A replication-competent smallpox vaccine LC16m8Δ-based COVID-19 vaccine

ABSTRACT

Viral vectors are a potent vaccine platform for inducing humoral and T-cell immune responses. Among the various viral vectors, replication-competent ones are less commonly used for coronavirus disease 2019 (COVID-19) vaccine development compared with replication-deficient ones. Here, we show the availability of a smallpox vaccine LC16m8Δ (m8Δ) as a replication-competent viral vector for a COVID-19 vaccine. M8Δ is a genetically stable variant of the licensed and highly effective Japanese smallpox vaccine LC16m8. Here, we generated two m8Δ recombinants: one harbouring a gene cassette encoding the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) glycoprotein, named m8Δ-SARS2(P7.5-S)-HA; and one encoding the S protein with a highly polybasic motif at the S1/S2 cleavage site, named m8Δ-SARS2(P7.5-S_HN)-HA. M8Δ-SARS2(P7.5-S)-HA induced S-specific antibodies in mice that persisted for at least six weeks after a homologous boost immunization. All eight analysed serum samples displayed neutralizing activity against an S-pseudotyped virus at a level similar to that of serum samples from patients with COVID-19, and more than half (5/8) also had neutralizing activity against the Delta/B.1.617.2 variant of concern. Importantly, most serum samples also neutralized the infectious SARS-CoV-2 Wuhan and Delta/B.1.617.2 strains. In contrast, immunization with m8Δ-SARS2(P7.5-S_HN)-HA elicited significantly lower antibody titres, and the induced antibodies had less neutralizing activity. Regarding T-cell immunity, both m8Δ recombinants elicited S-specific multifunctional CD8⁺ and CD4⁺ T-cell responses even after just a primary immunization. Thus, m8Δ provides an alternative method for developing a novel COVID-19 vaccine.

KEYWORDS:

• BALB/c mouse
• cellular immunity
• COVID-19
• Delta/B.1.617.2 variant of concern
• humoral immunity
• LC16m8
• prime-boost immunization
• SARS-CoV-2

SUBJECT CLASSIFICATION CODES:

• emerging and re-Emerging coronaviruses

Acknowledgements

We thank our colleagues for technical assistance, helpful comments, and discussion. We also thank Katie Oakley, PhD, from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.

Disclosure statement

S.Y., H.S., and M.I. are named inventors on filed patents related to viral-vectored malaria vaccines. H.S. is a named inventor on a filed patent related to m8Δ (WO 2005/054451 A1).

Author contributions

A.S., M.I., and S.Y. contributed to the conception and design of the study. S.Y. supervised the study. A.S., H.O., H.H., T.M., A.H., Y.A., Y.O., and R.O. performed experiments and analysed data. A.S. wrote the manuscript. H.S. and S.Y. edited the manuscript. All authors contributed to manuscript revision and have read and approved the submitted version.

Declaration of interest statement

S.Y., H.S., and M.I. are named inventors on filed patents related to viral-vectored malaria vaccines. H.S. is a named inventor on a filed patent related to m8Δ (WO 2005/054451 A1).

Data availability statement

The authors confirm that the data supporting the findings of this study are available within the article and its supplementary materials.

Additional information

Funding

This work was supported by the Japan Society for the Promotion of Science (JSPS) under Grant [number 21K06545] and Sumitomo Mitsui Trust Bank under Grant.