provide lasting protection A Healthy Immune System Can Resolve Hepatitis B InfectionEven if you have been vaccinated as a child itrsquos important to remember that you may not be protected from these risks and could still be infected via IV drug abuse sexual activity with an infected partner a blood transfusion with contaminated blood or even getting a manicure or pedicurehellipFortunately in most cases the hepatitis B infection will resolve on its own provided you have a well-functioning immune system Symptoms can be relieved bybullRestingbullAvoiding foods that weaken your immune function such as sugarsfructose grains and processed foods Healthful foods that help boost your immune system include fermented foods and organic vegetablesbullOptimizing your vitamin D levelsbullDrinking plenty of pure waterbullAvoiding alcohol and drugs
Причинно-следственныеbull Перееданиеbull Неадекватное питаниеbull Вредные привычкиbull Гиподинамия либо перегрузкиbull Неадекватное дыханиеbull Неадекватность мироощущения (стресс дефицит мотивации подавленность- депрессия)bull ИНТОКСИКАЦИЯbull ПОДАВЛЕННОСТЬ ИММУНИТЕТА
Предлагаемая схема клинического эксперимента на хронических носителях гепатитов В и С для изучения лечебных курсов
Курс оздоровления направленный на восстановление иммунной системы
Тераперапевтическая Вакцинация Курс анти-Вирусной ТерапииСовместное применение Вакцины и анти-Вирусного Курса
М О Н И Т О Р И Н Г по всем иммуно-параметрам ДНКРНК печеночные ферменты др
Ожидаемые результатыbull Влияние оздоровления-восстановления на течение хронического ГВbull Роль предварительного оздоровления-восстановления на каждый из методов леченияbull Сравнительная эффективность вакцины анти-вирусного курса и комбинации на фоне предварительного оздоровления-восстановления и без фона
() Курс относится к категории SPA
По современным оценкам частота мутаций HBsAg среди вакцинированных колеблется от 2 до 28
Из-за повсеместной вакцинации частота мутаций будет возрастать
Математическая модель предсказывает исчезновение ВГВ дикого типа в областях с HBsAg-эндемичностью и появление S генных мутаций в течение 100 лет как следствия универсальной ВГВ-вакцинации
Гилязова ДГ руководитель отдела Иммунохимия ООО Текан
httpwwwlabmedicinarufilesPREZENTACII20-2020122320Gilyazovapdf
HBV-дикий вирус
Anti-HBs пресс в результате массовой вакцинации Исходно5-7 мутантовЧерез 20 лет22 мутантов
Мутантные формы прогрессивно накапливаются у привитыхУ невакцинированных это случайные мутации а у привитых ndash MHR HBsAg
Анти-вирусная терапияс помощью нуклеозидных аналоговМутации происходят направленно в Pol-последовательности но фактически меняют аа последовательность в MHR HBsAg что приводит к неузнаванию anti-HBs
Мутанты иммунно-происхождения
Мутанты Pol-происхождения
Не узнают anti-HBs
Узнают anti-preS1 anti-preS2 anti-HBc
Вакцина 3-го пок
Вакцина 4в - пок
Drug-resistant mutations rtM204I (sI195M) and rtM204V (sW196S) caused significant reduction in antigenicity for the immune-escaped HBsAg mutants sG145K and sG145R which may hamper HBV diagnosis and disease controlVirology Journal 2013 10292
Type of Vaccine Vaccine Antigen Adjuvant Host Cell Target Current Status References
Peptide
(a) Palmitolylated TT830-843 HTL
epitope covalently linked to the HBcAg 18 ndash27 CTL epitope
NACytotoxic T Lymphocyt
e
Phase II clinical trial
Livingston et al 1999 [22]
(b) HBV core antigen 18-27
peptide + tetanus taxoid peptide 830
843+palmic acid molecules
NACytotoxic T Lymphocyt
e
Pre-clinical amp clinical
Vitiello et al 1995 [23]
ProteinHBsAganti-
HBsIgAlum
Cytotoxic T Lymphocyt
e
Phase II clinical trial
Wen et al 2003
Xu et al 2008 [28]
DNA
Small(S) and middle (preS2S) proteins of the HBV envelope
(HBsAg)
NACD8+ T
Lymphocyte
Phase I clinical trial
Mancini et al 2004
Vector-basedModified
prHBV13HBVcore protein
NA
CD4+ and CD8+ T
Lymphocyte
Pre-clinicalDeng et al
2009 [8]
Cell-based
DCs pulsed with HBs28-39 peptide or
recombinant preS2S particles
NACytotoxic T Lymphocyt
ePre-clinical
Akbar et al 2004 [36]
Therapeutic Vaccine for Hepatitis B virusJ Infect Dis Immunol Tech 2012 11
Release Summary February 12 2014httpwwwbusinesswirecomnewshome20140212005051enCreation-ABIVAX---Leader-Therapeutic-Vaccines-FrenchU3PoW_ldW8AAbivax creation of ABIVAX - a leader in therapeutic vaccines and the first French company to sign an exclusive partnering agreement with Cuba in healthcareABIVAX specializes in therapeutic vaccines and antivirals combining the technologies and the product portfolios of three French biotech companies financed by Truffle CapitaABIVAX already has two therapeutic vaccines in development one in a Phase IIb clinical trial in patients with chronic hepatitis B
The HBsAgndashHBcAg vaccine candidate was safe well tolerated and immunogenic in this phase I study in healthy adults To our knowledge this is the first demonstration of safety and immunogenicity for a nasal vaccine candidate comprising HBV antigensThe vaccine elicited anti-HBc seroconversion in 100 of subjects as early as day 30 of the immunization schedule while a seroprotective anti-HBs titer (ge10 IUl) was at a maximum at day 90 (75) International Journal of Infectious DiseasesVolume 11 Issue 5 September 2007
A novel therapeutic hepatitis B vaccine induces cellular and humoral immune responses and breaks tolerance in hepatitis B virus (HBV) transgenic miceBuchmann P1 Dembek C Kuklick L Jaumlger C Tedjokusumo R von Freyend MJ Drebber U Janowicz Z Melber K Protzer U
1Rhein Biotech GmbH Duesseldorf Germany pbuchmanneudynavaxcomVaccine 2013 631(8)A paradigm of therapeutic vaccination is the potent induction of T-cell responses against key viral antigens ndash besides activation of a humoral immune response We have evaluated the potential of a novel vaccine formulation comprising particulate hepatitis B surface (HBsAg) and core antigen (HBcAg) and the saponin-based ISCOMATRIXtrade adjuvant for its ability to stimulate T and B cell responses in C57BL6 mice and its ability to break tolerance in HBV transgenic (HBVtg) mice The vaccine induced multifunctional HBsAg- and HBcAg-specific CD8+ T cells detected by staining for IFNγ TNFα and IL-2 as well as high antibody titers against both antigens Vaccination of HBVtg animals induced potent HBsAg- and HBcAg-specific CD8+ T-cell responses in spleens and HBcAg-specific CD8+ T-cell responses in livers as well as anti-HBs seroconversion two weeks post injection Vaccination further reduced HBcAg expression in livers of HBVtg mice without causing liver damage In summary this study demonstrates therapeutic efficacy of a novel vaccine formulation in a mouse model of immunotolerant chronic HBV infection
HBsAg-HBcAg vaccine version - IV generation
PreS1 is the priority target antigen for the new HBV vaccines because PreS1 has a greater number of immunogenic T cell and B cell epitopes than the S protein (9 12 15) including a strong T cell epitope (aa 21 to 28) and an effective B cell epitope (aa 12 to 32 and 32 to 53) The PreS1 protein has binding sites for liver cells (aa 21 to 47) that play an important role in viral attachment and entry (13 15) Neurath et al have shown that direct immunization with a PreS1 polypeptide (aa 21 to 47) can protect against HBV infection in chimpanzees (21) Additionally the PreS1 antibody is produced earlier than the S antibody and the PreS1-specific cell-mediated immunity may help overcome immune unresponsiveness to the S protein in certain individuals (19 24) Therefore the PreS1 antigen may play an important role in the neutralization blockade and clearance of HBV infections
Clin Vaccine Immun 2011 18(11) 1789-1795
Inclusion of PreS2S antigen in vaccine formulation could also mitigate the chances of non-responsiveness of vaccines against escape variants (Yamada et al 2001) The PreS2S gene is comprises of S gene with an extra 165 nucleotides at 5rsquo end (Tai et al 1997) and antigen is involved in nucleocapsid interaction (Poisson et al 1997) and extra cellular secretion of HBV particles (Le Seyec et al 1998) playing an important role in full stimulation of humoral and cellular immune responses In addition the PreS2S protein is also important for immunological responses at T-cell level and has T-cell and B-cell recognition sites spanning amino acids 1-25 of the protein (Neurath et al 1986) making it most suitable candidate antigen for HBV vaccine development This study describes the heterologous expression of a characterized PreS2S gene from genotype D of HBV in P pastoris The antigen will help to increase the efficacy of HBV recombinant vaccines
Pak J Bot 2012 44 355-359
Use of Pre-S Protein-Containing Hepatitis B Virus Surface Antigens and a Powerful Adjuvant To Develop an Immune Therapy for Chronic Hepatitis B Virus InfectionJung Sun Yum Byung Cheol Ahn [] and Hong Mo Moon
Clin Vaccine Immun 19(2) 2012
Роль preS-областей
J Hep 2011 54 1286-1296
НИИ вакцин и сывороток им И И Мечникова РАМН Москва
Сочетанная терапия laquoвакцина + альфа-2 бета-интерферонraquo позволила получить подавление вирусной репликации в первые 1ndash2 месяца от начала лечения у 786 больных сероконверсию HВsAg на анти-HВs mdash у 964 Исчезновение HВеAg наблюдалось через 6 месяца у всех больных а анти-HВе через 2ndash3 месяца от начала лечения появились у всех больных Наблюдение за пациентами в течение трех лет и более показало что стойкий ответ на лечение отмечался у 24 (857) К концу лечения нормализовались все популяции лимфоцитов высоким оставался только уровень лимфоцитов экспрессирующих рецептор к ИЛ-2 (CD25+) оставались сниженными резервы фагоцитоза и кислородзависимого киллинга [5]Таким образом вакцинация против ГВ является актуальной и необходимой больным с ХЗП пациентам с ХГВ иили ХГС носителям ВГВ иили ВГС поскольку способствует подавлению вирусной репликации у хронических вирусоносителей может играть существенную роль в контроле над виремией значительно повышает эффективность лечения ХВГ
Афигенова ВП Костинов МП 2011
Study Calls Into Question Effectiveness of Hepatitis B Vaccine for NewbornsDecember 17 2013httparticlesmercolacomsitesarticlesarchive20131217newborn-hepatitis-b-vaccineaspxBy Dr JM Mercola
New Study Hepatitis B Vaccination at Birth May Not Prevent Hidden InfectionsA new study is raising another red flag that the practice of universally vaccinating all newborn babies for hepatitis B is seriously flawed The researchers followed 259 babies born to hepatitis-B-positive mothers for two years in order to determine whether vaccinating such babies prevents asymptomatic occult HBV (hepatitis B virus) infectionThe researchers found that while the vaccine may help prevent overt HBV transmission it was not effective in preventing occult HBV infection in babies which may occur in up to 40 percent of babies born to hepatitis B-positive mothersHepatitis B Shot May Be Ineffective by the Time Your Child Is a TeenagerAnother issue to consider if you are weighing the benefits and risks of giving your newborn infant or young child hepatitis B vaccine is that vaccine acquired immunity often does not persist until a child reaches his or her teenage years ndash the time when acquiring a hepatitis B infection may be more likely Research shows that by that time the protection from the childhood vaccine may have long since wanedOne study found that about 15 percent of teens who received the full series of hepatitis B shots as infants tested positive for hepatitis B surface antigen (HBsAg) which is an early indicator of infection or a sign that the person is a chronic carrier of the virus3This percentage was even higher among teens who had received the hepatitis B vaccine off schedule or whose mothers were high risk meaning they tested positive for hepatitis B e antigen (HBeAg) In other words it appears that in many children hepatitis B vaccine acquired immunity does NOT provide lasting protection A Healthy Immune System Can Resolve Hepatitis B InfectionEven if you have been vaccinated as a child itrsquos important to remember that you may not be protected from these risks and could still be infected via IV drug abuse sexual activity with an infected partner a blood transfusion with contaminated blood or even getting a manicure or pedicurehellipFortunately in most cases the hepatitis B infection will resolve on its own provided you have a well-functioning immune system Symptoms can be relieved bybullRestingbullAvoiding foods that weaken your immune function such as sugarsfructose grains and processed foods Healthful foods that help boost your immune system include fermented foods and organic vegetablesbullOptimizing your vitamin D levelsbullDrinking plenty of pure waterbullAvoiding alcohol and drugs
Причинно-следственныеbull Перееданиеbull Неадекватное питаниеbull Вредные привычкиbull Гиподинамия либо перегрузкиbull Неадекватное дыханиеbull Неадекватность мироощущения (стресс дефицит мотивации подавленность- депрессия)bull ИНТОКСИКАЦИЯbull ПОДАВЛЕННОСТЬ ИММУНИТЕТА
Предлагаемая схема клинического эксперимента на хронических носителях гепатитов В и С для изучения лечебных курсов
Курс оздоровления направленный на восстановление иммунной системы
Тераперапевтическая Вакцинация Курс анти-Вирусной ТерапииСовместное применение Вакцины и анти-Вирусного Курса
М О Н И Т О Р И Н Г по всем иммуно-параметрам ДНКРНК печеночные ферменты др
Ожидаемые результатыbull Влияние оздоровления-восстановления на течение хронического ГВbull Роль предварительного оздоровления-восстановления на каждый из методов леченияbull Сравнительная эффективность вакцины анти-вирусного курса и комбинации на фоне предварительного оздоровления-восстановления и без фона
() Курс относится к категории SPA
HBV-дикий вирус
Anti-HBs пресс в результате массовой вакцинации Исходно5-7 мутантовЧерез 20 лет22 мутантов
Мутантные формы прогрессивно накапливаются у привитыхУ невакцинированных это случайные мутации а у привитых ndash MHR HBsAg
Анти-вирусная терапияс помощью нуклеозидных аналоговМутации происходят направленно в Pol-последовательности но фактически меняют аа последовательность в MHR HBsAg что приводит к неузнаванию anti-HBs
Мутанты иммунно-происхождения
Мутанты Pol-происхождения
Не узнают anti-HBs
Узнают anti-preS1 anti-preS2 anti-HBc
Вакцина 3-го пок
Вакцина 4в - пок
Drug-resistant mutations rtM204I (sI195M) and rtM204V (sW196S) caused significant reduction in antigenicity for the immune-escaped HBsAg mutants sG145K and sG145R which may hamper HBV diagnosis and disease controlVirology Journal 2013 10292
Type of Vaccine Vaccine Antigen Adjuvant Host Cell Target Current Status References
Peptide
(a) Palmitolylated TT830-843 HTL
epitope covalently linked to the HBcAg 18 ndash27 CTL epitope
NACytotoxic T Lymphocyt
e
Phase II clinical trial
Livingston et al 1999 [22]
(b) HBV core antigen 18-27
peptide + tetanus taxoid peptide 830
843+palmic acid molecules
NACytotoxic T Lymphocyt
e
Pre-clinical amp clinical
Vitiello et al 1995 [23]
ProteinHBsAganti-
HBsIgAlum
Cytotoxic T Lymphocyt
e
Phase II clinical trial
Wen et al 2003
Xu et al 2008 [28]
DNA
Small(S) and middle (preS2S) proteins of the HBV envelope
(HBsAg)
NACD8+ T
Lymphocyte
Phase I clinical trial
Mancini et al 2004
Vector-basedModified
prHBV13HBVcore protein
NA
CD4+ and CD8+ T
Lymphocyte
Pre-clinicalDeng et al
2009 [8]
Cell-based
DCs pulsed with HBs28-39 peptide or
recombinant preS2S particles
NACytotoxic T Lymphocyt
ePre-clinical
Akbar et al 2004 [36]
Therapeutic Vaccine for Hepatitis B virusJ Infect Dis Immunol Tech 2012 11
Release Summary February 12 2014httpwwwbusinesswirecomnewshome20140212005051enCreation-ABIVAX---Leader-Therapeutic-Vaccines-FrenchU3PoW_ldW8AAbivax creation of ABIVAX - a leader in therapeutic vaccines and the first French company to sign an exclusive partnering agreement with Cuba in healthcareABIVAX specializes in therapeutic vaccines and antivirals combining the technologies and the product portfolios of three French biotech companies financed by Truffle CapitaABIVAX already has two therapeutic vaccines in development one in a Phase IIb clinical trial in patients with chronic hepatitis B
The HBsAgndashHBcAg vaccine candidate was safe well tolerated and immunogenic in this phase I study in healthy adults To our knowledge this is the first demonstration of safety and immunogenicity for a nasal vaccine candidate comprising HBV antigensThe vaccine elicited anti-HBc seroconversion in 100 of subjects as early as day 30 of the immunization schedule while a seroprotective anti-HBs titer (ge10 IUl) was at a maximum at day 90 (75) International Journal of Infectious DiseasesVolume 11 Issue 5 September 2007
A novel therapeutic hepatitis B vaccine induces cellular and humoral immune responses and breaks tolerance in hepatitis B virus (HBV) transgenic miceBuchmann P1 Dembek C Kuklick L Jaumlger C Tedjokusumo R von Freyend MJ Drebber U Janowicz Z Melber K Protzer U
1Rhein Biotech GmbH Duesseldorf Germany pbuchmanneudynavaxcomVaccine 2013 631(8)A paradigm of therapeutic vaccination is the potent induction of T-cell responses against key viral antigens ndash besides activation of a humoral immune response We have evaluated the potential of a novel vaccine formulation comprising particulate hepatitis B surface (HBsAg) and core antigen (HBcAg) and the saponin-based ISCOMATRIXtrade adjuvant for its ability to stimulate T and B cell responses in C57BL6 mice and its ability to break tolerance in HBV transgenic (HBVtg) mice The vaccine induced multifunctional HBsAg- and HBcAg-specific CD8+ T cells detected by staining for IFNγ TNFα and IL-2 as well as high antibody titers against both antigens Vaccination of HBVtg animals induced potent HBsAg- and HBcAg-specific CD8+ T-cell responses in spleens and HBcAg-specific CD8+ T-cell responses in livers as well as anti-HBs seroconversion two weeks post injection Vaccination further reduced HBcAg expression in livers of HBVtg mice without causing liver damage In summary this study demonstrates therapeutic efficacy of a novel vaccine formulation in a mouse model of immunotolerant chronic HBV infection
HBsAg-HBcAg vaccine version - IV generation
PreS1 is the priority target antigen for the new HBV vaccines because PreS1 has a greater number of immunogenic T cell and B cell epitopes than the S protein (9 12 15) including a strong T cell epitope (aa 21 to 28) and an effective B cell epitope (aa 12 to 32 and 32 to 53) The PreS1 protein has binding sites for liver cells (aa 21 to 47) that play an important role in viral attachment and entry (13 15) Neurath et al have shown that direct immunization with a PreS1 polypeptide (aa 21 to 47) can protect against HBV infection in chimpanzees (21) Additionally the PreS1 antibody is produced earlier than the S antibody and the PreS1-specific cell-mediated immunity may help overcome immune unresponsiveness to the S protein in certain individuals (19 24) Therefore the PreS1 antigen may play an important role in the neutralization blockade and clearance of HBV infections
Clin Vaccine Immun 2011 18(11) 1789-1795
Inclusion of PreS2S antigen in vaccine formulation could also mitigate the chances of non-responsiveness of vaccines against escape variants (Yamada et al 2001) The PreS2S gene is comprises of S gene with an extra 165 nucleotides at 5rsquo end (Tai et al 1997) and antigen is involved in nucleocapsid interaction (Poisson et al 1997) and extra cellular secretion of HBV particles (Le Seyec et al 1998) playing an important role in full stimulation of humoral and cellular immune responses In addition the PreS2S protein is also important for immunological responses at T-cell level and has T-cell and B-cell recognition sites spanning amino acids 1-25 of the protein (Neurath et al 1986) making it most suitable candidate antigen for HBV vaccine development This study describes the heterologous expression of a characterized PreS2S gene from genotype D of HBV in P pastoris The antigen will help to increase the efficacy of HBV recombinant vaccines
Pak J Bot 2012 44 355-359
Use of Pre-S Protein-Containing Hepatitis B Virus Surface Antigens and a Powerful Adjuvant To Develop an Immune Therapy for Chronic Hepatitis B Virus InfectionJung Sun Yum Byung Cheol Ahn [] and Hong Mo Moon
Clin Vaccine Immun 19(2) 2012
Роль preS-областей
J Hep 2011 54 1286-1296
НИИ вакцин и сывороток им И И Мечникова РАМН Москва
Сочетанная терапия laquoвакцина + альфа-2 бета-интерферонraquo позволила получить подавление вирусной репликации в первые 1ndash2 месяца от начала лечения у 786 больных сероконверсию HВsAg на анти-HВs mdash у 964 Исчезновение HВеAg наблюдалось через 6 месяца у всех больных а анти-HВе через 2ndash3 месяца от начала лечения появились у всех больных Наблюдение за пациентами в течение трех лет и более показало что стойкий ответ на лечение отмечался у 24 (857) К концу лечения нормализовались все популяции лимфоцитов высоким оставался только уровень лимфоцитов экспрессирующих рецептор к ИЛ-2 (CD25+) оставались сниженными резервы фагоцитоза и кислородзависимого киллинга [5]Таким образом вакцинация против ГВ является актуальной и необходимой больным с ХЗП пациентам с ХГВ иили ХГС носителям ВГВ иили ВГС поскольку способствует подавлению вирусной репликации у хронических вирусоносителей может играть существенную роль в контроле над виремией значительно повышает эффективность лечения ХВГ
Афигенова ВП Костинов МП 2011
Study Calls Into Question Effectiveness of Hepatitis B Vaccine for NewbornsDecember 17 2013httparticlesmercolacomsitesarticlesarchive20131217newborn-hepatitis-b-vaccineaspxBy Dr JM Mercola
New Study Hepatitis B Vaccination at Birth May Not Prevent Hidden InfectionsA new study is raising another red flag that the practice of universally vaccinating all newborn babies for hepatitis B is seriously flawed The researchers followed 259 babies born to hepatitis-B-positive mothers for two years in order to determine whether vaccinating such babies prevents asymptomatic occult HBV (hepatitis B virus) infectionThe researchers found that while the vaccine may help prevent overt HBV transmission it was not effective in preventing occult HBV infection in babies which may occur in up to 40 percent of babies born to hepatitis B-positive mothersHepatitis B Shot May Be Ineffective by the Time Your Child Is a TeenagerAnother issue to consider if you are weighing the benefits and risks of giving your newborn infant or young child hepatitis B vaccine is that vaccine acquired immunity often does not persist until a child reaches his or her teenage years ndash the time when acquiring a hepatitis B infection may be more likely Research shows that by that time the protection from the childhood vaccine may have long since wanedOne study found that about 15 percent of teens who received the full series of hepatitis B shots as infants tested positive for hepatitis B surface antigen (HBsAg) which is an early indicator of infection or a sign that the person is a chronic carrier of the virus3This percentage was even higher among teens who had received the hepatitis B vaccine off schedule or whose mothers were high risk meaning they tested positive for hepatitis B e antigen (HBeAg) In other words it appears that in many children hepatitis B vaccine acquired immunity does NOT provide lasting protection A Healthy Immune System Can Resolve Hepatitis B InfectionEven if you have been vaccinated as a child itrsquos important to remember that you may not be protected from these risks and could still be infected via IV drug abuse sexual activity with an infected partner a blood transfusion with contaminated blood or even getting a manicure or pedicurehellipFortunately in most cases the hepatitis B infection will resolve on its own provided you have a well-functioning immune system Symptoms can be relieved bybullRestingbullAvoiding foods that weaken your immune function such as sugarsfructose grains and processed foods Healthful foods that help boost your immune system include fermented foods and organic vegetablesbullOptimizing your vitamin D levelsbullDrinking plenty of pure waterbullAvoiding alcohol and drugs
Причинно-следственныеbull Перееданиеbull Неадекватное питаниеbull Вредные привычкиbull Гиподинамия либо перегрузкиbull Неадекватное дыханиеbull Неадекватность мироощущения (стресс дефицит мотивации подавленность- депрессия)bull ИНТОКСИКАЦИЯbull ПОДАВЛЕННОСТЬ ИММУНИТЕТА
Предлагаемая схема клинического эксперимента на хронических носителях гепатитов В и С для изучения лечебных курсов
Курс оздоровления направленный на восстановление иммунной системы
Тераперапевтическая Вакцинация Курс анти-Вирусной ТерапииСовместное применение Вакцины и анти-Вирусного Курса
М О Н И Т О Р И Н Г по всем иммуно-параметрам ДНКРНК печеночные ферменты др
Ожидаемые результатыbull Влияние оздоровления-восстановления на течение хронического ГВbull Роль предварительного оздоровления-восстановления на каждый из методов леченияbull Сравнительная эффективность вакцины анти-вирусного курса и комбинации на фоне предварительного оздоровления-восстановления и без фона
() Курс относится к категории SPA
Type of Vaccine Vaccine Antigen Adjuvant Host Cell Target Current Status References
Peptide
(a) Palmitolylated TT830-843 HTL
epitope covalently linked to the HBcAg 18 ndash27 CTL epitope
NACytotoxic T Lymphocyt
e
Phase II clinical trial
Livingston et al 1999 [22]
(b) HBV core antigen 18-27
peptide + tetanus taxoid peptide 830
843+palmic acid molecules
NACytotoxic T Lymphocyt
e
Pre-clinical amp clinical
Vitiello et al 1995 [23]
ProteinHBsAganti-
HBsIgAlum
Cytotoxic T Lymphocyt
e
Phase II clinical trial
Wen et al 2003
Xu et al 2008 [28]
DNA
Small(S) and middle (preS2S) proteins of the HBV envelope
(HBsAg)
NACD8+ T
Lymphocyte
Phase I clinical trial
Mancini et al 2004
Vector-basedModified
prHBV13HBVcore protein
NA
CD4+ and CD8+ T
Lymphocyte
Pre-clinicalDeng et al
2009 [8]
Cell-based
DCs pulsed with HBs28-39 peptide or
recombinant preS2S particles
NACytotoxic T Lymphocyt
ePre-clinical
Akbar et al 2004 [36]
Therapeutic Vaccine for Hepatitis B virusJ Infect Dis Immunol Tech 2012 11
Release Summary February 12 2014httpwwwbusinesswirecomnewshome20140212005051enCreation-ABIVAX---Leader-Therapeutic-Vaccines-FrenchU3PoW_ldW8AAbivax creation of ABIVAX - a leader in therapeutic vaccines and the first French company to sign an exclusive partnering agreement with Cuba in healthcareABIVAX specializes in therapeutic vaccines and antivirals combining the technologies and the product portfolios of three French biotech companies financed by Truffle CapitaABIVAX already has two therapeutic vaccines in development one in a Phase IIb clinical trial in patients with chronic hepatitis B
The HBsAgndashHBcAg vaccine candidate was safe well tolerated and immunogenic in this phase I study in healthy adults To our knowledge this is the first demonstration of safety and immunogenicity for a nasal vaccine candidate comprising HBV antigensThe vaccine elicited anti-HBc seroconversion in 100 of subjects as early as day 30 of the immunization schedule while a seroprotective anti-HBs titer (ge10 IUl) was at a maximum at day 90 (75) International Journal of Infectious DiseasesVolume 11 Issue 5 September 2007
A novel therapeutic hepatitis B vaccine induces cellular and humoral immune responses and breaks tolerance in hepatitis B virus (HBV) transgenic miceBuchmann P1 Dembek C Kuklick L Jaumlger C Tedjokusumo R von Freyend MJ Drebber U Janowicz Z Melber K Protzer U
1Rhein Biotech GmbH Duesseldorf Germany pbuchmanneudynavaxcomVaccine 2013 631(8)A paradigm of therapeutic vaccination is the potent induction of T-cell responses against key viral antigens ndash besides activation of a humoral immune response We have evaluated the potential of a novel vaccine formulation comprising particulate hepatitis B surface (HBsAg) and core antigen (HBcAg) and the saponin-based ISCOMATRIXtrade adjuvant for its ability to stimulate T and B cell responses in C57BL6 mice and its ability to break tolerance in HBV transgenic (HBVtg) mice The vaccine induced multifunctional HBsAg- and HBcAg-specific CD8+ T cells detected by staining for IFNγ TNFα and IL-2 as well as high antibody titers against both antigens Vaccination of HBVtg animals induced potent HBsAg- and HBcAg-specific CD8+ T-cell responses in spleens and HBcAg-specific CD8+ T-cell responses in livers as well as anti-HBs seroconversion two weeks post injection Vaccination further reduced HBcAg expression in livers of HBVtg mice without causing liver damage In summary this study demonstrates therapeutic efficacy of a novel vaccine formulation in a mouse model of immunotolerant chronic HBV infection
HBsAg-HBcAg vaccine version - IV generation
PreS1 is the priority target antigen for the new HBV vaccines because PreS1 has a greater number of immunogenic T cell and B cell epitopes than the S protein (9 12 15) including a strong T cell epitope (aa 21 to 28) and an effective B cell epitope (aa 12 to 32 and 32 to 53) The PreS1 protein has binding sites for liver cells (aa 21 to 47) that play an important role in viral attachment and entry (13 15) Neurath et al have shown that direct immunization with a PreS1 polypeptide (aa 21 to 47) can protect against HBV infection in chimpanzees (21) Additionally the PreS1 antibody is produced earlier than the S antibody and the PreS1-specific cell-mediated immunity may help overcome immune unresponsiveness to the S protein in certain individuals (19 24) Therefore the PreS1 antigen may play an important role in the neutralization blockade and clearance of HBV infections
Clin Vaccine Immun 2011 18(11) 1789-1795
Inclusion of PreS2S antigen in vaccine formulation could also mitigate the chances of non-responsiveness of vaccines against escape variants (Yamada et al 2001) The PreS2S gene is comprises of S gene with an extra 165 nucleotides at 5rsquo end (Tai et al 1997) and antigen is involved in nucleocapsid interaction (Poisson et al 1997) and extra cellular secretion of HBV particles (Le Seyec et al 1998) playing an important role in full stimulation of humoral and cellular immune responses In addition the PreS2S protein is also important for immunological responses at T-cell level and has T-cell and B-cell recognition sites spanning amino acids 1-25 of the protein (Neurath et al 1986) making it most suitable candidate antigen for HBV vaccine development This study describes the heterologous expression of a characterized PreS2S gene from genotype D of HBV in P pastoris The antigen will help to increase the efficacy of HBV recombinant vaccines
Pak J Bot 2012 44 355-359
Use of Pre-S Protein-Containing Hepatitis B Virus Surface Antigens and a Powerful Adjuvant To Develop an Immune Therapy for Chronic Hepatitis B Virus InfectionJung Sun Yum Byung Cheol Ahn [] and Hong Mo Moon
Clin Vaccine Immun 19(2) 2012
Роль preS-областей
J Hep 2011 54 1286-1296
НИИ вакцин и сывороток им И И Мечникова РАМН Москва
Сочетанная терапия laquoвакцина + альфа-2 бета-интерферонraquo позволила получить подавление вирусной репликации в первые 1ndash2 месяца от начала лечения у 786 больных сероконверсию HВsAg на анти-HВs mdash у 964 Исчезновение HВеAg наблюдалось через 6 месяца у всех больных а анти-HВе через 2ndash3 месяца от начала лечения появились у всех больных Наблюдение за пациентами в течение трех лет и более показало что стойкий ответ на лечение отмечался у 24 (857) К концу лечения нормализовались все популяции лимфоцитов высоким оставался только уровень лимфоцитов экспрессирующих рецептор к ИЛ-2 (CD25+) оставались сниженными резервы фагоцитоза и кислородзависимого киллинга [5]Таким образом вакцинация против ГВ является актуальной и необходимой больным с ХЗП пациентам с ХГВ иили ХГС носителям ВГВ иили ВГС поскольку способствует подавлению вирусной репликации у хронических вирусоносителей может играть существенную роль в контроле над виремией значительно повышает эффективность лечения ХВГ
Афигенова ВП Костинов МП 2011
Study Calls Into Question Effectiveness of Hepatitis B Vaccine for NewbornsDecember 17 2013httparticlesmercolacomsitesarticlesarchive20131217newborn-hepatitis-b-vaccineaspxBy Dr JM Mercola
New Study Hepatitis B Vaccination at Birth May Not Prevent Hidden InfectionsA new study is raising another red flag that the practice of universally vaccinating all newborn babies for hepatitis B is seriously flawed The researchers followed 259 babies born to hepatitis-B-positive mothers for two years in order to determine whether vaccinating such babies prevents asymptomatic occult HBV (hepatitis B virus) infectionThe researchers found that while the vaccine may help prevent overt HBV transmission it was not effective in preventing occult HBV infection in babies which may occur in up to 40 percent of babies born to hepatitis B-positive mothersHepatitis B Shot May Be Ineffective by the Time Your Child Is a TeenagerAnother issue to consider if you are weighing the benefits and risks of giving your newborn infant or young child hepatitis B vaccine is that vaccine acquired immunity often does not persist until a child reaches his or her teenage years ndash the time when acquiring a hepatitis B infection may be more likely Research shows that by that time the protection from the childhood vaccine may have long since wanedOne study found that about 15 percent of teens who received the full series of hepatitis B shots as infants tested positive for hepatitis B surface antigen (HBsAg) which is an early indicator of infection or a sign that the person is a chronic carrier of the virus3This percentage was even higher among teens who had received the hepatitis B vaccine off schedule or whose mothers were high risk meaning they tested positive for hepatitis B e antigen (HBeAg) In other words it appears that in many children hepatitis B vaccine acquired immunity does NOT provide lasting protection A Healthy Immune System Can Resolve Hepatitis B InfectionEven if you have been vaccinated as a child itrsquos important to remember that you may not be protected from these risks and could still be infected via IV drug abuse sexual activity with an infected partner a blood transfusion with contaminated blood or even getting a manicure or pedicurehellipFortunately in most cases the hepatitis B infection will resolve on its own provided you have a well-functioning immune system Symptoms can be relieved bybullRestingbullAvoiding foods that weaken your immune function such as sugarsfructose grains and processed foods Healthful foods that help boost your immune system include fermented foods and organic vegetablesbullOptimizing your vitamin D levelsbullDrinking plenty of pure waterbullAvoiding alcohol and drugs
Причинно-следственныеbull Перееданиеbull Неадекватное питаниеbull Вредные привычкиbull Гиподинамия либо перегрузкиbull Неадекватное дыханиеbull Неадекватность мироощущения (стресс дефицит мотивации подавленность- депрессия)bull ИНТОКСИКАЦИЯbull ПОДАВЛЕННОСТЬ ИММУНИТЕТА
Предлагаемая схема клинического эксперимента на хронических носителях гепатитов В и С для изучения лечебных курсов
Курс оздоровления направленный на восстановление иммунной системы
Тераперапевтическая Вакцинация Курс анти-Вирусной ТерапииСовместное применение Вакцины и анти-Вирусного Курса
М О Н И Т О Р И Н Г по всем иммуно-параметрам ДНКРНК печеночные ферменты др
Ожидаемые результатыbull Влияние оздоровления-восстановления на течение хронического ГВbull Роль предварительного оздоровления-восстановления на каждый из методов леченияbull Сравнительная эффективность вакцины анти-вирусного курса и комбинации на фоне предварительного оздоровления-восстановления и без фона
() Курс относится к категории SPA
Release Summary February 12 2014httpwwwbusinesswirecomnewshome20140212005051enCreation-ABIVAX---Leader-Therapeutic-Vaccines-FrenchU3PoW_ldW8AAbivax creation of ABIVAX - a leader in therapeutic vaccines and the first French company to sign an exclusive partnering agreement with Cuba in healthcareABIVAX specializes in therapeutic vaccines and antivirals combining the technologies and the product portfolios of three French biotech companies financed by Truffle CapitaABIVAX already has two therapeutic vaccines in development one in a Phase IIb clinical trial in patients with chronic hepatitis B
The HBsAgndashHBcAg vaccine candidate was safe well tolerated and immunogenic in this phase I study in healthy adults To our knowledge this is the first demonstration of safety and immunogenicity for a nasal vaccine candidate comprising HBV antigensThe vaccine elicited anti-HBc seroconversion in 100 of subjects as early as day 30 of the immunization schedule while a seroprotective anti-HBs titer (ge10 IUl) was at a maximum at day 90 (75) International Journal of Infectious DiseasesVolume 11 Issue 5 September 2007
A novel therapeutic hepatitis B vaccine induces cellular and humoral immune responses and breaks tolerance in hepatitis B virus (HBV) transgenic miceBuchmann P1 Dembek C Kuklick L Jaumlger C Tedjokusumo R von Freyend MJ Drebber U Janowicz Z Melber K Protzer U
1Rhein Biotech GmbH Duesseldorf Germany pbuchmanneudynavaxcomVaccine 2013 631(8)A paradigm of therapeutic vaccination is the potent induction of T-cell responses against key viral antigens ndash besides activation of a humoral immune response We have evaluated the potential of a novel vaccine formulation comprising particulate hepatitis B surface (HBsAg) and core antigen (HBcAg) and the saponin-based ISCOMATRIXtrade adjuvant for its ability to stimulate T and B cell responses in C57BL6 mice and its ability to break tolerance in HBV transgenic (HBVtg) mice The vaccine induced multifunctional HBsAg- and HBcAg-specific CD8+ T cells detected by staining for IFNγ TNFα and IL-2 as well as high antibody titers against both antigens Vaccination of HBVtg animals induced potent HBsAg- and HBcAg-specific CD8+ T-cell responses in spleens and HBcAg-specific CD8+ T-cell responses in livers as well as anti-HBs seroconversion two weeks post injection Vaccination further reduced HBcAg expression in livers of HBVtg mice without causing liver damage In summary this study demonstrates therapeutic efficacy of a novel vaccine formulation in a mouse model of immunotolerant chronic HBV infection
HBsAg-HBcAg vaccine version - IV generation
PreS1 is the priority target antigen for the new HBV vaccines because PreS1 has a greater number of immunogenic T cell and B cell epitopes than the S protein (9 12 15) including a strong T cell epitope (aa 21 to 28) and an effective B cell epitope (aa 12 to 32 and 32 to 53) The PreS1 protein has binding sites for liver cells (aa 21 to 47) that play an important role in viral attachment and entry (13 15) Neurath et al have shown that direct immunization with a PreS1 polypeptide (aa 21 to 47) can protect against HBV infection in chimpanzees (21) Additionally the PreS1 antibody is produced earlier than the S antibody and the PreS1-specific cell-mediated immunity may help overcome immune unresponsiveness to the S protein in certain individuals (19 24) Therefore the PreS1 antigen may play an important role in the neutralization blockade and clearance of HBV infections
Clin Vaccine Immun 2011 18(11) 1789-1795
Inclusion of PreS2S antigen in vaccine formulation could also mitigate the chances of non-responsiveness of vaccines against escape variants (Yamada et al 2001) The PreS2S gene is comprises of S gene with an extra 165 nucleotides at 5rsquo end (Tai et al 1997) and antigen is involved in nucleocapsid interaction (Poisson et al 1997) and extra cellular secretion of HBV particles (Le Seyec et al 1998) playing an important role in full stimulation of humoral and cellular immune responses In addition the PreS2S protein is also important for immunological responses at T-cell level and has T-cell and B-cell recognition sites spanning amino acids 1-25 of the protein (Neurath et al 1986) making it most suitable candidate antigen for HBV vaccine development This study describes the heterologous expression of a characterized PreS2S gene from genotype D of HBV in P pastoris The antigen will help to increase the efficacy of HBV recombinant vaccines
Pak J Bot 2012 44 355-359
Use of Pre-S Protein-Containing Hepatitis B Virus Surface Antigens and a Powerful Adjuvant To Develop an Immune Therapy for Chronic Hepatitis B Virus InfectionJung Sun Yum Byung Cheol Ahn [] and Hong Mo Moon
Clin Vaccine Immun 19(2) 2012
Роль preS-областей
J Hep 2011 54 1286-1296
НИИ вакцин и сывороток им И И Мечникова РАМН Москва
Сочетанная терапия laquoвакцина + альфа-2 бета-интерферонraquo позволила получить подавление вирусной репликации в первые 1ndash2 месяца от начала лечения у 786 больных сероконверсию HВsAg на анти-HВs mdash у 964 Исчезновение HВеAg наблюдалось через 6 месяца у всех больных а анти-HВе через 2ndash3 месяца от начала лечения появились у всех больных Наблюдение за пациентами в течение трех лет и более показало что стойкий ответ на лечение отмечался у 24 (857) К концу лечения нормализовались все популяции лимфоцитов высоким оставался только уровень лимфоцитов экспрессирующих рецептор к ИЛ-2 (CD25+) оставались сниженными резервы фагоцитоза и кислородзависимого киллинга [5]Таким образом вакцинация против ГВ является актуальной и необходимой больным с ХЗП пациентам с ХГВ иили ХГС носителям ВГВ иили ВГС поскольку способствует подавлению вирусной репликации у хронических вирусоносителей может играть существенную роль в контроле над виремией значительно повышает эффективность лечения ХВГ
Афигенова ВП Костинов МП 2011
Study Calls Into Question Effectiveness of Hepatitis B Vaccine for NewbornsDecember 17 2013httparticlesmercolacomsitesarticlesarchive20131217newborn-hepatitis-b-vaccineaspxBy Dr JM Mercola
New Study Hepatitis B Vaccination at Birth May Not Prevent Hidden InfectionsA new study is raising another red flag that the practice of universally vaccinating all newborn babies for hepatitis B is seriously flawed The researchers followed 259 babies born to hepatitis-B-positive mothers for two years in order to determine whether vaccinating such babies prevents asymptomatic occult HBV (hepatitis B virus) infectionThe researchers found that while the vaccine may help prevent overt HBV transmission it was not effective in preventing occult HBV infection in babies which may occur in up to 40 percent of babies born to hepatitis B-positive mothersHepatitis B Shot May Be Ineffective by the Time Your Child Is a TeenagerAnother issue to consider if you are weighing the benefits and risks of giving your newborn infant or young child hepatitis B vaccine is that vaccine acquired immunity often does not persist until a child reaches his or her teenage years ndash the time when acquiring a hepatitis B infection may be more likely Research shows that by that time the protection from the childhood vaccine may have long since wanedOne study found that about 15 percent of teens who received the full series of hepatitis B shots as infants tested positive for hepatitis B surface antigen (HBsAg) which is an early indicator of infection or a sign that the person is a chronic carrier of the virus3This percentage was even higher among teens who had received the hepatitis B vaccine off schedule or whose mothers were high risk meaning they tested positive for hepatitis B e antigen (HBeAg) In other words it appears that in many children hepatitis B vaccine acquired immunity does NOT provide lasting protection A Healthy Immune System Can Resolve Hepatitis B InfectionEven if you have been vaccinated as a child itrsquos important to remember that you may not be protected from these risks and could still be infected via IV drug abuse sexual activity with an infected partner a blood transfusion with contaminated blood or even getting a manicure or pedicurehellipFortunately in most cases the hepatitis B infection will resolve on its own provided you have a well-functioning immune system Symptoms can be relieved bybullRestingbullAvoiding foods that weaken your immune function such as sugarsfructose grains and processed foods Healthful foods that help boost your immune system include fermented foods and organic vegetablesbullOptimizing your vitamin D levelsbullDrinking plenty of pure waterbullAvoiding alcohol and drugs
Причинно-следственныеbull Перееданиеbull Неадекватное питаниеbull Вредные привычкиbull Гиподинамия либо перегрузкиbull Неадекватное дыханиеbull Неадекватность мироощущения (стресс дефицит мотивации подавленность- депрессия)bull ИНТОКСИКАЦИЯbull ПОДАВЛЕННОСТЬ ИММУНИТЕТА
Предлагаемая схема клинического эксперимента на хронических носителях гепатитов В и С для изучения лечебных курсов
Курс оздоровления направленный на восстановление иммунной системы
Тераперапевтическая Вакцинация Курс анти-Вирусной ТерапииСовместное применение Вакцины и анти-Вирусного Курса
М О Н И Т О Р И Н Г по всем иммуно-параметрам ДНКРНК печеночные ферменты др
Ожидаемые результатыbull Влияние оздоровления-восстановления на течение хронического ГВbull Роль предварительного оздоровления-восстановления на каждый из методов леченияbull Сравнительная эффективность вакцины анти-вирусного курса и комбинации на фоне предварительного оздоровления-восстановления и без фона
() Курс относится к категории SPA
PreS1 is the priority target antigen for the new HBV vaccines because PreS1 has a greater number of immunogenic T cell and B cell epitopes than the S protein (9 12 15) including a strong T cell epitope (aa 21 to 28) and an effective B cell epitope (aa 12 to 32 and 32 to 53) The PreS1 protein has binding sites for liver cells (aa 21 to 47) that play an important role in viral attachment and entry (13 15) Neurath et al have shown that direct immunization with a PreS1 polypeptide (aa 21 to 47) can protect against HBV infection in chimpanzees (21) Additionally the PreS1 antibody is produced earlier than the S antibody and the PreS1-specific cell-mediated immunity may help overcome immune unresponsiveness to the S protein in certain individuals (19 24) Therefore the PreS1 antigen may play an important role in the neutralization blockade and clearance of HBV infections
Clin Vaccine Immun 2011 18(11) 1789-1795
Inclusion of PreS2S antigen in vaccine formulation could also mitigate the chances of non-responsiveness of vaccines against escape variants (Yamada et al 2001) The PreS2S gene is comprises of S gene with an extra 165 nucleotides at 5rsquo end (Tai et al 1997) and antigen is involved in nucleocapsid interaction (Poisson et al 1997) and extra cellular secretion of HBV particles (Le Seyec et al 1998) playing an important role in full stimulation of humoral and cellular immune responses In addition the PreS2S protein is also important for immunological responses at T-cell level and has T-cell and B-cell recognition sites spanning amino acids 1-25 of the protein (Neurath et al 1986) making it most suitable candidate antigen for HBV vaccine development This study describes the heterologous expression of a characterized PreS2S gene from genotype D of HBV in P pastoris The antigen will help to increase the efficacy of HBV recombinant vaccines
Pak J Bot 2012 44 355-359
Use of Pre-S Protein-Containing Hepatitis B Virus Surface Antigens and a Powerful Adjuvant To Develop an Immune Therapy for Chronic Hepatitis B Virus InfectionJung Sun Yum Byung Cheol Ahn [] and Hong Mo Moon
Clin Vaccine Immun 19(2) 2012
Роль preS-областей
J Hep 2011 54 1286-1296
НИИ вакцин и сывороток им И И Мечникова РАМН Москва
Сочетанная терапия laquoвакцина + альфа-2 бета-интерферонraquo позволила получить подавление вирусной репликации в первые 1ndash2 месяца от начала лечения у 786 больных сероконверсию HВsAg на анти-HВs mdash у 964 Исчезновение HВеAg наблюдалось через 6 месяца у всех больных а анти-HВе через 2ndash3 месяца от начала лечения появились у всех больных Наблюдение за пациентами в течение трех лет и более показало что стойкий ответ на лечение отмечался у 24 (857) К концу лечения нормализовались все популяции лимфоцитов высоким оставался только уровень лимфоцитов экспрессирующих рецептор к ИЛ-2 (CD25+) оставались сниженными резервы фагоцитоза и кислородзависимого киллинга [5]Таким образом вакцинация против ГВ является актуальной и необходимой больным с ХЗП пациентам с ХГВ иили ХГС носителям ВГВ иили ВГС поскольку способствует подавлению вирусной репликации у хронических вирусоносителей может играть существенную роль в контроле над виремией значительно повышает эффективность лечения ХВГ
Афигенова ВП Костинов МП 2011
Study Calls Into Question Effectiveness of Hepatitis B Vaccine for NewbornsDecember 17 2013httparticlesmercolacomsitesarticlesarchive20131217newborn-hepatitis-b-vaccineaspxBy Dr JM Mercola
New Study Hepatitis B Vaccination at Birth May Not Prevent Hidden InfectionsA new study is raising another red flag that the practice of universally vaccinating all newborn babies for hepatitis B is seriously flawed The researchers followed 259 babies born to hepatitis-B-positive mothers for two years in order to determine whether vaccinating such babies prevents asymptomatic occult HBV (hepatitis B virus) infectionThe researchers found that while the vaccine may help prevent overt HBV transmission it was not effective in preventing occult HBV infection in babies which may occur in up to 40 percent of babies born to hepatitis B-positive mothersHepatitis B Shot May Be Ineffective by the Time Your Child Is a TeenagerAnother issue to consider if you are weighing the benefits and risks of giving your newborn infant or young child hepatitis B vaccine is that vaccine acquired immunity often does not persist until a child reaches his or her teenage years ndash the time when acquiring a hepatitis B infection may be more likely Research shows that by that time the protection from the childhood vaccine may have long since wanedOne study found that about 15 percent of teens who received the full series of hepatitis B shots as infants tested positive for hepatitis B surface antigen (HBsAg) which is an early indicator of infection or a sign that the person is a chronic carrier of the virus3This percentage was even higher among teens who had received the hepatitis B vaccine off schedule or whose mothers were high risk meaning they tested positive for hepatitis B e antigen (HBeAg) In other words it appears that in many children hepatitis B vaccine acquired immunity does NOT provide lasting protection A Healthy Immune System Can Resolve Hepatitis B InfectionEven if you have been vaccinated as a child itrsquos important to remember that you may not be protected from these risks and could still be infected via IV drug abuse sexual activity with an infected partner a blood transfusion with contaminated blood or even getting a manicure or pedicurehellipFortunately in most cases the hepatitis B infection will resolve on its own provided you have a well-functioning immune system Symptoms can be relieved bybullRestingbullAvoiding foods that weaken your immune function such as sugarsfructose grains and processed foods Healthful foods that help boost your immune system include fermented foods and organic vegetablesbullOptimizing your vitamin D levelsbullDrinking plenty of pure waterbullAvoiding alcohol and drugs
Причинно-следственныеbull Перееданиеbull Неадекватное питаниеbull Вредные привычкиbull Гиподинамия либо перегрузкиbull Неадекватное дыханиеbull Неадекватность мироощущения (стресс дефицит мотивации подавленность- депрессия)bull ИНТОКСИКАЦИЯbull ПОДАВЛЕННОСТЬ ИММУНИТЕТА
Предлагаемая схема клинического эксперимента на хронических носителях гепатитов В и С для изучения лечебных курсов
Курс оздоровления направленный на восстановление иммунной системы
Тераперапевтическая Вакцинация Курс анти-Вирусной ТерапииСовместное применение Вакцины и анти-Вирусного Курса
М О Н И Т О Р И Н Г по всем иммуно-параметрам ДНКРНК печеночные ферменты др
Ожидаемые результатыbull Влияние оздоровления-восстановления на течение хронического ГВbull Роль предварительного оздоровления-восстановления на каждый из методов леченияbull Сравнительная эффективность вакцины анти-вирусного курса и комбинации на фоне предварительного оздоровления-восстановления и без фона
() Курс относится к категории SPA
J Hep 2011 54 1286-1296
НИИ вакцин и сывороток им И И Мечникова РАМН Москва
Сочетанная терапия laquoвакцина + альфа-2 бета-интерферонraquo позволила получить подавление вирусной репликации в первые 1ndash2 месяца от начала лечения у 786 больных сероконверсию HВsAg на анти-HВs mdash у 964 Исчезновение HВеAg наблюдалось через 6 месяца у всех больных а анти-HВе через 2ndash3 месяца от начала лечения появились у всех больных Наблюдение за пациентами в течение трех лет и более показало что стойкий ответ на лечение отмечался у 24 (857) К концу лечения нормализовались все популяции лимфоцитов высоким оставался только уровень лимфоцитов экспрессирующих рецептор к ИЛ-2 (CD25+) оставались сниженными резервы фагоцитоза и кислородзависимого киллинга [5]Таким образом вакцинация против ГВ является актуальной и необходимой больным с ХЗП пациентам с ХГВ иили ХГС носителям ВГВ иили ВГС поскольку способствует подавлению вирусной репликации у хронических вирусоносителей может играть существенную роль в контроле над виремией значительно повышает эффективность лечения ХВГ
Афигенова ВП Костинов МП 2011
Study Calls Into Question Effectiveness of Hepatitis B Vaccine for NewbornsDecember 17 2013httparticlesmercolacomsitesarticlesarchive20131217newborn-hepatitis-b-vaccineaspxBy Dr JM Mercola
New Study Hepatitis B Vaccination at Birth May Not Prevent Hidden InfectionsA new study is raising another red flag that the practice of universally vaccinating all newborn babies for hepatitis B is seriously flawed The researchers followed 259 babies born to hepatitis-B-positive mothers for two years in order to determine whether vaccinating such babies prevents asymptomatic occult HBV (hepatitis B virus) infectionThe researchers found that while the vaccine may help prevent overt HBV transmission it was not effective in preventing occult HBV infection in babies which may occur in up to 40 percent of babies born to hepatitis B-positive mothersHepatitis B Shot May Be Ineffective by the Time Your Child Is a TeenagerAnother issue to consider if you are weighing the benefits and risks of giving your newborn infant or young child hepatitis B vaccine is that vaccine acquired immunity often does not persist until a child reaches his or her teenage years ndash the time when acquiring a hepatitis B infection may be more likely Research shows that by that time the protection from the childhood vaccine may have long since wanedOne study found that about 15 percent of teens who received the full series of hepatitis B shots as infants tested positive for hepatitis B surface antigen (HBsAg) which is an early indicator of infection or a sign that the person is a chronic carrier of the virus3This percentage was even higher among teens who had received the hepatitis B vaccine off schedule or whose mothers were high risk meaning they tested positive for hepatitis B e antigen (HBeAg) In other words it appears that in many children hepatitis B vaccine acquired immunity does NOT provide lasting protection A Healthy Immune System Can Resolve Hepatitis B InfectionEven if you have been vaccinated as a child itrsquos important to remember that you may not be protected from these risks and could still be infected via IV drug abuse sexual activity with an infected partner a blood transfusion with contaminated blood or even getting a manicure or pedicurehellipFortunately in most cases the hepatitis B infection will resolve on its own provided you have a well-functioning immune system Symptoms can be relieved bybullRestingbullAvoiding foods that weaken your immune function such as sugarsfructose grains and processed foods Healthful foods that help boost your immune system include fermented foods and organic vegetablesbullOptimizing your vitamin D levelsbullDrinking plenty of pure waterbullAvoiding alcohol and drugs
Причинно-следственныеbull Перееданиеbull Неадекватное питаниеbull Вредные привычкиbull Гиподинамия либо перегрузкиbull Неадекватное дыханиеbull Неадекватность мироощущения (стресс дефицит мотивации подавленность- депрессия)bull ИНТОКСИКАЦИЯbull ПОДАВЛЕННОСТЬ ИММУНИТЕТА
Предлагаемая схема клинического эксперимента на хронических носителях гепатитов В и С для изучения лечебных курсов
Курс оздоровления направленный на восстановление иммунной системы
Тераперапевтическая Вакцинация Курс анти-Вирусной ТерапииСовместное применение Вакцины и анти-Вирусного Курса
М О Н И Т О Р И Н Г по всем иммуно-параметрам ДНКРНК печеночные ферменты др
Ожидаемые результатыbull Влияние оздоровления-восстановления на течение хронического ГВbull Роль предварительного оздоровления-восстановления на каждый из методов леченияbull Сравнительная эффективность вакцины анти-вирусного курса и комбинации на фоне предварительного оздоровления-восстановления и без фона
() Курс относится к категории SPA
НИИ вакцин и сывороток им И И Мечникова РАМН Москва
Сочетанная терапия laquoвакцина + альфа-2 бета-интерферонraquo позволила получить подавление вирусной репликации в первые 1ndash2 месяца от начала лечения у 786 больных сероконверсию HВsAg на анти-HВs mdash у 964 Исчезновение HВеAg наблюдалось через 6 месяца у всех больных а анти-HВе через 2ndash3 месяца от начала лечения появились у всех больных Наблюдение за пациентами в течение трех лет и более показало что стойкий ответ на лечение отмечался у 24 (857) К концу лечения нормализовались все популяции лимфоцитов высоким оставался только уровень лимфоцитов экспрессирующих рецептор к ИЛ-2 (CD25+) оставались сниженными резервы фагоцитоза и кислородзависимого киллинга [5]Таким образом вакцинация против ГВ является актуальной и необходимой больным с ХЗП пациентам с ХГВ иили ХГС носителям ВГВ иили ВГС поскольку способствует подавлению вирусной репликации у хронических вирусоносителей может играть существенную роль в контроле над виремией значительно повышает эффективность лечения ХВГ
Афигенова ВП Костинов МП 2011
Study Calls Into Question Effectiveness of Hepatitis B Vaccine for NewbornsDecember 17 2013httparticlesmercolacomsitesarticlesarchive20131217newborn-hepatitis-b-vaccineaspxBy Dr JM Mercola
New Study Hepatitis B Vaccination at Birth May Not Prevent Hidden InfectionsA new study is raising another red flag that the practice of universally vaccinating all newborn babies for hepatitis B is seriously flawed The researchers followed 259 babies born to hepatitis-B-positive mothers for two years in order to determine whether vaccinating such babies prevents asymptomatic occult HBV (hepatitis B virus) infectionThe researchers found that while the vaccine may help prevent overt HBV transmission it was not effective in preventing occult HBV infection in babies which may occur in up to 40 percent of babies born to hepatitis B-positive mothersHepatitis B Shot May Be Ineffective by the Time Your Child Is a TeenagerAnother issue to consider if you are weighing the benefits and risks of giving your newborn infant or young child hepatitis B vaccine is that vaccine acquired immunity often does not persist until a child reaches his or her teenage years ndash the time when acquiring a hepatitis B infection may be more likely Research shows that by that time the protection from the childhood vaccine may have long since wanedOne study found that about 15 percent of teens who received the full series of hepatitis B shots as infants tested positive for hepatitis B surface antigen (HBsAg) which is an early indicator of infection or a sign that the person is a chronic carrier of the virus3This percentage was even higher among teens who had received the hepatitis B vaccine off schedule or whose mothers were high risk meaning they tested positive for hepatitis B e antigen (HBeAg) In other words it appears that in many children hepatitis B vaccine acquired immunity does NOT provide lasting protection A Healthy Immune System Can Resolve Hepatitis B InfectionEven if you have been vaccinated as a child itrsquos important to remember that you may not be protected from these risks and could still be infected via IV drug abuse sexual activity with an infected partner a blood transfusion with contaminated blood or even getting a manicure or pedicurehellipFortunately in most cases the hepatitis B infection will resolve on its own provided you have a well-functioning immune system Symptoms can be relieved bybullRestingbullAvoiding foods that weaken your immune function such as sugarsfructose grains and processed foods Healthful foods that help boost your immune system include fermented foods and organic vegetablesbullOptimizing your vitamin D levelsbullDrinking plenty of pure waterbullAvoiding alcohol and drugs
Причинно-следственныеbull Перееданиеbull Неадекватное питаниеbull Вредные привычкиbull Гиподинамия либо перегрузкиbull Неадекватное дыханиеbull Неадекватность мироощущения (стресс дефицит мотивации подавленность- депрессия)bull ИНТОКСИКАЦИЯbull ПОДАВЛЕННОСТЬ ИММУНИТЕТА
Предлагаемая схема клинического эксперимента на хронических носителях гепатитов В и С для изучения лечебных курсов
Курс оздоровления направленный на восстановление иммунной системы
Тераперапевтическая Вакцинация Курс анти-Вирусной ТерапииСовместное применение Вакцины и анти-Вирусного Курса
М О Н И Т О Р И Н Г по всем иммуно-параметрам ДНКРНК печеночные ферменты др
Ожидаемые результатыbull Влияние оздоровления-восстановления на течение хронического ГВbull Роль предварительного оздоровления-восстановления на каждый из методов леченияbull Сравнительная эффективность вакцины анти-вирусного курса и комбинации на фоне предварительного оздоровления-восстановления и без фона
() Курс относится к категории SPA
Study Calls Into Question Effectiveness of Hepatitis B Vaccine for NewbornsDecember 17 2013httparticlesmercolacomsitesarticlesarchive20131217newborn-hepatitis-b-vaccineaspxBy Dr JM Mercola
New Study Hepatitis B Vaccination at Birth May Not Prevent Hidden InfectionsA new study is raising another red flag that the practice of universally vaccinating all newborn babies for hepatitis B is seriously flawed The researchers followed 259 babies born to hepatitis-B-positive mothers for two years in order to determine whether vaccinating such babies prevents asymptomatic occult HBV (hepatitis B virus) infectionThe researchers found that while the vaccine may help prevent overt HBV transmission it was not effective in preventing occult HBV infection in babies which may occur in up to 40 percent of babies born to hepatitis B-positive mothersHepatitis B Shot May Be Ineffective by the Time Your Child Is a TeenagerAnother issue to consider if you are weighing the benefits and risks of giving your newborn infant or young child hepatitis B vaccine is that vaccine acquired immunity often does not persist until a child reaches his or her teenage years ndash the time when acquiring a hepatitis B infection may be more likely Research shows that by that time the protection from the childhood vaccine may have long since wanedOne study found that about 15 percent of teens who received the full series of hepatitis B shots as infants tested positive for hepatitis B surface antigen (HBsAg) which is an early indicator of infection or a sign that the person is a chronic carrier of the virus3This percentage was even higher among teens who had received the hepatitis B vaccine off schedule or whose mothers were high risk meaning they tested positive for hepatitis B e antigen (HBeAg) In other words it appears that in many children hepatitis B vaccine acquired immunity does NOT provide lasting protection A Healthy Immune System Can Resolve Hepatitis B InfectionEven if you have been vaccinated as a child itrsquos important to remember that you may not be protected from these risks and could still be infected via IV drug abuse sexual activity with an infected partner a blood transfusion with contaminated blood or even getting a manicure or pedicurehellipFortunately in most cases the hepatitis B infection will resolve on its own provided you have a well-functioning immune system Symptoms can be relieved bybullRestingbullAvoiding foods that weaken your immune function such as sugarsfructose grains and processed foods Healthful foods that help boost your immune system include fermented foods and organic vegetablesbullOptimizing your vitamin D levelsbullDrinking plenty of pure waterbullAvoiding alcohol and drugs
Причинно-следственныеbull Перееданиеbull Неадекватное питаниеbull Вредные привычкиbull Гиподинамия либо перегрузкиbull Неадекватное дыханиеbull Неадекватность мироощущения (стресс дефицит мотивации подавленность- депрессия)bull ИНТОКСИКАЦИЯbull ПОДАВЛЕННОСТЬ ИММУНИТЕТА
Предлагаемая схема клинического эксперимента на хронических носителях гепатитов В и С для изучения лечебных курсов
Курс оздоровления направленный на восстановление иммунной системы
Тераперапевтическая Вакцинация Курс анти-Вирусной ТерапииСовместное применение Вакцины и анти-Вирусного Курса
М О Н И Т О Р И Н Г по всем иммуно-параметрам ДНКРНК печеночные ферменты др
Ожидаемые результатыbull Влияние оздоровления-восстановления на течение хронического ГВbull Роль предварительного оздоровления-восстановления на каждый из методов леченияbull Сравнительная эффективность вакцины анти-вирусного курса и комбинации на фоне предварительного оздоровления-восстановления и без фона
() Курс относится к категории SPA
Предлагаемая схема клинического эксперимента на хронических носителях гепатитов В и С для изучения лечебных курсов
Курс оздоровления направленный на восстановление иммунной системы
Тераперапевтическая Вакцинация Курс анти-Вирусной ТерапииСовместное применение Вакцины и анти-Вирусного Курса
М О Н И Т О Р И Н Г по всем иммуно-параметрам ДНКРНК печеночные ферменты др
Ожидаемые результатыbull Влияние оздоровления-восстановления на течение хронического ГВbull Роль предварительного оздоровления-восстановления на каждый из методов леченияbull Сравнительная эффективность вакцины анти-вирусного курса и комбинации на фоне предварительного оздоровления-восстановления и без фона
() Курс относится к категории SPA
![[PPT] msu.rukodomo.fbb.msu.ru/FBB/lectures/Losev_1.ppt · Web viewПрофили экспрессии (паттерны) различаются у нормальных и раковых](https://img.dokumen.tips/doc/110x75/5f81e43372c37b248d6de421/ppt-msu-web-view-.jpg)
