A live attenuated influenza virus-vectored intranasal COVID-19 vaccine provides rapid, prolonged, and broad protection against SARS-CoV-2 infection

Abstract

Remarkable progress has been made in developing intramuscular vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); however, they are limited with respect to eliciting local immunity in the respiratory tract, which is the primary infection site for SARS-CoV-2. To overcome the limitations of intramuscular vaccines, we constructed a nasal vaccine candidate based on an influenza vector by inserting a gene encoding the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2, named CA4-dNS1-nCoV-RBD (dNS1-RBD). A preclinical study showed that in hamsters challenged 1 day and 7 days after single-dose vaccination or 6 months after booster vaccination, dNS1-RBD largely mitigated lung pathology, with no loss of body weight, caused by either the prototype-like strain or beta variant of SARS-CoV-2. Lasted data showed that the animals could be well protected against beta variant challenge 9 months after vaccination. Notably, the weight loss and lung pathological changes of hamsters could still be significantly reduced when the hamster was vaccinated 24 h after challenge. Moreover, such cellular immunity is relatively unimpaired for the most concerning SARS-CoV-2 variants. The protective immune mechanism of dNS1-RBD could be attributed to the innate immune response in the nasal epithelium, local RBD-specific T cell response in the lung, and RBD-specific IgA and IgG response. Thus, this study demonstrates that the intranasally delivered dNS1-RBD vaccine candidate may offer an important addition to fight against the ongoing COVID-19 pandemic, compensating limitations of current intramuscular vaccines, particularly at the start of an outbreak.

Safety and immunogenicity of a live-attenuated influenza virus vector-based intranasal SARS-CoV-2 vaccine in adults: randomised, double-blind, placebo-controlled, phase 1 and 2 trials

“… 20 Data from the preclinical study of dNS1-RBD showed that lung-resident memory RBD-specific CD4 + and CD8 + T cells could be induced by vaccination, and the T-cell immune response produced in lung tissue was about 26-times stronger than that in PBMCs in mice immunised with a single dose. 10 Nevertheless, it is difficult to observe the immune response in the lungs in clinical trials when human lung sampling is impractical, which might lead to underestimation of the intensity of cellular immunity of such vaccines clinically.…”

“…Notably, the levels of several cytokines or chemokines, including those from innate and adaptive immune responses, were significantly altered in the lung tissues of mice after dNS1-RBD immunisation in the preclinical study. 10 Additionally, vaccine-induced innate responses have been shown to be protective against viral infection in several studies. An important limitation of our study is the absence of an evaluation of local immune responses in humans, both innate and acquired immune responses; which might support the findings in animal studies that dNS1-RBD can act rapidly in the upper respiratory tract or nasal mucosa.…”

“…For the measurement of specific cellular immune responses, peripheral blood mononuclear cells (PBMCs) were collected at baseline (day 0) and at 14 days (in phase 2), 1 month, and 6 months after the second dose; following stimulation by a SARS-CoV-2 spike peptide pool (GL Biochem, Shanghai, China), PBMC IFN-γ expression was quantified using an enzyme-linked immunospot (ELISpot) assay (Dakewe Biotech, Shenzhen, China [phases 1 and 2]; Mabtech, Stockholm, Sweden [extension trial]), as described previously. 10 For the measurement of vaccine virus strain shedding in phase 1, nasopharyngeal swab samples were collected on days 0, 1, 7, 14, 15, and 21, and serum samples on days 0, 3, 14, and 17. Vaccine virus strain RNA was quantified using a real-time PCR assay, which was also used to measure vaccine virus strain in the environment in the extension trial.…”

“…The intranasal SARS-CoV-2 vaccine candidate CA4-dNS1-nCoV-RBD (dNS1-RBD) is manufactured with a cold-adapted influenza strain without non-structural protein 1 (NS1) as the genetic backbone, into which receptor-binding domain (RBD) genes from SARS-CoV-2 are inserted by gene reassortment. 9 In the preclinical study, currently reported as a preprint, 10 the vaccine showed rapid (onset of action after 24 h), long-lasting, and broad protection against SARS-CoV-2 challenge in hamsters by inducing strong innate and adaptive local immune responses in the respiratory tract, with weaker responses in the circulation, even when administered 24 h after SARS-CoV-2 infection. 9 months after two doses of dNS1-RBD, the protective effect against the SARS-CoV-2 beta variant provided by vaccination remained as good as that against the original strain of the virus.…”

“…9 months after two doses of dNS1-RBD, the protective effect against the SARS-CoV-2 beta variant provided by vaccination remained as good as that against the original strain of the virus. 10 dNS1-RBD is currently being assessed in an international, multicentre, phase 3 efficacy study (ChiCTR2100051391), with the first participant enrolled on Dec 16, 2021. Additionally, seven other intranasal spray SARS-CoV-2 vaccines are under clinical development worldwide, 11 although no human data have yet been published.…”