Adjuvanting a subunit SARS-CoV-2 vaccine with clinically relevant adjuvants induces durable protection in mice

Abstract

Adjuvants enhance the magnitude and the durability of the immune response to vaccines. However, there is a paucity of comparative studies on the nature of the immune responses stimulated by leading adjuvant candidates. In this study, we compared five clinically relevant adjuvants in mice—alum, AS03 (a squalene-based adjuvant supplemented with α-tocopherol), AS37 (a TLR7 ligand emulsified in alum), CpG1018 (a TLR9 ligand emulsified in alum), O/W 1849101 (a squalene-based adjuvant)—for their capacity to stimulate immune responses when combined with a subunit vaccine under clinical development. We found that all four of the adjuvant candidates surpassed alum with respect to their capacity to induce enhanced and durable antigen-specific antibody responses. The TLR-agonist-based adjuvants CpG1018 (TLR9) and AS37 (TLR7) induced Th1-skewed CD4+ T cell responses, while alum, O/W, and AS03 induced a balanced Th1/Th2 response. Consistent with this, adjuvants induced distinct patterns of early innate responses. Finally, vaccines adjuvanted with AS03, AS37, and CpG1018/alum-induced durable neutralizing-antibody responses and significant protection against the B.1.351 variant 7 months following immunization. These results, together with our recent results from an identical study in non-human primates (NHPs), provide a comparative benchmarking of five clinically relevant vaccine adjuvants for their capacity to stimulate immunity to a subunit vaccine, demonstrating the capacity of adjuvanted SARS-CoV-2 subunit vaccines to provide durable protection against the B.1.351 variant. Furthermore, these results reveal differences between the widely-used C57BL/6 mouse strain and NHP animal models, highlighting the importance of species selection for future vaccine and adjuvant studies.

Broad and Durable Humoral Responses Following Single Hydrogel Immunization of SARS-CoV-2 Subunit Vaccine

“…[48] Future studies will uncover whether the balanced Th1/Th2 responses in the PNP hydrogels, regardless of the nature of the adjuvant, have any impact on cellular immunity. Such studies could reveal a contrast to the previously reported, predominately Th1-skewed CD4 T cell response found in mice immunized with soluble vaccines comprising RBD NP and CpG/Alum [9] or the Th2skewed response we have observed with mice immunized with Soluble 3M052/Alum. Crucially, several previous studies have found little to no binding and neutralizing titers against the Omicron BA.1 and BA.2 variants after initial prime-boost immunization series with RBD NP soluble vaccines.…”

Virus-like particle displaying SARS-CoV-2 receptor binding domain elicits neutralizing antibodies and is protective in a challenge model

“…Further, we observed improved potency in naïve animals by formulating IVX-411 with MF59, an oil-in-water emulsion. Such results have been externally replicated for I53-50-based SARS-CoV-2 vaccines in naïve human patients [38,[41][42][43]. Our results are immunogenically similar to those observed from other RBD-based, single-component, SARS-…”

“…Further, we observed improved potency in naïve animals by formulating IVX-411 with MF59, an oil-in-water emulsion. Such results have been externally replicated for I53-50-based SARS-CoV-2 vaccines in naïve human patients [38,[41][42][43]. Our results are immunogenically similar to those observed from other RBD-based, single-component, SARS-CoV-2 VLP vaccines, which use nanoparticles such as ferritin [44,45], hepatitis B surface antigen [46], or mi3 (a variant of the I3-01 VLP) [47][48][49][50], as well as biochemical conjugation methods such as SpyCatcher and sortase [45,47].…”

Molecular engineering of a cryptic epitope in Spike RBD improves manufacturability and neutralizing breadth against SARS-CoV-2 variants

“…Future studies are merited to evaluate the use of this VLP-RBD candidate or other multimeric versions as a 1st or 2nd booster to an mRNA vaccination. We acknowledge that further optimization of a vaccine candidate based on the engineered immunogens tested here could benefit from the inclusion of one or more adjuvants, including CpG, SMNP, or other strategies for enhancing immunogenicity [11] , [29] , [67] .…”