Homologous and heterologous booster vaccinations of S-268019-b, a recombinant S protein-based vaccine with a squalene-based adjuvant, enhance neutralization breadth against SARS-CoV-2 Omicron subvariants in cynomolgus macaques

Hashimoto, Masayuki; Aoe, Shinpei; Kawazu, Yusuke; Seki, Naomi M.; Hashimoto, Kumi; Yoshihara, Ken; Homma, Tomoyuki; Sonoyama, Takuhiro; Omoto, Shinya

doi:10.1016/j.vaccine.2022.10.092

Cited by 6 publications

(6 citation statements)

References 22 publications

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“…A-910823 is a squalene-based adjuvant used in S-268019-b, a novel SARS-CoV-2 vaccine, and the duration and breadth of neutralizing antibodies induced by S-268019-b has been demonstrated in humans and monkeys ( 14 – 17 ). The potent induction of Tfh cells, which enhances the duration and breadth of neutralizing antibodies by generating GCB cells and long-lived plasma cells, has been revealed in our previous research ( 18 ); however, the component that contributed to the Tfh cell induction remained unclear.…”

Section: Discussionmentioning

confidence: 99%

“…Oil-in-water emulsion adjuvant A-910823, A-910823 with various proportions of squalene and α-tocopherol, and A-910823 at different average diameters were prepared at Shionogi & Co., Ltd. (Osaka, Japan) with a high-pressure homogenization technique as previously described ( 19 , 20 ), with some modifications, which are summarized in the Supplementary Methods . The LNP-formulated mRNA vaccine (LNP-mRNA) was prepared using ionizable Lipid8 and mRNA encoding the full-length SARS-CoV-2 spike protein from the Pango lineage A strain, as previously described ( 17 ). Lipid8, distearoylphosphatidylcholine (Nippon Fine Chemical Co., Ltd, Tokyo, Japan), cholesterol (Nippon Fine Chemical Co., Ltd), and 1,2-dimyristoyl-sn-glycerol methoxypolyethylene glycol 2000 (NOF Corporation, Osaka, Japan) were dissolved in ethanol.…”

Section: Methodsmentioning

confidence: 99%

“…Our recent immunological analysis showed the induction of T follicular helper (Tfh) cells, memory B cells, and memory T cells, which confer the duration and breadth of antigen-specific antibodies, by A-910823 in mice (18). Thus, a line of evidence has demonstrated the magnitude and durability of the immune responses induced by S-268019-b (13,14,(16)(17)(18). However, the mechanism of action and the contribution of each component of A-910823 as a vaccine adjuvant are yet to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

“…EPI_ISL_408667) in a non-human primate model ( 16 ). Further analysis demonstrated the enhanced neutralization breadth against the SARS-CoV-2 Omicron subvariant by homologous and heterologous booster vaccinations ( 17 ). Our recent immunological analysis showed the induction of T follicular helper (Tfh) cells, memory B cells, and memory T cells, which confer the duration and breadth of antigen-specific antibodies, by A-910823 in mice ( 18 ).…”

Section: Introductionmentioning

confidence: 99%

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A-910823, a squalene-based emulsion adjuvant, induces T follicular helper cells and humoral immune responses via α-tocopherol component

Yoshioka

Kobiyama²,

Hayashi³

et al. 2023

Front. Immunol.

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BackgroundAdjuvants are chemical or biological materials that enhance the efficacy of vaccines. A-910823 is a squalene-based emulsion adjuvant used for S-268019-b, a novel vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that is currently in clinical development. Published evidence has demonstrated that A-910823 can enhance the induction of neutralizing antibodies against SARS-CoV-2 in humans and animal models. However, the characteristics and mechanisms of the immune responses induced by A-910823 are not yet known.Methods and ResultsTo characterize A-910823, we compared the adaptive immune response profile enhanced by A-910823 with that of other adjuvants (AddaVax, QS21, aluminum salt-based adjuvants, and empty lipid nanoparticle [eLNP]) in a murine model. Compared with other adjuvants, A-910823 enhanced humoral immune responses to an equal or greater extent following potent T follicular helper (Tfh) and germinal center B (GCB) cell induction, without inducing a strong systemic inflammatory cytokine response. Furthermore, S-268019-b containing A-910823 adjuvant produced similar results even when given as a booster dose following primary administration of a lipid nanoparticle-encapsulated messenger RNA (mRNA-LNP) vaccine. Preparation of modified A-910823 adjuvants to identify which components of A-910823 play a role in driving the adjuvant effect and detailed evaluation of the immunological characteristics induced by each adjuvant showed that the induction of humoral immunity and Tfh and GCB cell induction in A-910823 were dependent on α-tocopherol. Finally, we revealed that the recruitment of inflammatory cells to the draining lymph nodes and induction of serum cytokines and chemokines by A-910823 were also dependent on the α-tocopherol component.ConclusionsThis study demonstrates that the novel adjuvant A-910823 is capable of robust Tfh cell induction and humoral immune responses, even when given as a booster dose. The findings also emphasize that α-tocopherol drives the potent Tfh-inducing adjuvant function of A-910823. Overall, our data provide key information that may inform the future production of improved adjuvants.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A-910823, a squalene-based emulsion adjuvant, induces T follicular helper cells and humoral immune responses via α-tocopherol component

Yoshioka

Kobiyama²,

Hayashi³

et al. 2023

Front. Immunol.

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“…Squalene is a linear triterpenoid widely distributed in plants and animals, including humans. It has significant anticancer and antitumor benefits, assists the transport of nucleoside antitumor drugs, the treatment of skin diseases, , and the preparation of vaccines. − Squalene was initially isolated from shark liver oil and more recently from plant sources . However, increasing demand may lead to overfishing and other environmental problems.…”

Section: Introductionmentioning

confidence: 99%

Regulation of Ethanol Assimilation for Efficient Accumulation of Squalene in Saccharomyces cerevisiae

Zhang

Wang

Wei

et al. 2023

J. Agric. Food Chem.

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Squalene is a triterpene that can be obtained from fish and plant oils. It is important in cosmetics and vaccines and is a precursor for many high-value terpenes and steroids. In order to increase squalene accumulation, the mevalonate pathway was systematically enhanced. Accumulation of squalene tended to increase when ethanol was added as a carbon source during fermentation, but a high concentration of ethanol affected both the strain growth and accumulation of products. By overexpressing the key trehalose synthesis gene TPS1 and the heat shock protein gene HSP104, the content of trehalose by Saccharomyces cerevisiae (S. cerevisiae) was enhanced, and stress caused by ethanol was relieved. The OD 600 value of the modified S. cerevisiae strain was increased by 80.2%, its ethanol tolerance was increased to 30 g/L, and it retained excellent activity with 50 g/L ethanol. After optimizing the fermentation conditions, the squalene titer in a 5 L bioreactor reached 27.3 g/L and the squalene content was 650 mg/g dry cell weight, the highest squalene production parameters reported to date for a microorganism.

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Subunit vaccine raised against the SARS‐CoV‐2 spike of Delta and Omicron variants

Feng,

Fan,

Zhou

et al. 2023

Journal of Medical Virology

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Vaccination has proven effective against SARS‐CoV‐2 infection but vaccines were originally based on the wild type and emerging variants have led to a decrease in protective efficacy. There is an urgent need for broad‐spectrum vaccine protection against emerging variants. A vaccine based on the Delta strain spike protein was created by optimization of vector, codon, and protein structure to produce a subunit immunogen (Delta‐6P‐S) containing six proline mutations, stable pre‐fusion conformation, and with high expression in CHO‐S cells. Immunogenicity and protective efficacy were evaluated in mice and golden hamsters using alum adjuvant. The Delta‐6P‐S recombinant protein induced strong immune responses in C57BL/6J mice and golden hamsters and sera had cross‐neutralization activity and neutralized wild type and Beta, Delta, Omicron BA.1, BA.2, and BA.5 variant strains. Golden hamsters were immunized against Delta, Omicron BA.1, and BA.2 variants. Viral RNA detected from throat swabs, lungs and tracheas decreased significantly in vaccine‐inoculated animals relative to alum‐treated controls and no infectious viruses were detected in lungs and tracheas. Almost no pathological damage to lung tissue was found in vaccinated animals by contrast with those treated only with alum. The Delta‐6P‐S recombinant protein rapidly eliminated replicating virus in the upper and lower airways of golden hamsters and merits further investigation as a candidate anti‐SARS‐CoV‐2 vaccine.

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Homologous and heterologous booster vaccinations of S-268019-b, a recombinant S protein-based vaccine with a squalene-based adjuvant, enhance neutralization breadth against SARS-CoV-2 Omicron subvariants in cynomolgus macaques

Cited by 6 publications

References 22 publications

A-910823, a squalene-based emulsion adjuvant, induces T follicular helper cells and humoral immune responses via α-tocopherol component

A-910823, a squalene-based emulsion adjuvant, induces T follicular helper cells and humoral immune responses via α-tocopherol component

Regulation of Ethanol Assimilation for Efficient Accumulation of Squalene in Saccharomyces cerevisiae

Subunit vaccine raised against the SARS‐CoV‐2 spike of Delta and Omicron variants

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