A randomized phase I/II safety and immunogenicity study of the Montanide-adjuvanted SARS-CoV-2 spike protein-RBD-Fc vaccine, AKS-452

Feitsma, Eline A.; Janssen, Yester F.; Boersma, Hendrikus; Sleen, Yannick van; Baarle, Debbie van; Alleva, David G.; Lancaster, Thomas M.; Sathiyaseelan, Thillainaygam; Murikipudi, Sylaja; Delpero, Andrea R.; Scully, Melanie; Ragupathy, Ramya; Kotha, Sravya; Haworth, Jeffrey; Shah, Nishit; Rao, Vidhya; Nagre, Shashikant; Ronca, Shannon E.; Aminetzah, Ari; Sollie, Frans; Kruijff, Schelto; Brom, Maarten; Dam, Gooitzen M. van; Zion, Todd C

doi:10.1016/j.vaccine.2023.02.057

Cited by 11 publications

(16 citation statements)

References 44 publications

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“…Moreover, RBD-Fc with Montanide ISA51 vaccine showed potent immune responses in obese mice, suggesting that this formulation is safe and effective for conditioned individual [20]. Another formulation, Montanide ISA720, formulated with CHO-produced RBD-Fc vaccine has entered clinical study, suggesting a promising use of this water in oil emulsion system in combating SARS-CoV-2 [25]. Novavax's Matrix M is saponin-based particulate adjuvant used in NVX-CoV2373 which passed phase III clinical trial and showed minimal side effects [61].…”

Section: Plos Onementioning

confidence: 99%

“…Currently, there are various adjuvants used in SARS-CoV-2 subunit vaccine development that are in clinical trials such as alum, CpG1018, Matrix-M, Montanide ISA 720, and botulin-based spherical nanoparticles [7,8,24,25,61,62]. Although alum has been used in various vaccine formulations, several studies demonstrated that alum could predominantly exhibit bias towards Th2 immune responses [63].…”

Section: Plos Onementioning

confidence: 99%

“…Additionally, RBD fused with human IgG Fc fragment (RBD-Fc) has been studied for SARS-CoV-2 vaccine development since it could enhance immunogenicity of RBD and its half-life [19][20][21][22][23][24]. Currently, at least two RBD-Fc-based vaccine candidates have been investigated in clinical trial studies including AKS-452 and Betuvax-CoV-2 [24,25] and evidence suggests that RBD-based subunit vaccines are indeed promising candidates.…”

Section: Introductionmentioning

confidence: 99%

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CHO-produced RBD-Fc subunit vaccines with alternative adjuvants generate immune responses against SARS-CoV-2

Laotee,

Duangkaew,

Jivapetthai

et al. 2023

PLoS ONE

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Subunit vaccines feature critical advantages over other vaccine platforms such as stability, price, and minimal adverse effects. To maximize immunological protection of subunit vaccines, adjuvants are considered as main components that are formulated within the subunit vaccine. They can modulate adverse effects and enhance immune outcomes. However, the most suitable formulation providing the best immunological outcomes and safety are still under investigation. In this report, we combined recombinant RBD with human IgG1 Fc to create an RBD dimer. This fusion protein was expressed in CHO and formulated with alternative adjuvants with different immune activation including Montanide ISA51, Poly (I:C), and MPLA/Quil-A® as potential vaccine candidate formulations. Using the murine model, a potent induction of anti-RBD IgG antibodies in immunized mice sera were observed. IgG subclass analyses (IgG1/IgG2a) illustrated that all adjuvanted formulations could stimulate both Th1 and Th2-type immune responses in particular Poly (I:C) and MPLA/Quil-A®, eliciting greater balance. In addition, Montanide ISA51-formulated RBD-Fc vaccination provided a promising level of neutralizing antibodies against live wild-type SARS-CoV-2 in vitro followed by Poly (I:C) and MPLA/Quil-A®, respectively. Also, mice sera from adjuvanted formulations could strongly inhibit RBD:ACE2 interaction. This study offers immunogenicity profiles, forecasted safety based on Vaccine-associated enhanced disease (VAED) caused by Th1-skewed immunity, and neutralizing antibody analysis of candidates of RBD-Fc-based subunit vaccine formulations to obtain an alternative subunit vaccine formulation against SARS-CoV-2.

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Section: Plos Onementioning

confidence: 99%

Section: Plos Onementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

CHO-produced RBD-Fc subunit vaccines with alternative adjuvants generate immune responses against SARS-CoV-2

Laotee,

Duangkaew,

Jivapetthai

et al. 2023

PLoS ONE

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“…No relevant laboratory assessment abnormalities were observed. Accordingly, a similar safety profile was evident in the 180-day predecessor phase I/II trials 17 , 18 . Note that while the Montanide™ adjuvant strongly enhances IgG titers in COVID-19-immunologically naïve subjects 17 , 18 , it is also known to strongly contribute to local injection site AEs 26 , in which the non-adjuvanted AKS-452 booster approach in immunologically-primed (i.e., priorly vaccinated) subjects avoids any untoward adjuvant effects.…”

Section: Discussionmentioning

confidence: 55%

“…Considering the reduced reactogenicity profile of the subunit vaccine format in addition to the need for an effective booster vaccination, we are developing a temperature-stable recombinant subunit vaccine, AKS-452, comprised of the WT SARS-CoV-2 SP/RBD and the human IgG1 Fc region 16 that has recently demonstrated excellent safety and immunogenicity profiles in phase I/II trials 17 , 18 . Here, AKS-452, in the absence of adjuvant (intended to reduce reactogenicity), was evaluated at a single subcutaneous dose of 90 µg for booster immunogenicity and safety in a non-randomized, single-group assignment, single center, open-label study ( Anti-COVID19 VaccinaTion AKS-452 BOOSTER, ACT-BOOSTER Study; NCT05124483; EudraCT: 2021-005509-28) with 71 healthy adults (18 to 64 years) who had completed a full-dosing regimen of a regulatory-approved vaccine.…”

Section: Introductionmentioning

confidence: 99%

Immunogenicity phase II study evaluating booster capacity of nonadjuvanted AKS-452 SARS-Cov-2 RBD Fc vaccine

Alleva,

Feitsma,

Janssen

et al. 2024

npj Vaccines

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AKS-452, a subunit vaccine comprising an Fc fusion of the ancestral wild-type (WT) SARS-CoV-2 virus spike protein receptor binding domain (SP/RBD), was evaluated without adjuvant in a single cohort, non-randomized, open-labelled phase II study (NCT05124483) at a single site in The Netherlands for safety and immunogenicity. A single 90 µg subcutaneous booster dose of AKS-452 was administered to 71 adults previously primed with a registered mRNA- or adenovirus-based vaccine and evaluated for 273 days. All AEs were mild and no SAEs were attributable to AKS-452. While all subjects showed pre-existing SP/RBD binding and ACE2-inhibitory IgG titers, 60–68% responded to AKS-452 via ≥2-fold increase from days 28 to 90 and progressively decreased back to baseline by day 180 (days 28 and 90 mean fold-increases, 14.7 ± 6.3 and 8.0 ± 2.2). Similar response kinetics against RBD mutant proteins (including omicrons) were observed but with slightly reduced titers relative to WT. There was an expected strong inverse correlation between day-0 titers and the fold-increase in titers at day 28. AKS-452 enhanced neutralization potency against live virus, consistent with IgG titers. Nucleocapsid protein (Np) titers suggested infection occurred in 66% (46 of 70) of subjects, in which only 20 reported mild symptomatic COVID-19. These favorable safety and immunogenicity profiles support booster evaluation in a planned phase III universal booster study of this room-temperature stable vaccine that can be rapidly and inexpensively manufactured to serve vaccination at a global scale without the need of a complex distribution or cold chain.

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Subunit protein-based vaccines

Apostolopoulos,

Chavda

2024

Advanced Vaccination Technologies for Infectious and Chronic Diseases

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A randomized phase I/II safety and immunogenicity study of the Montanide-adjuvanted SARS-CoV-2 spike protein-RBD-Fc vaccine, AKS-452

Cited by 11 publications

References 44 publications

CHO-produced RBD-Fc subunit vaccines with alternative adjuvants generate immune responses against SARS-CoV-2

CHO-produced RBD-Fc subunit vaccines with alternative adjuvants generate immune responses against SARS-CoV-2

Immunogenicity phase II study evaluating booster capacity of nonadjuvanted AKS-452 SARS-Cov-2 RBD Fc vaccine

Subunit protein-based vaccines

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