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Authors: J Yu et al.

Link to paper: https://science.sciencemag.org/content/early/2020/05/19/science.abc6284/tab-pdf

Journal: Science

Tags: Immunology/Immunity, Vaccines, Virology

Research Highlights

1. Developed six SARS-CoV-2 DNA vaccine candidates expressing different forms of S protein, which induced neutralising antibodies and a cellular (Th1-biased) response in rhesus macaques.

2. In rhesus macaques vaccinated with the DNA vaccine candidate expressing full-length S protein and subsequently infected with SARS-CoV-2, viral subgenomic mRNA from both bronchoalveolar lavage and nasal swab samples was significantly lower compared to sham controls.

3. There was a statistically significant inverse correlation between virus neutralising antibody titre at week five and peak viral subgenomic mRNA after viral challenge in the rhesus macaques, suggesting that neutralising antibodies elicited by the vaccine are an immune correlate of protection.

Summary 

Rhesus macaques were vaccinated with six different SARS-CoV-2 DNA vaccine candidates, each expressing different forms of the Spike (S) protein, which induced S-specific neutralising antibodies (NAb) and a Th-1 led response.

Vaccinated macaques underwent live SARS-CoV-2 challenge. Those vaccinated with full-length S protein, in both broncho-alveolar lavage and nasal swab samples, had significantly lower viral load and viral sub-genomic mRNA compared to sham controls.

A statistically significant inverse correlation between SARS-CoV-2 NAb titre at week five and the peak viral subgenomic mRNA after viral challenge was shown, highlighting NAbs as an immune correlate of protection. Antibody-dependent complement deposition is also significantly correlated with protective efficacy.

Impact for SARS-CoV-2/COVID19 research efforts

Understand the immune response to SARS-CoV-2/COVID19

· Demonstrates that neutralising antibodies are an immune correlate of protection against SARS-CoV-2 in vaccinated rhesus macaques and that DNA vaccines induce a Th-1 cellular immune response.

Develop a vaccine for SARS-CoV-2/COVID19

· Tests six SARS-CoV-2 DNA vaccine candidates expressing different forms of S protein in rhesus macaques. Vaccine candidate expressing full-length S protein provides protective efficacy to the macaques by inducing NAbs. Also, they show that adjuvants are not required for an immune response to their DNA vaccines.

Study Type

· In vivo study (e.g. mouse, NHP)

Strengths and limitations of the paper

Novelty:

· This study describes six SARS-CoV-2 DNA vaccine candidates expressing different forms of S protein, which induced NAbs in rhesus macaques. The vaccine expressing full-length S protein provided protection against a live SARS-CoV-2 challenge in rhesus macaques. Therefore, offering a good vaccine candidate to explore further.

· This study also identifies S-specific neutralising antibodies as an immune correlate of protection against SARS-CoV-2 in vaccinated rhesus macaques.

Standing in the field:

· There are currently several SARS-CoV-2 vaccine candidates in clinical and pre-clinical testing. This study provides evidence for protective efficacy in rhesus macaques for a DNA vaccine candidate expressing full-length S protein with no adjuvant.

· Currently, not a lot is known about immune correlates of protection from SARS-CoV-2 vaccination in animal models. This study provides evidence for neutralising antibodies as an immune correlate of protection in resus macaques.

Appropriate statistics:

· Yes. Although statistical analysis is lacking in figures 2 and 3.

Viral model used:

· SARS-CoV-2 (Wuhan/WIV04/2019) used to develop DNA vaccines.

· SARS-CoV-2 (strain not specified) used for viral challenge

Translatability:

· This study demonstrates protective efficacy of SARS-CoV-2 DNA vaccines expressing various S immunogens, with optimal efficacy observed with full-length S protein, by the induction of NAbs in rhesus macaques.

· This study does not however evaluate the longevity of this protection nor the safety of this vaccine in rhesus macaques. These will likely need to be evaluated before their vaccine candidates can progress into clinical trials.

Main limitations:

· The sample size is n=4 in each of the vaccine candidate groups, which is too small to confer statistical significance to the results.

· It is unclear why all six vaccines are tested in the macaque model. Perhaps a better set-up would have been to select one or two best candidates, thus allowing the macaque study to have larger sample sizes.

· Lack of long-term data on antibody titres and protective efficacy.

· There is no evaluation of safety of the vaccine candidates. Since they mention that no enhanced clinical disease was observed in the suboptimal vaccine constructs, it would have been useful to see this formally evaluated.

· None of the vaccine candidates tested provided sterilising immunity to the rhesus macaques, which may pose a future problem for these vaccine candidates, particularly in terms of onward spread of disease and in patients with more severe disease.