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. 2021 Oct 19;2(10):100420.
doi: 10.1016/j.xcrm.2021.100420. Epub 2021 Sep 28.

Intradermal-delivered DNA vaccine induces durable immunity mediating a reduction in viral load in a rhesus macaque SARS-CoV-2 challenge model

Ami Patel  1 , Jewell N Walters  2 , Emma L Reuschel  1 , Katherine Schultheis  2 , Elizabeth Parzych  1 , Ebony N Gary  1 , Igor Maricic  2 , Mansi Purwar  1 , Zeena Eblimit  2 , Susanne N Walker  1 , Diana Guimet  2 , Pratik Bhojnagarwala  1 , Opeyemi S Adeniji  1 , Arthur Doan  2 , Ziyang Xu  1 , Dustin Elwood  2 , Sophia M Reeder  1 , Laurent Pessaint  3 , Kevin Y Kim  1 , Anthony Cook  3 , Neethu Chokkalingam  1 , Brad Finneyfrock  3 , Edgar Tello-Ruiz  1 , Alan Dodson  3 , Jihae Choi  1 , Alison Generotti  2 , John Harrison  3 , Nicholas J Tursi  1 , Viviane M Andrade  2 , Yaya Dia  1 , Faraz I Zaidi  1 , Hanne Andersen  3 , Mohamed Abdel-Mohsen  1 , Mark G Lewis  3 , Kar Muthumani  1 , J Joseph Kim  2 , Daniel W Kulp  1 , Laurent M Humeau  2 , Stephanie J Ramos  2 , Trevor R F Smith  2 , David B Weiner  1 , Kate E Broderick  2
Affiliations

Intradermal-delivered DNA vaccine induces durable immunity mediating a reduction in viral load in a rhesus macaque SARS-CoV-2 challenge model

Ami Patel et al. Cell Rep Med. .

Abstract

Coronavirus disease 2019 (COVID-19), caused by the SARS-CoV-2 virus, has had a dramatic global impact on public health and social and economic infrastructures. Here, we assess the immunogenicity and anamnestic protective efficacy in rhesus macaques of an intradermal (i.d.)-delivered SARS-CoV-2 spike DNA vaccine, INO-4800, currently being evaluated in clinical trials. Vaccination with INO-4800 induced T cell responses and induced spike antigen and RBD binding antibodies with ADCP and ADCD activity. Sera from the animals neutralized both the D614 and G614 SARS-CoV-2 pseudotype viruses. Several months after vaccination, animals were challenged with SARS-CoV-2 resulting in rapid recall of anti-SARS-CoV-2 spike protein T cell and neutralizing antibody responses. These responses were associated with lower viral loads in the lung. These studies support the immune impact of INO-4800 for inducing both humoral and cellular arms of the adaptive immune system, which are likely important for providing durable protection against COVID-19 disease.

Keywords: COVID-19; ID DNA vaccine; SARS-CoV-2; challenge; coronavirus; electroporation; infectious disease; macaque; protection.

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Conflict of interest statement

A.P., E.L.R., E.P., E.N.G., M.P., S.N.W., P.B., Z.X., S.M.R., K.Y.K., N.C., E.T-R., J.C., N.J.T., K.M., and D.K.W. declare no competing interests. J.N.W., K.S., I.M., Z.E., D.G., A.D., D.E., A.G., V.M.A., J.J.K., L.M.H., S.J.R., T.R.F.S., and K.E.B. are employees of Inovio Pharmaceuticals and as such receive salary and benefits, including ownership of stock and stock options, from the company. D.B.W. discloses the following paid associations with commercial partners: GeneOne (Consultant), Geneos (Advisory Board), Astrazeneca (Advisory Board, Speaker), Inovio (BOD, SRA, Stock), Pfizer (Speaker), Merck (Speaker), Sanofi (Advisory Board), BBI (Advisory Board).

Figures

None
Graphical abstract
Figure 1
Figure 1
Humoral immune responses in rhesus macaques (A) The study outline showing the vaccination regimen and sample collection time points. (B) Schematic of SARS-CoV-2 spike protein. (C) SARS-CoV-2 S1+S2 ECD, S1, RBD, and S2 protein antigen binding of IgG in serially diluted NHP sera. The data represent the mean endpoint titers for each individual NHP. (D and E) Pseudovirus neutralization assay using NHP sera, showing the presence of SARS-CoV-2-specific neutralizing antibodies against the D614 (D) and G614 (E) variants of SARS-CoV-2. (F) Live virus neutralization using NHP serum. Isolate USA-WA1/2020. (G and H) Serum collected at week 6 from INO-4800-vaccinated NHPs inhibited ACE2 binding to SARS-CoV-2 Spike protein. A plate-based ACE2 competition assay (G) and a flow cytometry-based ACE2 competition assay (H) and showing inhibition of ACE2 binding to Spike protein by NHP sera. Bars represent the mean ± SD. ∗∗∗p < 0.001. See also Figures S1–S3.
Figure 2
Figure 2
Cellular immune responses in rhesus macaques (A) T cell responses were measured by IFN-γ ELISpot in PBMCs stimulated for 20 h with overlapping peptide pools spanning the SARS-CoV-2 Spike protein. (B and C) Cross-reactivity to SARS-CoV and MERS-CoV spike protein were analyzed by IFN-γ ELISpot after 20 h stimulation with overlapping peptide pools spanning the SARS-CoV-1 spike protein (B) and MERS-CoV spike protein (C). Individual animal responses are depicted by open symbols and filled symbols represent median values.
Figure 3
Figure 3
Recall of immune responses to SARS-CoV-2 after viral challenge (A) Study outline. (B and C) IgG binding ELISA. SARS-CoV-2 S1+S2 (B) and RBD (C) protein antigen binding of IgG in diluted NHP sera collected prior to challenge and post-challenge in INO-4800-vaccinated (right panels) and naive animals (left panels). (D) Live virus neutralization. (E) Pseudo-neutralization assay showing the presence of SARS-CoV-2-specific neutralizing antibodies against the D614 and G614 variants of SARS-CoV-2 before and after viral challenge. (F) T cell responses were analyzed pre- and post-challenge with SARS-CoV-2 virus by IFN-γ ELISpot in PBMCs stimulated with overlapping peptide pools spanning the SARS-CoV-2 spike protein. Individual animal responses are depicted by open symbols and filled symbols represent median values. ∗∗p < 0.01 Mann-Whitney test. See also Figures S3 and S4.
Figure 4
Figure 4
Viral loads in the BAL fluid and Nasal swabs after viral challenge At week 17, naive and INO-4800-immunized (5 per group) rhesus macaques were challenged by intranasal and intratracheal administration of 1.1 × 104 PFU SARS-CoV-2 (US-WA1 isolate). (A) Log sgmRNA copies/mL in BAL in naive (left panel) and INO-4800-vaccinated animals (right panel). (B and C) Peak sgmRNA (B) and viral RNA (C) in BAL 7 days post-challenge. (D) Log sgmRNA copies/mL in nasal swabs in naive (left panel) and INO-4800-vaccinated animals (right panel). (E and F) Peak sgmRNA (E) and viral RNA (F) in nasal swabs 7 days post-challenge. Black and blue lines represent median values.
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