Inovio Pharmaceuticals Inc (INO)

[Lakers_w]

1/25/22 SARS-CoV-2 DNA Vaccine INO-4800 Induces Durable Immune Responses Capable of Being Boosted in a Phase 1 Open-Label Trial
Received: 27 September 2021
Published: 25 January 2022

Abstract
Background
Additional SARS-CoV-2 vaccines that are safe and effective as primary vaccines and boosters remain urgently needed to combat the COVID-19 pandemic. We describe the safety and durability of the immune responses following two primary doses and a homologous booster dose of an investigational DNA vaccine (INO-4800) targeting the full-length spike antigen.
Methods
Three dosage strengths of INO-4800 (0.5 mg, 1.0 mg, and 2.0 mg) were evaluated in 120 age-stratified healthy adults. Intradermal injection of INO-4800 followed by electroporation at 0 and 4 weeks preceded an optional booster 6-10.5 months after the second dose.
Results
INO-4800 appeared well tolerated, with no treatment-related serious adverse events. Most adverse events were mild and did not increase in frequency with age and subsequent dosing. A durable antibody response was observed 6 months following the second dose; a homologous booster dose significantly increased immune responses. Cytokine producing T cells and activated CD8+ T cells with lytic potential were significantly increased in the 2.0 mg dose group.
Conclusion
INO-4800 was well tolerated in a 2-dose primary series and as a homologous booster in all adults, including the elderly. These results support further development of INO-4800 for use as a primary vaccine and as a booster.
https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiac016/6515374?login=false

238 Discussion
239 This report provides results for the expansion of a Phase 1 trial to include older and elderly
240 participants and an optional booster dose with the aim to evaluate the safety, tolerability, and
241 immunogenicity of INO-4800, a SARS-CoV-2 vaccine encoding the S protein[14], including the
242 immune responses 6 months following dose 2 and 2 weeks following the optional booster dose.
243 INO-4800 appeared to be well-tolerated at all three dose levels, with no treatment-related
244 serious adverse events (SAEs) reported. Most AEs were mild in severity and did not increase in
245 frequency with age and subsequent dosing. These results are consistent with the severity of
246 AEs and lack of treatment-related SAEs observed in the U.S. Phase 2 trial comparing the 1.0
247 mg and 2.0 mg doses of INO-4800 in approximately 400 subjects[15] and those studies
248 conducted outside the U.S. by Inovio collaborators (International Vaccine Institute, Advaccine –
249 manuscripts in preparation). The lower frequency of treatment-related AEs reported by older
250 and elderly participants in our study is consistent with findings of other studies evaluating
251 SARS-CoV-2 vaccines[19, 20]. Weaker inflammatory reactions consequent to
252 immunosenescence may explain the lower incidence of AEs among elderly participants[21, 22].
253 Induction of both humoral and cellular responses were observed across all three dose groups,
254 inclusive of binding and neutralizing antibodies and cytokine producing T cells as well as
255 exhibiting lytic potential. Immunization with the 2.0 mg dose resulted in the highest GMTs of
256 neutralizing and binding antibodies as well as the highest magnitudes of IFN? production to
257 SARS-CoV-2 of any dose in all age groups tested, and the increases in antibody levels were
258 statistically significant above baseline at 6 months following dose 2. Importantly, increases in
259 both humoral and cellular immune responses were statistically significant following the booster
260 dose.
261 The contribution of the CD8+T cell response to vaccine efficacy has become increasingly
262 recognized as they have been detected early after vaccination[23] and due to their role in
263 controlling infection[24, 25]. Specifically, it has been established that CD8+T cells expressing
264 cytokines such as IFN? and TNF? as well as markers involved in activation status and
265 proliferation such as CD38 and Ki67 contribute to limiting disease severity during SARS-CoV-2
266 infection[24]. Additional studies have identified the expression of CD69 and CD137 on SARS-
267 CoV-2 specific CD8+T cells being associated with less severe disease[25]. This expanded
268 Phase 1 trial demonstrates that immunization with INO-4800 induces SARS-CoV-2 specific
269 CD8+T cells exhibiting these specific characteristics, suggesting the induction of a vaccine-
270 induced cellular response that has potential to protect against severe COVID-19. As VoCs
271 continue to emerge, the generation of cross-reactive activated CD8+T cells with lytic potential is
272 likely to play an important role in preventing severe disease. We have previously demonstrated
273 that vaccination with INO-4800 induces T cells and neutralizing antibodies that are active
274 against the parental SARS-CoV-2 strain as well as the B.1.1.7, B.1.351, and P.1 VoCs[26]. We
275 acknowledge limitations to this trial that include the relatively small study population and the
276 limited number of PBMCs available for testing across more than one assay. This trial was not
277 powered to formally compare immune responses between dose groups or age stratifications. In
278 addition, due to different immune assays and methodologies employed by various groups, it is
279 not possible to directly compare immune responses observed in this trial to those elicited from
280 other vaccine platforms or to determine if the magnitudes observed in this trial are sufficient to
281 confer clinical benefit.
282 The immune responses observed in the current trial and in our larger Phase 2 trial[15] support
283 advancing the 2.0 mg dose of INO-4800 to a Phase 3 efficacy evaluation. This dose has elicited
284 the highest binding and neutralizing antibody titers, the highest T-cell cytokine production from
285 both CD4+ and CD8+T cells, and the highest expression of markers associated with attenuation
286 of severe COVID-19 on CD8+T cells.
287 This trial demonstrated that immune responses elicited by a 2-dose primary series of INO-4800
288 could be boosted by a third dose without safety or tolerability concerns and positions INO-4800
289 as an important candidate for continued development as a stand-alone SARS-CoV-2 vaccine,
290 as well as for continued examination in combination approaches. The potential ability to
291 administer INO-4800 multiple times, with high tolerability, along with its ease of scalability and
292 thermostability, contribute to its potential value in combatting the COVID-19 pandemic.