Development of Bivalent mRNA Vaccines against SARS-CoV-2 Variants

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected billions of individuals and is the cause of the current global coronavirus disease 2019 (COVID-19) pandemic. We previously developed an mRNA vaccine (LVRNA009) based on the S protein of the Wuhan-Hu-1 strain; the phases I and II clinical trials showed that LVRNA009 has a promising safety and immunogenicity profile. In order to counteract the immune escape by SARS-CoV-2 variants of concern, a panel of mRNA vaccines was developed based on the S proteins of the Wuhan-Hu-1, Delta, Omicron BA.1, BA.2, and BA.5 strains, and each vaccine’s protective potency against the virus variants was evaluated. Furthermore, to achieve excellent neutralization against SARS-CoV-2 variants, bivalent vaccines were developed and tested against the variants. We found that the monovalent Wuhan-Hu-1 or the Delta vaccines could induce high level of neutralization antibody and protect animals from the infection of the SARS-CoV-2 Wuhan-Hu-1 or Delta strains, respectively. However, serum samples from mice immunized with monovalent Delta vaccine showed relatively low virus neutralization titers (VNTs) against the pseudotyped virus of the Omicron strains. Serum samples from mice immunized with bivalent Delta/BA.1 vaccine had high VNTs against the pseudotyped Wuhan-Hu-1, Delta, and BA.1 strains but low VNTs against BA.2 and BA.5 (p < 0.05). Serum samples from mice immunized with Delta/BA.2 vaccine had high VNTs against the pseudotyped Wuhan-Hu-1, Delta, BA.1 and BA.2 strains but low VNTs against BA.5. Finally, serum samples from mice immunized with Delta/BA.5 vaccine had high VNTs against all the tested pseudotyped SARS-CoV-2 strains including the Wuhan-Hu-1, Delta, and Omicron variants (p > 0.05). Therefore, a bivalent mRNA vaccine with Delta/BA.5 combination is promising to provide broad spectrum immunity against all VOCs.

A bivalent subunit vaccine efficiently produced in Pichia pastoris against SARS-CoV-2 and emerging variants

“…Brinkkemper’s study showed that co-display of wild-type and Beta spike proteins of SARS-CoV-2 on self-assembling nanoparticle platform broadens the neutralizing antibody responses ( Brinkkemper et al, 2022 ). Vaccines based on other components, such as S1 or NTD, are also suggested to enhance the broad spectrum of neutralizing antibodies ( Jiang et al, 2021 ; Li et al, 2022 ; Scheaffer et al, 2022 ).…”

Adjuvant physiochemistry and advanced nanotechnology for vaccine development

“…Several other COVID-19 mRNA vaccine candidates use LNPs to deliver various immunocargos, including PTX-COVID19-B (Modified SARS-CoV-2, NCT04765436), 548 ChulaCov19 (S-spike mRNA, NCT04566276), RQ3013 (modified S-spike mRNA, NCT05396573), LVRNA009 (modified mRNA, LVRNA009). 549 In addition to pure LNPs as a carrier for mRNA, the use of hybrid nanoparticles combining LNPs with inorganic materials has been investigated in clinical trials for COVID-19 mRNA vaccines. One such vaccine is HDT-301 (phase 1, NCT05132907, NCT04844268), which utilizes cationic squalene emulsion containing Fe 3 O 4 nanoparticles, along with the cationic lipid DOTAP and self-replicating replicon RNA (repRNA).…”

“…Several other COVID-19 mRNA vaccine candidates use LNPs to deliver various immunocargos, including PTX-COVID19-B (Modified SARS-CoV-2, NCT04765436), 548 ChulaCov19 (S-spike mRNA, NCT04566276), RQ3013 (modified S-spike mRNA, NCT05396573), LVRNA009 (modified mRNA, LVRNA009). 549…”

RBD and Spike DNA-Based Immunization in Rabbits Elicited IgG Avidity Maturation and High Neutralizing Antibody Responses against SARS-CoV-2

“…The COVID-19 pandemic imposed new challenges to healthcare services, including requirement for novel immunoassays, immunotherapeutics based on neutralizing antibodies (nAbs), and new vaccinal platforms to assist the public health system and to reduce the increasing number of cases and deaths worldwide [ 4 , 5 , 6 , 7 , 8 ]. Since the onset of the COVID-19 pandemic, several variants of concern (VOCs) have emerged, including Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), and the super-spread Omicron (B.1.1.529, BA.1, BA.2, BA.3, BA.4, and BA.5) [ 9 , 10 ]. The major concern about VOCs is related to their ability to increase transmission and/or virulence, and/or to escape current vaccine-induced immunity.…”

“…Thus, it may provide a simple and rapid platform for large-scale production of SARS-CoV-2 nAbs without the need for time-consuming procedures associated with viral isolation and/or production and purification of viral antigens [ 21 , 28 ]. Several DNA and mRNA vaccines expressing mainly the spike protein have been developed against SARS-CoV-2 and are being tested in clinical trials against COVID-19, which have confirmed the strong protective humoral and cellular immune responses in animal models [ 7 , 9 , 24 , 29 , 30 ].…”