Inovio Pharmaceuticals Inc (INO)

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BioRxiv: Prime-boost vaccination regimens with INO-4800 and INO-4802 augment and broaden immune responses against SARS-CoV-2 in nonhuman primates
We recently described the design, immunogenicity, and efficacy of INO-4802, a synthetic DNA vaccine expressing a pan-Spike immunogen aimed at inducing broad immunity across SARS-CoV-2 VOCs [17]. In a hamster challenge model, INO-4802 conferred protection following intranasal challenge with either the Wuhan-Hu-1, B.1.1.7, B.1.351, P.1, or B.1.617.2 (Delta) SARS-CoV-2 variants. Additionally, INO-4802 showed promise as a heterologous booster vaccine by enhancing humoral responses against VOCs in hamsters previously immunized with INO-4800. Here, we addressed the immunogenicity of INO-4800 and INO-4802 as booster regimens in rhesus macaques previously immunized with INO-4800 using clinically relevant dosing parameters.

Rhesus macaques receiving booster immunizations of either INO-4800 or INO-4802 showed a robust induction of humoral responses, supporting the use of either vaccine in a prime/boost regimen. Importantly, boosting of INO-4800-primed animals with INO-4800 or INO-4802 resulted in neutralizing antibody responses that were magnitudes greater compared to pre-boost levels. Both treatment groups induced humoral responses capable of neutralizing wild-type and several VOC pseudoviruses, suggesting broad protection among SARS-CoV-2 variants. Pseudovirus neutralizing activity against the Beta and Gamma variants trended higher in animals 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 variants following boosting with the next-generation pan-SARS-CoV-2 vaccine.

Neutralizing antibody responses correlated with inhibition of ACE2 binding activity, further supporting the functional antibody responses following either a homologous or heterologous boost with synthetic DNA vaccine constructs. Levels of antibodies binding variant Spike proteins were also increased following the boost immunization in both treatment groups. Together, these data point to broad functional humoral responses following a boost with both the original INO-4800 and INO-4802 pan-SARS-CoV-2 DNA vaccines. The rapid boost in neutralizing antibody responses can likely be attributed to the maintenance of a memory B cell pool following the priming immunization. Similar increases in humoral responses are observed in COVID-19 convalescent individuals who later received SARS-CoV-2 mRNA vaccines [44]. Longitudinal analyses have also found that SARS-CoV-2-reactive memory B cell clones are stably maintained in convalescent COVID-19 patients for several months following infection [30, 45]. Memory B cell responses persist despite the natural decline of SARS-CoV-2-specific IgG binding titers, suggestive of high-quality and durable memory B cell responses [46].

Neutralizing antibody responses are predictive of immune protection against symptomatic SARS-CoV-2 infection [47], and as such, neutralizing antibodies are an important readout in the evaluation of SARS-CoV-2 vaccines [48–50]. Owing to the critical role of T follicular helper (Tfh) cells in providing help to maturing B cells in germinal centers, Tfh responses serve as a mechanistic indicator of neutralizing antibody responses in infection and vaccination, including for EUA SARS-CoV-2 vaccines [25–27, 51–53]. We observed a positive correlation between the frequency of circulating Tfh cells and functional antibody responses, further affirming the immunogenicity of SARS-CoV-2 DNA vaccine boosters in animals with existing vaccine-induced immunity.

Overall, the development of safe and effective booster vaccines will be critical in maintaining control of SARS-CoV-2 in the long term. Ideal treatment regimens should seek to expand immune coverage to emerging variants while maintaining immune responses to existing SARS-CoV-2 variants. Current focus has shifted to evaluating the cross-immunogenicity of booster vaccines against wild-type SARS-CoV-2 antigens and other VOCs and re-designing vaccines to investigate this important question. In this study, we report that the next-generation pan-SARS-CoV-2 vaccine INO-4802 boosts immune responses in animals primed with the wild-type-matched SARS-CoV-2 DNA vaccine INO-4800. These data support the immunogenicity and boosting capability of INO-4800 and INO-4802 in nonhuman primates, which may have broader application in the clinical setting.
https://www.biorxiv.org/content/10.1101/2021.10.27.466163v1.full