Vaccine AdjuvantsAdjuvant Application Protocol_virus infection

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Adjuvant의 사용은 백신의 면역반응을 크게 향상시키고 있고, 다양한 질병을 대상으로 하는 치료 전략에서 다양한 범주의 보조제가 연구되고 있습니다.

Alum은 Diphtheria-Tetanus-Pertussis, 인간 유두종 바이러스 및 간염 백신을 포함한 인간 백신에 가장 일반적으로 사용되는 Adjuvant입니다. Invivogen은 Aluminum hygroxide wet gel suspension 형태로 Alum 옵션인 Alhydrogel® Adjuvant 2%를 제공합니다. 

그러나 Alum 단독으로는 특정 면역 반응의 유도 및 조절에 충분하지 않으며, 이는 새로운 보조제 및 복합 면역 자극이 필요함을 시사합니다. Croda에서 생산된 GMP grade의 Quil-A® Adjuvant는 다양한 수의학 백신 뿐만 아니라 인간 및 수의학 적용에 대한 면역학 연구에도 사용됩니다. Invivogen은 Croda가 연구 목적으로 생산한 Quil-a® Adjuvant를 제공합니다. 

AS03 및 MF59®과 같은 Emulsion도 승인된 많은 백신에 사용되었습니다. 여러가지 Infulenza 백신은 Fluad®, Focetria® 및 Aflunov®와 같은 MF59®를 Adjuvant를 사용했습니다. Invivogen은 MF59®와 유사한 제형의 AddaVax®를 제공합니다.

일부 Influenza 백신은 Pandermrix® 및 Arepandix®와 같은 AS03®을 보조제로 사용했습니다. Invivogen의 AddaS03™ 은 Adjuvant system AS03®과 유사한 제형을 제공합니다.

AS01은 최초의 말라리아 백신인 Mosquirix의 구성 요소이며, 이는 인간 기생충 질환에 승인된 최초의 백신입니다. 이 Adjuvant는 면역 자극제 QS21과 MPL의 조합으로 단일 백신 (대상포진)으로 처음 허가되었습니다. Invivogen은 Agenus/SaponiQx의 독점 Saponin STIMULONTM QS21의 제제인 QS21 Vaccigrade 을 제공합니다. 

거의 모든 PRR 계열들은 Adjuvant의 잠재적인 표적입니다. Nexavant 은 또 다른 TLR3-agonistic adjuvant인 Poly(I:C)의 문제를 성공적으로 극복한 항바이러스 또는 항암 백신의 유망한 Adjuvant입니다.

또 다른 PRR Ligand CpG ODN1018은 허가된 HBV vaccine인 HEPLISAV-B®을 포함하여 승인된 여러 백신의 구성 요소입니다. 다양한 전임상 및 임상 시험에서는 현재 전염병이나 암에 대한 백신 전략에서 OND 1018을 단독 혹은 Alum과 함께 사용하고 있습니다. Invivogen은 in vivo에 적합한 고품질의 Preclinical grade인 OND 1018 Vaccigrade 을 제공합니다.


Adjuvant Application in Viral Infection
ApplicationVaccine Formulation (F) / Vaccination Protocol (P)PMID
CCHFV
F: 100µg Sindbis replicon expressing CCHFV NP was mixed with 50µg Poly(I:C) (HMW) VacciGrade™.
P: Mice were injected at the tibia anterior muscle with 100µl vaccine, 50µl in each of the tibia anterior muscles, at days 0, 21, and 42.
34960237
DENV
F: 20µg DENV nonstructural protein 1 or OVA was mixed with AddaVax™ or 1µg MPLA.
P: Mice were intraperitoneally injected three times at days 0, 14 and 42.
26355030
DENVF: 1, 5 or 20µg DENV-2 VLPs were mixed with 50µl AddaVax™, 50µl Alhydrogel® adjuvant 2%, or 25µg c-di-GMP VacciGrade™.
P: Mice were subcutaneously injected with vaccines at the tail base on weeks 0 and 12 
26382602
Ebola virusF: 10µg VLP was mixed with 10µg ODN 2395 VacciGrade™ or 10µg MPLA-SM*.
P: Mice were intramuscularly immunized twice with 3 weeks between vaccinations.
26870818
EV711 F: EV71 antigen was mixed with AddaVax™ in sterile PBS.
P: Mice were intramuscularly immunized twice with vaccine at days 0 and 14.
26287531
FMDVF: 0.75µg(mice) or 30µg (pig) antigens were formulated with 10% Al(OH)3, 50% Montanide ISA 206 VG, and 15μg (mice) or 150µg (pig) Quil-A® adjuvant.
P: Mice were intramuscularly immunized with 100µl vaccine 7 days before infection. Pigs were intramuscularly immunized with 1ml vaccine.
38006022
CCHFVF: 100µg Sindbis replicon expressing CCHFV NP was mixed with 50µg Poly(I:C) (HMW) VacciGrade™.
P: Mice were injected at the tibia anterior muscle with 100µl vaccine, 50µl in each of the tibia anterior muscle, at days 0, 21, and 42.
34960237
DENVF: 20µg DENV nonstructural protein 1 or OVA was mixed with AddaVax™ or 1µg MPLA.
P: Mice were intraperitoneally injected three times at days 0, 14 and 42.
26355030
DENVF: 1, 5 or 20µg DENV-2 VLPs were mixed with 50µl AddaVax™, 50µl Alhydrogel® adjuvant 2%, or 25µg c-di-GMP VacciGrade™.
P: Mice were subcutaneously injected with vaccines at the tail base on weeks 0 and 12.
26382602
Ebola virusF: 10µg VLP was mixed with 10µg ODN 2395 VacciGrade™ or 10µg MPLA-SM*.
P: Mice were intramuscularly immunized twice with 3 weeks between vaccinations.
26870818
EV71F: EV71 antigen was mixed with AddaVax™ in sterile PBS.
P: Mice were intramuscularly immunized twice with vaccine at days 0 and 14.
26287531
FMDVF: 0.75µg(mice) or 30µg (pig) antigens were formulated with 10% Al(OH)3, 50% Montanide ISA 206 VG, and 15μg (mice) or 150µg (pig) Quil-A® adjuvant.
P: Mice were intramuscularly immunized with 100µl vaccine 7 days before infection. Pigs were intramuscularly immunized with 1ml vaccine.
38006022
HIVF: 7.5pmol antigen was mixed with AddaVax™.
P: Mice were subcutaneously injected with vaccines at the base of the tail and boosted again 6 weeks later.
23159556
HIVF: The HIV-1 Env proteins were formulatd with appropriate AddaVax™.
P: Mice were immunized intramuscularly with 40µg DNA at weeks 0, 2 and 4, and subcutaneously with 15µg Env proteins at weeks 8 and 11.
25546013
HIVF: 40µg MPER peptide, 100µg soluble LACK1 helper peptide and 17.5µg MPLA was mixed with AddaVax™.
P: Mice were subcutaneously injected with 100µl vaccines at the tail base, 50µl on each flank,and boosted on days 21 and 42
2559188
HIVF: 20µg MPLAs Vaccigrade™ was prepared as adjuvant, and 100µg OVA protein was prepared in alum as vaccine.
P: Mice were intramuscularly or intraperitoneally injected with adjuvant one week prior to and at the time of immunization with vaccines.
30926296
HIV
F: Saponin-MPLA nanoparticles (SMNP) adjuvant was prepared by mixing Quil-A® adjuvant, cholesterol, DPPC, and MPLA at a mass ration of 10:2:1:1 and diluting to a final chlesterol concentration of 1mg/ml. 5µg antigen was loaded onto Alhydrogel® adjuvant 2% and 5µg SMNP adjuvant at a 1:10 antigen:alum mass ratio for 30min. 
P: Mice were subcutaneously injected with 50µl on each side of the base of the tail and boosted 6 wekks post-prime. 
37573422


Adjuvant Application in Viral Infection
Application
Vaccine Formulation (F) / Vaccination Protocol (P)
PMID
Influenza
F: 20μg hemagglutinin or 6μg neuraminidase was adjuvanted with AddaVax™, AddaS03™, ODN 2395, or Alhydrogel® adjuvant 2%.
P: Mice were subcutaneously injected with vaccines at days 0 and 28.
36851561
Influenza
F: 3μg hemagglutinin was mixed with 1/2 volume of AddaS03™.
P: Mice were subcutaneously injected with vaccines on each side of the mouse.
37951212
Influenza
F: 10μg OVA or 0.3μg HA was admixed with AddaS03™ or AddaVax™ at 1:1 volume ratio.
P: Mice were intramuscularly injected with vaccine.
38793782
Influenza

F: 2009 H1N1 vaccine in 25μl PBS was mixed with 4μg Poly(I:C) (HMW) VacciGrade™ in 25μl PBS or with AddaVax™ at 1:1 volume ratio.
P: Mice were intramuscularly or intranasally injected with 50μl vaccines.
23175362
Influenza

F: 1.7, 5, or 15μg HA was mixed with AddaVax™ at a 1:1 volume ratio.
P: Mice were intramuscularly injected with 100μl vaccine bilaterally, 50μl/quadricep.
23626728
Influenza

F: 10μg HA in PBS was mixed with AddaVax™ at 1:1 ratio or 2μg Poly(I:C) (HMW).
P: Mice were intramuscularly or intranasally injected with 50μl vaccines and voosted at 3 and 6 weeks after prime.
24223176
Influenza

F: 15 or 60μg TMV-HA conjugate was mixed with Alhydrogel® adjuvant 2% or AddaVax™ at 1:1 ratio with final 1%.
P: Mice were subcutaneously injected with 100-200μl vaccines at 2 or 4 week intervals.
24378714
Influenza

F: H1N1 influenza vaccine with 0.6μg HA content was mixed with AddaVax™ at 1:1 ratio.
P: Mice were intramuscularly injected with 20μl vaccine.
25033973
Influenza
F: Fluzone containing 0.75μg of each of influenza antigens was mixed with AddaVax™ at a 1:1 ratio.
P: Mice were intramuscularly injected with 50μl vaccine.
36533954
KSHV
F: 2μg VLV was mixed with 10μg ODN 2395 VacciGrade™.
P: Mice were intramuscularly immunized with 50μl vaccine twice with vaccine at days 0 and 21.
36757205
MERS-CoV
F: 10μg RBD-based subunit vaccine was formulatied with an equal amount of AddaVax™.
P: Mice were intramuscularly injected with vaccine once and again 3 weeks later.
26446606
PRRSV
F: 5μg glycoproteins was mixed in a 1:1 ratio with AddaVax™.
P: Mice were subcutaneously injected with vaccine twice with a 3-week interval.
24614617
PRRSV
F: 250μg PRRSV VLPs were mixed with 83.3μg 2’3’-cGAMP VacciGrade™.
P: Piglets were intranasally administered with vaccine and boosted after two weeks.
28403874
RabiesF: 25 or 50μg of both Imiquimod VacciGrade™ and 25μg Poly(I:C) (HMW) VacciGrade™ were mixed for injection.
P: Rabies infected-mice were treated intramuscularly at the same site of virus inoculation twice at 3h and 12h post infection.
34029660
RabiesF: Inactivated RABV was supplemented with 20μg MPLAs Vaccigrade™.
P: Mice were intramuscularly with 100μl vaccine.
31816996
RSV
F: 1.5μg RSV fusion protein was mixed with AddaVax™ or 20μg ODN 2395.
P: Mice were intramuscularly primed with vaccine at day 0 and boosted at day 14.
26090563
RSV
F: 2e6 PFU like RSV was mixed with ODN 2216 or ODN 1585 VacciGrade™ at 2.5μg for neonate or 5μg for adult.
P: Mice were primed by intranasal administration and boosted 5-6 days later.
37392972



Adjuvant Application in Viral Infection
Application
Vaccine Formulation (F) / Vaccination Protocol (P)
PMID
SARS-CoV-2
F: S1 protein was mixed with AddaS03™ adjuvant.
P: Mice were intramuscularly injected with vaccine on days 0, 14, and 28, separately.
34226895
SARS-CoV-2
F: Recombinant RBD was mixed with AddaS03™ with 1:1 ratio.
P: Mice were intramuscularly injected with vaccine at hind legs on days 0, 14, and 42.
34481699
SARS-CoV-2
F: A mixture of 5μg RBD and 5μg S1 or 5μg RBD-Fc was diluted and mixed with an equal volume of AddaS03™ at total 50μl/dose, or with an equal volume of AddaVax™ at total 100μl/dose, or with 100μg Alhydrogel® adjuvant 2%.
P: Mice were intramuscularly injected with 50μl vaccine and were boosted with the same vaccine at 2 or 3 weeks.
34579194
SARS-CoV-2
F: 10μg RBD or Spicke protein were mixed with 25μl AddaS03™ or 50μl Alhydrogel® adjuvant 2%.
P: Mice were vaccinated via subcutaneous injections into the front two hocks on days 0 and 21.
34634664
SARS-CoV-2
F: 10μg Spike protein or 20μg RBD were emulsified with AddaS03™.
P: Mice were primed and boosted at 3 weeks intervals with vaccines via intramuscular route.
34772941
SARS-CoV-2
F: Spike S1 recombinant protein were emulsified with AddaS03™.
P: Mice were intramuscularly injection with vaccines on days of 0, 14, and 28.
34952899
SARS-CoV-2
F: 1μg Flublok vaccine was formulated with AddaVax™, or 1μg Spike protein was formulated with AddaS03™.
P: Mice were intradermally injected with vaccine on day 0 and day 14.
35148840
SARS-CoV-2
F: 20μg RBD and 50μg AddaVax™ or AddaS03™ in 1st inoculation, 10μg RBD and 50μg AddaVax™ or AddaS03™ in 2nd inoculation
P: Mice were intramuscularly inoculated with vaccine on day 0 and 14.
35296091
SARS-CoV-2
F: 10μg RBD or Spicke protein were mixed with adjuvant of 5μg MPLA and 50μl Alhydrogel® adjuvant 2%, or with 25μl AddaS03™, or with 20μg ODN 1826.
P: Mice were intradermal injected in the two forelimbs at 25μl/hock on week 0 and 3.
36206332
SARS-CoV-2
F: 1μg or 3μg spike antigen was mixed with AddaS03™ as per the manufacturer’s instructions.
P: Mice were intramuscularly injected with 50μl vaccine into the left tibialis anterior muscle on days 0 and 21.
36224247
SARS-CoV-2
F: 0.3, 1, and 3μg SARS-CoV-2 antigens (RBD monomer, spike trimer, or RBD nanoparticles) were mixed with 25μl AddaS03™ or with 50μl AddaVax™.
P: Mice were intramuscularly injected with 50μl vaccine in the caudal thigh on day 0 and 14.
36788219
SARS-CoV-2
F: 10μg S1 were mixed with adjuvant AddaS03™ according to the instructions provided by the manufacturer.
P: Mice were intramuscularly injected with vaccines twice or thrice every 2 weeks.
36909295
SARS-CoV-2
F: 1μg RBD nanoparticles were formulated as a 1:1 ration in AddaVax™ or in AddaS03™.
P: Mice were subcutaneously injected with 100μl vaccines on day 0 and 21.
36943870
SARS-CoV-2
F: 1 or 3μg antigen was mixed with AddaS03™ as per the manufacturer’s instructions.
P: Mice were intramuscularly injected with 50μl vaccines into the left tibiolis anterior muscle on days 0 and 21.
37122746
SARS-CoV-2
F: 280.4μg antigen was mixed with AddaS03™ in a volume of 1:1.
P: Mice were intramuscularly injected with 100μl vaccine using a homologous prime-boost dose, 2 weeks apart.
37515173
SARS-CoV-2
F: 5μg S protein diluted in 25μl PBS was mixed with 25μl Alhydrogel® adjuvant 2%, or with 10μg Quil-A® adjuvant in 25μl, or with 25μl AddaS03™.
P: Mice were intramuscularly injected with vaccine twice, 2 weeks apart.
37635002
SARS-CoV-2
F: 10μg RBD and 10μg nuclear phosphoprotein were mixed with 250μl AddaS03™.
P: 0.5ml vaccine was intramuscularly injected into macaques, hamster, or ferret twice, 21 days apart.
38140175
SARS-CoV-2
F: 10μg RBD was mixed with 5μg 2’3’-c-di-AM(PS)2 (Rp,Rp) VacciGrade™, 2’3’-cGAMP VacciGrade™, or 2’3’-cGAM(PS)2 (Rp/Sp).
P: Mice were intramuscularly immunized on days 0, 11, and 21.
37324951
SARS-CoV-2
F: 200μg polypeptides were mixed with 25μg ODN 2395 VacciGrade™.
P: Mice were subcutaneously or intramuscularly injected thrice at days 0, 14, and 28.
38628551
SARS-CoV-2
F: 10μg inactivated rabies vector vaccine was formulated with 5μg MPLAs Vaccigrade™ or with 50μl AddaVax™.
P: Hamsters were intramuscularly injected with 100μl vaccine, 50μl per hind leg on days 0 and 28.
33765062
ZIKA
F: 10μg DNA was formulated with 20μg Imiquimod VacciGrade™, or 10μg ectodomain or 50μg peptides waere formulated with 500μg Alhydrogel® adjuvant 2% or with 10μg MPLA-SM* VacciGrade™.
P: Mice were intramuscularly immunized and boosted once at three weeks.
33979612


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