J&J pause adds to adenovirus vaccine doubts

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
BNT162b2 Biontech/Pfizer mRNA vaccine NCT04368728 37,864 enrolled of 44,000 target*
mRNA-1273 Moderna/NIAID mRNA vaccine Cove (NCT04470427) 28,618 enrolled of 30,000 target**
AZD1222 Astrazeneca/Uni of Oxford Chimp adenovirus vaccine NCT04516746 (US ph3);
NCT04400838 (UK ph2/3);
NCT04536051 (Brazil ph3)
US trial not yet restarted; UK & Brazil trials resumed
Ad26.COV2-S Johnson & Johnson Adenovirus type 26 vaccine Ensemble (NCT04505722) Trial paused due to "unexplained illness"
NVX-CoV2373 Novavax Recombinant protein vaccine EduraCT: 2020-004123-16  10,000-subject UK trial started Sep 2020
Ad5-nCoV Cansino Biologics Adenovirus type 5 vaccine NCT04526990 (Pakistan) 40,000 target
CoronaVac Sinovac Inactivated virus vaccine NCT04456595 (Brazil) & NCT04508075 (Indonesia) 8,800 & 1,600 target
Phase II 
CVnCoV Curevac mRNA vaccine NCT04515147 (Peru) 30,000-subject global ph2/3 trial to start Q4 2020
Phase I/II
SARS-CoV-2 vaccine GSK/Sanofi Recombinant protein vaccine NCT04537208 Results due early Dec, ph3 to start in Dec 2020
V591 Merck (Themis) Attenuated measles virus vaccine NCT04498247 Started Sep 2020
INO-4800 Inovio DNA vaccine NCT04447781 Ph2/3 study on partial clinical hold
AG0301-COVID19 Anges DNA vaccine NCT04463472 Primary completion Sep 2020
GX-19 Genexine DNA vaccine NCT04445389 Started Jul 2020
ARCT-021 Arcturus Self-amplifying mRNA vaccine NCT04480957 Started Aug 2020
Phase I
SCB-2019 Dynavax/Clover/GSK Recombinant subunit vaccine NCT04405908 Started Jun 2020
LNP-nCoVsaRNA Imperial College Self-amplifying RNA vaccine ISRCTN17072692 Started Jun 2020
Vaxine Covax19 Recombinant protein vaccine NCT04453852 Started Jun 2020
Coronavirus-like particle Covid-19 vaccine GSK/Medicago (M Tanabe) Coronavirus-like particle vaccine NCT04450004 Started Jul 2020
ZyCoV-D Zydus Cadila DNA vaccine Unknown, ph1 started Jul 2020  
GRAd-COV2 Reithera  Gorilla adenovirus vaccine NCT04528641 Started Aug 2020
VXA-CoV2-1 Vaxart Oral adenovirus type 5 vaccine NCT04563702 Started Oct 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.

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