Inovio Pharmaceuticals Inc (INO)

[Lakers_w]

10/29 Prime-boost vaccination regimens with INO-4800 and INO-4802 augment and broaden immune responses against SARS-CoV-2 in nonhuman primates

https://www.biorxiv.org/content/10.1101/2021.10.27.466163v1
We recently described the design, immunogenicity, and efficacy of INO-4802, a synthetic DNA 203 vaccine expressing a pan-Spike immunogen aimed at inducing broad immunity across SARS-204 CoV-2 VOCs [17]. In a hamster challenge model, INO-4802 conferred protection following 205 intranasal challenge with either the Wuhan-Hu-1, B.1.1.7, B.1.351, P.1, or B.1.617.2 (Delta) 206 SARS-CoV-2 variants. Additionally, INO-4802 showed promise as a heterologous booster vaccine 207 by enhancing humoral responses against VOCs in hamsters previously immunized with INO-4800. 208 Here, we addressed the immunogenicity of INO-4800 and INO-4802 as booster regimens in rhesus209 macaques previously immunized with INO-4800 using clinically relevant dosing parameters. 210 Rhesus macaques receiving booster immunizations of either INO-4800 or INO-4802 showed a 211 robust induction of humoral responses, supporting the use of either vaccine in a prime/boost 212 regimen. Importantly, boosting of INO-4800-primed animals with INO-4800 or INO-4802 213 resulted in neutralizing antibody responses that were magnitudes greater compared to pre-boost 214 levels. Both treatment groups induced humoral responses capable of neutralizing wild-type and 215 several VOC pseudoviruses, suggesting broad protection among SARS-CoV-2 variants.216 Pseudovirus neutralizing activity against the Beta and Gamma variants trended higher in animals 217 boosted with the heterologous INO-4802 vaccine compared to those receiving INO-4800,

indicating potential for an enhanced level of protection against some emerging SARS-CoV-2 219 variants following boosting with the next-generation pan-SARS-CoV-2 vaccine.220 221 Neutralizing antibody responses correlated with inhibition of ACE2 binding activity, further 222 supporting the functional antibody responses following either a homologous or heterologous boost223 with synthetic DNA vaccine constructs. Levels of antibodies binding variant Spike proteins were 224 also increased following the boost immunization in both treatment groups. Together, these data 225 point to broad functional humoral responses following a boost with both the original INO-4800 226 and INO-4802 pan-SARS-CoV-2 DNA vaccines. The rapid boost in neutralizing antibody 227 responses can likely be attributed to the maintenance of a memory B cell pool following the 228 priming immunization.

Neutralizing antibody responses are predictive of immune protection against symptomatic SARS-236 CoV-2 infection [47], and as such, neutralizing antibodies are an important readout in the 237 evaluation of SARS-CoV-2 vaccines [48-50]. Owing to the critical role of T follicular helper (Tfh) 238 cells in providing help to maturing B cells in germinal centers, Tfh responses serve as a239 mechanistic indicator of neutralizing antibody responses in infection and vaccination, including 240 for EUA SARS-CoV-2 vaccines [25-27, 51-53]. We observed a positive correlation between the 12 frequency of circulating Tfh cells and functional antibody responses, further affirming the 242 immunogenicity of SARS-CoV-2 DNA vaccine boosters in animals with existing vaccine-induced 243 immunity.244 245 Overall, the development of safe and effective booster vaccines will be critical in maintaining 246 control of SARS-CoV-2 in the long term. Ideal treatment regimens should seek to expand immune 247 coverage to emerging variants while maintaining immune responses to existing SARS-CoV-2 248 variants. Current focus has shifted to evaluating the cross-immunogenicity of booster vaccines 249 against wild-type SARS-CoV-2 antigens and other VOCs and re-designing vaccines to investigate 250 this important question. In this study, we report that the next-generation pan-SARS-CoV-2 vaccine 251 INO-4802 boosts immune responses in animals primed with the wild-type-matched SARS-CoV-2 252 DNA vaccine INO-4800. These data support the immunogenicity and boosting capability of INO-253 4800 and INO-4802 in nonhuman primate, which may have broader application in the clinical 254 setting. 255 256 Acknowledgements257 The studies described in this manuscript were funded by a grant from the Coalition for Epidemic 258 Preparedness Innovations (CEPI).