A recent study published in the journal Nature describes the safety and efficacy of a live-attenuated yellow fever 17D (YF17D) vector-based vaccine candidate expressing a non-cleavable form of the spike protein of severe acute respiratory coronavirus 2 (SARS-CoV2). The vaccine candidate, named YF-S0, is capable of inducing high levels of SARS-CoV-2-specific neutralizing antibodies together with T cell-mediated immune responses in various animal models.
To effectively curb the ever-growing trajectory of the coronavirus disease 2019 (COVID-19) pandemic, the entire scientific community has come forward to develop effective vaccine candidates against SARS-CoV-2. Currently, many potential vaccine candidates are in the pipeline, and a substantial proportion of these vaccines have shown promising results in human clinical trials. However, the feeling of uncertainty still exists regarding the long-term efficacy of these vaccines. There are studies suggesting that, as with influenza vaccines, repeated vaccination may be required to ensure long-lasting protection against SARS-CoV-2.
In vaccine research, live-attenuated viruses have been used extensively as candidate vectors to introduce target antigens inside the host body. YF17D is one such virus that has been used previously as a viral vector to develop vaccines for dengue and Japanese encephalitis. In the current study, the scientists have developed a potential COVID-19 vaccine candidate using YF17D as a backbone. They used the viral spike protein as a candidate antigen to trigger desired immune responses in various animal models.
Current study design
Using a reverse genetics approach, the scientists developed a set of YF17D-based vaccine candidates expressing the SARS-CoV-2 spike protein in multiple forms, including the native cleavable form (YF-S1/2), non-cleavable prefusion form (YF-S0), and S1- YF17D-E/NS1 fusion form (YF-S1). Next, they compared the safety level, immunogenicity, and efficacy of these vaccine candidates using different animal models.
Important observations
By conducting a series of experiments, the scientists confirmed that of all candidate vaccines, YF-S0 is highly attenuated, well-tolerated, and significantly less neurovirulent in animals.
Antibody-mediated immune response
To check whether the vaccine candidates can provide full protection against SARS-CoV-2, the scientists vaccinated hamsters with two vaccine doses at two time points (day 0 and day 7). After 21 days of vaccination, they observed that YF-S0 has the highest potency to generate high levels of SARS-CoV-2-specific immunoglobulin G (IgG) and neutralizing antibodies. Moreover, they experimentally infected the hamsters with SARS-CoV-2 and observed that YF-S0 vaccinated hamsters were protected from SARS-CoV-2-induced pathologic pulmonary lesions and systemic viral spreading. The vaccine also reduced the viral RNA level below the detection range. Since no further increase in neutralizing antibody level was observed after experimental viral infection, the scientists believe that YF-S0 is capable of inducing saturating levels of neutralizing antibodies. In SARS-CoV-2-infected hamsters, YF-S0 efficiently maintained normal or near-normal lung histology without any sign of bronchopneumonia. Moreover, the vaccine candidate reduced the levels of pro-inflammatory cytokines that are responsible for increasing COVID-19 severity.
Similar protective effects of YF-S0 were observed in non-human primates. Cynomolgus macaques vaccinated with YF-S0 exhibited significantly high levels of SARS-CoV-2 neutralizing antibodies after 14 day of vaccination.
Importantly, when the scientists vaccinated hamsters with a single dose of YF-S0, a significantly high level of antibody response was observed. The single-dose was also capable of providing full protection in SARS-CoV-2-infected hamsters. Long-term follow-up experiments suggested continuous protection against SARS-CoV-2.
T cell-mediated immune response
An experimental mouse model was used to investigate the abilities of vaccine candidates in inducing T cell-mediated immune responses. Initial findings revealed that YF-S0 was capable of inducing a similar antibody response as observed in hamsters.
By analyzing different white blood cell populations (splenocytes) from the spleen of vaccinated mice, the scientists observed that all vaccine candidates were capable of inducing spike protein-specific T cell responses with a satisfactory T helper type 1 (Th1) polarization. Interestingly, they observed that although not capable of inducing SARS-CoV-2-specific neutralizing antibodies, YF-S1 efficiently produced a greater number of spike protein-specific splenocytes than other vaccine candidates.
Using flow cytometry, they detected the presence of spike protein-specific CD8+ and CD4+ T cell populations in vaccinated mice. Specifically, CD8+ T cells isolated from YF-S0 and YF-S1/2 vaccinated mice predominantly expressed IFN-γ and TNF-α, with YF-S0 inducing higher expression of IFN-γ. Taken together, these findings indicate that YF-S0 is capable of inducing a robust and balanced cell-mediated immune response against SARS-CoV-2.
Overall, the study findings reveal that YF-S0 can induce a robust and long-lasting immunity against SARS-CoV-2. After a single-dose vaccination, immunity can be achieved within ten days.
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