October 13, 2020 J&J pause adds to adenovirus vaccine doubts Madeleine Armstrong Details are scant about the “unexplained illness” seen with Johnson & Johnson’s Covid-19 vaccine, but the news puts another dent in public confidence. The Covid-19 vaccine candidates being developed by Astrazeneca and Johnson & Johnson have a couple of things in common. Both have now been linked with a safety scare, and both use an adenoviral vector. So far, little is known about the adverse event that caused J&J to pause all of its Covid-19 vaccine trials, including the phase III Ensemble study. But if it turns out to be similar to the neurological issue that caused Astra’s US trial to be put on hold, it would be a big problem for the adenovirus approach. Fortunately, there are only a handful of Covid-19 vaccine candidates in development that use an adenoviral vector. Apart from J&J’s Ad26.COV2-S and Astra’s AZD1222, Cansino Biologics’ Ad5-nCoV and Reithera’s GRAd- COV2 have entered clinical trials, an analysis by Evaluate Vantage reveals. In addition, an oral adenovirus- based vaccine from Vaxart went into phase I today. And Sputnik V, the vaccine approved in Russia although only phase I/II data are available, is based on two adenoviral vectors, type 5 and type 26. Many unknowns It will take time to ascertain whether there is an issue with Ad26.COV2-S and, indeed, adenoviral vaccines more broadly. J&J only found out about the event on Sunday evening, Mathai Mammen, head of R&D for J&J’s Janssen unit, said during the company’s third-quarter earnings call today. The company informed the study’s data safety monitoring board immediately, then “quickly” posted a statement on its website on Monday, he explained. He also stressed that the study remains blinded and J&J does not know whether the event occurred in the vaccine or placebo arm. When asked if the event had been neurological – a nod to the suspected case of transverse myelitis that caused Astra’s trial halt – Mr Mammen answered that the company “knows very little at this point”. He added that J&J was committed to transparency and intends to provide an update once more details emerge, but that it would take “a few days, minimum” for the information to be evaluated. Mr Mammen declined to answer a question on how many patients have been dosed in Ensemble so far, but it cannot be many – the study only began in late September. He maintained that J&J’s plan to complete enrolment in two to three months “remains on track”. Warning signs? However, the signs so far with adenoviral vaccines do not augur well. Neurological events also led to the halt of studies of J&J’s Ebola vaccine, which uses adenovirus 26, the same vector as its Covid vaccine candidate. Still, the programme was resumed and the Ebola vaccine was approved in the EU in July. J&J was keen to stress the difference between a clinical trial halt and a pause in its statement: the former is a requirement of the FDA but the latter is not. Still, investors and the public at large will no doubt be watching to see if this pause becomes something more serious. Notably, while Astra has restarted studies of AZD1222 in the UK, Brazil and Africa, the US study is still on hold. Other approaches On the face of it, the latest news looks like a positive for the most advanced Covid-19 vaccine developers, Pfizer/Biontech and Moderna, as it puts them further ahead of some of their closest rivals. Both projects are mRNA vaccines. But it might not play out that way: public confidence in vaccines is already shaky, and another adverse event, even with a different platform, could add to overall vaccine hesitancy. People might be particularly reluctant to receive vaccines using novel technologies such as mRNA, should these receive emergency use authorisation. Until there is long-term follow-up in large numbers of patients, concerns about potential toxicity with new platforms are unlikely to be assuaged. So the winners might end up being companies testing more traditional approaches like recombinant protein vaccines. The most advanced of these is Novavax’s NVX-CoV2373, which began a 10,000-patient phase III UK trial of in September. Meanwhile, Sanofi and Glaxosmithkline have a candidate in phase I/II. The companies expect to have data by December; if this is positive, they will push on into phase III later that month. They hope to be able to submit their vaccine for approval in the first half of 2021. Selected Covid-19 vaccines in clinical development Project Company Description Trial ID Note Phase III 37,864 BNT162b2 Biontech/Pfizer mRNA vaccine NCT04368728 enrolled of 44,000 target* 28,618 enrolled of mRNA-1273 Moderna/NIAID mRNA vaccine Cove (NCT04470427) 30,000 target** US trial not yet Chimp NCT04516746 (US ph3); Astrazeneca/Uni of restarted; UK & AZD1222 adenovirus NCT04400838 (UK ph2/3); Oxford Brazil trials vaccine NCT04536051 (Brazil ph3) resumed Trial paused Adenovirus due to Ad26.COV2-S Johnson & Johnson Ensemble (NCT04505722) type 26 vaccine "unexplained illness" 10,000-subject Recombinant NVX-CoV2373 Novavax EduraCT: 2020-004123-16 UK trial started protein vaccine Sep 2020 Adenovirus Ad5-nCoV Cansino Biologics NCT04526990 (Pakistan) 40,000 target type 5 vaccine Inactivated NCT04456595 (Brazil) 8,800 & 1,600 CoronaVac Sinovac virus vaccine & NCT04508075 (Indonesia) target Phase II Selected Covid-19 vaccines in clinical development 30,000-subject global ph2/3 CVnCoV Curevac mRNA vaccine NCT04515147 (Peru) trial to start Q4 2020 Phase I/II Results due Recombinant early Dec, ph3 SARS-CoV-2 vaccine GSK/Sanofi NCT04537208 protein vaccine to start in Dec 2020 Attenuated Started Sep V591 Merck (Themis) measles virus NCT04498247 2020 vaccine Ph2/3 study on INO-4800 Inovio DNA vaccine NCT04447781 partial clinical hold Primary AG0301-COVID19 Anges DNA vaccine NCT04463472 completion Sep 2020 Started Jul GX-19 Genexine DNA vaccine NCT04445389 2020 Self-amplifying Started Aug ARCT-021 Arcturus NCT04480957 mRNA vaccine 2020 Phase I Recombinant Started Jun SCB-2019 Dynavax/Clover/GSK NCT04405908 subunit vaccine 2020 Self-amplifying Started Jun LNP-nCoVsaRNA Imperial College ISRCTN17072692 RNA vaccine 2020 Recombinant Started Jun Vaxine Covax19 NCT04453852 protein vaccine 2020 Coronavirus-like Coronavirus- GSK/Medicago (M Started Jul particle Covid-19 like particle NCT04450004 Tanabe) 2020 vaccine vaccine Unknown, ph1 started Jul ZyCoV-D Zydus Cadila DNA vaccine 2020 Gorilla Started Aug GRAd-COV2 Reithera adenovirus NCT04528641 2020 vaccine Oral adenovirus Started Oct VXA-CoV2-1 Vaxart NCT04563702 type 5 vaccine 2020 *As of Oct 11, 2020; **as of Oct 9, 2020. Source: EvaluatePharma & clinicaltrials.gov. This story has been updated to include details of Vaxart's oral adenovirus vaccine. More from Evaluate Vantage Evaluate HQ 44-(0)20-7377-0800 Evaluate Americas +1-617-573-9450 Evaluate APAC +81-(0)80-1164-4754 © Copyright 2021 Evaluate Ltd..